R. Breinbauer Textbooks of Heterocyclic Chemistrylamp3.tugraz.at/.../wbShow/codoc/Handouts-Heterocycles2005-06.pdf · Textbooks of Heterocyclic Chemistry ... (Ca-Channel blocker)

R. Breinbauer

Textbooks1-051005

Textbooks of Heterocyclic Chemistry

General Textbooks of Organic Chemistry Textbooks of Pharmaceutical Chemistry

Textbooks of Heterocyclic Chemistry

Reference Books

H. Beyer, W. Walter, "Lehrbuch der Organischen Chemie", 23rd ed., S. Hirzel, Stuttgart-Leipzig 1998, 1176 pages.

E. Mutschler, G. Geisslinger, H. K. Kroember, M. Schäfer-Korting, "Mutschler-Arzneimittelwirkungen", 8th ed., Wiss. Verlagsgesellschaft, Stuttgart 2001, 1186 pages.

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

Merck & Co., "The Merck Index", 13th ed., Merck & Co., Inc, Whitehouse Station, NJ 2001, 1818 pages.

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

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

(A very good introductory textbook of heterocyclic chemistry.)

(A very well understandable and very well organized introduction into the most important topics of heterocyclic chemistry. Good for learining, less useful for research.)

(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.)

(A classic textbook of pharmacology and toxicology which informs well about the structure and properties of drugs.)

(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.

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

Book Series"Advances in Heterocyclic Chemistry", Elsevier, San Diego 1963-2005, Vol. 1-88.

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

(Provides an annual literature update and some review articles)

(A series of monographs which contains high quality reviews of very specific topics of heterocyclic chemistry.)

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.)

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.)

N CO2HNH

O

F

OH OH

HN

NH3COS

ON

H3C OCH3

CH3

N

NH

S

N

NN

S

H CO2CH3

Cl O

H3CHO

H3C COSCH2F

H

F

F H

CH3

OCOC2H5

NHH3*HCl

ClCl

HN

NS

ON

H3C OCH2CF3

CH3

HO

OO

OHO

NH

O

O

O NH2

O

O

Cl

R. Breinbauer

TopPharmaceuticals1-061005

Best Selling Pharmaceuticals

World's Top Selling Drugs in 2004:

data source: www.forbes.com

LipitorTM

Atorvastatin(Pfizer)

(HMG-CoA-Reductase Inhibitor)10.3 billion $

NexiumTM

Omeprazol(Astra Zeneca)

(Gastric Proton Pump Inhibitor)3.8 billion $

ZyprexaTM

Olanzapine(Eli Lilly)

(Serotonin and Dopamine antagonist)4.8 billion $

PlavixTM

Clopidogrel(BMS, Sanofi-Aventis)

(Platelet Aggregation Inhibitor)3.7 billion $

AdvairTM

Fluticasone Propionate(GlaxoSmithKline)(against Asthma)

3.7 billion $

ZoloftTM

Sertraline(Pfizer)

(Selective Serotonin Reuptake Inhibitor)3.4 billion $

PrevacidTM

Lansoprazole(Abbott, Takeda)

(Gastric Proton Pump Inhibitor)4.0 billion $

ZocorTM

Simvastatin(Merck)

(HMG-CoA-Reductase Inhibitor)6.1 billion $

NorvascTM

Amlodipine(Pfizer)

(Ca-Channel blocker)4.5 billion $

ErypoTM

Recombinant Erythropoietin(Johnson&Johnson)

(growth factor for erythrocyctes)4.0 billion $

34 kDa glycosylated protein (165 aa)

R. Breinbauer Monocyclic Hetero Systems with Trivial Names

TrivialHeteroMono-120504

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 NH

NH

N N NH

Pyridine Piperidine 1H-Pyrrole 2H-Pyrrole 3H-Pyrrole Pyrrolidine

NN

Pyridazine

N

N

Pyrimidine

N

N

Pyrazine

NNH

NN

NN

1H-Pyrazole 3H-Pyrazole 4H-Pyrazole

NH

HN

Piperazine

N

NH

N

N

N

N

1H-Imidazole 2H-Imidazole 4H-Imidazole

HNNH

Pyrazolidine

NH

NH

Imidazolidine

NO

N

Furazan

NH

O

Morpholine

NO

Isoxazole

O

2H-Pyran

O

4H-Pyran

O

Furan

NSe

Isoselenazole

NS

Isothiazole

Se

Selenophen

Te

Tellurophen

NH

S

Thiomorpholine

S

Thiophen

HBHN

BH

NHBH

HN

Borazine

HBO

BH

OBH

O

Boroxin

HBS

BH

SBH

S

Borthiin

R. Breinbauer HANTZSCH-WIDMAN - Stems for Monocyclic Hetero Systems

Hantzsch-Widman-120504

No. ofmembers inthe ring

No. ofmembers inthe ring

Unsaturated UnsaturatedSaturated Saturated

Rings Containing Nitrogen Rings Containing No Nitrogen

3

4

5

6

7

8

9

10

3

4

5

6

7

8

9

10

-irine

-ete

-ole

-ine**

-epine

-ocine

-onine

-ecine

-irene

-ete

-ole

-in*

-epin

-ocin

-onin

-ecin

-iridine

-etidine

-olidine

*

*

*

*

*

* 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.

-irane

-etane

-olane

-ane**

-epane

-ocane

-onane

-ecane

* 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

Heterocycles1-240504

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

Thianthrene (3)

S

SHP

Phosphindole (1)

O

HN

HN

S

HN

Se

HN

Te

N

N

HP

NH

As

NH

Hg

NH

N

NHN N

NN

HNN

N

N

N

NN

N

N

N

N

NN NNN

N

NN

N

N N

HN

N

HN

HN

NNH

NN

NN

N

N

N

NN

NO

NS

N

HN

Phenoxazine (47)Phenothiazine (46)Phenselenazine (45)Phenotellurazine (44)Phenophosphazine (43)Phenarsazine (42)

Phenazine (40)1,7-Phenanthroline (39)Perimidine (38)Acridine (37)Phenanthridine (36)Carbazole (35)

Pteridine (33)Cinnoline (32)Quinazoline (31)Quinoxaline (30)1,8-Naphthyridine (29)Phthalazine (28)

