IJPCBS 2012, 3(1), 25-43 Rajputet al. ISSN: 2249-9504
INTERNATIONAL JOURNAL OF PHARMACEUTICAL, CHEMICAL AND BIOLOGICAL SCIENCES
Available online at www.ijpcbs.com
REVIEW ARTICLE ON VILSMEIER-HAACK REACTION
AP. Rajput1* and PD. Girase2
1P.G. Research Center, Department of Chemistry, Z.B. Patil College, Dhule, Maharashtra, India. 2S.V.S’s Dadasaheb Rawal College, Dondaicha, Dhule, Maharashtra, India.
INTRODUCTION
The application of the Vilsmeier-Haack (VH) reagent (POCl3/DMF) for the formylation of
a variety of both aromatic and
heteroaromatic substrates is well
documented1. The Vilsmeier-Haack reagent is an efficient, economical and mild reagent for the formylation of reactive aromatic and heteroaromatic substrates2. It is now used as a powerful synthetic tool for the
construction of many heterocyclic
compounds3.
The classical Vilsmeier-Haack reaction4, however, involves electrophilic substitution of an activated aromatic ring with a halomethyleniminium salt to yield the corresponding iminium species, which facilitates easy entry into various nitrogen
and oxygen based heterocycles5,3a,d.
Vilsmeier reagent serves not only as a formylating agent6, but also as an activating reagent for carboxylic acids to give esters7, amides8and acid chlorides9and for alcohols to give alkyl chlorides10, esters11, alkyl aryl sulfides12 and imides13. Besides this, the reagent has also been extensively used for effecting various chemical transformations with other classes of compounds.
There is a growing interest in formylation as an interesting strategy to form intermediate carboxaldehydes, due to their
intrinsic pharmacological properties and chemical reactivity14. Formylation reactions
have been described for
pyrido[2,3-d]pyrimidines as a key step for the
introduction of functionalities via the intermediate carboxaldehydes15.
The Vilsmeier-Haack reaction can also be applied to introduce an acetyl group on activated aromatic or hetero aromatic compounds, many other conversions can be achieved with this technology. In general,
N,N-dimethylformamide (DMF) and
phosphorus oxychloride (POCl3) are used to generate a halomethyleniminium salt used in the synthesis of a large number of heterocyclic compounds16-19.
In 1896, Friedel noted the formation of a
red dye on treatment of
N-methylacetanilide with phosphoryl chloride to which he assigned the problematic structure (1)20. This was corrected by Fischer, Miller and Vilsmeier in 192521 who assigned the cynine-dye structure (2) and argued cogently that this product derived from the self condensation of the quinolinium salt (3). It was the realization by Vilsmeier & Haack22 that one molecule of
N-methylacetanilide had acetylated a
second molecule prior to cyclisation that led to the discovery of the Vilsmeier-Haack formylation using N-dimethylformanilide.
Review Article
ABSTRACT
This review article represents a survey covering the literatures on Vilsmeier-Haack reaction, glutarimides and dihydropyridines. This short review also provides an update on recent reports and demonstrates the usefulness and the efficiency of this approach. The data on the methods of synthesis, chemical reactions, and biological activity of these heterocycles published over the last years are reviewed here for the first time.
N N
H C6H4
Me
Me C6H4
Cl Me N N Me Cl Cl N Me Cl Me Me Cl Cl Cl + C (1) + (2) (3) -- -+
The formyl group thus, introduced in to a substrate is, of course, a highly reactive species and the versatility of this reaction, to a large extent, is due to the variety of synthetically useful transformations that may subsequently be performed. The V.H. reaction has been extensively studied and reviewed23.
The structure of the electrophilic adduct has aroused much interest. The behavior of the adduct appears to be consistent with an ionic character rather than a covalent character24. The structures a & b were considered most likely for the DMF/POCl3 adduct. N C H OPOCl2 C H3 C H3 N C H OPOCl2 C H3 C H3 .. N C H C H3 C H3 Cl N C Cl H OPOCl2 C H3 C H3 .. OPOCl2 + + + + -a b
Structure of the Vilsmeier-Haack
Complex
Phosphorous oxychloride reacts with
tertiary amides to give adduct which exhibits salt like properties. These adducts have been referred to as the Vilsmeier complexes25.
R O
C N R1R2 P O C l3 R C
N R
1R2
O P O Cl
2
R
N R1R2
C C l
P O
2C l2
R O
C N R1R2 A rS O2Cl
C l
R C
O
N R
1R2
S O
O
A r R C
C l
N R1R2
A r S O3
( D ) P O2C l
+ + + + + (A ) -(B ) (E )
-C H A R T -I N a tu r e o f V ils m e ie r-H a a c k R e a g e n t -. . . . . . . . . .. . . . . . . . . . . -C l
C l
-.
(F )
+ +
Recent studies on the NMR spectra of the DMF/POCl3 complex pointed to the imidoyl chloride salt structure (B)26-28 (Chart-1). Challis and Challis29 suggested that O- acyl structure (A) might be more stable for POCl3 than for other halides such as SOCl2, COCl2 and PCl5.
R C O POCl2
NR1R2
R NR1R2
C Cl
PO2Cl2
C O R
NR1R2
Cl2X R C O
NR1R2 Cl
R NR1R2
C Cl X O Cl + + (A) -(B) + (C) --- X + (D)
X = CO, SO or PCl3 . . . . . . .. .. . . . . . . . . .. .. . . + -Cl -Cl +
The Vilsmeier complexes are generally prepared at low temperatures (250C). If the reaction with nucleophile is carried out
at low temperature (300C) the
rearrangement of (A) and (B) does not seem to be favoured. Furthermore, the Vilsmeier complex undergoes a much wide range of nucleophilic substitution reactions.
Reagents
The Vilsmeier complexes employed in the formylation reactions are usually derived from N,N-disubstituted amide and POCl3. N-Methyl formanilide and N,N- dimethyl formamide are commonly used. N-Methyl formamide, N-formylpiperidine27 and N-formylindeline28 have also been used. The use of unsubstituted formamide has also been investigated30, but the complex was found to be less reactive than the DMF / POCl3 or MFA / POCl3 complexes.
Other amides such as N, N-dimethyl acetamide, N-methyl acetamide, N, N-dimethyl
benzamide, N, N ׀
‘, ,,-pentamethyl acetamide, etc. have been employed in the presence of POCl3 but these amides are prone to undergo self condensation. Acid chlorides other than POCl3 have also been used in the Vilsmeier reactions. They are COCl231, SOCl232, ClOCl33, CH3COCl34, ArCOCl34,35, ArSO2Cl35, PCl536, Me2NSO2Cl37 and RO2CNH SO2Cl38.
