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R. Breinbauer

Textbooks of Heterocyclic Chemistry

General Textbooks of Organic Chemistry Textbooks of Pharmaceutical Chemistry

General Textbooks of Organic Chemistry

General Textbooks of Organic Chemistry Textbooks of Pharmaceutical Chemistry

Textbooks of Pharmaceutical Chemistry

H.

E.

Mutschler, G. Geisslinger, H. K. Kroember, M. Schäfer-Korting, "Mutschler-Arzneimittelwirkungen", 8th

Beyer, W. Walter, "Lehrbuch der Organischen Chemie", 23rd ed., S. Hirzel, Stuttgart-Leipzig 1998,

1176 pages.

ed., Wiss. Verlagsgesellschaft, Stuttgart 2001, 1186 pages.

 

(A

classic textbook of pharmacology and toxicology which informs well about the structure and

 

(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.)

properties of drugs.)

 
Reference Books

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.)

A.

Katritzky (Ed.), "Comprehensive Heterocyclic Chemistry II", 2nd ed., Pergamon, Oxford 1996, Vol. 1-11.

Textbooks of Heterocyclic Chemistry (One of the most useful reference works for heterocyclic chemistry. Not

Textbooks of Heterocyclic Chemistry

(One of the most useful reference works for heterocyclic chemistry. Not textbook but very helpful for research.)

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

"Science of Synthesis", Thieme, Stuttgart 2000-2004, Vol. 9-17.

heterocyclic chemistry. Good for learining, less useful for research.)

   

(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!)

T.

L. Gilchrist, "Heterocyclenchemie", Wiley-VCH, Weinheim 1995, 445 pp.

(A

very good introductory textbook of heterocyclic chemistry.)

 

J.

A. Joule, K. Mills, "Heterocyclic Chemistry", 4th ed., Blackwell Science, Oxford 2000, 589 pp.

J. A. Joule, K. Mills, " Heterocyclic Chemistry ", 4th ed., Blackwell Science, Oxford 2000 ,

Book Series

(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.)

"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.)

A. R. Katritzky, A. F. Pozharskii "Handbook of Heterocyclic Chemistry", 2nd ed., Pergamon, Oxford 2000, 734 pp.

"Progress in Heteroyclic Chemistry", Pergamon, Oxford 1989-2003, Vol. 1-15.

 

(A more comprehensive textbook with lots of information but not easy to read. More reference book than text book.)

 

(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

R. Breinbauer Best Selling Pharmaceuticals World's Top Selling Drugs in 2004: H H CH 3 N

World's Top Selling Drugs in 2004:

H

H

CH 3

N N N N S O S O OH OH N O N CH 3
N
N
N
N
S O
S O
OH
OH
N
O
N
CH 3
H 3 CO
CO 2 H
N
HO
O
H 3 C
N
OCH 2 CF 3
H 3 C
H
O
O
Prevacid TM
Nexium TM
Lansoprazole
Omeprazol
F
O
H
(Abbott, Takeda)
(Astra Zeneca)
Lipitor TM
(Gastric Proton Pump Inhibitor)
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Zocor TM
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HO
H
N
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6.1 billion $
CO 2 CH 3
H 3 C
H
CH 3
N
F
H
N
S
Cl
O
N
F
Plavix TM
N
Cl
S
Advair TM
O O
Clopidogrel
H
Fluticasone Propionate
(BMS, Sanofi-Aventis)
O
O
(GlaxoSmithKline)
Zyprexa TM
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O
NH 2
N
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H

(Eli Lilly) (Serotonin and Dopamine antagonist)

4.8 billion $

34 kDa glycosylated protein (165 aa)

Norvasc TM Amlodipine (Pfizer) (Ca-Channel blocker) 4.5 billion $ Cl
Norvasc TM
Amlodipine
(Pfizer)
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4.5 billion $
Cl
3.7 billion $ NHH 3 *HCl
3.7 billion $
NHH 3 *HCl

Cl

TopPharmaceuticals1-061005

Erypo TM

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(Johnson&Johnson)

(growth factor for erythrocyctes)

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Zoloft TM

Sertraline

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(Selective Serotonin Reuptake Inhibitor)

3.4 billion $

OCH 3

(Gastric Proton Pump Inhibitor)

COSCH 2 F OCOC 2 H 5

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".

