SYNTHESIS OF NOVEL HETEROCYCLIC COMPOUNDSUSING VILSMEIER REAGENT

P.T. PERUMALORGANIC CHEMISTRY DIVISIONCENTRAL LEATHER RESEARCH INSTITUTEADYAR, CHENNAI-600 020.

Aromatic Formylation

H2O ArCHOArCH=NH2Cl-+HClAr + Zn(CN)2

Reimer-Tiemann reactionOH

+ CHCl3OH

_

OH

CHO

ArH + Cl2CHOMe ArCHOAlCl3

Formylations using Friedel-Crafts catalyst

Gatterman reaction

VILSMEIER-HAACK FORMYLATION

NMe

+ ClNMe2

NMe2

CHH Cl

NMe2

NMe2

NMe2

+.

..... ..

...

+

+

Cl-

‘The Vilsmeier aldehyde synthesis’ or ‘The Vilsmeier-Haack formylation’ is a typical aldehyde synthesis employing a formylating agent derived from a formamide and POCl3. It is a

special type of Friedel-crafts reaction, which involves electrophilic substitution of an activated aromatic ring with a halomethyleniminium salt.

The scope of the Vilsmeier reagent is not confined to aromatic formylation reaction alone. A wide variety of alkene derivatives and activated methyl and methylene groups exhibit reactivity towards the Vilsmeier reagent. In addition to the carbon nucleophiles, some oxygen and nitrogen nucleophiles are also reactive towards Vilsmeier reagent. Numerous transformations of the iminium salts into products other than aldehydes have been achieved and these transformations enhance the scope and versatility of the Vilsmeier-Haack reaction

Formation, structure and nature of halomethyleniminium salts

M e N

M e

H

O

C l

M e 2 N O P O C l 2

H P O C l 3 +

M e N

M e C

H

C l O P O C l 2

- + + M e N

M e C

O P O C l 2

H C l -

1 2

Synthetic applications of Vilsmeier reagent

Chamaecin (2-hydroxy-4-isopropylbenzaldehyde) was synthesized using MFA and POCl3 and tested for its

tyrosinase inhibitory activity. It partially inhibits the oxidation of L-3,4-dihydroxyphenylalanine (L-DOPA) catalyzed by mushroom tyrosinase.

ORPOCl3

( 94 % )MFA

OR

CHO

•The styrene related alkene derivative under Vilsmeier condition provides cinnamaledhyde.

•Monoformylation and diformylation takes place upon reaction of Vilsmeier reagent with benzalacetones.

Reaction of carbonyl compounds with Vilsmeier reagent provides mainly 3-chloroacrolin derivatives.

n()X

Cl

CHO

X

O

()n

DMF/POCl3

X = CH2, O

CHO

O

R1

R2

R3

ClCHO

R1

R2

R3

ClCHO

R1

R2

R3

CHO

POCl3 DMF

0C0

0C09

M.Venugopal and P.T.perumal, Organic Prep. &Proce.Int. 749-766 (1991)

•One of the major forces that sustain interest in heterocyclic chemistry is the fact that nature elaborates many of these ring systems.

•Nearly all the alkaloids are derived from heterocyclic molecules and a reasonable number of them are used as medicines.

•Heterocycles are also present in fossil fuels, much to the chagrin of environmentalists.

N

C H 2 C O 2 H H O 2 C ( C H 2 ) 2

C H 2 N H 2

H

O H

O H O

N

H

C l

C l

N

N N

H

H

N

H

N N

O C H 3

H C H 3

C 5 H 1 1 H

N N

N N

M

Porphobilinogenpyoluteorin

prodigiosin

porphyrin

N N

H O

H

H 3 C O 2 C

O

S

N N

H ( C H 2 ) 4 C O 2 H

O

H H . .

