R. Breinbauer Textbooks of Heterocyclic Chemistry

R. Breinbauer
Textbooks of Heterocyclic Chemistry
General Textbooks of Organic Chemistry
Textbooks of Pharmaceutical Chemistry
H. Beyer, W. Walter, "Lehrbuch der Organischen Chemie", 23rd ed., S. Hirzel, Stuttgart-Leipzig 1998,
1176 pages.
(Although not very helpful when it comes to the description of mechanisms, it is still the only textbook
which informs about organic compounds and its properties. Excellent chapters about heterocycles.)
E. Mutschler, G. Geisslinger, H. K. Kroember, M. Schäfer-Korting, "Mutschler-Arzneimittelwirkungen", 8th
ed., Wiss. Verlagsgesellschaft, Stuttgart 2001, 1186 pages.
(A classic textbook of pharmacology and toxicology which informs well about the structure and
properties of drugs.)
Reference Books
Merck & Co., "The Merck Index", 13th ed., Merck & Co., Inc, Whitehouse Station, NJ 2001, 1818 pages.
(A comprehensive reference book of all drugs and most bioactive compounds. The information is
very densce. For organic chemists very interesting is a chpater with 446 name reactions.)
Textbooks of Heterocyclic Chemistry
T. Eicher, S. Hauptmann, "The Chemistry of Heterocycles", Wiley-VCH, Weinheim 2003, 572 pages.
(A very well understandable and very well organized introduction into the most important topics of
heterocyclic chemistry. Good for learining, less useful for research.)
T. L. Gilchrist, "Heterocyclenchemie", Wiley-VCH, Weinheim 1995, 445 pp.
(A very good introductory textbook of heterocyclic chemistry.)
A. Katritzky (Ed.), "Comprehensive Heterocyclic Chemistry II", 2nd ed., Pergamon, Oxford 1996, Vol. 1-11.
(One of the most useful reference works for heterocyclic chemistry. Not textbook but very helpful for
research.)
"Science of Synthesis", Thieme, Stuttgart 2000-2004, Vol. 9-17.
(Building on the excellent features of Houben-Weyl this new edition offers very well structured,
comprehensive and up-to-date information about heterocyclic compounds. In addition, experimental
procedures for the most important reactions are given. This terrific source of reference should be
consulted first when studying literature for a research project!)
J. A. Joule, K. Mills, "Heterocyclic Chemistry", 4th ed., Blackwell Science, Oxford 2000, 589 pp.
(The best and most informative textbook of heterocyclic chemistry. Includes the most recent updates
of modern synthetic methods and is very well referenced. This book fulfills all needs both for learning
and research.)
A. R. Katritzky, A. F. Pozharskii "Handbook of Heterocyclic Chemistry", 2nd ed., Pergamon, Oxford 2000,
734 pp.
(A more comprehensive textbook with lots of information but not easy to read. More reference book
than text book.)
Book Series
"Advances in Heterocyclic Chemistry", Elsevier, San Diego 1963-2005, Vol. 1-88.
(A series of monographs which contains high quality reviews of very specific topics of heterocyclic
chemistry.)
"Progress in Heteroyclic Chemistry", Pergamon, Oxford 1989-2003, Vol. 1-15.
(Provides an annual literature update and some review articles)
A. Weissberger, E. C. Taylor, P. Wipf (Ed.)"The Chemistry of Heterocyclic Compounds", Wiley-Interscience,
London 1970-2004, Vol. 1-62.
(Each volume is dedicated to a specific parent class of heterodycles. Very comprehensive in its
information content.)
Textbooks1-051005

R. Breinbauer
Best Selling Pharmaceuticals
World's Top Selling Drugs in 2004:
O
N
H
N
N
Lipitor TM
N
H
N
N
S
F
Atorvastatin
(Pfizer)
OH
OH
(HMG-CoA-Reductase Inhibitor)
10.3 billion $
Zyprexa TM
Olanzapine
(Eli Lilly)
(Serotonin and Dopamine antagonist)
4.8 billion $
CO 2 H
O
O
HO
O
H
Zocor TM
Simvastatin
(Merck)
O
N
H
O
O
(HMG-CoA-Reductase Inhibitor)
6.1 billion $
Cl
O
Norvasc TM
Amlodipine
(Pfizer)
O
O NH 2
(Ca-Channel blocker)
4.5 billion $
H
N
S
N
O
S
N
H CO 2 CH 3
Cl
N
CH 3
H 3 C OCH 2 CF 3
Prevacid TM
Lansoprazole
(Abbott, Takeda)
(Gastric Proton Pump Inhibitor)
4.0 billion $
Plavix TM
Clopidogrel
(BMS, Sanofi-Aventis)
(Platelet Aggregation Inhibitor)
3.7 billion $
NHH 3 *HCl
H 3 CO
O
HO
H 3 C
H
N
N
F
F
O
S
Nexium TM
Omeprazol
H 3 C
H
H
N
(Astra Zeneca)
CH 3
H 3 C OCH 3
(Gastric Proton Pump Inhibitor)
3.8 billion $
Advair TM
COSCH 2 F
OCOC 2 H 5
CH 3
Fluticasone Propionate
(GlaxoSmithKline)
(against Asthma)
3.7 billion $
TopPharmaceuticals1-061005
34 kDa glycosylated protein (165 aa)
Erypo TM
Recombinant Erythropoietin
(Johnson&Johnson)
(growth factor for erythrocyctes)
4.0 billion $
Cl
Cl
Zoloft TM
Sertraline
(Pfizer)
(Selective Serotonin Reuptake Inhibitor)
3.4 billion $
data source: www.forbes.com

R. Breinbauer Monocyclic Hetero Systems with Trivial Names
Certain 5- and 6-membered monocyclic hetero systems, both saturated and unsaturated are indexed at trivial names. Presence of a triple
bond in addition to the maximum number of noncumulative double bonds is expressed by the subtractive prefix "didehydro".
N
N
H
N
H
N N N
H
N
O
N
O
N
H
Pyridine Piperidine 1H-Pyrrole 2H-Pyrrole 3H-Pyrrole Pyrrolidine
Furazan
Morpholine
N N
N
N
N
N
H
N
N
H
N N
H
N
N
N N
N
O
Pyridazine
Pyrimidine
Pyrazine
Piperazine
1H-Pyrazole 3H-Pyrazole 4H-Pyrazole
Isoxazole
N
H
N
N
N
N
N
HN N
H
N
H
NH
O
O
O
1H-Imidazole 2H-Imidazole 4H-Imidazole
Pyrazolidine
Imidazolidine
2H-Pyran
4H-Pyran
Furan
N
Se
N
S
Se
Te
S
N
H
H
N
HB BH
HN NH B
H
O
HB BH
O O B
H
S
HB BH
S S B
H
S
Isoselenazole
Isothiazole
Selenophen
Tellurophen
Thiomorpholine
Borazine
Boroxin
Borthiin
Thiophen
TrivialHeteroMono-120504

R. Breinbauer HANTZSCH-WIDMAN - Stems for Monocyclic Hetero Systems
Rings Containing Nitrogen
Rings Containing No Nitrogen
No. of
members in
the ring
Unsaturated
Saturated
No. of
members in
the ring
Unsaturated
Saturated
3
-irine
-iridine
3
-irene
-irane
4
-ete
-etidine
4
-ete
-etane
5
-ole
-olidine
5
-ole
-olane
6
-ine**
*
6
-in*
-ane**
7
-epine
*
7
-epin
-epane
8
-ocine
*
8
-ocin
-ocane
9
-onine
*
9
-onin
-onane
10
-ecine
*
10
-ecin
-ecane
* Saturation is expressed by detachable prefixes such as "tetrahydro-", "hexahydro", etc. The prefix
"perhydro-" is not used.
** When the Hantzsch-Widman prefixes "phospha", "arsa" , or "stiba" are immediately followed by
the Hantzsch-Widman stems "-in" or "-ine", they are replaced by the prefixes "phosphor", "arsen"
or "stibin", respectively.
Hantzsch-Widman-120504
* When the Hantzsch-Widman prefixes "phospha", "arsa" , or "stiba" are immediately followed by
the Hantzsch-Widman stems "-in" or "-ine", they are replaced by the prefixes "phosphor", "arsen"
or "stibin", respectively.
** This stem is not used for saturated hetero systems based on the elements Si, Ge, Sn, or Pb.
Saturation of these rings is indicated by detachable prefixes such as "tetrahydro-", "hexahydro",
etc. when Hantzsch-Widman names are used. Saturation of 6-membered hetero systems
based on the elements B or P is denoted by the stem "-inane".

