Aryllithium and Hetaryllithium Compounds

8.1.14 Product Subclass 14:
Aryllithium and Hetaryllithium Compounds
G. W. Gribble
General Introduction
Previously published information regarding this product class can be found in Houben–
Weyl, Vol. 13/1, pp 89–253, and Vol. E 19d, pp 369–447.
Aryllithium and hetaryllithium compounds are immensely important in organic synthesis
and have surpassed Grignard reagents in this regard. Numerous reviews describe
the generation and reactions of aryllithium and hetaryllithium compounds formed via
both halogen–lithium exchange and directed lithiation methodologies. [1–13] These accounts
offer the reader access to the early literature. An outstanding summary of the
work of Gilman, who was the pioneer in organolithium chemistry, is given by Eisch. [14]
Likewise, the seminal work of Wittig, Parham, Beak, Snieckus, Meyers, Bailey, Wakefield,
Comins, and others is featured in relevant earlier reviews. [15–25] Several important studies
discuss the theoretical and mechanistic aspects of halogen–lithium exchange, [22,26] directed
lithiation, [27–32] and direct deprotonation [28,32–34] processes. A review of the role of
N,N,N¢,N¢-tetramethylethylenediamine, which is generally thought to be an important
additive for lithium, has appeared, [35] and a new ligand for lithium, N,N,N¢,N¢¢,N¢¢-pentamethyldipropylenetriamine,
is purported to be superior to N,N,N¢,N¢-tetramethylethylenediamine.
[36] Solvation of alkyllithium compounds and lithium amide bases is often a
key factor in the generation of aryllithium and hetaryllithium compounds. [16,37] Like aryllithium
compounds, hetaryllithium compounds can be generated by halogen–lithium exchange
and directed lithiation. However, the inherent inductive electron-withdrawing
ability of heteroatoms allows for the facile direct deprotonation of adjacent protons without
the assistance of a directing group per se.
Owing to their air and water sensitivity, aryllithium and hetaryllithium compounds
are never isolated when used in synthesis. All solvents and glassware must be dried and
all reactions should be performed under nitrogen or argon. Since alkyllithium compounds
degrade during storage, they must be standardized prior to use. This is especially
true for tert-butyllithium, which, for example, has a half-life of only 1 hour at 0 8C in
diethyl ether. [38] The commercial availability of several lithium amide bases of good
quality obviates the need to generate these in situ from alkyllithium compounds and
amines.
Synthesis of Product Subclass 14
8.1.14.1 Method 1:
Aryllithium Compounds by Halogen–Lithium Exchange
Aryl halides undergo halogen–lithium exchange with lithium metal or, more commonly,
with an alkyllithium compound. This interchange reaction follows the rate: I > Br >> Cl
>> F. Modern versions of this reaction employ alkyllithium compounds exclusively,
owing to their commercial availability and ease of handling. The “back reactions” such
as alkylation or elimination of the byproduct alkyl halide can be circumvented. For example,
halogen–lithium exchange reactions using tert-butyllithium should employ 2 equivalents
of the lithium reagent, wherein the second equivalent destroys the tert-butyl halide
357
for references see p 414
G. W. Gribble, Section 8.1.14, Science of Synthesis, 2006 Georg Thieme Verlag KG

358 Science of Synthesis 8.1 Lithium Compounds
bby an elimination reaction. Ether solvents are typically used, provided one remembers
that tetrahydrofuran reacts with alkyllithium compounds at or above room temperature.
8.1.14.1.1 Variation 1:
From Aryl Fluorides
The strength of the C-F bond has precluded fluorine–lithium exchange until recently.
Thus, reaction of fluoroarenes 1 with lithium and catalytic naphthalene affords the corresponding
aryllithium, which, upon treatment with electrophiles, provides the corresponding
products 2 (Scheme 1). [39]
Scheme 1 Fluorine–Lithium Exchange Induced by Lithium Metal and Naphthalene [39]
R 1
F
1. Li, 7% naphthalene, THF, −30 oC 2. E + , −30 to 0 oC 3. HCl, H2O 31−72%
1 2
R 1 = H, 2-Me, 3-Me, 4-Me, 4-OMe, 4-F; E = CH(OH)iPr, C(OH)Et 2, CH(OH)Ph, TMS, C(OH)MePh, 1-hydroxycyclohexyl
(4-Methoxyphenyl)phenylmethanol [2,R 1 = 4-OMe; X = CH(OH)Ph]; Typical Procedure: [39]
To a green suspension of Li powder (70 mg, 10.0 mmol) and naphthalene (18 mg,
0.14 mmol) in THF (5 mL), under N 2, was added dropwise a soln of 1-fluoro-4-methoxybenzene
(126 mg, 1.0 mmol) in THF (2 mL) over ca. 20 min at –308C. After 15 min of stirring at
the same temperature, PhCHO (127 mg, 1.2 mmol) was added and the mixture was stirred
for 3 h, allowing the temperature to rise to 08C. The resulting mixture was hydrolyzed
with H 2O (10 mL), acidified with 2 M HCl, and extracted with EtOAc (3 ” 20 mL). The organic
layers were successively washed with aq NaHCO 3 (5 mL), H 2O (5 mL), and sat. aq NaCl
(5 mL), and then dried (Na 2SO 4). After concentration of the solvents (15 Torr) the resulting
residue was purified by column chromatography (silica gel, hexane/EtOAc) to yield the
title compound; yield: 131 mg (61%).
8.1.14.1.2 Variation 2:
From Aryl Chlorides
Aryl chlorides are reluctant to undergo chlorine–lithium exchange under the usual conditions
with alkyllithium compounds, but this reaction is accomplished under Yus conditions.
[40] Alkyllithium compounds can effect chlorine–lithium exchange if the ortho position
is blocked, so as to prevent ortho-lithiation, and several examples are known. For
example, hexalithiobenzene (4) may be synthesized from hexachlorobenzene (3) (Scheme
2). [41] Derivatization of 4 with deuterium oxide gives benzene-d 6 (5). The lithio species 4 is
isolable as a colorless solid that undergoes a violent reaction when exposed to air.
Scheme 2 Synthesis of Hexalithiobenzene [41]
Cl
Cl
Cl
Cl
3
Cl
Cl
t-BuLi (excess)
pentane, dioxane
−125 oC 53%
G. W. Gribble, Section 8.1.14, Science of Synthesis, 2006 Georg Thieme Verlag KG
Li
Li
Li
Li
4
R 1
Li
Li
E
D 2O
D
D
D
D
5
D
D

8.1.14 Aryllithium and Hetaryllithium Compounds 359
bBenzene-d 6 (5) via Hexalithiobenzene (4): [41]
Hexachlorobenzene (3; 1.0 g, 3.5 mmol) was slowly added to a slurry consisting of pentane
(40 mL), 1.7 M t-BuLi (49.6 mL, 84 mmol), and 1,4-dioxane (28.7 mL, 337 mmol), maintained
at –1258C. The mixture was stirred for 24 h (the optimum reaction time) and then 4
(55% yield) was derivatized by the addition of excess D 2O and the reaction temperature
was slowly raised to rt. The deuteration products were analyzed by GC/MS. Benzene-d 6
(5; CAUTION: carcinogen) was identified by 13 C and 1 H NMR and by HRMS. Other products
were polymeric species from cross-linking and coupling reactions.
8.1.14.1.3 Variation 3:
From Aryl Bromides
Given their excellent reactivity and availability, aryl bromides are the aryl halide of
choice for most halogen–lithium exchange routes to aryllithium compounds. The isolation
and physical characterization, including X-ray structures, of aryllithium compounds
6–8 has utilized bromine–lithium exchange (Scheme 3). [42–44]
Scheme 3 Isolable Aryllithium Compounds via Bromine–Lithium Exchange [42–44]
Pr i
Li
Pri 6 (tetrameric)
Pr i
Mes
Li
7 (dimeric)
Mes
Ph
Li
Ph
8 (monomeric)
Bromine–lithium exchange may be employed on polybrominated substrates to achieve
polylithiation or excellent selective monolithiation. The reagents of choice are typically
butyllithium (1 equiv per bromine) or tert-butyllithium (2 equiv per bromine) and aryllithium
compounds 9 are synthesized in this fashion (Table 1). [45–50] The conditions used for
various quenching reactions are shown in Table 1, with the specific example shown for
the synthesis of 1,4-bis(trimethylsilyl)benzene (10). [46]
Ph
for references see p 414
G. W. Gribble, Section 8.1.14, Science of Synthesis, 2006 Georg Thieme Verlag KG

360 Science of Synthesis 8.1 Lithium Compounds
bTable 1 Selected Aryllithium Compounds via Bromine–Lithium Exchange and
Conditions for Subsequent Quenching [45–50]
R 5
R 4
Br
R 3
R 1
R 2
R 6 Li
R 5
R 4
Li
R3 9
R 1
R 2
TMSCl, THF, −78 o C to rt
R 1 = R 2 = R 4 = R 5 = H; R 3 = Li
TMS
TMS
10
R 1 R 2 R 3 R 4 R 5 Conditions Yield (%) a Ref
Br H H H H BuLi, THF/Et2O, –1108C, b [45]
30 min 95
H Br H H H t-BuLi, THF/pentane, –788C, c [46]
30 min 90
H H Br H H t-BuLi, Et2O/pentane, –788C, c [46]
2 h 86
H Br H Br H BuLi, Et2O/hexane, –788C, d [47]
1.5 h 80
OMe Br H Br H BuLi, pentane/hexane, –208C, e [48]
25 min 87
H H F H H t-BuLi, THF/pentane, –788C, c [46]
30 min 98
H Li H H H t-BuLi, THF/pentane, –788C, c [46]
1 h 95
H H Li H H t-BuLi, THF/pentane, –788C, c [46]
1 h 99
Li F F F F BuLi, Et2O/hexane, –788C, f [49]
30 min 46
OMe Li H Br H BuLi, pentane/hexane, –208C, e [48]
25 min 91
Br Br Li Cl Cl BuLi, toluene, –788C, g [50]
4.5 h 55
a Yields refer to products, e.g. 10, after quenching with an electrophile.
b Quenching with HCl.
c Quenching with TMSCl.
d Quenching with a perfluoroalkyl ether ester.
e Quenching with B(OMe)3.
f Quenching with CF3CO2Me. g Quenching with MeOH.
(2,4,6-Triphenylphenyl)lithium–Bis(diethyl ether) (8); Typical Procedure: [43]
1-Bromo-2,4,6-triphenylbenzene (7.7 g, 20 mmol) in Et 2O (30 mL) and hexane (5 mL) was
cooled in an ice bath. With vigorous stirring, 1.6 M BuLi in hexane (12.5 mL, 20 mmol)
was added dropwise. The soln, which was initially colorless, became yellow during the
addition. The ice bath was then removed and the soln was stirred for a further 2 h. The
solvent was removed under reduced pressure until a precipitate appeared. The soln was
then warmed to redissolve the pale yellow precipitate. Overnight cooling in a –208C freezer
gave the product as pale yellow crystals; yield: 8.2 g (87%); mp 72–74 8C.
1,4-Bis(trimethylsilyl)benzene (10): [46]
1,4-Dilithiobenzene (9,R 1 =R 2 =R 4 =R 5 =H;R 3 = Li):
To a stirred 2.1 M soln of t-BuLi in pentane (2.0 mL, 4.2 mmol) in THF (4.0 mL) was added
1,4-dibromobenzene (0.24 g, 1.0 mmol) in THF (1 mL) at –788C via cannula. The ensuing
reaction soln was stirred at –788C for 1 h, and then used in subsequent reactions..
1,4-Bis(trimethylsilyl)benzene (10):
TMSCl (0.3 mL, 2.2 mmol) was added at –788C to a soln of 9. The mixture was stirred at
–78 8C for 5 min and allowed to warm to rt and stirred overnight. H 2O (10 mL) was added
and the organic layer was separated. The aqueous portion was extracted with Et 2O. The
G. W. Gribble, Section 8.1.14, Science of Synthesis, 2006 Georg Thieme Verlag KG

8.1.14 Aryllithium and Hetaryllithium Compounds 361
bcombined organic layers were washed with brine and dried (MgSO 4). Filtration and removal
of the solvent under reduced pressure gave the product as colorless flakes; yield: 0.22 g
(99%); mp 93–95 8C.
8.1.14.1.4 Variation 4:
From Aryl Iodides
Aryl iodides undergo iodine–lithium exchange rapidly. A drawback to the use of aryl iodides
in organic synthesis is their relative inaccessibility and occasional instability. Nonetheless,
many important iodine–lithium exchange reactions have been described, and the
study of these reactions supports the intermediacy of iodine “ate” complexes in the iodine–lithium
exchange reaction. [51–53] Some representative reactions are illustrated in
Scheme 4, e.g. to give aryllithium compound 11.
Scheme 4 Selected Aryllithium Compounds via Iodine–Lithium Exchange [42,46,54]
I
I
I
Mes Mes
I
Ph Ph
t-BuLi (2 equiv), THF
−78 oC BuLi, hexane, rt
80%
BuLi, hexane, rt
73%
Li
I
TMSCl
−78 oC 78%
Li
Mes Mes
Li
Ph Ph
(2,6-Diphenylphenyl)lithium–Bis(diethyl ether) (11); Typical Procedure: [54]
To a suspension of 1-iodo-2,6-diphenylbenzene (30 g, 86 mmol) in degassed hexane
(150 mL) was added 1.6 M BuLi in hexanes (60 mL, 96 mmol) via syringe at rt over a period
of 10 min. The inert N 2 atmosphere was rigorously maintained throughout the procedure.
The soln was stirred for 24 h, after which it was cooled to –788C for 3 h and filtered. The
remaining colorless powder was washed with another portion of degassed hexane
(150 mL). The fine crude product was then dried under reduced pressure and extracted
(Et 2O). Cooling the soln to –258C afforded colorless rod-shaped crystals; yield: 24.2 g
(73%); X-ray-quality crystals were grown from a sat. Et 2O soln at rt, undisturbed on the
benchtop for 2 d; mp 1818C.
8.1.14.2 Method 2:
Aryllithium Compounds by Directed ortho-Lithiation
Lithiation of an unsubstituted arene ring is normally a very slow process and is of no synthetic
use. Calculations indicate that “it is less endothermic to remove a proton from
phenyllithium than from benzene!” [55] However, if the arene contains a substituent with
Lewis base character, which can “direct” an alkyllithium to a proximate proton, then lithiation
is possible (Scheme 5). The resulting lithiated arene 12 is stabilized by chelation
(e.g., Z = amide, alkylamine) and/or inductive stabilization (e.g., Z = alkoxy, halogen).
11
TMS
I
for references see p 414
G. W. Gribble, Section 8.1.14, Science of Synthesis, 2006 Georg Thieme Verlag KG

362 Science of Synthesis 8.1 Lithium Compounds
bDirected ortho-lithiation is an exceedingly powerful tactic in organic synthesis and is
widely practiced, with excellent results. [8,11,13,16,19]
Scheme 5 Directed ortho-Lithiation [8,11,13,16,19]
Z
•
H
R 1 Li
Z
R
H
1
Li
Numerous competition experiments reveal the following decreasing directing abilities:
OCONEt 2,SO 2NMe 2,SO 2NHMe, CONEt 2, dihydrooxazole, CONHMe, CH 2NMe 2 > OMe >
CH 2CH 2NMe 2, NMe 2,CF 3,F. [11,13,16,19,56–58] These trends vary, depending on the reaction conditions
and whether the competition is intermolecular or intramolecular. For example,
whereas methoxy is a poorer directing group than sulfonamide, carboxamide, or dihydrooxazole
when alkyllithium reagents are employed, it is superior to these other directing
groups when ethoxyvinyllithium is used. [59]
8.1.14.2.1 Variation 1:
Amine Directed ortho-Lithiation Groups
Amines are strong Lewis bases and were recognized early to be powerful directed lithiation
groups. [11,13,16,20] Reich has used multinuclear NMR to probe the structures of aryllithium
compounds, e.g. 13, with amine side chains (Scheme 6). [60,61] Normally, these lithiated
species are not isolated but treated directly with an electrophile.
− R 1 H
Scheme 6 Lithiation of N,N-Dimethylbenzylamine [61]
Ph NMe2
BuLi, Et2O, hexane
0 oC, then rt, 7 d
87%
A wide variety of benzylamines, aromatic amines, pyridines, and other amine-containing
arenes have been lithiated and used successfully in synthesis, e.g. 14–17 (Scheme 7). [62–65]
Other amine directing groups, such as dihydrooxazoles and imines, are discussed in Section
8.1.14.2.8.
Li
13
NMe2
Scheme 7 Selected Amine-Directed Lithiation Reactions [62–65]
MeN NMe2
NMe 2
BuLi, Et2O, hexane
rt, 22 h
50%
BuLi, TMEDA, pentane, hexane
rt, 2 d
63%
14 (dimer)
NMe 2
Li
MeN NMe2
15 (dimer)
G. W. Gribble, Section 8.1.14, Science of Synthesis, 2006 Georg Thieme Verlag KG
Li
Z
12
Li

8.1.14 Aryllithium and Hetaryllithium Compounds 363
bt-BuLi (1.4 equiv)
cumene, Et2O
−78 oC, 3 h
N Cl N Cl
Li
(MeS) 2
62%
SMe
16
17
N Cl
NMe2 BuLi
hexane, Et2O
NMe2 Li Me2N S NHMe
rt, 48 h
MeNCS
85%
Some in situ methods for the generation of amine directing groups are known, the most
important of which is that developed by Comins, e.g. to give aldehyde 18 (Scheme 8). [25,66–68]
Scheme 8 ortho-Lithiation Directed by Æ-Amino Alkoxides [66–68]
BuLi (3 equiv), THF
−20 o LiO
CHO
N
Li NMe2 C
Me
Me2N NHMe
R
MeI
62−90%
1 R1 R1 R 1 = H, Me, OMe, Cl
1. MeN NH
CHO BuLi (3 equiv), THF
reflux, 12 h
2. MeI
CHO
76%
2-Lithio-N,N-dimethylbenzylamine (13); Typical Procedure: [61]
N,N-Dimethylbenzylamine (2.99 g, 22.1 mmol) and Et 2O (20 mL) were added to a dried and
N 2-flushed 100-mL storage flask equipped with a stopcock and a septum. The soln was
cooled to 08C and 2.2 M BuLi in hexane (9.6 mL, 21.1 mmol) was added dropwise. The resulting
yellow soln was kept at rt for 7 d, during which time transparent crystals formed.
The supernatant was removed by cannula transfer and the crystals were washed with
Et 2O (3 ” 15 mL); yield: 2.71 g (87%). The crystals were used for the preparation of NMR
samples or dissolved in THF to give a stock soln (typically 1.0–1.5 M) used for subsequent
reactions.
Substituted Aryl Aldehydes 18; General Procedure: [68]
To a soln of N,N,N¢-trimethylethylenediamine (0.41 mL, 3.2 mmol) in THF (8 mL) at –208C
was added 2.2 M BuLi in hexane (1.4 mL, 3.1 mmol) dropwise. After 15 min, the aryl aldehyde
(3.0 mmol) was added, the mixture was stirred for 15 min, and further BuLi (4 mL,
CHO
18
for references see p 414
G. W. Gribble, Section 8.1.14, Science of Synthesis, 2006 Georg Thieme Verlag KG

364 Science of Synthesis 8.1 Lithium Compounds
b9 mmol) was added via syringe. After the mixture was stirred (or placed in a refrigerator)
for the designated time (–208C), the electrophile (18 mmol) was added (–428C). The mixture
was stirred for the designated time, poured into cold stirred 10% HCl, and extracted
with Et 2O. The Et 2O extracts were washed with brine, dried (MgSO 4), and concentrated to
give the crude product. Purification by preparative layer chromatography (silica gel, acetone/hexane)
gave the desired known aldehydes or lactols; yield: 60–90%.
8.1.14.2.2 Variation 2:
Amide Directed ortho-Lithiation Groups
The seminal work by Beak, [19,57,69–72] Snieckus, [8,11,13,19,73] and Gschwend [16,74,75] demonstrates
the importance of the amide directing group in aromatic lithiation. Examples 19,
21, and 22 in Scheme 9 are representative. Further reaction of aryllithium compound 19
with an electrophile, e.g. benzaldehyde, gives substituted benzamides such as 20. [73]
Scheme 9 Selected Amide-Directed ortho-Lithiation Reactions [69,73,75]
O NEt2 O NEt 2
BuLi, TMEDA, THF
−78 oC, 20 min
19
Li
E +
10−90%
E = CO 2H, CO 2Me, CONEt 2, CHO, OH, Br, F, TMS, PPh 2, SH, SPh, SeMe, SePh, SnMe 3, CH(OH)Ph
BuLi (2 equiv)
THF, hexane
0 o HN Bu
C, 2 h
N
t
O
O
O Bu t
Cl Cl
21
OLi
Li
(MeS)2
79%
HN
O NEt2
O NEt 2 O NEt2 O NEt2
s-BuLi, TMEDA, THF
−78 oC, 1 h
O
Li
MeI
O
O
97%
O
22
Similar alkyllithium reactions have led to the synthesis and subsequent reactions of the
lithiated amides in Scheme 10. [76–80]
Scheme 10 Selected Lithiated Amides [76–80]
Li
O O
N
Ph
OLi
Li
OLi
N
Ph
Li
Cl
O
N
Et
20
Bu t
E
SMe
O OMe
G. W. Gribble, Section 8.1.14, Science of Synthesis, 2006 Georg Thieme Verlag KG
Bu t

8.1.14 Aryllithium and Hetaryllithium Compounds 365
OLi
Bu t N
bLi
Li N Me OLi
Li
Substituted Benzamides, e.g. 20; General Procedure: [73]
To a stirred soln of a N,N-diethylbenzamide (2.1 mmol) in THF (50 mL) under N 2 at –788C
(dry ice/acetone bath) was injected sequentially through a septum inlet TMEDA
(2.2 mmol) and s-BuLi (2.2 mmol). The soln was stirred at –788C for 1 h. To this soln, the
electrophile (2.2 mmol) was added and the soln was allowed to warm to rt over 8–12 h,
at which time the mixture was treated with sat. aq NH 4Cl soln followed by extraction
with CH 2Cl 2. The organic extract was dried (Na 2SO 4) and the solvent was removed under
reduced pressure to afford the crude product. Subsequent flash chromatography of the
crude material followed by distillation or recrystallization afforded the pure product;
yield: 10–90%.
8.1.14.2.3 Variation 3:
Alkoxy Directed ortho-Lithiation Groups
The alkoxy group was one of the first directing groups to be recognized, as both Gilman
and Wittig discovered this property of methoxy and other aryl ethers. [14,81,82] At least part
of this property arises from the powerful inductive electron-withdrawing effect of oxygen
that greatly acidifies ortho hydrogens. The myriad of natural products that contain methoxy
groups often lend themselves to total synthesis via methoxy directed lithiation. A
sampling of lithiated aryl ethers is shown in Scheme 11 [83–101] and an example of their
use in Scheme 12 (e.g., to give 23).
Scheme 11 Selected Lithiated Aryl Ethers and Related Oxygen Arenes [83–101]
OMe
OBn
TBDMSO
Li
Li
OMOM
OMe
OTHP
Li
CF3
Li
OMe
O
Cl
O
Li
F 3C
OEt
O
OMe
Li
OEt
Li
Li
CF3
X
KO 2C
OPh
O
Li
OPh
O
OMe
Li
Li
OMe
F
O
O
CF 3
F
O
Li
OMe
Cl
Li
Li
for references see p 414
G. W. Gribble, Section 8.1.14, Science of Synthesis, 2006 Georg Thieme Verlag KG

366 Science of Synthesis 8.1 Lithium Compounds
bOMOM
O
O Li
Li
O
O
Me
Et 2N
S
OMe
Scheme 12 Synthesis of 3,5-Dimethoxy-4-methylbenzoic Acid [96]
MeO
CO 2H
OMe
1. t-BuOK, THF, −78 oC 2. BuLi, hexane, −78 oC, 40 min
3. MeI, −78 oC, 1 h
80%
O
MeO
Li
CO 2H
23
OMe
( )
O n OLi
Li
The ortho-lithiation of benzyl alcohols, [102,103] alkoxyphenols, [104] and phenol itself [105] has
been described, as has ortho-dilithiation of anisole, [106] 1,2,4,5-tetramethoxybenzene, [107]
diphenyl ether, [108,109] and oxygenated derivatives of 1,1¢-bi-2-naphthols. [110–112] The power
of this methodology is illustrated with the facile synthesis of 25 from dilithio compound
24 (Scheme 13). [109]
Scheme 13 Synthesis and Reaction of 2,2¢-Dilithiodiphenyl Ether [109]
BuLi (2 equiv)
TMEDA, hexane
rt, 90 min
O O
Extensive theoretical and experimental studies have been carried out on the lithiation of
anisole, [113–119] naphthols, [120] and 1-methoxynaphthalene. [29] One interesting observation
with the latter compound is that butyllithium affords the 2-lithiated (kinetic) product
whereas tert-butyllithium yields the 8-lithiated (thermodynamic) product. [29] Likewise,
the rate of anisole lithiation is dramatically affected by alkyllithium and N,N,N¢,N¢-tetramethylethylenediamine
concentrations. [114–117]
G. W. Gribble, Section 8.1.14, Science of Synthesis, 2006 Georg Thieme Verlag KG
Li Li
24
CO 2Et
N
91%
HO
n = 2−7
O
25
N

8.1.14 Aryllithium and Hetaryllithium Compounds 367
b3,5-Dimethoxy-4-methylbenzoic Acid (23); Typical Procedure: [96]
CAUTION: Inhalation, ingestion, or skin absorption of iodomethane can be fatal.
To a stirred soln of t-BuOK (0.246 g, 2.19 mmol) in THF (5 mL) was added a soln of 3,5-dimethoxybenzoic
acid (0.100 g, 0.55 mmol) in THF (5 mL) at –788C under argon, followed
by the addition of 1.6 M BuLi in hexanes (1.37 mL, 21.9 mmol). After stirring for 40 min
at –788C, MeI (70 ìL, 1.10 mmol) was added and the mixture was stirred for 1 h (–788C)
and was then allowed to warm to rt. It was quenched with aq NH 4Cl (3 mL) and washed
with Et 2O (5 mL). The aqueous layer was acidified with 2 M HCl. The colorless precipitate
obtained was extracted with Et 2O (2 ” 5 mL) and dried (Na 2SO 4). The solvent was removed
under reduced pressure and the residue was recrystallized (CHCl 3/Et 2O) to give the title
compound as a colorless crystalline solid; yield: 0.086 g (80%); mp 212–2148C.
2,2¢-Dilithiodiphenyl Ether (24); Typical Procedure: [109]
Diphenyl ether (1.7 g, 10 mmol) was placed in a dry, 100-mL round-bottomed flask and
then flushed with N 2. TMEDA (2.4 g, 20.7 mmol) was added via syringe followed by dry
hexane (10 mL) and 1.65 M BuLi in hexane (13 mL, 21.5 mmol). The mixture was stirred
at rt for 90 min or longer before the addition of an electrophile; yield: 89–91%.
8.1.14.2.4 Variation 4:
Halogen Directed ortho-Lithiation Groups
Despite the reputation of halogens as weak Lewis bases, fluorine, chlorine, bromine, and
even iodine are potent ortho-directing groups. Indeed, the powerful inductive electronwithdrawing
effect of fluorine greatly acidifies the ortho hydrogens in fluorobenzene.
[121,122] Thus, these protons are kinetically more acidic than the para proton by a factor
of 57 000. [121] While the lithiation directing ability of halogens has been known for
many years, the work of Schlosser has clarified, and greatly expanded, the nature and
utility of the halogen directing ability. [123,124] The major difference between halogen and
other directing groups is that the former usually requires the use of lithium amide bases
rather than alkyllithium compounds to avoid halogen–lithium exchange, especially with
bromine and iodine. Other potential hazards are the often notorious “halogen dance” reaction
[125] and aryne formation, which can occur at temperatures above –788C(I>Br>Cl
> F). A selection of lithiated aryl halides is summarized in Table 2. [126–137] The results reveal
that fluorine is most effective at directing ortho-lithiation (e.g., to give 26) and chlorine is
slightly better than bromine. Multiple brominated substrates are severely plagued by bromine
scrambling. [134] Such substrates are also prone to aryne formation. [138]
for references see p 414
G. W. Gribble, Section 8.1.14, Science of Synthesis, 2006 Georg Thieme Verlag KG

368 Science of Synthesis 8.1 Lithium Compounds
bTable 2 Selected Lithiated Aryl Halides [126–137]
R 5
R 4
H
R 3
R 1
R 2
R 5
R 4
Li
R 3
R 1 R 2 R 3 R 4 R 5 Conditions Yield (%) a Ref
F H H H H BuLi, t-BuOK, THF/hexane, –758C, 3 h 98 [126]
CF 3 H H H H BuLi, t-BuOK, THF/hexane, –758C, 3 h 94 [126]
OMe H H F H BuLi, THF, –758C, 50 h 50 [127]
F H H OMe H BuLi, t-BuOK, THF 85 [127]
F Li F H F t-BuLi (6 equiv), –758C 68 [128]
F H H H F s-BuLi, THF/cyclohexane, –78 8C, 2 h 78 [129]
F Me H H H BuLi, t-BuOK, THF, –758C 60 [130]
F H Me H H BuLi, t-BuOK, THF, –758C 65 [130]
F H H Cl H BuLi, t-BuOK, THF, –758C, 40 min 86 [131]
F Br H Br H LTMP, THF/hexane, –758C, 2 h 82 [131]
Cl H H Br H LTMP, THF/hexane, –758C, b [132]
0.7 h 56
Cl H H H Br LTMP, THF/hexane, –758C, 2 h 94 [132]
Br H H CF 3 H LTMP, THF/hexane, –1008C, 6 h 85 [133]
Br Br H Br F LTMP, THF/hexane, –758C 68 [134]
F Br H H F LDA, THF/hexane, –788C, c [135]
30 min 50
Cl H H H H LTMP, THF, –788C, d [136]
2 h 96
Br H H H Br LDA, THF, –708C, e [137]
30 min 70
a Yield of carbonylation product unless otherwise specified.
b 23% of 2-bromo-5-chlorobenzoic acid is formed.
c Quenching with acetone.
d Quenching with B(OiPr)3.
e Quenching with DMF.
The power of halogen directing groups is evident from the examples in Scheme 14, showing
that nitro groups are compatible with lithium dialkylamide lithiation conditions (see
27) [139] and iodine can direct ortho lithiation (and survive an aryne pathway) (see 28 and
29). [140,141] Moreover, the stability of 2-fluoroaryllithium compounds has allowed for a
low-temperature X-ray crystal structure of 1,2,3,4-tetrafluorophenyllithium. [142]
Scheme 14 Examples of Aryl Halide Lithiation [139–141]
F F
NO 2
LiHMDS, THF
−78 oC Li
R 1
R 2
F F
27
NO 2
TMSCl
78%
R 5
R 4
X
R 3
26
R 1
R 2
TMS
F F
G. W. Gribble, Section 8.1.14, Science of Synthesis, 2006 Georg Thieme Verlag KG
NO 2