O H 3 C O

C H 3

O C H 3

O

O

Di-O-methylstrepcillin

Biotin

Vincamine

dendrolasin

N

C O N H 2

N

C H 2 O H C H 2 O H

H O

H 3 C

N

N C H 3

N

N N

N

O H H

C H 2 O P O P O C H 2 O O

O H O -

N H 2

O

H H

OH HO N

C O N H 2

+

N

N O C H 3

C H 3

C H 3 N

N

O O H

( C H 2 ) 3 C H 3

H 3 C ( C H 2 ) 3

N

N N

N

H 2 N H

C H O

C H 2 N H C O N H C H ( C H 2 ) 2 C O 2 H

C O 2 H

Methoxy pyrazine

Aspergillic acid

Nicotinamide adenine dinucleotide

Folinic acid

Nicotinamide Pyridoxine

Nicotine

N

N

C H 2

N

S

C H 3

C H 2 C H 2 O P O P O H

O O

O H O H

N H 2 H 3 C

+

N

N N

N C H 2 ( C H O H ) 3 C H 2 O H

H

O

O

N

N O

H

O

O

O H

H O H 2 C

H

H O

N

H H O

H 3 C O N

Quinine

Riboflavin

Thiamine

Uridine riboside

Synthesis of Pyridine, Pyran and Oxazine derivative.

α-Hydroxyketenedithioacetals upon treatment with two equivalents of Vilsmeier reagent yield a iminium intermediate which on treatment with ammonium acetate result 2-methylsulfanyl substituted 4-aryl pyridines.

MeMgI / Et2O

HO

CH3

SCH3

SCH3(i) POCl3 / DMFrt, 24 h

(ii) NH4Ac,

80 oC, 2 h

N

Ar SMe

O

SCH3

SCH3

+2Cl-

+VR

Ph

NMe2

NMe2Ph

NMe2

NOHC

Ph

NH4ClH2O

2-Chloro-5-aryl-3-pyridine carboxylaldehydes was obtained from 4-aryl-3-butene-2-one.

R

NOH

R

N

O

H

DMF/POCl33-4h, 95oC

N

CHO

Cl

R.R.Amaresh,P.T.Perumal, Synth. Commu. 30, 2269 (2000)

Dibenzyl ketone undergoes diformylation followed by 6π-electrocyclic ring closure to yield 3,5-diphenyl-4-pyrone.

O

Ph Ph

O

Ph Ph

O

O

Ph Ph

HMe2N

Cl

VR

20-30%, 30-40%.

1,3,5-Triaryl-1,5-diketones on treatment with Vilsmeier reagent have furnished pentasubstituted 4(H)-pyrans in good yield.

X

OPh Ph

O

X

Ph PhO

CHOOHCDMF/POCl3

0C80

M. Venugopal , P.T. Perumal, Tetrahedron Letters 32, 3235-3238 (1991)

45-55%.

Mechanism for cyclisation

++

1

POCl3 + Me2NCHO Me2N=CHOPOCl Cl+ -

PhPH

Ph

OCl

NMe2

PhPH

Ph

O O

+ 1

O PhCl

NMe2Ph

Ph+

+

+ ++NMe2

O PhCl

Ph

Ph

+ 1

O Ph

Ph

Ph

NMe2 NMe2

+

O Ph

Ph

Ph

NMe2

O Ph

Ph

Ph

NMe2

CHOOHC

+

M. Venugopal , P.T. Perumal, Tetrahedron Letters 32, 3235-3238 (1991)

Synthesis of 2-imino-2H-pyran carboxaldehydes from β- keto amides.

N-Phenylacetoacetamide on treatment with 8 equivalents of Vilsmeier reagent in DMF solvent has undergone cyclisation to yield 2-phenylimino-4-chloro-2H-pyran-5-carboxaldehyde in 12% yield along with 2-phenylimino-4-chloro-2H-pyran-3-carboxaldehyde in 32% yield.

NH

O

O

R

R

R

N

R

R

RO

Cl

O

N

R

R

RO

Cl

O

1

2

1

2

1

2

+

Overall yield- 40 - 60 %product ratio 1:2.6

R.R.Amaresh, P. T. Perumal, Tetrahedron 55 (1999) 8083-8094

NH

O

O

PhO

N

O

Cl

Ph

NH2

O

O

O

O

NH

O

Cl

50%

23%

Synthesis of 2-(phenylmethyl)imino-4-chloro-2H-pyran-5-carboxaldehyde and 4-chloro-2-imino-2H-pyran-3,5-dicarboxaldehyde