O N O N N N N N N N N H H H H
O
N O N
N
N
N
N
N
N
N
H
H
H
H
2H-Pyrrole
Pyrrolidine
Morpholine
Pyridine
Piperidine
1H-Pyrrole
3H-Pyrrole
Furazan
H
N
N
N
N O
N N
N N
N N
N N
N
N
N
H
H
4H-Pyrazole
Isoxazole
Pyridazine
Pyrazine
Piperazine
1H-Pyrazole
3H-Pyrazole
Pyrimidine
N
N
NH
N
HN N
O
N
N
N
N
O
O
H
H
H
Imidazolidine
2H-Pyran
4H-Pyran
Furan
1H-Imidazole
2H-Imidazole
4H-Imidazole
Pyrazolidine
H
S
HB
N BH
HB
O
BH
HB
S BH
Te
N Se
N S
Se
HN
NH
O
S
S
N
B
O B
B
S
H H
H H
Borthiin
Isoselenazole
Isothiazole
Selenophen
Tellurophen
Thiomorpholine
Borazine
Boroxin
Thiophen

TrivialHeteroMono-120504

R. Breinbauer

HANTZSCH-WIDMAN - Stems for Monocyclic Hetero Systems

 

Rings Containing Nitrogen

 

Rings Containing No Nitrogen

No. of

Unsaturated

Saturated

No. of

Unsaturated

Saturated

members in

members in

the ring

the ring

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

-ocin

8

-ocine

*

-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.

** 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".

Hantzsch-Widman-120504

R. Breinbauer

Heterocycles as Parent Rings

The following list contains heterocycles which can function as parent rings in ascending order:

H

P

S

Phosphindole (1) Thiophene (2)

H

N

N

Pyrazole (11)

S

N

Isothiazole (12)

NH

S

S

Thianthrene (3)

O

N

Isoxazole (13)

N

Isoindole (20)

N

Quinoline (27)

3H-Indole (21)

N

N

Phthalazine (28)

 

H

N

N

4aH-Carbazole (34)

Hg

N

H

Phenomercazine (41)

Heterocycles1-240504

Carbazole (35)

As

N

H

Phenarsazine (42)

O

Furane (4)

O

O

O

4H-Pyrane (5) Isobenzofurane (6) 2H-Chromene (7)

S

O

Phenoxathine (8)

H

N

Pyrrole (9)

H

N

N

Imidazole (10)

N

Pyridine (14)

H

N

Indole (22)

N

N

Pyrazine (15)

N

N

Pyrimidine (16)

N

N

Pyridazine (17)

N

1H-Pyrrolizine (18)

H

N

N

Indazole (23)

N

N

H

N

N

7H-Purine (24)

N

4H-Quinolizine (25)

N

Indolizine (19)

N

Isoquinoline (26)

N

N

1,8-Naphthyridine (29)

N

N

Quinoxaline (30)

N N

N

N

Quinazoline (31)

HN

N

N

N

Cinnoline (32)

N

N

N

N

N

Pteridine (33)

 

N

N

N

Phenanthridine (36)

Acridine (37)

Perimidine (38)

1,7-Phenanthroline (39)

Phenazine (40)

H

P

N

H

Phenophosphazine (43)

H

N

Te

Phenotellurazine (44)

H

N

Se

Phenselenazine (45)

H

N

S

Phenothiazine (46)

H

N

O

Phenoxazine (47)

R. Breinbauer

Heterocyclic Chemistry - Week 1

11.-12.10.2005

Introduction:

 
Literature

Literature

Definition Classification Industrial Importance Top 10 Pharmaceuticals

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.)

Nomenclature:

J.

A. Joule, K. Mills, "Heterocyclic Chemistry", 4th ed., Blackwell Science, Oxford 2000, 589 pp. (Good introduction into heteroaromaticity.)

HANTZSCH-WIDMAN-System Replacement Nomenclature

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

Reactive Behaviour of Different Aromatics Resonance Energy 1H-NMR Data Literature

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.

Nucleobases Tautomers

 

(In this landmark publication Eschenmoser discusses within a 2 page long footnote why the C=O bond

- Iminol vs. Amido

is so much stronger than the C=C and C=N bond, a fact which is of utmost importance for Watson-Crick base pairing.)

- Amin vs. Imino

- Thion vs. Thiol

 

J.