8.1.14 Aryllithium and Hetaryllithium Compounds 369
bLTMP, THF
−78 o O
I O
I
C, 15 min I2
O
I
I
LDA (2 equiv)
TMSCI, THF
−75 oC, 30 min
77%
TMS
2,6-Difluorobenzoic Acid (26,R 1 =R 5 =F;R 2 =R 3 =R 4 =H;X=CO 2H); Typical Procedure: [129]
A soln containing 1,3-difluorobenzene (11 g, 0.10 mol) and s-BuLi (0.1 mol) in THF
(0.20 mL) and cyclohexane (60 mL) was kept for 2 h at –788C before being poured onto an
excess of freshly crushed dry ice. At 258C, 2.0 M HCl in Et 2O (0.12 mol) was added, the volatiles
were evaporated, and the residue was dissolved in hot water and the soln, after concentration,
was cooled to afford the product as colorless needles; yield: 12.3 g (78%); mp
155–1578C.
2,6-Dibromobenzaldehyde (26,R 1 =R 5 = Br; R 2 =R 3 =R 4 = H; X = CHO); Typical Procedure: [137]
A 2 M soln of LDA in THF (30 mL, 60 mmol) was added dropwise to a soln of 1,3-dibromobenzene
(11.8 g, 50 mmol) in THF (100 mL) at –70 8C. An orange precipitate formed. The
mixture was stirred for 30 min at –758C and then DMF (4.4 g, 60 mmol) was added dropwise
while maintaining the temperature at –708C. The purple soln was stirred for 30 min
at –708C and then hydrolyzed with dil aq H 2SO 4. The yellow organic phase was separated.
The aqueous phase was extracted with Et 2O (50 mL) and the extract was added to the organic
phase. The solvents were concentrated to leave the crude product as a yellow-brown
solid. It was washed with H 2O and petroleum ether, and recrystallized (cyclohexane,
50 mL) to give pale yellow needles; yield: 9.2 g (70%); mp 89–91 8C.
I
I
29
O
Li
28
TMS
8.1.14.2.5 Variation 5:
Sulfur-Based Directed ortho-Lithiation Groups
A variety of sulfur-based directing groups are known. Among them, sulfonamides, sulfones,
and sulfoxides are the most powerful of all directing groups; [5,8,11,13] however, the
oxygen atom of these groups is the actual director of lithiation. The ortho-lithiation of
benzenethiols and phenyl thioethers is well known and an X-ray crystal structure of
tert-butyl 2-lithiophenyl sulfide has been reported. [143] Examples of sulfur-based lithiation
reactions are shown in Scheme 15. [144–147] Other sulfur-based directing groups are
sulfinamides, [148,149] sulfonamides, [5,150] sulfonates, [151–153] sulfonic acids, [154] and thioamides.
[155]
Scheme 15 Selected Sulfur-Based Directed ortho-Lithiation Reactions [144–147]
BuLi
TMEDA, cyclohexane
0 o SH
C to rt, 24 h
SLi
Li
1. S8 2. LiAlH4 84%
85%
SH
O
O
SH
for references see p 414
G. W. Gribble, Section 8.1.14, Science of Synthesis, 2006 Georg Thieme Verlag KG
I
I

370 Science of Synthesis 8.1 Lithium Compounds
SO 2Bu t SO 2Bu t
bBuLi, THF
−78 oC, 30 min
E = D, Me, allyl, CHO, CONHPh, CONEt2, TMS, OH, I, NH2
Li
E +
35−97%
LTMP, THF, Me2SiCl2
0 o O O
O O
S
C
59%
S
Si
Me2 SOBu t SOBu t
BuLi, THF
−78 oC, 1 h
E = D, Me, Et, allyl, CH(OH)Ph, CONEt2, OH, Br, B(OH)2, TMS, SnMe3
Li
E +
41−96%
8.1.14.2.6 Variation 6:
Other Carbonyl Directed ortho-Lithiation Groups
SO 2Bu t
SOBu t
Like amides, other carbonyl groups (carbamates, carboxylates, esters, ureas) can engage in
directed lithiation. The most widely utilized of these groups is the carbamate, usually as a
tert-butoxycarbonylaniline or an O-aryl carbamate. The latter substrates have been extensively
exploited, particularly as an anionic equivalent of the Fries rearrangement. [156–163]
Examples of this transformation and the lithiation of tert-butoxycarbonylaniline are illustrated
in Scheme 16. Lithiated carbamate 30 can be trapped with a variety of electrophiles.
[156] Benzylic carbamates also undergo an anionic homo-Fries rearrangement, [164]
variations on the original methodology have been reported, [165] and applications to 1,1¢bi-2-naphthols
are known. [166]
Scheme 16 Selected ortho-Lithiation Reactions of Carbamates [156,167]
O
O
NEt 2
s-BuLi, TMEDA
THF, −78 oC, 1 h
t-BuLi (3 equiv)
Et2O, pentane
−10 o NHBoc NHBoc
C, 3 h
Li
O
O NEt2 Li
30
(MeS)2
89%
−78 oC to rt
75%
E
E
OH
NHBoc
SMe
Other carbonyl-based directing groups of note are summarized in Table 3. [168–172] Cyclic
ureas also serve as (weak) directing functionalities. [173] The carboxylic acid (carboxylate)
group is particularly effective at directing ortho-lithiation, [172,174] and competition experiments
reveal this group to be intermediate in capacity to direct lithiation. [174] The carboxylate
group is weaker than amides, sulfonamides, carbamates, and dihydrooxazole, but
G. W. Gribble, Section 8.1.14, Science of Synthesis, 2006 Georg Thieme Verlag KG
O
NEt 2

8.1.14 Aryllithium and Hetaryllithium Compounds 371
bstronger than methoxy and amino groups. Similarly, the N-carboxylate group is an ortholithiation
director. [175,176]
Table 3 Selected Carbonyl-Based DIrected ortho-Lithiation Reactions [168–172]
R 1
O Z
R 1
O Z
O Z
E +
R1 Li E
Z R 1a Conditions E Yield (%) Ref
NHNMe 2 H s-BuLi (2 equiv), THF, –708C, 10 min TMS 68 [168]
NHNMe 2 H s-BuLi (2 equiv), THF, –708C, 10 min SnBu 3 77 [168]
NHOMe H s-BuLi (2.4 equiv), THF, TMEDA,
–208C, 45 min
NHOMe H s-BuLi (2.4 equiv), THF, TMEDA,
–208C, 45 min
Me 91 [169]
(CH 2) 7Me 64 [169]
OCH 2t-Bu 4-Br LDA, THF, B(OiPr) 3 B(OiPr) 2 84 [170]
OCH 2t-Bu 4-OMe LDA, THF, B(OiPr) 3 B(OiPr) 2 70 [170]
NHCONMe 2 4-F BuLi, THF/heptane, 08C, 1.5 h D 88 [171]
NHCONMe 2 4-F BuLi, THF/heptane, 08C, 1.5 h C(OH)Ph 2 78 [171]
OLi H s-BuLi, THF, TMEDA, –908C, 30 min Me 65 [172]
a Locants refer to starting material.
8.1.14.2.7 Variation 7:
Phosphorus Directed ortho-Lithiation Groups
The di-tert-butylphosphoryl functionality is an excellent phosphorus-based directing
group. [177] Inter- and intramolecular competition experiments show that di-tert-butylphosphoryl
is superior to methoxy but inferior to diethylcarbamate and N,N-diethylamide.
Scheme 17 illustrates the scope of the di-tert-butylphosphoryl directing group in the synthesis
of ortho-substituted di-tert-butyl(phenyl)phosphine oxides 31.
Scheme 17 Selective Di-tert-Butylphosphoryl-Directed ortho-Lithiation Reactions [177]
Bu t
Bu t
P
O
t-BuLi, THF
−78 oC, 80 min
Bu t
P O
E = Me, Et, C(OH)Ph 2, CO 2H, CHO, B(OMe) 2, TMS, PPh 2, Cl, I
Li
E
39−82%
+
Although dialkyl phenyl phosphates can be ortho-lithiated, they undergo facile rearrangement
into dialkyl O-hydroxyphenylphosphonates, even at low temperature, thus precluding
the obtention of ortho-lithiated products. [178–180] However, aryl tetramethylphosphorodiamidates
are ortho-lithiated and can be trapped at –1058C to give ortho-substituted
products (Scheme 18). [180] At –788C, O-to-C migration occurs to produce 2-hydroxyarylphosphonic
tetramethyldiamides. Competition experiments reveal that the tetramethylphosphorodiamidate
group is superior to carbamoyl, methoxymethoxy, tert-butylsulfonyl,
and N,N-diethylamido groups in ortho-lithiation.
Bu t
Bu t
Bu t
P O
31
E
for references see p 414
G. W. Gribble, Section 8.1.14, Science of Synthesis, 2006 Georg Thieme Verlag KG

372 Science of Synthesis 8.1 Lithium Compounds
bScheme 18 ortho-Lithiation of Phenyl Tetramethylphosphorodiamidate [180]
O
O P NMe2 NMe2 s-BuLi, THF
−105 oC, 1 h
E = TMS, SPh, CH(OH)Me, CH(OH)Ar 1 , C(OH)Ph2, COAr 1
O P
O
NMe2 NMe2 Li
E
55−94%
+ , 105 oC O
O P NMe2 NMe2 E
Di-tert-butyl(2-iodophenyl)phosphine Oxide (31, E = I); Typical Procedure: [177]
To a soln of di-tert-butyl(phenyl)phosphine oxide (302 mg, 1.27 mmol) in anhyd THF (8 mL)
at < –708C (dry ice/acetone bath) was added a 1.4 M soln of t-BuLi in pentane (0.99 mL,
1.39 mmol) dropwise and the mixture was stirred for 80 min. The yellow suspension was
treated via cannula with a soln of I 2 (354 mg, 1.39 mmol) in THF (5 mL) and the resulting
red soln was warmed to rt over 8–10 h. Addition of aq Na 2S 2O 3 and standard workup, followed
by flash chromatography (silica gel, EtOAc/hexane 5:1) afforded the title compound
as a colorless solid; yield: 352 mg (76%); mp 164.5–1658C (Et 2O/CH 2Cl 2).
8.1.14.2.8 Variation 8:
Other Nitrogen Directed ortho-Lithiation Groups
Like amines (Section 8.1.14.2.1), several other nitrogen directing groups are important in
organic synthesis. Of these, the dihydrooxazole group has seen the greatest utility since
its initial discovery as a powerful ortho-directing group; [181,182] a review is available. [183] Simple
imines [184] and dihydroimidazoles [185] are directing groups but have not been extensively
used. Some examples of these directing groups are shown in Scheme 19.
Scheme 19 ortho-Lithiation of Other Nitrogen Directing Groups [184,186,187]
F
N
N N Li N
O O
LDA, TMEDA
benzene, rt, 7 h
O O
O
N
Ar 1 = 6-methoxy-2-naphthyl
BuLi, Et2O
hexane
−78 oC, 1 h
F
MeI
98%
Li
O
N
N
N
O O
Ar1CHO 76%
G. W. Gribble, Section 8.1.14, Science of Synthesis, 2006 Georg Thieme Verlag KG
F
Ar 1
O
O

8.1.14 Aryllithium and Hetaryllithium Compounds 373
Cy
bLTMP (2 equiv), THF
−10 o N
N
C, 1 h MeI
Li
63%
OMe
A relatively new ortho-lithiation group is the tetrazole moiety and several examples are
known (e.g., to give 32, Scheme 20). [188–191] Competition experiments indicate the tetrazol-5-yl
group to be superior to methoxy but less effective than diethylcarbamate or tertbutylamido.
[191]
Scheme 20 ortho-Lithiation of 5-Aryltetrazoles [188,189]
N
N
N NH
N NLi
E = Me, CH(OH)Me, CH(OH)CH CH 2
Cy
OMe
s-BuLi, TMEDA, THF
−30 oC, 45 min E +
Li
N NTr
N NTr
N N
N N
BuLi, TMEDA, THF
−20 oC, 1 h
N
N
Li
51−95%
1. B(OiPr)3
2. H2O
90%
N
N
N
N
N
32
NH
NTr
N
E
Cy
N
B(OH)2
5-(2-Tolyl)tetrazole (32, E = Me); Typical Procedure: [188]
CAUTION: Inhalation, ingestion, or skin absorption of iodomethane can be fatal.
A three-necked round-bottomed flask equipped with a low-temperature thermometer, N2 inlet, septum, and magnetic stirrer was charged with 5-phenyltetrazole (0.34 g,
2.3 mmol), TMEDA (0.35 mL, 2.3 mmol), and dry THF (20 mL). The soln was cooled to
–35 8C and a 1.3 M soln of s-BuLi in cyclohexane (5.4 mL, 7.0 mmol) was added over 2 min.
The yellow soln was maintained at –35 to –308C for 45 min and freshly distilled MeI
(0.43 mL, 6.9 mmol) was added in one portion. The cooling bath was removed; the mixture
was adjusted to pH 2 with dil aq HCl and concentrated with a rotary evaporator. The residue
was taken up in EtOAc (50 mL), washed with H2O (3 ” 20 mL), dried (MgSO4), and concentrated
to give a colorless amorphous solid (0.35 g). Recrystallization (abs EtOH) gave
the analytically pure title compound; yield: 0.29 g (78%); mp 156–1588C.
8.1.14.2.9 Variation 9:
Other Directed ortho-Lithiation Groups
One other ortho-directing lithiation group of synthetic interest is cyano, and the efficient
ortho-lithiation of phthalonitrile has been achieved (Scheme 21). [192] Lithiation is complete
within 3 minutes at –968C.
OMe
for references see p 414
G. W. Gribble, Section 8.1.14, Science of Synthesis, 2006 Georg Thieme Verlag KG

374 Science of Synthesis 8.1 Lithium Compounds
bScheme 21 ortho-Lithiation of Phthalonitrile [192]
LDA, THF
−96 o Li
NC CN C, 3 min NC CN
E = Me, Cl, Br, I, SPh, TMS
8.1.14.3 Method 3:
Furyllithium Compounds
E
68−83%
+
E
NC CN
The importance of the furan ring as a vehicle in organic synthesis and its presence in
many natural products has prompted extensive development of furyllithium syntheses.
8.1.14.3.1 Variation 1:
By Direct Deprotonation
The powerful electronegativity of oxygen allows for regioselective C2 deprotonation of
furan, which can be accomplished with alkyllithium reagents or lithium amides. Competitive
C3 lithiation is never a problem. Deprotonation of 2-methylfuran with butyllithium
(in diethyl ether/hexane, rt) affords 5-methyl-2-furyllithium, which adds to indan-1-one to
give 1-(5-methyl-2-furyl)indene (79%); [193] 2-furyllithium reacts with ribose derivatives [194]
and sugar nitrones [195] to give the expected 1,2-addition products. Transmetalation of
2-furyllithium to a cuprate provides a route to 2-(trifluoroacetyl)furan by acylation with
trifluoroacetic anhydride. [196] The presence of a potential directing group as in 33 does
not necessarily divert 2-lithiation (Scheme 22). [197] Oxime hydrolysis of 34 provides a convenient
2,5-disubstituted furan synthesis. Similarly, 2-(2-furyl)-1,3-dimethylimidazolidine
is lithiated regioselectively at C5. [198] Dilithiation of furan leads to 2,5-dilithiofuran, [199]
which affords 2,5-bis(butyltellanyl)furan (35), a compound useful in cross-coupling reactions.
[200]
Scheme 22 2-Furyllithium Compounds by Direct C2 Lithiation [197,200]
BuLi (2 equiv)
TMEDA, THF
−78 o HO
N
C, 1 h
HO
N
O
E = D, Me, Et, Pr, Bu, TMS, SnBu3, CH(OH)Et, CH(OH)(CH2)4Me, CH(OH)Ph, C(OH)Ph2
O
33
BuLi (2.5 equiv)
TMEDA, THF
reflux, 30 min
Li
O
Li
O
1. Te
2. BuBr
90%
Li
E
77−99%
+
HO
N
34
O
BuTe
O
35
TeBu
2,5-Bis(butyltellanyl)furan (35); Typical Procedure: [200]
To a two-necked, round-bottomed flask under an argon atmosphere containing a soln of
furan (1.36 g, 20 mmol) in freshly distilled dry THF (100 mL) and TMEDA (5.8 g, 50 mmol),
at rt, was added a 1.5 M soln of BuLi in hexane (33.3 mL, 50 mmol). The mixture was re-
G. W. Gribble, Section 8.1.14, Science of Synthesis, 2006 Georg Thieme Verlag KG
E

8.1.14 Aryllithium and Hetaryllithium Compounds 375
bfluxed for 30 min and cooled to 258C. Elemental Te (6.35 g, 50 mmol) was added in one
portion and the mixture was stirred until all the Te has disappeared. The reaction was
cooled to 08C and then BuBr (6.86 g, 25 mmol) was added and the mixture was stirred for
6 h at rt. After this period, the reaction was quenched with sat. NH 4Cl soln (50 mL) and extracted
with EtOAc (3 ” 50 mL). The combined organic layers were dried (MgSO 4) and concentrated
under reduced pressure. The residue was purified by flash chromatography
(silica gel, hexane) to give the product; yield: 0.39 g (90%).
8.1.14.3.2 Variation 2:
By Halogen–Lithium Exchange
The inherent greater stabilization of a 2-furyllithium over a 3-furyllithium allows for regioselective
C2 bromine–lithium exchange (i.e., 36 to 37) (Scheme 23). [201] This sequence
again illustrates that lithium amides (i.e., LDA) do not normally partake in bromine–lithium
interchange. Moreover, the 3-furyllithium generated by bromine–lithium exchange,
e.g. 38, do not rearrange to the more stable 2-furyllithium. [202]
Scheme 23 Furyllithium by Bromine–Lithium Exchange [201,202]
O
Br
Br
LDA
TMSCl, THF
86%
1. BuLi, Et2O
−78
84%
o Br
C, 3 min
2. H2O Br
TMS
O
Br
TMS
O
36
37
Br
BuLi, Et2O Li
1. S8
SBz
−78 2. Bz2O oC, 30 min
O O 80%
O
8.1.14.3.3 Variation 3:
By Directed ortho-Lithiation
If steric effects from the use of ostensibly bulky alkyllithium reagents do not intervene,
directing lithiation groups at the furan C3 position invariably effect C2 lithiation. Thus,
under the Comins amino alkoxide conditions, furan-3-carbaldehyde is lithiated at C2 to
give 39 upon methylation in high yield with greater than 96% regioselectivity (Scheme
24). [203] However, with bulkier lithium amides, C5 lithiation of furan-3-carbaldehyde occurs,
e.g. to give 40. [204] Lithiation at C4 does not occur.
Scheme 24 Directed ortho-Lithiation Reactions of
Furan-3-carbaldehyde [203,204]
CHO 1. BuLi, TMEDA
2. BuLi (2 equiv)
3. MeI
CHO
O
83%
O
38
39
for references see p 414
G. W. Gribble, Section 8.1.14, Science of Synthesis, 2006 Georg Thieme Verlag KG

376 Science of Synthesis 8.1 Lithium Compounds
CHO 1. morpholine
2. s-BuLi, THF, −78
CHO
oC, 7 h
3. E +
bO
30−73% E
O
40
E = CH(OH)(CH2)5Me, (CH2)7Me, 4-BrC6H4CH(OH), TMS, TES, TBDMS, SnBu3
Suitably powerful directing groups at the C2 furan position will effect lithiation at C3.
Weaker groups will not prevent the “default” C5 lithiation. [198] Examples of the former situation
are illustrated in Scheme 25. [205–207] One of the most effective such directing groups
is the rare (tetramethyldiamido)phosphate (e.g., 41 fi 42). [207] Dihydrooxazoles [208–210] are
also useful in this context, and 3,5-dilithiated furans are generated using the 4,4-dimethyloxazolin-2-yl
directing group. [209] The dihydroimidazole group is also an effective C3 director
in furans. [211] The generation and trapping of 2-(tert-butyldimethylsilyl)-3-(hydroxymethyl)-4-furyllithium
provides access to 3,4-disubstituted furans. [212]
Scheme 25 Directed ortho-Lithiation Reactions of 2-Substituted Furans [205–207]
1. t-BuLi (3 equiv), TMEDA, THF, −78 o C
O
2. MeCHO
O
52%
O
NHEt
1. s-BuLi (2 equiv), DME, −78
O O
oC, 1 h
O
NHBu
2. MeOD
91%
t
O
HO
D
O
NHEt
O
NHBu t
1. BuLi, THF, −78 oC 2. E +
O
O
P
40−95%
O
O
41 42
P
E
NMe2 NMe2
O
NMe2 NMe2
E = Me, Bn, TMS, SPh, CHO, C(OH)Me 2, C(OH)MePh, Bz
8.1.14.4 Method 4:
Thienyllithium Compounds
Lithiated thiophenes have assumed special importance in recent years owing to their role
in conducting polymers and other materials. Moreover, unlike oxygen and nitrogen heterocycles,
thiophenes can be reductively desulfurized to afford novel compounds that are
not available, for example, from furans and pyrroles.
8.1.14.4.1 Variation 1:
By Direct Deprotonation
Although the C2 lithiation of thiophene by deprotonation has been known for a long
time, several new developments and applications have been described in recent years.
Typical reaction conditions for thiophene itself are butyllithium, hexane/tetrahydrofuran,
08C, 30 minutes, to give 2-thienyllithium, which undergoes reaction with, for example,
ribose derivatives to give the corresponding C-nucleosides in high yields. [194,213] The
C2 lithiation of bis-thiophenes [214] and thieno[3,2-b]thiophenes [215] en route to polythio-
G. W. Gribble, Section 8.1.14, Science of Synthesis, 2006 Georg Thieme Verlag KG

8.1.14 Aryllithium and Hetaryllithium Compounds 377
bphenes has been reported. The synthesis and a reaction of 2-iodo-5-thienyllithium (43) are
illustrated in Scheme 26. [216] Dilithiation of thiophene is readily achieved and provides access
to 2,5-disubstituted thiophenes, e.g. 44. [217] Thiophene C2 lithiation has been used in
syntheses of 7-hydroxybenzo[b]thiophenes. [218]
Scheme 26 Lithiation and Reactions of Thiophenes [216,217]
I
S
LDA, THF
−40 to −10 oC I
S
Li
43
E = CHO, CO 2H, Ac, SnBu 3, CO(CH 2) 7Me, CH(OH)(CH 2) 7Me
BuLi (2 equiv)
TMEDA, hexane
40 oC to reflux, 30 min
S
Li
S
Li
8.1.14.4.2 Variation 2:
By Halogen–Lithium Exchange
E +
63−85%
O
H NMe 2
75%
I
S
E
OHC
S
CHO
Bromothiophenes have proven to be extraordinarily useful in organic synthesis, particularly
via bromine–lithium exchange and subsequent chemistry. The observed regioselectivity
(C2 bromine is exchanged faster than C3 bromine) is especially significant. The
readily available 2,5-dibromothiophenes (by electrophilic bromination) undergo smooth
lithiation with alkyllithium reagents to give 2,5-dilithiothiophenes. [219–221] Highly hindered
2,5-disilylated 3,4-di-tert-butylthiophenes have been prepared this way, [220] and
this inherent regioselectivity allows for the synthesis of bis-thiophene 45 by sequential
bromine–lithium exchange (Scheme 27). [221] Applications to the construction of chiral
3,3¢-bithiophenes [222] and polymer-supported oligo(3-arylthiophenes) [223] are known. In
cases where direct deprotonation with alkyllithium is not feasible, as for 46, a halogen–
lithium sequence is necessary, as shown for 47 to 48. [224] The synthetic power inherent in
thiophene bromine–lithium exchange reactions is seen in the conversion of 2,3-, 3,4-, and
2,5-dibromothiophenes into acetyl- and (trifluoroacetyl)azidothiophenes by sequential reactions
(e.g., 49 to 50). [225]
Scheme 27 Thienyllithium Compounds by Bromine–Lithium Exchange [221,224]
Ph Br
Ph Br
1. BuLi, Et2O 2. H
Br
S
Br
S
+
Ar 1 CO 2Et
S
46
Ar 1 = 4-FC6H4
Pr i
Br2, py
94%
Br
Ar 1 CO 2Et
S
47
Pr i
1. BuLi
Et2O, hexane
−70 oC, 1 h
2. SCl2 52%
1. t-BuLi (2 equiv)
THF, −78
quant
oC, 30 min
2. HCHO
44
Ph Ph
S
S
HO
45
S
S
Ar 1 CO 2Et
48
Pr i
for references see p 414
G. W. Gribble, Section 8.1.14, Science of Synthesis, 2006 Georg Thieme Verlag KG

378 Science of Synthesis 8.1 Lithium Compounds
bS
49
Br
Br
1. BuLi, Et2O, −70 oC, 45 min
2. CF3CONEt2 3. BuLi, −70 oC, 1 h
4. TsN3 45%
S
N3
O
50
Ethyl 4-(4-Fluorophenyl)-5-(hydroxymethyl)-2-isopropylthiophene-3-carboxylate
(48,Ar 1 = 4-FC 6H 4); Typical Procedure: [224]
CAUTION: Formaldehyde is a probable human carcinogen, a severe eye, skin, and respiratory
tract irritant, and a skin sensitizer.
To a soln of 47 (Ar 1 = 4-FC 6H 4; 3.4 g, 9.2 mmol) in THF (35 mL) at –788C under argon was
added a 1.7 M soln of t-BuLi in pentane (11 mL, 18.7 mmol) dropwise. The soln was stirred
at –788C for 30 min then the temperature was raised to –258C, at which point excess
HCHO (generated from cracking paraformaldehyde) was introduced over a period of 1 h.
The mixture was quenched with sat. NH 4Cl and was extracted with t-BuOMe. The organic
phase was dried (Na 2SO 4) and the solvent removed under reduced pressure to give an oil;
yield: 3.0 g (quant).
8.1.14.4.3 Variation 3:
By Directed ortho-Lithiation
Since the pioneering work of Slocum, [226] the lithiation of thiophenes substituted at C2 or
C3 with standard directing groups has been widely explored (dihydrooxazole, [209,227]
amides, [205,206,226,228,229] dihydroimidazoles, [198,211] amino alkoxides, [203] aminoalkyl, [226] alkoxyalkyl,
[226] carboxy, [205] and sulfonamides [230] ). Depending on the conditions (base, solvent,
directing group), with C2 thienyl directing groups one can achieve C3 or C5 monosubstitution
or C3+C5 disubstitution. Generally, alkyllithium reagents will deprotonate
C3 (kinetic) while amide bases will deprotonate C5 (thermodynamic). [230] Thiophenes substituted
at C3 with directing groups (aminoalkyl, [226] amide, [226,231] or carboxy [205] ) generally
afford C2 substitution. Selected examples are shown in Scheme 28. The order of deprotonation
in 51 is C5 > C3, which allows for tandem selective electrophile addition. [228] The
conversion 52 into 53 is a powerful quinone synthesis applicable to a range of structures.
[231]
Scheme 28 Directed ortho-Lithiation Reactions in Thiophenes [205,209,228,231]
S
51
O
NEt 2
s-BuLi (2.2 equiv)
TMEDA, THF
−78 oC E 1 = E 2 = H, D, Me, CONEt2, CH(OH)Ph, SMe, TMS
Li
S
Li
CF 3
1. (E 1 ) +
2. (E 2 ) +
26−85%
G. W. Gribble, Section 8.1.14, Science of Synthesis, 2006 Georg Thieme Verlag KG
O
NEt 2
E 2
S
E 1
O
NEt 2

S
8.1.14 Aryllithium and Hetaryllithium Compounds 379
O
N
E = CO2H, SMe, TMS
S
S
O
CO2H
52
NEt 2
s-BuLi (3.3 equiv), THF
−20 oC, 30 min
1. t-BuLi (3 equiv), TMEDA
THF, −78 oC 2. MeCHO
quant
1. s-BuLi, TMEDA
Et2O, −78 oC, 1 h
2.
S
CHO
3. s-BuLi, rt, 12 h
77%
S
Li
CO2H
OH
S
E +
Li
89−97%
Bromothiophenes undergo rapid lithiation with lithium diisopropylamide (THF, –708C)
but are prone to halogen dance rearrangements, a situation not without controversy
and misassignments. [232–234] Thus, treatment of 2,5-dibromothiophene with lithium diisopropylamide
(THF, –808C, 30 min) and quenching with electrophiles affords the 2-substituted
3,5-dibromothiophene. [234] Likewise, lithium diisopropylamide treatment of 2,3-dibromothiophene
and quenching with iodomethane yields 2,4-dibromo-5-methylthiophene
in 89% yield. [235]
8.1.14.5 Method 5:
Pyrrolyllithium Compounds
The intrinsic greater acidity of the C2 over the C3 proton in pyrrole is amplified by the
presence of an electron-withdrawing protecting group on the nitrogen, such as phenylsulfonyl,
tert-butoxycarbonyl, trialkylsilyl, carboxy, and others. [236] Such groups also act
as directing groups to the C2 position, so that C2 lithiation in N-substituted pyrroles is
particularly facile.
8.1.14.5.1 Variation 1:
By Direct Deprotonation
Since the C2 proton of 1-methylpyrrole is less acidic than that of furan (oxygen more electronegative
than nitrogen; pK a 39.5 vs 35.6 for 1-methylpyrrole and furan, respectively
[237] ), tert-butyllithium (tetrahydrofuran/pentane, –788C to rt) is normally required to
generate 1-methylpyrrol-2-yllithium, and many synthetic examples of this species are
known, [238] including those resulting from transmetalation with magnesium or zinc. [239]
The structure of 1-propylpyrrol-2-yllithium is dimeric by X-ray crystallography, [240] and
S
O
O
53
S
O
N
E
S
E
O
N
for references see p 414
G. W. Gribble, Section 8.1.14, Science of Synthesis, 2006 Georg Thieme Verlag KG

380 Science of Synthesis 8.1 Lithium Compounds
b1-methylpyrrole-2,5-diyldilithium is known. [199] Two examples are shown in Scheme
29. [236,241] Deprotection of 54 is accomplished with lithium hydroxide–methanol.
Scheme 29 C2 Lithiation of N-Protected Pyrroles [236,241]
N
O NHBu t
E = D, CH(OH)Ph, CH(OH)iPr, TMS
N
H
1. t-BuLi (2.2 equiv), THF
−78 o C, 30−90 min
2. E +
45−78%
1. BuLi, THF, hexane, −70 oC to rt
2. CO2 3. t-BuLi, THF, pentane, −70 oC to rt, 1 h
E = CO2H, CONHPh, C(OH)Ph2, CHO, Ts
N
E
O NHBu t
54
N
Li
CO2Li
E +
50−95%
Studies with N-arylpyrroles indicate that lithiation occurs either at C2 of pyrrole or in the
aryl ring, depending on reaction conditions and phenyl ring substitution. [242–244]
8.1.14.5.2 Variation 2:
By Halogen–Lithium Exchange
Halogen–lithium exchange is an important route to lithiated pyrroles. The reaction is extremely
useful for the synthesis of 3-substituted pyrroles since bulky N-trialkylsilyl
groups (e.g., triisopropylsilyl) undergo bromination regioselectively at C3. This sequence
is shown for 55 to 56 (Scheme 30). [245,246] The N-silyl group is readily removed with fluoride,
e.g. to give 57. Bromine–lithium exchange at C3 has been employed in syntheses of
benzodipyrrole analogues, [247] 3,4-disubstituted pyrroles, [246,248] and the lamellarin [249] and
lukianol [249,250] marine alkaloids. As expected, selective C2 bromine–lithium exchange is
possible in polybrominated pyrroles, [246,249] as for 58 to 59, both of which are natural products.
[251] Bromine–lithium exchange has been used to synthesize 1-(tert-butoxycarbonyl)pyrrol-2-yllithium,
-pyrrole-2,5-diyldilithium, and -5-bromopyrrol-2-yllithium. [252] Sequential
replacement of the bromines in 3,4-dibromo-1-(triisopropylsilyl)pyrrole affords a synthesis
of verrucarin E. [246] The dimer of 3-bromo-6-(dimethylamino)-1-azafulvene functions
as a formal equivalent of either 4-lithio- or 4,5-dilithiopyrrole-2-carbaldehyde. [253,254]
Scheme 30 Pyrrole C3 Lithiation by Halogen–Lithium Exchange [246,251]
N
TIPS
Br
t-BuLi (2 equiv), THF
−78 oC, 30 min
E = Me, (CH 2) 17Me, (CH 2) 2iPr, CO 2H, CH 2OH, Ac, TMS
Li
N
TIPS
E +
40−92%
N
TIPS
55 56
G. W. Gribble, Section 8.1.14, Science of Synthesis, 2006 Georg Thieme Verlag KG
E
TBAF
N
H
N
H
57
E
E

