Silyl Ethers - Thieme Chemistry

4.4.17 Product Subclass 17: 

Silyl Ethers 

J. D. White and R. G. Carter 

General Introduction 

FOR PERSONAL USE ONLY 

A useful feature of silyl ethers is that they greatly increase the volatility of an otherwise 

nonvolatile polyol. A highly polar and intractable oligosaccharide, for example, can be 

rendered amenable to gas chromatography and mass spectrometry through exhaustive 

silylation of its free hydroxy groups. However, the most frequent use made of silyl ethers 

is for the protection of alcohols. [1,2] Virtually any primary, secondary, or tertiary alcohol 

can be converted into a silyl ether, and there is usually the option of differential protection 

of polyhydroxylic structures with an appropriate choice of silylating agent. [3] By far 

the most general method for preparation of a silyl ether is through the reaction of an alcohol 

with a silylating agent that bears a leaving group. Chlorosilanes and silyl triflates 

are the most common reagents for this purpose, and are typically used in the presence 

of a base. The nature of this base can significantly affect the reactivity of the silylating 

agent. 

The ability to modulate the reactivity of the silylating agent through variation of the 

substituents on silicon contributes much versatility to the synthesis of silyl ethers. It is 

also an important factor in the selective cleavage of silyl ethers (deprotection). Both steric 

and electronic properties of the substituents at silicon play a role in the formation of silyl 

ethers and are especially important when considering the stability of a silyl ether toward 

acids and bases. For some of the most commonly used silyl ethers, the stability toward 

acid increases in the order trimethylsilyl (TMS, 1) < triethylsilyl (TES, 64) < tert-butyldimethylsilyl 

(TBDMS, 2 ” 10 4 ) < triisopropylsilyl (TIPS, 7 ” 10 5 )

ly common with tert-butyldimethylsilyl ethers, [9] but less so with triisopropylsilyl and tertbutyldiphenylsilyl 

ethers. Silyl migration of this type is most frequently seen where oxygens 

bear a 1,2-relationship [10] or a 1,3-relationship, [11] although more distant migrations 

are known. This aspect of silyl ether chemistry has sometimes presented problems in 

complex syntheses where a specific hydroxy protection is desired. It can pose severe difficulties 

for researchers in the fields of carbohydrate [12] and ribooligonucleotide [13] synthesis 

where unwanted silyl migrations often occur quite readily. 

Silyl migration between carbon and oxygen has long been recognized as an important 

feature of silicon chemistry; in fact, the rearrangement can be used as a preparative 

method for silyl ethers. [14] The transfer of a silyl group from carbon to oxygen was first described 

in the context of a [1,2]shift by Brook, [15] for whom the rearrangement is named. It 

was subsequently found that migration can occur between nonadjacent atoms, leading to 

[1,n]-Brook rearrangements where n £5. [16] It has been shown that silicon retains its configuration 

in the course of a Brook rearrangement. [17] The rearrangement requires the 

presence of a strong base and is synthetically most useful when the carbanion resulting 

from silyl migration is stabilized. [18] 

The reverse migration of silyl groups from oxygen to carbon (retro-Brook rearrangement) 

was discovered by West, initially as a [1,3]shift [19] and later as a [1,2]migration. [20] 

Longer range retro-Brook rearrangements have also been noted. [21] These reactions take 

place when silyl ethers are exposed to a strong base, such as an alkyllithium, which may 

be used to effect halogen±metal or metal±metal exchange. Silyl migration to the resultant 

carbanion is driven by the formation of a more stable alkoxide species. 

4.4.17.1 Trimethylsilyl Ethers 

As the least stable of the family of silyl ethers, trimethylsilyl (TMS) ethers have found only 

limited utility as protecting groups in complex synthesis. Their sensitivity toward mild 

acids (e.g., acetic acid) and bases (potassium carbonate in methanol) makes their survival 

through multistep operations in a synthetic sequence problematic. Even chromatography 

on silica gel can suffice to cleave a trimethylsilyl ether. The most frequent use made of 

trimethylsilyl ethers is to mask polar functional groups, primarily hydroxy and carboxy 

groups, for the purpose of increasing the volatility of an otherwise nonvolatile compound. 

Since trimethylsilyl ethers are thermally quite stable, the resultant (poly)silyl 

ether can be subjected to gas chromatography and mass spectrometry without fear of decomposition. 

This technique has been widely applied in the carbohydrate area where exhaustive 

silylation, for example with N-(trimethylsilyl)acetamide, leads to a persilylated 

sugar. [22] 

Formation 


372 Science of Synthesis 4.4 Silicon Compounds 

4.4.17.1.1 Method 1: 

Silylation ofAlcohols with Chlorotrimethylsilane 

A variety of silylating agents is available for the preparation of trimethylsilyl ethers, but 

chlorotrimethylsilane (TMSCl) is perhaps the most frequently employed. It is used in the 

presence of a base, typically imidazole or triethylamine, which removes hydrogen chloride 

formed during the silylation. There is very little difference in the rate of silylation 

of primary, secondary, and tertiary alcohols with this reagent, and selectivity in protection 

of alcohols is not usually possible. A typical silylation with chlorotrimethylsilane is 

that of alcohol 1 to give silyl ether 2 (Scheme 1); it is noteworthy that the terminal alkyne 

of 1 does not undergo silylation under these conditions. [23] 

White, J. D.; Carter, R. G., SOS, (2002) 4, 371. 2002 Georg Thieme Verlag KG

Scheme 1 Silylation with Chlorotrimethylsilane [23] 

H OH 

1 

OPMB 

TMSCl, imidazole 

CH2Cl2, rt, 10 h 

95% 

H OTMS 

2 

OPMB 

(4S,5R)-6-(4-Methoxybenzyloxy)-5-methyl-4-(trimethylsiloxy)hex-1-yne (2): [23] 

TMSCl (747 ìL, 5.92 mmol) followed by imidazole (619 mg, 9.10 mmol) were added to a 

stirred soln of alcohol 1 (1.129 g, 4.55 mmol) in CH 2Cl 2 (50 mL) at rt under N 2. A white precipitate 

formed immediately. The mixture was stirred for 10 h and was then diluted with 

EtOAc (100 mL). The organic phase, after washing with H 2O (15 mL) and sat. aq NaCl 

(15 mL), was dried (Na 2SO 4), filtered, and concentrated. Column chromatography (silica 

gel, hexanes/EtOAc 7:1) of the residue gave 2 as a clear, colorless oil; yield: 1.384 g (95%). 

4.4.17.1.2 Method 2: 

Silylation ofAlcohols with Trimethylsilyl Trifluoromethanesulfonate 

Trimethylsilyl trifluoromethanesulfonate (trimethylsilyl triflate, TMSOTf), a powerful silylating 

agent, [24] has gained popularity among synthetic chemists since it became readily 

available from commercial sources. Despite the highly electrophilic character of this reagent, 

it is remarkably tolerant of other functionalities providing it is used in the presence 

of a base such as a tertiary amine. All alcohols, regardless of their steric environment, 

are usually silylated with this reagent, an example being conversion of the ciguatoxin 

precursor 3 into its trimethylsilyl ether 4 (Scheme 2). [25] 

Scheme 2 Silylation with Trimethylsilyl Trifluoromethanesulfonate [25] 

I 

HO 

H H 

O 

BnO 

O 

H H 

3 


4.4.17 Silyl Ethers 373 

OTBDMS 

OTBDPS 

TMSOTf, Et3N 

CH2Cl2, −10 

98% 

oC I 

TMSO 

H H 

O 

BnO 

O 

H H 

4 

OTBDMS 

OTBDPS 

(1R,3S,4R,5S,6S,8R,9S)-5-Benzyloxy-9-(tert-butyldimethylsiloxy)-8-[2-(tert-butyldiphenylsiloxy)ethyl]-3-(2-iodoethyl)-4-(trimethylsiloxy)-2,7-dioxabicyclo[4.4.0]decane 

(4): [25] 

To a soln of alcohol 3 (68.4 mg, 82.3 ìmol) and Et 3N (45.9 ìL, 329 ìmol) in CH 2Cl 2 was 

added dropwise TMSOTf (31.8 ìL, 165 ìmol) at ±108C, and the mixture was stirred at that 

temperature for 10 min. The reaction was quenched with sat. aq NaHCO 3, and the aqueous 

layer was extracted repeatedly with Et 2O. The combined organic layers were washed 

with brine, dried (MgSO 4), filtered, and concentrated in vacuo. The residue was purified 

by column chromatography (silica gel, hexane/EtOAc 15:1) to afford 4 as a pale yellow 

oil; yield: 72.8 mg (98%). 

4.4.17.1.3 Method 3: 

Silylation ofAlcohols with Trimethylsilyl Cyanide 

CAUTION: All silyl cyanides should be treated as highly toxic in their own right, and are capable 

of generating hydrogen cyanide if exposed to water or moisture. Many silyl cyanide derivatives 

are also volatile. All reactions involving the preparation or use of these compounds should be carried 

out by appropriately trained personnel in a well-ventilated fume hood and in full compliance 

with all local safety regulations regarding the use of cyanides. 

for references see p 410 


Trimethylsilyl cyanide (TMSCN) is a reagent used for silylation where the presence of a 

base must be avoided. [26] Since the byproduct, hydrogen cyanide, is volatile and not sufficiently 

acidic to be deleterious, silylation can be carried out with the neat reagent or in a 

neutral solution. The reagent rapidly silylates alcohols, phenols and carboxylic acids, but 

reacts only slowly with amines and thiols. Amides are not silylated with this reagent. An 

example illustrating the application of this reagent is the conversion of the sensitive 

calicheamicinone precursor 5 into its trimethylsilyl ether 7 via the tris(silyl ether) 6 

(Scheme 3). [27] It is noteworthy that only the primary trimethylsilyl ether of intermediate 

6 is cleaved during workup in the presence of aqueous acetic acid. 

Scheme 3 Silylation with Trimethylsilyl Cyanide [27] 

TESO 

NHCO2Me 

OH 



OBoc OBoc 

Me 3SiCN 

TESO 

HO TMSO 

5 6 

AcOH, H2O, THF 

99% 

NHCO2Me 

OTMS 

TESO 

HO 

OBoc 

7 

NHCO2Me 

OTMS 

Methyl 11-(tert-Butoxycarbonyloxy)-13-(2-hydroxyethylidene)-1-(triethylsiloxy)-8á- 

(trimethylsiloxy)bicyclo[7.3.1]trideca-4,9,11-triene-2,6-diyn-10-ylcarbamate (7): [27] 

A soln of 5 (465 mg, 0.85 mmol) in TMSCN (1 mL) was stirred for 30 min and the volatiles 

were evaporated in vacuo. The residue was dissolved in a mixture of THF (50 mL), H 2O 

(10 mL), and glacial AcOH (1 mL). The mixture was stirred for 30 min (with close monitoring 

by TLC, Et 2O/petroleum ether 1:1), diluted with Et 2O (150 mL), washed with sat. aq 

NaHCO 3 (2 ” 50 mL), dried (MgSO 4), filtered, and evaporated in vacuo to give 7 as a pale 

yellow, solid foam; yield: 518 mg (99%). 

4.4.17.1.4 Method 4: 

Silylation ofAlcohols with N,O-Bis(trimethylsilyl)acetamide 

N,O-Bis(trimethylsilyl)acetamide (BSA) is a relatively unselective reagent that can convert 

hindered alcohols into their trimethylsilyl ethers when used in dimethylformamide at elevated 

temperature (80±1008C). [28] The byproduct acetamide must be removed, often requiring 

chromatography for purification of the silyl ether. The related reagent N,O-bis(trimethylsilyl)trifluoroacetamide, 

[29] although used less frequently, has the advantage that 

the byproduct, trifluoroacetamide, is removed more easily since it is quite volatile. An application 

of N,O-bis(trimethylsilyl)acetamide is seen in the conversion of the alcohol 8 

into its trimethylsilyl ether 9 (Scheme 4), an intermediate in a synthetic route to azinomycin. 

[30] 


Scheme 4 Silylation with N,O-Bis(trimethylsilyl)acetamide [30] 

AcHN 

AcO 

CO2Me 

Br 

HO NCbz 

8 

BSA, THF, 90 oC, 1 h 

92% 

AcHN 

AcO 

CO2Me 

Br 

TMSO NCbz 

Methyl (2E,4S,5R)-4-Acetoxy-2-(acetylamino)-5-[(2S)-1-(benzyloxycarbonyl)aziridin-2-yl]-3bromo-5-(trimethylsiloxy)pent-2-enoate 

(9): [30] 

A soln of 8 (52 mg, 0.104 mmol) in THF (0.1 mL) was treated with BSA (15.2 ìL, 

0.062 mmol, 1.2 equiv), and the mixture was warmed at 908C for 1 h. The reaction was 

cooled to 258C, diluted with EtOAc (25 mL), washed with sat. NaCl soln (2 ” 2 mL), and 

the organic layer was dried (MgSO 4) and concentrated in vacuo. The residue was purified 

by Sephadex LH-20 chromatography to afford 9; yield: 54.5 mg (92%). 

Cleavage 

4.4.17.1.5 Method 5: 

Cleavage ofTrimethylsilyl Ethers with Acidic Reagents 

Trimethylsilyl ethers are cleaved with exceptional ease under acidic conditions. Thus, it is 

quite feasible to unmask an alcohol protected as its trimethylsilyl ether without affecting 

other protected hydroxy functions; this includes alcohols protected in the form of virtually 

any other silyl ether. One acidic reagent that can be used to selectively cleave a trimethylsilyl 

ether is pyridinium 4-toluenesulfonate in methanol, as seen in the transformation 

of the sarcodictycine intermediate 10 to the alcohol 11 (Scheme 5). [31] Neither the triisopropylsilyl 

ether nor the 4-methoxybenzyl ether of 10 is removed under these conditions. 

