vilsmeir reagent reactions by perumal
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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
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