R. Breinbauer Heterocycles as Parent Rings
The following list contains heterocycles which can function as parent rings in ascending order:
H
P
S
S
S
O
O
O
O
S
O
H
N
H
N
N
Phosphindole (1) Thiophene (2)
Thianthrene (3)
Furane (4)
4H-Pyrane (5) Isobenzofurane (6)
2H-Chromene (7)
Phenoxathine (8)
Pyrrole (9)
Imidazole (10)
H
N
N
S
N
O
N
N
N
N
N
N
N
N
N
N
Pyrazole (11) Isothiazole (12) Isoxazole (13) Pyridine (14) Pyrazine (15)
Pyrimidine (16)
Pyridazine (17)
1H-Pyrrolizine (18)
Indolizine (19)
NH
Isoindole (20)
N
3H-Indole (21)
H
N
Indole (22)
H
N
N
Indazole (23)
N
N
H
N
N
7H-Purine (24)
N
4H-Quinolizine (25)
N
Isoquinoline (26)
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
Quinoline (27)
Phthalazine (28)
1,8-Naphthyridine (29)
Quinoxaline (30)
Quinazoline (31)
Cinnoline (32)
Pteridine (33)
N
H
N
N
N
HN
N
N
N
N
N
4aH-Carbazole (34)
Carbazole (35)
Phenanthridine (36)
Acridine (37)
Perimidine (38)
1,7-Phenanthroline (39)
Phenazine (40)
Hg
As
H
P
H
N
H
N
H
N
H
N
N
H
N
H
N
H
Te
Se
S
O
Phenomercazine (41)
Phenarsazine (42)
Phenophosphazine (43)
Phenotellurazine (44)
Phenselenazine (45)
Phenothiazine (46)
Phenoxazine (47)
Heterocycles1-240504

R. Breinbauer
Heterocyclic Chemistry - Week 1
11.-12.10.2005
Introduction:
Definition
Classification
Industrial Importance
Top 10 Pharmaceuticals
Nomenclature:
HANTZSCH-WIDMAN-System
Replacement Nomenclature
Literature
T. Eicher, S. Hauptmann, "The Chemistry of Heterocycles", Wiley-VCH, Weinheim 2003, 572 pages.
(Good chapter about the nomenclature of heterocycles.)
T. L. Gilchrist, "Heterocyclenchemie", Wiley-VCH, Weinheim 1995, 445 pp.
(Very good introductory chapter about heteroaromaticity.)
J. A. Joule, K. Mills, "Heterocyclic Chemistry", 4th ed., Blackwell Science, Oxford 2000, 589 pp.
(Good introduction into heteroaromaticity.)
Aromaticity:
Theoretical Criteria
Experimental Properties
Benzene
Electronpoor 6-membered ring heteroaromatics:
- Pyridine
- Pyridinium Ion
- Pyrylium Ion
Cyclopentadienyl-Ion
Electronrich 5-membered ring heteroaromatices
- Pyrrol
- Furan
- Thiophen
Dipolmoment
Bond Lengths
Solubility
Boiling Point
Lecture1-121005

R. Breinbauer
Heterocyclic Chemistry - Week 2
18.-19.10.2005
Aromaticity:
Reactive Behaviour of Different Aromatics
Resonance Energy
1H-NMR Data
Nucleobases
Tautomers
- Iminol vs. Amido
- Amin vs. Imino
- Thion vs. Thiol
General Principles of Reactions with Heterocycles:
Electrophilic Reaction on Imino-N
- Basicity of Nitrogen Heterocycles
- Nuleophilicity: Steric and Electronic Influences
Literature
K. Groebke, J. Hunziker, W. Fraser, L. Peng, U. Diederichsen, K. Zimmermann, A. Holzner, C. Leumann, A.
Eschenmoser, "Warum Penotse- und nicht Hexose-Nukleinsäuren, Teil V" Helv. Chim. Acta 1995, 81,
375-474.
(In this landmark publication Eschenmoser discusses within a 2 page long footnote why the C=O bond
is so much stronger than the C=C and C=N bond, a fact which is of utmost importance for
Watson-Crick base pairing.)
J. A. Joule, K. Mills, "Heterocyclic Chemistry", 4th ed., Blackwell Science, Oxford 2000, 589 pp.
(Contains an illuminating chapter about general reactivity principles. In addition, for each major
structure class a chapter describes the general behaviour of this class in the most reaction types.)
Electrophilic Reactions
- Reactive Behaviour of 5-Ring and 6-Ring Heterocycles
- Activation of Pyridines for S E Ar (N-Oxides, EDG-groups)
Nucleophilic Substitution
- Reactive Behaviour of 6-Ring Heterocycles (Substituents, Benzofused Rings)
- Synthesis of Ciprofloxacin
Radical Reactions
- Nuleophilic Radicals (Minisci-Reaction)
Lecture2-181005

R. Breinbauer
Heterocyclic Chemistry - Week 3
25.-26.10.2005
General Principles of Reactions with Heterocycles:
Literature
Radical Reactions
- Nucleophilic Radicals (Minisci-Reaction)
- Electrophilic Radicals
Lithiation Reactions
- Metallation
Governing Factors (CH-Acidity, Complexation, Directing Groups, Base, Solvent)
Metalation of Heteroaromatics
Side Chain Metalation
- Metal-Halogen Exchange
Metal-Halogen Exchange avoiding Electrophile Generation (2 equiv tBuLi)
Transition-Metal Cross-Coupling Reactions
- Oxidative Addition
- Transmetalation
- Cross-Coupling Reactions (Stille, Suzuki, Kumada, Negishi, Sonogashira)
J. A. Joule, K. Mills, "Heterocyclic Chemistry", 4th ed., Blackwell Science, Oxford 2000, 589 pp.
(Contains an illuminating chapter about general reactivity principles. For each major structure class a
chapter describes the general behaviour of this class in the most reaction types.)
WWW-links
http://www.chem.harvard.edu/groups/myers/chemistry115handouts.htm
(Prof. A. G. Myers at Harvard has made his terrific Chem115 handouts accessbile for the public. A
must read for every synthetic chemist. For this course in particular the handouts about Directed
Lithiation, Suzuki reaction, and Stille reaction are of special relevance.)
Oxidation-
- Resistance of Electronpoor Heteraromatics
- Conversion of Furans to Carboxylic Acids
Reduction
- Hydrogenation (pH-Dependence of Selectivitiy)
Lecture3-251005

R. Breinbauer Stability of Lithium-Reagents in Solution
Organolithium reagents react with etheral solvents under elimination of ethylene:
Half-Lives of BuLi in Etheral Solvents
-70 °C -40 °C -20 °C 0 °C +20 °C +35 °C
O
n-BuLi
O
Li
> -60 °C
+
H
OLi
t-BuLi
DME
t-BuLi
THF
11 min

R. Breinbauer
Heterocyclic Chemistry - Week 4
2.11.2005
General Concepts for the Synthesis of Heterocycles:
Ring Closures Involving Ionic Cyclizations
- C-X Bond Formation
- C-C Bond Formation
- Application: Hantzsch Dihydropyridine Synthesis
Synthon Selection by Analysis of Oxidation Levels of Ring Atoms
Literature
T. L. Gilchrist, "Heterocyclenchemie", Wiley-VCH, Weinheim 1995, 445 pp.
(Contains a very long and deep discussion about general principles and strategies for the synthesis
of heterocycles.)
J. A. Joule, K. Mills, "Heterocyclic Chemistry", 4th ed., Blackwell Science, Oxford 2000, 589 pp.
(Contains a short chapter about synthesis concepts.)
Important Ring Closing Reactions
- Heterocycles with 1 Heteroatom
- Heterocycles with 2 Adjacent Heteroatoms
- Heterocycles with 2 Non-Adjacent Heteroatoms
Mechanistic Understanding of Ring Closures
- Nucleophilic Attack on Electrophiles (tet, trig, dig)
Bürgi-Dunitz - Trajectorie
- Baldwin Rules
Lecture4-021105

R. Breinbauer
Heterocyclic Chemistry - Week 5
8.-9.11.2005
General Concept for the Synthesis of Heterocycles:
Mechanistic Understanding of Ring Closures
- Baldwin Rules
Intramolecular Substitution at Saturated C-Atom
- Rate Dependence on Ring Size
- Thorpe-Ingold Effect, gem-Dimethyl Effect (Activation Entropy)
- Feist-Benary- Furan Synthesis (5-exo-tet)
Literature
T. L. Gilchrist, "Heterocyclenchemie", Wiley-VCH, Weinheim 1995, 445 pp.
(Contains a very long and deep discussion about general principles and strategies for the synthesis
of heterocycles.)
J. A. Joule, K. Mills, "Heterocyclic Chemistry", 4th ed., Blackwell Science, Oxford 2000, 589 pp.
(Contains a short chapter about synthesis concepts.)
Intramolecular Addition at Carbonyl C-Atom
- Combes Quinoline Synthesis (6-exo-trig)
Intramolecular Addition across other Double Bonds
- Attack at Electrophilic Nitrogen (Synthesis of Quinoxalinoxide)
- Hegedus Indole Synthesis (5-exo-trig)
- Activation of Double Bonds through Electrophile
- Pictet-Spengler Isoquinoline Synthesis (6-endo-trig)
Cyclisation at Triple Bonds
- Attack at Nitrile, Alkyne, Isonitrile
- TOSMIC-Reagent
Carbene & Nitrene Cyclisation
- Addition across Multiple Bonds
- Insertion into CH-Bonds
Electrocyclic Reactions
- Woodward-Hoffmann-Rules
Lecture5-081105

