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 aformylating agent derived from a formamide and POCl3. It is a special type of Friedel-crafts reaction, which involveselectrophilic substitution of an activated aromatic ring with ahalomethyleniminium salt.

The scope of the Vilsmeier reagent is not confined to aromatic formylation reaction alone. A wide variety of alkene derivatives and activated methyl andmethylene groups exhibit reactivity towards theVilsmeier reagent. In addition to the carbonnucleophiles, some oxygen and nitrogen nucleophilesare 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 ofhalomethyleniminium salts

Me N

Me

H

O

Cl

M e 2 N OPOC l2

HPOCl3+

MeN

MeC

H

ClOPOCl 2

- ++MeN

MeC

OPOCl2

H Cl-

1 2

Synthetic applications of Vilsmeier reagent

Chamaecin (2-hydroxy-4-isopropylbenzaldehyde) was synthesized using MFA and POCl3 and tested for itstyrosinase inhibitory activity. It partially inhibits the oxidation of L-3,4-dihydroxyphenylalanine (L-DOPA) catalyzed by mushroom tyrosinase.

ORPOCl3

( 94 % )MFA

ORCHO

•The styrene related alkenederivative under Vilsmeiercondition providescinnamaledhyde.

•Monoformylation anddiformylation takes place upon reaction of Vilsmeier reagent withbenzalacetones.

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

n()X

ClCHO

X

O

()n

DMF/POCl3

X = CH2, O

CHO

O

R1

R2

R3

Cl CHO

R1

R2

R3

Cl CHO

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

C H 2N 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 3H

C H 3

C 5H 11H

N N

N N

M

Porphobilinogenpyoluteorin

prodigiosin

porphyrin

N N

H O

H

H 3C O 2 C

O

S

N N

H(CH2)4CO2 H

O

HH . .

OH3CO

CH3

OCH3

O

O

Di-O-methylstrepcillin

Biotin

Vincamine

dendrolasin

N

C O N H 2

N

CH2OHCH2OH

HO

H3C

N

N C H3

N

N N

N

OH H

CH 2 O P O P OC H2O O

OH O-

N H2

O

H H

OH HON

CONH2

+

N

N OC H 3

C H 3C H 3 N

N

OO H

(C H2)3C H 3

H 3 C ( C H 2)3

N

N N

N

H2N H

C HOC H 2 N H C ONHCH(C H2)2CO2H

CO2H

Methoxy pyrazine

Aspergillic acid

Nicotinamide adenine dinucleotide

Folinic acid

Nicotinamide Pyridoxine

Nicotine

N

N

C H 2N

S

C H3

CH2C H2O P O P OHO O

OH OH

N H 2 H3C

+

N

N N

NCH2(CH OH)3CH 2O H

H

O

O

N

NO

H

O

O

OH

H O H2C

H

HO

N

HHO

H3CON

Quinine

RiboflavinUridine riboside

Thiamine

Synthesis of Pyridine, Pyran and Oxazinederivative.

α-Hydroxyketenedithioacetals upon treatment with two equivalents of Vilsmeier reagent yield aiminium 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

OSCH3

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/POCl3

3-4h, 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 pentasubstituted4(H)-pyrans in good yield.

X

OPh PhO

X

Ph PhO

CHOOHCDMF/POCl3

0C80

45-55%.

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

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 carboxaldehydesfrom β- keto amides.

N-Phenylacetoacetamide on treatment with 8 equivalents ofVilsmeier 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

RR

R

N

RR

RO

Cl

O

N

RR

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

OP h

O

O

NH

O

C l

NH

OP h

C l

N

OP h

C l

N

OP h

C l

N

OP h

C l

N

OP h

C l

NH

OP h

C l

NH

OP h

C l

NH

OP h

C l

N M e 2

+

N M e 2

+

M e 2 N+

N M e 2

+

M e 2 N+

N M e 2+

N M e 2

+

N M e 2

N M e 2

+

N H M e+

N M e 2

+

M e 2 N+

N M e 2

+

N M e 2

+

N M e 2

N M e 2

+

N H M e+

Synthesis of Furan and benzo-4-pyrone derivatives

O

O

Me

O

OOH

Me

DMF/POCl380OC

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

Synthesis of 2, 4, 6- Triaryl- 2H- 1, 3- oxazines byVilsmeier 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/POCl380OCOO