Scheme 5 Selective Cleavage of a Trimethylsilyl Ether [31] 

PMBO 

H 

H 

10 

O 

OTIPS 

OTMS 

PPTS, MeOH 

rt, 30 min 

94% 

9 

PMBO 

H 

H 

11 

OH 

O 

OTIPS 

Dilute hydrochloric acid can also be used to cleave trimethylsilyl ethers, although other 

silyl ethers such as triethylsilyl and tert-butyldimethylsilyl are vulnerable under these 

conditions. An example illustrating the facile cleavage of a trimethylsilyl ether in the 

presence of an epoxide is the deprotection of 12 to give epoxy alcohol 13 (Scheme 6). [32] 

Scheme 6 Cleavage of a Trimethylsilyl Ether with Hydrochloric Acid [32] 

OH 

O 

O 

H 

H 

H 

OTMS 

( + 

−)-12 

O 



SiMe2Ph 

HCl, MeOH, CH2Cl2 0 oC, 30 min 

90% 

OH 

O 

O 

H 

H 

OH 

H 

( + 

−)-13 

O 

SiMe2Ph 



(1R,7S,8S,10R,14R)-7-Hydroxy-14-isopropyl-8-(4-methoxybenzyloxy)-7,11-dimethyl-3- 

(triisopropylsiloxymethyl)bicyclo[8.4.0]tetradeca-2,11-dien-5-yn-4-one (11): [31] 

To a soln of 10 (3.2 mg, 4.7 ìmol) in MeOH (1 mL) was added, at 258C, PPTS (1.18 mg, 

4.7 ìmol), and the mixture was allowed to stir at rt for 30 min. The reaction was quenched 

by the addition of sat. NaHCO 3 soln (1 mL), then extracted with Et 2O (2 ” 10 mL). The combined 

organic extracts were dried (Na 2SO 4) and concentrated. The crude product was purified 

by flash chromatography (silica gel, EtOAc/hexane 15:85) to provide alcohol 11 as a 

colorless oil; yield: 2.7 mg (94%). 

rac-(3R,4aS,5R,6S,6aS,12aS,12bR)-3-[Dimethyl(phenyl)silyl]-4a,5-epoxy-6,8-dihydroxy-3methyl-1,2,3,4,4a,5,6,6a,12a,12b-decahydrobenzo[a]anthracene-7,12-dione 

(13): [32] 

One drop of 1 M HCl was added to a soln of 12 (200 mg, 0.375 mmol) in MeOH (4 mL) and 

CH 2Cl 2 (2 mL) at 08C. The mixture was stirred for ca. 0.5 h at 08C and then extracted with 

CH 2Cl 2 (50 mL). The organic phase was washed with ice-cold H 2O (2 ” 20 mL), dried 

(Na 2SO 4), and the solvent was removed under reduced pressure to afford epoxy alcohol 

13 as an unstable, yellow oil containing some (5%) aromatization product; yield: 156 mg 

(90%). 

4.4.17.1.6 Method 6: 

Cleavage ofTrimethylsilyl Ethers under Basic Conditions 

One of the mildest methods for cleaving a trimethylsilyl ether is through its exposure to 

potassium carbonate in methanol, conditions which will not effect cleavage of any other 

silyl ether. The selective deprotection of the ciguatoxin precursor 14 bearing three different 

silyl ethers, as well as a benzyl ether and an epoxide, exemplifies an application of 

this method (Scheme 7). [33] 

Scheme 7 Selective Cleavage of a Trimethylsilyl Ether with Base [33] 

O 

O 

TMSO 

O 



H H 

O 

O OTBDPS 

H H 

BnO 

14 

OTBDMS 

O 

O 

O 

K2CO3, MeOH 

0 oC, 1.5 h 

96% 

H H 

O 

HO O OTBDPS 

H H 

BnO 

15 

OTBDMS 

The most widely used method for cleaving silyl ethers is through the use of tetrabutylammonium 

fluoride in tetrahydrofuran. This reagent can be used for cleaving trimethylsilyl 

ethers, but is not selective with respect to silyl ethers in general. Tetrabutylammonium 

fluoride is a sufficiently basic reagent to cause elimination and other side reactions with 

base-sensitive compounds, and it will sometimes promote migration of a silyl group to a 

neighboring free hydroxy group; however, esters are not usually cleaved with this reagent, 

as deprotection of the benzoate 16 reveals (Scheme 8). [34] 


Scheme 8 Cleavage of a Trimethylsilyl Ether with Tetrabutylammonium Fluoride [34] 

O 

H 

O 

O 

O 

H 

Bn 

TBAF, THF, 0 oC 98% 

OTMS OBz 

O 

OH 

16 17 

H 

O 

O 

O 

H 

(1R,3S,4R,5R,6S,8R,9S)-5-Benzyloxy-9-(tert-butyldimethylsiloxy)-8-[2-(tert-butyldiphenylsiloxy)ethyl]-3-{(2Z,4S,5R)-6-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-4,5-epoxyhex-2-enyl}-2,7dioxabicyclo[4.4.0]decan-4-ol 

(15): [33] 

To a soln of 14 (5.2 mg, 5.50 ìmol) in MeOH (1 mL) was added K 2CO 3 (an excess amount) at 

08C, and the mixture was stirred at the same temperature for 1.5 h. The mixture was diluted 

with Et 2O, and H 2O was added. The aqueous layer was extracted repeatedly with 

EtOAc. The combined organic layers were washed with brine, dried (MgSO 4), filtered, 

and concentrated in vacuo. The residue was purified by column chromatography (silica 

gel, hexane/EtOAc 3:1) to afford 15 as a colorless oil; yield: 4.6 mg (96%). 

[2S-(2á,3aâ,3bâ,6aâ,9aá,9bá,10á,11aâ)]-5-(Benzoyloxymethyl)-2-benzyl-2,9b-epoxy-6ahydroxy-11a-isopropenyl-8,10-dimethyl-3a,3b,6,6a,9a,10,11,11a-octahydro-7H-azuleno[5,4-e]-1,3-benzodioxol-7-one 

(17): [34] 

To a stirred soln of silyl ether 16 (8 mg, 12.4 ìmol) in THF (1 mL) at 08C was added 1.0 M 

TBAF in THF (24 ìL, 24.8 ìmol). After being stirred at 08C for 10 min, the mixture was 

poured into sat. aq NH 4Cl (5 mL) and extracted with EtOAc (3 ” 2 mL). The combined organic 

extracts were dried (MgSO 4), filtered, and concentrated in vacuo. Purification by flash 

chromatography (EtOAc/hexanes 2:8) gave alcohol 17; yield: 6.9 mg (98%). 

4.4.17.2 Triethylsilyl Ethers 

Triethylsilyl (TES) ethers are more stable and more resistant to acidic cleavage than trimethylsilyl 

ethers. They are often used where exhaustive silylation of a polyol is desired, 

but where a per(trimethylsilyl ether) is too labile for purification. The volatility of a triethylsilyl 

ether is only slightly less than that of a trimethylsilyl ether; however, the increased 

size of the substituents at silicon in a triethylsilyl ether can make this silylation of a tertiary 

alcohol quite sluggish, especially with chlorotriethylsilane. 

Formation 



4.4.17.2.1 Method 1: 

Silylation ofAlcohols with Chlorotriethylsilane 

Triethylsilyl ethers are most frequently prepared using chlorotriethylsilane (TESCl) [35] in 

the presence of a base such as imidazole, pyridine or 4-(dimethylamino)pyridine. [36] A typical 

silylation with this reagent is that of alcohol 18 carried out in dimethylformamide at 

room temperature to give triethylsilyl ether 19 (Scheme 9). [37] 

OBz 

Bn 



Scheme 9 Silylation with Chlorotriethylsilane in the Presence of Imidazole [37] 

OH O 

PMBO 

OMe 

N 

Me 

18 

TESCl, imidazole 

DMF, rt, 15 h 

70% 

TESO 

O 

R R OMe 

PMBO S N 

Me 

(3S)-19 

+ 

89:11 

TESO 

R R OMe 

PMBO R N 

Me 

(3R)-19 

(2R,3S,4R)-N-Methoxy-5-(4-methoxybenzyloxy)-N,2,4-trimethyl-3-(triethylsiloxy)pentanamide 

(19): [37] 

To a soln of a mixture of alcohol stereoisomers 18 (1.02 g, 3.14 mmol) in DMF (15 mL) were 

added imidazole (488 mg, 7.16 mmol) and TESCl (0.9 mL, 5.36 mmol) at rt. After being 

stirred for 15 h, the mixture was quenched with H 2O. The organic layer was separated, 

washed with 0.5 M aq NaHSO 4, sat. aq NaHCO 3 and brine, dried (Na 2SO 4), and concentrated 

to give a residue which was purified by flash chromatography (silica gel, EtOAc/hexane 

1:9) to give (3S)-19 as a colorless oil [yield: 855 mg (62%)]along with the 3R-diastereomer 

[yield: 106 mg (8%)]. 

4.4.17.2.1.1 Variation 1: 

With Chlorotriethylsilane in Pyridine 

Chlorotriethylsilane is more reactive when used with pyridine as the solvent. For example, 

a relatively difficult silylation of the hindered alcohol 20 to give triethylsilyl ether 21, 

an intermediate in a zaragozic acid synthesis, was carried out with chlorotriethylsilane in 

pyridine at room temperature (Scheme 10). [38] The tertiary alcohol in 20 was unaffected 

under these conditions. 

Scheme 10 Silylation with Chlorotriethylsilane in Pyridine [38] 

OHC 

HO 

O 

O 

Bu t O 2C 

O 

CO 2Bu t 

CO2Bu t 

20 

OH 



O 

TESCl, py, rt, 22 h 

82% 

OHC 

TESO 

O 

O 

Bu t O2C 

CO 2Bu t 

CO2Bu t 

White, J. D.; Carter, R. G., SOS, (2002) 4, 371. 2002 Georg Thieme Verlag KG 

O 

21 

OH 

O 

O

Tri-tert-butyl {1S-[1á,3á,4â,5á,6á(2E,4S,6S),7â]}-4-Hydroxy-6-(1-oxo-4,6-dimethyloct-2enyloxy)-1-(3-oxopropyl)-7-(triethylsiloxy)-2,8-dioxabicyclo[3.2.1]octane-3,4,5-tricarboxylate 

(21): [38] 

Alcohol 20 (48.2 mg, 71.9 ìmol) was dissolved in pyridine (2.5 mL), and the soln was 

cooled to 08C. A soln of TESCl (0.40 mL, 2.4 mmol) in pyridine (2.0 mL) was added over 

5 min, after which the ice bath was removed and the soln was stirred at rt for 22 h. The 

mixture was diluted with Et 2O (30 mL) and was washed with 0.5 M HCl (2 ” 30 mL), sat. aq 

NaHCO 3 (20 mL), H 2O (20 mL), and brine (20 mL). The aqueous layers were back-extracted 

with Et 2O (30 mL), and the combined organic layers were dried (MgSO 4), filtered, and 

evaporated. The crude product was purified by flash chromatography (silica gel, gradient 

elution, EtOAc/hexanes 1:7 to 1:5) to give 21; yield: 46.3 mg (82%). 

4.4.17.2.1.2 Variation 2: 

With Chlorotriethylsilane in the Presence of4-(Dimethylamino)pyridine 

Chlorotriethylsilane together with 4-(dimethylamino)pyridine is often used for the silylation 

of sterically hindered secondary alcohols. [36] This combination with imidazole in dichloromethane 

at low temperature was effective in promoting a selective silylation of 

one of the two secondary alcohols in compound 22 to yield the mono(triethylsilyl ether) 

23 (Scheme 11). [39] This selectivity, which was critical to a subsequent internal ketalization 

involving the free hydroxy group of 23, reflects the subtle steric factors that can impinge 

upon and differentiate the reactivity of cyclic and acyclic alcohols toward this silylating 

agent. 

Scheme 11 Silylation with Chlorotriethylsilane in the Presence of 4-(Dimethylamino)pyridine 

[39] 

O 

OH 

O O O 

H H H O O 

HO MeO 

22 



O 

TESCl, DMAP, imidazole 

CH2Cl2, −78 oC, 3 h 

98% 

OTES 

O O O 

H H H O O 

HO MeO 

(2S,2¢R,2¢¢R,3¢¢R,4¢¢R,5¢S,5¢¢S)-5¢¢-[(1R,2R,3S,4R)-1-Hydroxy-3-methoxy-2-methyl-4-(2-methyl- 

1,3-dioxolan-2-yl)pentyl]-2,3¢¢,5¢-trimethyl-4¢¢-(triethylsiloxy)decahydro-2,2¢:5¢,2¢¢-terfuran-5(2H)-one 

(23): [39] 

To a soln of alcohol 22 (210 mg, 420 ìmol) in CH 2Cl 2 (8.4 mL) at ±788C were added imidazole 

(71 mg, 1.05 mmol), DMAP (10 mg), and TESCl (78 ìL, 70 mg, 462 ìmol). After 3 h at 

±78 8C, the mixture was quenched by the addition of sat. aq NaHCO 3 (5 mL), and warmed 

to rt. The mixture was poured into EtOAc (25 mL) and then sat. aq NaHCO 3 (25 mL). The 

phases were separated, and the aqueous layer was extracted with EtOAc (2 ” 25 mL). The 

combined organic layers were dried (Na 2SO 4), filtered, and concentrated in vacuo. Purification 

by flash chromatography (EtOAc/hexane 45:55) afforded 23 as a clear oil; yield: 

253 mg (98%). 

23 



4.4.17.2.2 Method 2: 

Silylation ofAlcohols with Triethylsilyl Trifluoromethanesulfonate 

Triethylsilyl trifluoromethanesulfonate (TESOTf) [40] is now available commercially. It is often 

employed for the triethylsilylation of less reactive alcohols and is invariably used in 

the presence of pyridine or a substituted pyridine. The conversion of alcohol 24 into its 

triethylsilyl ether 25, an intermediate in a route to various macrolides, illustrates an 

application of this reagent (Scheme 12). [41] The presence of both triethylsilyl and triisopropylsilyl 

ethers in 25 was a design element that permitted selective cleavage of the triethylsilyl 

ether at a later step in the synthesis. 

Scheme 12 Silylation with Triethylsilyl Trifluoromethanesulfonate [41] 

O 

O 

N 

O 

Bn 

24 

OH OTIPS 

TESOTf, 2,6-lut 

CH2Cl2, rt 

99% 

O 

O 

N 

O 

Bn 

25 

OTES OTIPS 

(4R)-4-Benzyl-3-[(2R,3S,4R,5R)-2,4-dimethyl-1-oxo-3-(triethylsiloxy)-5-(triisopropylsiloxy)hexyl]oxazolidin-2-one 

(25): [41] 

To a soln of alcohol 24 (1.835 g, 3.74 mmol) in CH 2Cl 2 (75 mL) at rt was added 2,6-lutidine 

(0.653 mL, 5.61 mmol), followed by TESOTf (0.930 mL, 4.11 mmol). The resultant colorless 

soln was stirred for 40 min before the addition of sat. aq NaHCO 3 (50 mL). The layers were 

separated, and the aqueous layer was extracted with CH 2Cl 2 (2 ” 30 mL). The combined organic 

phases were washed with 1 M NaHSO 4 (20 mL), H 2O (20 mL), and brine (20 mL), dried 

(Na 2SO 4), filtered, and concentrated in vacuo. The product was purified by flash chromatography 

(5 ” 15 cm silica gel column, EtOAc/hexanes 1:9) to give 25 as a clear colorless 

oil; yield: 2.28 g (99%). 