R. Breinbauer 1,3 - Dipoles
a
b
c
Type 1
a
b
c
a
b
c
Type 2
a
b
c
R'
R'
Azide
Diazoalkane
Nitrous oxide
R
R
N
N N
N
C N
R
N
O N
R
R
N
N
N
C
R
N
O
N
N
N
Azomethine imine
Azoxy compound
Azomethine ylide
R
R
N
C N R''
R
R'
N
O N R''
R'
N
C C R''
R R''
R
R
N
C N R''
R
R'
N
O N R''
R'
N
C C R''
R R''
Nitrile imine
R
N
N
C
R'
R
N
N
C
R'
Nitrone
O
R'
N
C
R''
O
R'
N
C
R''
R''
R''
Nitrile ylide
R
C
R
N
C
R'
R
C
R
N
C
R'
Carbonyl oxide
O
O
C
R
O
O
C
R
R
R
Nitrile oxide
O
N
C
R'
O
N
C
R'
Ozone
O
O
O
O
O
O
Out of 12 thinkable 1,3-dipoles containing C, H, N, and O 9 have been used for [3+2]-cycloadditions.
1,3-Dipols1-100102

R. Breinbauer Heterocycles made by 1,3 - Dipolar Cycloaddition
N
N
N
N
O
N
N
S
X
N
N
N
N
N
N
N
N
N N
X = O, S, NR
Imidazoles
Imidazolidines
1,2,4-Triazolidines
N
N
N
N
N
N
N
N
N
N
O
N
Oxazoles
O
N
Oxazolines
O
N
Oxazolidines
Pyrazoles
Pyrazolines
N
N
N
N
N
N
O
N
O
N
O
N
O
N
NR
O
Isoxazoles
Isoazolines
Isoxazolidines
Pyrazolidines
N
N
N
N
N
H
N
N
N
N
N
N
N
O
N
N
O
N
N
1,2,3-Triazoles
1,2,3-Triazolines
1,2,4-Oxadiazoles
1,2,4-Oxadiazolines
N
N
N
1,2,4-Triazoles
X
N
N
N
X N
NH
N
1,2,4-Triazolines
X
N
N
N
X = O, S, NR
S
N
S
N
S
N
N
Isothiazoles Isothiazolines 1,2,4-Thiadiazoles
1,3-Dipol-Cycloaddition-091105
A. R. Katritzky, A. F. Pozharskii "Handbook of Heterocyclic Chemistry", 2nd ed., Pergamon, Oxford 2000.

R. Breinbauer Synthesis of 1,3-Dipols I
R
H
Nitrile Oxides:
N
OH
R
NO
H 2
H
Ph
Nitrile Imides:
R 2
R 1
NCS
R
N
N
N
N
N
Cl OH
HN Ph
N C O R O
N O
H O
R 1 HN R 2
N
Et 3 N
Cl
h*ν or ∆
Et 3 N
Et 3 N
R N O
Nitrile Oxides
R 1 N N R
2
Nitrile Imides
Nitrile Ylides:
Ar
N R 1
Cl
H R 2
Ar
N
R 1 R 2
R N
R
N
PhS SiMe 3
Et 3 N
h*ν
CH 2 N 2
h*ν
:CH 2
F
Ar
R 1
N C
R 2
Aromatic Nitrile Ylides
R N CH 2
Aliphatic Nitrilmethylide
Nitrile Imides:
N
S
R O
O
110 - 160 °C
R
N S
Nitrile Sulfides
Nitrones:
R 1
H
R 2
H
R 3
N
OH
R 1
N
OH
HgO
O
R 2 R 3
R 2 R 1
N
R 3 O
Nitrones
1,3-Dipol-Synthesis1-091105
T. L. Gilchrist, "Heterocyclenchemie", Wiley-VCH, Weinheim 1995.

R. Breinbauer Synthesis of 1,3-Dipols II
Azomethinimides:
O
Carbonyl Ylides:
R 1 O
H
N
N R
2
H
R 3
H
H R 3
O
R 1 N
N R
2
Azomethinimides
Ar
O
N 2
H
O
Rh 2 (OAc) 4
Ar O
O
Carbonyl Ylides
N
N R H
Base
N
N R
R = -H, -Ar, -COR, -CO 2 R
Pyridinium N-Imides
Thiocarbonyl Ylides:
R 1 R 2
Azomethin-Ylides:
TMSOTf
R 3
N
TMS
F
R 1 R 2
N CH 2
Ar
Ar
S
Ar
CH 2 N 2 Ar S
-78 °C
N N -40 °C
Ar
Ar
S CH2
N R 3 R 1 R 2
- N 2
Thiocarbonyl Ylides
OTf
Ar
RO 2 C
R 3 N
Azomethin-Ylides
heat
Ar
N CO 2 R
H H
N
RO 2 C
CO 2 R
h*ν
RO 2 C
Ar
H
H
CO 2 R
Ar
N
H
CO 2 R
heat
tautomerism
Ar
H
N
H
CO 2 R
1,3-Dipol-Synthesis2-091105
T. L. Gilchrist, "Heterocyclenchemie", Wiley-VCH, Weinheim 1995.

R. Breinbauer
Heterocyclic Chemistry - Week 6
15.11.2005
General Concept for the Synthesis of Heterocycles:
Cycloaddition Reactions
1,3-Dipolar Cycladdtions
- 1,3-Dipoles: Types and Synthesis
- FMO Considerations
Literature
T. L. Gilchrist, "Heterocyclenchemie", Wiley-VCH, Weinheim 1995, 445 pp.
(Contains a very long and deep discussion about general principles and strategies for the synthesis
of heterocycles.)
Lecture6-151105

R. Breinbauer HUISGEN Azide-Alkyne-Coupling
Review: R. Breinbauer, M. Köhn, ChemBioChem 2003, 4, 1147-1149.
Challenge in Chemical Biology:
A common problem in Chemical Biology is the attachment of a probe molecule to a
biopolymer or the ligation of two entities in a living cell. Such a ligation reaction,
should have the following features:
- works smoothly in high yield
- works under physiological conditions (water, pH 7, RT, air, atmospheric pressure)
- uses bioorthogonal functional groups
- works without addtional reagents
Azide-Alkyne-Coupling:
Cu(I) catalysis allows to run this process at room temperature instead of >130°C typical for
the uncatalyzed version:
V. V. Rostovtsef, L. G. Green, V. V. Fokin, K. B. Sharpless, Angew. Chem. 2002, 114, 2708-2711.
C. W. Tornoe, C. Christensen, M. Meldal, J. Org. Chem. 2002, 67, 3057-3064.
R 1
N
N
N R
2
CuSO 4
ligand (L)
reducing agent
[CuL n ]
+
R 1
H
H
Modification of CMV-Virus:
N
H
O
H
117 eq
N
H
[N 3 ] 60
DYE
HO
:
50 eq CuSO 4
100 eq 2
100 eq TCEP
Activity Based Enzyme Profiling:
O
O
N
H
pH 8
O
COOH
H
O
DYE
phosphate buffer / 5% tBuOH
16 h / 4 °C
N
N
N
Ligand:
N
H
N
O
DYE
60
Q. Wang, T. R. Chan, R. Hilgraf, V. V. Fokin, K. B. Sharpless, M. G. Finn, J. Am. Chem. Soc. 2002, 124,
14397-14402.
N 3 (CH 2 ) 6 OSO 2 Ph (2.5µM)
3
N
N
N
2
Ph
3
Nu
N 3
(CH 2 ) 6
R 1 CuL n
R 1 CuL n
N N
N
R
2
Protein Extract
H
RHODAMINE (20 µM)
4
CuSO 4 (1 mM )
Ligand (2 mM )
TCEP (1 mM )
pH 8 phosphate buffer / 5% tBuOH
1 h / Rt
N
N
+
R 2
N
-
RHODAMINE
N
N
N
(CH 2 ) 6
Azide-Alkyne-Coupling1-091105
A. E. Speers, G. C. Adam, B. F. Cravatt, J. Am. Chem. Soc. 2003, 125, 4686-4687.