IJPCBS 2012, 3(1), 25-43 Rajputet al. ISSN: 2249-9504
Solvents
In the case of amides like DMF, dimethyl acetamide, N-methyl pyrrolidone, etc. which are liquids, an excess of the amide can be used as solvent. Other solvents like
chloroform, methylchloride, benzene,
toluene, o-dichlorobenzene, dioxane and tetrahydrofuran have also been used.
Temperatures
Normally the reactions are carried out at room temperature or between 600 and 800C. Reactions at temperature as high as 1200C have also been described39. The Vilsmeier reaction has been the subject of many review articles of varying scope and length. Some of the reviews are enlisted here in chronological order. Vilsmeier (1951)40, Bayer (1954)41, Bredereck et al.
(1959)42, Eilingsfeld, Seefeder and
Weidinger (1960)43, Minkin and Darofeenko (1960)44,Oda and Yamamoto (1960)45, De Maheas (1962)46, Hofner et al. (1963)47, Gore (1964)48, Hazebroucq (1966)49, Jutz (1968)50, Ulrich (1968)51, Kuehne (1969)52, Seshadri (1973)24, Jutz (1976)53, Meth-cohn and Tarnowski (1982)54, Smichen (1983)55, Marson (1992)56 , Meth-cohn and Stanforth
(1991)57 and Meth-cohn (1993)58,
Arumugam S. (1994)59, Duduzile M. M. (2007)60, Carsten Borek (2008)61, Jones G. and Stanforth S. P. (1997)62, Kantlehner (1976)63 has reviewed adducts from acid amides and acylation reagents and also the
preparation and reaction of
chloromethyliminium salt with
nucleophiles. Liebscher and Hartmann (1979)64 have published anarticle relating to vinylogous chloroiminium salts. These excellent reviews deal with the Vilsmeier reaction, its mechanism and the structure of the various eletrophilic reagents. In this study we have restricted our coverage to important concepts rather than reiterate all the literature material.
Synthetic Applications of the Vilsmeier-Haack Reaction
i) Formylation of aromatic
hydrocarbons, phenols, phenolethers, olefins, ketones, Beta-chlorovinylal dehydes.
ii) Diformylation reactions.
iii) Formylation with aromatization.
iv) Regiospecific formylation.
v) Oxygen and nitrogen nucleophiles are
also reactive towards Vilsmeier reagent.
vi) Formylation with dimerization. vii)Transformation of iminium salt into
product other than aldehyde. viii) Miscellaneous V-H reactions.
In view of the vastness of the literature, we have endeavored in this review to demonstrate the powerful potential of Vilsmeier-Haack reaction in the synthesis of
different compounds. Only few
representative reactions are illustrated under the following titles.
A) Synthesis of Pyrroles
Gupton J. T. et al.65 have studied and
reported the synthesis of
4-Aryl-2-carbethoxypyrrole (6) from compound (4) with POCl3, DMF and heat followed by NaPF6/H2O via formation of Vinylogous iminium salt (5) (Scheme-1).
COOH
N N
Me Me Me
Me
PF6
N CO2Et
H POCl3 / DMF
NaPF6/H2O H
2N CO2Et
DABCO.DMF and heat +
-and heat followed by
(4)
(5) (6)
(Scheme-1)
They have also reported microwave accelerated Vilsmeier-Haack formylation of pyrrole (7) into formyl pyrrole (8) (Scheme-2).
N Y X
CO2Et N
Y X
CO2Et
OHC POCl3,DMF
Microwave heating
(Scheme-2)
(7) (8)
Z= H, Me
Z Z
Pfefferkorn J. A. et al.66 have described formylation of pyrrole (9) under
Vilsmeier-N N
N O
O R2 R1
CF3
(105-106)
-Haack conditions into pyrrole
carboxaldehyde (10) as a part of
development of an efficient and scalable second generation synthesis of novel,
pyrrole-based HMG-COA reductase
inhibitors (Scheme-3).
N
F F
EtO2C N
F F
CHO EtO2C
POCl3, DMF
DCE 800C
(9) (10)
(Scheme-3)
Cho T. P. et al.67 have discovered the series of novel pyrrolopyridazine derivatives by carrying out synthesis of pyrrolopyridazine (14) from pyrrole diesters (11) by using V-H reagents (Scheme-4).
POCl3
NH2NH2.H2O,
POCl3,
CH3CN,
N O O
O H O
N O O
O H O O
H
N H
N NH O EtOOC N
H N N EtOOC Cl
2.0 equiv DMF, 100 0C, 2 h 77%
1.5 equiv
EtOH 90 0C, 3 h, 72%
2.0 equiv 80 0C, 5 h
(11)
(14)
(12)
(13) (Scheme-4)
B) Synthesis of Functionalized Pyridines
Xiang D. et al.68 developed a facile and efficient one- pot synthesis of highly substituted pyridin-2(1H)-ones(18), (19) and (20) via Vilsmeier-Haack reactions of radily available 2-arylamino-3-acetyl-5,6-dihydro-4H-pyrans (15), (16) and (17) respectively (scheme-5).
O
Ar H N O
N
X ( C H2)3Br
O
O H C A r
O
O
N
B r
( C H2)3Br
O
O H C P h C l
P Br3/ D M F
( C H2)3Br N H P h C l
O O
O P h N H
O
N B r
( C H2)3Br
O O H C P h
P Br3/ D M F
(5 .0 e q u iv )
8 00C , 1 0 m in
- 4
+
- 4
(1 6 )
(1 7 )
(1 9 )
(2 0 ) (S c h e m e -5 )
(3 .0 e q u iv )
8 00C
(1 5 ) (1 8 )
P B r3/D M F (5 .0 e q u iv ) 8 00C
4 -C lP h H N
Pan W. et al.69 also reported the synthesis of functionalized pyridine-2(1H)-ones (22) and (23) from 1-acetyl, 1-carbamoyl cyclopropanes (21) by using POCl3 and DMF
under different temperature conditions (scheme 6).
Functionalized pyridine-2(1H)-ones and
their benzo/hetero-fused analogues
represent an important class of organic heterocycles for their presence in numerous natural products and synthetic organic compounds along with diverse bio-physico and pharmacological activities70-71.
DMF/POCl3 DMF/POCl3
NHPhCl O O
N
Cl CH2CH2Cl
O PhCl OHC
N
Cl CH2CH2Cl
O PhCl 800C, 1 h
1200C, 2 h
- 4
(10.0 equiv)
(10.0 equiv)
- 4
- 4 (21)
(22)
(23) (Scheme-6)
Asokan C. V. et al.72 have reported the conversion of enolizable ketones such as acetophenones and benzal acetones (24) into 2-chloronicotinonitriles (25) upon
treatment with malononitrile under
Vilsmeier-Haack reaction conditions.