NH

O

OPh

O

O

NH

O

Cl

NH

OPh

Cl

N

OPh

Cl

N

OPh

Cl

N

OPh

Cl

N

OPh

Cl

NH

OPh

Cl

NH

OPh

Cl

NH

OPh

Cl

NMe2

+

NMe2

+

Me2N+

NMe2

+

Me2N+

NMe2+

NMe2

+

NMe2

NMe2

+

NHMe2

+

NMe2

+

Me2N+

NMe2

+

NMe2

+

NMe2

NMe2

+

NHMe2

+

Synthesis of Furan and benzo-4-pyrone derivatives

O

O

Me

O

OOH

Me

DMF/POCl380O

C

M.Venugopal,B.Balasundaram ,P.T.Perumal, Synth.Commu. 23,2593 (1993)

Synthesis of 2, 4, 6- Triaryl- 2H- 1, 3- oxazines by Vilsmeier reagent from 3-(α-hydroxybenzyl-N-hydroxylamine)-1, 3- diarylpropen-1-ols.

O NH

OHOH

H

O N

Yield- 30-42%

B.Balasundarm ,P.T.Perumal ,Indian J.Chem 32B, 1061, 1993.

Synthesis of pyroles and furans1,4- Ketoacids were converted to furan

carboxaldehydes

Acetylacetone was converted to furan aldehyde

O

CHO

DMF/POCl380O

COO

M.Venugopal,B.Balasundaram ,P.T.Perumal, Synth.Commun. 23,2593 (1993)

O

OH

OR

O

OHC

R

ClVR , 90oC

70-85%

68%

N-Acetylglycine was converted to dichlorodiformylpyrrole

N C H 3

O O H O

H

VR

N C l

O C l

N M e 2

H

+

N O H C

C l

C l

C H O

H

Cl -

COOH

NH

COOH

NH

Cl

CHO

OHC

VR

V.J.Majo, P.T.Perumal, J.Org.Chem. 61, 6523,1996

82%

30%

B.Balasundaram,M.Venugopal, P.T.Perumal, Tetrahedron letters 34, 4249, 1993.

Synthesis of chlorodiformylpyrrole

Synthesis of Oxazolines & IsoxazolinesOxazolidin-5-ones from N-acetyl amino acids

NHOH

O

RO

NH

O

O

HO

R

R = Me, iso-Pro, iso-butyl

or CH2CH2COOH

VR

30 - 45%

The azido group possesses the essential qualities required to make it an excellent precursor in organic synthesis. Intramolecular cyclizations of aryl and heteroaryl azides are well known general, high yielding processes for the construction of five-, six- and seven - membered heterocyclic rings.

SYNTHESIS OF OXAZOLE CARBOXALDEHYDES

R

O

N3

DMF/POCl3

O

N

RCHO

R

O

N3

DMF/POCl3

RCHO

Cl

N3

RT

R

O

Br

DMF/POCl3

O

N

RCHONaN3

V.J.Majo, P.T.Perumal, Tetrahedron Letters. 38,6889,1997. V.J.Majo, P.T.Perumal, J.Org.Chem. 63, 7136,1998.

45-61%

62-80%

45-61%

O

N3

O

N3

S

O

N3

O

Br

A possible mechanism of the formation of oxazole carboxaldehydes is outlined below.