R. Breinbauer
Heterocyclic Chemistry - Week 7
22.-23.11.2005
General Concept for the Synthesis of Heterocycles:
Cycloaddition Reactions
1,3-Dipolar Cycladdtions
- 1,3-Dipoles: Types and Synthesis
- FMO Considerations
- Heterocycles Produced by 1,3-Dipolar Cycloadditions
- Huisgen Azide-Alkyne Coupling
Literature
T. L. Gilchrist, "Heterocyclenchemie", Wiley-VCH, Weinheim 1995, 445 pp.
(Contains a very long and deep discussion about general principles and strategies for the synthesis
of heterocycles.)
R. Breinbauer, M. Köhn, "Azide-Alkyne-Coupling: A Powerful Ligation Reaction for Bioconjugate
Chemistry", ChemBioChem 2003, 4, 1147-1149.
Hetero Diels-Alder Reaction
- Jacobi-Reaction
- Enantioselecitve Hetero-Diels-Alder-Reaction: "Mighty Fist"- Cr-salen catalyst
- Synthesis of 1,4-Aminoalcohols
- Diels-Alder-Reaction with Inverse Electron Demand
[2+2]-Cycloaddition
- Synthesis of β-Lactams
- Synthesis of Oxetanes: Paterno-Büchi-Reaction
Cheletropic Reactions
- Aziridination
- SO 2 -Extrusion: Bromoprene-Synthesis
Lecture7-221105

R. Breinbauer
Heterocyclic Chemistry - Week 8
29.-30.11.2005
Synthesis, Reactivity, and Use of Heterocycles:
Literature
3-Ring-Systems:
Epoxides:
Synthesis:
- Direct Oxidation (Ethylene, Butadiene)
- Preparation of Propyleneoxide
- Prileschajew-Oxidation with Peracid
- Corey-Chaykovsky-Reaction with Sulphur-Ylides: Synthesis of Fluconazole
- Becker-Adler-Oxidation
- Sharpless Asymmetric Epoxidation
- Jacobsen Asymmetric Epoxidation: Synthesis of Indinavir
- Shi Asymmetric Epoxidation: Synthesis of Glabroscol
- Jacobsen Hydrolytic Kinetic Resolution (HKR)
T. Eicher, S. Hauptmann, "The Chemistry of Heterocycles", Wiley-VCH, Weinheim 2003, 572 pages.
(Excellent chapters about ring systems.)
J. A. Joule, K. Mills, "Heterocyclic Chemistry", 4th ed., Blackwell Science, Oxford 2000, 589 pp.
(The chapters about small rings are not as comprehensive and terrific as for 5- and 6-membered
rings, but nevertheless worth reading.)
T. L. Gilchrist, "Heterocyclenchemie", Wiley-VCH, Weinheim 1995, 445 pp.
(Descrption of ring systems not very well structured but nevertheless insightful.)
Reactions:
- Reactions with External Nucleophiles
- Payne-Rearrangement
- Conversion of Epoxides to Thiiranes
Oxaziridines:
Synthesis:
- Photoisomerization of Nitrones
- Amination of Carbonyl Compounds
- Oxidation of Imines with Peroxyacids
Reactions:
- DAVIS- Oxaziridine
Lecture8-291105

R. Breinbauer JACOBI - Reaction
R
N
O
R''
R'
O
R
R'
MeO
MeO
OMe
H
N
Boc
O
TosMIC
82 %
MeO
MeO
OMe
N
Boc
90 %
o-dichlorobenzene
reflux
P. A. Jacobi, D. G. Walker, J. Am. Chem. Soc. 1981, 103, 4611.
P. A. Jacobi, D. G. Walker, I. M. A. Odeh, J. Org. Chem. 1981, 46, 2065.
P. A. Jacobi, T. A. Craig, D. G. Walker, B. A. Arrick, R. F. Frechette, J. Am. Chem. Soc. 1984, 106, 5585.
B. Liu, A. Padwa, Tetrahedron Lett. 1999, 40, 1645.
MeO
MeO
OMe
N
MeO
MeO
N O N
OMe
Examples:
O
OMe
O
MeO
O
O
O
O
N
H
N
O
N
O
(rac)-Stemoamide
1) NaBH 4
2) MeOH, H +
3) CH 3 CCSnBu 3 , BF 3
64 % (3 steps)
in situ
epimerization
73 %
MeO
O
O
O
N
H
N
N
O
diethylbenzene
O
182 °C
- MeCN
NiCl 2 , NaBH 4
MeO
MeOH, -30 °C
O
O
O
H
N
N
53 %
O
(H 2 O)
P. A. Jacobi, K. Lee, J. Am. Chem. Soc. 1997, 119, 3409-3410.
O
Imerubrine
J. C. Lee, J. K. Cha, J. Am. Chem. Soc. 2001, 123, 3243-3246.
First example for a highly selective intermolecular cycloaddition-retrofragmentation
O
H
OTBS
O
O
Ph N
tetralin, 205 °C TBSO H
O
O O
O
AcO
O O
52 % (at 90% conv.)
O
exclusive regioisomer
(-)-Teubrevin G
I. Efremov, L. A. Paquette, J. Am. Chem. Soc. 2000, 122, 9324-9325.
O
O
O
O
Jacobi1-080301

R. Breinbauer DAVIS - Oxaziridine
1) Base
R
O
R'
2)
Ph
O
N
SO 2 Ph
O
R'
R
OH
1.5 eq tBuLi
0.2 eq Et 2 NH
O O THF, -78 °C, 1 h
H then 10 eq Davis oxaziridine
OMe
-78 °C to 0 °C, 1 h
O O
OMe
60 %
CMe 3
O O OH OMe
O O
OMe
CMe 3
O
HO
HO O
O
H
CMe
O 3
Me HO O H
O
(rac)-Ginkgolide B
F. A. Davis, L. C. Vishwakarma, J. M. Billmers, J. Finn, J. Org. Chem. 1984, 49, 3241-3243.
F. A. Davis, A. C. Sheppard, Tetrahedron. 1989, 45, 5703.
M. T. Crimmins, J. M. Pace, P. G. Nantermet, A. S. Kim-Meade, J. B. Thomas, S. H. Watterson, A. S.
Wagman, J. Am. Chem. Soc. 2000, 122, 8453-8463.
O
O
O
O
O Ph
O
O TBS
O
O
O
1) 1.5 eq KHMDS
THF, -78 °C
2) 1.5 eq O
Ph N
SO 2 Ph
THF, -78 °C, 45 min
83 %
O
OH
O
O
O
O
Ph
O
O TBS
O
O
O
HO
OH
OH
OH OH
J. D. White, H. Shin, T.-S. Kim, N. S. Cutshall, J. Am. Chem. Soc. 1997, 119, 2404-2419.
OH
OH
OH OH
Euonyminol
O
OH
CO 2 Et
1 eq. KHMDS
2 eq Davis oxaziridine
-78 °C to -20 °C / THF
97 % @ 57 % conv.
OH
O
OH
CO 2 Et
Taxol
P. A. Wender, N. F. Badham, S. P. Conway, P. E. Floreancig, T. E. Glass, C. Gränicher, J. B. Houze, J.
Jänichen, D. Lee, D. G. Marquess, P. L. McGrane, W. Meng, T. P. Mucciaro, M. Mühlebach, M. G.
Natchus, H. Paulsen, D. B. Rawlins, J. Satkofsky, A. J. Shuker, J. C. Sutton, R. E. Taylor, J. Tomooka,
J. Am. Chem. Soc. 1997, 119, 2755-2756.
Davis-Oxaziridine1-9.4.2001

R. Breinbauer
Mitomycin C
Mitomycin C
Bioreductive Activation and Biological Action:
H 2 N
Me
O
O
O
NH 2
O
OMe
N NH
H 2 N
Me
O
O
O
NH 2
O
OMe
N NH
[H]
inside cell
H 2 N
Me
OH
OH
O
NH 2
O
OMe
N NH
H-A
H 2 N
Me
OH
OH
O
NH 2
O H
OMe
N NH
- isolated from Streptomyces caespitosus
- marketed as an anti-cancer drug ("Mutamycin", Bristol-Myers-Squibb)
H 2 N
OH
O
O
NH 2
H 2 N
OH
O
O
NH 2
H-A
H 2 N
OH
O
O
H
NH 2
A
Compound with similar properties:
Me
OH
N NH 2
A
Me
OH
N
NH
H A
Me
OH
N
NH
H
O
OH
O
O
N O
FR-900482
NH 2
OH
NH
+ 2 e , +2 H
- H 2 O
H
O
OH
O
O
N
NH 2
NH
H 2 N
Me
OH
OH
N
O
O
NH 2
:DNA
NH 2
H 2 N
Me
OH
OH
N
O
O
NH 2
DNA
NH 2
H 2 N
Me
OH
OH
N
:DNA
DNA
NH 2
:DNA
Mitomycin-021105
H
O
OH
N
DNA
DNA
NH 2
Apoptosis
Inhibition of Replication
H 2 N
Me
OH
OH
N
DNA
DNA
NH 2

R. Breinbauer
PAAL-KNORR - Synthesis:
Synthesis of Furans
from α-Hydroxy ketones
R 2 R 3 ZnCl R 2 R 3
2 or PPA
R 1
R 4
Br
O O
or conc. H R 1 O R 4
R 2
2 SO 4
O
+
R 1 OH
EtO
R 1 O
EWG
Na 2 CO 3
R 1 EWG
+
X O R 2 O R 2
X = Br, Cl
R 2 R 3
FEIST-BENARY - Synthesis:
JACOBI - Synthesis:
from Allenyl ketones
R 1 O
PPh 3
Ag, Pd
NaH
R 2
R 1
O
R 2
R 1 O R 3
R'
N
+
R
R'
R 1 O
R 2
via DIELS-ALDER
- R-CN
(works especially well for intramolecular reactions)
R'
R'
R 1 O
R 2
R' = EWG, TMS, R 3 Sn
from Alkynyl ketones
O
R 1 R 2
Pd (0)
or
R 1 O
R 2
O R 2
R 1
Furan-Synthesis1-301105