(Scheme-7).
O
N Cl
CN
(25) (24)
(Scheme-7)
R1 R
2
R2
R1
1. POCl3, DMF, rt, 12h
2. NCCH2CN, 90 0C, 2h
3. Aq. K2CO3
Quiroga J. et al17 formylated
pyrazolopyridine (26) into pyrazolo[3,4-b] pyridine-5-carbaldehyde (27) by using DMF and POCl3 (Scheme-8).
They have concluded that, the formylation on the pyridine ring only takes place when there is a dihydroderivative on the appropriate pyrazolo-fused system. They have also observed that the use of the Vilsmeier-Haack condition developed a fast and efficient method for the formation of
pyrazolo[3,4-b] pyridine-5-carbaldehyde
(27)
N N
N C H3
R
R' Ph
N N
N C H3
R
R' Ph
CHO POCl3/DM F
R=H, C6H5
(Schem e-8)
IJPCBS 2012, 3(1), 25-43 Rajputet al. ISSN: 2249-9504
Tabuchi Y. et al73 used Vilsmeier-Haack condition for the synthesis of 4-chloro-3-formylbenzo[b]furo[3,2-b] pyridine (29) from 2-acetyl-3-acylaminobenzo[b] furans (28) (Scheme-9).
O COCH3
O N
CHO
Cl R1
R2
NHCOR3
R1
R2
POCl3 , DMF, 24 0C
(28) (29)
(Scheme-9)
C) Synthesis of Pyrimidines
Quiroga J. et al17 suggested the
regioselective formylation of pyrazolo
[1,5-a] pyrimidine system using Vilsmeier-Haack
conditions. They have synthesized pyrazolo [1,5-a] pyrimidine-3,6-dicarbaldehyde (31) from 6,7-dihydroderivatives (30).They have also converted 6,7-dihydroderivative (30) into aromatic pyrazolo pyrimidine (32) which was formylated with DMF & POCl3
and afforded
pyrazolopyrimidine-3-carbaldehyde (33) (Scheme-10).
N N
R' R
A r
N
N N
R' R
A r
N H
O H
C H O
N N
R' R
A r
N
N N
R' R
A r
N C H O
...
P O C l3 / D MF
N BS/ Et h ano l
P OC l3 / D MF
(3 3) (32)
(Sch em e-10)
(30 ) (31)
Quiroga J. et al74 extended their work & carried out microwave assisted synthesis of pyrazolo[3,4-d]pyrimidines from 2-amino-4,6-dichloropyrimidine-5-carbaldehyde under solvent free conditions (Scheme-11).
PO C l3 / D M F
N
N OH
OH N H2
N
N Cl
C l N H2
O N
N Cl
N H2
O
N
N N H2
N N H Ethanol, TEA
HN R1R2
R eflux
M ethod A or M ethod B
NR1R2
N R1R2 (Scheme-11)
D) Synthesis of Pyrazoles
Aruna kumar D. B. et al75 converted benzofurans (34) into benzofuran phenyl hydrozone (35) by treatment with phenyl
hydrazine in ethanol and acetic acid. The intermediate phenyl hydrazone (35) when subjected to Vilsmeier-Haack reaction condition, cyclized to afford substituted pyrazoles (36) which are well documented to posses antihypertensive, antibacterial,
anti-inflammatory and antitumor
activities76 (Scheme-12).
O C H3
N N H
N N
O O H
N H
N H2
O O
C H3
(35) (34)
(Scheme-12) (36)
R1
R1= H, CH3
R2= H, NO2
R1
R2
EtOH / AcOH
R1
R2
DM F / POCl3
R2
Goudarshivannanavar B. C. et al77 have
reported that, 2-acetyl
benzofurohydrozones (37) on reaction with Vilsmeier-Haack reagent at appropriate molar ratio, underwent smooth cyclization followed by formylation afforded
3(1-benzofuran-2-yl)-1-(substituted
phenyl)-1H-pyrazole-4-carbaldehyde (38) (Scheme-13).
O N NH
R
O NN
R OHC
DMF / POCl3
R= H, NO2, CH3, OCH3, Cl, F, Br
Reflux / 2 hr
(37) (38)
(Scheme - 13)
Damljanovic I. et al78 reported that the condensation of acetylferrocene (39) with
phenyl hydrazine (40) followed by
intramolecular cyclization of the
intermediate hydrazone (41) under
Vilsmeier-Haack conditions formed
1H-3-ferrocenyl-1-phenyl
pyrazole-4-carboxaldehyde (42) (Scheme-14)79.
O
N H N H
2
P h
N N H
P h
N N
P h
C H O
( 4 2 )
( 4 1 )
( S c h e m e - 1 4 )
F e F e
+
E th a n o l
r e f l u x
F e P O C l3 ( 3 e q u i v )
D M F , r . t .
( 3 9 )
Vera-Divaio M. A. F. et al80 illustrated Vilsmeier-Haack formylation of compound
(43) into
1-Phenyl-1H-pyrazole-4-carboxaldehyde (44) in 65% yield. The aldehyde functional group has been utilized to synthesize corresponding acid (45) (Scheme-15).
N
N DMF / POCl3 NN
(43) (44)
Ph COOH Et3N, Ac2O
N N
COOH
(45) (Scheme-15)
CHO
E) Synthesis of Quinolines
Some S. et al81 developed a new protocol for the preparation of quinolines (50) involving the subjection of certain enolizable ketones (46) to a Vilsmeier-Haack haloformylation reaction (Scheme-16)82.
O Br
CHO
CHO
O2N N
X
O2N POBr3,
DMF
Cu, DMSO,
(X=Br or l)
10% Pd on C
+
Pd[O] (10 mol%)
H2
(46) (47) (48)
(49) (50)
(Scheme -16)
F) Synthesis of Indoles
Diana P. et al83 have reported a rapid access to 1,4-Bis-indolyl-diketones (54) using Vilsmeier-Haack reaction (Scheme-17).
N R
H
N R
H CHO
N R
SO2Ph
CHO
N R
H O
N R
SO2Ph
O POCl3 / DMF
NaOH
NaH / THF ClSO2Ph
Thiazolium Salt, EtOH
(54)
(Scheme- 17)
They have also converted N-methyl derivatives (55) into 1, 4-diketones (57) by
Vilsmeier-Haack reaction using
phosphorous oxychloride and tetramethyl succinamide (56) (Scheme-18).