ArN3 NMe2CHCl

O

O

NAr

NMe2

NMe2

N N

O

N N

NN

Ar

NMe2

N

O

NMe2

Ar

-N3

N

O

OH

Ar

+

+

+

+

-

+

+

+

H2O

+

O

B r

C H 3 (i) DMF/NaN 3

(ii) POCl 3 O

N

C l

C l

N C H

C H O

DMF NaN 3 , 0 C

_ N 3

O

N 3

R

0

+

O H

B r

C H 2

R O

B r

C H 3

R O

N 3 C H 3

R

N M e 2 C l O

N

C l R

Synthesis of 5-benzyl-2-chlorooxazoles from 1-bromo-1-aryl acetone

33-38%

CH3

Br

O

Ar CH2

Br

OH

Ar

N3-

NaN3,DMF

00C N3Ar

O

NMe2

+

O

N

N

N

+

-

NMe2+

ArH2C

O N

ArH2C

NN

+

NHMe2

+

:O N

ArH2C

NN

+

Cl-

+

O N

ArH2C

NN

+Cl H

O N

ArH2C

Cl

N

C O O H O

H Ph(Me)NCHO

POCl 3

N

O

O

N M e 2

PhNCHO

CH3

POCl3

N

O O

NPh

Me

N

O

COOHH

N

O

COOH

NO2

HV.R

NO2

N

O O

NPh

Me

L.Vijalakshmi, V.Parathasarathi, P.T.Perumal, V.J.Majo, Acta Cryst C54,1683,1998

78%

Synthesis of isoxazolines from chalcones

X

O

Y

X,Y = Me, OMe, Cl, NO2

2NH2OHEtOH, H2O, CH3COONa

/ 15min X

O

Y

HN-OH

NO

Y

H

Cl

DMF/POCl380 C/ 3hO

M.Venugopal ,P.T.Perumal, Proc.Indian Acad.Sci, 105,19,1993

40-50%

Synthesis of Imidazoles from 2-azidoacetanilide

N

N

O NH

O

N3

NN

NMe2

ClCHO

VR

45-62%

V.J.Majo, P.T.Perumal, J.Org.Chem. 63, 7136,1998.

N

O NMe2

Me2N

NMe2

N

N O

N3

HCl

NMe2

N N

N

O NMe2

NMe2

NMe2N N N

N

NMe2

NMe2N

Cl

HN N

N

NMe2

NMe2N

Cl

N

NMe2N

Cl

CHO

_+-

+

+ +

+

+

:

_+-

+

+

_+

+

+

H2O

Mechanism for Cyclization

Pyrazole derivatives which have been the basis of numerous dyes, are also useful as analgesic, antipyretic, anti-inflammatory and anaesthetic drugs. They are also used as chemical bleaching agents, luminescent, fluorescent substances and as antioxidants in motor fuels. Sulphonamides based pyrazoles has prolonged bacteriostatic action in vivo. Pyrazole-4-carboxamide and acetamide have been used as antialcoholic agents.

Synthetic Studies on Pyrazole

Pyrazoles are synthesised from hydrazone derivatives. Pyrazole synthesis exploits the reaction of 1,3-diketones with hydrazine derivativest to give 3,5-Dimethylpyrazole in 80% yield

CH3COCH2COCH3 + N2H4 NNH3C

CH3

H

Ethyl diazoacetate reacts with the acetylacetone to yield ethyl 4-methyl-3-acetylpyrazole-5-carboxylate via the pyrazoline

H2O

O O+N2CHCOOEt HN

N

COCH3

H3C

HO

EtOOCHN

N

COCH3H3C

EtOOC

NNHCH3

CH3+

H3C

COOCH3

O

NNCPh

O

CHCH3

CH3

CH3

PCl3

The Michael addition / elimination protocol has been extended to the hydrazides and semicarbazides providing a general route to 1-aryl-3-hydroxy-1H-pyrazoles from 4-ethoxymethylene-2-phenyloxazol-5(4H)-one via the intermediates.

The reaction of ketone arylhydrazone with phosphorous trichloride and methyl acetoacetate r gives 2-alkenylpyrazole-3(2H)-one.

The one-pot synthesis of the enaminoketone by treatment of α-phthaloylaminoacetophenone with dimethylformamide-dimethylacetal, followed by cyclization to form 4-aminopyrazole.

NN

OHPhCONH

CX R1

N

O

HC

O

Ph

EtO

R1CXNHNH2

1, 4 Dioxane NHN

CXR1

O

PhCNH

OR XC N

H

NH

PhO

HC

O

N

1

Br

ONH

O

O

OO

O

N

DMF, rt

to 40 Co

DMF / DMA

OO

O

N

NMe2

N N

NH2

R

DMF / DMA1-16 h, reflux

NH2NHR, EtOH

Synthesis of pyrazoles under Vilsmeier conditions

Kira et al have reported the formation of pyrazole-4-carboxaldehyde by treating acetophenone phenylhydrazone with DMF/POCl3 complex.

H

CH3

N N N N

CHO

DMF/POCl3

Acetophenone azine has also been converted into the pyrazole-4-carboxaldehyde derivative on treatment with the Vilsmeier reagent.

Synthesis of [1]benzopyrano[4,3-c]pyrazoles has been achieved by the Vilsmeier cyclization of o-hydroxyacetophenone phenylhydrazones followed by the treatment of the resulting pyrazole-4-carboxaldehydes with mineral acid.

CH3

N N

H3C

N N

CHO

CH2DMF/POCl3

We have reported the synthesis of 4-alkyl-1,3-diarylpyrazoles with DMF and POCl3 using

conventional thermal methods.

