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.
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