N R
Me
N R
Me O
N R
Me O POCl3 / DMF
N
O O
N Me
Me Me
Me
(57) (Scheme- 18)
(56) (55)
Popowycz F. et al84 have prepared dimer
(59) from
5-Methyoxy-1-methyl-7-azaindole (58) using Vilsmeier-Haack reaction conditions (Scheme-19).
N N
MeO
N N
O H
N N
O Br
n
N N
O OHC
N N
O n
CHO
N N
O AcHN
N N
O n
NHAc
(58)
(59) (Scheme- 19)
NaBH4, SiO2, i-PrOH/CHCl3, rt, 12h
BBr3, CH2Cl2,
0 0C,1 h,
K2CO3, DMF, Br(CH2)nBr,
n=4-6, rt, 4h,
K2CO3, DMF, 80 0C, 6h,
POCl3, DMF, rt, 3h,
MeNO2, NH4OAc, 120 0C, 4h
H2, Raney Ni, MeOH, 60 0C,6 h,
Ac2O, CH2Cl2, rt, 12h,
Barraja P. et al85 have synthesized choro-bis-formylated derivatives (62) and (63) from substituted tetrahydroindolones (60) and (61) by using DMF/POCl3 and DCM at 00C (Scheme20).
N Me Me O
N Me Me Cl OHC
CHO
N Me O
Me N
Me Cl OHC
Me CHO DMF/POCl3,DCM
00C then reflux
(60)
(62)
DMF/POCl3,DCM
00C then reflux
(61)
(63) (Scheme-20)
G) Synthesis of Pyranones and
Naphthaldehydes
Xiang-Ying Tang and Min shi86 have
developed a convenient and efficient method to synthesize3-(2-Chloroethyl)-5-aryl-4H-pyran-4-ones(65) and 2-Chloro-3-(2-chloroethyl)-1-napthaldehydes (66) in moderate to good yields via the Vilsmeier-Haack reaction of readily available
1-Cyclopropyl-2-aryl ethanones (64) at
IJPCBS 2012, 3(1), 25-43 Rajputet al. ISSN: 2249-9504
O R
O O
C l R
C l
C l C H O
R
DM F/ POCl3
D M F/PO Cl3
(12.0 equiv), 80-100 0C
(12.0 equiv), 120-135 0C (64)
(65)
(66) (Scheme-21)
H) Synthesis of Oxazines
Damodiran M. et al87 have reported the synthesis of highly functionalized oxazines (68) by Vilsmeier-cyclization of amidoalkyl naphthols (67) (Scheme-22).
OH N H O
O NH
CHO
R R
(68) (Scheme-22)
(67) R1= H, CH3, Ph
R2 = CH3, Ph, CHO
DMF / POCl3
R1
R2
3 h, 90 0C
Tabuchi Y. et al73 have suggested, the ring closure reaction of 2-acetyl-(E)-3-aral-Kenylcarbonylaminobenzo[b] furans (69) using Vilsmeier reagent which generated oxazine (70) (Scheme-23).
O COCH3
O O N
CHCHO R1
R2
NHCOR3
R1
R2
R3
1) POCl3, DMF, 25 0C
2) Method A (NaOH aq. sol.) or
Method B (Et3N), 16-46%
(69) (70)
(Scheme-23)
I) Synthesis of Chromones
Wang B. D. et al88 have prepared the
6-hydroxy-3-carbaldehyde chromone via
Vilsmeier-Haack reaction. The compounds 6-hydroxy-4-chromone-3-carbaldehydes (72) were easily prepared by the reaction of 2,5,-dihydroxy acetophenone (71) with DMF in POCl3 solution (Scheme-24).
OH
OH (CH3CO)2CO
H2SO4 98%
OCOCH3
OCOCH3
OH
OH COCH3
AlCl3 DMF, POCl3
O
O O
H CHO
(71) (72)
(Scheme- 24)
J) Synthesis of Bithiophenes and
Benzothiophene dioxides
Herbivo C. et al89 synthesized a series of formyl substituted 5-aryl-2,2-bithiophenes (74) starting from acetophenones (73)
using Vilsmeier-Haack reaction (Scheme-25). Formyl thiophene derivatives are versatile “Crossroads” intermediates.
C H3
O
R C l
H O
R
S O R
C l C H2C O C H3 / K2C O3
S C l R
H O
C l C H2C H O / K2C O3 S
R
S C H O
( 7 4 ) ( S c h e m e - 2 5 ) ( 7 3 )
P O C l3 / D M F / 6 0 0C N a2S . 9 H2O / D M F
P O C l3 / D M F / 6 0 0C
N a2S . 9 H2O / D M F
Bhatti H.S. and Seshadri S.90 formylated benzo[b] thiophene-3(2H)-one-1,1-dioxide (75) by using DMF and POCl3 to give (76) (Scheme 26).
S O
O O
DMF/POCl3 S Cl
O O
CH=N(CH3)2
S OH
O O
CHO +
75 76
(Scheme-26) Cl_
H2O
K) Synthesis of Naphthyridinepyrazoles Mogilaiah K. et al91 used V-H reaction condition to develope a simple and efficient method for the synthesis of 1-[3-(3- fluorophenyl)[1,8]naphthyridin-2-yl]-3-(2-oxo-2H-chromenyl)-H-4-pyrazolecarbalde- hydes (78) from (77) (Scheme 27).
N N NHN
F
O O CH
3
O O N N
N N
F
CHO POCl3-DMF / SiO2
MW
(Scheme-27)
R2
R1
C
R2
R1
(77)
(78)
L) Synthesis of Quindolines
CH3
O NO2
Cl NO2
H CHO
(79) (80)
POCl3,DMF,00C,1h
800C,4h
(Scheme-28)
M) Formylation of Pyrrolones
Becker C. et al93 have used Vilsmeier-Haack reaction conditions for the synthesis of enaminoimine (85) and enaminoaldehyde (86) starting from Pyrrolin-3-on-1-oxide derivatives (81) (Scheme 29).
N R
O
N R
O Cl
N R
Cl Cl
N
Cl Cl
O
N
Cl Cl
N
N H
Cl Cl
O
(81) (82) (83)
(84)
(85) (86)
-DMF - H+
_
DMF POCl3
DMF POCl3
(Scheme-29)
They have also reported, the reaction of exo-cyclic enhydroxylaminone (87) with the Vilsmeier reagent to form chlorosubstituted compound (88) (Scheme 30).
OH O
N
N
O
N H
N Cl POCl3, DMF
2. OH _ 1.
(Scheme-30)
(87) (88)
N) Formylation of Phloroglucinols
Naturally occurring phloroglucinol
compounds have shown diverse range of biological activities94. Bharate S. B. et al95 formylated monoacyl phloroglucinol (89) to acylphloroglucinols (90) using V-H reaction (Scheme 31).