Cleavage 



4.4.17.2.3 Method 3: 

Cleavage ofTriethylsilyl Ethers under Acidic Conditions 

Although triethylsilyl ethers are more stable toward acidic reagents than their trimethylsilyl 

counterparts, [42] they can be cleaved under acidic conditions to give the parent alcohol 

in good yield. Hydrogen fluoride±pyridine complex is a commonly used reagent for 

accomplishing this cleavage, and is often selective, as the example in Scheme 13 illustrates. 

Thus, the triethylsilyl ether of 26 was removed in the presence of hydrogen fluoride±pyridine 

complex without affecting either the triisopropylsilyl ether or the benzylidene 

acetal in this structure. [41] The resultant alcohol 27 was obtained in nearly quantitative 

yield. 


Scheme 13 Cleavage of a Triethylsilyl Ether with Hydrogen Fluoride±Pyridine Complex [41] 

O 

O 

N 

O 

Bn 

O 

Ph 

O 

26 

O OTES OTIPS 

O 

O 

N 

O 

Bn 

O 

HF•py, py, THF, 0 oC 95% 

Ph 

O 

27 

O OH OTIPS 

(4R)-4-Benzyl-3-[(2R)-2-{(2S,4S,5R,6S)-6-[(1S,5R,6S,7R,8R)-6-hydroxy-1,5,7-trimethyl-3-methylene-4-oxo-8-(triisopropylsiloxy)nonyl]-5-methyl-2-phenyl-1,3-dioxan-4-yl}-1-oxopropyl]oxazolidin-2-one 

(27): [41] 

To a soln of 26 (162.5 mg, 0.180 mmol) in THF (5 mL) at 0 8C in a Nalgene bottle was added 

ca. 4 mL of a HF·pyridine stock soln [HF·pyridine (2 mL), pyridine (4 mL), and THF (16 mL)]. 

After 2.5 h, the reaction was quenched by the dropwise addition of sat. aq NaHCO 3 

(50 mL), and the resultant mixture was stirred at 08C for 30 min. The mixture was then 

partitioned between CH 2Cl 2 (10 mL) and H 2O (10 mL). The aqueous layer was separated 

and extracted with CH 2Cl 2 (5 ” 10 mL). The combined organic layers were washed with 

1 M aq NaHSO 4, dried (Na 2SO 4), filtered, and concentrated in vacuo. The residue was purified 

by flash chromatography (2 ” 13.5 cm silica gel column, linear gradient 10 to 20% 

EtOAc/hexanes) to afford 27 as a clear colorless oil; yield: 135.2 mg (95%). 

4.4.17.2.3.1 Variation 1: 

In the Presence of4-Toluenesulfonic Acid 

Highly selective cleavage of triethylsilyl ethers can be realized with the acidic catalyst 4toluenesulfonic 

acid in the presence of an alcohol such as methanol. [4] For example, the 

triethylsilyl ether 28 undergoes cleavage using these conditions without affecting the 

methoxymethyl, tert-butyldimethylsilyl, or 4-methoxybenzyl ethers present in this structure 

(Scheme 14). The resultant alcohol 29 is a pivotal intermediate in Marshall s synthesis 

of discodermolide. [43] 

Scheme 14 Cleavage of Triethylsilyl Ethers Using 4-Toluenesulfonic Acid as a Catalyst [43] 

O 

OPMB OTBDMS OMOM 

O 



OMOM 

28 

OPMB OTBDMS OMOM 

OPMB OTES 

OMOM 

29 

OPMB OH 

TsOH, MeOH 

0 oC, 1 h 

72% 



(3R,4S,5R,6S,8S,9Z,11S,12S,13S,14Z,17S,18R,19R,20S,21S,22E)-6-(tert-Butyldimethylsiloxy)-20-hydroxy-4,18-bis(4-methoxybenzyloxy)-8,12-bis(methoxymethoxy)- 

3,5,11,13,15,17,19,21-octamethylpentacosa-9,14,22,24-tetraen-2-one (29): [43] 

To a cold (0 8C) soln of triethylsilyl ether 28 (40 mg, 0.035 mmol) in MeOH (5 mL) was 

added TsOH·H 2O (ca. 2 mg, 0.010 mmol). The resultant mixture was stirred for 1 h at 0 8C. 

Et 3N (2 mL) was added, and the mixture was concentrated under reduced pressure. The 

residue was purified by flash chromatography (hexanes/EtOAc 4:1 to 2:1) to provide alcohol 

29 as a clear oil; yield: 26 mg (72%). 

4.4.17.2.3.2 Variation 2: 

With Trifluoromethanesulfonic Acid 

Aqueous trifluoromethanesulfonic acid has been used to cleave a triethylsilyl ether with 

high selectivity, as in the conversion of 30 into the calicheamicinone precursor 31 

(Scheme 15). [44] Neither the tert-butyldimethylsilyl ether nor any other acid-sensitive functionality 

was compromised in this process. 

Scheme 15 Cleavage of Triethylsilyl Ethers with Trifluoromethanesulfonic Acid [44] 

BocO 

Boc2N 

TBDMSO O 

30 

OTES 



TfOH, H2O, THF, rt 

95% 

BocO 

Boc2N TBDMSO O 

10-[Bis(tert-butoxycarbonyl)amino]-11-(tert-butoxycarbonyloxy)-1-(tert-butyldimethylsiloxy)-8â-hydroxybicyclo[7.3.1]trideca-4,9,11-triene-2,6-diyn-13-one 

(31): [44] 

To a soln of 30 (906 mg, 1.17 mmol) in THF (10.6 mL) under argon at rt was added dropwise 

a soln of TfOH (1.37 mL) in H 2O (3.87 mL) by cannula with stirring. The mixture was stirred 

for 10 min, diluted with Et 2O (50 mL), and washed with sat. aq NaHCO 3 (20 mL). After drying 

(MgSO 4) and evaporation of the solvents in vacuo, the product was purified by chromatography 

(silica gel, Et 2O/hexanes 2:8) to give 31; yield: 730 mg (95%). 

4.4.17.2.4 Method 4: 

Cleavage ofTriethylsilyl Ethers with Tetrabutylammonium Fluoride 

Triethylsilyl ethers are appreciably more stable to basic reagents than trimethylsilyl 

ethers and will survive conditions such as potassium carbonate in methanol; [41] however, 

they are readily cleaved with tetrabutylammonium fluoride in tetrahydrofuran. The rate 

of cleavage with this reagent is sufficiently rapid such that a triethylsilyl group can be removed 

without perturbing a more resistant ether, such as a tert-butyldiphenylsilyl ether. 

This is illustrated in the selective cleavage of the triethylsilyl ether in 32 to give alcohol 

33, in which the tert-butyldiphenylsilyl ether as well as the 4-methoxybenzyl ether are retained 

(Scheme 16). [45] 


31 

OH

Scheme 16 Cleavage of Triethylsilyl Ethers with Tetrabutylammonium Fluoride [45] 

O 

O 

OTBDPS 

O 

MsO 

PMBO OTES 

32 

TBAF, THF, 0 o C, 45 min 

94% 

O 

O 

OTBDPS 

O 

MsO 

PMBO OH 

(7R)-5-O-(tert-Butyldiphenylsilyl)-7-{(2S)-4-[(2R)-2-hydroxy-4-(4-methoxybenzyloxy)butyl]-2- 

(methylsulfonyloxy)pent-4-enyl}-1,2-O-isopropylidene-3,7-anhydro-4,6-dideoxy-d-riboheptitol 

(33): [45] 

To a soln of 32 (167 mg, 180 ìmol) in THF (8 mL) at 08C was added a soln of 1.0 M TBAF in 

THF (270 ìL, 270 ìmol). The soln was stirred at 0 8C for 45 min then diluted with EtOAc 

(60 mL), washed with H 2O (10 mL) and brine (10 mL), and the combined aqueous phases 

were extracted with EtOAc (10 mL). The combined organic phases were dried (MgSO 4), filtered 

and concentrated by rotary evaporation. Flash chromatography (hexanes/EtOAc 2:1) 

afforded 33 as a colorless oil; yield: 137 mg (94%). 

4.4.17.3 tert-Butyldimethylsilyl Ethers 

The tert-butyldimethylsilyl (TBDMS) group [46] has become extremely popular among synthetic 

chemists as a protecting device for alcohols, and is now the most widely used silyl 

ether for this purpose. Both tert-butyldimethylsilyl chloride and tert-butyldimethylsilyl 

trifluoromethanesulfonate are effective silylating agents for primary alcohols and many 

secondary alcohols; tertiary alcohols are often resistant to silylation with these reagents. 

A wide variety of conditions has been developed for the preparation of tert-butyldimethylsilyl 

ethers, some of which permit selective silylation of seemingly similar hydroxy 

functions. 

tert-Butyldimethylsilyl ethers are much more stable toward basic reagents than are 

trimethylsilyl and triethylsilyl ethers. They are readily cleaved with tetrabutylammonium 

fluoride or hydrogen fluoride±pyridine complex, however, and are sometimes removed 

in the course of reduction with hydride reagents such as lithium aluminum 

hydride and diisobutylaluminum hydride. tert-Butyldimethylsilyl ethers, although less 

sensitive toward acidic reagents than their trimethylsilyl counterparts, are nevertheless 

quite readily cleaved in the presence of acetic acid or trifluoroacetic acid. This mode of 

cleavage of tert-butyldimethylsilyl ethers can have the advantage of avoiding the strongly 

basic reaction medium associated with tetrabutylammonium fluoride. 

Formation 



4.4.17.3.1 Method 1: 

Silylation ofAlcohols with tert-Butyldimethylsilyl Chloride 

A widely employed method for the preparation of tert-butyldimethylsilyl ethers utilizes 

tert-butyldimethylsilyl chloride (TBDMSCl) together with imidazole in dimethylformamide 

at temperatures ranging from ambient to 808C. [46] Primary alcohols are readily silylated 

under these conditions, as exemplified in the conversion of the triol 34 into the 

tris(tert-butyldimethylsilyl ether) 35 (Scheme 17). [47] 

33 



Scheme 17 Silylation with tert-Butyldimethylsilyl Chloride and Imidazole [47] 

HO 

O 

NMe 2 

34 

OH 

OH 

TBDMSCl, imidazole 

DMF, 70 oC 94% 

TBDMSO 

O 

NMe 2 

35 

OTBDMS 

OTBDMS 

(4S,5E)-9-(tert-Butyldimethylsiloxy)-4,8-bis(tert-butyldimethylsiloxymethyl)-N,N,4-trimethylnon-5-enamide 

(35): [47] 

A mixture of the triol 34 (100 mg, 0.366 mmol), imidazole (177 mg, 2.6 mmol), and 

TBDMSCl (200 mg, 1.3 mmol) in dry DMF (5 mL) was kept at 70 8C overnight. The mixture 

was partitioned between Et 2O and H 2O, and the ethereal soln was washed thoroughly 

with H 2O, dried (MgSO 4), and evaporated. Purification on silica gel (Et 2O) afforded 35 as a 

colorless liquid; yield: 214 mg (94%). 

4.4.17.3.1.1 Variation 1: 

In the Presence of4-(Dimethylamino)pyridine 

Silylation of more sterically hindered alcohols, such as 36, with tert-butyldimethylsilyl 

chloride requires replacement of imidazole (Section 4.4.17.3.1) with a stronger base such 

as 4-(dimethylamino)pyridine. [48] Under these conditions, 36 can be converted into its tertbutyldimethylsilyl 

ether 37 in high yield (Scheme 18). [49] 

Scheme 18 Silylation with tert-Butyldimethylsilyl Chloride in the Presence 

of 4-(Dimethylamino)pyridine [49] 

H 

HO 

36 

CN 

TBDMSCl, DMAP 

DMF, 21 

81% 

oC, 3 d 

H 

TBDMSO 

rac-(5R)-5-[(1R,2E)-1-(tert-Butyldimethylsiloxy)penta-2,4-dienyl]-2,6,6-trimethylcyclohex-1eneacetonitrile 

(37): [49] 

To a soln of alcohol 36 (213 mg, 0.87 mmol) in dry DMF (5 mL) was added sequentially 

TBDMSCl (170 mg, 1.13 mmol) and DMAP (270 mg, 2.21 mmol). The resulting soln was 

stirred at 21 8C for 3 d. H 2O was added, the mixture was extracted with Et 2O, and the combined 

extracts were washed with brine, dried, and concentrated. The residual oil was 

chromatographed (petroleum ether/Et 2O 19:1) to give 37; yield: 254 mg (81%). 

4.4.17.3.1.2 Variation 2: 

In Dichloromethane 



Replacement of dimethylformamide as the solvent (Section 4.4.17.3.1.1) by dichloromethane 

has the effect of moderating the reactivity of tert-butyldimethylsilyl chloride, so that 

the reagent becomes more selective in silylation of alcohols. Thus, the primary alcohol of 

38 was protected as its tert-butyldimethylsilyl ether 39 in the course of work on lankacyclins 

by using dichloromethane as the solvent (Scheme 19). [50] An advantage of dichloromethane 

over dimethylformamide is its easier removal from the product, but since imi- 


37 

CN

dazole has diminished solubility in dichloromethane alternative bases, usually 4-(dimethylamino)pyridine 

or triethylamine, or sometimes both as in this case, are necessary to 

achieve a sufficiently reactive silylating agent. 

Scheme 19 Silylation with tert-Butyldimethylsilyl Chloride in Dichloromethane [50] 

OH 

CO 2Me 

OH 

38 

TBDMSCl, Et3N 

DMAP, CH2Cl2 73% 

TBDMSO 

39 

CO 2Me 

Methyl (3S)-4-(tert-Butyldimethylsiloxy)-3-hydroxybutanoate (39): [50] 

Et 3N (16 g, 0.158 mol), DMAP (0.6 g, 4.9 mmol) and TBDMSCl (20 g, 0.133 mol) were added 

to a soln of dihydroxy ester 38 (16.2 g, 0.121 mol) in CH 2Cl 2 (150 mL). The mixture was 

stirred overnight then poured into H 2O. The two phases were separated and the aqueous 

layer was extracted with CH 2Cl 2. The combined organic extracts were dried (MgSO 4) and 

concentrated under reduced pressure. Chromatography of the residue gave 39 as an oil; 

yield: 22 g (73%). 