Phenomercazine (41)

4aH-Carbazole (34)

Quinoline (27)

Isoquinoline (26)4H-Quinolizine (25)7H-Purine (24)Indazole (23)Indole (22)3H-Indole (21)Isoindole (20)

Indolizine (19)1H-Pyrrolizine (18)Pyridazine (17)Pyrimidine (16)Pyridine (14)Isoxazole (13)Pyrazole (11) Pyrazine (15)Isothiazole (12)

N

HN

HN

O

SOO

O O

Imidazole (10)Pyrrole (9)Phenoxathine (8)2H-Chromene (7)Isobenzofurane (6)4H-Pyrane (5)

S

Furane (4)Thiophene (2)

R. Breinbauer

Lecture1-121005

11.-12.10.2005Heterocyclic Chemistry - Week 1

DefinitionClassificationIndustrial ImportanceTop 10 Pharmaceuticals

Introduction:Literature

HANTZSCH-WIDMAN-SystemReplacement Nomenclature

Nomenclature:

Theoretical CriteriaExperimental PropertiesBenzene

Electronpoor 6-membered ring heteroaromatics:- Pyridine- Pyridinium Ion- Pyrylium Ion

Cyclopentadienyl-Ion

Electronrich 5-membered ring heteroaromatices- Pyrrol- Furan- Thiophen

DipolmomentBond LengthsSolubilityBoiling Point

Aromaticity:



(Very good introductory chapter about heteroaromaticity.)

(Good chapter about the nomenclature of heterocycles.)


(Good introduction into heteroaromaticity.)

R. Breinbauer

Lecture2-181005


LiteratureAromaticity:


(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 SEAr (N-Oxides, EDG-groups)

Nucleophilic Substitution- Reactive Behaviour of 6-Ring Heterocycles (Substituents, Benzofused Rings)- Synthesis of Ciprofloxacin

Radical Reactions- Nuleophilic Radicals (Minisci-Reaction)

General Principles of Reactions with Heterocycles:

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.)

Reactive Behaviour of Different AromaticsResonance Energy1H-NMR Data

NucleobasesTautomers- Iminol vs. Amido- Amin vs. Imino- Thion vs. Thiol

R. Breinbauer

Lecture3-251005


Literature


(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.)

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)

Oxidation-- Resistance of Electronpoor Heteraromatics- Conversion of Furans to Carboxylic Acids

Reduction- Hydrogenation (pH-Dependence of Selectivitiy)

General Principles of Reactions with Heterocycles:

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

WWW-links

(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.)

O

n-BuLi

O Li

n-BuLiO LiOEt

H OLi

n-BuLiEt2O

n-BuLiTHF

n-BuLiTHP

t-BuLiTHF

t-BuLiEt2O

s-BuLiTHF

s-BuLiEt2O

R. Breinbauer Stability of Lithium-Reagents in Solution

Li-Stabilitäten1-9.10.2001 P. Stanetty, M. D. Mihovilovic, J. Org. Chem. 1997, 62, 1514-1515.

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

-70 °C -40 °C -20 °C 0 °C +20 °C +35 °C

t-BuLiDME

t-BuLi/TMEDATHF

t-BuLi/TMEDAEt2O

s-BuLiDME

s-BuLi/TMEDATHF

s-BuLi/TMEDAEt2O

n-BuLiDME

n-BuLi/TMEDATHF

n-BuLi/TMEDAEt2O

11 min <2 min

5.6 h 42 min

45 min

stable

8.05 h 61 min "complex"

2 h 2 min

stable 28 min

stable 78 min

stable

19.8 h 2.32 h

1.85 h

55.2 h 5.63 h 38 min

17.3 h 1.78 h

10.1 h

21.0 h 4.63 h

153 h 31 h

Half-Lives of BuLi in Etheral Solvents

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

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

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

Organolithium reagents react with etheral solvents under elimination of ethylene:

> -60 °C

+

+

Kinetic Studies of the decomposition of organolithium reagents

R. Breinbauer

Lecture4-021105

2.11.2005Heterocyclic Chemistry - Week 4

Literature


(Contains a short chapter about synthesis concepts.)

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

General Concepts for the Synthesis of Heterocycles: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

Lecture5-081105


Literature


(Contains a short chapter about synthesis concepts.)

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)

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

General Concept for the Synthesis of Heterocycles:T. L. Gilchrist, "Heterocyclenchemie", Wiley-VCH, Weinheim 1995, 445 pp.


R. Breinbauer 1,3 - Dipoles

1,3-Dipols1-100102

Type 1 Type 2

ba c b

a cb

a c ba c

NN NR

NN NR

NC NR

NC NR

R R

NO N

NO N

NN CR

NN CRR' R'

NC CR

NC CR

R R

R'R'

NO C

NO CR' R'

Azide

Diazoalkane

Nitrous oxide

Nitrile imine

Nitrile ylide

Nitrile oxide

NC NR

NC NR

R R

OO O

OO O

Azomethine imine

Ozone

R''

R'R'

R''

NO N

NO NAzoxy compound R''

R'R'

R''

OO C

OO C

Carbonyl oxideR

R

R

R

NO C

NO CNitrone R''

R'R'

R''

R'' R''

NC CR

NC CR

R RAzomethine ylide R''

R'R'

R''

R'' R''

Out of 12 thinkable 1,3-dipoles containing C, H, N, and O 9 have been used for [3+2]-cycloadditions.