O O
R O
H
OH O
O R O
H CHO
OH
R1 R1
POCl3,DMF
EtOAc,rt.1h
(89) (90)
(Scheme-31)
O) Formylation of Pyrenopyrrole
Gandhi V. et al96 carried out, Vilsmeier-Haack formylation of pyrenopyrrole (91) to afford monoaldehyde (92) which after protection of pyrrole and further treatment with POCl3-DMF afforded the dialdehyde (94) (Scheme 32).
N
H N
H CHO
N H
C H N
H CHO OHC
CN
CO2Et
POCl
3 / DMF
Piperidine EtO2C-CH2-CN
POCl3
DMF 1.
NaOH 2.
C
(91)
(93) (94)
(92)
(Scheme-32)
P) Synthesis of Azeteochlorins
Banerji S. et al97 have reported the formation of chlorophin monoaldehyde (96) from chlorophin (95) upon treatment with DMF/POCl3 in CHCl3 followed by addition of aq.NaHCO3. The reaction of (96) with methyl-Grignard, followed by an acid-catalyzed ring-closure reaction, generated
the compound
[meso-tetraphenyl-2-methylazeteo-chlorinato] Ni (II) (97) in good yields (Scheme 33).
N Ph
Ph
N
Ph
N
Ph N Ni
N Ph
Ph N
Ph CHO
N
Ph N Ni
N Ph
Ph N
Ph Me
N
Ph N Ni
N Ph
Ph
N
Ph Me
OH
N
Ph N Ni
D MF-POCl3
NaHCO3
CH2Cl2
NaHCO3
(95) (96)
MeMgBr, dry THF
(97)
(Scheme-33)
,CHCl3
(1)
(2) aq.
(1) TMSOTf,
(2) aq
Q) Miscellaneous V-H reactions
Bera R. et al98 used Vilsmeier-Haack reaction condition for alkynylation of β -Chloroacroleins. β-Chloroacroleins(99)
were readily prepared from the
IJPCBS 2012, 3(1), 25-43 Rajputet al. ISSN: 2249-9504
in the presence of 10% Pd/C, PPh3, CuI and Et3N under nitrogen to afford 4-alkynyl-2H-chromene-3-carbaldehydes (100) (Scheme 34).
O n O DMF / POCl3
Z
(98)
O n
Z
HC R Pd/C, PPh3, CuI
Et3N, CH3CN
80°, 2-3h O n
Z C R
(99) (100)
(Scheme-34)
CHO CHO
Cl
n= 1, 2 Z= H, Br
Bubenyak M. et al99 showed that,
Deoxyvasicinone (101), upon Vilsmeier-Haack formylation using two equiv. of POCl3 in DMF at 600C for 3 hrs. gave the 3-dimethylaminomethylene derivative (102) in 94% yield (Scheme-35).
N
N
O
N
N
O 3
1 (101)
(102)
(Scheme- 35) Dimethylformamide,
2 equiv POCl3, rt, 1h, 60 0C
3h (94% yield)
Glutarimides
Piperidine-2,6-diones(glutarimides, cyclic
imides) have various biological
activities100 and the 2,6-piperidinedione
moiety constitutes an important
substructure in several new anticancer agents which have recently been introduced
into experimental chemotherapy101,102.
Furthermore, these have been used as precursors in the synthesis of a variety of heterocyclic compounds103. Therefore, the
synthesis of piperidine-2,6-dione
derivatives have attracted considerable attention of synthetic chemists and several methods have been reported in the literature104-112, most of which have used multi-step reactions using harsh reaction conditions. Many compounds possessing a cyclic imide moiety exhibit pharmacological
activity such as antitumor113,
immunosuppressive113, sedative113,
anxiolytic113, anticonvulsive114 and
others115.
Paluchowska M. H. et al116 have showed that, the glutarimides 103 and 105 demonstrated anxiolytic activity while the
glutarimides 103, 104and 106
demonstrated antidepressant like activity in the four-plate and the swim tests in mice,
respectively. These glutarimides also
inhibited the locomotor activity of mice. The antidepressant-like effect of 106 was reported significantly stronger than that induced by imipramine used as a reference antidepressant.
N N
N O
O R2 R1
CF3
(103-104)
103, R1=R2 =H 104, R1=R2 = -(CH
2)2
-Shaabani A. et al117 havesynthesized fully functionalized N-alkyl-2-triphenyl phosph-
ora-hylidene glutarimides (107) and
concluded that these glutarimide
derivatives constitute an essential part of many natural products with antibacterial, antitumor or fungicidal activity.
Chen C. Y. et al107 have reported one-pot facile synthesis of N-alkyl 3-(E)-alkylidine-5-substituted sulfonylpiperidine-2,6-dione (108).
Kiyota H. et al118 suggested the synthesis of actiketal (RK-441S) (109) as a new acetal type glutarimide antibiotic119 which is expected to be a new anti-cancer agent and an immunosuppressant because of its low cytotoxicity119,120.
In recent years Fu R. et al121 have developed protected (R) and (S)-glutarimides (110) as a versatile building blocks122,123 for the asymmetric synthesis of substituted
3-piperidinol containing alkaloids and
pharmaceutically relevant molecules.
N O
R' Ph3P
O CO2R
2
CO2R 2
(107)
N O
R2 O
(1 0 8 )
S R1
O
=
O
R3
N N
N O
O R2 R1
CF3
(105-106)
-In view of these useful pharmacological
properties, biological activities and
synthetic applications of glutarimides, various methods have been developed for their synthesis. Some of the important methods are described in the following schemes.
1) Method due to Kiyota H. et al118
O CO2Me
CO2Me
+ O
CO2Me
CO2Me
O NH O
O
(Scheme-36)
O CO2Me
CO2Me
Pd(OAc)2 ( 1eq.), AcOH,60 0
C
H2,Pd Powder,EtOA c (98%) i. KOH,MeOH
ii.Ac2O,heat
iii.NH3gas,Et2O
iV.NaOAc,Ac2O,heat
2) Method due to Huang C. G. et al124
Cl Cl O
1. R'NH2
2. NaSPh 3. NaIO4
PhS
O N R' O
1.NaH (2eq.)
2.