4.4.17.3.2 Method 2: 

Silylation ofAlcohols with tert-Butyldimethylsilyl 

Trifluoromethanesulfonate 

The more powerful silylating agent tert-butyldimethylsilyl trifluoromethanesulfonate 

(tert-butyldimethylsilyl triflate, TBDMSOTf) has become widely used for the preparation 

of tert-butyldimethylsilyl ethers in spite of the fact that it is more susceptible to degradation 

by moisture than tert-butyldimethylsilyl chloride and has a shorter storage lifetime. 

[51] One reason for the popularity of this reagent is that whereas silylation of alcohols 

can take many hours with tert-butyldimethylsilyl chloride, even with an excess of that reagent, 

it occurs in minutes with tert-butyldimethylsilyl trifluoromethanesulfonate. As a 

result, silylation with tert-butyldimethylsilyl trifluoromethanesulfonate can be carried 

out at low temperature, a feature that is used to advantage in selective silylation of two 

or more hydroxy groups in different steric environments. Thus, exposure of the steroidal 

diol 40 to tert-butyldimethylsilyl trifluoromethanesulfonate in the presence of pyridine 

at ±78 8C results in virtually instantaneous silylation of the 3-hydroxy substituent to give 

41 whilst leaving the D-ring hydroxy untouched (Scheme 20). [52] As in this example, silylation 

with tert-butyldimethylsilyl trifluoromethanesulfonate is almost always carried out 

in dichloromethane as the solvent. 

Scheme 20 Silylation with tert-Butyldimethylsilyl Trifluoromethanesulfonate [52] 

HO 

H 

40 

H 

H H 



Ac 

OH 

TBDMSOTf 

py, CH2Cl2, −78 oC 90% 

OH 

TBDMSO 

H 

41 

H 

H H 

3â-(tert-Butyldimethylsiloxy)-15â-hydroxy-5á-pregn-16-en-20-one (41): [52] 

To a soln of diol 40 (300 mg, 0.9 mmol) in pyridine (5 mL) and CH 2Cl 2 (5 mL) cooled to 

±78 8C was added dropwise a soln of TBDMSOTf (0.23 mL, 0.9 mmol) in CH 2Cl 2 (2 mL). Additional 

TBDMSOTf in CH 2Cl 2 soln was added (0.1 equiv at a time) until the reaction was 

Ac 

OH 



complete. The reaction was quenched at ±788C by the addition of a sat. NH 4Cl soln. The 

aqueous layer was extracted with EtOAc, and the extract was concentrated under vacuum. 

Purification of the residue by flash chromatography (silica gel, hexane/EtOAc 3:1) 

gave 41 as a white solid; yield: 363 mg (90%). 

4.4.17.3.2.1 Variation 1: 

Selective Silylation ofPhenols 

Silylation with tert-butyldimethylsilyl trifluoromethanesulfonate at low temperature can 

be used to discriminate between phenols and aliphatic hydroxy functions, as in the conversion 

of 42 into the aryl silyl ether 43 (Scheme 21). [53] This reaction illustrates the general 

observation that phenols are converted into their tert-butyldimethylsilyl ethers more 

rapidly than are aliphatic alcohols. 

Scheme 21 Selective Silylation, with tert-Butyldimethylsilyl Trifluoromethanesulfonate, of 

a Phenol in the Presence of an Aliphatic Alcohol [53] 

MeO 

OBn 

OMe 

O 

42 

4' 

OH 



OH 

TBDMSOTf, 2,6-lut, CH 2Cl2, −78 o C, 5 min 

90% (2 steps from the 4'-OMEM derivative) 

MeO 

OBn 

OMe 

O 

43 

OH 

OTBDMS 

(1R)-1-[(2R,3S)-9-Benzyloxy-4-(tert-butyldimethylsiloxy)-6,7-dimethoxy-2,3,8-trimethyl-2,3dihydronaphtho[1,2-b]furan-3-yl]-4-methylpent-3-en-1-ol 

(43): [53] 

The crude diol 42 (16 mg, prepared in situ from the 4¢-OMEM derivative) was dissolved in 

CH 2Cl 2 (1 mL), to which was added 2,6-lutidine (26.1 mg, 0.24 mmol) and TBDMSOTf 

(38.1 mg, 0.14 mmol) at ±788C. After the soln was stirred for 5 min, the reaction was 

quenched by adding pH 7 phosphate buffer, and the products were extracted with EtOAc. 

The combined organic extracts were washed with brine, dried (Na 2SO 4), and concentrated 

in vacuo. The residue was purified by preparative TLC (hexane/EtOAc 7:3) to give aryl silyl 

ether 43 as a pale yellow oil; yield: 13.0 mg (90% for 2 steps from the 4¢-OMEM derivative). 

4.4.17.3.2.2 Variation 2: 

Selective Silylation ofAlcohols 

The effect of reaction temperature on selectivity in silylation with tert-butyldimethylsilyl 

trifluoromethanesulfonate can be striking, as seen in the conversion of triol 44 into the 

bis(tert-butyldimethylsilyl ether) 45 at ±208C (Scheme 22). [54] Although both secondary hydroxy 

groups in this cis-fused decahydronaphthalene are equatorial, only the alcohol that 

is remote from the quaternary center is silylated. In structures such as 44, where two hydroxy 

substituents are in spatial proximity, the initial silylation of one hydroxy group will 

often retard reaction of the second hydroxy with this silylating agent, due to steric reasons. 

This will, of course, augment selectivity arising from a temperature effect. 


Scheme 22 Selective Silylation of Secondary Alcohols with tert-Butyldimethylsilyl Trifluoromethanesulfonate 

[54] 

HO 

HO OH 

H 

H 

TBDMSOTf, Et3N 

DMAP, CH2Cl2 −20 

87% 

oC, 30 min 

TBDMSO 

44 45 

HO OTBDMS 

H 

(1á,3â,4aá,5á,8â,8aá)-8-(tert-Butyldimethylsiloxy)-3-(tert-butyldimethylsiloxymethyl)-5isopropyl-3-methyldecahydro-1-naphthol 

(45): [54] 

To a stirred mixture of triol 44 (92 mg, 0.36 mmol), Et 3N (109 mg, 1.08 mmol), and DMAP 

(2 mg, 0.016 mmol) in CH 2Cl 2 (5 mL) at ±20 8C, was added TBDMSOTf (190 mg, 0.72 mmol). 

The mixture was stirred at ±208C for 30 min, diluted with Et 2O (40 mL), washed with 5% 

HCl (2 mL), brine (5 mL) and H 2O (5 mL), dried (Na 2SO 4), and concentrated in vacuo. Flash 

chromatography of the residue (silica gel, EtOAc/hexane 5:95) afforded 45 as a colorless 

oil; yield: 152 mg (87%). 

4.4.17.3.3 Method 3: 

Migration ofa tert-Butyldimethylsilyl Group from 

a tert-Butyldimethylsilyl Ether to an Alcohol 

The tert-butyldimethylsilyl group of a tert-butyldimethylsilyl ether will migrate to the oxygen 

atom of an adjacent alcohol under basic conditions if the new tert-butyldimethylsilyl 

ether is sterically less crowded than its precursor. [14] Thus, the direction of migration is 

invariably from a secondary to a primary alcohol or from a tertiary to either a secondary 

or primary alcohol. Migration between 1,2-substituted and 1,3-substituted diol derivatives 

is particularly common, although transfer of a tert-butyldimethylsilyl group between 

oxygens that span four or more carbons can occur if the oxygens are in spatial 

proximity. [16] The mechanism usually envisioned for these migrations involves intramolecular 

attack by an alkoxide oxygen on silicon to produce a pentacoordinate intermediate 

that collapses toward the more thermodynamically stable tert-butyldimethylsilyl 

ether. While silyl migration between oxygen atoms can pose an inconvenience in certain 

polyhydroxylated systems such as carbohydrates, where site-specific silylation may be desired, 

a virtue can be made of this chemistry in the deprotection of a silyl ether that may 

be difficult to cleave. Thus, if the silyl group can be forced to move to a less sterically 

crowded oxygen, its cleavage can become more facile. 

An example of an efficient migration of a tert-butyldimethylsilyl group is seen in the 

rearrangement of secondary tert-butyldimethylsilyl ether 46 to its isomeric primary silyl 

ether 47 (Scheme 23). [55] 

Scheme 23 Rearrangement of a Secondary tert-Butyldimethylsilyl Ether 

to a Primary tert-Butyldimethylsilyl Ether [55] 

OTBDMS 

F3C OH 

46 



t-BuOK, THF/DMF (1:4) 

−78 oC, 4 h 

99% 

OH 

47 

H 

F 3C OTBDMS 

Another example, in this case involving migration of the tert-butyldimethylsilyl group 

from a tertiary to a secondary alcohol, occurred in the course of an approach to the core 

structure of esperamicin A. [56] The rearrangement was triggered by S,S-diphenylsulfil- 



imine used for the elaboration of the aziridine 49 from á,â-unsaturated ketone 48 

(Scheme 24). 

Scheme 24 Migration of a tert-Butyldimethylsilyl Group to a Secondary Alcohol [56] 

HO 

TBDMSO 

O 

Ph 2S NH H 2O 

CH2Cl 2, rt, 16 h 

60% 

TBDMSO 

HO 

MeO 

H 

MeO 

48 49 

4-(tert-Butyldimethylsiloxy)-1,1,1-trifluorobutan-2-ol (47): [55] 

A 0.5 M soln of alcohol 46 in a mixed solvent of THF and DMF (1:4) was reacted with t- 

BuOK (1.1 equiv) at ±788C. After stirring for 4 h at that temperature, the reaction was 

quenched with aq NH 4Cl and extracted with Et 2O (3 ”). The combined extracts were dried 

(MgSO 4), filtered, concentrated in vacuo, and purified by column chromatography 

(EtOAc/hexanes 14:86) to afford 47 in quantitative yield. 

(+)-(1S,8S,9S,10S,12R)-12-(tert-Butyldimethylsiloxy)-1-hydroxy-9,10-imino-8-methoxybicyclo[7.3.1]tridec-4-ene-2,6-diyn-11-one 

(49): [56] 

To a soln of ketol 48 (59 mg, 0.16 mmol) in dry CH 2Cl 2 (5 mL) was added S,S-diphenylsulfilimine 

monohydrate (359 mg, 1.64 mmol), and the resulting suspension was stirred at rt 

for 16 h. The reaction was quenched with sat. NaHCO 3 and extracted with CH 2Cl 2 (3 ”). 

The combined organics were washed with H 2O (2 ”) and brine (1 ”), dried (Na 2SO 4), filtered, 

and concentrated. The resulting crude material was subjected to flash chromatography 

(Et 2O/heptane 1:1) to give aziridine 49 as white needles; yield: 36 mg (60%). 

Cleavage 



4.4.17.3.4 Method 4: 

Cleavage of tert-Butyldimethylsilyl Ethers with 

Tetrabutylammonium Fluoride 

The most general method for cleaving tert-butyldimethylsilyl ethers is with tetrabutylammonium 

fluoride in tetrahydrofuran. Unhindered silyl ethers of this class are transformed 

quite readily to their respective alcohols with this reagent at room temperature. 

[46] Conversion of the bis(tert-butyldimethylsilyl ether) 50 into diol 51 illustrates this 

cleavage and demonstrates that a tert-butyldiphenylsilyl ether can be retained intact under 

these conditions (Scheme 25). [57] 


O 

HN 

H

Scheme 25 Cleavage of Primary and Secondary tert-Butyldimethylsilyl Ethers with Tetrabutylammonium 

Fluoride [57] 

TBDPSO 

MeO 

TBDMSO 

NBoc O 

OTBDMS 

O 

50 

O 

OMe 

O O O 

OMe 

O 

TBAF, THF, rt, 2 h 

71% 

TBDPSO 

MeO 

HO 

OH 

NBoc O 

O 

51 

O 

OMe 

O O O 

More sterically crowded tert-butyldimethylsilyl ethers are sometimes stable toward tetrabutylammonium 

fluoride. For example, the tris(silyl ether) 52 undergoes selective cleavage 

of only one of the three secondary ether functions with tetrabutylammonium fluoride 

to afford hydroxy acid 53 (Scheme 26). [58] A possible explanation for this selectivity 

is intramolecular transfer of the most remote tert-butyldimethylsilyl group to the carboxylate 

formed when 52 is exposed to the basic fluoride reagent; subsequent acidic 

hydrolysis of the silyl ester would lead to 53. 

Scheme 26 Selective Cleavage of a tert-Butyldimethylsilyl Ether with Tetrabutylammonium 

Fluoride [58] 

TBDMSO 



OTBDMS 

CO2H O OTBDMS 

52 

S 

N 

TBDMSO 

TBAF, THF 

25 oC, 8 h 

78% 

OH 

CO2H 

O OTBDMS 

53 

OMe 

S 

N 

O 



(4S,6R)-4-[(1R,2S,3E)-2-{[1-(tert-Butoxycarbonyl)-2-piperidyl]carbonyloxy}-4-[(1R,3R,4R)-4- 

(tert-butyldiphenylsiloxy)-3-methoxycyclohexyl]-1,3-dimethylbut-3-enyl]-11-[(1E,4S,6S)-6- 

{(2R,3S,5R,6R)-6-[(1S)-1,2-dihydroxyethyl]-3-methoxy-5-methyltetrahydropyran-2-yl}-6methoxy-2,4-dimethylhex-1-enyl]-2,2-dimethyl-1,3,7-trioxaspiro[5.5]undec-10-en-9-one 

(51): [57] 

To a soln of bis(tert-butyldimethylsilyl ether) 50 (879 mg, 0.61 mmol) in THF (15 mL) was 

added 1 M TBAF in THF (1.84 mL, 1.84 mmol). After 2 h, the reaction was quenched with 

NH 4Cl, and the THF was removed in vacuo. The product was extracted into EtOAc, and 

the organic extracts were dried (MgSO 4), filtered, and concentrated in vacuo. The residue 

was chromatographed (silica gel, 20±50% EtOAc/hexanes) to give diol 51; yield: 525 mg 

(71%). 