A. Joule, K. Mills, "Heterocyclic Chemistry", 4th ed., Blackwell Science, Oxford 2000, 589 pp.

General Principles of Reactions with Heterocycles:

 

(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 Reaction on Imino-N

 

- Basicity of Nitrogen Heterocycles

- Nuleophilicity: Steric and Electronic Influences

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:

General Principles of Reactions with Heterocycles: Literature

Literature

Radical Reactions

J. A. Joule, K. Mills, "Heterocyclic Chemistry", 4th ed., Blackwell Science, Oxford 2000, 589 pp.

- Nucleophilic Radicals (Minisci-Reaction)

 

(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.)

- Electrophilic Radicals

Lithiation Reactions

 

- Metallation Governing Factors (CH-Acidity, Complexation, Directing Groups, Base, Solvent) Metalation of Heteroaromatics Side Chain Metalation

WWW-links

WWW-links

- Metal-Halogen Exchange Metal-Halogen Exchange avoiding Electrophile Generation (2 equiv tBuLi)

http://www.chem.harvard.edu/groups/myers/chemistry115handouts.htm

Transition-Metal Cross-Coupling Reactions

(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.)

- Oxidative Addition

- Transmetalation

- Cross-Coupling Reactions (Stille, Suzuki, Kumada, Negishi, Sonogashira)

 

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:

O

n-BuLi

O

O

Li

n-BuLi

> -60 °C

LiOEt

+

+

H

OLi

Kinetic Studies of the decomposition of organolithium reagents

S.

C. Honeycutt, J. Organomet. Chem. 1971, 29, 1-5.

J.

J. Fitt, H. W. Gschwend, J. Org. Chem. 1984, 49, 209-210.

P.

Stanetty, H. Koller, M. D. Mihovilovic, J. Org. Chem. 1992, 57, 6833.

P.

Stanetty, M. D. Mihovilovic, J. Org. Chem. 1997, 62, 1514-1515.

Li-Stabilitäten1-9.10.2001

Half-Lives of BuLi in Etheral Solvents

t-BuLi

DME

t-BuLi

THF

t-BuLi/TMEDA

THF

t-BuLi

Et 2 O

t-BuLi/TMEDA Et 2 O

s-BuLi

DME

s-BuLi

THF

s-BuLi/TMEDA

THF

s-BuLi Et 2 O

s-BuLi/TMEDA Et 2 O

n-BuLi

DME

n-BuLi

THF

n-BuLi/TMEDA

THF

n-BuLi Et 2 O

n-BuLi/TMEDA Et 2 O

n-BuLi

THP

-70 °C

-40 °C

-20 °C

0 °C

+20 °C

+35 °C

11 min

<2 min

5.6 h

42 min

 
 

45 min

8.05

h

61 min

"complex"

 

stable

 

2 h

2 min

stable

78 min

 

stable

28 min

 

19.8

h

2.32 h

stable

1.85 h

 

17.3 h

1.78 h

 

55.2

h

5.63 h

38 min

 
 

153 h

31 h

10.1

h

21.0

h

4.63 h

P. Stanetty, M. D. Mihovilovic, J. Org. Chem. 1997, 62, 1514-1515.

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

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

trig, dig) Bürgi-Dunitz - Trajectorie - Baldwin Rules Literature T. L. Gilchrist, " Heterocyclenchemie ",

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.)

Lecture4-021105

R. Breinbauer

Heterocyclic Chemistry - Week 5

8.-9.11.2005

General Concept for the Synthesis of Heterocycles:

General Concept for the Synthesis of Heterocycles: Literature

Literature

Mechanistic Understanding of Ring Closures

T. L. Gilchrist, "Heterocyclenchemie", Wiley-VCH, Weinheim 1995, 445 pp.

-

Baldwin Rules

 

(Contains a very long and deep discussion about general principles and strategies for the synthesis of heterocycles.)

Intramolecular Substitution at Saturated C-Atom

J. A. Joule, K. Mills, "Heterocyclic Chemistry", 4th ed., Blackwell Science, Oxford 2000, 589 pp.

- Rate Dependence on Ring Size

 

(Contains a short chapter about synthesis concepts.)