O R2 MeO
N O
S
R' Ph O
(Scheme-37)
R2
3) Methods due to Mederski Werner
W. K. R. et al125
N H2N
H2N
Cl
HO2C CO 2H
PPA, 80°C, 2h
N
N NH2
Cl O
O
(Scheme-38)
NO2
NH2
HO2C
CO2H PPA, 80°C, 12h
NO2
N O
O (Scheme-39)
R
R
4) Method due to Chen B. F. et al126
Ts
O NH R
+ O EtO
OMe 3 eq. NaOH
N O O Ts OMe
R 5
6
(Scheme-40)
5) Method due to Shaabani A. et al117
N C
R' +
CO2R2
CO2R 2
+EtO PPh3Br
O CH2Cl2
r.t. 24h O N R' Ph3P
O CO2R
2 CO2R
2
(Scheme-41)
Dihydropyridines
1,4-dihydropyridines and their derivatives are an important class of bioactive molecules in the pharmaceutical field127. The dihydropyridine heterocyclic ring is a common feature of a variety of bioactive
compounds including anticonvulsant,
antidiabetic, antianxiety, antidepressive, antitumor, analgesic, sedative, vasodilator,
bronchodilator, hypnotic and
anti-inflammatory agents128.
Diydropyridines are reported as calcium channel blockers129 and are clinically useful agents for the treatment of cardiovascular diseases such as anginapectoris130 and hypertension131.These are also used as
antioxidants and are important for
developing drugs. However, these are relatively difficult to synthesize.
During the years 1980-1990 considerable importance was acquired by derivatives of
1,4-dihydropyridines, as the first
representatives of highly effective
vasodilators and antihypertensive agents, the calcium channel blockers (Nicardipine, Nifedipine, Felodipine, etc)132-134. Many derivatives of 1,4-dihydropyridines with
more valuable pharmacological
properties135-137, which make further searches in the 1,4-dihydropyridine series extremely urgent. Till date an enormous number of symmetrical and unsymmetrical derivatives of 1,4-dihydropyridine with various functional substituents have been synthesized, and a great number of methods of obtaining them (including microwave)
have been developed by further
conversions and aromatization138-142.
Scientists from the Latvian Institute of Organic Synthesis have carried out the
systematic synthesis of numerous
derivatives of 1,4-dihydropyridines with the aim of searching for new cardiotonic
and ionotropic preparations, and
clarification of structure–activity
IJPCBS 2012, 3(1), 25-43 Rajputet al. ISSN: 2249-9504
dihydropyridine molecules make them promising precursors for further synthetic transformations.
The use of formylation reaction as synthetic strategy to form versatile carboxaldehyde intermediates is still of interest, due to both their intrinsic pharmacological properties and chemical reactivity146. Formylation
reactions have been described for
pyrazoles147, pyridines148 and
pyrimidines149 as a key step to the
introduction of functionalities via the intermediate carboxaldehydes, and further
cyclization to fused heterocycles.
Vilsmeier–Haack reaction carried out on methylene-active compounds leads mainly to the formation of β-halo-carboxaldehyde derivatives, which are useful precursors in the construction of different heterocyclic
compounds by means of numerous
transformations150-151. We have
concentrated much of our recent work on the preparation of bioactive nitrogen-containing heterocycles.
By considering the importance of formyl
pyridines different researchers have
developed the various methods for the synthesis of chloroformylation of pyridines and dihydropyridines as described in the following schemes.
1. Method due to Kvitko I. Y. et al.15
N Ph
O O
N Ph HOC CHO
Cl Cl DMF / POCl3
(Scheme-42)
2. Method due to Maddox M. L. et al.153
N O
O R
H
POCl3 or (COCl)2
H Cl CH= R
Cl
HC NaOAc
N R
Cl Cl HOC
NMe2
R
Cl
HOC CHO
Cl N
H
(NH4)2Ce(NO3)6
R
Cl
HOC CHO
Cl N
+ +
-DMF NMe
2
Cl Me2N =
H2O
H3O
+
(Scheme-43)
a, R= C6H5
b, R= 3-ClC6H4
c, R= 3-NO2C6H4
d, R= 3-CF3C6H4
e, R= H
Cl
3. Method due to Pan W. et al.69
DMF/POCl3 NHPhCl
O O
N
Cl
CH2CH2Cl O PhCl OHC
800C, 1 h
- 4 (10.0 equiv)
- 4
(Scheme-44)
4. Method due to Tabuchi Y. et al.73
O COCH3
O N
CHO
Cl R1
R2
NHCOR3
R1
R2
POCl3, DMF, 24 0C
(Scheme-45)
5. Method due to Quiroga J. et al.154
N N N
H Ph
O Ar
DMF / POCl3
N N N Ph
Ar CHO
Cl
(Scheme-46)
Rajput A. P.155 have synthesized 1,4-diazepine type compounds and reported their useful
biological activities, pharmaceutical
properties and therapeutic applications.
Rajput A. P.156 have formylated 2-
Aryliminothiazolid-4-ones using V-H
reagent. The formylated synthones were
used to synthesize various fused
heterocyclic ring systems containing
thiazole moiety and some heterocyclic Schiff bases to get some compounds of interesting biological activities
Rajput A. P. and Rajput S. S.157 have reported that, the condensation of 4-chlorophenyl carboxylic acid hydrazide
with different acetophenones and
acetaldehydes afforded the corresponding
acetophenones/acetaldehydes
4-chlorophenyl carbonyl hydrazones which on V-H reaction formylated the compound
1-(3-aryl/alkyl-4-formyl
pyrazole-1-carbonyl)-4-chlorobenzenes.
Cl C NH
O
N C
CH3
N N
CHO
Cl C
O
Scheme-47
DMF / POCl3
00C
O
N H O
O O
O H
( 1 0 9 )
N O
P1 O
( 1 1 0 )
They158 have also prepared various dichloro, diformyl derivatives of pyrrole on formylation using V-H reagent from various succinimide derivatives.
N O O
R
N Cl Cl
HOC CHO
R
R: a =H, b = 2-Cl, c = 3-Cl, d = 4-Cl, e = 4-CH3, f = 4-OCH3 DMF / POCl3
0-50C
111a-f 112a-f
(Scheme-48)
Rajput A. P. and Rajput S. S.159 have
formylated benzaldehyde substituted
phenyl carbonyl hydrazones by using V-H reaction.
Rajput A. P. and Bhadane S. J.160 have carried out formylation of N-substituted
phenyl succinimides. From these
compounds various heterocyclic
compounds have been synthesized.
Rajput A. P. and Girase P. D.161-166 have reported the synthesis, characterization and microbial screening of various nitrogen,
oxygen and sulphur heterocyclic
compounds from 2,6-dichloro 3,5-diformyl (N-substituted Phenyl)-4-hydropyridines.