NN

NX

N

O

NO

NN

N

NN

N

N

N

O

NN

O

NNH

NX

NN

N H

NN

NN O

NN

N

NN

NX

NN

O

N

O

NN

NN S

NS

NO

NN

NX

NN

NN

N

NS

NN

NN

N

NO

NN

NR

NN

S

NN

NN

N

N NN

N

NO

NN

O

R. Breinbauer Heterocycles made by 1,3 - Dipolar Cycloaddition

1,3-Dipol-Cycloaddition-091105

Imidazoles Imidazolidines

Pyrazoles Pyrazolines

Pyrazolidines

1,2,3-Triazoles 1,2,3-Triazolines

1,2,4-Triazoles

X = O, S, NR

1,2,4-Triazolines

1,2,4-Triazolidines

Oxazoles Oxazolines Oxazolidines

Isoxazoles Isoazolines Isoxazolidines

1,2,4-Oxadiazoles 1,2,4-Oxadiazolines

Isothiazoles Isothiazolines 1,2,4-Thiadiazoles

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

X = O, S, NR

NO2

R

HH

NH

R

OH

Ph N C O

NCS

N

O

S

RO

NCl

R1 HN R2

N

NN

N

R1R2

NCl

R

OH

NH

O

O

RO

HN Ph

h*ν or ∆

Et3N

Et3N

Et3N

R N S

R1 N NR2

R N O

NCl

Ar

H

R1

R2

NAr

R1 R2

NPhS

R

SiMe3

NR

NH

R1

OH

NR1

OHR3

R2

H

h*ν

Et3N

HgO

F

:CH2

CH2N2

R2 R3

O

h*ν

Ar N CR1

R2

NR3

R2 R1

O

R N CH2

R. Breinbauer Synthesis of 1,3-Dipols I

1,3-Dipol-Synthesis1-091105T. L. Gilchrist, "Heterocyclenchemie", Wiley-VCH, Weinheim 1995.

Nitrile Oxides

Nitrile Oxides:

Nitrile Imides:

Nitrile Ylides:

Nitrile Imides

Nitrile Imides:

Nitrile Sulfides

110 - 160 °C

Aromatic Nitrile Ylides

Aliphatic Nitrilmethylide

Nitrones:

Nitrones

NN

RH

R1

O

NH

HN

R2

O

HR3

R1

R2

N R3

R1

R2

NR3

TMSTMSOTf

OTf

N

Ar

RO2C CO2R

ArN

H

CO2R

F

h*ν

NN

R

R1

O

NN

R2

H R3

ArN

H

CO2RH

NAr

RO2C

H

CO2R

H

R1

R2

N CH2

R3

NAr

RO2C

H

H

CO2R

Ar

ArS

Ar

O

OH

N2

CH2N2 SN

N

ArAr

Rh2(OAc)4

Ar

Ar SCH2

OAr

O

R. Breinbauer Synthesis of 1,3-Dipols II

1,3-Dipol-Synthesis2-091105T. L. Gilchrist, "Heterocyclenchemie", Wiley-VCH, Weinheim 1995.

Azomethinimides

Azomethinimides:

Azomethin-Ylides:

Carbonyl Ylides:

Base

R = -H, -Ar, -COR, -CO2R Pyridinium N-Imides

Azomethin-Ylides

heat

heat

tautomerism

Carbonyl Ylides

Thiocarbonyl Ylides:

-78 °C -40 °C

- N2

Thiocarbonyl Ylides

R. Breinbauer

Lecture6-151105


Literature

Cycloaddition Reactions

1,3-Dipolar Cycladdtions- 1,3-Dipoles: Types and Synthesis- FMO Considerations



R. Breinbauer HUISGEN Azide-Alkyne-Coupling

Azide-Alkyne-Coupling1-091105

Review: R. Breinbauer, M. Köhn, ChemBioChem 2003, 4, 1147-1149.

Azide-Alkyne-Coupling:

Modification of CMV-Virus:

Activity Based Enzyme Profiling:

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

CuSO4

NN

N R2

R1

HR1

NN

N R2

R1 CuLn

CuLnR1

R2NNN

[CuLn]

ligand (L)reducing agent

+

-+

[N3]60

NH DYE

OH

OHO O

COOH

NH

OH

NH DYE

OH NN

N

Ph

N

NNN N

H

O

DYE60

117 eq

pH 8

phosphate buffer / 5% tBuOH

50 eq CuSO4100 eq 2

100 eq TCEP

16 h / 4 °C

:Ligand:

3

2

N3 (CH2)6 OSO2Ph

H RHODAMINE

Nu

(CH2)6NNN

RHODAMINE

(CH2)6N3

pH 8 phosphate buffer / 5% tBuOH

CuSO4(1 mM )Ligand (2 mM )TCEP (1 mM )

1 h / Rt

(2.5µM)

(20 µM)

3

4

Protein Extract

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.

Cu(I) catalysis allows to run this process at room temperature instead of >130°C typical for the uncatalyzed version:

Q. Wang, T. R. Chan, R. Hilgraf, V. V. Fokin, K. B. Sharpless, M. G. Finn, J. Am. Chem. Soc. 2002, 124, 14397-14402.

A. E. Speers, G. C. Adam, B. F. Cravatt, J. Am. Chem. Soc. 2003, 125, 4686-4687.

R. Breinbauer

Lecture7-221105


Literature

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

[2+2]-Cycloaddition- Synthesis of β-Lactams- Synthesis of Oxetanes: Paterno-Büchi-Reaction

Cheletropic Reactions- Aziridination- SO2-Extrusion: Bromoprene-Synthesis



R. Breinbauer, M. Köhn, "Azide-Alkyne-Coupling: A Powerful Ligation Reaction for Bioconjugate Chemistry", ChemBioChem 2003, 4, 1147-1149.

R. Breinbauer

Lecture8-291105


Literature

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)

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

Synthesis, Reactivity, and Use of Heterocycles:

3-Ring-Systems: T. Eicher, S. Hauptmann, "The Chemistry of Heterocycles", Wiley-VCH, Weinheim 2003, 572 pages.


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

(Excellent chapters about ring systems.)


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

N

OH

MeO

MeOOMe

Boc

TosMIC

N

O

Ph

O O

N

O

N

O

MeOO

N

O

O

OH

H

O

OTBS

N

O

N

O

MeO

N

O

O

OH

O

TBSO

O

H

O O

N

O

O

MeO

N

O

O

OH

O

OO

O

O

O

AcO

(H2O)

NMeO

MeOOMe

OMeO

NMeO

MeOOMe

Boc

N O

NMeO

MeOOMe

O

(-)-Teubrevin GI. Efremov, L. A. Paquette, J. Am. Chem. Soc. 2000, 122, 9324-9325.

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.

R. Breinbauer JACOBI - Reaction

Jacobi1-080301

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.