- Thorpe-Ingold Effect, gem-Dimethyl Effect (Activation Entropy)

- Feist-Benary- Furan Synthesis (5-exo-tet)

 

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 b b b b a c a c a c
R. Breinbauer
1,3 - Dipoles
b
b
b
b
a
c
a
c
a
c
a
c
Type 2
Type 1
R'
R'
N
N
N
N
R
C
N
R''
Azomethine imine
R
C
N
R''
Azide
R
N
N
R
N
N
R
R
R'
R'
N
N
N
N
R
C
N
O
N
R''
Diazoalkane
R
C
Azoxy compound
O
N
R''
N
R
R
R'
R'
N
N
N
N
R
C
C
R''
Azomethine ylide
R
C
C
R''
Nitrous oxide
O
N
O
N
R
R''
R
R''
R'
R'
N
N
Nitrile imine
R
N
C
R'
N
R
N
C
R'
N
Nitrone
O
C
R''
O
C
R''
R''
R''
N
N
Nitrile ylide
R
C
C
R'
R
C
C
R'
Carbonyl oxide
O
O
R
R
O
C
R
O
C
R
R
R
Nitrile oxide
N
N
Ozone
O
O
C
O
R'
O
R'
C
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

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

R. Breinbauer

Synthesis of 1,3-Dipols I

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

R. Breinbauer

Synthesis of 1,3-Dipols II

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

R. Breinbauer

Heterocyclic Chemistry - Week 6

15.11.2005

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

R. Breinbauer

HUISGEN Azide-Alkyne-Coupling

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

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

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

- Diels-Alder-Reaction with Inverse Electron Demand Literature T. L. Gilchrist, " Heterocyclenchemie ",

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.

[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

Literature

3-Ring-Systems:

T.

Eicher, S. Hauptmann, "The Chemistry of Heterocycles", Wiley-VCH, Weinheim 2003, 572 pages.

(Excellent chapters about ring systems.)

Epoxides:

 

Synthesis:

J.

A. Joule, K. Mills, "Heterocyclic Chemistry", 4th ed., Blackwell Science, Oxford 2000, 589 pp.

- Direct Oxidation (Ethylene, Butadiene)

(The chapters about small rings are not as comprehensive and terrific as for 5- and 6-membered rings, but nevertheless worth reading.)

- Preparation of Propyleneoxide

- Prileschajew-Oxidation with Peracid

 

- Corey-Chaykovsky-Reaction with Sulphur-Ylides: Synthesis of Fluconazole

T.

L. Gilchrist, "Heterocyclenchemie", Wiley-VCH, Weinheim 1995, 445 pp.

- Becker-Adler-Oxidation

 
 

(Descrption of ring systems not very well structured but nevertheless insightful.)

- Sharpless Asymmetric Epoxidation

- Jacobsen Asymmetric Epoxidation: Synthesis of Indinavir

 

- Shi Asymmetric Epoxidation: Synthesis of Glabroscol

- Jacobsen Hydrolytic Kinetic Resolution (HKR)

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 OMe OMe R TosMIC MeO MeO R R'' N N
R. Breinbauer
JACOBI - Reaction
OMe
OMe
R
TosMIC
MeO
MeO
R
R''
N
N
MeO
Boc
N
MeO
Boc
82 %
R'
R'
O
O
O
O
H
N
o-dichlorobenzene
90 %
reflux
OMe
MeO
P.
A. Jacobi, D. G. Walker, J. Am. Chem. Soc. 1981, 103, 4611.
OMe
P.
A. Jacobi, D. G. Walker, I. M. A. Odeh, J. Org. Chem. 1981, 46, 2065.
N
MeO
MeO
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.
N
MeO
O
O
Examples:
OMe
Imerubrine
J. C. Lee, J. K. Cha, J. Am. Chem. Soc. 2001, 123, 3243-3246.
O
N
1) NaBH 4
2) MeOH, H +
3) CH 3 CCSnBu 3 , BF 3
O
O
diethylbenzene
N
182 °C
N
O
O
O
MeO
64 % (3 steps)
- MeCN
MeO
MeO
O
N
N
First example for a highly selective intermolecular cycloaddition-retrofragmentation
O
O
(H
2 O)
H
OTBS
O
O
Ph
O
N
O
O
TBSO
H
in situ
O
tetralin, 205 °C
N
epimerization
NiCl 2 , NaBH 4
N
O
O
N
AcO
O
O
O
O
O
MeOH, -30 °C
52 % (at 90% conv.)
O
O
O
O
O
O
H
O
H
H
O
73 %
53 %
exclusive regioisomer
(rac)-Stemoamide
(-)-Teubrevin G
I. Efremov, L. A. Paquette, J. Am. Chem. Soc. 2000, 122, 9324-9325.
P. A. Jacobi, K. Lee, J. Am. Chem. Soc. 1997, 119, 3409-3410.
Jacobi1-080301