R. Breinbauer
PAAL - Synthesis:
Thiophens
FIESSELMANN - Syntheses:
R 2 R 3
H 2 S or P 4 S 10
R 1
R 4
O O
or LAWESSON reagent
GEWALD - Synthesis:
R 2 O
+
EWG
S 8
R 1
CN
Morpholin
EtOH
HINSBERG - Synthesis:
R 1 R 2
O O RONa
R 1 R 2
+
RO 2 C
S CO 2 R
RO 2 C S CO 2 R
R 2 R 3
VILSMEIER-HAACK
R 1 S R 4
R 2
H
DMF/POCl 3
HS EWG
R 2
O
R 1 O
R 1
Piperidin
Cl
Pyridin
R 2 HCO H
2R
HS EWG
R 2
O
R 1 O
R 1 O
R 2 EWG
R 1
S NH 2
HS EWG
RO 2 C
R 1
Starting from conjugated diynes:
H 2 S or Na 2 S
R
R
NaOH
1) NaOH
R 1 R 2 2) H 3 O
3) ∆
S
R 1 S
R 2
S EWG
R 2 R 1
S
EWG
OH
R 1 EWG
R
S
R
R = alkyl, aryl
(instead of -CO 2 R other EWGs can be used as well)
Thiophen-Synthesis1-301105

R. Breinbauer
Bioisosterism I
Definitions:
Isosterism: Replacement of an atom or a group of atoms in an
active molecule by another one, presenting a comparable electronic
and steric arrangement.
GABA agonists:
Key parameters of GABA A receptor agonists are an acidic (pKa: ca 4) and a basic (protonated nitrogen)
functions with a ca. 5.1 Angsstrom interchange distance.
HO
O
HO
O
HO
N
O
Bioisosteres are compounds which fit the broadest definition of
isosteres and have the same type of biological activity.
H
H
GABA
N
H
Isoguvacine
N
H
THIP
C. G. Wermuth in C. G. Wermuth (Ed.), The Practice of Medicinal Chemistry, Elsevier, London (2003).
Antiulcer H 2 -receptor histamine antagonists:
Reviews:
G. A. Patani, E. J. LaVoie "Bioisosterism: A Rational Approach in Drug Design", Chem. Rev. 1996, 96,
3147-3176.
HN N
S
N
H
N
N
H
N
N
O
S
H
N
O
N
O
H
N
N
S
N
S
H
N
O
N
O
H
N
P. H. Olesen "The use of bioisosteric groups in lead optimization", Chem. Rev. 1996, 96, 3147-3176.
Cimetidine
Ranitidine
Nizatidine
C. G. Wermuth in C. G. Wermuth (Ed.), The Practice of Medicinal Chemistry, Elsevier, London (2003),
189-214.
Carboxylic Acid Isosteres:
Ring Isosterism:
O
M = 26 g/mol
bp
:S
M = 32 g/mol
bp
O H
O
N OH
H
high chelating power
Benzene
Methylbenzene
Chlorobenzene
Acetylbenzene
80 °C
110 °C
132 °C
200 °C
Thiophene
2-Methyl-thiophene
2-Chloro-thiophene
2-Acetyl-thiophene
84 °C
113 °C
130 °C
214 °C
N N
N N
H
N O
N
H
O
increased bioavailability, widely used, pKa = 6.6 -7.2
lipophilic replacement
Bioisosterism1-041205

R. Breinbauer
Heterocyclic Chemistry - Week 9
6.-7.12.2005
Synthesis, Reactivity, and Use of Heterocycles:
3-Ring-Systems:
3H-Diazirines:
Synthesis:
- Oxidation of Diaziridines
Application:
- Photoaffinity Labelling
Aziridines:
Polyethylenimine (PEI)
Reduced Pyrimidal Inversion of N, Bearing EWG Groups
4-Ring-Systems:
Azetidines
Azetidinones (β-Lactams):
Synthesis:
- Reaction between Imines and Ketenes (STAUDINGER-Reaction)
- [2+2]-Cycloaddition between Olefins and Chlorosulfonylisocyanate
Reactivity:
- Nucleophilic Opening
- Carbonly-Reactivity: Wittig-Reaction
Application:
-β-Lactam-Antibiotics (Penicillin, Cephalosporin, Resistence, β-Lactamase)
Synthesis:
- Cyclisation of β-Substituted Amines (GABRIEL-Synthesis,
WENKER-Synthesis)
- Cyloaddition of Nitrenes to Olefins
- N 2 -Extrusion of Triazolines
Reactions:
- Ring Opening Reactions with Nucleophiles
- Thermal /Photochemical Preparation of 1,3-Dipoles
Application:
Chemotherapy: DNA Cross-Linking through N-Lost and Mitomycin
Literature
T. Eicher, S. Hauptmann, "The Chemistry of Heterocycles", Wiley-VCH, Weinheim 2003, 572 pages.
(Excellent chapters about ring systems.)
J. A. Joule, K. Mills, "Heterocyclic Chemistry", 4th ed., Blackwell Science, Oxford 2000, 589 pp.
(The chapters about small rings are not as comprehensive and terrific as for 5- and 6-membered
rings, but nevertheless worth reading.)
T. L. Gilchrist, "Heterocyclenchemie", Wiley-VCH, Weinheim 1995, 445 pp.
(Description of ring systems not very well structured but nevertheless insightful.)
WWW-Link
http://www.ch.ic.ac.uk/video/woodward/index_embed.html
Lecture9-061205
(A video showing the first minutes of R. B. Woodward's recorded lecture at the Technion in Haifa
1966 about the Synthesis of Cephalosporin C.)

R. Breinbauer ACHMATOWICZ - Rearrangement
E. F. Ullman, J. E. Milks, J. Am. Chem. Soc. 1962, 84, 1315.
The pyranulose products allow the generation of 3-oxidopyryllium species, which undergo cycloaddition
reactions.
J. B. Hedrickson, J. S. Farina, J. Org. Chem. 1980, 45, 3359.
Review: P. G. Sammes, Gazz. Chim. Ital. 1986, 116, 109-114.
O
OH
R 1 R 2
MeO
O
OMe
R 1 R 2
OH
O
O
H
HO R 2
R 1
HO
O
O
R 1
R 2
O OBn
O CH 3 OAc
1) NaBH 4 , MeOH, 0 °C
2) mCPBA, THF, 0 °C
3) Ac 2 O,pyr, DMAP
96 % (3 steps)
TBSO
AcO
O
O
OBn
CH 3 OAc
OTBS
C6-epimers
Ph
O
OH
Me
Br 2 , MeOH, -35 °C
then NH 3(g)
92 %
MeO
O
2% H 2 SO 4 , 90 min, RT
OMe
Me
O. Achmatowicz Jr., P. Bukowski, B. Szechner, Z. Zwierzchowska, A. Zamojski,
Tetrahedron 1970, 27, 1973-1996.
OH
99 %
HO
O
O
Me
H O
O O
OHO
O
O
(+)-Resiniferatoxin
OMe
OH
P. A. Wender, C. D. Jesudason, H. Nakahira, N. Tamaura, A. L. Tebbe, Y. Ueno,
J. Am. Chem. Soc. 1997, 119, 12976-12977.
HO
MeO
OH
O
O
mCPBA
O
65 %
MeO
Y. Lefebvre, Tetrahedron Lett. 1972, 13, 133-136.
O
OTBS
OHCH 3
OAc
1) VO(acac) 2
tBuOOH, DCM
2) Ac 2 O,pyr, DMAP
88 %
TBSO
AcO
O
O
CH 3
OAc
2:1 C6-epimers
OH
H OH
OH
OHO
OH
Phorbol
Achmatowicz-Rearrangement1-30.5.2001 P. A. Wender, K. D. Rice, M. E. Schnute J. Am. Chem. Soc. 1997, 119, 7897-7898.

R. Breinbauer Aza - ACHMATOWICZ - Rearrangement
Review:
M. A. Ciufolini, C. Y. W. Hermann, Q. Dong, T. Shimizu, S. Swaminathan, N. Xi, Synlett 1998, 105-114.
O
R 1
HN R
2
Ox
O
R 1
N
R 2
OH
N 3
O
H
H
N
H
Br 2 , MeOH, -20 °C
then NH 3
95 %
MeO
H H
N 3 O
OMe
N
O H
Raney-Ni
H 2 , 1500 psi
50 °C
99 %
MeO
H H
H 2 N
N
H
O
OMe
H
iBuO HN
O
O
O
N
O
This direct oxidation route, is only amenable if R 2 = SO 2 R, otherwise 3-pyridinols form by aromatization.
Hydrogenation of the double bond before the rearrangement prevents the substrate from aromatization.
O
H
OMe
10 % TFA
CHCl 3 , 0 °C
99 %
MeO
H H
iBuO HN
O N
O H
O
OMe
85 %
iBuOOCCl
satd. NaHCO 3
0 °C
O
HN
X O
Br 2 , MeOH, Et 2 O, -40 °C
then NH 3(g)
85 - 95 %
MeO
O
OMe
HN
X O
M. A. Ciufolini, Q. Dong, J. Chem. Soc., Chem. Commun. 1996, 881.
X = CH 2 , O
O
H
N
OH
X
O
15 mol-% TfOH
2 eq H 2 O
THF, RT
80 - 91 %
95 - 99 %
MeO
O
Raney-Ni
H 2 , 1500 psi
50 °C
OMe
HN
M. A. Ciufolini, C. Wood, Tetrahedron Lett. 1986, 27, 5085.
X
O
O
OCH 3
NHTs
Ti(OiPr) 4 , L-(+)-DIPT
TBHP, silica gel, CaH 2
DCM, RT, 5 d
40 %
(from 2-furaldehyde)
O
HO
OCH 3
NHTs
OH
N
H
OH
OH
Deoxymannojirimycin
+
HO
N
Ts
O
OCH 3
Achmatowicz-Rearrangement2-27.9.2001
Y.-M. Xu, W.-S. Zhou, Tetrahedron Lett. 1996, 37, 1461-1462.