First example for a highly selective intermolecular cycloaddition-retrofragmentation

tetralin, 205 °C

52 % (at 90% conv.)

exclusive regioisomer

P. A. Jacobi, K. Lee, J. Am. Chem. Soc. 1997, 119, 3409-3410.

(rac)-Stemoamide

1) NaBH42) MeOH, H+

3) CH3CCSnBu3, BF3

64 % (3 steps)

diethylbenzene182 °C

53 %

NiCl2, NaBH4

MeOH, -30 °C

73 %

in situepimerization

- MeCN

J. C. Lee, J. K. Cha, J. Am. Chem. Soc. 2001, 123, 3243-3246.Imerubrine

o-dichlorobenzenereflux

90 %

82 %

Examples:

O

N

O R'

RR''

R

R'

R

OR'

ON

Ph SO2Ph

O

O O TBSO

O

O

O

OO

O

Ph

ONPh SO2Ph

O

O O TBSO

O

O

O

OO

O

Ph

OH

R

OR'

OH

HOOH OH

OH

OH OHOH

OH

OH

CO2Et

O

OH

OO

OO

CMe3

H OMe

OMe

CO2Et

O

OH

OH

OO

OO

CMe3

OHOMe

OMe

O

OO

OO

OHO

HO

Me HO H

CMe3

H

R. Breinbauer DAVIS - Oxaziridine

Davis-Oxaziridine1-9.4.2001

F. A. Davis, L. C. Vishwakarma, J. M. Billmers, J. Finn, J. Org. Chem. 1984, 49, 3241-3243.

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.

1 eq. KHMDS2 eq Davis oxaziridine

-78 °C to -20 °C / THF

97 % @ 57 % conv.Taxol

F. A. Davis, A. C. Sheppard, Tetrahedron. 1989, 45, 5703.

J. D. White, H. Shin, T.-S. Kim, N. S. Cutshall, J. Am. Chem. Soc. 1997, 119, 2404-2419.

Euonyminol

1) 1.5 eq KHMDSTHF, -78 °C

2) 1.5 eq

THF, -78 °C, 45 min

83 %

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.

(rac)-Ginkgolide B

1.5 eq tBuLi0.2 eq Et2NHTHF, -78 °C, 1 h

then 10 eq Davis oxaziridine-78 °C to 0 °C, 1 h

60 %

1) Base

2)

O

OMe

H2N

N NH

O

NH2O

OMeO

OMe

H2N

N NH

ONH2

O

OMe[H]

OH

OHMe

H2N

N NH2

ONH2

O

A

OH

OHMe

H2N

N

ONH2

O

NH2

:DNA

OH

H

ON

O

O

O

NH2OH

NH

FR-900482

OH

N NH

ONH2

O

H

O

OH

NNH2

DNA

DNA

H

O

:DNA

OH

OHMe

H2N

N

ONH2

O

NH2

DNA

OH

OHMe

H2N

N NH

ONH2

O

OH

OHMe

H2N

N NH

ONH2

O

OMe

H A

H-A

H-A

OH

OHMe

H2N

NNH2

DNA

DNA

OH

OHMe

H2N

NNH2

DNA

OH

OHMe

H2N

N NH

ONH2

O

OMeH

OH

OHMe

H2N

N NH

ONH2

O

H

:DNA

A

R. Breinbauer

Mitomycin-021105

Mitomycin C

Mitomycin C

- isolated from Streptomyces caespitosus

Inhibition of Replication

Bioreductive Activation and Biological Action:

- marketed as an anti-cancer drug ("Mutamycin", Bristol-Myers-Squibb)

inside cell

Apoptosis

Compound with similar properties:

+ 2 e , +2 H

- H2O

R1 O

X

R4

OR1

O

R2 R3

EWG

O R2

Na2CO3

O R4

R3R2

R1

O R2

EWGR1

R1 OH

R2 O

OR1

R2 R3

BrPPh3

EtO

NaH

R1

O

R2

OR1 R2

R' R'

N

OR1 R2

R

R' R'

R1

O R2OR1 R2

O

R2

R1 R3

O

R2

R1

R. Breinbauer

Furan-Synthesis1-301105

Synthesis of Furans

FEIST-BENARY - Synthesis:

+

PAAL-KNORR - Synthesis:

ZnCl2 or PPA

from α-Hydroxy ketones

JACOBI - Synthesis:

or conc. H2SO4

X = Br, Cl

(works especially well for intramolecular reactions)

+

- R-CN

via DIELS-ALDER

R' = EWG, TMS, R3Sn

+

from Allenyl ketones

Ag, Pd

from Alkynyl ketones

Pd (0)or

R4

OR1

O

R2 R3

O

R1 R2

O

SRO2C CO2RS

R1 R2

RO2C CO2R

RONa

R2 O

R1

EWG

CN

S8

EtOH

S R4

R3R2

R1

S NH2

EWGR2

R1

S

R1 R2

R1 O

R2

R1 O

R2 HCO2R

R R

R1

R2O

H

Cl

R1

R2O

H

O

RO2C

R1

NaOH

HS EWG

HS EWG

HS EWG

SR R

S EWG

R2

R1

S EWG

OH

R1

S EWG

R2 R1

R. Breinbauer

Thiophen-Synthesis1-301105

Thiophens

HINSBERG - Synthesis:

GEWALD - Synthesis:

+

1) NaOH

2) H3O

3) ∆

+Morpholin

PAAL - Synthesis:

H2S or P4S10

FIESSELMANN - Syntheses:

PiperidinPyridin

DMF/POCl3

VILSMEIER-HAACK

(instead of -CO2R other EWGs can be used as well)

Starting from conjugated diynes:

R = alkyl, aryl

H2S or Na2S

or LAWESSON reagent

:S

H

HO O

HN

HO O

HN

NHOO

H

THIP

HN NS

HN

HN

NN

OS

HN

HN

NO

O

N

S NS

HN

HN

NO

O

N

O

O H

O

N OHH

N

N NN

H

N

N

O

HO

R. Breinbauer

Bioisosterism1-041205

Bioisosterism I

Definitions: GABA agonists:

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

Reviews:

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.