R. Breinbauer

DAVIS - Oxaziridine

1) Base O 2) N 1.5 eq tBuLi Ph SO 2 Ph O O 0.2
1) Base
O
2)
N
1.5
eq tBuLi
Ph
SO 2 Ph
O
O
0.2
eq Et 2 NH
O
THF, -78 °C, 1 h
R'
R'
O
O
R
R
O
HO
O
H
OH OMe
O
OMe
then 10 eq Davis oxaziridine
-78 °C to 0 °C, 1 h
HO
OH
H
O
O
O
O
O
CMe
OMe
OMe
O
3
60 %
Me
HO
H
O
CMe 3
CMe 3
O
(rac)-Ginkgolide B
F. A. Davis, L. C. Vishwakarma, J. M. Billmers, J. Finn, J. Org. Chem. 1984, 49, 3241-3243.
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.
F. A. Davis, A. C. Sheppard, Tetrahedron. 1989, 45, 5703.
1) 1.5 eq KHMDS
THF, -78 °C
OH
2) 1.5 eq
O
O
O
N
OH
OH
Ph
O
OH
O
O
TBS
SO 2 Ph
THF, -78 °C, 45 min
O
TBS
HO
OH
O
O
O
O
O
O
OH
O
O
O
O
OH
83 %
OH
O
O
Ph
Ph
O
O
OH
Euonyminol
1 eq. KHMDS
2 eq Davis oxaziridine
OH
O
-78 °C to -20 °C / THF
O
J. D. White, H. Shin, T.-S. Kim, N. S. Cutshall, J. Am. Chem. Soc. 1997, 119, 2404-2419.
Taxol
97 % @ 57 % conv.
OH
OH
CO 2 Et
CO 2 Et
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: O NH 2 O O O NH 2
Mitomycin C
Bioreductive Activation and Biological Action:
O
NH 2
O
O
O
NH 2
NH 2
NH
2
O
O
OH
O
O
O
OH
O
H
H
2 N
OMe
[H]
H-A
H
H
H
2 N
OMe
2 N
2 N
OMe
OMe
N
NH
Me
inside cell
N
NH
N
NH
N
NH
Me
Me
Me
O
OH
O
OH
- isolated from Streptomyces caespitosus
- marketed as an anti-cancer drug ("Mutamycin", Bristol-Myers-Squibb)
O
O
O
NH 2
NH
NH 2
2
O
OH
O
OH
O
OH
H-A
H
H
H
H
2 N
2 N
2 N
A
N
NH
Compound with similar properties:
N
NH 2
N
NH
Me
Me
Me
OH
OH
OH
H
A
A
O
O
OH
O
NH 2
NH 2
O
O
OH
NH 2
OH
O
NH 2
+
2 e
, +2 H
:DNA
OH
O
OH
O
H
NH
OH
N O
H
2 N
H
2 N
H
H
:DNA
2 N
DNA
O
N
NH
DNA
- H 2 O
N
O
Me
N
Me
N
Me
FR-900482
OH
NH 2
OH
NH 2
OH
NH 2
:DNA
DNA
OH
DNA
OH
DNA
H
2 N
H
DNA
N
Apoptosis
Inhibition of Replication
N
O
NH 2
Me
OH
NH 2
Mitomycin-021105

R. Breinbauer

Synthesis of Furans

R. Breinbauer Synthesis of Furans from α-Hydroxy ketones R 2 R 3 2 3 ZnCl 2
from α-Hydroxy ketones R 2 R 3 2 3 ZnCl 2 or PPA R R
from α-Hydroxy ketones
R 2
R 3
2
3
ZnCl 2 or PPA
R
R
1
4
Br
R
R
2
R
1
2
NaH
PPh 3
or conc. H 2 SO 4
R
R 4
R
O
O
O
O
+
1
R
1
R
OH
EtO
O
from Allenyl ketones
1
Na 2 CO 3
R
EWG
EWG
O
+
R 2
O
X
O
R 2
2
R
2
R
R 3
Ag, Pd
1
3
R
1
R
R
O
O
R'
R'
R'
R'
via DIELS-ALDER
+
1
from Alkynyl ketones
2
R
R
R
O
N
- R-CN
1
2
R
R
O
O
1
R' = EWG, TMS, R 3 Sn
R
2
R
Pd (0)
or
1
2
R
R
O
O
R 2
1
R

(works especially well for intramolecular reactions)

PAAL-KNORR - Synthesis:

FEIST-BENARY - Synthesis:well for intramolecular reactions) PAAL-KNORR - Synthesis: R 1 X = Br, Cl JACOBI - Synthesis:

R 1

X = Br, Cl

JACOBI - Synthesis:for intramolecular reactions) PAAL-KNORR - Synthesis: FEIST-BENARY - Synthesis: R 1 X = Br, Cl Furan-Synthesis1-301105

Furan-Synthesis1-301105

R. Breinbauer

Thiophens

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

R. Breinbauer

Bioisosterism I

R. Brei nbauer Bioisosterism I Definitions: Isosterism: Replacement of an atom or a group of atoms

Definitions:

R. Brei nbauer Bioisosterism I Definitions: Isosterism: Replacement of an atom or a group of atoms

Isosterism: Replacement of an atom or a group of atoms in an active molecule by another one, presenting a comparable electronic and steric arrangement.

presenting a comparable electronic and steric arrangement. GABA agonists: Key parameters of GABA A receptor

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 HO O HO O N O H N N H H H THIP GABA
HO
HO
O
HO
O
N
O
H
N
N
H
H
H
THIP
GABA
Isoguvacine
Antiulcer H 2 -receptor histamine antagonists:
H
H
H
H
H
H
N
N
N
N
S
N
S
S
S N
N
O
HN
O
O
N
N
N
N
N
O
N
N
O
Nizatidine
Cimetidine
Ranitidine
Carboxylic Acid Isosteres:
O
O
H
M = 26 g/mol
M = 32 g/mol
:S
O
high chelating power
N
OH
bp
bp
H
Thiophene
N
84 °C
80 °C
N
2-Methyl-thiophene
increased bioavailability, widely used, pKa = 6.6 -7.2
113
°C
110
°C
N
N
2-Chloro-thiophene
130
°C
132
°C
2-Acetyl-thiophene
214
°C
H
200
°C
N
O lipophilic replacement
N O

H

Bioisosteres are compounds which fit the broadest definition of isosteres and have the same type
Bioisosteres are compounds which fit the broadest definition of
isosteres and have the same type of biological activity.

C.

G. Wermuth in C. G. Wermuth (Ed.), The Practice of Medicinal Chemistry, Elsevier, London (2003).

Reviews:Practice of Medicinal Chemistry , Elsevier, London ( 2003 ). G. A. Patani, E. J. LaVoie

G. A. Patani, E. J. LaVoie "Bioisosterism: A Rational Approach in Drug Design", Chem. Rev. 1996, 96,

3147-3176.

P.

H. Olesen "The use of bioisosteric groups in lead optimization", Chem. Rev. 1996, 96, 3147-3176.

C.

189-214.

G. Wermuth in C. G. Wermuth (Ed.), The Practice of Medicinal Chemistry, Elsevier, London (2003),

Ring Isosterism:Practice of Medicinal Chemistry , Elsevier, London ( 2003 ), Benzene Methylbenzene Chlorobenzene Acetylbenzene

Benzene

Methylbenzene

Chlorobenzene

Acetylbenzene

Bioisosterism1-041205

R. Breinbauer

Heterocyclic Chemistry - Week 9

6.-7.12.2005

 

4-Ring-Systems:

Synthesis, Reactivity, and Use of Heterocycles:

 

Azetidines

3-Ring-Systems:

Azetidinones (β-Lactams):

3H-Diazirines:

Synthesis:

Synthesis:

- Reaction between Imines and Ketenes (STAUDINGER-Reaction)

- [2+2]-Cycloaddition between Olefins and Chlorosulfonylisocyanate

-

Oxidation of Diaziridines

 

Reactivity:

Application:

- Nucleophilic Opening

-

Photoaffinity Labelling

- Carbonly-Reactivity: Wittig-Reaction

Aziridines:

Application:

Polyethylenimine (PEI) Reduced Pyrimidal Inversion of N, Bearing EWG Groups

-β-Lactam-Antibiotics (Penicillin, Cephalosporin, Resistence, β-Lactamase)

 

Synthesis:

-

Cyclisation of β-Substituted Amines (GABRIEL-Synthesis, WENKER-Synthesis)

 
Literature

Literature

- Cyloaddition of Nitrenes to Olefins

 

- N 2 -Extrusion of Triazolines

T.

Eicher, S. Hauptmann, "The Chemistry of Heterocycles", Wiley-VCH, Weinheim 2003, 572 pages.