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

OOH

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

30%

82%

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

ON

RCHO

R

O

N3

DMF/POCl3

RCHO

ClN3

RT

R

O

Br

DMF/POCl3

ON

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%

ON3

ON3

SO

N3

O

Br

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

A rN 3 N M e 2C HC l

O

ON

A r

N M e 2

N M e 2

N N

ON N

NN

A r

N M e 2

NO

N M e 2

A r

- N 3

NO

OH

A r

+

+

+

+

-

+

+

+

H 2 O

+

O

B r

C H 3 (i) DMF/NaN3

(ii) POCl3O

N

C l

C l

N C H

C H O

DMFNaN3,0 C

_N3

ON3

R

0

+

OH

BrCH2

RO

BrC H 3

RO

N3

CH3

R

NMe2

C l ON

ClR

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

NMe 2+

ON

NN

+-

NMe 2+

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)NCHOPOCl 3

N

O O

N M e 2

PhNCHO

CH3

POCl3

N

O O

NPh

MeN

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

40-50%

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

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

NN O

N3

HCl

NMe2

N N

N

O NMe2

NMe2

NMe2N N N

N

NMe2

NMe2N

Cl

HN N

N

NMe2

NMe2N

Cl

NN

Me2N

ClCHO

_ +-+

+ +

+

+

:

_ +-

+

+

_ +

+

+

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 basedpyrazoles 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 hydrazonederivatives. 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 acetylacetoneto yield ethyl 4-methyl-3-acetylpyrazole-5-carboxylate via the pyrazoline

H2OO O

+N2CHCOOEt HNN

COCH3

H3CHO

EtOOCHN

N

COCH3H3C

EtOOC

NNHCH3

CH3+

H3C

COOCH3

O

NNCPh

O

CHCH3

CH3

CH3

PCl3

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

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

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

NN

OHPhCONH

CX R1

N

O

HC

O

Ph

EtO

R1CXNHNH21, 4 Dioxane NH

N

CXR1

O

PhCNH

OR XC N

H

NH

PhO

HC

O

N

1

Br

ONH

O

O

OO

O

N

DMF, rtto 40 C

o

DMF / DMA

OO

O

N

NMe2

N N

NH2

RDMF / DMA1-16 h, reflux

NH2NHR, EtOH

Synthesis of pyrazoles under Vilsmeierconditions

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

H

CH3

N N N N

CHODMF/POCl3

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

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.

NNR5

R1R2

R3

R4

DMF/POCl3

MWI, 30-50 secor , 4-5 h

NN

R1R2

R3

R4

R5

H

MWI 49-70%, Δ 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 achievedby the Vilsmeier cyclization of o-hydroxyacetophenonephenylhydrazones 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'

NH

C6H3(NO2)2NN

COOR'

R"

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

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

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.

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

Δ -70-88%, 83-92 %,87- 94%

Reaction with commercially available Vilsmeierreagent.

R"

N

COOR'

NH

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-carboxylatesafter the removal of –CONH2 group upon neutralisation.

R"

N

COOR'

NH

CONH2NN

COOR'

R"

H

where R = H

70-80oC, 6h

[ClCH=NMe2]Cl+

86%

85-92%

During our studies it was observed that when the activemethylene 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'

NH

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 withVilsmeier reagent.

CH3 CO2R

N NH

NO2

XNN NO2

X

RO2CCHO

70-80oC, 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 withVilsmeier reagent.

CH3 CO2R

N NH

NO2

XNN NO2

X

RO2CCHO

70-80oC, 4h

DMF, POCl3

79-88%

Synthesis of 3-arylethenylpyrazole-4-carboxaldehydes

The synthesis of pyrazole derivatives by theVilsmeier cyclization of acetophenone phenylhydrazonesprompted 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 tautomerismunder acidic conditions to give the correspondingpyrazolines 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 thepyrazole aldehyde

Reaction of 4-aryl-3-buten-2-one 2,4-dinitrophenylhydrazones 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 ofacetylcarbazoles to chlorovinylaldehydes, condensation followed by cyclization with hydrazine hydrate.

(iii)

(ii)

N

R1

R2

(i)

N

R1

R2 COCH3

N

R1

R2Cl

CHO

R1=CH3, or C2H5R2=H, or CH3

N

R1

R2N

N

H

71-80%

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

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

Synthesis of substituted indoles, Benzoxazolinesand benzthiazolines

N NVR

H H

COOH

COOH CHO

Cl80oC

S SVR

COOH

COOH CHO

Cl80oC

O OVR

80oCCOOH

COOH CHO

Cl

V.J. Majo, P.T. Perumal; J.Org. Chem. 61, 6523, 1996.61-75%

51%

21%

NVR

H

COOH

COOH

COOH

HN

O

O

CH =NMe2+

N

OO

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 -HCl N

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 ofacyl 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 sodiumazide to form the acyl azide in excellent yield.