8.1.14 Aryllithium and Hetaryllithium Compounds 381
b1. BuLi, −78 o Br Br
C
Me
2. C2Cl6 N
Br
Br
N
80%
Me
Br
58
Br
3-Allylpyrrole (57,E=CH 2CH=CH 2); Typical Procedure: [245]
To a soln of 3-bromo-1-(triisopropylsilyl)pyrrole (247 mg, 0.82 mmol) in dry THF (10 mL),
cooled to –238C (dry ice/CCl 4 bath), was added dropwise a 1.5 M soln of BuLi in hexanes
(1.1 mL, 1.65 mmol). The mixture was kept at –238C for 2 h, and then a soln of allyl bromide
(ca. 350 mg, ca. 3 mmol, 3–4 equiv) in THF (10 mL) was added. The mixture was allowed
to warm to rt over a 20-min period and quenched with H 2O (2 mL). The mixture
was extracted with Et 2O, and the combined extracts were dried (MgSO 4) and concentrated.
The residue was passed through a short silica gel column to afford a mixture (198 mg) of
the starting pyrrole and the title compound (ratio » 1:6). This mixture was conveniently
separated by chromatography (silica gel, hexane) after desilylation (TBAF, THF) to provide
the pure product; yield: 173 mg (80%).
8.1.14.5.3 Variation 3:
By Directed ortho-Lithiation
Given the successes cited in Sections 8.1.14.5.1 and 8.1.14.5.2, directed lithiation procedures
with pyrroles have not been extensively pursued. However, both the dihydrooxazole
[208] and the N-ethylcarboxamide [205] groups at C2 direct lithiation to C3 of 1-methylpyrrole
in modest yields, whereas amino alkoxide affords C5 or N-methyl lithiation. [203]
Lithiation of the pyrrole alcohol 61 under kinetic conditions gives diol 60, whereas under
thermodynamic conditions the diol 62 is obtained (Scheme 31). [255] Diol 62 has been employed
in a synthesis of the furo[3,4-b]pyrrole ring system.
Scheme 31 Directed Lithiation in Pyrroles [255]
HO
N
Et
SO2Ph
60
OH
1. LDA, −78 oC 2. MeCHO
60%
8.1.14.6 Method 6:
Imidazolyllithium Compounds
N
Et
SO 2Ph
61
Cl
Br
OH
N
Me
Br
Br
59
1. LDA
Me
N
Br
−78 to −20 oC 2. MeCHO
90%
Cl
N
Et
SO 2Ph
The presence of the imidazole ring in a multitude of natural products (e.g., histidine) and
the pronounced acidity of the C2 proton (between two stabilizing nitrogens) has led to extensive
lithiation studies of this molecule, via both direct deprotonation and halogen–
lithium exchange.
8.1.14.6.1 Variation 1:
By Direct Deprotonation
Chadwick has pioneered the exploration of imidazole C2 lithiation by direct deprotonation
with a variety of N-protecting groups [Bn, CH 2OR 1 , Tr, SO 2Ar 1 , CH(OR 1 ) 2, TMS,
SO 2NMe 2] and subsequent reactions with electrophiles. [256,257] Other N-protecting groups
62
OH
OH
for references see p 414
G. W. Gribble, Section 8.1.14, Science of Synthesis, 2006 Georg Thieme Verlag KG

382 Science of Synthesis 8.1 Lithium Compounds
bfunctioning in this capacity are alkoxymethyl, [258,259] methyl, [259–263] 2-(trimethylsilyl)ethoxymethyl,
[264,265] 1-ethoxyethyl, [266] and benzyloxy. [267] Examples of C2 imidazole lithiation–quenching
are listed in Table 4. Mono- and dilithiation at C2 of bis(imidazol-1-yl)methane
have been reported; [268] if C2 is blocked (protected), then lithiation at C5 occurs.
[257,260,261,265,266,269,270] This latter sequence is particularly effective for the synthesis of
4(5)-substituted imidazoles. [257]
Table 4 C2 Lithiation and Reactions of Imidazoles [256,259,262–268]
N R 1
N
E +
E
N
N
1 R 2 E1 R 1 Conditions E + E 1 E 2 Yield (%) Ref
Bn BuLi, Et2O, 208C, 2 h MeI Me H 64 [256]
Tr BuLi, Et2O, 208C, 2 h Ph2CO C(OH)Ph2 H 98 [256]
SO2NMe2 BuLi, Et2O, –788C, 15 min MeI Me H 82 [256]
CH 2OMe BuLi (2 equiv), Et 2O, TMEDA MeI Me Me 86 [256]
CH 2OMe BuLi (2 equiv), Et 2O, TMEDA PhCHO CH(OH)Ph CH(OH)Ph 84 [256]
SO 2NMe 2 BuLi, hexane/THF, –788C PhOCN CN H 69 [268]
Me BuLi, hexane, 0 8C TBDMSCl TBDMS H – [259]
CH 2OMe BuLi, hexane, 0 8C TBDMSCl TBDMS H – [259]
Me BuLi, hexane/THF, –788C, 30 min S SH H 42 [262]
Me BuLi, hexane/THF, –788C, 35 min Se SeH H 58 [262]
Me BuLi, THF, –708C CCl 4 Cl H 75 [263]
SEM BuLi, hexane/THF, –408C, 15 min DMF CHO H 96 [264]
SEM BuLi, hexane/THF, –788C (TMSO) 2 OH H 98 [265]
CH(Me)OEt BuLi, hexane/THF, –408C, 30 min DMF CHO H 90 [266]
CH(Me)OEt BuLi, hexane/THF, –408C, 30 min Ph 2CO C(OH)Ph 2 H 88 [266]
OBn BuLi, hexane/THF, –788C, 7 min MeI Me H 95 [267]
OBn BuLi, hexane/THF, –788C, 7 min C 2Cl 6 Cl H 93 [267]
8.1.14.6.2 Variation 2:
By Halogen–Lithium Exchange
Polyhalogenated imidazoles have been extensively utilized in synthesis, most notably by
exploiting the decreasing halogen–lithium exchange reactivity trend: C2 > C5 > C4 (anion
stability order in N-substituted imidazoles); a review is available. [271] Iddon has been the
pioneer in this exploration; [271–275] he has shown that, by sequential lithiation and electrophile
addition, a variety of mono-, di-, and trisubstituted imidazoles can be prepared. The
power of this method is illustrated in Scheme 32, including a simple synthesis of a precursor
63 (R 1 = Me; E 1 = SMe; E 2 =E 3 = CHO) of the antitumor agent carmethizole. [276] This selective
bromine–lithium exchange tactic has been used in a synthesis of the nortopsentin
marine alkaloids. [277,278] The triiodo compound 64 can be manipulated similarly. [279] In
both cases one can stop at mono- or disubstitution, and several such studies are known
with both brominated and iodinated imidazoles. [280–283] For example, monolithiation of
1-benzyl-4,5-dibromo-2-phenylimidazole (BuLi, Et 2O/hexane, –408C, 15 min) followed by
quenching with dimethylformamide affords 1-benzyl-4-bromo-2-phenylimidazole-5-carbaldehyde
(82% yield). [280]
G. W. Gribble, Section 8.1.14, Science of Synthesis, 2006 Georg Thieme Verlag KG

8.1.14 Aryllithium and Hetaryllithium Compounds 383
bScheme 32 Sequential Halogen–Lithium Exchange in 2,4,5-Trihaloimidazoles [276,279]
Br
Br
N
N
R1 Br
1. BuLi, THF, −78 oC, 5 min
2. (E1 ) +
3. BuLi, THF, −78 oC, 15 min
4. (E2 ) +
5. BuLi, THF, −78 oC, 15 min
6. (E3 ) +
40−71%
R1 = Me, Bn
E1 = SMe, SPh; E2 = H, TMS; E3 = C(OH)Me2, CH(OH)(CH2) 5Me, CH(OH)Ph, CHO, CH(OH)(CH2) 4Me, SnBu3, Cl
I
N
I
N
I
OBn
64
1. BuLi, −78 oC 2. TMSCl
3. BuLi, −78 oC 4. Me2NN(Me)CHO 5. BuLi, −78 oC 6. (MeO2C)2O
25%
MeO2C
1-Benzyl-4-(2-hydroxyprop-2-yl)-2-(methylsulfanyl)imidazole [63,E 1 = SMe; E 2 =H;
E 3 = C(OH)Me 2;R 1 = Bn]; Typical Procedure: [276]
1-Benzyl-2,4,5-tribromoimidazole (200 mg, 0.51 mmol), dried azeotropically with toluene,
was dissolved in THF (5 mL), cooled to –788C, and then a 2.45 M soln of BuLi in hexane
(0.21 mL, 0.51 mmol) was added via syringe and the soln was stirred for 5 min at –788C.
(MeS) 2 (45.6 ìL, 0.51 mmol) was then added and the mixture was stirred for 5 min at
–78 8C. The second aliquot of BuLi (0.21 mL, 0.51 mmol) was then added and stirred for
15 min at –788C prior to the introduction of iPrOH (38.8 ìL, 0.51 mmol). After another
5 min at –788C, the third aliquot of BuLi (0.21 mL, 0.51 mmol) was added and following
another 15 min period at –788C, acetone (37.2 ìL, 0.51 mmol) was added and the soln
was stirred for 15 min at –788C. The mixture was poured into sat. aq NH 4Cl (30 mL) and
the whole was extracted with EtOAc (3 ” 30 mL) and dried (Na 2SO 4). The solvent was removed
under reduced pressure to give an orange oil (169 mg), which was purified by flash
chromatography (silica gel, hexane/EtOAc 4:1) to give the title compound as a colorless
oil; yield: 94.8 mg (71%).
OHC
E 2
N
N
E 3
OBn
8.1.14.7 Method 7:
Oxazolyllithium and Isoxazolyllithium Compounds
The lithiation of oxazoles and isoxazoles has been extensively reviewed by Iddon. [284,285]
Gilchrist has summarized the propensity of metalated heterocycles in general to undergo
ring opening, [286] which can be a problem with oxazol-2-yllithium, although it is a reversible
transformation. [287–291]
8.1.14.7.1 Variation 1:
Lithiation of Oxazoles
Oxazoles undergo preferential C2 lithiation with alkyllithium reagents and numerous
examples are known; [284] a typical case is shown in Scheme 33. [292] Transmetalation with
zinc(II) chloride [289,293,294] or copper(I) iodide [293] is described; the latter reaction affords a
useful oxazole acylation with acid chlorides, as shown for the synthesis of 65. This se-
N
N
R1 63
E 1
for references see p 414
G. W. Gribble, Section 8.1.14, Science of Synthesis, 2006 Georg Thieme Verlag KG

384 Science of Synthesis 8.1 Lithium Compounds
bquence circumvents the ring-opening process that previously thwarted attempts to synthesize
2-acyloxazoles. If the C2 position of the oxazole is occupied, lithiation can occur
at C4 or C5; [288,295] if a methyl group is present at C2, lateral methyl lithiation is known to
occur. [288,296] An elegant solution to the oxazol-2-yllithium ring-opening problem is provided
by Vedejs. [290] Thus, Lewis acid complexation with borane at the N-atom allows for
smooth C2 lithiation and trapping with electrophiles, as for 66 to 67. However, it must
be noted that the ring opening to the acyclic valence bond tautomer can be exploited to
introduce electrophiles to the C4 position. [291,297]
Scheme 33 Lithiation of Oxazoles [292,293]
Pr i
R 1
OTBDMS
O
O
N
N
1. BuLi, THF, −78 oC 2. I2 90%
1. BuLi, THF, −70 oC, 20 min
2. ZnCl2 3. Cul
4. R2COCl 54−80%
R H
1 = H, Ph; R2 = iPr, t-Bu, Ph, 4-MeOC6H4, 4-O2NC6H4, C
Ph
O
N
BH3 THF, THF, rt
98%
E = Me, CH 2CH 2Ph, CH(OH)Ph, Cl, TMS
.1.14.7.2 Variation 2:
Lithiation of Isoxazoles
Ph
>− 8
O
66
Pr i
R 1
CHPh
−
BH3 +
N
OTBDMS
O
O
N
N
65
I
R 2
O
1. BuLi, THF, −78 o C
2. E +
65−88%
The metalation of isoxazoles has been reviewed in depth. [285] A route to the pharmacologically
important isoxazolamines employs lithiation of N-(tert-butoxycarbonyl)-5-methylisoxazol-3-amine
(68) (Scheme 34). [298]
Scheme 34 Lithiation of Isoxazoles [298]
N
O
68
NHBoc
E = Me, Et, allyl, Bn, CO 2H, CHO, SPh, TMS
8.1.14.8 Method 8:
Pyrazolyllithium Compounds
1. BuLi (2.3 equiv), THF, −78 to −30 o C
2. E +
50−97%
N
O
NHBoc
Suitably N-protected pyrazoles undergo lithiation at C5, the position corresponding to C2
in pyrroles. Lithiation of 1-tosylpyrazole (69) and trapping with electrophiles proceeds
smoothly (Scheme 35). [299] Related examples are known, [268,300,301] e.g. to introduce cya-
G. W. Gribble, Section 8.1.14, Science of Synthesis, 2006 Georg Thieme Verlag KG
E
Ph
O
67
N
E

8.1.14 Aryllithium and Hetaryllithium Compounds 385
bno [268] or tosyl [301] at C5. Lithiation and transmetalation of 1-(benzyloxy)pyrazole with butyllithium–zinc(II)
halides, followed by palladium cross coupling, yields 5-aryl-, 5-hetaryl-,
and 5-acylpyrazoles in good to excellent yields. [302] Lithiation of 1-(benzyloxy)pyrazole and
direct quenching with a variety of electrophiles proceeds to give 5-substituted derivatives
in high yield. [303] Debenzylation affords the 1-hydroxypyrazoles.
Scheme 35 Lithiation of 1-Tosylpyrazole [299]
N
N
Ts
69
1. t-BuLi, THF, −78 o C, 10 min
2. E +
55−100%
E = Me, allyl, C(OH)Me2, CO2Me, Bn, I, TMS,
8.1.14.9 Method 9:
Thiazolyllithium Compounds
OH
E
N
N
Ts
Thiazole is easily lithiated at C2 with butyllithium or via 2-bromothiazole, which is readily
available, with butyllithium. Several examples of each method are known. [304] Treatment
of thiazole with butyllithium (Et 2O, –788C), followed by addition of an electrophile,
affords the expected 2-substituted thiazole (trimethylsilyl, 93%; [305] trimethylstannyl,
96%; [306] chloro, 90%; [263] bromo, 80%). [263] Lithiation of 2-methyl-4-phenylthiazole under
the same conditions and subsequent reaction with iodomethane gives 2,5-dimethyl-4phenylthiazole
(95%). [307] A small amount of lateral lithiation product (2-ethyl-4-phenylthiazole,
5%) is also obtained. Lithiation of 2-(trimethylsilyl)thiazole and quenching with
chlorotrimethylstannane leads to 2-(trimethylsilyl)-5-(trimethylstannyl)thiazole (90%). [306]
Despite the excellent yields and clean regioselectivity observed for direct C2 thiazole lithiation,
another route to lithiated thiazoles is bromine–lithium exchange. Treatment of
2-bromothiazole (70) with butyllithium (–788C) followed by chlorotrimethylsilane gives
2-(trimethylsilyl)thiazole in 95% yield, [305] comparable to the yield obtained by deprotonation
of thiazole (vide supra). The 2-thiazolyllithium thus generated from 70 adds to sugar
nitrones, e.g. to give 71 (Scheme 36). [195,308,309] Sequential replacement of the bromines in
2,4-dibromothiazole (C2 > C4) is facile [305,306] and has been employed in regioselective Negishi,
Sonogashira, and Stille reactions, [310] and in the synthesis of micrococcinic acid, a
sequence that features conversion of 72 to 73. [311,312]
Scheme 36 Lithiation of Thiazoles [308,311]
Br
S
N
70
N
S
72
Br
Br
1. BuLi, Et2O, hexane, −70 oC N
O
BnO OBn
−
2.
BnO
OH Bn
+
1. BuLi, Et 2O
−78 oC 2. TMSCl
86%
75%
Br
S
N
TMS
BnO
OH
BnO
71
1. BuLi, Et 2O
−78 oC 2. t-BuNCO
73%
OBn
BnN
N
OH
S
Bu t HN
O
S
73
N
TMS
for references see p 414
G. W. Gribble, Section 8.1.14, Science of Synthesis, 2006 Georg Thieme Verlag KG

386 Science of Synthesis 8.1 Lithium Compounds
b8.1.14.10 Method 10:
Benzofuryllithium Compounds
Like furan, benzo[b]furan is readily lithiated at C2, [313] with either butyllithium [196,301,314] or
lithium diisopropylamide, [315] although yields are only fair to good. Treatment of benzo[b]furan
with lithium diisopropylamide (THF, –708C) and quenching with carbon dioxide affords
the 2-carboxylic acid (60%). Further treatment with lithium diisopropylamide and
then carbon dioxide affords the 2,3-dicarboxylic acid, plus some of the ring-cleaved product.
[286] Treatment of benzo[b]furan-2-yllithium with 4-toluenesulfonyl fluoride gives the
2-tosyl compound in 30% yield, [301] and exposure of benzo[b]furan-2-yllithium to copper(I)
bromide and then trifluoroacetic anhydride furnishes 2-(trifluoroacetyl)benzo[b]furan
(68%). [196] Reaction of the lithiated species with sulfur leads to the novel heterocycle 74
(Scheme 37). [314]
Scheme 37 Lithiation of Benzo[b]furan and Reaction with Sulfur [314]
O
1. BuLi, THF, −78 oC 2. S8 35%
8.1.14.11 Method 11:
Benzothienyllithium Compounds
S S
S S
O O
Benzo[b]thiophenes undergo C2 lithiation with various alkyllithium reagents and the resulting
2-lithiated species react smoothly with electrophiles such as sulfur (68%), [316] trifluoro-N,N-dimethylacetamide
(75%) [317] [85% with added copper(I) bromide], [196] acetaldehyde
(84%), [318] and 4-toluenesulfonyl fluoride (55%). [301] The potential interfering directing
groups, methoxy and N,N-diethylcarboxamido, at C4 in benzo[b]thiophene do not deter
C2 lithiation. [319] If the C2 position contains a potential directing group, then C3 lithiation
is achieved. [320–322] Two examples of these strategies are illustrated in Scheme 38. Even 4,6dimethoxybenzo[b]thiophene
undergoes C2 lithiation, [320] indicative of the high acidity of
the C2 proton.
Scheme 38 ortho-Lithiation of Benzo[b]thiophenes [320–322]
S S
N
O
1. BuLi, Et 2O
2. E +
E = I 95%
E = SnBu3 91%
74
E
S S
G. W. Gribble, Section 8.1.14, Science of Synthesis, 2006 Georg Thieme Verlag KG
N
O

8.1.14 Aryllithium and Hetaryllithium Compounds 387
b1. s-BuLi, TMEDA
THF, −78 o OMe
C
2. Et2NCOCl
71%
S
OMe
S
1. s-BuLi, CuBr
THF, −78 oC 2. Br
Halogen–lithium exchange is also used for accessing lithiated benzo[b]thiophenes. For example,
3-bromobenzo[b]thiophene and butyllithium at low temperature, followed by
exposure to trifluoroacetamide [317] or trifluoroacetic anhydride, [196] affords 3-(trifluoroacetyl)benzo[b]thiophene
(61 and 78%, respectively). 3-Iodobenzo[b]thiophenes behave similarly.
[318] As anticipated, 2,3-dibromobenzo[b]thiophene undergoes regioselective sequential
bromine–lithium exchange, the C2 bromine being more reactive than the C3 bromine.
[317]
8.1.14.12 Method 12:
Indolyllithium Compounds
Lithiation of indole (one of nature s beloved heterocycles) has been extensively studied,
to become one of the most important reactions of indole. Deprotonation at the acidic C2
position, halogen–lithium exchange, and directed lithiation all play significant roles in
the functionalization of the indole ring.
8.1.14.12.1 Variation 1:
By Direct Deprotonation
Like pyrrole (see Section 8.1.14.5.1), N-substituted indoles are preferentially deprotonated
at C2, a position acidified by the inductive electron-withdrawing ability of nitrogen. Following
studies on the lithiation of 1-methylindole with butyllithium (Et 2O, reflux, 8 h)
and carboxylation to give 1-methylindole-2-carboxylic acid (78%), [323] Sundberg explored
the use of N-protecting/activating groups that permit C2 lithiation under milder conditions
and whereby the N-protecting group can be removed (unlike N-methyl). [324] Snieckus
has summarized the use of indole N-protecting groups in C2 lithiation, [236] and a selected
list of indole C2 lithiation reactions (e.g., to give 75) is shown in Table 5. This list is not
complete, but depicts only a few examples with each N-protecting group. Depending on
the end use, all of these N-protecting groups have utility in synthesis; with the exception
of N-methyl, all of the protecting groups are usually easily removed.
O
NEt 2
82%
OMe
S
O
NEt2
for references see p 414
G. W. Gribble, Section 8.1.14, Science of Synthesis, 2006 Georg Thieme Verlag KG

388 Science of Synthesis 8.1 Lithium Compounds
bTable 5 C2 Lithiation Reactions of Indole [236,323–344]
N
R 1
lithiation
N
R 1
Li
R 1 Conditions E + E Yield (%) Ref
Me BuLi, Et2O, reflux, 8 h CO2 CO2H 78 [323]
Me BuLi, Et2O/hexane, reflux, 5 h (CO2Et) 2 COCO2H a 59 [325]
Me BuLi, Et 2O/hexane, reflux, 3 h I 2 I 77 [326]
Me BuLi, Et 2O/hexane, reflux, 6 h acetone C(OH)Me 2 80 [327]
SO 2Ph t-BuLi, pentane, TMEDA, rt, 20 min PhCHO CH(OH)Ph 55 [324]
SO 2Ph t-BuLi, pentane, TMEDA, –11 8C, 20 min MeCOCO 2Et C(OH)MeCO 2Et 64 [328]
SO 2Ph LDA, THF/hexane, –75 to 5 8C, 1 h MeI Me 85 [329]
SO 2Ph LDA, THF/hexane, –75 to 5 8C, 1 h MeCHO CH(OH)Me 93 [329]
SO 2Ph LDA, THF/hexane, –75 to –5 8C, 1 h t-BuNCO CONHt-Bu 83 [330]
SO 2Ph LDA, THF/hexane, –78 to 0 8C, 1 h BrCN Br 85 [331]
SO 2Ph LDA, THF/hexane, –70 to 5 8C, 1 h PhSO 2Cl Cl 93 [332]
SO 2Ph s-BuLi, THF/cyclohexane, –708C to rt, 4 h Ac 2O Ac 76 [333]
SO 2Ph t-BuLi, THF, –788C, 1 h N 2O 4 NO 2 67 [334]
CH 2OMe t-BuLi, hexane/Et 2O, 0 8C to rt, 1 h PhCN Bz 84 [324]
CH 2OMe t-BuLi PhN(Me)CHO CHO 53 [335]
CH(OEt) 2 t-BuLi, pentane/THF, 0 8C to rt, 30 min PhCH=CHNO 2 CH(Ph)CH 2NO 2 46 [336]
Boc t-BuLi, hexane/THF, –788C, 40 min (CO 2Me) 2 COCO 2Me 66 [337]
Boc s-BuLi, TMEDA, –788C Bu 3SnCl SnBu 3 97 [338]
Boc t-BuLi, THF, –788C, 1 h N 2O 4 NO 2 78 [336]
Boc BuLi, pentane/THF, –78 8C, 1 h ClCO 2Me CO 2Me 84 [339]
Boc LDA, THF, 0–58C, 1 h B(OiPr) 3 B(OH) 2 96 [340]
CH 2NMe 2 BuLi, Et 2O, rt, 2 h Ph 2CO C(OH)Ph 2 71 [341]
CH 2NMe 2 BuLi, hexane/THF, –78 to 0 8C, 40 min (PhS) 2 SPh 87 [342]
CO 2Li BuLi, hexane/THF, –708C; then CO 2,
then t-BuLi, –708C, 1 h
E +
75
N
R 1
E
BzCl Bz 59 [343]
CONHt-Bu t-BuLi (2.2 equiv), THF, –78 to 08C, 90 min TMSCl TMS 95 [236]
COCEt 3 s-BuLi, t-BuOK, THF, –788C, 1 h MeI Me 93 [344]
a The initial ester product was saponified.
Numerous applications of these indole C2 lithiations in synthesis are known, including
the synthesis of 2-iodotryptamines, [345] ellipticine and other pyridocarbazoles, [346–350] benzocarbazoles,
[351] 2,2¢-biindolyls, [326] 2-(2-pyridyl)indoles, [352] yuehchukene, [353] carbazole-
3,4-quinones, [354] furo[3,4-b]indoles, [355–358] â-carbolines, [359] pentathiepino[6,7-b]indoles, [360]
2,3-dihaloindoles, [329,332,361–363] 2-substituted 4-azaindoles, [364] and 2,3-disubstituted indoles
that might be difficult to prepare otherwise. [361,365–368] For example, C2 lithiation of
N-protected indole-3-carboxylic acid or indole-3-carboxamides followed by electrophilic
quench gives the corresponding 2-substituted indoles [TMS, Me, CH(OH)Ph, C(OH)Ph 2,
C(OH)Me 2, Et, C(OH)MePh] in very good to excellent yields. [367] Lithiations at C2 are generally
not perturbed by substituents in the benzene ring, e.g. 4-Cl, 5-Cl, 5-Br, 5-OMe, 5-CN,
G. W. Gribble, Section 8.1.14, Science of Synthesis, 2006 Georg Thieme Verlag KG

8.1.14 Aryllithium and Hetaryllithium Compounds 389
b5-F [1-(tert-butoxycarbonyl)indole with lithium diisopropylamide], [340] but 5-methoxy-1methylindole
with butyllithium (but not tert-butyllithium) undergoes lithiation at C2,
C4, and C6. [369] A cautionary note with 1-(phenylsulfonyl)indole and alkyllithium reagents
is that the phenylsulfonyl group can be lithiated ortho to sulfonyl, [324,370] a side reaction
avoided with lithium diisopropylamide. [329] The 2-lithiated indoles are readily transmetalated
with boron, [371,372] zinc, [373] and tin [374] for cross-coupling reactions.
1-[1-(Phenylsulfonyl)indol-2-yl]ethanol [75,R 1 =SO 2Ph; E = CH(OH)Me];
Typical Procedure: [329]
To a soln of LDA (8.40 mmol) [prepared from iPr 2NH (9.00 mmol) and a 1.58 M soln of BuLi
in hexane (5.32 mL, 8.40 mmol) in dry THF (20 mL) under argon at –788C] was added dropwise,
via syringe, over 5 min a soln of 1-(phenylsulfonyl)indole (2.06 g, 8.01 mmol) in dry
THF (22 mL), keeping the internal temperature below –608C. The mixture was stirred for
1.5 h below –708C and then allowed to warm slowly to 58C over 1 h. The resulting bright
red soln was cooled to –788C. A magnetically stirred soln of the 1-(phenylsulfonyl)indol-2yllithium
(11.66 mmol) in dry THF (40 mL) at –658C under argon was treated rapidly via
syringe with a soln of freshly distilled MeCHO (1.00 g, 22.7 mmol) in dry THF (5 mL). The
mixture was allowed to warm slowly to rt overnight, poured into 1% aq HCl (350 mL), and
the whole was extracted with CH 2Cl 2 (3 ” 250 mL). The combined extracts were washed
with H 2O (400 mL) and brine (2 ” 400 mL), dried (K 2CO 3), and rotary evaporated to afford
a light orange oil. Flash chromatography (silica gel, CH 2Cl 2) gave a light amber viscous
oil which was further dried (608C/0.5 Torr) for 6 h to provide the analytically pure title
compound as colorless crystals; yield: 3.28 g (93%); mp 101–1028C.
8.1.14.12.2 Variation 2:
By Halogen–Lithium Exchange
The ease of indole C3 electrophilic halogenation begs for halogen–lithium exchange and
subsequent chemistry at this site. The first example of a 3-indolyllithium was described
by Gribble, as summarized in Scheme 39. [329] Quenching of 77 at low temperatures
(

390 Science of Synthesis 8.1 Lithium Compounds
bN-Silylated 3-indolyllithiums, prepared by halogen–lithium exchange, do not undergo rearrangement
to the 2-lithio species [380,381] and have found wide applicability in synthesis
(Scheme 40). Both triisopropylsilyl and tert-butyldimethylsilyl substitution work well.
N-Silylated 3-indolyllithiums have been used to synthesize secodine, [382] nortopsentin, [278]
and grossularine [383] alkaloids, â-methyltryptophan via a boronic acid, [261,384] oxygenated
tryptamines, [385] homotryptophan, [386] 3-(arylaminomethyl)indoles, [387] and 5H-pyrido-
[4,3-b]indole. [388] Extension to 4-, 5-, and 6-methoxy-substituted 1-silylindol-3-yllithium
compounds is known, [389] and transmetalation to 3-indolylzinc chlorides is facile. [389,390]
Regioselective C3 bromine–lithium exchange is observed with 3,6-dibromo-1-(tert-butyldimethylsilyl)indole,
[278] and regioselective C2 bromine–lithium exchange is the case
with 2,3-dibromo-1-methylindole. [391] The latter compound lends itself to sequential replacement
of the C2 and C3 bromines, with concomitant electrophilic quenching. For
example, in one pot, 2,3-dibromo-1-methylindole is converted into 1,2-dimethylindole-3carbaldehyde
(88% yield) by sequential treatment with tert-butyllithium, iodomethane,
tert-butyllithium, and dimethylformamide. [391]
Scheme 40 Reactions of N-Silylated 3-Indolyllithiums [380,381]
N
Br
TIPS
1. t-BuLi, THF, pentane
−78 o C, 10 min
2. E +
65−90%
E = Me, Et, Bu, CHO, CO 2Me, CO 2H, Bz, CH(OH)Ph, CH 2CH 2OH
Initial attempts to generate a 2,3-dilithioindole, from 2,3-diiodo-1-(phenylsulfonyl)indole
and tert-butyllithium, were thwarted by indole ring fragmentation, even at temperatures
as low as –1008C. [392] However, 2,3-dibromo-1-methylindole undergoes bis-bromine–lithium
exchange to give dilithioindole 78, which reacts smoothly with electrophiles to give
2,3-disubstituted indoles 79 (Scheme 41). [393] Reaction of 78 with phthalic anhydride gives
5-methyl-5H-benzo[b]carbazole-6,11-dione (41% yield). Treatment of 2-iodoindole with excess
butyllithium (3 equiv, –708C) generates 1,2-dilithioindole, which, upon quenching
with electrophiles, leads to 2-substituted indoles (CO 2H, CONHPh, CONHBu, Cl, CHO,
Me; 17–62%). [394]
Scheme 41 Reactions of 2,3-Dilithioindole [393]
Br
N
Me
Br
E = H, CHO, CO2H, CO2Me
t-BuLi (5−10 equiv)
THF , −78 oC, 20 min
N
Li
N
Me
78
E
TIPS
Li
E +
66−99%
Several studies demonstrate that C4, C5, C6, and C7 bromine–lithium exchange is feasible
with brominated indoles. [395–397] N-Unsubstituted indoles are conveniently protected as
the potassium salt with potassium hydride, allowing for clean bromine–lithium exchange
with tert-butyllithium and subsequent reactions with electrophiles. [395,397] For example,
4-, 5-, 6-, and 7-bromoindoles can be formylated with dimethylformamide to give
the respective indolecarbaldehydes in 53–61% yields. [395] The same protocol applied to
5-bromoindole affords a range 5-substituted indoles [CHO, Ac, C(OH)Me 2, CONH 2, TMS,
SMe, B(OH) 2, SnMe 3] in 18–94% yields. [397]
G. W. Gribble, Section 8.1.14, Science of Synthesis, 2006 Georg Thieme Verlag KG
E
N
Me
79
E