NN

R5

R1R2

R3

R4

DMF/POCl 3

MWI, 30-50 sec

or , 4-5 h

NN

R1R2

R3

R4

R5

H

MWI 49-70%, ∆ 41-76%

S. Selvi, P.T. Perumal, J. Heterocyclic Chem. 39, 1129, 2002.

H+, CH3CH2OH

DMF/POCl3RT, 4 h

NN

CHO

NO2

O2N

OHR1

R2

NN NO2

O2N

O OCH2CH3R1

R2

CH3

N N

OH

O2N

NO2

R2

R1

H

53-76%

S. Selvi, P.T. Perumal, Indian J. Chem. 41B, 1887, 2002.

Synthesis of [1]benzopyrano[4,3-c]pyrazoles has been achieved

by the Vilsmeier cyclization of o-hydroxyacetophenone

phenylhydrazones followed by the treatment of the resulting

pyrazole-4-carboxaldehydes with mineral acid.

R. Sridhar, P.T.Perumal, Synth. Comm. 33, 1483, 2003.

R. Sridhar et al , Bioorganic & Med. Chem. Letters, 14, 6035-6040, 2004.

R"

N

COOR'

N

H

C6H3(NO2)2NN

COOR'

R"

C6H3(NO2)2i. DMF/POCl3MWI 3-5 min

or ii. DMF/POCl3SiO2 /MWI 3-5 min

Hydrazones of β-keto esters upon treatment with three equivalents of Vilsmeier reagent gave a 1H-pyrazole-4-carboxylate.(pale yellow solid )

i) by heating at 80 C for 3-4 hr

ii) by irradiating the reaction mixture in excess DMF and

(iii) by removing the solvent by evaporation followed by irradiation

of the reaction mixture on SiO2 support.

∆ -70-88%, 83-92 %,87- 94%

Reaction with commercially available Vilsmeier reagent.

R"

N

COOR'

N

H

R NN

COOR'

R"

R

[ClCH=NMe2]Cl+

70-80oC, 6h

where R = C6H3(NO2)2

When semicarbazones of β-keto esters were chosen as substrates, we obtained 1H-pyrazole-4-carboxylates after the removal of –CONH2 group upon

neutralisation.

R"

N

COOR'

N

H

CONH2NN

COOR'

R"

H

where R = H

70-80oC, 6h

[ClCH=NMe2]Cl+

85-92%

86%

During our studies it was observed that when the active methylene proton was substituted with more electronegative chlorine atom, the reaction resulted in the formation of 1H-pyrazole-4-carboxylate substituted with N,N-dimethyl amino group at 5-position.

R"

N

COOR'

N

H

R

Cl

NN

COOR'

R" NMe2

R

[ClCH=NMe2]Cl+

70-80oC, 6h

Where R = C6H5(NO2)2

75-88%

Synthesis of 4-formyl-1H-pyrazole-3-carboxylate

Synthesis of 2,4-dinitrophenyl-4-formyl-1(H)-pyrazole-3-carboxylate was achieved by us from hydrazones of α-keto esters upon treatment with Vilsmeier reagent.

CH3 CO2R

N N

H

NO2

X

NN NO2

X

RO2C

CHO70-80oC, 4h

DMF, POCl3

79-88%

R. Sridhar, G.Sivaprasad, P.T.Perumal, J. Heterocyclic Chem., 41, 405, 2004.

Synthesis of 4-formyl-1H-pyrazole-3-carboxylateSynthesis of 2,4-dinitrophenyl-4-formyl-1(H)-

pyrazole-3-carboxylate was achieved by us from hydrazones of α-keto esters upon treatment with Vilsmeier reagent.

CH3 CO2R

N N

H

NO2

X

NN NO2

X

RO2C

CHO70-80oC, 4h

DMF, POCl3

79-88%

Synthesis of 3-arylethenylpyrazole-4-carboxaldehydes

The synthesis of pyrazole derivatives by the Vilsmeier cyclization of acetophenone phenylhydrazones prompted us to study the effect of Vilsmeier reagents on the 4-aryl-3-buten-2-one phenylhydrazones. 4-aryl-3-buten-2-one phenylhydrazones are known to undergo tautomerism under acidic conditions to give the corresponding pyrazolines and we expected such a rearrangement to occur under the Vilsmeier conditions followed by formylation of the resulting pyrazoline system to give 1,2-diphenyl-3-N,N-dimethylaminomethylene-4-methyl-1H-pyrazolines or the pyrazole aldehyde