OH

OR'

R"

OR'

R"

N3

R'

R"

CO2H CON3R'

R"

NaN3, DMF

POCl3

NaN3, DMF

POCl3

90-95%

80-90%

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

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"

CO2HR

NH2

R'

R"

R

NH

NH

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 POCl3replaces –OH group with –Cl yielding 94% of 2-chlorobenzothiazole.

R'

R"

CO2HR

SH

R'

R"

R

S

NCl

R'

R"

CON3

R

SH

R'

R"

R

S

NH

O

NH4N3, DMF

3 equiv. POCl3

NH4N3, DMF8 equiv. POCl3

94% 70%

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

Synthesis of Quinoline derivatives

DMF/POCl3

N

CHO

Cl

N O

N OH

H

N

CHO

ClRN

NMe2 N M e 2

C l RN

C H3

OH R

DMF/POCl3

75oC, 4-6 h

N O

C H ONMe 2

HR N

CHO

OHR

PPA

aq.

Synthesis of Chloro methyl quinoline

NH2

O

NH2

CH=NMe2

Cl

NH2

CH=NMe2

ClCH-NMe2

NH2

CH-NMe2

ClCH-NMe2

N

ClCH-NMe2

H

NHMe2 N

ClCHO

+ + +

++

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

R

NH

O

O

Cl

NMe2N

ClCHO

CHO

Cl

N

ClCHO

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

ClCH-NMe2

NHMe2 N

ClCHO

ON

ClCH-NMe2

HNMe2

O

+

+

+ +

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

The Vilsmeier cyclization of 2'-aminochalconesprovides 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 ofquinolines 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.

NO

OR

O

ON

CHO

R1

F

Cl

+ POCl3NN

N

FO

CO2H

RH

114 a; R = Et114 b; R=

Synthesis of quinolone antibiotics ciprofloxacin, and norfloxacin

Synthesis of carbazolyl-dihydroquinolines

N O

NH2

N

NCHO

ClOHC

N

NCHO

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

+

DMF/POCl3

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

N 3

O

R

DMF/POCl3

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

DMF/POCl3

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

30-60%

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

32-46%

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

O COOH

NH2

R V.R

O

N

CHO

H

RO

N

CHNMe2

Cl

RT

50-82%

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

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

RO

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

NMe2H

N

R RN

O

0

C90=+

H

H

-HCl

-HCl

H

H

RNH2

RT

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

N H

OCOOH

R N

O H

NM e

M e

O

R

VR

a; R = Hb; R = Ph

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

NH

O

N3

COOHR

R

D M F / POCl3R T

N

N N

CHOC l

OMeR

R

N

N N

CH

OMe

NMe2OR

R

1

2

11

22

42-60%

NMe2H

Cl

+

++ _

+

N

NMe2

N

O

CH O N Me2

N N

XO

N

O C O O H

N3

H

N

NMe2

N

O

CHO NMe2

XO

N

N

N

O

CH O N Me2

Me

N

NMe2

N

O

CHO NMe2

XO

H

N N

N2_

N

N

N

O M e

Cl C H O

Attempted synthesis of indazoles

HN NN N

R1

R2DMF/POCl3

R1

R2

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

R1 , R2 = NO2

HN N

HN N

O

NH2

DMF/POCl3

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

Synthesis of benzindazoles bycyclisation of tetralone hydrazones

N N NNH

R1R2

R3

R4

R5

R1

R2

R3

R4

R5

DMF/POCl3

MWI 71-87%

Δ 54-67 %

NNH

NN

R1R2

R3

R4

R5

R1R2

R3

R4

R5

DMF/POCl3

NN

O

NH2 NNHH

R3 R3

DMF/POCl3

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

5%

MWI 76-77%

Δ 53-59 %

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

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

Synthesis of 4,5dihydropyrazolo[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 Δ (90oC) = 35-60%, MWI=55-85%

Acknowledgement

1. Dr. M. Venugopal

2. Dr. B. Balasundaram

3. Dr. V. J. Majo

4. Dr. R. R. Amaresh

5. Dr. S. Selvi

6. Dr. S. Akila

7. Dr. R. Nagarajan

8. Dr. R. Sridhar

9. Mr. K. Hemanth kumar

10. Ms. Y. Zulykama

11. Mr. G. Sivaprasad