8.1.14 Aryllithium and Hetaryllithium Compounds 391
b8.1.14.12.3 Variation 3:
By Directed ortho-Lithiation
Given the success of both indole C2 deprotonation and C3 halogen–lithium exchange
methods (see Sections 8.1.14.12.1 and 8.1.14.12.2), only a few directed lithiation strategies
have been pursued. The first example of an indole C2 directing group effecting lithiation
at C3 is the 2-pyridyl group, as shown for 80 to 81 (Scheme 42). [398] Indole ring fragmentation
of 81 occurs only at higher temperatures (508C) and is not a problem. Reaction of 81
with bromoacetaldehyde affords a simple route to the indolo[2,3-a]quinolizine alkaloids,
including flavopereirine, [399] sempervirine, [330] and analogues. [400] Other indole C2 directing
groups that lithiate C3 are CONHt-Bu, [398] CONEt 2, [205] CONHEt, [205] carboxy, [401] amino
alkoxide, [203] and hydrazides. [402] The last study is the most extensive and affords the highest
yields, as for 82 to 83. However, a C2 carboxamide group on 1-(phenylsulfonyl)indole
leads to indole ring opening at –788C. [398]
Scheme 42 Directed Lithiation of Indoles [398,402]
N
SO2Ph
80
N
E = Me, Ac, CO 2H, CO 2Et, CH(OH)Me, TMS
N
Me
82
BuLi, THF
−78 oC N
Li
SO 2Ph
81
E +
N
51−74%
t-BuLi (3 equiv)
TMEDA, THF
−78 o Li
H H
N NMe2 N
C, 3 h
O
E = Me, Et, TMS, CH(OH)Me, COt-Bu, CH(OH)t-Bu, CH(OH)(CH 2) 4Me, 4-MeOC 6H 4
E +
59−85%
N O
Me
NMe 2
E
N
E
SO 2Ph
H
N
N O
Me
The bulky N-protecting groups 2,2-diethylbutanoyl [344] and triisopropylsilyl [403] undergo direct
C3 lithiation with sec-butyllithium (hexane, N,N,N¢,N¢¢,N¢¢-pentamethyldiethylenetriamine,
–788C, 1 hour) and tert-butyllithium (hexane, N,N,N¢,N¢-tetramethylethylenediamine,
08C, 3 h), respectively. In the latter case, yields of C3 substitution products are
69–92% (Me, TMS, Br, CHO, CO 2H, CO 2Et, CONEt 2, CONHt-Bu), and this method represents
an excellent C3 lithiation technique. Yields of C3 substitution products from 1-(2,2-diethylbutanoyl)indol-3-yllithium
are lower (34–59%). Interestingly, lithiation of 1-(2,2-diethylbutanoyl)-3-methylindole
using sec-butyllithium (diethyl ether, N,N,N¢,N¢-tetramethylethylenediamine,
–788C, 1 h) affords the indol-7-yllithium and, following electrophilic
83
N
NMe2
for references see p 414
G. W. Gribble, Section 8.1.14, Science of Synthesis, 2006 Georg Thieme Verlag KG

392 Science of Synthesis 8.1 Lithium Compounds
bquenching, good yields of 7-substituted indoles (Me, CHO, CO 2H, CO 2Et, Cl, Br, TMS, SPh;
17–81%). [404] Lithiation at C7 is also the case with indoletricarbonylchromium(0) complexes,
and the corresponding N-[(2-trimethylsilyl)ethoxymethyl] protecting group appears
to be the most useful in synthesis, affording 7-substituted indoles in 65–95% yields
(Me, CHO, allyl, TMS, CO 2Et, SnMe 3). [405]
Iwao was the first to achieve C4 lithiation from a C3 directing group. Thus, 1-(triisopropylsilyl)gramine
(84) undergoes efficient C4 lithiation to give 85, which, upon electrophilic
quenching, affords 86 (Scheme 43). [406–412] This strategy has led to syntheses of
clavicipitic acids, [408,409] ergot alkaloid analogues, [398] 4-substituted tryptophans, [410] and
4-arylated gramines by cross-coupling methodologies. [411] This last study also discloses a
retro-Mannich fragmentation to afford 4-substituted 3-haloindoles. Other C3 potential
directing groups, such as CH 2CH 2NMe 2,CH 2OMe, CH 2CH 2OMe, CONEt 2, and CON(iPr) 2,
are decidedly less successful than CH 2NMe 2. [412] If a C5 directing group is present
(OCONEt 2, [412,413] carboxy [414] ), then lithiation occurs preferentially at C4. These directing
groups have been applied to the solid phase [414] and to the first generation of indolo-4,5quinodimethane.
[415]
Scheme 43 C4 Lithiation of Gramine [406–412]
84
N
TIPS
NMe2
t-BuLi, Et2O 0 oC, 1 h
Li N
Me2 85
N
TIPS
E +
20−98%
E = Me, Et, Pr, allyl, CHO, Bn, CH(OH)CH CMe2, CH(OH)Me, CH2CH(OH)Me, CH(OH)CH CH2
CH 2CH CMe 2, Br, Cl, I, OH, TMS
8.1.14.13 Method 13:
Pyridyllithium Compounds
Unlike pyrrole and indole that have enhanced C2 proton acidity due to the inductive electron-withdrawing
effect of nitrogen, the relative kinetic acidity of pyridine is C4 > C3 >
C2 (12:9.3:1). [415,416] This reversal of relative acidities is thought to arise from a combination
of decreased percent s character in the C2 and C6 C-H bonds and nitrogen lonepair
repulsion in the developing carbanionic transition state. Consequently, direct base
deprotonation of pyridine is difficult and not regioselective. [417] Moreover, alkyllithium
reagents tend to add to the electron-deficient C2 and C4 positions. [418] Pyridinium salts
and pyridine N-oxides show the well-known opposite acidity order: C2 > C3 > C4. [419,420]
Caub›re and Fort have developed the first efficient deprotonation system for pyridine
not involving heteroatom assistance. [421,422] The base system butyllithium–lithium 2-(dimethylamino)ethanolate
lithiates pyridine, to give, after electrophilic addition, 87, and
4-(dimethylamino)pyridine cleanly at C2 (Scheme 44), and would appear to be a solution
to the problem of regioselective, efficient pyridine lithiation. Noteworthy is that this base
system lithiates C6, rather than the more usual C3, of 2-chloro- and 2-methoxypyridine
(see Section 8.1.14.13.2). [423]
G. W. Gribble, Section 8.1.14, Science of Synthesis, 2006 Georg Thieme Verlag KG
E
86
N
TIPS
NMe2

8.1.14 Aryllithium and Hetaryllithium Compounds 393
bScheme 44 Lithiation of Pyridines [421,422]
N
BuLi, Me2N(CH2)2OLi
hexane, −78 oC, 1 h
E = D, Me, (CH2)5Me, Bn, CH(OH)(CH2)4Me, CH(OH)Ph, C(OH)Me2, CHO, Bz, Br, SMe, TMS
NMe2
N
1. BuLi, Me2N(CH2)2OLi
hexane, 0 oC, 1 h
2. E +
65−94%
E = D, Bz, PPh2, Cl, Br, I, SnBu3
E +
25−80%
N Li N
87
E
NMe 2
N E
2-Substituted Pyridines 87; General Procedure: [421]
A 1.6 M soln of BuLi in hexane (10 mL, 16 mmol) was cooled to 0 8C under N 2 and a soln of
N,N-dimethylaminoethanol (0.72 g, 8 mmol) in anhyd hexane (10 mL) was added dropwise
over 15 min. The mixture was then cooled to –788C, after which a soln of pyridine (0.32 g,
4 mmol) in hexane (5 mL) was added dropwise. After 1 h, an orange soln was obtained and
an appropriate electrophile (10–40 mmol), as a soln in anhyd THF (25 mL), was added rapidly
to it. After 1 h at –788C the mixture was treated with 10% aq HCl (20 mL). The aqueous
layer was separated and extracted with Et 2O (20 mL). The combined extracts were dried
(MgSO 4) and concentrated, and the crude product was purified on a Chromatotron
(EtOAc/hexane); yield: 25–80%.
8.1.14.13.1 Variation 1:
By Halogen–Lithium Exchange
Prior to the discovery of lithium amide bases and directed lithiation concepts, the sole efficient
route to pyridyllithium compounds was halogen–lithium exchange. This wellknown
reaction [125,424] is normally performed on bromo- or iodopyridines and the resulting
pyridyllithium compounds are stable. An excellent typical example, which is suitable
on a kilogram scale, is shown in Scheme 45 for the preparation of compounds 88. [425] If
dihalopyridines are subjected to halogen–lithium exchange conditions with butyllithium,
then halogen-dance rearrangements can occur.
Scheme 45 Halogen–Lithium Exchange of Halopyridines [425]
N
Br
1. BuLi, toluene, hexane, −60 oC 2. E + , THF
87−94%
E = CHO, C(OH)Ph 2, , C(OH)EtPh, B(OiPr) 2
N
OH
Other pyridyllithium compounds, as generated by bromine– or iodine–lithium exchange,
include 6-fluoro-3-pyridyllithium, [426] 5-(trifluoromethyl)-3-pyridyllithium, [427] 2-(trifluoromethyl)-3-pyridyllithium,
[427] 2-chloro-5-(trifluoromethyl)-3-pyridyllithium, [427] 2-chloro-5-
(trifluoromethyl)-4-pyridyllithium, [427] 5-(trifluoromethyl)-2-pyridyllithium, [427] 4-(trifluoromethyl)-2-pyridyllithium,
[427] 3-(trifluoromethyl)-2-pyridyllithium, [427] 6-(trifluoromethyl)-2-pyridyllithium,
[427] 6-(trifluoromethyl)-3-pyridyllithium, [427] 2-(trifluoromethyl)-4-pyr-
N
88
E
for references see p 414
G. W. Gribble, Section 8.1.14, Science of Synthesis, 2006 Georg Thieme Verlag KG

394 Science of Synthesis 8.1 Lithium Compounds
bidyllithium, [427] 2-chloro-5-(trifluoromethyl)-4-pyridyllithium, [427] and 5-bromo-2-pyridyllithium.
[427,428] Although the last species is thermodynamically favored, 2,5-dibromopyridine
is lithiated to 6-bromo-3-pyridyllithium with butyllithium in diethyl ether. [428,429]
Each of these pyridyllithium compounds reacts smoothly with electrophiles. Also, 6-bromo-2-pyridyllithium,
[430] 6-chloro-3-pyridyllithium, [429,431] 6-methoxy-3-pyridyllithium, [429]
2-fluoro-4-pyridyllithium, [432] 2-chloro-4-pyridyllithium, [432] 2-bromo-4-pyridyllithium, [432]
2-chloro-3-pyridyllithium, [433] 2-bromo-3-pyridyllithium, [433] and 2-fluoro-3-pyridyllithium
[433] are readily generated by halogen–lithium exchange. These species can be converted
to boronic acids [432–435] or transmetalated with zinc(II) chloride. [426,431,436] Synthetic applications
of these pyridyllithium compounds are multifold, and include intermediates
in the synthesis of camptothecin, [437,438] azatetralone, [439] harzianopyridone, [440] caerulomycins,
[441,442] collismycins, [442] naphthyridines, [443] planar polypyridines, [444] pyridine–zirconium
complexes, [193] polyhalopyridines, [445,446] and 3,4,5-trisubstituted pyridines. [447]
Although butyllithium is routinely used to effect halogen–lithium exchange, mesityllithium
has been advocated for this transformation, at least in the synthesis of a camptothecin
intermediate. [448] Obviously, the mesityl halide byproduct cannot engage in the side
reactions that are typical of butyl bromide. Moreover, mesityllithium is less nucleophilic
than butyllithium, e.g. toward carbonyl groups. A second important new development in
this field is that chlorine–lithium exchange can be effected using lithium naphthalenide
(THF, –788C, 1 h), [449] based on earlier work with this reagent by Yus. [450–452] The resulting
2-, 3-, and 4-pyridyllithium compounds react smoothly with electrophiles, although yields
are higher for C2 and C4 substitution (10–93%) than for C3 substitution (6–69%). Successful
electrophiles include iodine, aldehydes (e.g., PhCHO to give 89), ketones, nitriles, and
acyl sources (Scheme 46).
Scheme 46 Lithiation of 2-Chloropyridines [449]
N
Cl
1. Li, naphthalene, THF, rt, 12 h, then −78 oC, 6 h
2. PhCHO, −78 oC, 10 min
3. aq NH4Cl 72%
3-Substituted Pyridines 88; General Procedure: [425]
Toluene (600 mL) in a 2-L three-necked flask, equipped with an overhead stirrer, was
cooled to –608C. A 2.5 M soln of BuLi in hexane (220 mL, 0.55 mol) was mixed with the toluene.
After the internal temperature reached –608C, a soln of 3-bromopyridine (79.0 g,
48.2 mL, 0.50 mol) in toluene (200 mL) was added. The internal temperature was maintained
at

8.1.14 Aryllithium and Hetaryllithium Compounds 395
b8.1.14.13.2 Variation 2:
By Directed ortho-Lithiation
The development of directed lithiation groups in arene chemistry was soon extended to
pyridines, and this area has been extensively reviewed. [6,12,453] The three main directing
groups used on pyridines are halogens, amides, and alkoxy groups. Given that alkyllithium
compounds add to the ð-deficient pyridine ring, early attempts to effect ortho-lithiation
of halopyridines with alkyllithium reagents were generally not successful. [12,453]
Gribble [454,455] and QuØguiner [456,457] independently discovered that lithium diisopropylamide
effects ortho-lithiation of halopyridines, which leads to excellent syntheses of disubstituted
pyridines following electrophilic quenching. For example, 3-halopyridines are regioselectively
lithiated at C4, as expected from the acidifying effect of halogen [121–124] and
the fact that the C4 proton is more acidic than the C2 proton in pyridine. [416] Since halopyridyllithium
compounds are prone to pyridyne formation, [455] electrophilic quenching
must be performed at low temperature. For example, 3-bromo-4-pyridyllithium is only
stable for 10–15 minutes at –788C and must be cooled to –1008C prior to quenching, and
3-iodo-4-pyridyllithium is only fleetingly stable at –958C. Some reactions of 3-halo-4-pyridyllithium
compounds are summarized in Scheme 47. [454,455] The regioselectivity is 96%
C4 and about 2% each at C2 and C5. [454,455] Reaction of 3-chloro-4-pyridyllithium (90,
X = Cl) with iodobutane gives a mixture of 4-butyl-3-chloropyridine (91, E = Bu) and 3-chloro-4-(oct-4-yl)pyridine,
the product of deprotonation of the acidic benzylic methylene
group and subsequent alkylation. Likewise, iodomethane quenching affords some 3-chloro-4-ethylpyridine.
[457]
Scheme 47 Reactions of 3-Halo-4-pyridyllithium Compounds [454,455]
N
X
LDA, THF, −78 o C
Li
N
90
X
E +
36−96%
E = Et, Bu, CH(OH)Ph, C(OH)Ph2, CH(OH)Me, C(OH)MePh, SO 2Ph, I, SPh, TMS; X = F, Cl, Br
The generation of ortho-substituted halopyridyllithium compounds with lithium diisopropylamide
has found extensive use in organic synthesis. Examples include applications
to the synthesis of 2-amino-3-aroylpyridines, [456] other 2,3-disubstituted pyridines, [457] annulated
nicotine analogues, [458] furopyridines, [459] naphthyridines, [443,460] other fused pyridines,
[460] louisianin C, [461] azaindoles, [462] acylindoles, [463] camptothecin, [438] harzianopyridone,
[440] caerulomycins. [441,442] collismycins, [442] 4-substituted 3,5-dibromopyridines, [447]
pyridinecarboxylic acids, [427,464] pyridylzincates, [426,465–467] iodopyridines, [468] pyridynes,
[454,455,469] pyridineboronic acids, [426,432,433] pyrido prostaglandins, [470] and pyridotropanes.
[471]
Synthetic applications of halogen-dance (“homotransmetalation”) reactions of halopyridines
have been pioneered by QuØguiner. [472–477] These reactions can occur in the
halogen–lithium exchange mode [472–474] or via lithium diisopropylamide deprotonation
of a halopyridine. [475–477] This novel transformation (Scheme 48) has been utilized in syntheses
of 5H-pyrido[4,3-b]indole, [475] perlolidine, [475] diazaphenanthrenes, [475] meridine
analogues, [476] pyridoacridine alkaloids, [477] camptothecin, [438] mappicine, [478] and iodopyridines
(e.g., 92). [468]
E
N
91
X
for references see p 414
G. W. Gribble, Section 8.1.14, Science of Synthesis, 2006 Georg Thieme Verlag KG

396 Science of Synthesis 8.1 Lithium Compounds
bScheme 48 Halogen-Dance Reactions of an Iodopyridine [476]
N
I
O
NPr i 2
E = H, D, Et, CH(OH)Ph, CHO, TMS, I
1. LDA (2 equiv), THF, −75 oC, 1 h
2. E +
3. H2O
80−97%
The amide group has also been employed extensively as a directed lithiation group on the
pyridine ring, and both N-acylpyridines and pyridinecarboxamides are smoothly ortholithiated
with alkyllithium reagents (Scheme 49). [479,480] This pyridine lithiation strategy,
first described by Snieckus [231] and Katritzky, [481] has been used to synthesize substituted
pyridines, [440,482–488] pyridoacridines, [477] polycyclic aromatic quinones, [231] sesbanine, [489]
bostrycoidin, [490] nevirapine and derivatives, [491] berninamycinic acid, [492] azaphenoxathiines,
[493] thiazolo[5,4-c]pyridines, [494] and thiazolo[4,5-b]pyridines. [495] Similarly, O-pyridyl
carbamates are lithiated with alkyllithium reagents and behave similarly to their arene
counterparts. [496,497]
Scheme 49 Directed ortho-Lithiation of Pyridine Amides [479,480]
HN
N
E = D, Me, CHO, SMe, TMS
N
O
Bu t
O
NHPh
1. BuLi (2 equiv), THF, 0 o C
2. E +
60−94%
1. BuLi, THF, −78 oC 2. (BnS) 2
77%
Alkoxypyridines can be ortho-lithiated with butyllithium; [498,499] however, in the case of
simple 2-, 3-, and 4-methoxypyridines, mesityllithium is the preferred base (e.g., Scheme
50). [500,501] Phenyllithium is also excellent for the lithiation of 4-methoxypyridine, and butyllithium
is a better choice than mesityllithium for the lithiation (at C2) of 3,4-dimethoxypyridine
(Scheme 50). [502] The power of this method is illustrated by the one-pot conversion
of 2-chloro-6-methoxypyridine into 2-chloro-4-iodo-6-methoxypyridine-5-carbaldehyde
by sequential stages of lithiation and electrophilic quenching. [437] Such a tandem
lithiation sequence is the starting point in a short synthesis of camptothecin. [501] In some
cases, lithium diisopropylamide can effect lithiation of methoxypyridines. [441]
HN
N
N
O
I
N
Bu
E
t
SBn
O
92
NHPh
E
O
NPr i 2
Scheme 50 Directed ortho-Lithiation of Methoxypyridines [500,502]
OMe
N
E = CHO, CH(OH)Ph, SMe, SePh
1. MesLi (1.3 equiv), THF, −23 o C, 3 h
2. E +
65−84%
G. W. Gribble, Section 8.1.14, Science of Synthesis, 2006 Georg Thieme Verlag KG
OMe
N
E

8.1.14 Aryllithium and Hetaryllithium Compounds 397
OMe
b1. BuLi (2.2 equiv), THF, −70 oC (or 0 oC), 1 h
2. E +
OMe
N
45−90%
E = D, Me, CHO, CH(OH)Ph, CH(OH)Me, TMS, Br, I
Other directing groups used to lithiate pyridines include dihydrooxazole, [503,504] amino
alkoxides, [437,501,505] sulfonamides, [506,507] sulfoxides, [508] carboxy, [509,510] arylcarbonyl, [511]
and trifluoromethyl groups. [512] The C4 lithiation of nicotinic acid (as the lithium salt) proceeds
cleanly with lithium 2,2,6,6-tetramethylpiperidide (e.g., to give 93), but not with
the less basic lithium diisopropylamide (Scheme 51). [510]
Scheme 51 Directed ortho-Lithiation of Nicotinic Acid [510]
CO2H
1. LTMP, hexane, THF, −78 oC, 10 min
2. E + , THF
3. Amberlyst IR-120
E = Cl 75%
N E = I unstable
N
93
The superbase system butyllithium–lithium 2-(dimethylamino)ethoxide effects a novel
C6 lithiation of 2-chloropyridine (25–100% with assorted electrophiles), [513] an unusual
result previously observed with 2-methoxypyridine. [514] Similar results are seen with 3and
4-chloropyridines, [515] and with 2-bromopyridine under slightly different conditions
(LTMP, Et 2O). [467] A discussion of these phenomena with regard to the mechanism of the
lithiation of 2-chloro- and 2-methoxypyridines with lithium amides has been advanced.
[516] The lithiation of various pyridine N-oxides has been pursued [517] and applied
to the synthesis of the caerulomycins and collismycins. [442] As expected, the greatly enhanced
acidity of the C2 proton leads to lithiation at this site in pyridine N-oxides.
3-Chloro-4-(trimethylsilyl)pyridine (91, E = TMS; X = Cl); Typical Procedure: [454,455]
An oven-dried, 100-mL, three-necked, round-bottomed flask fitted with an internal thermometer,
an addition funnel, a N 2 adapter, a rubber septum, and a magnetic stirring bar
was charged with dry THF (20 mL) and dry iPr 2NH (3.70 mL, 26.4 mmol). To this was added
a 1.6 M soln of BuLi in hexane (16.5 mL, 30 mmol) at –788C under N 2 with magnetic stirring.
This soln was stirred at –788C for 20 min and then to this soln of LDA was added,
over 15 min, a soln of 3-chloropyridine (2.51 mL, 26.4 mmol) in dry THF (5 mL) with magnetic
stirring and keeping the temperature below –78 8C. The resulting 3-chloro-4-pyridyllithium
precipitated as a white solid in a light yellow soln. The mixture was stirred for
30 min at –788C and then treated over 5–10 min with a soln of TMSCl (3.60 mL,
28.4 mmol) in dry THF (15 mL), keeping the temperature at –788C. The mixture was allowed
to warm to rt overnight, partially concentrated under reduced pressure, poured
into 5% aq NaHCO 3 (50 mL), and extracted with Et 2O (3 ” 100 mL). The Et 2O extracts were
washed with H 2O (75 mL) and brine (2 ” 75 mL), dried (K 2CO 3), and concentrated under reduced
pressure to afford a light amber oil (5.37 g). Distillation gave the pure product;
yield: 4.72 g (96%); bp 75–77 8C/1 Torr.
Isomerized Iodopyridines 92; General Procedure: [476]
3-Iodo-N,N-diisopropylpyridine-2-carboxamide (0.010 mol) in THF (100 mL) was slowly
added to a cold (–758C) soln of LDA (0.020 mol) in THF (100 mL). The resulting mixture
was stirred for 1 h at –788C before addition of the required electrophile (0.020 mol) in
THF (10 mL). Stirring was continued for 2 h at the same temperature before hydrolysis at
E
OMe
N
CO2H
OMe
E
for references see p 414
G. W. Gribble, Section 8.1.14, Science of Synthesis, 2006 Georg Thieme Verlag KG

398 Science of Synthesis 8.1 Lithium Compounds
b–78 8C byH 2O (50 mL) and further addition of H 2O (100 mL) at rt. Extraction with Et 2O
(3 ” 150 mL), drying (MgSO 4), and removal of solvent afforded a crude product, which
was purified by flash chromatography (silica gel); yield: 80–97%.
Nicotinic Acid Derivatives 93; General Procedure: [510]
A 2.5 M soln of BuLi in hexane (16 mL, 40 mmol) and, 15 min later, nicotinic acid (1.2 g,
10 mmol) were added at –788C to a soln of 2,2,6,6-tetramethylpiperidine (5.1 mL,
30 mmol) in THF (50 mL). After 10 min at –788C, the mixture was stirred for 30 min at
–55 8C and transferred dropwise to a cooled (–558C) soln of the required electrophile
(30 mmol) in THF (50 mL). After 15 min at –558C, the mixture was allowed to reach rt before
hydrolysis (5 mL) and removal of the solvents under reduced pressure. The residue
was dissolved in H 2O (20 mL) and the resulting soln washed with CH 2Cl 2 (30 mL) and Et 2O
(2 ” 30 mL). The aqueous phase was then evaporated to dryness and the residue chromatographed
(silica gel, CH 2Cl 2 then CH 2Cl 2/MeOH 7:3) to give the crude product. This was dissolved
in MeOH (30 mL) and treated for 15 min with Amberlyst IR-120 (25 g). The resin was
removed by filtration; the solvents were evaporated, and the residue washed with acetone
(20 mL) to give, after drying, the pure nicotinic acid derivative; yield: 45–80%.
8.1.14.14 Method 14:
Quinolyllithium Compounds
The lithiation of quinolines, [6,12] either by deprotonation or halogen–lithium exchange,
parallels those reactions encountered with pyridines. Both 3- [434] and 7-bromoquinoline
[518] undergo halogen–lithium exchange with butyllithium and are converted into
their respective boronic acids (79 and 60% yields, respectively). Likewise, 2-chloroquinolines
are converted into quinolin-2-yllithium compounds under Yus conditions, [450] and
more highly substituted bromo- and iodoquinolines undergo halogen–lithium exchange
and subsequent chemistry. [427,519,520] For example, 4,8-dibromo-2-(trifluoromethyl)quinoline
undergoes double metal–halogen exchange with butyllithium and is quenched with
iodine to give 4,8-diiodo-2-(trifluoromethyl)quinoline in 69% yield. [520] Halogenated quinolines
also undergo directed ortho-lithiation reactions. Whereas 2-, 3-, 5-, 6-, and 7-fluoroquinolines
suffer C2 nucleophilic addition with butyllithium, lithium diisopropylamide
smoothly removes a proton adjacent to fluorine. [521,522] Similar regiochemistry is observed
with 2-, 3-, and 4-chloroquinolines and lithium diisopropylamide, [523] and more highly
substituted quinolines (Scheme 52). [427,520] The lithiation of (trifluoromethyl)quinolines is
markedly base dependent. [512]
Scheme 52 Directed ortho-Lithiation of Halogenated Quinolines [520,523]
R 1
Br
N
CF 3
R 1 = H, 6-Me, 6-CF3, 7-OMe, 6-F, 8-F, 8-Br, 8-I
1. LDA, THF, hexane, −75 oC, 2 h
2. CO2 62−89%
1. LDA, THF, hexane, −75 E
45−85%
N Cl N Cl
oC, 2 h
2. E +
R 1 = TMS, CH(OH)Ph, CHO, CO 2H, B(OH) 2, I
R 1
Br
N
CO 2H
G. W. Gribble, Section 8.1.14, Science of Synthesis, 2006 Georg Thieme Verlag KG
CF 3

8.1.14 Aryllithium and Hetaryllithium Compounds 399
b8.1.14.15 Method 15:
Diazinyllithium, Benzodiazinyllithium, and Other Azinyllithium Compounds
Although the lithiation of the diazines (pyrazines, pyrimidines, and pyridazines) is much
less developed than that of pyridines, some important studies have been performed,
mainly by QuØguiner, and excellent reviews are available. [7,12] As with other ð-deficient
nitrogen heterocycles, nucleophilic addition to the azine ring is always a threat. An important
property of diazines that is often overlooked is that they are extremely weak bases
compared to pyridine (3–4 orders of magnitude). This property of diazines may explain
the lack of Lewis base nitrogen complexation as a factor in controlling the regiochemistry
of lithiation.
8.1.14.15.1 Variation 1:
Pyrazinyllithium Compounds
The symmetrical pyrazine ring has an inherent advantage in lithiation chemistry since all
four positions are equivalent. Conditions for monolithiation of pyrazines are lithium
2,2,6,6-tetramethylpiperidide in tetrahydrofuran at –758C, to give the expected products
after quenching with an electrophile (PhCHO, MeCHO, I 2) in 44–65% yield. [524] As predicted,
lithiation of 2-chloropyrazine with lithium diisopropylamide or lithium 2,2,6,6-tetramethylpiperidide
(–708C, THF) gives 2-chloropyrazin-3-yllithium, which, upon reaction
with electrophiles, affords the 3-substituted 2-chloropyrazines in 30–90% yield. [525] Other
pyrazine C2 substituents direct lithiation to the C3 position, including methoxy, [526,527]
methylsulfanyl, [527] fluorine, [528] and iodine [529] (Scheme 53). This methodology has been
applied to the synthesis of multisubstituted pyrazine C-nucleosides by employing sequential
dilithiation–quenching of 2,6-dichloropyrazine. [530] Halogen–lithium exchange chemistry
of halopyrazines is seen with 2-chloropyrazine and 2-chloro-6-methylpyrazine to
give the 2-pyrazinyllithium compounds under Yus conditions (Li, naphthalene, THF,
–78 8C) [450] and under Barbier conditions (Li, THF, rt, ultrasound) with 2-iodopyrazines
(e.g., 94 to 95) (Scheme 53). [531]
Scheme 53 Lithiation of 2-Iodopyrazines [529,531]
N
N
1. LTMP, THF, −78 oC, 5 min
2. E +
N
24−82%
I N
E = Me, CO2H, I, TMS, CHO, SPh, CH(OH)Ph, C(OH)Ph2, CH(OH)Ph
N
X
1. Li (2.2 equiv), THF, ))), rt, 30 min
2. E +
33−70%
N I N
94 95
E = CH(OH)Ph, CH(OH)(CH 2) 4Me, SPh; X = H, Cl
Substituted Pyrazines 95: [531]
The diazine 94 (1.0 mmol), Li powder (2.2 mmol), and the electrophile (1.1 mmol) were introduced
in THF (3 mL) under dry argon. The reaction medium was placed in the ultrasound
cleaning bath for 30 min. Decomposition of the remaining Li was then carried out
using EtOH (3 mL). The reaction medium was diluted with H 2O (3 mL) and concentrated.
The aqueous layer was extracted with EtOAc (4 ” 10 mL). The organic layer was then dried
(MgSO 4) and concentrated. The crude product was purified by column chromatography
(silica gel, CH 2Cl 2); yield: 33–70%.
E
I
N
X
E
for references see p 414
G. W. Gribble, Section 8.1.14, Science of Synthesis, 2006 Georg Thieme Verlag KG