(3S,6R,7S,12Z,15S,16E)-3,7-Bis(tert-butyldimethylsiloxy)-15-hydroxy-4,4,6,16-tetramethyl- 

17-(2-methyl-1,3-thiazol-4-yl)-5-oxoheptadeca-12,16-dienoic Acid (53): [58] 

A soln of tris(tert-butyldimethylsilyl ether) 52 (300 mg, 0.36 mmol) in THF (7.0 mL) at 258C 

was treated with 1 M TBAF in THF (2.2 mL, 2.2 mmol, 6.0 equiv). After being stirred for 8 h, 

the mixture was diluted with EtOAc (10 mL) and washed with 1 M aq HCl (10 mL). The 

aqueous soln was extracted with EtOAc (4 ” 10 mL), and the combined organic phase was 

washed with brine (10 mL), dried (MgSO 4), and concentrated. The crude mixture was purified 

by flash column chromatography (silica gel, MeOH/CH 2Cl 2 5:95) to provide hydroxy 

acid 53 as a yellow oil; yield: 203 mg (78%). 

4.4.17.3.5 Method 5: 

Cleavage of tert-Butyldimethylsilyl Ethers with 

Tris(dimethylamino)sulfur (Trimethylsilyl)difluoride 

Tris(dimethylamino)sulfur (trimethylsilyl)difluoride (TASF) [59] is a source of fluoride ion 

that is sometimes more effective than tetrabutylammonium fluoride (Section 4.4.17.3.4) 

for removing silyl ethers, [60] especially where the basicity associated with the latter reagent 

presents a problem. Thus, cleavage of the tert-butyldimethylsilyl ether 54 with 

tris(dimethylamino)sulfur (trimethylsilyl)difluoride gives the taxol precursor 55 in high 

yield (Scheme 27), whereas exposure of 54 to tetrabutylammonium fluoride results in 

cleavage of the benzoate as well as the silyl group. [61] Attempts to cleave the silyl ether of 

54 with hydrogen fluoride±pyridine complex led to products of rearrangement. 

Scheme 27 Cleavage of a tert-Butyldimethylsilyl Ether with Tris(dimethylamino)sulfur 

(Trimethylsilyl)difluoride [61] 

TBDMSO 

AcO 

HO 

BzO 

AcO 

54 



O 

OBOM 

O 

TASF, THF, rt, 1 h 

94% 

HO 

AcO 

HO 

BzO 

AcO 

55 

O 

OBOM 

7-O-(Benzyloxymethyl)baccatin III (55): [61] 

A soln of silyl ether 54 (16.3 mg, 19.9 ìmol) in THF (0.5 mL) was added to TASF (37 mg, 

0.134 mmol) at rt under a N 2 atmosphere. The mixture was stirred for 1 h, diluted with 

EtOAc, poured into sat. aq NaHCO 3 (20 mL) and extracted with CHCl 3 (3 ” 30 mL). The combined 

organic phase was dried (Na 2SO 4) and concentrated under reduced pressure to give 

a pale yellow oil (16 mg), which was filtered through a pad of silica gel using EtOAc/hexane 

(7:3) as eluent. The filtrate was concentrated to give diol 55; yield: 13.5 mg (94%). 


O

4.4.17.3.6 Method 6: 

Cleavage of tert-Butyldimethylsilyl Ethers under Acidic Conditions 

A wide variety of acidic reagents has been used for the cleavage of tert-butyldimethylsilyl 

ethers. Several of these reagents exhibit good selectivity for the removal of a particular 

tert-butyldimethylsilyl ether while leaving other silyl ethers, even a trimethylsilyl ether, 

intact. For example, exposure of the bis(silyl ether) 56 to hydrofluoric acid in acetonitrile 

cleaves the primary tert-butyldimethylsilyl ether but does not alter the angular trimethylsilyl 

ether (Scheme 28). [34] The resulting alcohol 57 would have been difficult to obtain 

from 56 by other silyl ether cleavage methods; the selectivity observed probably reflects 

more facile protonation of the primary ether oxygen. 

Scheme 28 Selective Cleavage of a tert-Butyldimethylsilyl Ether with Hydrofluoric Acid [34] 

H 

O 

O OTMS 

Ac 

56 

O 



O 

O 

49% aq HF 

H 

O 

MeCN, 0 

O 

o H C, 6 min 

H 

90% 

OTBDMS 

O OTMS 

(3aR,3bS,5S,6aR,8S,9aS,9bR,10R,11aS)-11a-Acetyl-5,9b-epoxy-5-(hydroxymethyl)-8,10-dimethyl-6a-(trimethylsiloxy)dodecahydroazuleno[5,4-e]-1,3-benzodioxole-2,7(3aH)-dione 

(57): [34] 

49% Aq HF (4.0 mL) was added dropwise to a soln of the silyl ether 56 (1.30 g, 2.23 mmol) in 

MeCN (30 mL) at 08C. After being stirred for 6 min, the mixture was quenched with sat. aq 

NaHCO 3 (CAUTION: careful addition was required until the evolution of CO 2 was no longer observed), 

diluted with H 2O (150 mL), and extracted with EtOAc (3 ” 100 mL). The combined 

organic extracts were dried (MgSO 4), filtered, and concentrated in vacuo. Purification by 

flash chromatography (EtOAc/hexanes 1:1) gave the alcohol 57; yield: 0.934 g (90%). 

4.4.17.3.6.1 Variation 1: 

With Hydrogen Fluoride±Pyridine Complex 

Hydrogen fluoride±pyridine complex, a reagent which is often used in a mixed solvent 

system comprising pyridine and tetrahydrofuran, is highly effective for the cleavage of 

tert-butyldimethylsilyl ethers. [62] In general, primary tert-butyldimethylsilyl ethers are 

cleaved much more rapidly than their secondary or tertiary ether counterparts with hydrogen 

fluoride±pyridine complex, and selective cleavage is usually possible with this reagent. 

Reaction temperature is the critical factor in achieving selective cleavage in these 

cases. A representative silyl ether cleavage with hydrogen fluoride±pyridine complex is 

the conversion of the chlorothricolide intermediate 58 into the primary alcohol 59 

(Scheme 29). [63] None of the other functional or protecting groups of thioester 58 (which 

was a mixture of two diastereomers resulting from the convergence of racemic subunits) 

are affected by this reagent. 

57 

Ac 

O 

OH 

O 



Scheme 29 Cleavage of a tert-Butyldimethylsilyl Ether with Hydrogen Fluoride±Pyridine 

Complex [63] 

PhS 

O 

TBDMSO 

MeO 

O 

O 

SEMO 

H 

O 

O 

H 

H OMOM 

+ diastereomer 

58 

PhS 

O 

HF py, py 

THF, rt, 2 h 

97% 

SEMO 

O 

HO 

MeO 

O 

H 

O 

O 

H 

H OMOM 

+ diastereomer 

rac-[1á(5S*,6S*,8R*,9R*),2á,4aâ,5â,8aá]-6-(Hydroxymethyl)-4-methoxy-9-methyl-2-oxo-8- 

[2-(trimethylsilyl)ethoxymethoxy]-1-oxaspiro[4.5]dec-3-en-3-yl 5-(Methoxymethoxy)-1methyl-2-[4-oxo-4-(phenylsulfanyl)butyl]-1,2,4a,5,6,7,8,8a-octahydronaphthalene-1-carboxylate 

(59): [63] 

To a rapidly stirred soln of the thioester 58 (mixture of 2 diastereomers; 762 mg, 

0.83 mmol) in THF (1 mL) was added a HF x ·pyridine soln [5 mL, prepared by diluting Aldrich 

HF x ·pyridine (13 g) with pyridine (31 mL) and THF (100 mL)], and the resulting mixture 

was stirred at rt for 2 h. After the mixture was poured into sat. NaHCO 3 (50 mL), the 

aqueous layer was extracted with Et 2O (3 ” 100 mL) and the combined organic layers were 

dried (MgSO 4). After removal of the solvent at reduced pressure, the crude residue was 

chromatographed (size C Lobar silica gel column, EtOAc/petroleum ether 28:72) to give 

the ªfasterº eluting alcohol 59 as a colorless oil; yield: 289 mg (43%). Further elution afforded 

the diastereomeric alcohol as a colorless oil; yield: 360 mg (54%). 

4.4.17.3.6.2 Variation 2: 

With Mineral Acid 



A solution of a mineral acid such as hydrochloric acid can accomplish selective cleavage 

of certain silyl ethers, including tert-butyldimethylsilyl ethers. [64] An illustration of this selectivity 

is seen in the reaction of the differentially protected tetrakis(silyl ether) 60 with 

10% hydrochloric acid, which leads to the diol 61 (Scheme 30). [65] Only the trimethylsilyl 

and tert-butyldimethylsilyl ethers are cleaved under these conditions, the triisopropylsilyl 

and tert-butyldiphenylsilyl ethers being unreactive. 


59

Scheme 30 Selective Cleavage of a tert-Butyldimethylsilyl Ether with Hydrochloric Acid [65] 

TIPSO 

O 

OTMS 

TBDPSO 

OTBDMS 

60 

O 

O 

Pr i 

TIPSO 

O 

10% aq HCl 

THF, rt, 3 h 

87% 

OH 

TBDPSO 

(3E,3aS,4S,6S,7S,7aR)-3-{(2E,4R,6E)-8-[(2R,4S,8R,9S)-4-(tert-Butyldiphenylsiloxy)-8-isopropyl-9-methyl-1,7-dioxaspiro[5.5]undec-2-yl]-4,6-dimethylocta-2,6-dienylidene}-4-(hydroxymethyl)-6-methyl-7-(triisopropylsiloxy)hexahydrobenzofuran-3a(4H)-ol 

(61): [65] 

To a soln of tetrakis(silyl ether) 60 (0.41 g, 0.36 mmol) in THF (40 mL) was added 10% aq 

HCl (5.5 mL). The mixture was stirred at rt for 3 h and cooled to 0 8C. Solid NaHCO 3 was 

added carefully in small portions until all the bubbling subsided. The aqueous layer was 

extracted with Et 2O (4 ” 20 mL), and the combined organic extracts were dried (MgSO 4), 

filtered, and concentrated in vacuo. Purification of the residue by column chromatography 

(silica gel, 5±10% EtOAc/hexanes) provided diol 61 as a white foam; yield: 0.30 g (87%). 

4.4.17.3.6.3 Variation 3: 

With Organic Acids 

Organic acids used for cleavage of tert-butyldimethylsilyl ethers include formic, [66] acetic, 

[67] trifluoroacetic, [68] and certain sulfonic acids. [69] Formic acid is the least selective of 

these reagents, showing little discrimination in the cleavage of tert-butyldimethylsilyl 

ethers in different steric or electronic environments. An example of a deprotection with 

this reagent is the reaction of the bis(tert-butyldimethylsilyl ether) 62 to give lankacidin C 

(63, Scheme 31). [66] 

Scheme 31 Cleavage of tert-Butyldimethylsilyl Ethers with Formic Acid [66] 

O 

O O 

TBDMSO OTBDMS 

62 

O 

HN 



O 

HCO2H, THF 

H2O, rt, 3 h 

86% 

OH 

61 

O 

O 

HN 

O O 

O 

Pr i 

HO OH 

The use of trifluoroacetic acid for cleavage of tert-butyldimethylsilyl ethers is confined to 

compounds that are stable to a moderately strong acid, but the reagent can offer a valuable 

means for selective cleavage of these ethers. For example, the bis(tert-butyldimethyl- 

63 

O 

O 



silyl ether) 64 undergoes selective scission with trifluoroacetic acid, giving alcohol 65 in 

high yield (Scheme 32). [70] The more sterically hindered secondary silyl ether of 64 remains 

unaffected by this reagent. 

Scheme 32 Selective Cleavage of a tert-Butyldimethylsilyl Ether with Trifluoroacetic Acid [70] 

MeO 

MeO 

MeO N 

OMe 

OMe 

64 

OTBDMS 

OTBDMS 

TFA, THF 

H2O, 0 oC, 3 h 

91% 

MeO 

MeO 

MeO N 

OMe 

OMe 

65 

OTBDMS 

Selectivity in the cleavage of tert-butyldimethylsilyl ethers can also be achieved with 10camphorsulfonic 

acid. Thus, the secondary silyl ether but not the angular silyl ether of 

compound 66 is removed with 10-camphorsulfonic acid in dichloromethane containing 

a small amount of methanol to afford the diol 67 in excellent yield (Scheme 33). [71] 

Scheme 33 Selective Cleavage of a tert-Butyldimethylsilyl Ether with 

10-Camphorsulfonic Acid [71] 

HO 

H 

O 

OTBDMS 

O 

OTBDMS 



CSA, CH2Cl2, MeOH, 25 oC, 1 h 

100% 

HO 

66 67 

H 

O 

OH 

O 

OTBDMS 

Lankacidin C (63): [66] 

A soln of bis(silyl ether) 62 (15 mg, 0.022 mmol) in a mixture of THF/HCO 2H/H 2O (6:3:1, 

2.0 mL) was stirred at rt for 3 h. The mixture was cooled to 08C and neutralized with sat. 

aq NaHCO 3 (2 mL). This mixture was poured into EtOAc (10 mL) and brine (10 mL). The 

aqueous layer was extracted with EtOAc (10 mL). The combined organic layers were dried 

(MgSO 4), filtered, and concentrated in vacuo. Purification by preparative TLC (EtOAc) gave 

lankacidin C (63) as a white solid; yield: 8.7 mg (86%). 


OH

(2Z,4S,5R,6E,8S,9R,10S,12S,13R)-5-(tert-Butyldimethylsiloxy)-13-[3-(2,5-dimethyl-1H-pyrrol-1-yl)-2,5-dimethoxyphenyl]-9,10,13-trimethoxy-4,6,8,12-tetramethyltrideca-2,6-dien- 

1-ol (65): [70] 

A soln of bis(silyl ether) 64 (42 mg, 0.051 mmol) in THF (2 mL) containing TFA/H 2O (9:1, 

400 ìL) was stirred at 08C for 3 h. Sat. NaHCO 3 (5 mL) was added, and the mixture was extracted 

with Et 2O (3 ” 10 mL). The combined organic layers were dried (MgSO 4) and concentrated 

under reduced pressure; the residue was purified by flash chromatography 

(hexanes/EtOAc 3:1) to give alcohol 65 as a colorless, viscous oil; yield: 33 mg (91%). 