R. Breinbauer
Synthesis of Pyrroles I
PAAL-KNORR - Synthesis:
R 1
R 1
X
O
R 2 R 3
O
O
R 2 R 3
R 4
R 1 R 4
O
CH 3 O OCH 3
HANTZSCH - Synthesis:
X = Br, Cl
KNORR - Synthesis:
R 1 O
EWG
+
R 2 NH 2 O R 3
R 3
R 2 O +
H 2 N CO 2 R
R 1 O
+
(can be produced
by in-situ-reduction
of α-oximinoketones)
NH 3 or R-NH 2
AcOH
EWG
NH 3 or R-NH 2
R 2
R 3
AcOH
R 1
N R 4
NH 3 or R-NH 2
from 1,3-Dicarbonyls and Glycine Esters
R
VAN LEUSEN - Synthesis:
R 1
EWG
R 1 EWG
R 1 R 2
R 2 N R 3
Zn/AcOH
RO 2 C CO 2 R
H
N N
(from Hetero--Diels-Alder-reaction)
HUISGEN - Synthesis
R 3 EWG
R 2 R 3
+
R 1
R 1 R 1
N
CO 2 R
HN
O
H
N
O
R 2 O
R 2 O
Tos N C
R 2 R 3
(TosMIC)
R 1
N R 4
R
BARTON-ZARD - Synthesis:
R 1 NO 2
EWG
R 2
+
DBU
R 1
RO
N
R 2
2 C N C
R
(isocyanoacetate)
Ring Contraction of Pyridazines:
+
NaH
R 1
N
H
RO 2 C
RO 2 C
EWG
R 1 R 2
R 1
R 2 R 3
N
H
N
H
N
H
R 2
CO 2 R
EWG
R 1
(azlactone)
Pyrrole-Synthesis1-061205

R. Breinbauer
Synthesis of Imidazoles
MARCKWALD - Synthesis:
R 2 O H 2 N
+
C
N
R 1 NH 2
(cyanamide)
R 2 O R 3
N
+ C
R 1 NH 2 S
(isothiocyanate)
R 2 O
+ NH 2
R 1 X HN R 2
X = Br, Cl, OH
from Amidines:
BREDERECK - Synthesis:
R 1 O
+
R 2 OH
O
H 2 N
H
from 1,2-Dicarbonyls:
2
R 2 O H
+
R 1 O
O R 3
2 NH 3
VAN LEUSEN - Synthesis:
R 2
N
Tos N C
R 1 N NH 2
(TosMIC)
H
K 2 CO 3
N
+
H
R 1 N
R 1 R 2 N
R 2
R 2 R 3
N
R 1 N S
H
by Dehydrogenation:
MnO 2 or
R 2
R 2
CuBr 2 /Base or
N
R 2 NH
BrCCl 3 /DBU
R 1
N
R 1 N
N R 3
R 1 N
H
NR 3
H
H
(from 1,2- diamines and aldehydes)
R 1
R 2 N
H
(2-unsubstituted imidazoles)
R 2 N
R 1 N
R 3
H
R 3
Imidazole-Synthesis1-071205

R. Breinbauer TosMIC - Imidazol-Synthesis
Large Scale Preparation of Aryl-substituted TosMIC:
Process by GlaxoSmithKline:
F
O
H
HCONH 2
TMSCl
50 °C
PhMe/CH 3 CN
F
H
O
N
H
O
N H
H
TolSO 2 H
50 °C
93 %
F
SO 2 O
N
H
H
SPr 3 N HCl
N N
OMe
OMe
SPr
N N
H
O
+
OH
NH 2
N
SPr
N
N
OH
2 eq POCl 3
ex Et 3 N
THF, 0 °C
HO
O
O
H
50 % aqueous
+ +
H 2 N CO 2 Me
Cl
Tol
Cl
SO 2
N
C
>500 kg scale
K 2 CO 3
DMF
F
Cl
Cl
SO 2
N
C
J. Sisko, M. Mellinger, P. W. Sheldrake, N. H. Baine, Tetrahedron Lett. 1996, 37, 8113-8116.
J. Sisko, M. Mellinger, P. W. Sheldrake, N. H. Baine, Org. Synth. 2000, 77, 198-205.
J. Sisko, M. Mellinger, Pure Appl. Chem. 2002, 74, 1349-1357.
87 %
(98 % ee)
N
N
CO 2 Me
MeO
N
F
N
OH
N
N
p38 Kinase Inhibitor
F
1) Oxone
MeOH, H 2 O
2) NaOH
90 %
SO 2
N
C
K 2 CO 3
DMF, RT
PrS
N
F
60 % (one pot)
N
OH
J. Sisko, M. Mellinger, Pure Appl. Chem. 2002, 74, 1349-1357.
N
N
O
H
+ NH 4 OH +
S
Tol
SO 2
N
C
piperazine
THF, RT
78 %
H
N
N
S
TOSMIC-Imidazol-221002
J. Sisko, M. Mellinger, Pure Appl. Chem. 2002, 74, 1349-1357.

R. Breinbauer
Synthesis of Oxazoles
ROBINSON-GABRIEL - Synthesis:
Rh 2 (OAc) 4
R 2 R 2
H
H 2 SO 4 or PPA
N
N
R 1
R 3
R 1 O R 3
O O
R 1 O NH 2
R 2
+
R 2 X O R 3 N
R 1 O R 3
(α-(acylimino)ketones)
H
R 2 NH 3
R 2 O
O
R 1
R 3 R 1 N
R 3
O O
R 1 O
Cl
R 1 O
from α-(Acyloxy)ketones:
BLÜMLEIN-LEWY - Synthesis:
X = Br, Cl, OH
VAN LEUSEN - Synthesis:
+
Tos
Li
R 2
N C
(TosMIC)
SCHÖLLKOPF - Synthesis:
+
by Dehydrogenation:
R 1 R 2
N C
(α-metallated isonitrile
NH
O R 3
K 2 CO 3
MnO 2 or
CuBr 2 /Base or
BrCCl 3 /DBU
N
R 1
O
R 2
N
R 1 O
R 2
N
R 1 O R 3
(from β-aminoalcohols and aldehydes)
from α-Diazocarbonyl Compounds:
R 2 N 2 N
+ C R
3
R 1 O
R 1 R 2
N
O R 3
(via carbene intermediate)
Oxazole-Synthesis1-071205

R. Breinbauer WIPF - Oxazole Synthesis
One-Pot method:
R
NH
HO
O R'
R
O
N
R'
A. J. Phillips, Y. Uto, P. Wipf, M. J. Reno, D. R. Williams, Organic Lett. 2000, 2, 1165-1168.
CO 2 Me
CO 2 Me
H
O
DAST, DCM, -20 °C
NH
N
N
OH
BrCCl 3 , DBU, 0 °C
O
O
O
64 %
NHCO 2 Me
NHCO 2 Me
NHCO 2 Me
P. Wipf, S. Lim, J. Am. Chem. Soc. 1995, 117, 558.
Application:
O
OH
Boc O
Me
N
OTES
O
Me Me
Phorboxazole A
+
HO
H 2 N O
PMBO
O
OTBDPS
Boc
N
O
1) EDC*MeI, HOBt, DCM
87 %
2) Dess-Martin-periodinane
3) a) (BrCCl 2 ) 2 , Ph 3 P, DCM
2,6-lutidine
b) DBU, CH 3 CN
Me
77% (2 steps)
O
Me
O
Me
N
OTES
O
PMBO
OTBDPS
O
MeO 2 C
N 3
K. R. Hornberger, C. L. Hamblett, J. L. Leighton, J. Am. Chem. Soc. 2000, 122,
12894-12895.
In the Smith Calyculin Synthesis the Wipf method proved out to be superior to other methods, which all
led to empimerization at the α-methyl group:
HN
O
OH
1) MeO 2 CNSO 2 NEt 3
THF, 55 °C
84 %
2) CuBr 2 , HMTA, DBU
DCM
80 %
CN
MeO 2 C
N 3
OH
N
OH
O
HO
HO
P O
O
OMe
MeO
(+)-Calyculin A
O
20
O
OH
OH
NMe 2
OH
O
25
N
H
N
O
Wipf-Oxazol-101205
C. J. Forsyth, F. Ahmed, R. D. Cink, C. S. Lee, J. Am. Chem. Soc. 1998, 120, 5597-5598.
A. B. Smith III, G. K. Friestad, J. Barbosa, E. Bertounesque, K. G. Hall, M. Iwashima, Y. Qiu, B. A.
Salvatore, P. G. Spoors, J. J.-W. Duan, J. Am. Chem. Soc. 1999, 121, 10478-10486.