400 Science of Synthesis 8.1 Lithium Compounds
b8.1.14.15.2 Variation 2:
Pyrimidyllithium Compounds
Given that the pyrimidine ring is present in DNA and RNA, an enormous amount of chemistry
has been devoted to this heterocycle, including lithiation studies. [7] Although most
pyrimidine lithiations involve a directing group (chlorine, methoxy), pyrimidine itself is
lithiated with difficulty (LTMP, THF, –758C, 2 h) and using the in situ electrophilic
quenching technique, lest the 4,4¢-bipyrimidine dimer becomes the major product. [524]
Under these conditions, for example, 4-(trimethylsilyl)pyrimidine is isolated in 54% yield.
Other electrophiles (benzaldehyde, benzophenone) afford lower yields. Lithiation at C4 is
consistent with the acidity order of C4 > C2. [532] Similar C4 lithiation is observed with
2-chloro-, 2-methoxy-, and 2-(4-methoxyphenyl)pyrimidine using the in situ or normal
electrophilic quench, but yields are usually below 50% [4-substituted 2-methoxypyrimidines:
CH(OH)Ph (29%), CH(OH)Me (26%), 2,3,4-(MeO) 3C 6H 2 (28%), D (56%), CHO (16%),
C(OH)Ph 2 (48%)]. Although dimerization can still intrude, lithiations of 4- and 5-substituted,
2,4- and 4,6-disubstituted, and 2,4,6-trisubstituted pyrimidines are generally more successful.
Directing substituents include methoxy, [526,533] chlorine, [534,535] fluorine, [536] and trifluoromethyl
(e.g. reaction of 96 to give 97) [537] (Scheme 54). The last result appears to be
due to a steric effect. The importance of these results is that the substituted pyrimidines
can be hydrolyzed to uracils or elaborated to pyrimidine-fused indoles. [536]
Scheme 54 Directed ortho-Lithiation Reactions of Substituted Pyrimidines [526,535–537]
MeO
N
N
E = Me, TMS, CH(OH)Ph
OMe
N
MeO N OMe
E = Me, TMS, CH(OH)Ph, Bz
N
Cl N Cl
F
N
Cl
N SMe
1. LTMP, THF, −78 o C, 15 min
2. E +
47−49%
1. LTMP, THF, −78 oC, 15 min
2. E +
91−99%
1. LDA, THF, −80 o C, 30 min
2. E +
E = CH(OH)Ph 84%
E = TMS 67%
1. LDA (2.3 equiv), THF, −70 o C, 30 min
2. E +
48−87%
E = CHO, CO 2H, CH(OH)Me, CH(OH)Ph, 2-MeOC6H4CH(OH), I
MeO
E
E
N
E
N
OMe
N
MeO N OMe
Cl
N
Cl N Cl
E
F
N
N SMe
G. W. Gribble, Section 8.1.14, Science of Synthesis, 2006 Georg Thieme Verlag KG

8.1.14 Aryllithium and Hetaryllithium Compounds 401
CF3
b19−98%
N SMe
N
96
TMP (3 equiv), E + , THF
−100 oC E = TMS, SPh, CH(OH)Ph, C(OH)Ph 2, Cl, I
E
CF3
N
N SMe
Halogen–lithium exchange has been employed to convert 5-bromopyrimidine, [434,538] a
4-iodopyrimidine, [539] a 4-chloropyrimidine, [450] and stannylpyrimidines (via tin–lithium
exchange) [539] into the respective lithiated pyrimidines. In this fashion, pyrimid-5-ylboronic
acid is crafted in 76% yield. [434]
Substituted Pyrimidines 97; General Procedure: [537]
A mixture of 96 (0.51 mmol) in THF (5 mL) and the required electrophile (1.5 mmol) in THF
(15 mL) were added simultaneously to a cold (–1008C) soln of LTMP (1.5 mmol) in dry THF
(20 mL) over 30 min. The mixture was stirred for 1 h at –1008C, then for 1 h at –75 8C, before
hydrolysis by a mixture of 35% HCl (1 mL), EtOH (2 mL), and THF (2 mL). The soln was
gently warmed to rt, treated with sat. NaHCO 3 (5 mL), and concentrated under reduced
pressure to near dryness. The residue was extracted with CH 2Cl 2 (3 ” 20 mL). The organic
extract was dried (MgSO 4) and evaporated. The crude product was purified by column
chromatography (silica gel); yield: 19–98%.
8.1.14.15.3 Variation 3:
Pyridazinyllithium Compounds
Unlike their more famous pyrazine and pyrimidine cousins, the lithiation chemistry of
pyridazines is underexplored; [7] however, a few important studies are known. Lithiation
of pyridazine with lithium 2,2,6,6-tetramethylpiperidide (THF, –75 8C), followed by electrophilic
quenching (or in situ technique), affords the C3 products in most cases (7–47%,
with benzaldehyde, benzophenone, diphenyl disulfide, [ 2 H]hydrogen chloride, acetaldehyde,
iodine). [524] Lithiation yields are much higher if methoxy or chlorine is present on
the ring (Scheme 55). Further lithiation of the C5 position of 98 is facile [538,540] and affords
tetrasubstituted pyrazines. [538] Likewise, 99 can be desilylated in the presence of aldehydes
and the resulting alcohols further elaborated by lithiation, as for 99 to 100. [540]
Scheme 55 Directed ortho-Lithiation of Substituted Pyridazines [526,538,540]
MeO
N N
OMe
E = Me, TMS, CH(OH)Ph, SO-4-Tol
1. LTMP, THF, −78 oC, 15 min
2. E +
76−86%
97
E
MeO
N N
98
OMe
for references see p 414
G. W. Gribble, Section 8.1.14, Science of Synthesis, 2006 Georg Thieme Verlag KG

402 Science of Synthesis 8.1 Lithium Compounds
bLDA, TMSCl, THF
−70 oC, 2 h
88%
N N
OMe
Cl
Cl
HO Ph
N N
OMe
8.1.14.15.4 Variation 4:
Benzodiazinyllithium Compounds
Cl
N N
TMS PhCHO (5 equiv)
OMe
TBAF, THF
20 oC, 2 h
71%
99
1. LTMP (4 equiv), THF
−30 oC, 3 min
2. MeCHO
91%
HO Ph
HO
Lithiation of benzodiazines (quinoxalines, quinazolines, cinnolines) has seen limited attention,
and generally mimics their azine parents. [7] Lithiation of 2-methoxy- and 2-(methylsulfanyl)quinoxaline
(LTMP, THF/hexane, –788C, 20 min) and quenching with a Weinreb
amide gives the respective 3-benzoylquinoxalines in 42–43% yield, [527] and similar lithiation–quenching
of 2-chloroquinoxaline yields 3-substitution (with acetaldehyde and
benzaldehyde, 66 and 52% yields). [541] This latter study also describes the ortho-lithiation
of 2-(pivaloylamino)quinoxaline and quenching with acetaldehyde, benzaldehyde, carbon
dioxide, and iodine (32–65%). The lithiation of 3-(acylamino)-4(3H)-quinazolinones
101 is exceptionally efficient (Scheme 56). [542] Lithiation of 3- and 4-chloro- and 3- and
4-methoxycinnolines affords good yields of the expected products. [543] In the case of
4-chloro-4-methoxycinnoline, lithiation occurs at C8 to afford the corresponding iodinated
compound using iodine as an electrophile (83% yield).
Scheme 56 Lithiation of Quinazolinones [542]
O
N
N
101
H
N
1. LDA (2.2 equiv), THF, −78 oC, 1 h
2. E +
76−92%
R 1 = Me, t-Bu; E = D, Me, C(OH)Ph 2, C(OH)MePh, CONHPh, 1-hydroxycyclohexyl
8.1.14.15.5 Variation 5:
Other Azinyllithium Compounds
O
R 1
A few studies have described the lithiation of other azines and fused azines. The Yus naphthalene-catalyzed
reductive lithiation of 2-chloro-4,6-dimethoxytriazine (102) and electrophilic
trapping leads to the products 103, [450] and 3-phenyl-1,2,4,5-tetrazine (104) is
lithiated at C6 with lithium 2,2,6,6-tetramethylpiperidide to give low yields of desired
products (in situ trapping), accompanied by lithium 2,2,6,6-tetramethylpiperidide addition
and ring-opening side products (Scheme 57). [544] Lithiated 1,2,3-triazines and 1,2,4-triazines
[545,546] are also known. Both halogen–lithium exchange and ortho-lithiation have
been studied in imidazo[1,2-a]pyrazines, [547] and telluride intermediates, via chlorine–tellurium
exchange, have afforded routes to lithiated pyrazolo[3,4-d]pyrimidines (Scheme
57), [548,549] purines, [549] and other heterocycles. [549]
G. W. Gribble, Section 8.1.14, Science of Synthesis, 2006 Georg Thieme Verlag KG
O
N
Cl
N
H
N
E
N N
100
O
R 1
OMe

8.1.14 Aryllithium and Hetaryllithium Compounds 403
bScheme 57 Lithiation of Miscellaneous Azines [450,544,548,549]
MeO
N
N
102
OMe
N
Cl
E = C(OH)Me2, C(OH)Et2
N
N
N N
104
Ph
Li, naphthalene, THF, −78 oC 13−50%
LTMP, E + , THF
−100 oC 8−30%
N N
E = CH(OH)Me, CH(OH)Ph, C(OH)Ph 2, 4-BrC 6H 4CH(OH), CH(OH)-4-Tol
N
Cl
N
N
N
Ph
1. BuTeLi, THF, rt
2. BuLi, −78 oC E
N
N
N
Li
N
Ph
N
N
Ph
MeO
E = CHO, CH(OH)t-Bu, CH(OH)Ph, C(OH)Me2, C(OH)Ph 2, C(OH)MeCH CH 2
8.1.14.16 Method 16:
Other Azolyllithium Compounds
N
N
103
OMe
E +
N
48−82%
Besides pyrrole, imidazole, pyrazole, and indole, other azoles have been lithiated. Lithiation
of 1-(benzyloxy)-1,2,3-triazole (105), followed by an electrophile quench, affords excellent
yields of C5 products (Scheme 58). [550] Catalytic debenzylation gives the corresponding
1,2,3-triazol-1-ols. Lithiation of N2-protected tetrazole 106 gives rise to the desired
107, whereas lithiation of the corresponding N1 isomer results in ring fragmentation
and loss of nitrogen, even at –1008C. [551] Clean lithiation of 1,2,4-triazole 108 is
known. [552] N-Methylbenzimidazole is lithiated at C2 with butyllithium, [263] and 1-(tertbutoxycarbonylamino)benzotriazole
is lithiated at C6 to give, after electrophilic quenching,
a variety of C7 products (65–95%; with tributylchlorostannane, benzaldehyde, dimethylformamide,
deuterium oxide, trimethyl borate, hexanal, 4-methoxybenzaldehyde,
hex-2-enal). [553,554] These aminobenzotriazoles are potential aryne precursors.
Scheme 58 Lithiation of Miscellaneous Azoles [550–552]
1. BuLi, THF, −78 oC, 5 min
2. E +
E
N
N
N
105
OBn 67−97%
N
N
N
OBn
E = D, Me, CHO, CO2Me, CONMe2, Cl, Br, I, SMe, TMS, SnBu3
N
N N
N
106
1. BuLi, TMEDA, Et2O, −78 oC, 5 min
2. Bu3SnCl 67%
BOM BOM
SnBu3 N
N N
N
107
E
N
E
N
N
N
Ph
for references see p 414
G. W. Gribble, Section 8.1.14, Science of Synthesis, 2006 Georg Thieme Verlag KG

404 Science of Synthesis 8.1 Lithium Compounds
b1. BuLi, THF, −78 o N
C
Cl
2. PhOCN
N N
75%
O
108
S
O
NMe2
Cl
N
N N
CN
O S
O
NMe2 2-(Benzyloxymethyl)-5-(tributylstannyl)tetrazole (107); Typical Procedure: [551]
To a soln of tetrazole 106 (2.00 g, 10.5 mmol) and TMEDA (3.2 mL, 21 mmol) in Et 2O
(30 mL) at –788C was added a 2.5 M soln of BuLi in hexanes (4.2 mL, 10.5 mmol) and a
dark red soln resulted. This was stirred for 5 min at –788C and then added via cannula
needle to a precooled (–788C) soln of Bu 3SnCl (3.42 g, 10.5 mmol) in Et 2O (20 mL). The resulting
pale yellow soln was stirred at –788C for 30 min and then diluted with H 2O and
Et 2O. The Et 2O layer was separated, washed with brine, dried (MgSO 4), and concentrated.
The residue was subjected to chromatography (silica gel, hexane/EtOAc) to provide the
product as a colorless oil; yield: 3.35 g (67%).
8.1.14.17 Method 17:
Dibenzo-Fused Hetaryllithium Compounds
With dibenzo-fused heterocycles, such as dibenzofurans, dibenzothiophenes, carbazoles,
and others, the heteroatom can direct lithiation to one or both flanking positions on the
benzene rings. This strategy has led to a rich array of substituted heterocycles unavailable
by conventional methods such as electrophilic substitution.
8.1.14.17.1 Variation 1:
Dibenzofuryllithium Compounds
As Gilman found many years ago, dibenzofuran is regioselectively lithiated at C4 with butyllithium
or sec-butyllithium (diethyl ether, room temperature or reflux) and the lithio
species can be quenched with various electrophiles to give the C4 products (carbon dioxide,
75%; [555] oxygen, 50–60%; [556] dimethylformamide, 79%; [557] tosyl fluoride, 49% [301] ). This
topic has been reviewed. [558] A second lithiation sequence usually affords the C6 lithio species.
[555–557] Lithiation of 4-methoxybenzofuran and quenching with sulfur gives 6-methoxy-4-sulfanylbenzofuran
(43% yield), a compound used in solid-phase peptide synthesis.
[556] However, lithiation of pivaloylamino-substituted dibenzofurans can give amide-directed
products, depending on the position of the pivaloylamino group; nevertheless, 109
is obtained cleanly (Scheme 59). [559]
Scheme 59 Lithiation of a Dibenzofuran [559]
O
HN
O
Bu t
1. BuLi, hexane, THF
0
O
H NMe2 oC, 1 h
2.
67%
G. W. Gribble, Section 8.1.14, Science of Synthesis, 2006 Georg Thieme Verlag KG
OHC
O
109
HN
O
Bu t

8.1.14 Aryllithium and Hetaryllithium Compounds 405
b8.1.14.17.2 Variation 2:
Dibenzothienyllithium Compounds
Gilman discovered the C4 lithiation of dibenzothiophene many years ago; [560] more recently,
this has been extended by Katritzky to C4 and C6 disubstitution by two sequential
steps of monolithiation and quenching, rather than a single dilithiation–quenching operation.
[561] The range of C4 dibenzothiophenes obtained by lithiation is illustrated in
Scheme 60, and the method has been applied to the synthesis of potential amino acid receptors
111 from dibenzothiophene 110. [555]
Scheme 60 Lithiation of Dibenzothiophenes [555,561]
1. BuLi (2 equiv), THF, 5 h, rt
2. E +
52−93%
S S
E = Me, Et, Pr, Cl, Br, CH 2OH, CO 2H
Ph
O
Ph
O
NH
110
E = CHO, CONHPh, CONHBn, P(O)Ph 2
S
1. s-BuLi (3 equiv), TMEDA, Et2O, rt, 4 h
2. E +
50−56%
2-Oxo-N,4,4-triphenyl-1,4-dihydro-2H-[1]benzothieno[3,2-g][3,1]benzoxazine-9-carboxamide
(111, E = CONHPh); Typical Procedure: [555]
CAUTION: Phenyl isocyanate is a skin, eye, and respiratory tract irritant. Chronic exposure can
cause sensitization of the respiratory tract.
Dibenzothiophene 110 (200 mg, 0.49 mmol) was suspended in Et 2O (2 mL) and TMEDA
(0.22 mL, 1.47 mmol) was added with stirring at rt. The soln was cooled to –788C and a
1.3 M soln of s-BuLi in cyclohexane (1.3 mL, 1.47 mmol) was added dropwise, warming to
rt and stirring for 4 h to give a dark red soln. The soln was cooled to –788C and PhNCO
(0.21 mL, 1.96 mmol) in Et 2O (2 mL) was added dropwise and the mixture allowed to
warm to rt. After 1 h the reaction was quenched by addition of sat. aq NH 4Cl (10 mL) and
the aqueous phase was extracted with EtOAc (3 ” 10 mL). The combined organic extracts
were dried (Na 2SO 4) and the solvent removed under reduced pressure. Purification by
flash chromatography (silica gel, EtOAc/petroleum ether 1:9 to 1:1, then Et 2O/CH 2Cl 2 0:1
to 1:19) gave the product; yield: 129 mg (50%).
8.1.14.17.3 Variation 3:
Carbazolyllithium Compounds
The lithiation of carbazole is difficult and very low yields of C1 substitution products are
invariably obtained, deuteration being the sole exception. [562] However, certain N-directing
groups make carbazole lithiation synthetically useful. [563] The best of these groups appears
to be pyrrolidin-1-ylmethyl (Scheme 61). Dilute acid readily hydrolyses the aminal
directing group. This method can be applied to benzo[c]carbazole and dibenzo[c,g]carbazole
to afford aminal-directed lithiation products. In contrast, the aminal of benzo[a]carbazole
(112) could not be prepared; however, as shown, direct lithiation is possible.
Ph
E
O
Ph
O
NH
111
S
E
for references see p 414
G. W. Gribble, Section 8.1.14, Science of Synthesis, 2006 Georg Thieme Verlag KG

406 Science of Synthesis 8.1 Lithium Compounds
bScheme 61 Lithiation of Carbazoles [563]
N
N
1. t-BuLi, hexane, rt, 16 h
2. E +
38−100%
E = Me, Pr, CO2H, Cl, OH, NO2, Bz, C(OH)Ph2
N
H
112
1. BuLi (2.5 equiv), Et2O, rt, 28 h
2. E +
E = CO2H 70%
E = Cl 100%
8.1.14.17.4 Variation 4:
Dibenzo[1,4]dioxinyllithium Compounds
Whilst the lithiation of dibenzo[1,4]dioxin (oxanthrene) has been known for many years,
only recently has this reaction been made synthetically useful (Scheme 62). [564] Lithiation
[t-BuLi (2 equiv), TMEDA, THF, –788C, 1 h] of dibenzo[1,4]dioxin-1-carboxylic acid 113
(E 1 =CO 2H) leads to 9-substitution (e.g., to give 114) upon quenching with carbon dioxide
(75%), iodomethane (73%), chlorotrimethylsilane (60%), N-chlorosuccinimide (74%), hexachloroethane
(68%), bromine (62%), or acetaldehyde (56%). [564,565]
Scheme 62 Lithiation of Dibenzo[1,4]dioxin [564]
O
O
1. BuLi, TMEDA, THF, −30 o C, 1 h
2. (E 1 ) +
80−84%
E 1 = Me, CO 2H, CHO; E 2 = Me, CO 2H, TMS, Cl, Br, CH(OH)Me
1. t-BuLi (2 equiv), TMEDA, THF, −78 o C, 1 h
2. (E 2 ) +
N
E 1 = CO2H 56−75%
Dimethyl Dibenzo[1,4]dioxin-1,9-dicarboxylate (114,E 1 =E 2 =CO 2H); Typical Procedure: [564]
A soln of the acid 113 (E 1 =CO 2H; 1.00 g, 4.38 mmol) and TMEDA (0.73 mL, 4.82 mmol) in
THF (50 mL) was cooled to –788C and treated with a 1.7 M soln of t-BuLi in pentane
(5.28 mL, 8.98 mmol) and the soln was stirred at this temperature for 1 h. CO 2 gas was bubbled
through as the mixture warmed to rt, and the soln was then concentrated to dryness
under reduced pressure. The residue was dissolved in MeOH (30 mL) containing concd
H 2SO 4 (3 mL) and refluxed for 3 h before being poured into sat. aq NaHCO 3 and extracted
with EtOAc. Workup gave a solid that was chromatographed (silica gel, EtOAc/petroleum
ether 1:50) to give the product, which crystallized as rods (acetone); yield: 1.12 g (75%); mp
149–1528C.
G. W. Gribble, Section 8.1.14, Science of Synthesis, 2006 Georg Thieme Verlag KG
N
E
O
O
N
H
113
E
E 1
E 2
O
O
114
E 1

8.1.14 Aryllithium and Hetaryllithium Compounds 407
b8.1.14.17.5 Variation 5:
Thianthrenyllithium Compounds
Similar to dibenzo[1,4]dioxin, the sulfur analogue, thianthrene, is smoothly lithiated at
C1 with tert-butyllithium at –788C (Scheme 63). [566] By comparison, butyllithium affords
poor yields of lithiation products. [567] Metal–halogen exchange of 2-bromothianthrene
with butyllithium (–788C) affords 2-thianthrenyllithium, which isomerizes to the more
stable 1-lithio isomer. Treatment of thianthrene with lithium and catalytic 4,4¢-di-tert-butylbiphenyl
(THF, –90 to –788C) cleaves the central ring to afford various products after
workup or quenching with aldehydes or ketones. [568] Thus, quenching with water gives
2-(phenylsulfanyl)benzenethiol (98% yield).
Scheme 63 Lithiation of Thianthrene [566]
S
S
1. t-BuLi, THF, −78 o C to rt, 30 min
2. E +
35−84%
E = Me, CO2H, Br, I, B(OH)2, SnBu3, CHO, CH(OH)Ph, C(OH)Ph2
8.1.14.17.6 Variation 6:
Phenothiazinyllithium Compounds
Whereas the dilithiation of phenothiazine and quenching to give 1-substituted phenothiazines
has been known for many years, [569,570] the lithiation of N-alkylphenothiazines
leads to 4-substitution, as shown in Scheme 64, [571] a method which is an improvement
over previous reports. Lithiation of N-methylphenothiazine with lithium [catalytic 4,4¢di-tert-butylbiphenyl
(DTBB), THF, –90 8C] ruptures the central ring to afford 2-(N-methylanilino)benzenethiol
in 95% yield. [568] A bromine–lithium exchange reaction of 3-bromo-
10-hexylphenothiazine affords the stable 3-lithio species, which can be trapped with iodine.
[572]
Scheme 64 Lithiation of Phenothiazines [571]
1. s-BuLi (2.5 equiv), TMEDA, Et2O, rt, 30 min
2. E +
Et Et
N
N
S
50−72%
E = Me, CHO, CO 2H, CH(OH)t-Bu, Cl, I, TMS, SMe, CH 2OH
8.1.14.17.7 Variation 7:
Dibenzo[b,f ]azepinyllithium Compounds
Both 5H-dibenzo[b,f ]azepine and its 10,11-dihydro derivative are dilithiated to afford
4-substituted products after quenching with electrophiles (Scheme 65). [573,574] Both C4
and C6 can be deuterated in 93% yield using five repetitions of lithiation–quenching. [574]
S
S
E
S
E
for references see p 414
G. W. Gribble, Section 8.1.14, Science of Synthesis, 2006 Georg Thieme Verlag KG

408 Science of Synthesis 8.1 Lithium Compounds
bScheme 65 Lithiation of 5H-Dibenzo[b,f ]azepine [573]
N
H
E = CHO, Bz, 4-MeOC6H4CO, 3-pyridylmethyl
1. BuLi, EtO2, rt, 24 h
2. E +
40−61%
8.1.14.17.8 Variation 8:
Pyrido[3,4-b]indolyllithium Compounds
Lithiation of the ubiquitous 9H-pyrido[3,4-b]indoles has been little studied. However, C3
amide directing groups, such as the phenylamide on 115, direct lithiation at C4, to give
116, as shown in Scheme 66. [575,576] Only methyllithium is satisfactory in this lithiation.
Scheme 66 Directed ortho-Lithiation of a 9H-Pyrido[3,4-b]indole [576]
N
O
S
NMe2 O
115
O
N
E = N3, Br, 4-MeOC6H4CH(OH)
NHPh
1. MeLi (2.5 equiv), THF
−78 oC, 45 min
2. E +
90−100%
N
H
E
E
N
O
S
NMe2 O
116
O
N
NHPh
4-Bromo-9-[(dimethylamino)sulfonyl]-N-phenyl-9H-pyrido[3,4-b]indole-3-carboxamide
(116, E = Br); Typical Procedure: [576]
CAUTION: Bromine is a severe irritant of the eyes, mucous membranes, lungs, and skin. Liquid
bromine causes severe and painful burns on contact with eyes and skin.
A soln of compound 115 (200 mg, 0.51 mmol) in THF (40 mL) was treated dropwise at
–78 8C under argon with a 1 M soln of MeLi in THF (1.1 mL, 1.1 mmol). The mixture was
stirred for 1 h at –788C, then Br 2 (57 ìL, 1.1 mmol) was added dropwise, and stirring was
continued for 15 min. After addition of H 2O (10 mL), the soln was allowed to warm to rt,
and was then concentrated to one-half of its volume and diluted with Et 2O (50 mL). The
soln was washed with sat. aq NH 4Cl (20 mL) and H 2O (20 mL). The organic phase was dried
(Na 2SO 4) and evaporated to dryness under reduced pressure. The residual solid was suspended
in MeOH (5 mL) and collected by filtration, affording the product as a colorless
powder; yield: 241 mg (quant); mp 2208C.
Applications of Product Subclass 14 in Organic Synthesis
Of the myriad applications of aryllithium and hetaryllithium compounds in organic synthesis,
many of which are illustrated earlier, only a small number can be presented here.
The reader is referred to the excellent reviews cited at the beginning of this article. It is no
exaggeration to say that aryllithium compounds (and hetaryllithium compounds) have
become a dominant force in the methodology of organic synthesis and will remain so in
the future.
G. W. Gribble, Section 8.1.14, Science of Synthesis, 2006 Georg Thieme Verlag KG

8.1.14.18 Method 18:
Aryne Formation
8.1.14 Aryllithium and Hetaryllithium Compounds 409
It was recognized early that ortho-lithiated aryl halides readily lose lithium halide to form
arynes. While this reaction is prevented or minimized at low temperature (depending on
the halide), it represents a powerful aryne generation method and has been used in Diels–
Alder reactions to construct naphthalenes, [577,578] anthracenes, [578,579] phenanthrenes, [580]
naphthacenes, [581] chrysenes, [582] benzo[a]anthracenes, [583] iptycenes, [584] biphenylenes, [577]
and benzonorbornadienes (e.g., 117 to 118) (Scheme 67). [585] Benzyne, which is easily generated
from iodobenzene and lithium 2,2,6,6-tetramethylpiperidide, can also be trapped
with nucleophiles. [586]
Scheme 67 Generation and Trapping of Arynes [585]
Br
BuLi, Et2O, hexane
−78 oC to rt
94%
F F
F F
117
6-Fluoro-9-oxabenzonorbornadiene (118); Typical Procedure: [585]
A 1000-mL, four-necked, round-bottomed flask, equipped with an overhead stirrer, condenser,
thermometer, rubber septum, gas adapter, and stirring bar, was flame-dried under
argon and charged with Et 2O (400 mL) and 1-bromo-2,4-difluorobenzene (17.6 mL,
0.156 mol). To the soln, which was cooled to –788C in an acetone/dry ice bath, was added,
via a gas-tight syringe, a 2.5 M soln of BuLi in hexanes (72 mL, 0.180 mol) over a 1-h period
at such a rate as to keep the reaction temperature below –708C. The mixture was stirred
for 35 min at –788C before furan (120 mL, 1.65 mol) was added over 20 min at such a rate
as to keep the temperature below –738C. It was then allowed to warm slowly to rt overnight.
The cloudy orange mixture was poured into stirred deionized water (600 mL), vacuum
filtered, separated, and the aqueous phase was washed (2 ” 75 mL) with Et 2O. The
combined organic phases were dried (MgSO 4), vacuum filtered, and concentrated by rotary
evaporation under reduced pressure to give a clear gold liquid; yield: 23.76 g (94%); this
was purified by Kugelrohr distillation to give a clear yellow liquid, bp 1008C/0.25 Torr.
8.1.14.19 Method 19:
Functional Group Interchange
An important application of aryllithium compounds in synthesis is the site-specific
replacement of lithium with other functional groups that are otherwise difficult or impossible
to introduce. These groups include fluorine, [587,588] iodine, [589,590] amino, [591,592]
nitro, [593,594] hydroxy, [595–597] cyano, [598] and phosphorus. [599] An example of each is shown
in Scheme 68.
O
118
O
for references see p 414
G. W. Gribble, Section 8.1.14, Science of Synthesis, 2006 Georg Thieme Verlag KG

410 Science of Synthesis 8.1 Lithium Compounds
bScheme 68 Functionalization of ortho-Lithiated Aromatic Compounds [587,591,594,596,598,599]
MeO
Br
Z
O
O
O
NPr i 2
N
NEt 2
BuLi, Et2O
−78 oC A: BuLi, Et2O B: t-BuLi, THF
s-BuLi, THF
−78 oC s-BuLi, TMEDA
THF, −78 oC, 1 h
s-BuLi, TMEDA
THF, −78 oC, 20 min
Z = CON(iPr) 2, dihydrooxazolyl, OMOM, SO 2NEt 2, NHBoc
BuLi, TMEDA
THF, rt, 2 h
Li
OMOM OMOM
MeO
Li
(PhSO2)2NF
78%
Li
82%
O
O
1. TsN3
2. NaBH 4, Bu 4NHSO 4
N
NEt2
MeO
MeNO3 55%
F
NH 2
Li O
NO2 NPr i 2
Li OTMS
OH
Z
Li
(TMSO) 2
Et 2O, rt, 3 h
8.1.14.20 Method 20:
Transmetalation and Coupling Reactions
PhOCN
40−98%
P(OPh)3
0
73%
oC Z
HCl
MeOH
CN
OMOM
3
P
Another important synthetic application of aryllithium compounds is their conversion
into various metalated arenes, i.e. transmetalation, for subsequent chemistry. Grignard
reagents are accessible in this fashion, [600–602] as are cuprates, [603] mercury reagents, [601]
G. W. Gribble, Section 8.1.14, Science of Synthesis, 2006 Georg Thieme Verlag KG
O
N
O
O
NEt 2
NPr i 2
83%