Reaction of 4-aryl-3-buten-2-one 2,4-dinitrophenyl hydrazones with vilsmeier reagent gave the corresponding 1-(2,4-dinitrophenyl)-3-(2-arylethenyl)-1H-pyrazole-4-carboxaldehydes in excellent yields

1

2

1

2

33

DMF/POCl3CH3

N NH

R

R

R

N N

CH

CHOR

R

R

72-85%

DMF/POCl3

N N Ar

CH NMe2

CH

NMe2

H

+

N N Ar

CH NMe2

CH

NMe2

N N Ar

CH

CHO

CH3

NNArH

N N Ar

CH

CH

NMe2+

Mechanism

Synthesis of pyrazolylcarbazolesWe have synthesized pyrazolylcarbazoles from

carbazoles. The key steps include conversion of acetylcarbazoles to chlorovinylaldehydes, condensation followed by cyclization with hydrazine hydrate.

(iii)

(ii)

N

R1

R2

(i)

N

R1

R2 COCH3

N

R1

R2

Cl

CHO

R1=CH3, or C2H5R2=H, or CH3

N

R1

R2

NN

H

71-80%

i ) BiCl3, Ac2O, ii)DMF, POCl3, iii) N2H4.H2O

R. Nagarajan, P.T.Perumal, Synthesis, 1269, 2004.

Synthesis of substituted indoles, Benzoxazolines and benzthiazolines

 

N NVR

H H

COOH

COOH CHO

Cl80oC

S SVR

COOH

COOH CHO

Cl80oC

O OVR

COOH

COOH CHO

Cl80o

C

V.J. Majo, P.T. Perumal; J.Org. Chem. 61, 6523, 1996.

51%

61-75%

21%

NVR

H

COOH

COOH

COOH

HN

O

O

CH =NMe2+

N

O

O

O

HHN

O

N

Cl

NMe2

Cl

CHOHN

N

O

NMe2+ +

NMe2

+

RT

Cl

CHON

CHO

Mechanism

Phosgene reacts with o-phenylenediamines to gives 2(3H)-benzimidazolones in excellent yield in organic solvents such as benzene, toluene or chloroform.

NH2

NH2

.2HCl + COCl2 -HClN

N

H

H

O

Wright, J. B. Chem. Rev. 1951, 48, 446.

Usually the synthesis of 2(3H)-benzothiazolones is achieved by the reaction of o-amino thiophenol with urea.

NH2

SH

+ H2NCONH2

N

S

H

O

Most of the synthetic routes to 2(3H)-benzimidazolone involve o-phenylenediamine as the starting material, which is a suspected carcinogen and is costlier. And there is no generalized strategy available for the synthesis of these title compounds in one-pot. Hence we aimed at a simplified generalized procedure for the preparation of 2(3H)-benzimidazolones, 2(3H)-benzoxazolone and 2(3H)-benzothiazolone.

Synthesis of acyl azidesPhosgene employed along with DMF in the earlier

method for the synthesis of acyl azide, is highly toxic. We have chosen DMF and POCl3, which are milder, for the preparation of

acyl azide. Addition of POCl3 facilitates the reaction to be one-

pot since it forms the Vilsmeier adduct with DMF at first, which then complexes with the carboxylic acid and reacts with sodium azide to form the acyl azide in excellent yield.

OH

O

R'

R"

O

R'

R"

N3

R'

R"

CO2H CON3R'

R"

NaN3, DMF

POCl3

NaN3, DMF

POCl3

R. Sridhar, P.T.Perumal, Synth. Comm.,33, 607, 2003.

90-95%

80-90%

Acyl azides are derived in situ from ortho amino benzoic acids upon treatment with DMF/POCl3 and azide ion.

These acyl azides after curtius rearrangement upon stirring for 8-10 hours yield 2(3H)-benzimidazolones.

R'

R"

CO2H

R

NH2

R'

R"

R

NH

N

H

ONH4N3, DMF/POCl3

75-88%

R. Sridhar, P.T.Perumal, Synth. Comm.,34, 735, 2004

Synthesis of 2(3H)-benzothiazolone and 2-chlorobenzothiazole

Salicylic acid and thiosalicylic acid yield 2(3H)-benzoxazolone and 2(3H)-benzothiazolone respectively in good yields upon treatment with ammonium azide and three equivalents of DMF-POCl3 complex.