HOOC COOH
N
O O
R
N
Cl Cl
CHO OHC
R SOCl2
DMF, POCl3
NH2
R
(Scheme-49)
113 114 a-d 115 a-d Reflux
0-50C
R, a = -H, b = -4Me, c = -4Cl, d = -2Me
O H C
N a2S
D M F , R1
O H C
N N
C l C l
C H O O H C
R
N
R1S S R1
C H O
R
N
C H O N3 N3
R
N
C l C l
R
N
1 1 5 a - g
R , a = - H , b = - 4 C H3
d = - 4 C l , g = - 2 C H3
1 1 6 a - g
1 1 7 a - g
1 1 8 a - f
R , a = - H , b = -4 C H3
d = -4 C l , g = - 2 C H3
R , a = - H , b = - 4 C H3
d = - 4 C l , f = - 4 O C H3
C A N
N H3,00C
N a N3
P T S A , E t O H
S c h e m e - 5 0
R1 , a = - C2H5
b = - C2H5
d = - C2H5
g = - C2H5
C C
IJPCBS 2012, 3(1), 25-43 Rajputet al. ISSN: 2249-9504
R' C O
CH3 NH2-NH2.H2O
N Cl
R' O R'
O
Cl N C l
N N
C l N N
H H
R' R'
N Cl
CHO OHC
Cl
R a = - H b = - 4 CH3 c = - 2 C l d = - 4 C l e = - 3 C l f = - 4 OCH3
R', (i) = -Ph (ii) = -4OH-Ph
R R
119a-f(i) 119a-f(ii)
120a-f(i) 120a-f(ii)
(Scheme-51) R
115 a-f
N C l
C l
C H O O H C
R
N C l
C l
CH =N N =H C
R N H2
N C l
C l
N S S
N
R
O O
H S C H2C O O H
R1
2m oles
R1
R1
R1 R1
2 m oles
Sch em e -5 3 R , a = -H , b = - 4 M e, c = - 2C l, d = - 4 C l, e = - 3C l, f = - 4 O M e
R1, (i) = - 4 M e (ii) = - 4 C l
1 1 5 a-f 1 2 2 a-f ( i ), ( ii )
1 2 3 a-f ( i ), ( ii )
O H C
N
C l C l
C H O O H C
R
N
C H O
N3 N3
R
O H C
N
C H O
N H2 N
H2
R
N N
N N H2
N H2
R
N N
N a2S2O4 C H2( C N )2
1 1 5 a - d 1 2 4 a - d
R , a = -H , b = - 4 C H3
c = - 4 C l, d = - 2 C H3
N a N3
P T S A , E tO H
C C
1 2 5 a - d
2 2
( S c h e m e - 5 4 )
1 2 6 a - d N
Cl
R' O R'
O
Cl
N Cl O
N
Cl O N
R' R'
NH2OH.HCl
CH3COONa in CH3COOH
R a = - H b = - 4 CH3 c = - 2 C l d = - 4 C l e = - 3 C l f = - 4 OCH3
R', (i) = -Ph (ii) = -4OH-Ph
(Scheme-52) R
119a-f (i) 119a-f(ii)
CONCLUSIONS
This review has attempted to summarize the synthetic methods and reactions of glutarimides and dihydropyridines. Many biologically active heterocyclic compounds
have been synthesized from that
heterocycle. These reactions greatly
extended synthetic possibilities in organic chemistry.
REFERENCES
1. Jones, G.; Stanforth, S. P. Org. React. 2001, 49, 1.
2. (a) Meth-Cohn, O.; Narine, A. B. Tetrahedron Lett. 1978, 23, 2045. (b) Khan, A. K.; Shoeb, A. Indian J. Chem. Sect. B, 1985, 24, 62
3. (a) Sreenivasulu, M.; Rao, K. G. S. Indian J. Chem. Sect. B, 1989, 28,
584.(b) Mahata, P. K.;
Venkatesh, C.; Syam Kumar, U. K.; Ila, H.; Junjappa, H. J. Org. Chem. 2003, 68, 3966.(c) Chupp, J. P.; Metz, S. J. Heterocycl. Chem. 1979, 16, 65; (d) Katrtizky, A.R.; Arend, M. J. Org. Chem. 1998, 63, 9989
4. Vilsmeier, A. and Haack, A. Che. Ber. 1927, 60, 199
5. (a) Lilienkampf, A.; Johansson, M. P.; Wähälä, K. Org. Lett. 2003, 5, 3387; (b) Perumal, P. T. Indian J. Heterocycl. Chem. 2001, 11, 1;(c) Wang, K.-W.; Xiang, D.-X.; Dong, D.-W. Org. Lett. 2008, 10, 1691; (d) Jones, G.; Stanforth, S. P. Org. React. 2000, 56, 355; (e) Chen, L.; Zhao, Y.-L.; Liu, Q.; Cheng, C.; Piao, C.-R. J. Org. Chem. 2007, 72, 9259; (f) Zhang, R.; Zhang, D.; Guo, Y.; Zhou, G.; Jiang, Z.; Dong, D. J. Org. Chem. 2008, 73, 9504;(g) Wuts, P. G. M.; Northuis, J. M.; Kwan, T. A. J.Org. Chem. 2000, 65, 9223. 6. (a) Campaigne, E.; Archer, W. L.
J. Am. Chem. Soc. 1953, 75, 989; (b) Treihs, W.; Neupert, H. J.; Hiebsch J. Chem. Ber. 1959, 92, 141
7. (a) Procopiou, P. A.; Brodie, A. C.; Deal, M. J.; Hayman, D. F.
Tetrahedron Lett.1993, 34,
7483; (b) Procopiou, P. A.; Brodie, A. C.; Deal, M. J.; Hayman, D. F. J. Chem. Soc. Perkin Trans. 1 1996, 2249.
8. Zaoral, M.; Arnold, Z.
Tetrahedron Lett. 1960, 1, 9 9. Eilingsfeld, H.; Seefelder, M.;
Weidinger, H. Angew. Chem. 1960, 72, 836.
10.Hepburn, D. R.; Hudson, H. R. J. Chem. Soc., Perkin Trans. 1 1976, 754
11.(a) Barrett, A. G. M.; Braddock, D. C.; James, R. A.; Koike, N.; Procopiou, P. A. J. Org. Chem. 1998, 63, 6273;(b) Barrett, A. G. M.; Koike, N.; Procopiou, P. A. Chem. Commun. 1995, 1403.
12. Kawano, Y.; Kaneko, N.;
Mukaiyama, T. Chem. Lett. 2005, 34, 1612.
13. Barrett, A. G. M.; Braddock, D. C.; James, R. A.; Procopiou, A. Chem. Commun. 1997, 433. 14.(a) Vovk, M. V.; Mel’nichenko, N.
