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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

O

X

R1

+H2N NHAc

NH2 DMF or 

MeCNNH

NR

R1

NHAc

R

O

OH

R1

+HN NH2

R2

NH

N

R2

R

R1

R

HN

HN

S

R

O

OH

hexanol reflux

N N RR

S

  -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

O

NHR2HCONH2

heat

NN

R

1

R2

R1

NH3ClR

O

+ R2NCSHN

N

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

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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

N

R

NH

COOH

NH2

+   CH(OEt)3HCl

N

N

MnO2   N

N

NH2NC

NC   NH2

HC(OEt)3

anisole,

1350C   NH

N

NC

NC

ClCN

NH

NNC

NC

NH2

THF,500C

COCl

dioxane

500C

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

+   ONH

N

O

HN

R

R

2  HCl

N

N   NR

R

R

Cl-

H2O

N

N

CHO

R

R   Cl-

hv

NH

NNC

H2N

N3NC  HCl

MeOH  NH2

MeO

N3  Cl-

1.Et3N, rt

2.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.

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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

O

O

NHR1

R2

PCl5, POCl3

reflux

N

N

Cl

R2

R1

NH

R1

OHN

CHO

PCl5, POCl3reflux

N

N

Cl R1

H2N

OHN R1

O

Et3O+BF4-, DCM

rtNH

N

R2

EtO

NOH

NH2Ar +   CO2R

MeOHreflux

O

CO2R

NH

NH

Ar  NH

NRO2C

Ar heat

Ring Transformation

  -Ring enlargement of azirines by reaction with nitriles

 

-From Dihydropyrazines

  -From Aminoisoxazoles

 

-From 1,2,4-oxadiazoles

N

R1 R2

+ R3CNBF3

.OEt or 

HClO4 NH

N

R3

R1

R2

N

Nhv, MeOH

N

N

NO

HN

O

H2, Pt/C

EtOH, rt

H2N

HN

O

ONaOHEtOH

  NNH

O

N

O

N

NH2

R

+

O

R1 R2

O

N

O

N

HN

R

R1

COR

2

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

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Synthesis of Imidazoles  Alexandros ZografosThe Baran Group Meeting

Natural Products:

Oroidin

Sceptrin

 Ageliferin

 Axinellamine

Dragmacydin D

Stevensine

Temozolomide

HN

NH

N

NH2

O

NH

Br 

NH

N

N

H

N

NH

HN

NH2

NH2

O

O

NH

NHBr 

Br 

N

HNHN

HN

N

HN

O

O

HN

NH

H2N

NH2

Br 

Br 

N

NH

HN

OH

HN

NH

HO

Cl

HN

H HN

NH

OONHN

H

Br 

Br 

Br 

Br 

NH

OH

NH

N

O

NH

Br 

NHN

H2N

NH

NH

Br 

Br 

O

N

HN

H2N

N NN

NN

O

H2N

O