Stirring the reaction mixture at room temperature for about 6-10 hours effected both rearrangement and cyclization. Excess POCl3

replaces –OH group with –Cl yielding 94% of 2-chlorobenzothiazole.

R'

R"

CO2H

R

SH

R'

R"

R

S

NCl

R'

R"

CON3

R

SH

R'

R"

R

S

N

H

O

NH4N3, DMF

3 equiv. POCl3

NH4N3, DMF8 equiv. POCl3

R. Sridhar, P.T.Perumal, Synth. Comm.,34, 735, 2004

94% 70%

Synthesis of Quinoline derivatives

DMF/POCl3

N

CHO

Cl

N O

N OH

H

N

C H O

C l R N

N M e 2 N M e 2

C l R N

C H 3

O H R

D M F / P O C l 3 75 o C, 4-6 h

N O

C H O

N M e 2

H R N

C H O

O H

R

P P A

aq. NaOH

Synthesis of Chloro methyl quinoline

NH2

O

NH2

CH=NMe2

Cl

NH2

CH=NMe2

Cl

CH-NMe2

NH2

CH-NMe2

Cl

CH-NMe2

N

Cl

CH-NMe2

H

NHMe2 N

Cl

CHO

+ + +

++

R.R Amaresh, P.T.Perumal, Synthetic communications, 1997, 27, 337.

R

NH

O

O

Cl

NMe2N

Cl

CHO

CHO

Cl

N

Cl

CHO

R1

NH

O

OR2

Cl

N

R1

R2

CHOCl

N

R1

R2

+

YIELD- 14 , 60 %

R1

NH

O

OR2

Cl

N

R1

R2

YIELD - 89%

NH

O

O

NHCH=NMe2

Cl

O

N

Cl

CH-NMe2

NHMe2 N

Cl

CHO

O

N

Cl

CH-NMe2

HNMe2

O

+

+

+ +

R.R.Amaresh, P.T.Perumal, Indian journal of chemistry, 36 B 541, 1997

The Vilsmeier cyclization of 2'-aminochalcones provides a mild one pot synthesis of 2-aryl-4-chloro-N-formyl-1,2-dihydroquinolines. The scope of the reaction has been extended for the synthesis of quinolines themselves, by replacing 2'-aminochalcones with 2'-azidochalcones as the starting material.

NH2 Ar

O

DMF, POCl3

, 90oC

N Ar

Cl

CHO

68-85%

R.Nagarajan, P.T.Perumal, Synthesis, 1269, 2004.

N

OOR

O

ON

CHO

R1

F

Cl

+ POCl3NN

N

F

O

CO2H

RH

114 a; R = Et114 b; R=

Synthesis of quinolone antibiotics ciprofloxacin, and norfloxacin

Synthesis of carbazolyl-dihydroquinolines

N O

NH2

N

N

CHO

Cl

OHC

N

N

CHO

Cl25%

+

10%

VR,90oC

C H 3

N 3

O

N

C H O

N M e 2

C l

N N M e 2

C l

+

D M F / P O C l 3

a) R = CH 3 b) R = C 2 H 5

N 3

O

R

D M F / P O C l 3

N

R

N M e 2

C l

+

N

C l

R

N CHOPh

CH3

POCl3O

N CHO POCl3 N CHO POCl3

,,

R.R.Amaresh, P.T.Perumal, Tetrahedron letters, 1998,39, 3837, Tetrahedron, 1998,54, 14327.

SYNTHESIS OF 2-ARYL 4-CHLORO QUINOLINES

N 3

O

A r N A r

C l

D M F / P O C l 3

A possible mechanism for the formation of 2-aryl-4-chloro quinolines is presented below.

O

ArN

Cl

ArNMe2

Cl

Ar

H

OCHNMe2

42

N

N

N

++

N

N

N

+

+

62-72%

Synthesis of tetrahydro-1-2H-benzazepine-oxo-2-carboxaldehydes and dihydro-5-oxo-1,4-benzoxoazepine-4-(5H)-carboxaldehydes.