(3aR,4R,5S,7aS)-7a-(tert-Butyldimethylsiloxy)-5-hydroxy-4-(hydroxymethyl)-4-methyl- 

3a,4,5,7a-tetrahydroisobenzofuran-1(3H)-one (67): [71] 

A soln of alcohol 66 (43.9 g, 99 mmol) in CH 2Cl 2 (250 mL) and MeOH (20 mL) was treated 

with CSA (0.52 g, 2.24 mmol) and stirred at 258C for 1 h. After dilution with CH 2Cl 2 

(300 mL), the reaction was quenched with aq NaHCO 3 (150 mL). The organic layer was separated, 

and the aqueous layer was extracted with Et 2O (2 ” 200 mL). The combined organic 

layer was dried (Na 2SO 4), concentrated, and purified by flash chromatography (silica gel, 

Et 2O/petroleum ether 1:1) to give diol 67 as white crystals; yield: 32.6 g (100%). 

4.4.17.3.6.4 Variation 4: 

With Lewis Acids 

Lewis acids have found limited use as reagents for cleaving silyl ethers, in part because 

they coordinate weakly with the oxygen atom of ethers of this class; however, they can 

sometimes effect a remarkably efficient cleavage of a tert-butyldimethylsilyl ether, [72] as 

in the conversion of silyl ether 68 into alcohol 69 with boron trifluoride±diethyl ether 

complex (Scheme 34). [73] A noteworthy feature of this transformation is that the trisubstituted 

epoxide of 68 does not suffer rearrangement to a ketone under the reaction conditions. 

Scheme 34 Cleavage of a tert-Butyldimethylsilyl Ether with Boron Trifluoride±Diethyl 

Ether Complex [73] 

O 

BnO 

H 

H 

68 

O 

O 

OTBDMS 



BF3 OEt2, CH2Cl2 

0−10 oC 92% 

(4aá,8aá,9aá)-1á-Benzyloxy-6á-hydroxy-4á,6aâ,7aâ,9bâ-tetramethyldodecahydrophenanthro[2,3-b]oxirene-2,7-dione 

(69): [73] 

To a soln of silyl ether 68 (53 mg, 0.10 mmol) in dry CH 2Cl 2 (8 mL) was added BF 3 ·OEt 2 

(63 ìL, 0.50 mmol) at 08C under N 2. The mixture was allowed to warm to ca. 108C and 

was then stirred for 6 h. The reaction was quenched with sat. aq NH 4Cl (2 mL), and the 

aqueous phase was extracted with CH 2Cl 2 (3 ” 10 mL). The combined organic extracts 

were washed with brine (2 mL), dried (MgSO 4), and filtered. Concentration of the filtrate 

followed by flash column chromatography (hexane/EtOAc 7:1) gave alcohol 69 as a white 

solid; yield: 38 mg (92%). 

O 

BnO 

H 

69 

H 

O 

OH 

O 



4.4.17.4 Triisopropylsilyl Ethers 

Triisopropylsilyl (TIPS) ethers are used as protection for primary and certain secondary 

alcohols, [74] the large steric bulk of the silyl group ensuring good selectivity in most instances. 

[75] Secondary alcohols can only be converted into their triisopropylsilyl ethers under 

more forcing conditions, and tertiary alcohols in general cannot be converted into triisopropylsilyl 

ethers. A principal advantage of triisopropylsilyl ethers is their stability 

toward basic conditions which cause cleavage of other functional groupings, including 

silyl ethers such as tert-butyldimethylsilyl. [76] Thus, esters can be saponified without destruction 

of a triisopropylsilyl ether, and strong bases such as tert-butyllithium, which 

can deprotonate the methyl group of a tert-butyldimethylsilyl ether, are without effect 

on a triisopropylsilyl ether. The triisopropylsilyl ether is among the weakest of the silyl 

ethers in terms of coordination to metal cations. [77] It is advisable not to use an excess of 

silylating agent, since it is sometimes contaminated with the more reactive, isomeric diisopropyl(propyl)silyl 

reagent. [78] 

Formation 

4.4.17.4.1 Method 1: 

Silylation ofAlcohols with Triisopropylsilyl 

Trifluoromethanesulfonate and 2,6-Lutidine 

The large steric demand imposed by the triisopropylsilyl group makes triisopropylsilyl 

trifluoromethanesulfonate (TIPSOTf) the most useful reagent for silylations in this class. 

In the presence of 2,6-lutidine and with dichloromethane as solvent, it is generally feasible 

to convert a primary alcohol into its triisopropylsilyl ether without affecting a secondary 

alcohol. [51] The conversion of diol 70 containing a primary and secondary hydroxy substituent 

into its mono(silyl ether) 71 reflects the selectivity that can be attained with this 

reagent (Scheme 35). [79] 

Scheme 35 Selective Silylation of a Primary Alcohol with 

Triisopropylsilyl Trifluoromethanesulfonate [79] 

H 

O O 

70 

OH 



HO TIPSO 

TIPSOTf, 2,6-lut 

CH2Cl2, −8 oC 91% 

H 

O O 

(4aR,5R,6RS,8aR)-6-Hydroxy-5,8a-dimethyl-5-[2-(triisopropylsiloxy)ethyl]octahydronaphthalen-1(2H)-one 

Ethylene Ketal (71): [79] 

To a soln of the diol 70 (5.28 g, 18 mmol) and 2,6-lutidine (3.15 mL, 27 mmol) in CH 2Cl 2 

(25 mL) was added a soln of TIPSOTf (4.85 mL, 18 mmol) in CH 2Cl 2 (5 mL) over 1 h at ±88C. 

After the mixture had been stirred for 4 h, the reaction was quenched by the addition of 

aq NaHCO 3. After separation of the organic layer, the aqueous layer was extracted with 

EtOAc (2 ”). The combined extracts were washed with brine and evaporated to dryness. 

The residue was purified by column chromatography (silica gel, hexane/EtOAc 5:1) to 

give alcohol 71; yield: 7.47 g (91%). 


71 

OH

4.4.17.4.1.1 Variation 1: 

With Triisopropylsilyl Trifluoromethanesulfonate 

in the Presence of4-(Dimethylamino)pyridine 

As with other silylating agents, triisopropylsilyl trifluoromethanesulfonate becomes 

more reactive when used in the presence of 4-(dimethylamino)pyridine, especially when 

pyridine is the solvent. Under these conditions, secondary alcohols are converted into 

their triisopropylsilyl ethers rapidly and in high yield. The silylation of diol 72 to give 

the tris(silyl ether) 73 illustrates this increased reactivity of the silylating agent (Scheme 

36). [80] 

Scheme 36 Silylation of Secondary Alcohols with Triisopropylsilyl Trifluoromethanesulfonate 

[80] 

TBDPSO 

HO 

HO 

H 

O 

72 

O 

O 

O 

O 

TBDPSO 

TIPSO 

TIPSOTf 

DMAP, py, rt, 15 h 

99% 

TIPSO 

(1S,1¢S,3R,5S,5¢S,6S,6¢S)-8-[(1S,3R)-4-(tert-Butyldiphenylsiloxy)-1,3-bis(triisopropylsiloxy)butyl]-5,5¢-dimethyl-8¢-oxo-3,3¢-spirobi(2,7-dioxabicyclo[4.3.0]nonane) 

(73): [80] 

Diol 72 (125 mg, 0.200 mmol) was combined with DMAP (44 mg, 0.36 mmol) under a N 2 

atmosphere and then dissolved in dry pyridine (0.6 mL). TIPSOTf (0.4 mL, 1.49 mmol) was 

added via syringe, and the mixture was stirred for 15 h. Excess TIPSOTf was consumed by 

the addition of dry MeOH (1.5 mL). After 15 min, the reaction was transferred to a separatory 

funnel with Et 2O and washed first with 5% HCl (15 mL) and then with a mixture of sat. 

aq NaHCO 3 and brine (1:1, 20 mL). The aqueous layers were extracted with Et 2O 

(2 ” 40 mL), and the combined organics were dried (MgSO 4). Filtration through a short silica 

gel plug with additional Et 2O, and concentration in vacuo provided the crude, fully protected 

lactone which was purified by chromatography (silica gel, Et 2O/hexanes 1:3) to afford 

73 as a pale yellow oil; yield: 187 mg (99%). 

Cleavage 



4.4.17.4.2 Method 2: 

Cleavage ofTriisopropylsilyl Ethers with 


The most general method for cleavage of a triisopropylsilyl ether is with tetrabutylammonium 

fluoride, however, this reagent typically exhibits no selectivity between silyl ethers 

of this class that are situated in different structural environments. Nevertheless, it is possible 

to retain a triisopropylsilyl ether while a more susceptible silyl ether, including a 

secondary tert-butyldiphenylsilyl ether, is cleaved with this reagent (see Scheme 48, Section 

4.4.17.5.4). The conventional protocol for removing a triisopropylsilyl ether is illus- 

H 

O 

73 

O 

O 

O 

O 



trated in the conversion of 74 into diol 75 (Scheme 37), a late intermediate in a synthesis 

of milbemycin D. [65] 

Scheme 37 Cleavage of a Triisopropylsilyl Ether with Tetrabutylammonium Fluoride [65] 

TIPSO 

O 

OH 

O 



74 

O 

O 

O 

Pr i 

HO 

O 

TBAF 

THF, rt 

95% 

(4S,6R,25R)-25-Isopropyl-5-O-demethyl-28-deoxy-3,4-dihydro-6,28-epoxymilbemycin B 

(75): [65] 

1 M TBAF in THF (0.23 mL, 0.23 mmol) was added to a soln of macrolactone 74 (0.054 g, 

0.075 mmol) in THF (1.0 mL). The resulting soln was stirred overnight at rt, concentrated 

in vacuo, and purified by column chromatography (silica gel, 10±50% EtOAc/hexanes) to 

afford diol 75 as a white foam; yield: 0.040 g (95%). 

4.4.17.4.3 Method 3: 

Cleavage ofTriisopropylsilyl Ethers with Tris(dimethylamino)sulfur 

(Trimethylsilyl)difluoride 

Tris(dimethylamino)sulfur (trimethylsilyl)difluoride (TASF) as a source of fluoride ion has 

been used to cleave triisopropylsilyl ethers in situations where the basicity of tetrabutylammonium 

fluoride would be destructive toward other functionality. An example in 

which only tris(dimethylamino)sulfur (trimethylsilyl)difluoride could be employed to 

successfully cleave a triisopropylsilyl ether is seen in the conversion of 76 into baccatin 

III (78, Scheme 38). [81] Cleavage of the silyl ether to yield alcohol 77 was followed by treatment 

with phenyllithium, which removed the 2,2,2-trichloroethoxycarbonyl (Troc) protection 

and opened the cyclic carbonate en route to triol 78 (accompanied by a 46% yield 

of 10-O-deacetylbaccatin III). 


OH 

O 

75 

O 

O 

O 

Pr i

Scheme 38 Cleavage of a Triisopropylsilyl Ether with Tris(dimethylamino)sulfur (Trimethylsilyl)difluoride 

[81] 

AcO O OTroc 

TIPSO H 

O O OAc 

O 

76 



O 

TASF, THF, 0 oC, 5 min 

96% 

PhLi, THF 

33% 

AcO O OTroc 

HO H 

O O OAc 

O 

77 

O 

AcO O OH 

10 

HO H O 

HO BzO 

78 

OAc 

[3aS-(3aá,5â,8á,9aá,10á,11aâ,13aâ,13bâ,13cá)]-8,13a-Diacetoxy-5-hydroxy-3a,7-methano-6,9a,14,14-tetramethyl-2,9-dioxo-4,5,8,9,9a,10,11,11a,13,13a,13b,13c-dodecahydro- 

3aH-oxeto[2¢¢,3¢¢:5¢,6¢]benzo[1¢,2¢:3,4]cyclodeca[1,2-d]-1,3-dioxol-10-yl 2,2,2-Trichloroethyl 

Carbonate (77): [81] 

To silyl ether 76 (3.2 mg, 4 ìmol) in THF (0.8 mL) at 08C was added TASF (4.0 mg, 15 ìmol), 

and the mixture was stirred for 5 min at 0 8C. The reaction was quenched by addition of 

sat. aq NaHCO 3. The aqueous layer was extracted with Et 2O. The combined organic layers 

were washed with H 2O and sat. brine, and then dried (anhyd Na 2SO 4). The crude mixture 

was filtered and concentrated under reduced pressure. Purification of the resultant residue 

by flash chromatography (silica gel, EtOAc/hexanes 3:7) provided alcohol 77; yield: 

2.5 mg (96%). 

4.4.17.4.4 Method 4: 

Cleavage ofTriisopropylsilyl Ethers with 

Hydrogen Fluoride±Pyridine Complex 

Hydrogen fluoride±pyridine complex, used in a mixed tetrahydrofuran/pyridine solvent 

system, affords a convenient method for removing the triisopropylsilyl residue from oxygen. 

The final step in a synthesis of the immunosuppressant rapamycin (80) involved unmasking 

of both a triisopropylsilyl and a tert-butyldimethylsilyl ether, for which hydrogen 

fluoride±pyridine complex treatment of 79 served well (Scheme 39). [82] 



Scheme 39 Cleavage of a Triisopropylsilyl and a tert-Butyldimethylsilyl Ether with Hydrogen 

Fluoride±Pyridine Complex [82] 

TIPSO 

MeO 

O 

HO 

N 

O 

O 

O 

MeO 

O 



79 

O 

TBDMSO 

OMe 

O 

HO 

MeO 

HF py, py, THF 

0 oC to rt, 48 h 

69% 

O O HO 

(±)-Rapamycin (80): [82] 

At 0 8C a soln of synthetic hemiketal (±)-79 (5.1 mg, 4.3 ìmol) in THF (0.5 mL) was treated 

with pyridine (0.5 mL) followed by HF·pyridine (0.5 mL). The mixture was warmed to rt, 

stirred for 48 h, and then partitioned between Et 2O (10 mL) and H 2O (10 mL). The organic 

phase was washed with sat. aq CuSO 4 (5 mL), sat. aq NaHCO 3 (5 mL), H 2O (5 mL), and brine 

(5 mL), dried (MgSO 4), filtered, and concentrated. Flash chromatography (hexanes/EtOAc 

1:1 then 1:3) provided synthetic rapamycin (80) as a clear oil; yield: 2.7 mg (69%). Recrystallization 

(acetone/hexanes 4:6) gave (±)-80 as a white solid. 

(−)-80 

4.4.17.4.5 Method 5: 

Cleavage ofTriisopropylsilyl Ethers under Acidic Conditions 

Although acidic conditions are not often used to cleave triisopropylsilyl ethers, available 

evidence suggests that silyl ethers of this class are quite susceptible to cleavage in the 

presence of acidic reagents. [76,83] Thus, the triisopropylsilyl blocking group was removed 

from the mycotrienin precursor 81 with 4-toluenesulfonic acid in methanol to yield alcohol 

82 without affecting the adjacent tert-butyldimethylsilyl ether (Scheme 40). [84] The 

sensitive triene unit of 81 was also stable under these conditions. 