Reactions:

(Excellent chapters about ring systems.)

- Ring Opening Reactions with Nucleophiles

J.

A. Joule, K. Mills, "Heterocyclic Chemistry", 4th ed., Blackwell Science, Oxford 2000, 589 pp.

- Thermal /Photochemical Preparation of 1,3-Dipoles

(The chapters about small rings are not as comprehensive and terrific as for 5- and 6-membered rings, but nevertheless worth reading.)

Application:

 

Chemotherapy: DNA Cross-Linking through N-Lost and Mitomycin

T.

L. Gilchrist, "Heterocyclenchemie", Wiley-VCH, Weinheim 1995, 445 pp.

(Description of ring systems not very well structured but nevertheless insightful.)

 
WWW-Link

WWW-Link

http://www.ch.ic.ac.uk/video/woodward/index_embed.html

 

(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.)

Lecture9-061205

R. Breinbauer

ACHMATOWICZ - Rearrangement

E. F. Ullman, J. E. Milks, J. Am. Chem. Soc. 1962, 84, 1315.

O O OMe 1 1 R R O R 2 R 2 H R 1
O
O
OMe
1
1
R
R
O
R 2
R 2
H
R 1
O
MeO
O
HO
O
HO
R 2
OH
OH
R 2
R 1
Br 2 , MeOH, -35 °C 2% H 2 SO 4 , 90 min, RT
Br 2 , MeOH, -35 °C
2% H 2 SO 4 , 90 min, RT
Me then NH 3(g)
OMe
Me
O
MeO
O
OH
92 %
OH
OH
O mCPBA
65 %
MeO
MeO

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.

1) NaBH 4 , MeOH, 0 °C

2) mCPBA, THF, 0 °C

3) Ac 2 O,pyr, DMAP

, MeOH, 0 °C 2) mCPBA, THF, 0 °C 3) Ac 2 O,pyr, DMAP 96 %

96 % (3 steps)

TBSO

O OBn O AcO CH 3 OAc C6-epimers Ph H O O O O HO
O OBn
O
AcO
CH 3
OAc
C6-epimers
Ph
H
O
O
O
O HO
O
O