8.1.14 Aryllithium and Hetaryllithium Compounds 411
bmanganese reagents, [604] zinc reagents, [605–607] tin reagents, [601,608–610] and boron reagents.
[611–613] The latter three reagents are the starting points for the palladium-catalyzed
cross-coupling Negishi, Stille, and Suzuki reactions, respectively.
Whereas lithiated bis(trifluoromethyl)benzene 119 fails to react with allyl bromide,
the corresponding Grignard reagent 120 reacts with this electrophile to give the allyl derivative
in 75% yield (Scheme 69). [602] A useful aryl ketone synthesis employs arylmanganese
halides (e.g., 121 to 122). [604] This method is applicable to halogenated benzonitriles
and to the synthesis of esters. The previously unknown 1,3,5-tris(bromomagnesio)benzene
and 1,3,5-tris(trimethylstannyl)benzene are accessible via transmetalation of 1,3,5trilithiobenzene.
[601] The readily available arylboronic acid 123 undergoes facile Suzuki
coupling to afford unsymmetrical biaryls 124. [611] This protocol has been developed into
an efficient syntheses of oxygenated dibenzo[b,d]pyran-6-ones, [612] kinamycin antibiotics,
[613] the fluorenone dengibsin, [614] phenanthrenes, [615] and the Amaryllidaceae alkaloid
buflavine. [616] Application of the Negishi reaction to a substrate prepared by transmetalation
with zinc(II) chloride affords an efficient route to 4-hydroxy-2H-1-benzopyran-2-ones
(4-hydroxycoumarins) and a synthesis of isoeugenetin derivatives. [617] The power of this
tandem directed-lithiation, palladium-catalyzed Suzuki cross-coupling reaction is further
revealed by the construction of highly conjugated molecular materials such as p-quinquephenyls,
[618] poly(p-phenylene) derivatives, [619] and kinked oligophenylenes. [620]
Scheme 69 Transmetalation of ortho-Lithiated Aromatic Compounds [602,604,611]
Cl
CF3
BuLi, TMP, THF
−78 oC, 1.5 h
Li
CF3
MgCl2, THF
−78 oC to rt
CF 3 CF 3 CF 3
I
1. BuLi, Et2O
−78 oC 2. MnI2, −40 oC R 1 = (CH 2) 6Me, (CH 2) 3Cl, (CH 2) 10Br, OEt
O
NPr i 2
1. s-BuLi, TMEDA
THF, −78 oC 2. B(OMe) 3
3. aq HCl
80%
Cl
MgCl
119 120
121
(HO) 2B
MnI
Ar 1 = Ph, 2-MeOC6H4, 6-methoxy-2-naphthyl, 2-thienyl, 3-pyridyl, 2-thiazolyl
123
O
NPr i 2
R 1 COCl
74−82%
Cl
Ar 1 Br, Pd(PPh 3) 4
Na2CO3
toluene, H 2O
44−95%
Ar 1
122
O
124
CF 3
O
R 1
NPr i 2
for references see p 414
G. W. Gribble, Section 8.1.14, Science of Synthesis, 2006 Georg Thieme Verlag KG

412 Science of Synthesis 8.1 Lithium Compounds
b8.1.14.21 Method 21:
Aryllithium Compounds in Ring Formation and Heterocycle Construction
An inherent benefit with aryllithium compounds prepared via the directed ortho-lithiation
protocol is the possibility of ring formation, since the ortho-disubstituted product is
often ideally predisposed for cyclization. This tactic leads to syntheses of phthalides, [621–623]
including applications to the solid phase, [623] benzo[b]furans, [624–627] including solid-phase
variations, [626] dihydrobenzo[b]furans, [628] indoles, [625,627] isatins, [629] oxindoles, [630] benzo[b]thiophenes,
[625,631] benzothiazoles, [632,633] benzoisothiazoles, [634] benzo[e][1,3]thiazines, [635]
benzo[d]isoselenazol-3-ones, [635] 2H-1-benzopyran-2-one, [636,637] 8aH-1-benzopyrans, [638]
3,4-dihydro-1H-2-benzopyrans, [639] quinolines, [640] isoquinolines, [641,642] benzocyclobutenes,
[643] acridones, [644] anthraquinones, [645] thioxanthen-9-ones, [646] benzazepines, [647]
benzazocines, [647] benzodiazepines (such as 125), [648] and biscavitands. [649] Illustrative examples
of these ring-forming reactions are shown in Scheme 70.
Scheme 70 Ring-Forming Reactions from Aryllithium Compounds [629,635]
R 1
Br
O
N
H
R 1 = H, Me, iPr, F, Cl
O
O
NHMe
NHMe
NMe2
1. MeLi, 0 oC 2. t-BuLi, 0 oC 3. CO
4. H3O +
71−79%
1. BuLi (2 equiv)
THF, hexane
−78 to 0 oC 2. Se, 50 oC 1. BuLi (2.2 equiv), THF
−78 to 0 o C, 30 min
2.
Ar1 3. H 3O +
Ar 1
Ar 1 = Ph, 3-MeOC6H4, 4-MeOC6H4, 4-Tol, 4-FC6H4, 4-BrC6H4
O
O
R 1
O
Li
N
Me
SeLi
O
O
N
H
O
CSCl 2
72%
NMe
OH
Ar1 Ar1 OH
TMSCl
NaI, MeCN
84−92%
G. W. Gribble, Section 8.1.14, Science of Synthesis, 2006 Georg Thieme Verlag KG
O
O
NMe
Se S
Ar 1
NMe
Ar 1

8.1.14 Aryllithium and Hetaryllithium Compounds 413
b1. BuLi, THF, −10 oC 2. ZnBr2
NHR1 O
R
3. Bt N Bt
2
36−82%
R 1 = Me, t-Bu, Ph, 4-ClC6H4; R 2 = Bu, Ph, (CH2)2Ph, Cy
2,4-Disubstituted 2,3,4,5-Tetrahydro-1H-2,4-benzodiazepin-1-ones (125);
General Procedure: [648]
The N-substituted benzamide (3 mmol) was dissolved in THF (30 mL) and BuLi (6.6 mmol)
was added dropwise at –108C. The mixture was gradually warmed to 0 8C and stirred for
30 min. After the mixture was cooled to –108C, ZnBr 2 (7 mmol) was added to the mixture,
followed by the addition of the N,N-bis(benzotriazolyl)amine (3 mmol). The resulting mixture
was allowed to warm to rt and stirred for 24 h. The reaction was quenched with 2 M
NaOH and the whole was washed with brine and extracted with EtOAc. Column chromatography
(alumina, hexanes/EtOAc 10:1 to 6:1) afforded the analytically pure benzodiazepinones;
yield: 36–82%.
8.1.14.22 Method 22:
Natural Product Synthesis
Applications of halogen–lithium exchange and directed-lithiation methodologies to the
synthesis of natural products are too numerous to describe here. A few examples for
which a crucial reaction step or a key intermediate involves an aryllithium species are anthraquinone
natural products, [650] phthalideisoquinoline alkaloids, [651] cryptopleurine and
antofine, [652] isoochracinic acid, [653] resistomycin, [654] anthracyclinones, [655,656] vineomycinone
B2, [657] catechin, [658] xanthen-9-one natural products, [659] gossypol, [660] Æ-herbertenol,
[661] lunularic acid, [662] radulanin A and helianane, [663] complement inhibitor K-76, [664]
and semivioxanthin. [320]
Aryllithium compounds also play an essential role in the synthesis of many important
commercial products. The first step in the synthesis of the antiinflammatory drug
etodolac is directed lithiation of 3-methoxy-2,3-dimethylpropionanilide, [665] and the
breast cancer drug fluorotamoxifen is synthesized by ortho-lithiation and quenching
with perchloryl fluoride. [666] Aryllithium methodology is used to prepare crixivan HIV protease
inhibitors, [667] salicylic acids, [668] naphthoquinones, [669] and compounds derived from
2,6-dichlorophenol, which have extensive commercial applications. [670,671]
O
125
NR 1
NR 2
for references see p 414
G. W. Gribble, Section 8.1.14, Science of Synthesis, 2006 Georg Thieme Verlag KG

414 Science of Synthesis 8.1 Lithium Compounds
bReferences
[1] Sotomayor, N.; Lete, E., Curr. Org. Chem., (2003) 7, 275.
[2] Nµjera, C.; Sansano, J. M.; Yus, M., Tetrahedron, (2003) 59, 9255.
[3] Organometallics in Synthesis: A Manual, Schlosser, M., Ed.; Wiley: New York, (2002).
[4] Clayden, J., Organolithiums: Selectivity for Synthesis, Pergamon: Oxford, (2002).
[5] Familoni, O. B., Synlett, (2002), 1181.
[6] Mongin, F.; QuØguiner, G., Tetrahedron, (2001) 57, 4059.
[7] Turck, A.; PlØ, N.; Mongin, F.; QuØguiner, G., Tetrahedron, (2001) 57, 4489.
[8] Green, L.; Chauder, B.; Snieckus, V., J. Heterocycl. Chem., (1999) 36, 1453.
[9] Bailey, W. F.; Longstaff, S. C., Chimica Oggi, (2001) 19 (1/2), 27; Chem. Abstr., (2001) 135, 76908.
[10] Ramón, D. J.; Yus, M., Eur. J. Org. Chem., (2000), 225.
[11] Snieckus, V., Chem. Rev., (1990) 90, 879.
[12] QuØguiner, G.; Marsais, F.; Snieckus, V.; Epsztajn, J., Adv. Heterocycl. Chem., (1991) 52, 187.
[13] Hartung, C.; Snieckus, V., In Modern Arene Chemistry, Astruc, D., Ed.; Wiley: New York, (2002);
p 330.
[14] Eisch, J. J., Organometallics, (2002) 21, 5439.
[15] Mallan, J. M.; Bebb, R. L., Chem. Rev., (1969) 69, 693.
[16] Gschwend, H. W.; Rodriguez, H. R., Org. React. (N. Y.), (1979) 26, 1.
[17] Omae, I., Chem. Rev., (1979) 79, 287.
[18] Parham, W. E.; Bradsher, C. K., Acc. Chem. Res., (1982) 15, 300.
[19] Beak, P.; Snieckus, V., Acc. Chem. Res., (1982) 15, 306.
[20] Narasimhan, N. S.; Mali, R. S., Synthesis, (1983), 957.
[21] Beak, P.; Meyers, A. I., Acc. Chem. Res., (1986) 19, 356.
[22] Bailey, W. F.; Patricia, J. J., J. Organomet. Chem., (1988) 352,1.
[23] Wakefield, B. J., Organolithium Methods, Academic: London, (1990).
[24] Wakefield, B. J., The Chemistry of Organolithium Compounds, 2nd ed., Pergamon: New York, (1990).
[25] Comins, D. L., Synlett, (1992), 615.
[26] Wiberg, K. B.; Sklenak, S.; Bailey, W. F., J. Org. Chem., (2000) 65, 2014.
[27] van Eikema Hommes, N. J. R.; Schleyer, P. v. R., Angew. Chem., (1991) 104, 768; Angew. Chem. Int.
Ed. Engl., (1992) 31, 755.
[28] Chadwick, S. T.; Rennels, R. A.; Rutherford, J. L.; Collum, D. B., J. Am. Chem. Soc., (2000) 122, 8640.
[29] Betz, J.; Bauer, W., J. Am. Chem. Soc., (2002) 124, 8699.
[30] Saµ, J. M., Helv. Chim. Acta, (2002) 85, 814.
[31] Slocum, D. W.; Dumbris, S.; Brown, S.; Jackson, G.; LaMastus, R.; Mullins, E.; Ray, J.; Shelton, P.;
Walstrom, A.; Wilcox, J. M.; Holman, R. W., Tetrahedron, (2003) 59, 8275.
[32] van Eikema Hommes, N. J. R.; Schleyer, P. v. R., Tetrahedron, (1994) 50, 5903.
[33] Saµ, J. M.; Martorell, G.; Frontera, A., J. Org. Chem., (1996) 61, 5194.
[34] Bachrach, S. M.; Hare, M.; Kass, S. R., J. Am. Chem. Soc., (1998) 120, 12 646.
[35] Collum, D. B., Acc. Chem. Res., (1992) 25, 448.
[36] Thurner, A.; Faigl, F.; Agai, B.; Töke, L., Synth. Commun., (1998) 28, 443.
[37] Lucht, B. L.; Collum, D. B., J. Am. Chem. Soc., (1996) 118, 2217.
[38] Stanetty, P.; Mihovilovic, M. D., J. Org. Chem., (1997) 62, 1514.
[39] Guijarro, D.; Yus, M., Tetrahedron, (2000) 56, 1135.
[40] Yus, M.; Ramón, D. J.; Gómez, I., Tetrahedron, (2003) 59, 3219.
[41] Baran, J. R., Jr.; Hendrickson, C.; Laude, D. A., Jr.; Lagow, R. J., J. Org. Chem., (1992) 57, 3759.
[42] Ruhlandt-Senge, K.; Ellison, J. J.; Wehmschulte, R. J.; Pauer, F.; Power, P. P., J. Am. Chem. Soc.,
(1993) 115, 11 353.
[43] Olmstead, M. M.; Power, P. P., J. Organomet. Chem., (1991) 408,1.
[44] Girolami, G. S.; Riehl, M. E.; Suslick, K. S.; Wilson, S. R., Organometallics, (1992) 11, 3907.
[45] Chen, L. S.; Chen, G. J.; Tamborski, C., J. Organomet. Chem., (1980) 193, 283.
[46] Stephens, E. B.; Kinsey, K. E.; Davis, J. F.; Tour, J. M., Macromolecules, (1993) 26, 3519.
[47] Tamborski, C.; Chen, L. S., J. Fluorine Chem., (1995) 75, 117.
[48] Green, K., J. Org. Chem., (1991) 56, 4325.
[49] Prabhu, U. D. G.; Eapen, K. C.; Tamborski, C., J. Org. Chem., (1984) 49, 2792.
[50] Nwokogu, G. C.; Hart, H., Tetrahedron Lett., (1983) 24, 5725.
[51] Farnham, W. B.; Calabrese, J. C., J. Am. Chem. Soc., (1986) 108, 2449.
[52] Reich, H. J.; Phillips, N. H.; Reich, I. L., J. Am. Chem. Soc., (1985) 107, 4101.
G. W. Gribble, Section 8.1.14, Science of Synthesis, 2006 Georg Thieme Verlag KG

References 415
b[53] Reich, H. J.; Green, D. P.; Phillips, N. H., J. Am. Chem. Soc., (1989) 111, 3444.
[54] Crittendon, R. C.; Beck, B. C.; Su, J.; Li, X.-W.; Robinson, G. H., Organometallics, (1999) 18, 156.
[55] Bachrach, S. M.; Miller, J. V., Jr., J. Org. Chem., (2002) 67, 7389.
[56] Slocum, D. W.; Jennings, C. A., J. Org. Chem., (1976) 41, 3653.
[57] Beak, P.; Brown, R. A., J. Org. Chem., (1979) 44, 4463.
[58] Meyers, A. I.; Lutomski, K., J. Org. Chem., (1979) 44, 4464.
[59] Shimano, M.; Meyers, A. I., J. Am. Chem. Soc., (1994) 116, 10 815.
[60] Reich, H. J.; Goldenberg, W. S.; Sanders, A. W.; Tzschucke, C. C., Org. Lett., (2001) 3, 33.
[61] Reich, H. J.; Goldenberg, W. S.; Gudmundsson, B. Ö.; Sanders, A. W.; Kulicke, K. J.; Simon, K.;
Guzei, I. A., J. Am. Chem. Soc., (2001) 123, 8067.
[62] Belzner, J.; Schär, D.; Dehnert, U.; Noltemeyer, M., Organometallics, (1997) 16, 285.
[63] Fort, Y.; Rodriguez, A. L., J. Org. Chem., (2003) 68, 4918.
[64] Kirby, A. J.; Percy, J. M., Tetrahedron, (1988) 44, 6903.
[65] Kiefl, C.; Mannschreck, A., Synthesis, (1995), 1033.
[66] Comins, D. L.; Brown, J. D.; Mantlo, N. B., Tetrahedron Lett., (1982) 23, 3979.
[67] Comins, D. L.; Brown, J. D., Tetrahedron Lett., (1983) 24, 5465.
[68] Comins, D. L.; Brown, J. D., J. Org. Chem., (1984) 49, 1078.
[69] Beak, P.; Brown, R. A., J. Org. Chem., (1982) 47, 34.
[70] Beak, P.; Tse, A.; Hawkins, J.; Chen, C.-W.; Mills, S., Tetrahedron, (1983) 39, 1983.
[71] Beak, P.; Kerrick, S. T.; Gallagher, D. J., J. Am. Chem. Soc., (1993) 115, 10628.
[72] Anderson, D. R.; Faibish, N. C.; Beak, P., J. Am. Chem. Soc., (1999) 121, 7553.
[73] de Silva, S. O.; Reed, J. N.; Billedeau, R. J.; Wang, X.; Norris, D. J.; Snieckus, V., Tetrahedron, (1992)
48, 4863.
[74] Barsky, L.; Gschwend, H. W.; McKenna, J.; Rodriguez, H. R., J. Org. Chem., (1976) 41, 3651.
[75] Fuhrer, W.; Gschwend, H. W., J. Org. Chem., (1979) 44, 1133.
[76] Katritzky, A. R.; Fan, W.-Q., Org. Prep. Proced. Int., (1987) 19, 263.
[77] Metallinos, C.; Nerdinger, S.; Snieckus, V., Org. Lett., (1999) 1, 1183.
[78] Phillion, D. P.; Walker, D. M., J. Org. Chem., (1995) 60, 8417.
[79] Simig, G.; Schlosser, M., Tetrahedron Lett., (1988) 29, 4277.
[80] Kawase, T.; Asai, N.; Ogawa, T.; Oda, M., J. Chem. Soc., Chem. Commun., (1990), 339.
[81] Gilman, H.; Young, R. V., J. Am. Chem. Soc., (1934) 56, 1415.
[82] Wittig, G.; Pockels, U.; Dröge, H., Chem. Ber., (1938) 71, 1903.
[83] Slocum, D. W.; Reed, D.; Jackson, F., III; Friesen, C., J. Organomet. Chem., (1996) 512, 265.
[84] Rennels, R. A.; Maliakal, A. J.; Collum, D. B., J. Am. Chem. Soc., (1998) 120, 421.
[85] Geneste, H.; Schäfer, B., Synthesis, (2001), 2259.
[86] Yamamoto, H.; Maruoka, K., J. Org. Chem., (1980) 45, 2739.
[87] Smith, J. R. L.; O Brien, P.; Reginato, G., Tetrahedron: Asymmetry, (1997) 8, 3415.
[88] Castagnetti, E.; Schlosser, M., Eur. J. Org. Chem., (2001), 691.
[89] Simas, A. B. C.; Coelho, A. L.; Costa, P. R. R., Synthesis, (1999), 1017.
[90] Lukµcs, G.; Porcs-Makkay, M.; Simig, G., Tetrahedron Lett., (2003) 44, 3211.
[91] Wada, A.; Kanatomo, S.; Nagai, S., Chem. Pharm. Bull., (1985) 33, 1016.
[92] Campbell, A. L.; Khanna, I. K., Tetrahedron Lett., (1986) 27, 3963.
[93] Schlosser, M.; Gorecka, J.; Castagnetti, E., Eur. J. Org. Chem., (2003), 452.
[94] Trost, B. M.; Saulnier, M. G., Tetrahedron Lett., (1985) 26, 123.
[95] Dmowski, W.; Piasecka-Maciejewska, K., J. Fluorine Chem., (1996) 78, 59.
[96] Sinha, S.; Mandal, B.; Chandrasekaran, S., Tetrahedron Lett., (2000) 41, 3157.
[97] Slocum, D. W.; Dietzel, P., Tetrahedron Lett., (1999) 40, 1823.
[98] Reddy, T. J.; Iwama, T.; Halpern, H. J.; Rawal, V. H., J. Org. Chem., (2002) 67, 4635.
[99] Ronald, R. C.; Winkle, M. R., Tetrahedron, (1983) 39, 2031.
[100] Davis, S. E.; Davis, A. O.; Kuyper, L. F., Synth. Commun., (1997) 27, 2487.
[101] Salteris, C. S.; Kostas, I. D.; Micha-Screttas, M.; Heropoulos, G. A.; Screttas, C. G., J. Org. Chem.,
(1999) 64, 5589.
[102] Meyer, N.; Seebach, D., Chem. Ber., (1980) 113, 1304.
[103] Perozzi, E. F.; Martin, J. C., J. Am. Chem. Soc., (1979) 101, 1591.
[104] Morey, J.; Costa, A.; Deyµ, P. M.; Suæer, G.; Saµ, J. M., J. Org. Chem., (1990) 55, 3902.
[105] Posner, G. H.; Canella, K. A., J. Am. Chem. Soc., (1985) 107, 2571.
[106] Crowther, G. P.; Sundberg, R. J.; Sarpeshkar, A. M., J. Org. Chem., (1984) 49, 4657.
[107] Bringmann, G.; Geuder, T.; Harmsen, S., Synthesis, (1994), 1143.
G. W. Gribble, Section 8.1.14, Science of Synthesis, 2006 Georg Thieme Verlag KG

416 Science of Synthesis 8.1 Lithium Compounds
b[108] Kranz, M.; Dietrich, H.; Mahdi, W.; Müller, G.; Hampel, F.; Clark, T.; Hacker, R.; Neugebauer, W.;
Kos, A. J.; Schleyer, P. v. R., J. Am. Chem. Soc., (1993) 115, 4698.
[109] Birman, V. B.; Chopra, A.; Ogle, C. A., Tetrahedron Lett., (1996) 37, 5073.
[110] Cox, P. J.; Wang, W.; Snieckus, V., Tetrahedron Lett., (1992) 33, 2253.
[111] Stock, H. T.; Kellogg, R. M., J. Org. Chem., (1996) 61, 3093.
[112] Kitajima, H.; Ito, K.; Aoki, Y.; Katsuki, T., Bull. Chem. Soc. Jpn., (1997) 70, 207.
[113] Bauer, W.; Schleyer, P. v. R., J. Am. Chem. Soc., (1989) 111, 7191.
[114] Slocum, D. W.; Moon, R.; Thompson, J.; Coffey, D. S.; Li, J. D.; Slocum, M. G.; Siegel, A.;
Gayton-Garcia, R., Tetrahedron Lett., (1994) 35, 385.
[115] Slocum, D. W.; Thompson, J.; Friesen, C., Tetrahedron Lett., (1995) 36, 8171.
[116] Slocum, D. W.; Hayes, G.; Kline, N., Tetrahedron Lett., (1995) 36, 8175.
[117] Stratakis, M., J. Org. Chem., (1997) 62, 3024.
[118] Maggi, R.; Schlosser, M., Tetrahedron Lett., (1999) 40, 8797.
[119] Napolitano, E.; Fiaschi, R., Tetrahedron Lett., (2000) 41, 4663.
[120] Suæer, G. A.; Deyµ, P. M.; Saµ, J. M., J. Am. Chem. Soc., (1990) 112, 1467.
[121] Streitwieser, A., Jr.; Mares, F., J. Am. Chem. Soc., (1968) 90, 644.
[122] Streitwieser, A., Jr.; Hudson, J. A.; Mares, F., J. Am. Chem. Soc., (1968) 90, 648.
[123] Schlosser, M., Angew. Chem., (1998) 110, 1538; Angew. Chem. Int. Ed., (1998) 37, 1496.
[124] Schlosser, M., Eur. J. Org. Chem., (2001), 3975.
[125] Fröhlich, J., Prog. Heterocycl. Chem., (1994) 6,1.
[126] Schlosser, M.; Katsoulos, G.; Takagishi, S., Synlett, (1990), 747.
[127] Katsoulos, G.; Takagishi, S.; Schlosser, M., Synlett, (1991), 731.
[128] Schlosser, M.; Guio, L.; Leroux, F., J. Am. Chem. Soc., (2001) 123, 3822.
[129] Rausis, T.; Schlosser, M., Eur. J. Org. Chem., (2002), 3351.
[130] Takagishi, S.; Schlosser, M., Synlett, (1991), 119.
[131] Mongin, F.; Schlosser, M., Tetrahedron Lett., (1996) 37, 6551.
[132] Mongin, F.; Schlosser, M., Tetrahedron Lett., (1997) 38, 1559.
[133] Mongin, F.; Desponds, O.; Schlosser, M., Tetrahedron Lett., (1996) 37, 2767.
[134] Mongin, F.; Marzi, E.; Schlosser, M., Eur. J. Org. Chem., (2001), 2771.
[135] Coe, P. L.; Waring, A. J.; Yarwood, T. D., J. Chem. Soc., Perkin Trans. 1, (1995), 2729.
[136] Kristensen, J.; LysØn, M.; Vedsø, P.; Begtrup, M., Org. Lett., (2001) 3, 1435.
[137] Lulinski, S.; Serwatowski, J., J. Org. Chem., (2003) 68, 5384.
[138] Leroux, F.; Schlosser, M., Angew. Chem., (2002) 114, 4447; Angew. Chem. Int. Ed., (2002) 41, 4272.
[139] Black, W. C.; Guay, B.; Scheuermeyer, F., J. Org. Chem., (1997) 62, 758.
[140] Mattson, R. J.; Sloan, C. P.; Lockhart, C. C.; Catt, J. D.; Gao, Q.; Huang, S., J. Org. Chem., (1999) 64,
8004.
[141] Lulinski, S.; Serwatowski, J., J. Org. Chem., (2003) 68, 9384.
[142] Kottke, T.; Sung, K.; Lagow, R. J., Angew. Chem., (1995) 107, 1612; Angew. Chem. Int. Ed. Engl.,
(1995) 34, 1517.
[143] Bauer, W.; Klusener, P. A. A.; Harder, S.; Kanters, J. A.; Duisenberg, A. J. M.; Brandsma, L.;
Schleyer, P. v. R., Organometallics, (1988) 7, 552.
[144] Block, E.; Eswarakrishnan, V.; Gernon, M.; Ofori-Okai, G.; Saha, C.; Tang, K.; Zubieta, J., J. Am.
Chem. Soc., (1989) 111, 658.
[145] Iwao, M.; Iihama, T.; Mahalanabis, K. K.; Perrier, H.; Snieckus, V., J. Org. Chem., (1989) 54, 24.
[146] Krizan, T. D.; Martin, J. C., J. Am. Chem. Soc., (1983) 105, 6155.
[147] Quesnelle, C.; Iihama, T.; Aubert, T.; Perrier, H.; Snieckus, V., Tetrahedron Lett., (1992) 33, 2625.
[148] Katritzky, A. R.; Lue, P., J. Org. Chem., (1990) 55, 74.
[149] Stanetty, P.; Emerschitz, T., Synth. Commun., (2001) 31, 961.
[150] MacNeil, S. L.; Familoni, O. B.; Snieckus, V., J. Org. Chem., (2001) 66, 3662.
[151] Bonfiglio, J. N., J. Org. Chem., (1986) 51, 2833.
[152] Spangler, L. A., Tetrahedron Lett., (1996) 37, 3639.
[153] Metallinos, C.; Snieckus, V., Org. Lett., (2002) 4, 1935.
[154] Figuly, G. D.; Martin, J. C., J. Org. Chem., (1980) 45, 3728.
[155] Fitt, J. J.; Gschwend, H. W., J. Org. Chem., (1976) 41, 4029.
[156] Sibi, M. P.; Snieckus, V., J. Org. Chem., (1983) 48, 1935.
[157] Mills, R. J.; Horvath, R. F.; Sibi, M. P.; Snieckus, V., Tetrahedron Lett., (1985) 26, 1145.
[158] Wang, W.; Snieckus, V., J. Org. Chem., (1992) 57, 424.
[159] Sengupta, S.; Leite, M.; Raslan, D. S.; Quesnelle, C.; Snieckus, V., J. Org. Chem., (1992) 57, 4066.
G. W. Gribble, Section 8.1.14, Science of Synthesis, 2006 Georg Thieme Verlag KG

References 417
b[160] Quesnelle, C. A.; Familoni, O. B.; Snieckus, V., Synlett, (1994), 349.
[161] Kalinin, A. V.; da Silva, A. J. M.; Lopes, C. C.; Lopes, R. S. C.; Snieckus, V., Tetrahedron Lett., (1998)
39, 4995.
[162] Chauder, B. A.; Kalinin, A. V.; Snieckus, V., Synthesis, (2001), 140.
[163] Focken, T.; Hopf, H.; Snieckus, V.; Dix, I.; Jones, P. G., Eur. J. Org. Chem., (2001), 2221.
[164] Zhang, P.; Gawley, R. E., J. Org. Chem., (1993) 58, 3223.
[165] Kauch, M.; Hoppe, D., Can. J. Chem., (2001) 79, 1736.
[166] Dennis, M. R.; Woodward, S., J. Chem. Soc., Perkin Trans. 1, (1998), 1081.
[167] Stanetty, P.; Koller, H.; Mihovilovic, M., J. Org. Chem., (1992) 57, 6833.
[168] McCombie, S. W.; Lin, S.-I.; Vice, S. F., Tetrahedron Lett., (1999) 40, 8767.
[169] Fisher, L. E.; Caroon, J. M.; Jahangir; Stabler, S. R.; Lundberg, S.; Muchowski, J. M., J. Org. Chem.,
(1993) 58, 3643.
[170] Caron, S.; Hawkins, J. M., J. Org. Chem., (1998) 63, 2054.
[171] Smith, K.; El-Hiti, G. A.; Shukla, A. P., J. Chem. Soc., Perkin Trans. 1, (1999), 2305.
[172] Bennetau, B.; Mortier, J.; Moyroud, J.; Guesnet, J.-L., J. Chem. Soc., Perkin Trans. 1, (1995), 1265.
[173] Meigh, J.-P.; lvarez, M.; Joule, J. A., J. Chem. Soc., Perkin Trans. 1, (2001), 2012.
[174] Ameline, G.; Vaultier, M.; Mortier, J., Tetrahedron Lett., (1996) 37, 8175.
[175] Katritzky, A. R.; Fan, W.-Q.; Akutagawa, K., Tetrahedron, (1986) 42, 4027.
[176] Katritzky, A. R.; Black, M.; Fan, W.-Q., J. Org. Chem., (1991) 56, 5045.
[177] Gray, M.; Chapell, B. J.; Felding, J.; Taylor, N. J.; Snieckus, V., Synlett, (1998), 422.
[178] Melvin, L. S., Tetrahedron Lett., (1981) 22, 3375.
[179] Dhawar, B.; Redmore, D., Synth. Commun., (1985) 15, 411.
[180] Watanabe, M.; Date, M.; Kawanishi, K.; Hori, T.; Furukawa, S., Chem. Pharm. Bull., (1990) 38, 2637.
[181] Gschwend, H. W.; Hamdan, A., J. Org. Chem., (1975) 40, 2008.
[182] Meyers, A. I.; Mihelich, E. D., J. Org. Chem., (1975) 40, 3158.
[183] Gant, T. G.; Meyers, A. I., Tetrahedron, (1994) 50, 2297.
[184] Flippin, L. A.; Muchowski, J. M.; Carter, D. S., J. Org. Chem., (1993) 58, 2463.
[185] Houlihan, W. J.; Parrino, V. A., J. Org. Chem., (1982) 47, 5177.
[186] Harris, T. D.; Neuschwander, B.; Boekelheide, V., J. Org. Chem., (1978) 43, 727.
[187] Harvey, R. G.; Cortez, C., Tetrahedron, (1997) 53, 7101.
[188] Flippin, L. A., Tetrahedron Lett., (1991) 32, 6857.
[189] Larsen, R. D.; King, A. O.; Chen, C. Y.; Corley, E. G.; Foster, B. S.; Roberts, F. E.; Yang, C.;
Lieberman, D. R.; Reamer, R. A.; Tschaen, D. M.; Verhoeven, T. R.; Reider, P. J.; Lo, Y. S.;
Rossano, L. T.; Brookes, A. S.; Meloni, D.; Moore, J. R.; Arnett, J. F., J. Org. Chem., (1994) 59, 6391.
[190] Liepa, A. J.; Jones, D. A.; McCarthy, T. D.; Nearn, R. H., Aust. J. Chem., (2000) 53, 619.
[191] Rhonnstad, P.; Wensbo, D., Tetrahedron Lett., (2002) 43, 3137.
[192] Krizan, T. D.; Martin, J. C., J. Org. Chem., (1982) 47, 2681.
[193] Dreier, T.; Fröhlich, R.; Erker, G., J. Organomet. Chem., (2001) 621, 197.
[194] Yokoyama, M.; Tanabe, T.; Toyoshima, A.; Togo, H., Synthesis, (1993), 517.
[195] Dondoni, A.; Junquera, F.; Merchµn, F. L.; Merino, P.; Scherrmann, M.-C.; Tejero, T., J. Org. Chem.,
(1997) 62, 5484.
[196] Kerdesky, F. A. J.; Basha, A., Tetrahedron Lett., (1991) 32, 2003.
[197] Ager, D. J., Tetrahedron Lett., (1983) 24, 5441.
[198] Carpenter, A. J.; Chadwick, D. J., Tetrahedron, (1985) 41, 3803.
[199] Chadwick, D. J.; Wilbe, C., J. Chem. Soc., Perkin Trans. 1, (1977), 887.
[200] Zeni, G.; Nogueira, C. W.; Silva, D. O.; Menezes, P. H.; Braga, A. L.; Stefani, H. A.; Rocha, J. B. T.,
Tetrahedron Lett., (2003) 44, 1387.
[201] Katsumura, S.; Fujiwara, S.; Isoe, S., Tetrahedron Lett., (1988) 29, 1173.
[202] Alvarez-Ibarra, C.; Quiroga, M. L.; Toledano, E., Tetrahedron, (1996) 52, 4065.
[203] Comins, D. L.; Killpack, M. O., J. Org. Chem., (1987) 52, 104.
[204] Lee, G. C. M.; Holmes, J. M.; Harcourt, D. A.; Garst, M. E., J. Org. Chem., (1992) 57, 3126.
[205] Grimaldi, T.; Romero, M.; Pujol, M. D., Synlett, (2000), 1788.
[206] Carpenter, A. J.; Chadwick, D. J., J. Org. Chem., (1985) 50, 4362.
[207] Näsman, J. H.; Kopola, N.; Pensar, G., Tetrahedron Lett., (1986) 27, 1391.
[208] Chadwick, D. J.; McKnight, M. V.; Ngochindo, R., J. Chem. Soc., Perkin Trans. 1, (1982), 1343.
[209] Carpenter, A. J.; Chadwick, D. J., Tetrahedron Lett., (1985) 26, 5335.
[210] Domínguez, C.; Csµky, A. G.; Plumet, J., Tetrahedron, (1992) 48, 149.
[211] Chadwick, D. J.; Ennis, D. S., Tetrahedron, (1991) 47, 9901.
G. W. Gribble, Section 8.1.14, Science of Synthesis, 2006 Georg Thieme Verlag KG