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

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

C. G. Wermuth in C. G. Wermuth (Ed.), The Practice of Medicinal Chemistry, Elsevier, London (2003), 189-214.

Ring Isosterism:

M = 26 g/mol M = 32 g/mol

bp

80 °C110 °C132 °C200 °C

bp

84 °C113 °C130 °C214 °C

Thiophene2-Methyl-thiophene2-Chloro-thiophene2-Acetyl-thiophene

BenzeneMethylbenzeneChlorobenzeneAcetylbenzene

Key parameters of GABAA receptor agonists are an acidic (pKa: ca 4) and a basic (protonated nitrogen) functions with a ca. 5.1 Angsstrom interchange distance.

GABA Isoguvacine

Antiulcer H2-receptor histamine antagonists:

Cimetidine Ranitidine Nizatidine

Carboxylic Acid Isosteres:

high chelating power

increased bioavailability, widely used, pKa = 6.6 -7.2

lipophilic replacement

R. Breinbauer

Lecture9-061205


Literature

3H-Diazirines:Synthesis:- Oxidation of Diaziridines

Application:- Photoaffinity Labelling

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

Synthesis:- Cyclisation of β-Substituted Amines (GABRIEL-Synthesis, WENKER-Synthesis)- Cyloaddition of Nitrenes to Olefins- N2-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


3-Ring-Systems:



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




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

WWW-Link

(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.)

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)

OOH

R1

R2

OOH

Me

O

OH

MeO

OOH

R1

R2MeO

OMe

OOH

MeMeO

OMe

O

HO R2R1

O

H

MeO

O

O

HO

O

O

R1

R2HO

O

O

HO Me

O

OTBS

OH

CH3

OAc

O

OTBS

O

CH3 OAc

OBn

O

O

AcOTBSO

CH3

OAc

O

O

AcOTBSO

CH3

OBn

OAc

OOHO

H

O

OO

Ph

O

OMe

OH

OH

OH

O

OH

HO

H

OH

R. Breinbauer ACHMATOWICZ - Rearrangement

Achmatowicz-Rearrangement1-30.5.2001 P. A. Wender, K. D. Rice, M. E. Schnute J. Am. Chem. Soc. 1997, 119, 7897-7898.

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

Review: P. G. Sammes, Gazz. Chim. Ital. 1986, 116, 109-114.

88 %

Phorbol

1) VO(acac)2tBuOOH, DCM

2) Ac2O,pyr, DMAP

2:1 C6-epimers

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

(+)-Resiniferatoxin

96 % (3 steps)

2) mCPBA, THF, 0 °C3) Ac2O,pyr, DMAP

C6-epimers

1) NaBH4, MeOH, 0 °C

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

Br2, MeOH, -35 °Cthen NH3(g)

92 %

2% H2SO4, 90 min, RT

99 %

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.

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

mCPBA

65 %

OHN

X

O

OR1

HN R2

N

O

OH

X

O

H

N

OR1

R2

OH

OHN

X

O

MeOOMe

OHN

X

O

MeOOMe

ONHTs

OCH3

NHO

HHN3 O

NO

HHHN

O

iBuO

O

OMe

NHO

HHN3 O OMe

MeO

ONHTs

OCH3

NH

OH

OH

HOOH

NHO

HHHN O OMe

MeO

O

iBuO

NHOTs

O

OCH3

NHO

HHH2N O OMe

MeO

R. Breinbauer Aza - ACHMATOWICZ - Rearrangement

Achmatowicz-Rearrangement2-27.9.2001

M. A. Ciufolini, C. Y. W. Hermann, Q. Dong, T. Shimizu, S. Swaminathan, N. Xi, Synlett 1998, 105-114.Review:

Ox

This direct oxidation route, is only amenable if R2 = SO2R, otherwise 3-pyridinols form by aromatization. Hydrogenation of the double bond before the rearrangement prevents the substrate from aromatization.

M. A. Ciufolini, C. Wood, Tetrahedron Lett. 1986, 27, 5085.

X = CH2, O

Br2, MeOH, Et2O, -40 °Cthen NH3(g)

85 - 95 %

Raney-NiH2, 1500 psi

50 °C95 - 99 %

15 mol-% TfOH2 eq H2OTHF, RT

80 - 91 %

Br2, MeOH, -20 °Cthen NH3

95 %

Raney-NiH2, 1500 psi

50 °C

99 %

iBuOOCClsatd. NaHCO3

0 °C

85 %

10 % TFACHCl3, 0 °C

99 %

M. A. Ciufolini, Q. Dong, J. Chem. Soc., Chem. Commun. 1996, 881.

Y.-M. Xu, W.-S. Zhou, Tetrahedron Lett. 1996, 37, 1461-1462.

Deoxymannojirimycin

+

Ti(OiPr)4, L-(+)-DIPTTBHP, silica gel, CaH2

DCM, RT, 5 d

40 %

(from 2-furaldehyde)

R4

OR1

O

R2 R3

R1 O

X EWG

O R2

AcOHOCH3O OCH3

R1 R4

R2 R3

R1 O

R2 NH2

EWG

O R3

O

R3

R1 O

R2

H2N CO2R

AcOH N R4

R3R2

R1

R

N R4

R3R2

R1

R

N R2

EWG

R

R1

NH

R3

EWG

R2

R1

NH

CO2R

R3

R1

R2

Tos N C

(isocyanoacetate)

RO2C N C

(TosMIC)

N

OR2

R1

O

EWGR3

N NRO2C CO2R

R1 R2

R1 EWG

R1 NO2

R2

HN

OO

R1

R2

NaH

DBU

Zn/AcOH

NH

R1 EWG

NH

R1 R2

RO2C

NH

CO2R

R2

RO2C

R1

NH

R1

EWG

R2

R3

R. Breinbauer

Pyrrole-Synthesis1-061205

Synthesis of Pyrroles I

HANTZSCH - Synthesis:

+

PAAL-KNORR - Synthesis:

NH3 or R-NH2

VAN LEUSEN - Synthesis:

X = Br, Cl

+

BARTON-ZARD - Synthesis:

NH3 or R-NH2

NH3 or R-NH2

KNORR - Synthesis:

+

(can be producedby in-situ-reduction

of α-oximinoketones)

+

from 1,3-Dicarbonyls and Glycine Esters

+

Ring Contraction of Pyridazines:

(from Hetero--Diels-Alder-reaction)

HUISGEN - Synthesis

+

(azlactone)

R1

OR2

NH2

CN

H2N

R1

OR2

X

NH2

HN R2

R1 O

R2 OH

O

R1 O

R2

O R3

H

(cyanamide)