R. Breinbauer
Synthesis of Thiazoles
GABRIEL - Synthesis:
R 2 R 2
H
P 4 S 10
N
N
R 1
R 3 R 1 S R 3
O O
(α-(acylimino)ketones)
R 1 O NH 2
R 2
+
R 2 X S R 3
N
R 1 S
R 3
X = Br, Cl
R 1 R
NH 1
2
N
S
C + C
H 2 N
N
S
S SH
(α-aminonitriles)
R 2 NH 3 R 2
S
S
R 1
R 3 R 1 N R 3
O O
HANTZSCH - Synthesis:
COOK-HEILBRON - Synthesis
from α-(Acylthio)ketones:
by Dehydrogenation:
R 2
NH
R 1 S
R 3
(from β-aminothiols and aldehydes)
MnO 2 or
CuBr 2 /Base or
BrCCl 3 /DBU
R 1 R 2
N
S R 3
Thiazole-Synthesis1-071205

R. Breinbauer
Synthesis, Reactivity, and Use of Heterocycles:
Heterocyclic Chemistry - Week 10
Literature
14.12.2005
5-Ring-Systems:
Furans:
Synthesis:
Reactions:
- Achmatowicz-Rearrangement
- Aza-Achmatowicz-Rearrangement
Thiophens:
Synthesis:
- Mechanism of GEWALD-Synthesis
Application:
-Bioisosterism
T. Eicher, S. Hauptmann, "The Chemistry of Heterocycles", Wiley-VCH, Weinheim 2003, 572 pages.
(Excellent chapters about ring systems.)
J. A. Joule, K. Mills, "Heterocyclic Chemistry", 4th ed., Blackwell Science, Oxford 2000, 589 pp.
(The chapters about small rings are not as comprehensive and terrific as for 5- and 6-membered
rings, but nevertheless worth reading.)
T. L. Gilchrist, "Heterocyclenchemie", Wiley-VCH, Weinheim 1995, 445 pp.
(Descrption of ring systems not very well structured but nevertheless insightful.)
G. Pohnert, "Wundverschlüsse durch Biopolymerisation", Nachrichten Chemie 2005, Heft 6, 638ff.
(Descrption of the green algae Caulerpa taxifolia and how it spread through the mediterrean sea.)
Pyrroles:
Synthesis:
Application:
- Neurotoxicity of n-Hexanes
- Wound Healing of Caulerpa taxifolia
Lecture10-090106

R. Breinbauer
Privileged Structures
Definition:
Privileged Structures:
Privileged structures are defined as a single molecular framework
able to provide ligands for diverse protein receptors.
N
"...judicious modification of such structures could be a viable alternative in the
search for new receptor agonists and antagonists"
H
N
N
N N
N
R
R
N
R
B. E. Evans, K. E. Rittle, M. G. Bock, R. M. DiPrado, R. M. Freidinger, W. L. Whitter, G. F. Lundell, D. F.
Veber, P. S. Anderson, R. S. L. Chang, V. J. Lotti, D. J. Cerino, T. B. Chen, P. J. Kling, K. A. Kunkel, J. P.
Springer, J. Hirshfield, J. Med. Chem. 1988, 31, 2235-2246.
Biphenyltetrazoles Diphenylmethanes Arylspiropiperidines Arylalkylamines
Cl
Benzodiazepines:
H
N
N
O
N
H
F
H 3 C
N
N
NH
O
S
H
N
N
O
O
N
CH 3
CF 3
CF 3
Substructure Analysis of Drugs:
5120 known drugs were analysed for molecular frameworks and side chains:
- 1179 frameworks identified; 32 of these account for half of all drugs
(Cholecystokinin antagonist)
Trifluadom
(Opiate receptor)
(NK-1 antagonist)
606 247 195 142 129 119 119
H 3 C
N
N
N
O
N
H
O
H
N
O
(K-Secretase inhibitor)
F
F
N
H
N
N
N
N
O
O
F 3 C
(Farnesyl transferase inhibitor)
G. W. Bemis, M. A. Murcko, J. Med. Chem. 1996, 39, 2887-2893.
- 20 different side-chains account for 75 % of the total
CH 3 OH OCH 3 Cl HN CH 3 NH 2 O
OH
3125 2566 916 823 719 549 454
F S O
O
OH CH 3
O
NO 2
355 331 235 214 155 137
PrivilegedStructures1-111202
G. W. Bemis, M. A. Murcko, J. Med. Chem. 1999, 42, 5095-5099.

R. Breinbauer
Heterocyclic Chemistry - Week 11
10.-11.1.2006
Synthesis, Reactivity, and Use of Heterocycles:
5-Ring-Systems:
Imidazoles:
Synthesis:
- Mechanism of the Reaction based on TosMIC
Application:
- Histidine: Metalloenzymes, Ser-Proteases
- Histamine:
- Coupling with 1,1'-Carbonyldiimidazolide (CDI)
- Ionic Liquids: BASIL-Process
- Organocatalysis: MACMILLAN's Catalyst: Asymmetric Hydrogenation
Oxazoles:
Literature
T. Eicher, S. Hauptmann, "The Chemistry of Heterocycles", Wiley-VCH, Weinheim 2003, 572 pages.
(Excellent chapters about ring systems.)
J. A. Joule, K. Mills, "Heterocyclic Chemistry", 4th ed., Blackwell Science, Oxford 2000, 589 pp.
(The chapters about small rings are not as comprehensive and terrific as for 5- and 6-membered
rings, but nevertheless worth reading.)
T. L. Gilchrist, "Heterocyclenchemie", Wiley-VCH, Weinheim 1995, 445 pp.
(Description of ring systems not very well structured but nevertheless insightful.)
J. W. Yang, M. H. Fonseca, Ni. Vignola, B. List, "Metal-Free, Organocatalytic Asymmetric Transfer
Hydrogenation of α,β-Unsaturated Aldehydes", Angew. Chem. 2005, 117, 110-112.
Synthesis:
- Mechanism of the WIPF-Synthesis
Application:
- Ligands: Bis(oxazolines), PhoBox-Ligand
- Auxiliary: EVANS-Auxiliary
Thiazoles:
Synthesis:
Application:
- DONDONI-Reagent
1,2-Azoles:
Synthesis:
- from 1,3-Dicarbonyl Compounds
- by [3+2]-Cycloaddition
- Isothiazoles by Oxidation of β-Iminothiones
Lecture11-110106

R. Breinbauer Isoxazol - Coupling
Preparation of nitro compunds from bromides
Isoxazoles are a synthon for 1,3-diketones.
N. Kornblum, B. Taub, H. E. Ungnade, J. Am. Chem. Soc. 1954, 76, 3209-3211.
N. Kornblum, H. E. Ungnade, Org. Synth. 1963, Coll Vol. IV, 724-727.
Preparation of Nitrile Oxides from Nitroalkanes:
T. Mukaiyama, T. Hoshino, J. Am. Chem. Soc. 1960, 82, 5339-5342.
Macrolactonization via intramolecular [3+2] cycloaddition:
Br
O
Me
Me
Me
OTBS
1) AgNO 2 , Et 2 O
78 %
2) HF.pyr, pyr/THF
85 %
O 2 N
O
Me
Me
Me
OH
S. S. Ko, P. N. Confalone, Tetrahedron 1985, 41, 3511-3518.
Me
O
N
O
O
Me
Me
O
O
Me
OTES O
Me
OMe
3-ClPhNCO, DIPEA
benzene, 90 °C
20 h addition of substrate
68 %
O 2 N
Me
O
Me
Me
O O
O
Me
OTES O
Me
OMe
Me
Me
X p
Me
O
OPMB
CO 2 Me
X p
Me
O
OPMB
CO 2 Me
M
e
O
X p
N
O
O
Me
O
Me
O
O
Me
OTES
O
OPMB
Me
OH
CO 2 Me
A: Mo(CO) 6
H 2 O, MeCN, 70 °C
B:
69 %
or
W-2 Raney-Ni
1 atm H 2
EtOAc/AcOH
74 %
Me
H
O
O
Me
Me
OH
Me
O
O
O
OPMB
CO 2 Me
D. A. Evans, D. H. B. Ripin, D. P. Halstead, K. R. Campos, J. Am. Chem. Soc. 1999, 121, 6816-6826.
H
N
Me
OH
H
O
Me
O
O
Me
Me
O
O
Me
OH O
Me
OH
1) pH 10 buffer
95 %
2) DDQ, H 2 O, DCM
77 %
Me
O
H
Me
Me
O
O
OH
Me
O O
Me
OH
Me
OPMB
CO 2 Me
OH
Me
OH
CO 2 Me
(+)-Miyakolide
Isoxazol-coupling1-15.3.2001
D. A. Evans, D. H. B. Ripin, D. P. Halstead, K. R. Campos, J. Am. Chem. Soc. 1999, 121, 6816-6826.

