Synthesis of Imidazoles Alexandros ZografosThe Baran Group Meeting

Indroduction: -Planar, five membered heteroaromatic molecule with pyrrole type and

pyridine type annular nitrogens.

-Named first as gluoxaline (first synthesis with glyoxal and ammonia).

-Aphoteric nature, susceptible to electrophilic and nucleophilic attack.

-High stability to thermal, acid, base, oxidation and reduction conditions.

-Extensive intramolecular hydrogen bonding.

Biological Properties: -Against fungal infections.

-Treatment of hypoxic tumor cells.

-Anticancer agents.

-Anti-HIV agents

Synthesis of Imidazoles: "There are no really general ways of synthesizing imidazoles and it is

invariably necessary to consider a number of divergent methods whenever

a synthesis is contemplated"

NH

N

N

NHH

N

NH

H Ring Formation:

-Fragments C-C, N, C and N: 1. Combination of an alkene, carbon monoxide and ammonia 2. A dicarbonyl compound with aldehyde and ammonia 3. Hydroxycarbonyl reagent with aldehyde and ammonia 4. The Maquenne synthesis

R+ CO + NH3

Rh4(CO)12

MeOH-H2O NH

NR

R

R

R

O

OO

O

R1 H

O+

NH4OAc

AcOH NH

NO

O

R

R1

CH2OHOHHOOHHOHH

CH2OH

+ 2NH3 + HCHO

CuIIH2Spicric acidHCl

NH

N

OH

HHO HN

OH

HOHO O

ONaIO4

NH4OAcHCHO, Cu(II)

N

NH HN

O

HO

H

COOH

H

HOOC

NO2HOOC

NO2+ RCHO NH3

NH

NHOOC

HOOC

R

J. Org. Chem., 1971, 36, 25,.

Tetr. Lett., 1994, 35, 1635

JACS, 1979, 101, 3983

Synthesis of Imidazoles Alexandros ZografosThe Baran Group Meeting

Ring Formation:

-Fragments a C-C-N, C and N: 1. Hydroxyimino ketone, aldehyde and ammonia

2. Aminonitrile, orthoformate and primary amine -Fragments N-C-N and C-C 1. Halocarbonyl or dicarbonyl compounds with guanidines 2. Amidines and hydroxy or halocarbonyl compounds 3.Ureas and thioureas with carbonyl compounds

R2 O

NOHR3

+ R3NH2 + RCHON

N+

R

R3

R2

O-

NC

NH2

NH2

O

+ CH(OEt)3 + NH

H2N EtN

N

CONH2

NH2

NHEt

rt,MeCN

R

OX

R1

+H2N NHAc

NH2 DMF or

MeCNNH

NR

R1

NHAc

R

OOH

R1

+ HN NH2

R2

NH

NR2

R

R1

RHN

HN

SR

O

OH

hexanol refluxN

N R

RS

-Fragments N-C-N and C-C 4. Cyanoepoxides and amidines or guanidines -Fragments C-C-N and C-N 1. Aminocarbonyl compounds with N-C reagents 2. Marckwald Synthesis. Aminocarbonyl compounds with cyanates or cyanamide 3. Amidates and aminocarbonyl compounds

O

R1

R2

CN

CO2Et+ R3 N

NH2

R4 NN

R3

R4

OHNC

R1

ONHR2 HCONH2

heatN

N

R1

R2

R1

NH3ClR

O+ R2NCS

HNN

S

R1

R

EtO OEt

NHR1R

+ NH2CN1.EtOH

2. HCl N

N

R

NH3Cl

R1

NH O

REtO+ H2N

OEt

OEt

acid

NH

N O

R

R3

R2

J. Org. Chem., 1963, 1620

Synthesis, 1991, 823

J. Org. Chem., 1994, 59, 7299

Synthesis, 1993, 561

Tetr. Lett, 1995, 36, 547

J. Org. Chem., 1994, 59, 1589

JACS., 1949, 71, 644

Synthesis of Imidazoles Alexandros ZografosThe Baran Group Meeting

Ring Formation:

-Fragments N-C-C-N and C: 1. 1,2-Diaminoalkanes and carbon reagents 2. Use of diaminomaleonitrile (DAMN)

NH2

NH2

+HO

O

R

H2 alumina Pt 4000C

NH

NR

NH

COOH

NH2

+ CH(OEt)3HCl

N

N

MnO2 N

N

NH2NC

NC NH2

HC(OEt)3

anisole,1350C N

H

NNC

NC

ClCN

NH

NNC

NC

NH2THF,500C

COCldioxane500C

NH

HNNC

NC

O

MeC(NH)(OEt)2anisole

NH

NNC

NC

3. Involving cyclization of diiminocompounds. 4. Pinner salt method 5. From 2-amino-azidoacrylates

NHNC

NHNC

+ NH2+ O

NH

N

O

HN

R

R

2 HCl

N

N NRR

R

Cl-

H2O

N

NCHO

R

R Cl-

hv

NH

NNC

H2N

N3NC HClMeOH

NH2

MeO

N3 Cl-

1.Et3N, rt2.Ph3P, DCM, rt NH

MeO

N PPh3

NH

N

NH

NR

MeO

NHR

MeO

S

NHR

RNCSrt

RCOClrt

R1 N3

NHZROOC

Ph3P, DCM R1 N

NHZROOC

PPh3 R2NCO

DCM

R1 N

NHZROOC

C NR2

N

NR1

ROOC

NHR2

Z

MeOH

OO

OO

J. Org. Chem., 1993, 58, 3387

J. Org. Chem.,, 1974, 39, 2341

Synthesis, 1995, 449

Synthesis, 1996, 1459.

Synthesis of Imidazoles Alexandros ZografosThe Baran Group Meeting

Ring Formation:

-Fragment C-N-C-C-N: 1. Wallach Synthesis 2. From acylated glycines and formamido acetamides -Fragment N-C-N-C-C: 1. Cyclization of amidines

NH

OO

NHR1R2

PCl5, POCl3reflux

N

N

Cl

R2

R1

NH

R1O

HN

CHOPCl5, POCl3reflux

N

N

ClR1

H2N

OHN R1

O

Et3O+BF4-, DCM

rtNH

NR2

EtO

NOH

NH2Ar+ CO2R

MeOHreflux

O

CO2R

NH

NH

Ar NH

NRO2C

Arheat

Ring Transformation

-Ring enlargement of azirines by reaction with nitriles -From Dihydropyrazines

-From Aminoisoxazoles -From 1,2,4-oxadiazoles

N

R1 R2

+ R3CNBF3

.OEt orHClO4 N

H

NR3

R1

R2

N

Nhv, MeOH

N

N

N O

HN

O

H2, Pt/CEtOH, rt

H2N

HN

O

O NaOHEtOH N

NH

O

N

ON

NH2

R

+

O

R1 R2

O

N

ON

HN

R

R1

COR2

EtONaDMF

N

NHRCOHN

R1

COR2

JACS, 1967, 1259

J. Med. Chem., 1975, 18, 90

JACS, 1967, 89, 4457.

JACS, 1967, 89, 2375.

Tetr. Lett., 1971, 18, 1459.

J. Org. Chem., 1987, 52, 2714

Tetrahedron, 1974, 30, 3859

Synthesis of Imidazoles Alexandros ZografosThe Baran Group Meeting

Natural Products:

Oroidin

Sceptrin

Ageliferin

Axinellamine

Dragmacydin D

Stevensine

Temozolomide

HN N

H

NNH2

O

NH

Br

NH

N

NH

N

NH

HN

NH2

NH2

O

ONH

NHBr

Br

N

HNHN

HN

NHN

O

O

HN

NH

H2N

NH2

Br

Br

NNH

HN

OH

HN

NH

HOCl

HNH H

N

NH

OONHN

H

Br

Br

Br

Br

NH

OH

NH

N

O

NH

Br

NHN

H2N

NH

NH

Br

BrO

N

HN

H2N

N NN

NN

O

H2NO