H2NO

H

2 NH3

(isothiocyanate)

R1

OR2

NH2

NC

R3

SN

NH

SR1

R2 R3

N

NH

R3R1

R2

N

NH

R2

R1

N

NH

NH2R1

R2

N

NH

R3R1

R2

R1 N

HR2

Tos N C

(TosMIC) K2CO3 N

NR1

R2

R. Breinbauer

Imidazole-Synthesis1-071205

Synthesis of Imidazoles

from Amidines:

+

MARCKWALD - Synthesis: VAN LEUSEN - Synthesis:

X = Br, Cl, OH

+

BREDERECK - Synthesis:

+

from 1,2-Dicarbonyls:

+

2

+

+

(2-unsubstituted imidazoles)

by Dehydrogenation:

N

NH

R3R1

R2MnO2or CuBr2/Base or BrCCl3/DBUNH

NH

R3R1

R2

(from 1,2- diamines and aldehydes)

NN

SPr

N

OH

N

NNN

PrS

F

OH

F

N

SO2

C

K2CO3

NH2

OH

NN

SPr

H

O

N

NNN

MeO

F

OH

3 N HCl

NN

SPr

OMe

OMe

N

N

CO2Me

Cl

Cl

N

HN

S

F

NH

O

H

SO2

F

N

SO2

C

THF, RT

piperazine

DMF

K2CO3

N

SO2Tol

CS

Cl

N

SO2Tol

C

Cl

F

N

N

H

O

H

H

O

H

NH4OH

HCONH2

H2N CO2Me

TMSCl

F

H

O

O

H

HO

O

O

H

R. Breinbauer TosMIC - Imidazol-Synthesis

TOSMIC-Imidazol-221002

J. Sisko, M. Mellinger, Pure Appl. Chem. 2002, 74, 1349-1357.

J. Sisko, M. Mellinger, P. W. Sheldrake, N. H. Baine, Org. Synth. 2000, 77, 198-205.

Large Scale Preparation of Aryl-substituted TosMIC:

J. Sisko, M. Mellinger, P. W. Sheldrake, N. H. Baine, Tetrahedron Lett. 1996, 37, 8113-8116.

50 °CPhMe/CH3CN

TolSO2H50 °C

93 %

2 eq POCl3

THF, 0 °C

ex Et3N

>500 kg scale

+

DMF, RT

60 % (one pot)

1) OxoneMeOH, H2O

2) NaOH

90 %

p38 Kinase Inhibitor


Process by GlaxoSmithKline:

+ +

87 %

(98 % ee)

+ +

78 %


50 % aqueous

R1

HN

R2

O OR3

N2

R1 O

R2

CR3

N

(α-(acylimino)ketones)

R1O

R2

O OR3

NH3

R1 O

XR2

NH2

O R3

Rh2(OAc)4

N

O R3R1

R2

N

O R3R1

R2

N

O R3R1

R2

O

N R3R1

R2

R1 O

H

R1 O

ClLi N C

R2

Tos N C

(TosMIC)

(α-metallated isonitrile

K2CO3

N

OR1

R2

N

OR1

R. Breinbauer

Oxazole-Synthesis1-071205

Synthesis of Oxazoles

from α-(Acyloxy)ketones:

+

ROBINSON-GABRIEL - Synthesis: VAN LEUSEN - Synthesis:

X = Br, Cl, OH

+

+

H2SO4 or PPA

BLÜMLEIN-LEWY - Synthesis:

SCHÖLLKOPF - Synthesis:

+

from α-Diazocarbonyl Compounds:

(via carbene intermediate)

by Dehydrogenation:

N

O R3R1

R2MnO2or CuBr2/Base or BrCCl3/DBUNH

O R3R1

R2

(from β-aminoalcohols and aldehydes)

P. Wipf, S. Lim, J. Am. Chem. Soc. 1995, 117, 558.

R. Breinbauer WIPF - Oxazole Synthesis

Wipf-Oxazol-101205

NH

O

NHCO2Me

OH

CO2Me

N

NHCO2Me

O

CO2Me

N

NHCO2Me

O

OH

K. R. Hornberger, C. L. Hamblett, J. L. Leighton, J. Am. Chem. Soc. 2000, 122, 12894-12895.

DAST, DCM, -20 °CBrCCl3, DBU, 0 °C

64 %

HN O

MeO2C

N3

OH

DCM

N O

MeO2C

N3

OO

N O

NH

O

MeO

CN

OHOMe

NMe2OH

OH OH

O

OH

POHO

HO

(+)-Calyculin A

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.

20

25

1) MeO2CNSO2NEt3THF, 55 °C

84 %

2) CuBr2, HMTA, DBU

80 %

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:

A. J. Phillips, Y. Uto, P. Wipf, M. J. Reno, D. R. Williams, Organic Lett. 2000, 2, 1165-1168.

Application:

One-Pot method:

O

PMBO

O

HOOTBDPS

H2N

N

O Me

O

O

OH

BocMe

OTESMe

O

PMBO

OO

OTBDPS

N

N

O Me

OBocMe

OTESMe

Phorboxazole A

C. J. Forsyth, F. Ahmed, R. D. Cink, C. S. Lee, J. Am. Chem. Soc. 1998, 120, 5597-5598.

+

1) EDC*MeI, HOBt, DCM87 %

2) Dess-Martin-periodinane3) a) (BrCCl2)2, Ph3P, DCM

2,6-lutidineb) DBU, CH3CN

77% (2 steps)

NH

O R'HO

R

N

O R'

R

R1

HN

R2

O OR3

P4S10

C

R1 NH2

N

(α-(acylimino)ketones)

R1 O

XR2

NH2

S R3

CS

S

R1S

R2

O OR3

NH3

N

S R3R1

R2

N

S SHH2N

R1

S

N R3R1

R2

N

S R3R1

R2

NH

S R3R1

R2MnO2or CuBr2/Base or BrCCl3/DBU N

S R3R1

R2

R. Breinbauer

Thiazole-Synthesis1-071205

Synthesis of Thiazoles

from α-(Acylthio)ketones:

+

GABRIEL - Synthesis:

X = Br, Cl

+


by Dehydrogenation:

COOK-HEILBRON - Synthesis

(α-aminonitriles)

(from β-aminothiols and aldehydes)

R. Breinbauer

Lecture10-090106


Literature

Furans:Synthesis:

Reactions:- Achmatowicz-Rearrangement- Aza-Achmatowicz-Rearrangement

Thiophens:Synthesis:- Mechanism of GEWALD-Synthesis

Application:-Bioisosterism

Pyrroles:Synthesis:

Application:- Neurotoxicity of n-Hexanes- Wound Healing of Caulerpa taxifolia


5-Ring-Systems: T. Eicher, S. Hauptmann, "The Chemistry of Heterocycles", Wiley-VCH, Weinheim 2003, 572 pages.