418 Science of Synthesis 8.1 Lithium Compounds
b[212] Bures, E. J.; Keay, B. A., Tetrahedron Lett., (1988) 29, 1247.
[213] Yokoyama, M.; Toyoshima, H.; Shimizu, M.; Togo, H., J. Chem. Soc., Perkin Trans. 1, (1997), 29.
[214] Silcoff, E. R.; Asadi, A. S. I.; Sheradsky, T., J. Polym. Sci., Part A: Polym. Chem., (2001) 39, 872.
[215] Nakayama, J.; Dong, H.; Sawada, K.; Ishii, A.; Kumakura, S., Tetrahedron, (1996) 52, 471.
[216] De Sousa, P. T., Jr.; Taylor, R. J. K., Synlett, (1990), 755.
[217] Feringa, B. L.; Hulst, R.; Rikers, R.; Brandsma, L., Synthesis, (1988), 316.
[218] Samanta, S. S.; Ghosh, S. C.; De, A., J. Chem. Soc., Perkin Trans. 1, (1997), 2683.
[219] Wilson, W. D.; Tanious, F. A.; Watson, R. A.; Barton, H. J.; Strekowska, A.; Harden, D. B.;
Strekowski, L., Biochemistry, (1989) 28, 1984.
[220] Nakayama, J.; Yu, T.; Sugihara, Y.; Ishii, A.; Kumakura, S., Heterocycles, (1997) 45, 1267.
[221] Sotgiu, G.; Zambianchi, M.; Barbarella, G.; Aruffo, F.; Cipriani, F.; Ventola, A., J. Org. Chem., (2003)
68, 1512.
[222] Benincori, T.; Cesarotti, E.; Piccolo, O.; Sannicolò, F., J. Org. Chem., (2000) 65, 2043.
[223] Briehn, C. A.; Kirschbaum, T.; Bäuerle, P., J. Org. Chem., (2000) 65, 352.
[224] Coppola, G. M.; Damon, R. E.; Yu, H., J. Heterocycl. Chem., (1996) 33, 687.
[225] Spagnolo, P.; Zanirato, P., J. Chem. Soc., Perkin Trans. 1, (1996), 963.
[226] Slocum, D. W.; Gierer, P. L., J. Org. Chem., (1976) 41, 3668.
[227] Della Vecchia, L.; Vlattas, I., J. Org. Chem., (1977) 42, 2649.
[228] Doadt, E. G.; Snieckus, V., Tetrahedron Lett., (1985) 26, 1149.
[229] Mukherjee, S.; De, A., J. Chem. Res., Synop., (1994), 238.
[230] Graham, S. L.; Scholz, T. H., J. Org. Chem., (1991) 56, 4260.
[231] Watanabe, M.; Snieckus, V., J. Am. Chem. Soc., (1980) 102, 1457.
[232] Kano, S.; Yuasa, Y.; Yokomatsu, T.; Shibuya, S., Heterocycles, (1983) 20, 2035.
[233] van Pham, C.; Macomber, R. S.; Mark, H. B., Jr.; Zimmer, H., J. Org. Chem., (1984) 49, 5250.
[234] Fröhlich, H.; Kalt, W., J. Org. Chem., (1990) 55, 2993.
[235] Sauter, F.; Fröhlich, H.; Kalt, W., Synthesis, (1989), 771.
[236] Gharpure, M.; Stoller, A.; Bellamy, F.; Firnau, G.; Snieckus, V., Synthesis, (1991), 1079.
[237] Fraser, R. R.; Mansour, T. S.; Savard, S., Can. J. Chem., (1985) 63, 3505.
[238] Brittain, J. M.; Jones, R. A.; Arques, J. S.; Saliente, T. A., Synth. Commun., (1982) 12, 231.
[239] Minato, A.; Tamao, K.; Hayashi, T.; Suzuki, K.; Kumada, M., Tetrahedron Lett., (1981) 22, 5319.
[240] Bauer, W.; Müller, G.; Pi, R.; Schleyer, P. v. R., Angew. Chem., (1986) 98, 1130; Angew. Chem. Int. Ed.
Engl., (1986) 25, 1103.
[241] Katritzky, A. R.; Akutagawa, K., Org. Prep. Proced. Int., (1988) 20, 585.
[242] Faigl, F.; Schlosser, M., Tetrahedron, (1993) 49, 10271.
[243] Faigl, F.; Fogassy, K.; Thurner, A.; Töke, L., Tetrahedron, (1997) 53, 4883.
[244] Faigl, F.; Fogassy, K.; Szµntó, Z.; Lopata, A.; Töke, L., Tetrahedron, (1998) 54, 4367.
[245] Kozikowski, A. P.; Cheng, X.-M., J. Org. Chem., (1984) 49, 3239.
[246] Bray, B. L.; Mathies, P. H.; Naef, R.; Solas, D. R.; Tidwell, T. T.; Artis, D. R.; Muchowski, J. M., J. Org.
Chem., (1990) 55, 6317.
[247] Sundberg, R. J.; Pearce, B. C., J. Org. Chem., (1985) 50, 425.
[248] Liu, J.-H.; Chan, H.-W.; Wong, H. N. C., J. Org. Chem., (2000) 65, 3274.
[249] Banwell, M. G.; Flynn, B. L.; Hamel, E.; Hockless, D. C. R., Chem. Commun. (Cambridge), (1997), 207.
[250] Liu, J.-H.; Yang, Q.-C.; Mak, T. C. W.; Wong, H. N. C., J. Org. Chem., (2000) 65, 3587.
[251] Gribble, G. W.; Blank, D. H.; Jasinski, J. P., Chem. Commun. (Cambridge), (1999), 2195.
[252] Chen, W.; Cava, M. P., Tetrahedron Lett., (1987) 28, 6025.
[253] Muchowski, J. M.; Hess, P., Tetrahedron Lett., (1988) 29, 3215.
[254] Muchowski, J. M.; Hess, P., Tetrahedron Lett., (1988) 29, 777.
[255] Moskalev, N. V.; Gribble, G. W., Tetrahedron Lett., (2002) 43, 197.
[256] Chadwick, D. J.; Ngochindo, R. I., J. Chem. Soc., Perkin Trans. 1, (1984), 481.
[257] Carpenter, A. J.; Chadwick, D. J., Tetrahedron, (1986) 42, 2351.
[258] Thang, C. C.; Davalian, D.; Huang, P.; Breslow, R., J. Am. Chem. Soc., (1978) 100, 3918.
[259] Walters, M. A.; Lee, M. D., Tetrahedron Lett., (1994) 35, 8307.
[260] Ohta, S.; Yamamoto, T.; Kawasaki, I.; Yamashita, M.; Katsuma, H.; Nasako, R.; Kobayashi, K.;
Ogawa, K., Chem. Pharm. Bull., (1992) 40, 2681.
[261] Kawasaki, I.; Katsuma, H.; Nakayama, Y.; Yamashita, M.; Ohta, S., Heterocycles, (1998) 48, 1887.
[262] Guziec, L. J.; Guziec, F. S., Jr., J. Org. Chem., (1994) 59, 4691.
[263] Boga, C.; Vecchio, E. D.; Forlani, L.; Todesco, P. E., J. Organomet. Chem., (2000) 601, 233.
[264] Whitten, J. P.; Matthews, D. P.; McCarthy, J. R., J. Org. Chem., (1986) 51, 1891.
G. W. Gribble, Section 8.1.14, Science of Synthesis, 2006 Georg Thieme Verlag KG

References 419
b[265] Lipshutz, B. H.; Huff, B.; Hagen, W., Tetrahedron Lett., (1988) 29, 3411.
[266] Manoharan, T. S.; Brown, R. S., J. Org. Chem., (1988) 53, 1107.
[267] Eriksen, B. L.; Vedsø, P.; Morel, S.; Begtrup, M., J. Org. Chem., (1998) 63, 12.
[268] Díez-Barra, E.; de la Hoz, A.; Sµnchez-Migallón, A.; Tejeda, J., J. Chem. Soc., Perkin Trans. 1, (1993),
1079.
[269] Demuth, T. P., Jr.; Lever, D. C.; Gorgos, L. M.; Hogan, C. M.; Chu, J., J. Org. Chem., (1992) 57, 2963.
[270] Phillips, B. T.; Claremon, D. A.; Varga, S. L., Synthesis, (1990), 761.
[271] Iddon, B., Heterocycles, (1985) 23, 417.
[272] Iddon, B.; Khan, N., Tetrahedron Lett., (1986) 27, 1635.
[273] Iddon, B.; Khan, N., J. Chem. Soc., Perkin Trans. 1, (1987), 1445.
[274] Iddon, B.; Khan, N., J. Chem. Soc., Perkin Trans. 1, (1987), 1453.
[275] Iddon, B.; Petersen, A. K.; Becher, J.; Christensen, N. J., J. Chem. Soc., Perkin Trans. 1, (1995), 1475.
[276] Lipshutz, B. H.; Hagen, W., Tetrahedron Lett., (1992) 33, 5865.
[277] Kaswasaki, I.; Yamashita, M.; Ohta, S., J. Chem. Soc., Chem. Commun., (1994), 2085.
[278] Kawasaki, I.; Yamashita, M.; Ohta, S., Chem. Pharm. Bull., (1996) 44, 1831.
[279] Groziak, M. P.; Wie, L., J. Org. Chem., (1992) 57, 3776.
[280] Becher, J.; Pluta, K.; Krake, N.; Brøndum, K.; Christensen, N. J.; Vinader, M. V., Synthesis, (1989),
530.
[281] Hawkins, D. W.; Iddon, B.; Longthorne, D. S., Tetrahedron, (1995) 51, 12807.
[282] Groziak, M. P.; Wie, L., J. Org. Chem., (1991) 56, 4296.
[283] Holden, K. G.; Mattson, M. N.; Cha, K. H.; Rapoport, H., J. Org. Chem., (2002) 67, 5913.
[284] Iddon, B., Heterocycles, (1994) 37, 1321.
[285] Iddon, B., Heterocycles, (1994) 37, 1263.
[286] Gilchrist, T. L., Adv. Heterocycl. Chem., (1987) 41, 41.
[287] Hodges, J. C.; Patt, W. C.; Connolly, C. J., J. Org. Chem., (1991) 56, 449.
[288] Whitney, S. E.; Rickborn, B., J. Org. Chem., (1991) 56, 3058.
[289] Crowe, E.; Hossner, F.; Hughes, M. J., Tetrahedron, (1995) 51, 8889.
[290] Vedejs, E.; Monahan, S. D., J. Org. Chem., (1996) 61, 5192.
[291] Vedejs, E.; Luchetta, L. M., J. Org. Chem., (1999) 64, 1011.
[292] Barrett, A. G. M.; Kohrt, J. T., Synlett, (1995), 415.
[293] Harn, N. K.; Gramer, C. J.; Anderson, B. A., Tetrahedron Lett., (1995) 36, 9453.
[294] Anderson, B. A.; Harn, N. K., Synthesis, (1996), 583.
[295] Clapham, B.; Sutherland, A. J., J. Org. Chem., (2001) 66, 9033.
[296] Evans, D. A.; Cee, V. J.; Smith, T. E.; Santiago, K. J., Org. Lett., (1999) 1, 87.
[297] Vedejs, E.; Barda, D. A., Org. Lett., (2000) 2, 1033.
[298] Konoike, T.; Kanda, Y.; Araki, Y., Tetrahedron Lett., (1996) 37, 3339.
[299] Booker-Milburn, K. I., Synlett, (1992), 327.
[300] Heinisch, G.; Holzer, W.; Pock, S., J. Chem. Soc., Perkin Trans. 1, (1990), 1829.
[301] Aboutayab, K.; Caddick, S.; Jenkins, K.; Joshi, S.; Khan, S., Tetrahedron, (1996) 52, 11 329.
[302] Kristensen, J.; Begtrup, M.; Vedsø, P., Synthesis, (1998), 1604.
[303] Vedsø, P.; Begtrup, M., J. Org. Chem., (1995) 60, 4995.
[304] Iddon, B., Heterocycles, (1995) 41, 533.
[305] Dondoni, A.; Fantin, G.; Fogagnolo, M.; Medici, A.; Pedrini, P., J. Org. Chem., (1988) 53, 1748.
[306] Dondoni, A.; Mastellari, A. R.; Medici, A.; Negrini, E.; Pedrini, P., Synthesis, (1986), 757.
[307] Meyers, A. I.; Knaus, G. N., J. Am. Chem. Soc., (1973) 95, 3408.
[308] Dondoni, A.; Giovannini, P. P.; Perrone, D., J. Org. Chem., (2002) 67, 7203.
[309] Dondoni, A., Lect. Heterocycl. Chem., (1985) 8, 13.
[310] Bach, T.; Heuser, S., J. Org. Chem., (2002) 67, 5789.
[311] Kelly, T. R.; Jagoe, C. T.; Gu, Z., Tetrahedron Lett., (1991) 32, 4263.
[312] Kelly, T. R.; Lang, F., Tetrahedron Lett., (1995) 36, 9293.
[313] Cugnon de Sevricourt, M.; Robba, M., Bull. Soc. Chim. Fr., (1977), 142.
[314] Janosik, T.; Stensland, B.; Bergman, J., J. Org. Chem., (2002) 67, 6220.
[315] Costa, A. M. B. S. R. C. S.; Dean, F. M.; Jones, M. A.; Smith, D. A.; Varma, R. S., J. Chem. Soc., Chem.
Commun., (1980), 1224.
[316] Chapman, N. B.; Hughes, C. G.; Scrowston, R. M., J. Chem. Soc. C, (1970), 2431.
[317] DiMenna, W. S., Tetrahedron Lett., (1980) 21, 2129.
[318] Yokoyama, Y.; Shiraishi, H.; Tani, Y.; Yokoyama, Y.; Yamaguchi, Y., J. Am. Chem. Soc., (2003) 125,
7194.
G. W. Gribble, Section 8.1.14, Science of Synthesis, 2006 Georg Thieme Verlag KG

420 Science of Synthesis 8.1 Lithium Compounds
b[319] Mandal, S. S.; Samanta, S. S.; Deb, C.; De, A., J. Chem. Soc., Perkin Trans. 1, (1998), 2559.
[320] Kamila, S.; Mukherjee, C.; Mondal, S. S.; De, A., Tetrahedron, (2003) 59, 1339.
[321] Tanaka, K.; Suzuki, H.; Osuga, H., Tetrahedron Lett., (1997) 38, 457.
[322] Kamila, S.; Mukherjee, C.; De, A., Tetrahedron Lett., (2001) 42, 5955.
[323] Shirley, D. A.; Roussel, P. A., J. Am. Chem. Soc., (1953) 75, 375.
[324] Sundberg, R. J.; Russell, H. F., J. Org. Chem., (1973) 38, 3324.
[325] Ziegler, F. E.; Spitzner, E. B., J. Am. Chem. Soc., (1973) 95, 7146.
[326] Bergman, J.; Eklund, N., Tetrahedron, (1980) 36, 1439.
[327] Akgün, E.; Tunali, M.; Erdönmez, G., J. Heterocycl. Chem., (1989) 26, 1869.
[328] Sundberg, R. J.; Bloom, J. D., J. Org. Chem., (1980) 45, 3382.
[329] Saulnier, M. G.; Gribble, G. W., J. Org. Chem., (1982) 47, 757.
[330] Gribble, G. W.; Barden, T. C.; Johnson, D. A., Tetrahedron, (1988) 44, 3195.
[331] Ketcha, D. M.; Lieurance, B. A.; Homan, D. F. J.; Gribble, G. W., J. Org. Chem., (1989) 54, 4350.
[332] Gribble, G. W.; Allison, B. D.; Conway, S. C.; Saulnier, M. G., Org. Prep. Proced. Int., (1992) 24, 649.
[333] Jiang, J.; Gribble, G. W., Synth. Commun., (2002) 32, 2035.
[334] Jiang, J.; Gribble, G. W., Tetrahedron Lett., (2002) 43, 4115.
[335] Molina, P.; Almendros, P.; Fresneda, P. M., Tetrahedron Lett., (1993) 34, 4701.
[336] Kraxner, J.; Gmeiner, P., Synthesis, (2000), 1081.
[337] Hasan, I.; Marinelli, E. R.; Lin, L.-C. C.; Fowler, F. W.; Levy, A. B., J. Org. Chem., (1981) 46, 157.
[338] Beak, P.; Lee, W. K., J. Org. Chem., (1993) 58, 1109.
[339] Coulton, S.; Gilchrist, T. L.; Graham, K., Tetrahedron, (1997) 53, 791.
[340] Vazquez, E.; Davies, I. W.; Payack, J. F., J. Org. Chem., (2002) 67, 7551.
[341] Hlasta, D. J.; Bell, M. R., Heterocycles, (1989) 29, 849.
[342] Katritzky, A. R.; Lue, P.; Chen, Y.-X., J. Org. Chem., (1990) 55, 3688.
[343] Katritzky, A. R.; Akutagawa, K., Tetrahedron Lett., (1985) 26, 5935.
[344] Fukuda, T.; Mine, Y.; Iwao, M., Tetrahedron, (2001) 57, 975.
[345] Kline, T., J. Heterocycl. Chem., (1985) 22, 505.
[346] Saulnier, M. G.; Gribble, G. W., J. Org. Chem., (1982) 47, 2810.
[347] Saulnier, M. G.; Gribble, G. W., J. Org. Chem., (1983) 48, 2690.
[348] Ketcha, D. M.; Gribble, G. W., J. Org. Chem., (1985) 50, 5451.
[349] Gribble, G. W.; Fletcher, G. L.; Ketcha, D. M.; Rajopadhye, M., J. Org. Chem., (1989) 54, 3264.
[350] Gribble, G. W.; Saulnier, M. G.; Obaza-Nutaitis, J. A.; Ketcha, D. M., J. Org. Chem., (1992) 57, 5891.
[351] Fraser, H. L.; Gribble, G. W., Can. J. Chem., (2001) 79, 1515.
[352] Caixach, J.; Capell, R.; Galvez, C.; Gonzalez, A.; Roca, N., J. Heterocycl. Chem., (1979) 16, 1631.
[353] Bergman, J.; Venemalm, L., Tetrahedron Lett., (1988) 29, 2993.
[354] Aygün, A.; Pindur, U., Synlett, (2000), 1757.
[355] Saulnier, M. G.; Gribble, G. W., Tetrahedron Lett., (1983) 24, 5435.
[356] Gribble, G. W.; Keavy, D. J.; Davis, D. A.; Saulnier, M. G.; Pelcman, B.; Barden, T. C.; Sibi, M. P.;
Olson, E. R.; BelBruno, J. J., J. Org. Chem., (1992) 57, 5878.
[357] Gribble, G. W.; Jiang, J.; Liu, Y., J. Org. Chem., (2002) 67, 1001.
[358] Jiang, J.; Gribble, G. W., Org. Prep. Proced. Int., (2002) 34, 533.
[359] Abbiati, G.; Beccalli, E. M.; Marchesini, A.; Rossi, E., Synthesis, (2001), 2477.
[360] Rewcastle, G. W.; Janosik, T.; Bergman, J., Tetrahedron, (2001) 57, 7185.
[361] Conway, S. C.; Gribble, G. W., Heterocycles, (1992) 34, 2095.
[362] Liu, Y.; Gribble, G. W., Tetrahedron Lett., (2000) 41, 8717.
[363] Liu, Y.; Gribble, G. W., J. Nat. Prod., (2002) 65, 748.
[364] Macor, J. E.; Ryan, K.; Chalabi, P. M.; Windels, J. C.; Roth, R. W., J. Labelled Compd. Radiopharm.,
(1990) 28, 1293.
[365] Cheng, A. C.; Shulgin, A. T.; Castagnoli, N., Jr., J. Org. Chem., (1982) 47, 5258.
[366] Katritzky, A. R.; Akutagawa, K.; Jones, R. A., Synth. Commun., (1988) 18, 1151.
[367] Buttery, C. D.; Jones, R. G.; Knight, D. W., Synlett, (1991), 315.
[368] Nakagawa, K.; Somei, M., Heterocycles, (1994) 39, 31.
[369] Sundberg, R. J.; Parton, R. L., J. Org. Chem., (1976) 41, 163.
[370] Sundberg, R. J.; Broome, R.; Walters, C. P.; Schnur, D., J. Heterocycl. Chem., (1981) 18, 807.
[371] Ishikura, M.; Agata, I., Heterocycles, (1995) 41, 2437.
[372] Ishikura, M.; Agata, I., Heterocycles, (1996) 43, 1591.
[373] Sakamoto, T.; Kondo, Y.; Takazawa, N.; Yamanaka, H., J. Chem. Soc., Perkin Trans. 1, (1996), 1927.
[374] Labadie, S. S.; Teng, E., J. Org. Chem., (1994) 59, 4250.
G. W. Gribble, Section 8.1.14, Science of Synthesis, 2006 Georg Thieme Verlag KG

References 421
b[375] Achab, S., Tetrahedron Lett., (1996) 37, 5503.
[376] Kondo, Y.; Yoshida, A.; Sato, S.; Sakamoto, T., Heterocycles, (1996) 42, 105.
[377] Conway, S. C.; Gribble, G. W., Heterocycles, (1990) 30, 627.
[378] Gribble, G. W.; Barden, T. C., J. Org. Chem., (1985) 50, 5900.
[379] Zheng, Q.; Yang, Y.; Martin, A. R., Heterocycles, (1994) 37, 1761.
[380] Amat, M.; Hadida, S.; Sathyanarayana, S.; Bosch, J., J. Org. Chem., (1994) 59, 10.
[381] Amat, M.; Sathyanarayana, S.; Hadida, S.; Bosch, J., Heterocycles, (1996) 43, 1713.
[382] Amat, M.; Pshenichnyi, G.; Bosch, J.; Molins, E.; Miravitlles, C., Tetrahedron: Asymmetry, (1996) 7,
3091.
[383] Choshi, T.; Yamada, S.; Sugino, E.; Kuwada, T.; Hibino, S., J. Org. Chem., (1995) 60, 5899.
[384] Hoerrner, R. S.; Askin, D.; Volante, R. P.; Reider, P. J., Tetrahedron Lett., (1998) 39, 3455.
[385] Gerasimov, M.; Marona-Lewicka, D.; Kurrasch-Orbaugh, D. M.; Qandil, A. M.; Nichols, D. E.,
J. Med. Chem., (1999) 42, 4257.
[386] Ma, C.; Yu, S.; He, X.; Liu, X.; Cook, J. M., Tetrahedron Lett., (2000) 41, 2781.
[387] Wynne, J. H.; Stalick, W. M., J. Org. Chem., (2002) 67, 5850.
[388] Wynne, J. H.; Stalick, W. M., J. Org. Chem., (2003) 68, 4845.
[389] Amat, M.; Seffar, F.; Llor, N.; Bosch, J., Synthesis, (2001), 267.
[390] Amat, M.; Hadida, S.; Bosch, J., Tetrahedron Lett., (1994) 35, 793.
[391] Liu, Y.; Gribble, G. W., Tetrahedron Lett., (2002) 43, 7135.
[392] Gribble, G. W.; Saulnier, M. G., J. Org. Chem., (1983) 48, 607.
[393] Liu, Y.; Gribble, G. W., Tetrahedron Lett., (2001) 42, 2949.
[394] Herbert, J. M.; Maggiani, M., Synth. Commun., (2001) 31, 947.
[395] Moyer, M. P.; Shiurba, J. F.; Rapoport, H., J. Org. Chem., (1986) 51, 5106.
[396] Soll, R. M.; Humber, L. G.; Deininger, D.; Asselin, A. A.; Chau, T. T.; Weichman, B. M., J. Med.
Chem., (1986) 29, 1457.
[397] Yang, Y.; Martin, A. R.; Nelson, D. L.; Regan, J., Heterocycles, (1992) 34, 1169.
[398] Johnson, D. A.; Gribble, G. W., Heterocycles, (1986) 24, 2127.
[399] Gribble, G. W.; Johnson, D. A., Tetrahedron Lett., (1987) 28, 5259.
[400] Lipinska, T., Tetrahedron Lett., (2002) 43, 9565.
[401] Yokoyama, Y.; Uchida, M.; Murakami, Y., Heterocycles, (1989) 29, 1661.
[402] Romero, M.; Pujol, M. D., Synlett, (2003), 173.
[403] Matsuzono, M.; Fukuda, T.; Iwao, M., Tetrahedron Lett., (2001) 42, 7621.
[404] Fukuda, T.; Maeda, R.; Iwao, M., Tetrahedron, (1999) 55, 9151.
[405] Masters, N. F.; Mathews, N.; Nechvatal, G.; Widdowson, D. A., Tetrahedron, (1989) 45, 5955.
[406] Iwao, M., Heterocycles, (1993) 36, 29.
[407] Iwao, M.; Motoi, O., Tetrahedron Lett., (1995) 36, 5929.
[408] Iwao, M.; Ishibashi, F., Tetrahedron, (1997) 53, 51.
[409] Shinohara, H.; Fukuda, T.; Iwao, M., Tetrahedron, (1999) 55, 10989.
[410] Nettekoven, M.; Psiorz, M.; Waldmann, H., Tetrahedron Lett., (1995) 36, 1425.
[411] Chauder, B.; Larkin, A.; Snieckus, V., Org. Lett., (2002) 4, 815.
[412] PØrez-Serrano, L.; Casarrubios, L.; Domínguez, G.; Freire, G.; PØrez-Castells, J., Tetrahedron, (2002)
58, 5407.
[413] Griffen, E. J.; Roe, D. G.; Snieckus, V., J. Org. Chem., (1995) 60, 1484.
[414] Tois, J.; Koskinen, A., Tetrahedron Lett., (2003) 44, 2093.
[415] Kinsman, A. C.; Snieckus, V., Tetrahedron Lett., (1999) 40, 2453.
[416] Zoltewicz, J. A.; Grahe, G.; Smith, C. L., J. Am. Chem. Soc., (1969) 91, 5501.
[417] Verbeek, J.; Brandsma, L., J. Org. Chem., (1984) 49, 3857.
[418] Vorbrüggen, H., Adv. Heterocycl. Chem., (1990) 49, 117.
[419] Zoltewicz, J. A.; Helmick, L. S., J. Am. Chem. Soc., (1970) 92, 7547.
[420] Zoltewicz, J. A.; Kauffman, G. M., J. Org. Chem., (1969) 34, 1405.
[421] Gros, P.; Fort, Y.; Caub›re, P., J. Chem. Soc., Perkin Trans. 1, (1997), 3597.
[422] Cuperly, D.; Gros, P.; Fort, Y., J. Org. Chem., (2002) 67, 238.
[423] Gros, P.; Choppin, S.; Mathieu, J.; Fort, Y., J. Org. Chem., (2002) 67, 234.
[424] Gilman, H.; Spatz, S. M., J. Org. Chem., (1951) 16, 1485.
[425] Cai, D.; Larsen, R. D.; Reider, P. J., Tetrahedron Lett., (2002) 43, 4285.
[426] Sutherland, A.; Gallagher, T.; Sharples, C. G. V.; Wonnacott, S., J. Org. Chem., (2003) 68, 2475.
[427] Cottet, F.; Marull, M.; Lefebvre, O.; Schlosser, M., Eur. J. Org. Chem., (2003), 1559.
G. W. Gribble, Section 8.1.14, Science of Synthesis, 2006 Georg Thieme Verlag KG