R. Breinbauer
FISCHER - Indole Synthesis:
Synthesis of Indoles
REISSERT - Synthesis:
H
or Lewis-acid
R 2 R 1
N
H
N
H
R 2
R 3
+
R 3 NH
CH 3 R 2 O OR 2
N 2
R 1
CO 2 R 2 H 2 /Pd
O
R 1 R
H
1 R 1
NO
O
2
NO 2
works best if R 3 = EDG
BATCHO-LEIMGRUBER - Synthesis:
NENITZESCU - Synthesis:
MeO
O
CO 2 R
NMe 2
R 1
HO
+
CH 3 MeO
NMe 2 H 2 /Pd
R 1 R 1
R 1
O NH 2
N
H
NO 2
NO 2
LAROCK - Synthesis:
MADELUNG - Synthesis:
cat. Pd(OAc) 2
I
CH 3O NaNH 2
R 1 R 1 R 2
R 1
R 3 Base
+
R 2 DMF
R 1
N
NH
N
H
R 2
250 °C
H
R
due to harsh reaction conditions is limited to R 2 = alkyl
BARTOLI - Synthesis:
BISCHLER - Synthesis:
3 eq MgBr
R 3
O R 3
H
R 3
NO 2
R 1 R1 N R 3
N
R 1 R 1
R 2 R 2
O
O
ortho-substituted nitrobenzenes
N
H
CO 2 R
R 1
R 3
N
H
N
R
R 2
CO 2 R 2
Indole-Synthesis1-110106

R. Breinbauer
BORCHARDT - Indole -Synthesis
The reductive cyclization of 2,β-dinitrostyrenes is the most convenient method for the
synthesis of N-unsubstituted alkoxyindoles. The usually moderate yields (30-50 %)
can be increased by the addition of silica following the modificaton by Borchardt.
excess Fe-powder
R 2 silica gel
R 3 NO 2
AcOH
R 4 R 1 benzene/cyclohexane
NO 2 or
R 5 toluene
reflux, 1 h
R 3 R 2 R 1
R 4 R 5 N
H
NO 2
NO 2
OMe
OMe
excess Fe-powder
silica gel
AcOH/toluene
reflux, 15 min
71 %
MeO
OMe
N
H
MeO
F. He, Y. Bo, J. D. Altom, E. J. Corey, J. Am. Chem. Soc. 1999, 121, 6771-6772.
N
O
N H
OMe Me
Aspidophytine
O
A. K. Sinhababu, R. T. Borchardt, J. Org. Chem. 1983, 48, 3347.
Examples:
MeO
NO 2
Me
MeO NO 2
excess Fe-powder
silica gel
AcOH
benzene/cyclohexane = 1:3
reflux, 1 h
93 %
MeO
MeO
N
H
Me
O
O
NO 2
NO 2
excess Fe-powder
silica gel
AcOH
benzene/cyclohexane = 1:3
reflux, 1 h
91 %
O
O
N
H
PhCH 2 O
PhCH 2 O
NO 2
NO 2
excess Fe-powder
silica gel
AcOH
toluene
reflux, 1 h
75 %
PhCH 2 O
PhCH 2 O
N
H
Borchardt-Indole-Synthesis1-2.6.2001

R. Breinbauer FUKUYAMA - Synthesis of 2,3-disubstituted Indoles
S
NH
R'
R
1-2 eq Bu 3 SnH
0.1 eq Et 3 B
toluene, RT, 5-40 min
N
H
R
R'
Alternative method starting from phenyl isonitriles:
S. Kobayashi, G. Peng, T. Fukuyama, Tetrahedron Lett. 1999, 40, 1519-1522.
H. Tokuyama, T. Yamashita, M. T. Reding, Y. Kaburagi, T. Fukuyama, J. Am. Chem. Soc. 1999, 121,
3791-3792.
Mechanism:
R
. SnBu3
R
H
R
S
NH
R'
N
H
R'
SSnBu 3
N
H
R'
SSnBu 3
- HSSnBu 3
N
R
R'
N
H
R
R'
Examples:
Br
N
H
OTHP
N
H
OAc
N
H
OTHP
O
NTBS
N
H
OH
81 % yield 89 % yield 93 % yield
71 % yield
Fukuyama-Indol-Synthesis1-100703

R. Breinbauer
HANTZSCH - Synthesis:
Synthesis of Pyridines
BOHLMANN-RAHTZ - Synthesis:
R 1 R 2 R 2 H
O H
NH 3 EWG EWG
EWG
+ + EWG
R 1 N
R 1 O O R 1
H
R 1
R 2 R 2 H
O
H 2 N R 3
R 1 N
H
R 3
EWG
EWG EWG
EWG
+
Synthesis via 1,5-Dicarbonyl Compounds:
oxidation
oxidation
R 2 R 3
R 2 +
EWG EWG
R 1 NH 2
O R 4
R 1 N R 1
R 2
EWG EWG
R 1 N R 3
KRÖHNKE - Reaction:
R 2
N
+
R 1 O
O R 3
NH 4 OAc
AcOH
R 3
R 2 R 1 N R 4
R 2
R 1 N R 3
R 1 R 2
OO
H 2 NOH
R 1 R 2
OO
R 3
O +
EWG
R 1 O
H 2 N R 4
H
R 1 N R 2
OH
NH 3
Synthesis via 1,3-Dicarbonyl Compounds:
H
R 1 N R 2
R 1 +
N
- HNMe 2
EWG
R 1 N R 2
NMe 2
R 2
R 3
N
+
R 3
N N
N R 4 - N 2
R 2 EWG
R 1 - HN
R 1 N R 4
Synthesis via Cycloaddition:
EWG
BÖNNEMANN - Synthesis:
R 1 EWG
N EWG
R 3
R 2 R 4
N R 1
R 1
CpCo(I)-complex
N R 1
Pyridine-Synthesis1-110106

R. Breinbauer
Synthesis of Quinolines
FRIEDLÄNDER - Synthesis:
DOEBNER-MILLER - Synthesis:
R 1
O
R 2
NH 2
O
KOH
R 1 R 1 O
N
H
isatin
+ O
R 2
NH 2 O
R 3
O
R 3
R 4
PFITZINGER - Synthesis:
COMBES - Synthesis:
+
isatic acid
COO
NH 2
O
R 1
- H 2 O
O
N
H
1)
2)
R 2
O
H
R 3
R 2
R 3
H
R 1 R 1 R 1
N
R 2 R 2
R 3
O R 2
O R 3 R 3
H
R 1 +
R 1 R 1
R 4
NH 2
R 3
N R 4 As 2 O
N R 4
5
R 4
H (oxidant)
SKRAUP - Synthesis: involves in situ-preparation of acrolein from glycerin/H 2 SO 4
(is best synthesis for quinolines unsubstituted on the hetero-ring)
METH-COHN - Synthesis:
CO 2 H
R 2
R 3
DMF
N
R 2
Cl
R 1 POCl 3
R 2
R 2
R 1 R 1
R 2 N O
N O
N Cl
H
H
N R 3
R 2 N
Quinoline-Synthesis1-110106

R. Breinbauer
GOULD-JACOBS - Synthesis:
Synthesis of Quinolones
GROHE - Synthesis:
NH 2
+
RO
O
R'O
O
OR
O
N
H
O
OR
O
F
Cl
+
O
N
O R1
1) CHCl 3 , Et 3 N
2) H 2 N R 2
O
N
O
O R1
O
N
H
R
F
F
O
F
Cl
O
N
O
2) H 2 N
F
F
O
F
O
O
N H
R 2
O
O
N
H R 1
OH
O
N
H
R 2
R 1
HN
O O
F
OH
N N
Ciprofloxacin
HN
NH
F
F
R 2 O
Industrial Application:
KONRAD-LIMPACH - Synthesis:
OR
250 °C
+ O
diphenylether
NH 2 O R
+
1) CHCl 3 , Et 3 N
KOtBu/tBuOH
NMP
CAMPS - Synthesis:
1)
2) NaOH
N
O
O
R 2
N
H
O
O
R 1
OH
R 2
N
H
R 1
O
Quinolone-Synthesis1-061205

R. Breinbauer
BISCHLER-NAPIERALSKI - Synthesis:
Synthesis of Isoquinolines
POMERANZ-FRITSCH - Synthesis:
R 1
R 1
O
R 2
NH
R 1 N
R 2 R 2
OH
PPA or POCl 3
R 1 R 1
NH
O
R 2
NH 2
+
H O
PPA or POCl 3
PICTET-GAMS - Synthesis:
PICTET-SPENGLER - Synthesis:
H
R 1
R 2
NH
dehydration
R 2
N
dehydration
R 1 R 1
OR
OR
RO
N R 1 + RO
R 1
NH 2 N
R 2 CHO
N
R 2
H
R 1
N
Isoquinoline-Synthesis1-110106