OMe 

O

Scheme 40 Selective Cleavage of a Triisopropylsilyl Ether under Acidic Conditions [84] 

TBDMSO 

TIPSO 

81 

OMe 

OMe O 

NH 

OMe 

TsOH, MeOH, rt, 30 min 

90% 

TBDMSO 

HO 

82 

OMe 

OMe O 

(5R,6E,8E,10E,13S,14S,15S,16Z)-15-(tert-Butyldimethylsiloxy)-13-hydroxy-5,22,24-trimethoxy-14,16-dimethyl-2-azabicyclo[18.3.1]tetracosa-1(24),6,8,10,16,20,22-heptaen-3-one 

(82): [84] 

A soln of triene 81 (50 mg, 0.066 mmol) in MeOH (6.0 mL) was treated with catalytic TsOH 

(3.0 mg, 0.017 mmol, 0.25 equiv). The mixture was stirred at rt for 30 min and subsequently 

diluted with NaHCO 3 and H 2O (20 mL). The mixture was extracted with EtOAc 

(3 ” 25 mL), dried (MgSO 4), and concentrated in vacuo. Purification on silica gel (20 to 

30% EtOAc/petroleum ether) afforded alcohol 82 as a colorless oil; yield: 36 mg (90%). 

4.4.17.5 tert-Butyldiphenylsilyl Ethers 

The tert-butyldiphenylsilyl (TBDPS) ether as a masking device for alcohols was introduced 

by Hanessian in order to provide a protecting group more stable toward acidic reagents 

than other silyl ethers. [85] tert-Butyldiphenylsilyl ethers are inert under acidic conditions 

which can cleave tert-butyldimethylsilyl ethers, and they typically survive those acidic reagents 

used to cleave alkyl ethers such as trityl and tetrahydropyranyl. The diminished 

reactivity of tert-butyldiphenylsilyl ethers toward electrophiles is thought to be due to 

the electron-withdrawing effect of the phenyl substituents attached to silicon. However, 

the tert-butyldiphenylsilyl group is more easily cleaved than the tert-butyldimethylsilyl 

group with sodium hydroxide. [86] 

Formation 



4.4.17.5.1 Method 1: 

Silylation ofAlcohols with tert-Butyldiphenylsilyl Chloride 

Both primary and secondary alcohols can be converted into their tert-butyldiphenylsilyl 

ethers, the usual reagent for this being the chlorosilane (tert-butyldiphenylsilyl chloride, 

TBDPSCl). Secondary alcohols, if sterically hindered, may require elevated reaction temperatures 

for efficient silylation with this reagent, as seen in the protection of ethyl (2S)-2hydroxy-3-methylbutanoate 

(83) as its tert-butyldiphenylsilyl ether 84 (Scheme 41). [85] 

NH 

OMe 



Scheme 41 Silylation of a Secondary Alcohol with tert-Butyldiphenylsilyl Chloride [87] 

OH 

83 

CO 2Et 

TBDPSCl, imidazole 

DMF, 80 oC, 7 h 

92% 

CO 2Et 

OTBDPS 

84 

Ethyl (2S)-2-(tert-Butyldiphenylsiloxy)-3-methylbutanoate (84): [87] 

To a soln of ethyl (2S)-2-hydroxy-3-methylbutanoate (83; 2.22 g, 15.2 mmol) in DMF 

(20 mL) were added imidazole (1.24 g, 18.2 mmol) and TBDPSCl (5.00 g, 18.2 mmol) and 

the mixture was stirred at 808C. After being stirred for 7 h, the mixture was diluted with 

H 2O (60 mL) and extracted with CH 2Cl 2 (3 ” 60 mL). The combined extracts were washed 

with brine, dried (MgSO 4), and concentrated in vacuo. Column chromatography (silica 

gel, hexane) gave silyl ether 84 as a colorless oil; yield: 5.40 g (92%). 

4.4.17.5.1.1 Variation 1: 

In the Presence of4-(Dimethylamino)pyridine 

Silylation with tert-butyldiphenylsilyl chloride can be carried out at room temperature if 

4-(dimethylamino)pyridine is included in the reaction mixture, [88] as seen in the quantitative 

conversion of the hydroxyspiroketal 85 into its silyl ether 86 (Scheme 42). [65] 

Scheme 42 Silylation with tert-Butyldiphenylsilyl Chloride in the Presence of 

4-(Dimethylamino)pyridine [65] 

HO 

O 

85 

O Pr i 

TBDPSCl, DMAP 

imidazole, DMF, 25 oC, 60 h 

100% 

TBDPSO 

O 

86 

O Pr i 

(2R,3S,8S,10S)-10-(tert-Butyldiphenylsiloxy)-2-isopropyl-3-methyl-8-vinyl-1,7dioxaspiro[5.5]undecane 

(86): [65] 

To a soln of alcohol 85 (4.470 g, 17.6 mmol), imidazole (2.64 g, 38.7 mmol) and DMAP 

(220 mg, 1.8 mmol) in dry DMF (300 mL) at 25 8C was added TBDPSCl (4.83 g, 17.6 mmol), 

and the mixture was stirred for 60 h. To this soln was added pentane (500 mL) and H 2O 

(300 mL). The aqueous phase was extracted with pentane (2 ” 100 mL), and the organic extracts 

were combined and dried (Na 2SO 4). The extracts were concentrated and the residue 

was purified by flash chromatography to give silyl ether 86 as a clear viscous oil; yield: 

8.67 g (100%). 

4.4.17.5.1.2 Variation 2: 

Using Butyllithium 



The reaction of butane-1,4-diol (87) with tert-butyldiphenylsilyl chloride at ±788C using 

butyllithium as a base gives the monosilylation product 88 in high yield (Scheme 43). [89] 

This useful method of desymmetrizing a diol is undoubtedly assisted by the large steric 

bulk of the tert-butyldiphenylsilyl group. 


Scheme 43 Monosilylation of Butane-1,4-diol with tert-Butyldiphenylsilyl Chloride and 

Butyllithium [89] 

HO 

87 

OH 

TBDPSCl (0.33 equiv), BuLi (0.33 equiv) 

THF, −78 oC to rt 

90% 

HO 

88 

OTBDPS 

4-(tert-Butyldiphenylsiloxy)butan-1-ol (88): [89] 

A soln of butane-1,4-diol (6.0 g, 66.6 mmol) in THF (35 mL) was cooled to ±788C under N 2, 

and the resulting white suspension was treated in dropwise fashion, with vigorous stirring, 

with 2.5 M BuLi in hexanes (8.9 mL, 22.2 mmol, 0.33 equiv). The mixture became 

very viscous. After being stirred for an additional 5 min, the mixture was treated in dropwise 

fashion with TBDPSCl (5.76 mL, 22.2 mmol, 0.33 equiv), and the resulting mixture 

was allowed to warm to rt, which gave a white suspension. After being stirred at rt for 

40 min, the mixture was treated with H 2O (35 mL) and sat. aq NH 4Cl (35 mL), and the separated 

aqueous layer was extracted with Et 2O (3 ” 50 mL). The combined organic extracts 

were dried (MgSO 4), filtered, concentrated under reduced pressure, and chromatographed 

(hexanes/EtOAc 100:15) to give 88 as a colorless oil; yield: 6.58 g (90%). 

4.4.17.5.2 Method 2: 

Silylation ofAlcohols with tert-Butyldiphenylsilyl 

Trifluoromethanesulfonate 

The more reactive tert-butyldiphenylsilyl trifluoromethanesulfonate (TBDPSOTf) is used 

to silylate hindered alcohols that will not react with tert-butyldiphenylsilyl chloride. An 

example is silylation of the breynolide intermediate 89 to give ether 90 (Scheme 44). [90] 

As with other silyl triflates, this reagent is commonly used with 2,6-lutidine in dichloromethane. 

Scheme 44 Silylation with tert-Butyldiphenylsilyl Trifluoromethanesulfonate [90] 

CO2Me 

H 

HO OMEM 

H 

S 

89 



TBDPSOTf, 2,6-lut 

CH2Cl2, 0 oC to rt 

94% 

TBDPSO 

H 

90 

S 

CO 2Me 

H OMEM 

Methyl (3R,3aR,6S,7S,7aS)-3-(tert-Butyldiphenylsiloxy)-7-[(2-methoxyethoxy)methoxy]octahydrobenzo[b]thiophene-6-carboxylate 

(90): [90] 

A soln of alcohol 89 (1.01 g, 3.16 mmol) in CH 2Cl 2 (25 mL) was cooled to 08C and treated 

with 2,6-lutidine (3.65 mL, 31.6 mmol) and TBDPSOTf (2.45 g, 6.32 mmol). The mixture 

was stirred at 08C for 30 min and at rt for 2 h, and then was quenched with sat. NaHCO 3 

soln. After the addition of CH 2Cl 2 (100 mL), the pH of the aqueous phase was adjusted to 

ca. 7.0 with 1 M HCl. The aqueous phase was extracted with CH 2Cl 2 (3 ” 150 mL), and the 

combined organic phases were dried (K 2CO 3), filtered, and concentrated in vacuo. Flash 

chromatography (EtOAc/hexanes 2:8) afforded silyl ether 90 as a clear, colorless oil; yield: 

1.66 g (94%). 

4.4.17.5.3 Method 3: 

Migration ofa tert-Butyldiphenylsilyl Group to an Alcohol 

Although the tert-butyldiphenylsilyl group is considered to be less prone to migration 

than the tert-butyldimethylsilyl group (Section 4.4.17.3.3) [91] and other silyl derivatives, it 

can migrate to a hydroxy substituent under basic conditions. Migration of this silyl group 



can occur from a carbon atom or from oxygen. Thus, while it is usually very difficult to 

silylate a tertiary alcohol with tert-butyldiphenylsilyl chloride or trifluoromethanesulfonate, 

intramolecular rearrangement of a hydroxylated tert-butyldiphenylsilane can provide 

a means of accomplishing this protection. An example of tert-butyldiphenylsilyl migration 

is seen in the rearrangement of hydroxylated silane 91 to silyl ether 92 mediated 

by 1,8-diazabicyclo[5.4.0]undec-7-ene as the base (Scheme 45). [92] 

Scheme 45 Rearrangement of a Hydroxylated tert-Butyldiphenylsilane 

to a tert-Butyldiphenylsilyl Ether [92] 

TBDPS 

O OAc 

OH 

91 

OAc 

DBU, CH2Cl2 

rt, 6 h 

90% 

O OAc 

OAc 

OTBDPS 

92 

The severe steric crowding that attends a tertiary tert-butyldiphenylsilyl ether such as 92 

may prompt migration of the silyl residue to a less congested site, if one is available. For 

example, exposure of 93 to sodium hydroxide is sufficient to cause an internal rearrangement 

of the tertiary silyl ether to yield the secondary tert-butyldiphenylsilyl ether 94 

(Scheme 46); [92] the primary tert-butyldimethylsilyl ether remained unaffected under 

these reaction conditions. 

Scheme 46 Rearrangement of a Tertiary tert-Butyldiphenylsilyl Ether to 

a Secondary tert-Butyldiphenylsilyl Ether [92] 

O 

OH OAc 

OTBDPS 

93 

OTBDMS 

NaOH, t-BuOH 

H2O, rt, 3 h 

70% 

TBDPSO OAc 

O 

OH 

94 

OTBDMS 

(4S,5R)-5,6-Diacetoxy-4-(tert-butyldiphenylsiloxy)-4-methylhex-1-en-3-one (92): [92] 

To a soln of enone 91 (150 mg, 0.31 mmol) in CH 2Cl 2 (0.5 mL) at rt was added DBU (10 mg). 

The mixture was stirred for 6 h and then quenched with aq NH 4Cl and extracted with 

Et 2O. The ethereal layer was washed with brine and dried (MgSO 4). After removal of solvent 

under reduced pressure, the residue was chromatographed (silica gel, Et 2O/hexanes 

1:10) to afford enone 92 as a clear oil; yield: 135 mg (90%). 

(2R,3S,4S,5R)-2-Acetoxy-1-(tert-butyldimethylsiloxy)-4-(tert-butyldiphenylsiloxy)-5,6epoxy-3-methylhexan-3-ol 

(94): [92] 

A soln of epoxide 93 (200 mg, 0.35 mmol) in 1 M NaOH/t-BuOH (1:6, 1.0 mL) was stirred at 

rt for 3 h. The mixture was quenched with aq NH 4Cl and extracted with Et 2O. The ethereal 

layer was dried (MgSO 4) and concentrated. The residue was chromatographed (silica gel, 

Et 2O/hexanes 1:4) to afford tertiary alcohol 94 as a clear oil; yield: 140 mg (70%). 

Cleavage 



4.4.17.5.4 Method 4: 

Cleavage of tert-Butyldiphenylsilyl Ethers with 


In common with other silyl ethers, tert-butyldiphenylsilyl ethers are readily cleaved with 

tetrabutylammonium fluoride in tetrahydrofuran. [93] The reagent shows no selectivity for 

tert-butyldiphenylsilyl ethers in different structural environments. For example, the final 

step in a synthesis of (+)-isobretonin A (96) involves deprotection of both the phenolic and 

the secondary tert-butyldiphenylsilyl ether of 95 with tetrabutylammonium fluoride 

(Scheme 47). [94] 


Scheme 47 Cleavage of a Bis(tert-butyldiphenylsilyl ether) with Tetrabutylammonium 

Fluoride [94] 

TBDPSO 

O 

OTBDPS 

O O 

95 

HO 

3 

O 

OH 

O O 

96 

TBAF, THF 

0 oC to rt, 12 h 

83% 

A tert-butyldiphenylsilyl ether is more susceptible to attack by fluoride ion than a triisopropylsilyl 

ether, a property that can be attributed to electron withdrawal by the phenyl 

substituents on silicon. This distinction is manifested, for example, in the selective cleavage 

of the tert-butyldiphenylsilyl ether of 97, yielding alcohol 98 in which the triisopropylsilyl 

ether is left intact (Scheme 48). [65] 

Scheme 48 Cleavage of a tert-Butyldiphenylsilyl Ether with Tetrabutylammonium 

Fluoride [65] 

TIPSO 

O 

CO2H 



TBDPSO 

97 

O 

O 

Pr i 

TIPSO 

TBAF, THF 

rt, 4 d 

68% 

(+)-Isobretonin A (96): [94] 

To a soln of bis(silyl ether) 95 (190 mg, 0.2 mmol) in THF (20 mL) at 08C under argon was 

added 1 M TBAF in THF (0.5 mL, 0.5 mmol). The mixture was allowed to reach rt and was 

stirred for 12 h. The reaction was then quenched with silica gel (2 g) and the soln was concentrated. 