OMe

OH

(+)-Resiniferatoxin

O OBn O CH 3 OAc OTBS O HO O Me 99 % P. HO
O OBn
O CH 3 OAc
OTBS
O
HO
O Me
99 %
P.
HO
O
O
OH OAc
O CH 3

OTBS

O. Achmatowicz Jr., P. Bukowski, B. Szechner, Z. Zwierzchowska, A. Zamojski, Tetrahedron 1970, 27, 1973-1996.

A. Wender, C. D. Jesudason, H. Nakahira, N. Tamaura, A. L. Tebbe, Y. Ueno, J. Am. Chem. Soc. 1997, 119, 12976-12977.

OH H OH OH O HO OH
OH
H OH
OH
O HO
OH

Phorbol

1) VO(acac) 2 tBuOOH, DCM 2) Ac 2 O,pyr, DMAP

1) VO(acac) 2 t BuOOH, DCM 2) Ac 2 O,pyr, DMAP 88 % O OAc O

88 %

O OAc O AcO CH 3
O OAc
O
AcO
CH 3

2:1 C6-epimers

TBSO

Y. Lefebvre, Tetrahedron Lett. 1972, 13, 133-136.

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

R. Breinbauer

Synthesis of Pyrroles I

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

R. Breinbauer

Synthesis of Imidazoles

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

R. Breinbauer

TosMIC - Imidazol-Synthesis

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

R. Breinbauer

Synthesis of Oxazoles

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

R. Breinbauer

WIPF - Oxazole Synthesis

One-Pot method: A. J. Phillips, Y. Uto, P. Wipf, M. J. Reno, D. R. Williams,
One-Pot method:
A. J. Phillips, Y. Uto, P. Wipf, M. J. Reno, D. R. Williams, Organic Lett. 2000, 2, 1165-1168.
R
R
N
NH
HO
O
H
R'
CO 2 Me
CO 2 Me
O
R'
O
NH
DAST, DCM, -20 °C
BrCCl 3 , DBU, 0 °C
N
N
OH
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:
K. R. Hornberger, C. L. Hamblett, J. L. Leighton, J. Am. Chem. Soc. 2000, 122,
12894-12895.
OTBDPS
O
HO
OH
H
O
2 N
1) EDC*MeI, HOBt, DCM
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:
87 %
Me
+
O
O
Boc
1) MeO 2 CNSO 2 NEt 3
N
OTES
2) Dess-Martin-periodinane
3) a) (BrCCl 2 ) 2 , Ph 3 P, DCM
MeO 2 C
MeO 2 C
THF, 55 °C
OH
Me
Me
2,6-lutidine
O
PMBO
84
%
N
O
b) DBU, CH 3 CN
HN
O
2) CuBr 2 , HMTA, DBU
77% (2 steps)
DCM
N
N
3
3
80
%
HO
O
OTBDPS
P
HO
20
O
O
O
25
O
OH
O
N
O
N
OH
OH
OMe
OH
O
O
Phorboxazole A
MeO
N
Me
H
O
Boc
NMe 2 OH
N
PMBO
OTES
CN
Me
Me
O
(+)-Calyculin A
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.
Wipf-Oxazol-101205

R. Breinbauer

Synthesis of Thiazoles

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

R. Breinbauer

Heterocyclic Chemistry - Week 10

14.12.2005

Synthesis, Reactivity, and Use of Heterocycles:

Synthesis, Reactivity, and Use of Heterocycles: Literature

Literature

5-Ring-Systems:

T.

Eicher, S. Hauptmann, "The Chemistry of Heterocycles", Wiley-VCH, Weinheim 2003, 572 pages.

(Excellent chapters about ring systems.)

 

Furans:

 

Synthesis:

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.)

Reactions:

- Achmatowicz-Rearrangement

- Aza-Achmatowicz-Rearrangement

T.

L. Gilchrist, "Heterocyclenchemie", Wiley-VCH, Weinheim 1995, 445 pp.

Thiophens:

 

(Descrption of ring systems not very well structured but nevertheless insightful.)

Synthesis:

 

-

Mechanism of GEWALD-Synthesis

G.

Pohnert, "Wundverschlüsse durch Biopolymerisation", Nachrichten Chemie 2005, Heft 6, 638ff.

Application:

(Descrption of the green algae Caulerpa taxifolia and how it spread through the mediterrean sea.)

-Bioisosterism

 
 

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

R. Breinbauer

Heterocyclic Chemistry - Week 11

10.-11.1.2006

Synthesis, Reactivity, and Use of Heterocycles:

 
 
Literature

Literature

5-Ring-Systems:

 
 

Imidazoles:

T.

Eicher, S. Hauptmann, "The Chemistry of Heterocycles", Wiley-VCH, Weinheim 2003, 572 pages.

 

(Excellent chapters about ring systems.)

Synthesis:

 

-

Mechanism of the Reaction based on TosMIC

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.)

Application:

- Histidine: Metalloenzymes, Ser-Proteases

 

- Histamine:

T.

L. Gilchrist, "Heterocyclenchemie", Wiley-VCH, Weinheim 1995, 445 pp.

- Coupling with 1,1'-Carbonyldiimidazolide (CDI)

 

(Description of ring systems not very well structured but nevertheless insightful.)

- Ionic Liquids: BASIL-Process

 

- Organocatalysis: MACMILLAN's Catalyst: Asymmetric Hydrogenation

J.

W. Yang, M. H. Fonseca, Ni. Vignola, B. List, "Metal-Free, Organocatalytic Asymmetric Transfer

Oxazoles:

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

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:

S. S. Ko, P. N. Confalone, Tetrahedron 1985, 41, 3511-3518.

M

e

Me

   

Me

 

N

O

O

O

O O   Me

O

 
O O   Me

Me

Me OH

Me

OH

 

O

OTES

O

   
   
 

Me

 

OPMB

 

X

p

O

A:

Mo(CO) 6

H 2 O, MeCN, 70 °C

69 %

  X p O A: Mo(CO) 6 H 2 O, MeCN, 70 °C 69 % B:

B:

or

W-2 Raney-Ni 1 atm H 2 EtOAc/AcOH

74 %

CO 2 Me

Me

Me

Me H O H N O Me O OH Me O O OH
Me
H
O
H
N
O
Me
O
OH
Me
O
O
OH

Me

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.

Isoxazol-coupling1-15.3.2001

Isoxazoles are a synthon for 1,3-diketones.

Br

Me

Me

Me

Me

1) AgNO 2 , Et 2 O

O
O

Me

78 %

 
   
 
 

2) HF.pyr, pyr/THF

85 %

O 2 N

OH

OTBS

Me

Me

Me

   

Me

 
 

N

O