NOH

R

N-CHO

R

O

VR

O

NOH

R

O

N-CHO

O

R

Ph

VR

V.J. Majo, A.M. Prince, M.Venugopal & P.T.Perumal, Synth. Comm.25, 3863, 1995.

32-46%

30-60%

2-Dimethylaminoformylidene-3-chloro-1,4-benzoxazine

O COOH

NH2

R V.R

O

N

CHO

H

R

O

N

CHNMe2

Cl

RT

S.Selvi, P.T.Perumal. Synth. Comm. 31, 2199, 2001.

50-82%

2-Dimethylaminoformylidene-3-chloro-1,4-benzthiazine

S COOH

NH2

V.RRT

S

N

CHNMe2

Cl

Dimerization reactionsPreparation of 2-[3,4-dihydro-4-oxo-3-quinazolinyl]-N,N-dimethylbezamide

NH2

R COOH N

N

R

O

N

R

R

CONMe2

N

O

+

x

60-72%

80-86%

V. J. Majo, P.T.Perumal, Tetrahedron Letters, 37, 5015, 1996.

NH2

COOHN

N

O

Ph

VRRNH2

MechanismNH2

R COOH

N

R

R

CONMe2

N

O

NHCH

R COCl

NMe2 N

RN

R

COCl

COCl

NMe2

NH2

R COCl

NMe2

Cl+

N

RN

RCOCl

NMe2

N

R

R

N

O

NMe2COCl

H

N

R RN

O

NMe2

HN

R RN

O

0

C90=+

H

H

-HCl

-HCl

H

H

RNH2

RT

3-Substituted-1-oxo-2,4-benzoxazine fromN-acetyl anthranilic acid

NH

OCOOH

R N

O H

NMe

Me

O

R

VR

a; R = Hb; R = Ph

Synthesis of imidazoquinozolindiones from 2-(2-azido)acetamido benzoic acid

N H

O

N 3

C O O H R

R

D M F / P O C l 3 R T

N

N N

C H O C l

O

M e R

R

N

N N

C H

O

M e

N M e 2 O R

R

1

2

1 1

2 2

42-60%

N M e 2 H C l

+ + +

_

+

N

N M e 2

N

O

C H O N M e 2

N N

X O

N

O C O O H

N 3

H

N

N M e 2

N

O

C H O N M e 2

X O

N

N

N

O

C H O N M e 2

M e

N

N M e 2

N

O

C H O N M e 2

X O

H

N N

N 2 _

N

N

N

O M e

C l C H O

Attempted synthesis of indazoles

HN NN N

R1

R2

DMF/POCl3R1

R2

Conditions: DMF/POCl3, (Solvent-DMF), 60-65 0C.

R1 , R2 = NO2

HN N

H

N N

O

NH2

DMF/POCl3

Conditions: DMF/POCl3, (Solvent-DMF), 60-65 0C.

Synthesis of benzindazoles by cyclisation of tetralone hydrazones

N N NNH

R1

R2

R3

R4

R5

R1

R2

R3

R4

R5

DMF/POCl3

MWI 71-87%

∆ 54-67 %

N

NH

N

N

R1

R2

R3

R4

R5

R1

R2

R3

R4

R5

DMF/POCl3

NN

O

NH2 NNHH

R3R3

DMF/POCl3

G.Sivaprasad, R.Sridhar, P.T.Perumal.(Communicated)

Synthesis of 4,5-dihydro-2H-benzo[e]indazole from aryl hydrazones

Synthesis of 4,5-dihydro-2H-benzo[g]indazole from semi carbazones

5%

MWI 76-77%

∆ 53-59 %

Synthesis of 4,5 dihydropyrazolo[4,3c]quinolinesfrom

tetrahydroquinoline hydrazones

R

NN

N

H

N

R

NN

CHO

NO2

HNO2

DMF/POCl3

K.Hemanth kumar, S. Selvi, P.T.Perumal. J Chem Research 218, 2004.

Yield ∆ (90oC) = 35-60%, MWI=55-85%

Acknowledgement

1. Dr. M. Venugopal

3. Dr. B. Balasundaram

5. Dr. V. J. Majo

7. Dr. R. R. Amaresh

9. Dr. S. Selvi

11.Dr. S. Akila

7. Dr. R. Nagarajan

8. Dr. R. Sridhar

9. Mr. K. Hemanth kumar

10. Ms. Y. Zulykama

11. Mr. G. Sivaprasad