(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.)

N

HN

O

Cl

NH

N

NH3C NH

O S

FN

NH O

ON

CF3

CF3CH3

N

N

N

H3C O

NH

O HN

O

F

F

N

NO

HN

N

ON

F3C

HN

NN N

NR

N

NR

R

CH3 OH OCH3 Cl HN CH3 NH2

OH

O

F S OOH CH3

O

ONO2

R. Breinbauer

PrivilegedStructures1-111202

Privileged Structures

Definition: Privileged Structures:

Privileged structures are defined as a single molecular framework able to provide ligands for diverse protein receptors.

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.

Benzodiazepines:

"...judicious modification of such structures could be a viable alternative in the search for new receptor agonists and antagonists"

(Cholecystokinin antagonist) (Opiate receptor)Trifluadom

(NK-1 antagonist)

(K-Secretase inhibitor) (Farnesyl transferase inhibitor)

Biphenyltetrazoles Diphenylmethanes Arylspiropiperidines Arylalkylamines

Substructure Analysis of Drugs:

5120 known drugs were analysed for molecular frameworks and side chains:

G. W. Bemis, M. A. Murcko, J. Med. Chem. 1996, 39, 2887-2893.

- 1179 frameworks identified; 32 of these account for half of all drugs

606 247 195 142 129 119 119

G. W. Bemis, M. A. Murcko, J. Med. Chem. 1999, 42, 5095-5099.

- 20 different side-chains account for 75 % of the total

3125 2566 916 823 719 549 454

355 331 235 214 155 137

R. Breinbauer

Lecture11-110106


Literature

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:

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

Synthesis, Reactivity, and Use of Heterocycles:5-Ring-Systems:



(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.

O

BrMe

OTBS

Me

Me

MeO

Me

Me

O

O

CO2Me

O

Me

Me

OHMeOH

OPMB

OO

H

O

MeO

Me

Me

O

O

CO2Me

O

Me

Me

OMeMe

OXp

OTES

OPMB

NO

O

O2NMe

OH

Me

Me

MeO

Me

Me

O

O

CO2MeMe

Me

OHO

OH

HMe

OH

OHO

O

O2NMe

O

Me

Me

O

O

CO2Me

O

Me

Me

OMeMe

OXp

OTES

OPMB

D. A. Evans, D. H. B. Ripin, D. P. Halstead, K. R. Campos, J. Am. Chem. Soc. 1999, 121, 6816-6826.

R. Breinbauer Isoxazol - Coupling

Isoxazol-coupling1-15.3.2001

N. Kornblum, H. E. Ungnade, Org. Synth. 1963, Coll Vol. IV, 724-727.

Isoxazoles are a synthon for 1,3-diketones.

N. Kornblum, B. Taub, H. E. Ungnade, J. Am. Chem. Soc. 1954, 76, 3209-3211.

Preparation of nitro compunds from bromides

1) AgNO2, Et2O

2) HF.pyr, pyr/THF

78 %

85 %

Macrolactonization via intramolecular [3+2] cycloaddition:

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

3-ClPhNCO, DIPEAbenzene, 90 °C

20 h addition of substrate

68 %

1) pH 10 buffer95 %

2) DDQ, H2O, DCM77 %

(+)-Miyakolide

T. Mukaiyama, T. Hoshino, J. Am. Chem. Soc. 1960, 82, 5339-5342.

Preparation of Nitrile Oxides from Nitroalkanes:

O

MeO

Me

Me

O

O

CO2Me

O

Me

Me

OHMe

OXp

OTES

OPMB

NO

A: Mo(CO)6

B:Me

O

Me

Me

O

O

CO2Me

O

Me

Me

OHMeOH

OPMB

NO

HH

D. A. Evans, D. H. B. Ripin, D. P. Halstead, K. R. Campos, J. Am. Chem. Soc. 1999, 121, 6816-6826.

H2O, MeCN, 70 °C69 %

orW-2 Raney-Ni

1 atm H2EtOAc/AcOH

74 %

R3

R1

R1

NO2

CH3

NH

NH2

NH

CH3O

R2

N

R3O

R3

R2

NMe2MeO

MeO

R1

R2

O

H

H

R1

NaNH2

NO2

NMe2

R1

R3

NR3

R2

R3

NH

R2

R1

NH

R2

R1

NH

R1

R1

O

O

NO2

CH3

NH

I

R

O

OR2R2O

O

CO2RR1

NH2

R1NO2

R3

R2

R1

DMF

NO2

CO2R2

O

MgBr

R1 R1

R1

NH

R1HO

CO2R

R1

NHR1

NR2

R

R3

NH

CO2R2

R. Breinbauer

Indole-Synthesis1-110106

Synthesis of Indoles

FISCHER - Indole Synthesis:

+

or Lewis-acid

works best if R3 = EDG

BATCHO-LEIMGRUBER - Synthesis:

H2/Pd

MADELUNG - Synthesis:

250 °C

due to harsh reaction conditions is limited to R2 = alkyl

BISCHLER - Synthesis:

REISSERT - Synthesis:

H2/Pd

NENITZESCU - Synthesis:

+

LAROCK - Synthesis:

+

cat. Pd(OAc)2Base

BARTOLI - Synthesis:

3 eq

ortho-substituted nitrobenzenes

MeO NO2

NO2MeO

Me

R4

R5NO2

NO2R3R2

R1

AcOH

AcOH

PhCH2ONO2

NO2PhCH2O AcOH

NO2

NO2O

O

AcOH

NH

O

O

R4

R5NH

R3R2

R1

MeO NH

MeOMe

PhCH2ONH

PhCH2O

OMeOMe

NO2

NO2

MeOOMe

NH

N

N

MeOMeMeO

OO

H

R. Breinbauer

Borchardt-Indole-Synthesis1-2.6.2001

BORCHARDT - Indole -Synthesis

F. He, Y. Bo, J. D. Altom, E. J. Corey, J. Am. Chem. Soc. 1999, 121, 6771-6772.

Aspidophytine

excess Fe-powdersilica gel

AcOH/toluene

71 %

reflux, 15 min

A. K. Sinhababu, R. T. Borchardt, J. Org. Chem. 1983, 48, 3347.

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.


reflux, 1 h

benzene/cyclohexaneor

toluene

Examples:


reflux, 1 hbenzene/cyclohexane = 1:3

93 %


reflux, 1 htoluene


reflux, 1 hbenzene/cyclohexane = 1:3

91 %

75 %

R

NH

R'S

R

NH

R'S

R

NH

R'SSnBu3

R

N R'

.SnBu3

NH

Br

OTHP

NH

OAc

NH

OTHP

NTBS

O

NH

R'

R

NH

R'

R

NH

R'

RH

SSnBu3

NH

OH

R. Breinbauer FUKUYAMA - Synthesis of 2,3-disubstituted Indoles

Fukuyama-Indol-Synthesis1-100703

H. Tokuyama, T. Yamashita, M. T. Reding, Y. Kaburagi, T. Fukuyama, J. Am. Chem. Soc. 1999, 121, 3791-3792.

S. Kobayashi, G. Peng, T. Fukuyama, Tetrahedron Lett. 1999, 40, 1519-1522.

Mechanism:

- HSSnBu3

1-2 eq Bu3SnH

0.1 eq Et3B

toluene, RT, 5-40 min

Examples:

81 % yield 89 % yield 71 % yield93 % yield

Alternative method starting from phenyl isonitriles:

R2

HO NH3

NH

EWG EWG

R1 R1

R2 H

N

EWG EWG

R1 R1

R2

NH2R1

R2

O R4

R3

EWG

OR1

EWG

R1O

EWG

OR1

R2EWG

R3H2N NH

EWG EWG

R1 R3

R2 H

N

EWG EWG

R1 R3

R2

R1 R2O O NR1 R2

HH2NOH

NOH

R1 R2

H

R1

R1 R2O O

NH3

NR1 R2

O

R3

OR1

R2

R4H2N

EWG

N

EWG

R1 R4

R3

R2

R1

NNMe2

EWG

EWG

NN

N

R2

R1

R4N

R3

HN

R1 O

N

R3O

R2 NH4OAc

AcOH

N R1

NR1 R3

R2

NR1

R2R3

R4

N

R2 R4

R1

R3

N

R1 EWG

EWG

R. Breinbauer

Pyridine-Synthesis1-110106

Synthesis of Pyridines


Synthesis via Cycloaddition:

Synthesis via 1,5-Dicarbonyl Compounds:

BÖNNEMANN - Synthesis:

+ +oxidation

+oxidation

CpCo(I)-complex

Synthesis via 1,3-Dicarbonyl Compounds:

+

BOHLMANN-RAHTZ - Synthesis:

+

+

+ - N2-

- HNMe2

KRÖHNKE - Reaction:

+

NH2

O

R2

O

R3

R4

NH

O

O

R1

O

R2

R3KOH

NH2

O

COO

H

R1

NH2

R1

R2

O

R3O NH

R3

OR2

R1H

R1

R1

R1

N

R3

R4

R2

N

R2

R3

CO2H

N R3

R2

R1

R1

NH2

NH

O

R2

O

R3

R2

R4

DMF

POCl3R1

R1

NH

O

R2

NCl

NH

R4

OR2

R3 H

As2O5

R1

R1

N

R2

R3

R4

N

R2

Cl

R. Breinbauer

Quinoline-Synthesis1-110106

Synthesis of Quinolines

PFITZINGER - Synthesis:

FRIEDLÄNDER - Synthesis:

COMBES - Synthesis:

+- H2O

1)

2)

isatin isatic acid

+

DOEBNER-MILLER - Synthesis:

+

(oxidant)

SKRAUP - Synthesis: involves in situ-preparation of acrolein from glycerin/H2SO4

METH-COHN - Synthesis:

(is best synthesis for quinolines unsubstituted on the hetero-ring)

NH2 R'O

O O

ORRO

O

N

O

OR

H

Cl

OF

F F

Cl

O

F

O

OR1

N

O

O

N

H2N R2

NH2 O R

O

OR

O

R2

NH R1

O

O

R2

NH O

R1

OH

OH

NH

O

R1

R2

NH

O

R1R2

NH

O

R

OF

N N

O

OH

HN

H2N

HN NH

OF

F F

O

O

NH

O

N

O

OR1

R2

OF

F N

O

O

NMP

R. Breinbauer

Quinolone-Synthesis1-061205

Synthesis of Quinolones

KONRAD-LIMPACH - Synthesis:

GOULD-JACOBS - Synthesis: GROHE - Synthesis:

250 °C

diphenylether+

CAMPS - Synthesis:

+

1) CHCl3, Et3N

2)

1)

2) NaOH

KOtBu/tBuOH

Ciprofloxacin

Industrial Application:

+

1) CHCl3, Et3N

2)

+

R1NH

OR2

R1N

R2

NHO

R2

OH

N

R2

R1 R1

NH2R1

NH

R2

R1

R2

H O

H

R1

R1

N

R2

N

R2

R1

CHO

OR

RONH2

R1N

ORROH

R1N

R. Breinbauer

Isoquinoline-Synthesis1-110106

Synthesis of Isoquinolines

BISCHLER-NAPIERALSKI - Synthesis: POMERANZ-FRITSCH - Synthesis:

+

PICTET-SPENGLER - Synthesis:

PPA or POCl3 dehydration

PICTET-GAMS - Synthesis:

PPA or POCl3

dehydration

+

Documents

R. Breinbauer Textbooks of Heterocyclic Chemistrylamp3.tugraz.at/.../wbShow/codoc/Handouts-Heterocycles2005-06.pdf · Textbooks of Heterocyclic Chemistry ... (Ca-Channel blocker)