The mixture was dissolved in CH 2Cl 2 (1 mL) and purified by column chromatography 

(silica gel, EtOAc/hexane 1:3) to give isobretonin A (96); yield: 68.38 mg (83%). 

(3Z,3aR,4R,6S,7S,7aS)-3-{(2E,4R,6E)-8-[(2R,4S,8R,9S)-4-Hydroxy-8-isopropyl-9-methyl-1,7dioxaspiro[5.5]undec-2-yl]-4,6-dimethylocta-2,6-dienylidene}-6-methyl-7-(triisopropylsiloxy)octahydrobenzofuran-4-carboxylic 

Acid (98): [65] 

1 M TBAF in THF (0.24 mL, 0.24 mmol) was added to a soln of acid 97 (0.24 g, 0.25 mmol) in 

THF (5.0 mL). The resulting soln was stirred for 3 d at rt, and more TBAF soln (0.12 mL, 

0.12 mmol) was added. Following an additional 1 d of stirring, the soln was concentrated 

O 

CO 2H 

98 

HO 

O 

O 

3 

Pr i 



in vacuo and purified by column chromatography (silica gel, 25±50% EtOAc/hexanes, then 

10±30% MeOH/hexanes) to provide hydroxy acid 98 as a white foam; yield: 0.123 g (68%). 

4.4.17.5.5 Method 5: 


Tetrabutylammonium Fluoride in Acetic Acid 

Acetic acid may be used as a buffer in the cleavage of tert-butyldiphenylsilyl ethers with 

tetrabutylammonium fluoride in tetrahydrofuran. [95] This valuable technique moderates 

the basicity that accompanies this source of fluoride ion and which can sometimes lead to 

destruction of base-sensitive substrates. An application of this method is seen in the final 

step of a synthesis of (+)-acutiphycin (100), where a tert-butyldiphenylsilyl ether is 

smoothly removed from 99 (Scheme 49). [96] An attempt to unmask this ether with unbuffered 

tetrabutylammonium fluoride led to decomposition. 

Scheme 49 Cleavage of a tert-Butyldiphenylsilyl Ether with Tetrabutylammonium 

Fluoride in the Presence of Acetic Acid [96] 

OTBDPS 

O 

OH H 

O O 

O 

99 



OH 

TBAF, AcOH 

THF, rt, 42 h 

95% 

OH 

O 

OH H 

O O 

O 

(+)-Acutiphycin (100): [96] 

A stock soln was prepared by addition of AcOH (0.15 mL) to a soln of 1.0 M TBAF in THF 

(2.5 mL). Silyl ether (+)-99 (6.0 mg, 8.7 ìmol) was dissolved in THF (3.3 mL) and treated 

with a portion of the stock soln (1.5 mL). After 42 h at rt, the mixture was diluted with 

EtOAc (25 mL), washed with sat. aq NaHCO 3 (2 ” 15 mL) and brine (15 mL), dried (MgSO 4), 

filtered, and concentrated. Flash chromatography (hexane/EtOAc 2:1) afforded (+)-100 as a 

colorless, amorphous solid; yield: 3.8 mg (95%). 

4.4.17.5.6 Method 6: 


Tris(dimethylamino)sulfur (Trimethylsilyl)difluoride 

The mild fluoride source tris(dimethylamino)sulfur (trimethylsilyl)difluoride (TASF) [59] 

can be employed to cleave a tert-butyldiphenylsilyl ether in the presence of certain other 

silyl ethers, including a tert-butyldimethylsilyl ether. This valuable selectivity arises from 

the increased propensity of a silicon atom to suffer nucleophilic attack when it carries 

aryl substituents as compared to alkyl groups. A demonstration of the unique selectivity 

of tris(dimethylamino)sulfur (trimethylsilyl)difluoride has been provided in the conversion 

of the bis(silyl ether) 101 into alcohol 102 (Scheme 50). [97] 


100 

OH

Scheme 50 Selective Cleavage of a tert-Butyldiphenylsilyl Ether with Tris(dimethylamino)sulfur 

(Trimethylsilyl)difluoride [97] 

TBDMSO 

TBDPSO 

101 

O 

O 

O 

Bu t 

TASF (1.2 equiv) 

DMF, 0 oC to rt 

84% 

TBDMSO 

(2R,5S,6S,9R)-2-tert-Butyl-6-[(1E,3S)-3-(tert-butyldimethylsiloxy)-2-methylhexa-1,5-dienyl]- 

8-(hydroxymethyl)-9-methyl-1,3-dioxaspiro[4.5]dec-7-en-4-one (102): [97] 

To a 08C soln of bis(silyl ether) 101 (57 mg, 0.080 mmol) in DMF (0.500 mL) was added 

1.30 M TASF in DMF (0.073 mL, 0.095 mmol). The reaction was stirred at 0 8C for 2 h, then 

warmed to rt for 2 h. The mixture was diluted with EtOAc and washed with pH 7 buffer. 

The aqueous layer was extracted with EtOAc (3 ” 10 mL) and the combined organic layers 

were dried (MgSO 4), filtered and concentrated in vacuo. The crude oil was purified by 

chromatography (silica gel, Et 2O/hexanes 1:1) to give 102; yield: 32 mg (84%). 

4.4.17.5.7 Method 7: 


Hydrogen Fluoride±Pyridine Complex 

Hydrogen fluoride±pyridine complex in tetrahydrofuran [98] and hydrogen fluoride in 

aqueous acetonitrile [99] are effective reagents for unmasking a tert-butyldiphenylsilyl 

ether. They are relatively unselective but are valuable for cleaving a tert-butyldiphenylsilyl 

ether where basic conditions (e.g., see Section 4.4.17.5.5) cannot be employed. An application 

of the hydrogen fluoride±pyridine reagent is seen in the deprotection of the tertbutyldiphenylsilyl 

ether 103 to give alcohol 104 (Scheme 51), an intermediate in a route 

to (+)-acetoxycrenulide. [100] 

Scheme 51 Cleavage of a tert-Butyldiphenylsilyl Ether with Hydrogen 

Fluoride±Pyridine Complex [100] 

TBDPSO 

O 

O H H 

103 



HF py 

MeCN, H2O, 6 h 

85% 

HO 

O 

104 

102 

O 

HO 

O H H 

H OAc 

H OAc 

(4S,5R,7R,7aS,8aS)-5-Acetoxy-4-[(1R)-4-hydroxy-1-methylbutyl]-7-methyl-3,4,5,6,7,7a,8,8aoctahydro-1H-cyclopropa[3,4]cycloocta[1,2-c]furan-1-one 

(104): [100] 

A soln of silyl ether 103 (153 mg, 0.27 mmol) in MeCN (8 mL) was treated with HF·py soln 

[prepared by adding 48% HF (1 mL) to a mixture of MeCN (1 mL) and pyridine (2.4 mL) at 

08C]in three equal aliquots (0.33 mL each) over 6 h. The mixture was then diluted with 

H 2O and extracted with EtOAc. The combined organic extracts were washed with 5% 

HCl, sat. NaHCO 3 soln, and brine prior to drying and solvent evaporation. Chromatography 

of the residual gel (EtOAc/hexanes 9:1) afforded alcohol 104 as a colorless oil; yield: 

77 mg (85%). 

O 

O 

Bu t 



4.4.17.5.7.1 Variation 1: 

Cleavage with Hydrogen Fluoride±Triethylamine Complex 

The use of triethylamine in place of pyridine with hydrogen fluoride renders the fluoride 

ion a potent nucleophile while suppressing side reactions that occasionally result from 

acid catalysis by hydrogen fluoride±pyridine complex. The hydrogen fluoride±triethylamine 

system in acetonitrile as the solvent is particularly useful for cleaving tert-butyldiphenylsilyl 

ethers in structures that contain acid-sensitive functional groups. The deprotection 

of tert-butyldiphenylsilyl ether 105, which bears numerous appendages that 

would be susceptible to acidic hydrolysis, illustrates an application of this reagent 

(Scheme 52). The resultant primary alcohol 106 was a key intermediate in a synthesis of 

(+)-damavaricin D. [101] 

Scheme 52 Cleavage of a tert-Butyldiphenylsilyl Ether with Hydrogen Fluoride±Triethylamine 

Complex [101] 

MOMO 

O 

OMOM 

O 

OMOM 



O 

SiMe 3 

O OAc OAc O O OTBDPS 

O O 

105 

MOMO 

O 

Et3N HF, MeCN, reflux, 12 h 

89% 

OMOM 

O 

OMOM 

O 

SiMe3 

O OAc OAc O O OH 

106 

O O 

2-(Trimethylsilyl)ethyl 8-Allyloxy-5-[(2E,4S,5S,6R,7R,8R,9R,10R,11R,12R)-5,7-diacetoxy-8- 

(allylcarbonyloxy)-13-hydroxy-9,11-(isopropylidenedioxy)-2,4,6,10,12-pentamethyl-1-oxotridec-2-enyl]-1,4,6-tris(methoxymethoxy)-3,7-dimethylnaphthalene-2-carboxylate 

(106): [101] 

A soln of silyl ether 105 (0.70 g, 0.53 mmol) and Et 3N·HF (250 mg, 2.1 mmol) in MeCN 

(6.0 mL) was heated at reflux for 12 h. The soln was allowed to cool to 238C then partitioned 

between Et 2O (400 mL) and H 2O (150 mL). The organic phase was washed with 

NaHCO 3 soln (50 mL) and H 2O (50 mL), dried (MgSO 4), filtered, and concentrated, which 

afforded a yellow oil. Purification of the crude product by flash chromatography 

(EtOAc/hexanes 3:7) gave the alcohol 106 as a ca. 1:1 mixture of atropisomers (white 

foam); yield: 0.51 g (89%). 


4.4.17.6 Other Silyl Ethers 



The need for selectivity in the protection of alcohols has brought forth a suite of silylating 

agents bearing a variety of substituents at the silicon atom that extend beyond the structural 

types described in Sections 4.4.17.1±4.4.17.5. Silyl ethers prepared with these reagents 

possess reactivity toward cleavage which varies widely and which can be ªtunedº 

to particular applications. The combination of steric and electronic effects of substituents 

at silicon in these silyl ethers leads to properties that are often difficult to predict, and 

most of the information about silyl ethers in this group has been obtained from empirical 

observation. 

Although ethers in this group have been less extensively exploited in synthesis than 

the silyl ethers described in the foregoing sections, specific examples suggest that they 

can play a valuable role in the differential protection of alcohols during a complex synthesis, 

and may find more general application as their reactivity becomes better understood. 

All of the silyl ethers in this group can be prepared by one or more of the methods described 

for silyl ethers in Sections 4.4.17.1±4.4.17.5, the most frequently used method being 

reaction of an alcohol with either the silyl chloride, bromide or triflate. The subtle but 

real variation in the behavior of these silyl ethers towards cleavage reagents forms the basis 

for their utility as specific protection devices for alcohols. 

Thus, diethylisopropylsilyl ethers are more stable than triethylsilyl ethers, but are 

more easily cleaved than tert-butyldimethylsilyl ethers. Conditions have been described 

that result in retention of a secondary tert-butyldimethylsilyl ether while removing a diethylisopropylsilyl 

ether. [101] As an operational principle, a diethylisopropylsilyl ether is 

considered to be approximately 90 times more stable than a trimethylsilyl ether towards 

acidic hydrolysis and 600 times more resistant than a trimethylsilyl ether towards cleavage 

with fluoride ion. 

An isopropyldimethylsilyl ether [102] is even more labile towards acidic hydrolysis 

than a diethylisopropylsilyl ether, and is cleaved rapidly in aqueous acetic acid at room 

temperature. [103] Other hydroxy protecting groups, such as a tetrahydropyranyl ether, 

will survive conditions that typically cleave an isopropyldimethylsilyl ether. 

Triphenylsilyl ethers are usually prepared from the corresponding silyl chloride, [104] 

and are quite labile towards basic hydrolysis. They are approximately 400 times less reactive 

towards acidic cleavage than trimethylsilyl ethers. 

Methyldiphenylsilyl ethers [105] are intermediate in stability between trimethylsilyl 

and triethylsilyl ethers. Unlike most trimethylsilyl ethers, they will survive chromatography 

on silica gel, but a serious limitation is that they do not withstand many of the common 

reagents used in synthesis, including acids, bases, reducing agents, and oxidants. 

tert-Butylmethoxyphenylsilyl ethers provide protection for alcohols where selectivity 

is desired in the presence of other silyl ethers, especially tert-butyldimethylsilyl or tertbutyldiphenylsilyl 

ethers. [106] The tert-butylmethoxyphenylsilyl ether is appreciably more 

stable towards acidic hydrolysis than a tert-butyldimethylsilyl ether. On the other hand, a 

tert-butylmethoxyphenylsilyl ether is cleaved more readily with fluoride than either a 

tert-butyldimethylsilyl or a tert-butyldiphenylsilyl ether, allowing for removal of the former 

in the presence of the latter two classes of ethers. [107] Primary, secondary, and tertiary 

alcohols can be converted quite readily into their tert-butylmethoxyphenylsilyl ethers, 

but the fact that the silicon atom in this class of ethers is stereogenic will result in diastereomers 

if the parent alcohol is chiral. 

Tris(trimethylsilyl)silyl (sisyl) ethers are among the most stable of the silyl ethers. [108] 

Readily prepared by reaction of an alcohol with tris(trimethylsilyl)silyl chloride in the 

presence of 4-(dimethylamino)pyridine, these ethers withstand strongly acidic conditions 

that will cleave most other silyl ethers. Tris(trimethylsilyl)silyl ethers are cleaved with tetrabutylammonium 

fluoride, however, and they can be cleanly removed by photolysis in 

methanol. 



tert-Butoxydiphenylsilyl ethers possess stability towards acidic hydrolysis that is 

comparable to that of tert-butylmethoxyphenylsilyl ethers. [109] Like the latter group, they 

are also quite labile towards fluoride. An advantage of the tert-butoxydiphenylsilyl group 

over the tert-butylmethoxyphenylsilyl residue is that it is achiral and, hence, does not produce 

diastereomeric silyl ethers. 

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