422 Science of Synthesis 8.1 Lithium Compounds
b[428] Wang, X.; Rabbat, P.; O Shea, P.; Tillyer, R.; Grabowski, E. J. J.; Reider, P. J., Tetrahedron Lett., (2000)
41, 4335.
[429] Parry, P. R.; Wang, C.; Batsanov, A. S.; Bryce, M. R.; Tarbit, B., J. Org. Chem., (2002) 67, 7541.
[430] Cai, D.; Hughes, D. L.; Verhoeven, T. R., Tetrahedron Lett., (1996) 37, 2537.
[431] Baxter, P. N. W., J. Org. Chem., (2000) 65, 1257.
[432] Bouillon, A.; Lancelot, J.-C.; Collot, V.; Bovy, P. R.; Rault, S., Tetrahedron, (2002) 58, 4369.
[433] Bouillon, A.; Lancelot, J.-C.; Collot, V.; Bovy, P. R.; Rault, S., Tetrahedron, (2002) 58, 3323.
[434] Li, W.; Nelson, D. P.; Jensen, M. S.; Hoerrner, R. S.; Cai, D.; Larsen, R. D.; Reider, P. J., J. Org. Chem.,
(2002) 67, 5394.
[435] Bouillon, A.; Lancelot, J.-C.; Collot, V.; Bovy, P. R.; Rault, S., Tetrahedron, (2002) 58, 2885.
[436] Lützen, A.; Hapke, M., Eur. J. Org. Chem., (2002), 2292.
[437] Comins, D. L.; Baevsky, M. F.; Hong, H., J. Am. Chem. Soc., (1992) 114, 10 971.
[438] Comins, D. L.; Saha, J. K., Tetrahedron Lett., (1995) 36, 7995.
[439] Quallich, G. J.; Fox, D. E.; Friedmann, R. C.; Murtiashaw, C. W., J. Org. Chem., (1992) 57, 761.
[440] TrØcourt, F.; Mallet, M.; Mongin, O.; QuØguiner, G., J. Heterocycl. Chem., (1995) 32, 1117.
[441] TrØcourt, F.; Gervais, B.; Mallet, M.; QuØguiner, G., J. Org. Chem., (1996) 61, 1673.
[442] TrØcourt, F.; Gervais, B.; Mongin, O.; Le Gal, C.; Mongin, F.; QuØguiner, G., J. Org. Chem., (1998) 63,
2892.
[443] Numata, A.; Kondo, Y.; Sakamoto, T., Synthesis, (1999), 306.
[444] Yao, Y.; Lamba, J. J. S.; Tour, J. M., J. Am. Chem. Soc., (1998) 120, 2805.
[445] Schlosser, M.; Bobbio, C., Eur. J. Org. Chem., (2002), 4174.
[446] Benmansour, H.; Chambers, R. D.; Sandford, G.; McGowan, G.; Dahaoui, S.; Yufit, D. S.;
Howard, J. A. K., J. Fluorine Chem., (2001) 112, 349.
[447] Gu, Y. G.; Bayburt, E. K., Tetrahedron Lett., (1996) 37, 2565.
[448] Kondo, Y.; Asai, M.; Miura, T.; Uchiyama, M.; Sakamoto, T., Org. Lett., (2001) 3, 13.
[449] Gómez, I.; Alonso, E.; Ramón, D. J.; Yus, M., Tetrahedron, (2000) 56, 4043.
[450] Yus, M.; Ramón, D. J., J. Chem. Soc., Chem. Commun., (1991), 398.
[451] Alonso, E.; Guijarro, D.; Martínez, P.; Ramón, D. J.; Yus, M., Tetrahedron, (1999) 55, 11 027.
[452] Ramón, D. J.; Yus, M., Eur. J. Org. Chem., (2000), 225.
[453] Marsais, F.; QuØguiner, G., Tetrahedron, (1983) 39, 2009.
[454] Gribble, G. W.; Saulnier, M. G., Tetrahedron Lett., (1980) 21, 4137.
[455] Gribble, G. W.; Saulnier, M. G., Heterocycles, (1993) 35, 151.
[456] Güngör, T.; Marsais, F.; QuØguiner, G., J. Organomet. Chem., (1981) 215, 139.
[457] Marsais, F.; Breant, P.; Ginguene, A.; QuØguiner, G., J. Organomet. Chem., (1981) 216, 139.
[458] Lennox, J. R.; Turner, S. C.; Rapoport, H., J. Org. Chem., (2001) 66, 7078.
[459] Cho, S. Y.; Kim, S. S.; Park, K.-H.; Kang, S. K.; Choi, J.-K.; Hwang, K.-J.; Yum, E. K., Heterocycles,
(1996) 43, 1641.
[460] TrØcourt, F.; Marsais, F.; Güngör, T.; QuØguiner, G., J. Chem. Soc., Perkin Trans. 1, (1990), 2409.
[461] Beierle, J. M.; Osimboni, E. B.; Metallinos, C.; Zhao, Y.; Kelly, T. R., J. Org. Chem., (2003) 68, 4970.
[462] Estel, L.; Marsais, F.; QuØguiner, G., J. Org. Chem., (1988) 53, 2740.
[463] Miki, Y.; Tada, Y.; Matsushita, K., Heterocycles, (1998) 48, 1593.
[464] Bobbio, C.; Schlosser, M., Eur. J. Org. Chem., (2001), 4533.
[465] Karig, G.; Spencer, J. A.; Gallagher, T., Org. Lett., (2001) 3, 835.
[466] Karig, G.; Thasana, N.; Gallagher, T., Synlett, (2002), 808.
[467] Imahori, T.; Uchiyama, M.; Sakamoto, T.; Kondo, Y., Chem. Commun. (Cambridge), (2001), 2450.
[468] Mongin, F.; Tognini, A.; Cottet, F.; Schlosser, M., Tetrahedron Lett., (1998) 39, 1749.
[469] Connon, S. J.; Hegarty, A. F., J. Chem. Soc., Perkin Trans. 1, (2000), 1245.
[470] Corey, E. J.; Pyne, S. G.; Schafer, A. I., Tetrahedron Lett., (1983) 24, 3291.
[471] Turner, S. C.; Zhai, H.; Rapoport, H., J. Org. Chem., (2000) 65, 861.
[472] Mallet, M.; QuØguiner, G., Tetrahedron, (1979) 35, 1625.
[473] Mallet, M.; QuØguiner, G., Tetrahedron, (1985) 41, 3433.
[474] Mallet, M.; QuØguiner, G., Tetrahedron, (1986) 42, 2253.
[475] Rocca, P.; Cochennec, C.; Marsais, F.; Thomas-dit-Dumont, L.; Mallet, M.; Godard, A.;
QuØguiner, G., J. Org. Chem., (1993) 58, 7832.
[476] Cochennec, C.; Rocca, P.; Marsais, F.; Godard, A.; QuØguiner, G., Synthesis, (1995), 321.
[477] Godard, A.; Rocca, P.; Guillier, F.; Duvey, G.; Nivoliers, F.; Marsais, F.; QuØguiner, G., Can. J. Chem.,
(2001) 79, 1754.
[478] Comins, D. L.; Saha, J. K., J. Org. Chem., (1996) 61, 9623.
G. W. Gribble, Section 8.1.14, Science of Synthesis, 2006 Georg Thieme Verlag KG

References 423
b[479] Turner, J. A., J. Org. Chem., (1983) 48, 3401.
[480] Wright, S. W.; Petraitis, J. J.; Abelman, M. M.; Batt, D. G.; Bostrom, L. L.; Corbett, R. L.; Decicco, C. P.;
Di Meo, S. V.; Freimark, B.; Giannaras, J. V.; Green, A. M.; Jetter, J. W.; Nelson, D. J.; Orwat, M. J.;
Pinto, D. J.; Pratta, M. A.; Sherk, S. R.; Williams, J. M.; Magolda, R. L.; Arner, E. C., J. Med. Chem.,
(1994) 37, 3071.
[481] Katritzky, A. R.; Rahimi-Rastgoo, S.; Ponkshe, N. K., Synthesis, (1981), 127.
[482] Epsztajn, J.; Bieniek, A.; Plotka, M. W.; Suwald, K., Tetrahedron, (1989) 45, 7469.
[483] Epsztajn, J.; Józwiak, A.; Czech, K.; Szczesniak, A. K., Monatsh. Chem., (1990) 121, 909.
[484] Epsztajn, J.; Brzezinski, J. Z.; Czech, K., Monatsh. Chem., (1993) 124, 549.
[485] Epsztajn, J.; Bieniek, A.; Kowalska, J. A., Tetrahedron, (1991) 47, 1697.
[486] Epsztajn, J.; Plotka, M. W.; Grabowska, A., Synth. Commun., (1997) 27, 1075.
[487] Güngör, T.; Marsais, F.; QuØguiner, G., Synthesis, (1982), 499.
[488] Dunbar, P. G.; Martin, A. R., Heterocycles, (1987) 26, 3165.
[489] Iwao, M.; Kuraishi, T., Tetrahedron Lett., (1983) 24, 2649.
[490] Watanabe, M.; Shinoda, E.; Shimizu, Y.; Furukawa, S.; Iwao, M.; Kuraishi, T., Tetrahedron, (1987)
43, 5281.
[491] Kelly, T. A.; Patel, U. R., J. Org. Chem., (1995) 60, 1875.
[492] Kelly, T. R.; Echavarren, A.; Chandrakumar, N. S.; Köksal, Y., Tetrahedron Lett., (1984) 25, 2127.
[493] Smith, K.; Anderson, D.; Matthews, I., J. Org. Chem., (1996) 61, 662.
[494] Smith, K.; Lindsay, C. M.; Morris, I. K.; Matthews, I.; Pritchard, G. J., Sulfur Lett., (1994) 17, 197.
[495] Smith, K.; Anderson, D.; Matthews, I., Sulfur Lett., (1995) 18, 79.
[496] Miah, M. A. J.; Snieckus, V., J. Org. Chem., (1985) 50, 5436.
[497] Tsukazaki, M.; Snieckus, V., Heterocycles, (1993) 35, 689.
[498] Marsais, F.; Le Nard, G.; QuØguiner, G., Synthesis, (1982), 235.
[499] Tamura, Y.; Fujita, M.; Chen, L.-C.; Inoue, M.; Kita, Y., J. Org. Chem., (1981) 46, 3564.
[500] Comins, D. L.; LaMunyon, D. H., Tetrahedron Lett., (1988) 29, 773.
[501] Comins, D. L.; Hong, H.; Saha, J. K.; Jianhua, G., J. Org. Chem., (1994) 59, 5120.
[502] TrØcourt, F.; Mallet, M.; Mongin, O.; Gervais, B.; QuØguiner, G., Tetrahedron, (1993) 49, 8373.
[503] Meyers, A. I.; Gabel, R. A., Tetrahedron Lett., (1978), 227.
[504] Bisagni, E.; Rautureau, M., Synthesis, (1987), 142.
[505] Comins, D. L.; Killpack, M. O., J. Org. Chem., (1990) 55, 69.
[506] Marsais, F.; Cronnier, A.; TrØcourt, F.; QuØguiner, G., J. Org. Chem., (1987) 52, 1133.
[507] Alo, B. I.; Familoni, O. B.; Marsais, F.; QuØguiner, G., J. Heterocycl. Chem., (1992) 29, 61.
[508] Shibutani, T.; Fujihara, H.; Furukawa, N., Tetrahedron Lett., (1991) 32, 2947.
[509] Mongin, F.; TrØcourt, F.; QuØguiner, G., Tetrahedron Lett., (1999) 40, 5483.
[510] Lazaar, J.; Rebstock, A.-S.; Mongin, F.; Godard, A.; TrØcourt, F.; Marsais, F.; QuØguiner, G.,
Tetrahedron, (2002) 58, 6723.
[511] Epsztajn, J.; Józwiak, A.; Krysiak, J. K.; Lucka, D., Tetrahedron, (1996) 52, 11 025.
[512] Schlosser, M.; Marull, M., Eur. J. Org. Chem., (2003), 1569.
[513] Choppin, S.; Gros, P.; Fort, Y., Org. Lett., (2000) 2, 803.
[514] Gros, P.; Fort, Y.; Caub›re, P., J. Chem. Soc., Perkin Trans. 1, (1998), 1685.
[515] Choppin, S.; Gros, P.; Fort, Y., Eur. J. Org. Chem., (2001), 603.
[516] Gros, P.; Choppin, S.; Fort, Y., J. Org. Chem., (2003) 68, 2243.
[517] Mongin, O.; Rocca, P.; Thomas-dit-Dumont, L.; TrØcourt, F.; Marsais, F.; Godard, A.; QuØguiner, G.,
J. Chem. Soc., Perkin Trans. 1, (1995), 2503.
[518] Wada, K.; Mizutani, T.; Kitagawa, S., J. Org. Chem., (2003) 68, 5123.
[519] Narasimham, N. S.; Ammanamanchi, R. K., J. Chem. Soc., Chem. Commun., (1985), 1368.
[520] Marull, M.; Schlosser, M., Eur. J. Org. Chem., (2003), 1576.
[521] Marsais, F.; Bouley, E.; QuØguiner, G., J. Organomet. Chem., (1979) 171, 273.
[522] Shi, G.; Takagishi, S.; Schlosser, M., Tetrahedron, (1994) 50, 1129.
[523] Marsais, F.; Godard, A.; QuØguiner, G., J. Heterocycl. Chem., (1989) 26, 1589.
[524] PlØ, N.; Turck, A.; Couture, K.; QuØguiner, G., J. Org. Chem., (1995) 60, 3781.
[525] Turck, A.; Mojovic, L.; QuØguiner, G., Synthesis, (1988), 881.
[526] Mattson, R. J.; Sloan, C. P., J. Org. Chem., (1990) 55, 3410.
[527] Ward, J. S.; Merritt, L., J. Heterocycl. Chem., (1991) 28, 765.
[528] PlØ, N.; Turck, A.; Heynderickx, A.; QuØguiner, G., Tetrahedron, (1998) 54, 4899.
[529] PlØ, N.; Turck, A.; Heynderickx, A.; QuØguiner, G., Tetrahedron, (1998), 54, 9701.
[530] Liu, W.; Wise, D. S.; Townsend, L. B., J. Org. Chem., (2001) 66, 4783.
G. W. Gribble, Section 8.1.14, Science of Synthesis, 2006 Georg Thieme Verlag KG

424 Science of Synthesis 8.1 Lithium Compounds
b[531] LeprÞtre, A.; Turck, A.; PlØ, N.; QuØguiner, G., Tetrahedron, (2000) 56, 3709.
[532] Machado, H. J. S.; Hinchliffe, A., J. Mol. Struct. (Theochem), (1995) 339, 255.
[533] Wada, A.; Yamamoto, J.; Hamaoka, Y.; Ohki, K.; Nagai, S.; Kanatomo, S., J. Heterocycl. Chem.,
(1990) 27, 1831.
[534] Turck, A.; PlØ, N.; Mojovic, L.; QuØguiner, G., J. Heterocycl. Chem., (1990) 27, 1377.
[535] Radinov, R.; Chanev, C.; Haimova, M., J. Org. Chem., (1991) 56, 4793.
[536] PlØ, N.; Turck, A.; Heynderickx, A.; QuØguiner, G., J. Heterocycl. Chem., (1994) 31, 1311.
[537] PlØ, N.; Turck, A.; Heynderickx, A.; QuØguiner, G., J. Heterocycl. Chem., (1997) 34, 551.
[538] Pollet, P.; Turck, A.; PlØ, N.; QuØguiner, G., J. Org. Chem., (1999) 64, 4512.
[539] Sandosham, J.; Undheim, K., Tetrahedron, (1994) 50, 275.
[540] TrØcourt, F.; Turck, A.; PlØ, N.; Paris, A.; QuØguiner, G., J. Heterocycl. Chem., (1995) 32, 1057.
[541] Turck, A.; PlØ, N.; Tallon, V.; QuØguiner, G., J. Heterocycl. Chem., (1993) 30, 1491.
[542] Smith, K.; El-Hiti, G. A.; Abdel-Megeed, M. F.; Abdo, M. A., J. Org. Chem., (1996) 61, 647.
[543] Turck, A.; PlØ, N.; Tallon, V.; QuØguiner, G., Tetrahedron, (1995) 51, 13045.
[544] Nfflnez-Polo, P. P.; Neunhoeffer, H., Heterocycl. Commun., (1998) 4, 301.
[545] PlØ, N.; Turck, A.; QuØguiner, G.; Glassl, B.; Neunhoeffer, H., Liebigs Ann. Chem., (1993), 583.
[546] Glassl, B.; Sinks, U.; Neunhoeffer, H., Heterocycl. Commun., (1996) 2, 513.
[547] Vitse, O.; Bompart, J.; Subra, G.; Viols, H.; Escale, R.; Chapat, J. P.; Bonnet, P. A., Tetrahedron,
(1998) 54, 6485.
[548] Sugimoto, O.; Sudo, M.; Tanji, K., Tetrahedron Lett., (1999) 40, 2139.
[549] Sugimoto, O.; Sudo, M.; Tanji, K., Tetrahedron, (2001) 57, 2133.
[550] Uhlmann, P.; Felding, J.; Vedsø, P.; Begtrup, M., J. Org. Chem., (1997) 62, 9177.
[551] Bookser, B. C., Tetrahedron Lett., (2000) 41, 2805.
[552] Dudfield, P. J.; Ekwuru, C. T.; Hamilton, K.; Osbourn, C. E.; Simpson, D. J., Synlett, (1990), 277.
[553] Li, S. K. Y.; Knight, D. W.; Little, P. B., Tetrahedron Lett., (1996) 37, 5615.
[554] Knight, D. W.; Little, P. B., J. Chem. Soc., Perkin Trans. 1, (2000), 2343.
[555] Tye, H.; Eldred, C.; Wills, M., Synlett, (1995), 770.
[556] Kemp, D. S.; Galakatos, N. G., J. Org. Chem., (1986) 51, 1821.
[557] Jean, F.; Melnyk, O.; Tartar, A., Tetrahedron Lett., (1995) 36, 7657.
[558] Sargent, M. V.; Stransky, P. O., Adv. Heterocycl. Chem., (1984) 35,1.
[559] Deady, L. W.; Sette, R. M. D., Aust. J. Chem., (2001) 54, 177.
[560] Gilman, H.; Jacoby, A. L., J. Org. Chem., (1938) 3, 108.
[561] Katritzky, A. R.; Perumal, S., J. Heterocycl. Chem., (1990) 27, 1737.
[562] Hallberg, A.; Martin, A. R., J. Heterocycl. Chem., (1984) 21, 837.
[563] Katritzky, A. R.; Rewcastle, G. W.; Vazquez de Miguel, L. M., J. Org. Chem., (1988) 53, 794.
[564] Palmer, B. D.; Boyd, M.; Denny, W. A., J. Org. Chem., (1990) 55, 438.
[565] Lee, H. H.; Palmer, B. D.; Boyd, M.; Baguley, B. C.; Denny, W. A., J. Med. Chem., (1992) 35, 258.
[566] Lovell, J. M.; Joule, J. A., J. Chem. Soc., Perkin Trans. 1, (1996), 2391.
[567] Gilman, H.; Stuckwisch, C. G., J. Am. Chem. Soc., (1943) 65, 1461.
[568] Yus, M.; Foubelo, F.; Ferrµndez, J. V., Tetrahedron, (2003) 59, 2083.
[569] Gilman, H.; Shirley, D. A.; Van Ess, P. R., J. Am. Chem. Soc., (1944) 66, 625.
[570] Hallberg, A.; Martin, A., J. Heterocycl. Chem., (1982) 19, 433.
[571] Ebdrup, S.; Jensen, M. S.; Vedsø, P., J. Chem. Soc., Perkin Trans. 1, (1998), 351.
[572] Sailer, M.; Gropeanu, R.-A.; Müller, T. J. J., J. Org. Chem., (2003) 68, 7509.
[573] Dahlgren, T.; Hallberg, A.; Helitzer, R.; Martin, A. R., J. Heterocycl. Chem., (1983) 20, 341.
[574] Hallberg, A.; Al-Showaier, I.; Martin, A. R., J. Heterocycl. Chem., (1984) 21, 197.
[575] Mehta, A.; Dodd, R. H., J. Org. Chem., (1993) 58, 7587.
[576] Batch, A.; Dodd, R. H., J. Org. Chem., (1998) 63, 872.
[577] Hart, H.; Teuerstein, A., Synthesis, (1979), 693.
[578] Gribble, G. W.; Allen, R. W.; LeHoullier, C. S.; Eaton, J. T.; Easton, N. R., Jr.; Slayton, R. I.;
Sibi, M. P., J. Org. Chem., (1981) 46, 1025.
[579] Fitzgerald, J. J.; Drysdale, N. E.; Olofson, R. A., J. Org. Chem., (1992) 57, 7122.
[580] Hart, H.; Shamouilian, S., J. Org. Chem., (1981) 46, 4874.
[581] LeHoullier, C. S.; Gribble, G. W., J. Org. Chem., (1983) 48, 2364.
[582] LeHoullier, C. S.; Gribble, G. W., J. Org. Chem., (1983) 48, 1682.
[583] Gribble, G. W.; LeHoullier, C. S.; Sibi, M. P.; Allen, R. W., J. Org. Chem., (1985) 50, 1611.
[584] Hart, H.; Shamouilian, S.; Takehira, Y., J. Org. Chem., (1981) 46, 4427.
[585] Caster, K. C.; Keck, C. G.; Walls, R. D., J. Org. Chem., (2001) 66, 2932.
G. W. Gribble, Section 8.1.14, Science of Synthesis, 2006 Georg Thieme Verlag KG

References 425
b[586] Tripathy, S.; LeBlanc, R.; Durst, T., Org. Lett., (1999) 1, 1973.
[587] Snieckus, V.; Beaulieu, F.; Mohri, K.; Han, W.; Murphy, C. K.; Davis, F. A., Tetrahedron Lett., (1994)
35, 3465.
[588] Davis, F. A.; Han, W.; Murphy, C. K., J. Org. Chem., (1995) 60, 4730.
[589] Blackmore, I. J.; Boa, A. N.; Murray, E. J.; Dennis, M.; Woodward, S., Tetrahedron Lett., (1999) 40,
6671.
[590] Harrowven, D. C.; Nunn, M. I. T.; Fenwick, D. R., Tetrahedron Lett., (2001) 42, 7501.
[591] Reed, J. N.; Snieckus, V., Tetrahedron Lett., (1983) 24, 3795.
[592] Mori, S.; Ohno, T.; Harada, H.; Aoyama, T.; Shioiri, T., Tetrahedron, (1991) 47, 5051.
[593] Tani, K.; Lukin, K.; Eaton, P. E., J. Am. Chem. Soc., (1997) 119, 1476.
[594] Stagliano, K. W.; Malinakova, H. C.; Takayama, A., Synth. Commun., (1997) 27, 2413.
[595] Hoffmann, R. W.; Ditrich, K., Synthesis, (1983), 107.
[596] Taddei, M.; Ricci, A., Synthesis, (1986), 633.
[597] Coleman, R. S.; Mortensen, M. A., Tetrahedron Lett., (2003) 44, 1215.
[598] Sato, N.; Yue, Q., Tetrahedron, (2003) 59, 5831.
[599] Jeganathan, S.; Tsukamoto, M.; Schlosser, M., Synthesis, (1990), 109.
[600] Sibi, M. P.; Miah, M. A. J.; Snieckus, V., J. Org. Chem., (1984) 49, 737.
[601] Rot, N.; Bickelhaupt, F., Organometallics, (1997) 16, 5027.
[602] Shi, Y.-J.; Wells, K. M.; Pye, P. J.; Choi, W.-B.; Churchill, H. R. O.; Lynch, J. E.; Maliakal, A.;
Sager, J. W.; Rossen, K.; Volante, R. P.; Reider, P. J., Tetrahedron, (1999) 55, 909.
[603] Casas, R.; CavØ, C.; d Angelo, J., Tetrahedron Lett., (1995) 36, 1039.
[604] Klement, I.; Stadtmüller, H.; Knochel, P.; Cahiez, G., Tetrahedron Lett., (1997) 38, 1927.
[605] Koch, K.; Chambers, R. J.; Biggers, M. S., Synlett, (1994), 347.
[606] Evans, P. A.; Nelson, J. D.; Stanley, A. L., J. Org. Chem., (1995) 60, 2298.
[607] Hirao, T.; Takada, T.; Ogawa, A., J. Org. Chem., (2000) 65, 1511.
[608] Seitz, D. E.; Tonnesen, G. L.; Hellman, S.; Hanson, R. N.; Adelstein, S. J., J. Organomet. Chem., (1980)
186, C33.
[609] Chen, G. J.; Tamborski, C., J. Organomet. Chem., (1983) 251, 149.
[610] de Boer, H. J. R.; Akkerman, O. S.; Bickelhaupt, F., Organometallics, (1990) 9, 2898.
[611] Sharp, M. J.; Snieckus, V., Tetrahedron Lett., (1985) 26, 5997.
[612] Alo, B. I.; Kandil, A.; Patil, P. A.; Sharp, M. J.; Siddiqui, M. A.; Snieckus, V.; Josephy, P. D., J. Org.
Chem., (1991) 56, 3763.
[613] Mohri, S.; Stefinovic, M.; Snieckus, V., J. Org. Chem., (1997) 62, 7072.
[614] Wang, W.; Snieckus, V., J. Org. Chem., (1992) 57, 424.
[615] Fu, J.; Snieckus, V., Can. J. Chem., (2000) 78, 905.
[616] Patil, P. A.; Snieckus, V., Tetrahedron Lett., (1998) 39, 1325.
[617] Kalinin, A. V.; Snieckus, V., Tetrahedron Lett., (1998) 39, 4999.
[618] Goldfinger, M. B.; Crawford, K. B.; Swager, T. M., J. Org. Chem., (1998) 63, 1676.
[619] Lamba, J. J. S.; Tour, J. M., J. Am. Chem. Soc., (1994) 116, 11723.
[620] Hensel, V.; Schlüter, A. D., Eur. J. Org. Chem., (1999), 451.
[621] Starling, S. M.; Raslan, D. S.; de Oliveira, A. B., Synth. Commun., (1998) 28, 1013.
[622] Epsztajn, J.; Bieniek, A.; Kowalska, J. A.; Kulikiewicz, K. K., Synthesis, (2000), 1603.
[623] Garibay, P.; Vedsø, P.; Begtrup, M.; Hoeg-Jensen, T., J. Comb. Chem., (2001) 3, 332.
[624] Luteijn, J. M.; Spronck, H. J. W., J. Chem. Soc., Perkin Trans. 1, (1979), 201.
[625] Johnson, F.; Subramanian, R., J. Org. Chem., (1986) 51, 5040.
[626] Boehm, T. L.; Showalter, H. D. H., J. Org. Chem., (1996) 61, 6498.
[627] Le Strat, F.; Maddaluno, J., Org. Lett., (2002) 4, 2791.
[628] Marburg, S.; Tolman, R. L., J. Heterocycl. Chem., (1980) 17, 1333.
[629] Smith, K.; El-Hiti, G. A.; Hawes, A. C., Synlett, (1999), 945.
[630] Smith, K.; Pritchard, G. J., Angew. Chem., (1990) 102, 298; Angew. Chem. Int. Ed. Engl., (1990) 29,
282.
[631] Bridges, A. J.; Lee, A.; Maduakor, E. C.; Schwartz, C. E., Tetrahedron Lett., (1992) 33, 7499.
[632] Stanetty, P.; Krumpak, B., J. Org. Chem., (1996) 61, 5130.
[633] Stanetty, P.; Krumpak, B.; Emerschitz, T.; Mereiter, K., Tetrahedron, (1997) 53, 3615.
[634] Hermann, C. K. F.; Campbell, J. A.; Greenwood, T. D.; Lewis, J. A.; Wolfe, J. F., J. Org. Chem., (1992)
57, 5328.
[635] Wright, S. W., J. Heterocycl. Chem., (2001) 38, 723.
[636] Kraus, G. A.; Pezzanite, J. O., J. Org. Chem., (1979) 44, 2480.
G. W. Gribble, Section 8.1.14, Science of Synthesis, 2006 Georg Thieme Verlag KG

426 Science of Synthesis 8.1 Lithium Compounds
b[637] Harvey, R. G.; Cortez, C.; Ananthanarayan, T. P.; Schmolka, S., J. Org. Chem., (1988) 53, 3936.
[638] Talley, J. J., Synthesis, (1983), 845.
[639] Bieniek, A.; Epsztajn, J.; Kowalska, J. A.; Malinowski, Z., Tetrahedron Lett., (2001) 42, 9293.
[640] Cho, I.-S.; Gong, L.; Muchowski, J. M., J. Org. Chem., (1991) 56, 7288.
[641] Fisher, L. E.; Muchowski, J. M.; Clark, R. D., J. Org. Chem., (1992) 57, 2700.
[642] Kiselyov, A. S., Tetrahedron Lett., (1995) 36, 493.
[643] Iwao, M., J. Org. Chem., (1990) 55, 3622.
[644] MacNeil, S. L.; Gray, M.; Briggs, L. E.; Li, J. J.; Snieckus, V., Synlett, (1998), 419.
[645] Wang, X.; Snieckus, V., Synlett, (1990), 313.
[646] Beaulieu, F.; Snieckus, V., J. Org. Chem., (1994) 59, 6508.
[647] Lane, C.; Snieckus, V., Synlett, (2000), 1294.
[648] Katritzky, A. R.; Nair, S. K.; Rodriguez-Garcia, V.; Xu, Y.-J., J. Org. Chem., (2002) 67, 8237.
[649] Barrett, E. S.; Irwin, J. L.; Turner, P.; Sherburn, M. S., Org. Lett., (2002) 4, 1455.
[650] de Silva, S. O.; Watanabe, M.; Snieckus, V., J. Org. Chem., (1979) 44, 4802.
[651] de Silva, S. O.; Ahmad, I.; Snieckus, V., Tetrahedron Lett., (1978), 5107.
[652] Iwao, M.; Mahalanabis, K. K.; Watanabe, M.; de Silva, S. O.; Snieckus, V., Tetrahedron, (1983) 39,
1955.
[653] Trost, B. M.; Rivers, G. T.; Gold, J. M., J. Org. Chem., (1980) 45, 1835.
[654] Keay, B. A.; Rodrigo, R., J. Am. Chem. Soc., (1982) 104, 4725.
[655] Watanabe, M.; Maenosono, H.; Furukawa, S., Chem. Pharm. Bull., (1983) 31, 2662.
[656] Morrow, G. W.; Swenton, J. S.; Filppi, J. A.; Wolgemuth, R. L., J. Org. Chem., (1987) 52, 713.
[657] Tius, M. A.; Gomez-Galeno, J.; Gu, X.; Zaidi, J. H., J. Am. Chem. Soc., (1991) 113, 5775.
[658] Jew, S.; Lim, D.; Bae, S.; Kim, H.; Kim, J.; Lee, J.; Park, H., Tetrahedron: Asymmetry, (2002) 13, 715.
[659] Familoni, O. B.; Ionica, I.; Bower, J. F.; Snieckus, V., Synlett, (1997), 1081.
[660] Meyers, A. I.; Willemsen, J. J., Tetrahedron, (1998) 54, 10493.
[661] Harrowven, D. C.; Hannam, J. C., Tetrahedron Lett., (1998) 39, 9573.
[662] Reitz, D. B.; Massey, S. M., J. Org. Chem., (1990) 55, 1375.
[663] Stefinovic, M.; Snieckus, V., J. Org. Chem., (1998) 63, 2808.
[664] Corey, E. J.; Das, J., J. Am. Chem. Soc., (1982) 104, 5551.
[665] Soll, R. M.; Guinosso, C.; Asselin, A., J. Org. Chem., (1988) 53, 2844.
[666] Seitz, D. E.; Blaszczak, L. C., Synth. Commun., (1988) 18, 2353.
[667] Coburn, C. A.; Young, M. B.; Hungate, R. W.; Isaacs, R. C. A.; Vacca, J. P.; Huff, J. R., Bioorg. Med.
Chem. Lett., (1996) 6, 1937.
[668] Lau, S. Y. W.; Keay, B. A., Can. J. Chem., (2001) 79, 1541.
[669] Kraus, G. A.; Kim, J., J. Org. Chem., (2002) 67, 2358.
[670] Kress, T. H.; Leanna, M. R., Synthesis, (1988), 803.
[671] Saednya, A.; Hart, H., Synthesis, (1996), 1455.
G. W. Gribble, Section 8.1.14, Science of Synthesis, 2006 Georg Thieme Verlag KG