V.; Sukach, V. A.; Chubaruk, N. G. Chem. Heterocycl. Compd. 2004, 40, 1485; (b) Lipson, V. V.; Desenko, S. M.; Shirobokova, M. G.; Borodina, V. V.; Musatov, V. I. Chem. Heterocycl. Comp. 2005, 41, 492.
15.Girreser, U.; Heber, D.; Schu¨tt, M. Tetrahedron 2004, 60, 11511 16.(a) Ali, M. M.; Tasneem; Rajanna, K. C.; Saiprakash, P. K. Synlett 2001, 251;(b) Rajanna, K. C.; Ali, M. M.; Sana, S.; Tasneem; Saiprakash, P. K. Synth.Commun. 2002, 32, 1351; (c) J. Disp. Sci.Tech. 2004, 25, 17.
17.Quiroga, J.; Trilleras, J.; Insuasty, B.; Abonı´a, R.; Nogueras, M.; Marchal, A.; Cobo, J. Tetrahedron Lett. 2008, 49, 2689.
18.Marson, C. M.; Giles, P. R.
Synthesis Using Vilsmeier
Reagents. CRC Press: Boca Raton, FL, 1994.
IJPCBS 2012, 3(1), 25-43 Rajputet al. ISSN: 2249-9504
20. Friedel, M. C. Bull. Soc. Chim. Fr. 1896, 11, 1028.
21. Fischer, O; Miller, A; Vilsmeier, A. J. Prakt. Chem. 1925, 69, 109 22. Vilsmeier A. and Haack A. Ber.
1927, 60B, 119.
23. (a) Minkin, V. I. and
Dorrofeebko, G. N. Russ. Chem.
Review 1960, 29, 599.(b)
Demeheas, M. Bull. Soc. Chim. Fr. 1962, 1989.(c) Burn D. Chem. Ind; 1973, 870.
24. Sheshadri, S. J. Sci. Ind. Res; 1973, 32, 128
25. Minkin, V. I. and Dorofenco, G. N. Ospkihm 1960, 29, 25
26. Martin, G. S. and Martin, M. Bull. Soc. Chem. Fr; 1963,1637
27. Filleux-Blanchard, M. L.;
Quemneur, M.T. and Martin, G. J. Chem. Commun. 1968, 83 28. Martin, G. J.; Poignant, S.;
Filleux-Blanchard, M. L. and Quemneur, M.T. Tetrahedron lett. 1970, 58, 5061.
29. Challis, B. C. and Challis, J. A. cited in chemistry of amides. The chemistry of functional group series, edited by S. Patai, Interscience Publishers Inc; New York, 1970, 731.
30. Nenitzescu, C. D. and Suceseu, D. I. Chem. Abstr. 1930, 24, 2442 . 31. King, W. J. and Nord, F. F. J. Org.
Chem. 1949, 14, 405.
32. Clark, B. A. J.; Parrick, J.; West, P. J. and Kelly, A. H. J. Chem. Soc. 1970, 498.
33. Jutz, C. and Muller, W. Chem. Ber. 1967, 100, 1536.
34. Brasshard, N. and Zollinger, H. Angew. Chem. 1959, 71, 375.
35. Ermili, A.; Castro, A. and
Westfall, P. J. Org. Chem. 1965, 30, 339.
36. King, W. J. and Nord, F. F. J. Org. Chem. 1948,13, 635.
37. Scott, F. L. and Barry, J. A. Tetrahedron Lett. 1968, 2457. 38. Cohous, G. Chem. Ber. 1967,
100, 2719.
39. Brown, M. D. and Giner, A. S. J. Chem. Soc. 1971, 128
40.Vilsmeier, A. Chem. Ztg. 1951, 75, 133.
41.Bayer, O. in Methoden der
Organischem Chemic (Houben-weyl) Thieme, Stuttgart 1954 42.Bredereck, H.; Gompper, R.; Van
Schuh, H.G.; Theiling, G. Agnew. Chem.1959, 71, 753.
43.Eilingsfeld, H.; Seefelder, M.; Weidinger, H. Angew Chem. 1960, 72, 830.
44. Minkin, V. I.; Dorofeenko, G. N.; Ospekhi, Khim. 1960, 29, 1301. (Chem. Abstr. 55,12265h, 1961) 45.Oda, R.; Yamamoto, K.; Kagaku
(Kyoto). 1960, 15, 384. (Chem. Abstr. 54, 24325c, 1960). 46.De Maheas, M.R. Bull. Soc. Chim.
Fr. 1962,1989.
47. Hofner, K.; Hafner, K. H.; Konig, C.; Kreuder, M.; Ploss, G.; Sehulz, G.; Strum, E.; Vopel, K. H. Angew Chem. Int. Ed. Engl. 1963, 2, 123. 48.Gore, P. H. in Friedel Crafts and related reactions ed. Vol. III, Wiley, New York 1964.
49.Hazebroucq, G. Ann. Pharm. Fr. 1966, 24, 793.
50. Jutz, C. Chem. Lab. Betrieb 1968, 19, 289 and 337
51.Ulrich, H. In the Chemistry of Imidoyl Halides, Plenum press, New York 1968
52.Kuehne, M. E. in Emanines,
synthesis, structure and
reactions, Cook, A.G. Edt.
Dekker, New York 1969
53.Jutz, C. in advances in organic chemistry, methods and results, Taylor, E. C; Ed Bochme. H;
Vieche, H.G. Eds. Vol. 9.
Interscience, New York, P. 225, 1976.
54.Meth-Cohn, O; Tarnowski, B.
Adv. Heterocycl. Chem. 1982, 31, 207
55.Simchen, G. in Methoden Der Organischen Chemic (Houben-Weyl) Thieme, Stuttgart 1983.
56.Marson, C. M. Tetrahedron.
1992, 48, 3659.
57.Meth-Cohn, O.; Stanforth, S. P. in
comprehensive organic
I. Eds. Vol. 2, Heathcock, C. H. Vol. Ed. Pergamon, Oxford, P. 777, 199
58. Meth-Cohn, O. Heterocycles
1993, 35, 539
59. Arumugam, S. Ph.D. thesis, I.I.T. Banglore, 1994
60. Duduzile, M. M. Ph.D. thesis, Rhodes University, 2007.
61. Borek, C. Ph.D. thesis, University of Southern California, 2008. 62. Jones, G.; Stanforth, S. P. Organic
reaction Vol. 49 edited by Leo, A.; Paquette et al. Organic reactions Inc. published by John Wiley and sons Inc.
63. Kantlehner, W. in Advances in organic chemistry, methods and results, Taylor, E. C. Ed. Vol. 9 Boecheme, H.; Viehe, H.G. Vol. Eds. Interscience, New York, Pp. 5 and 65 ,1976.
64. Liebscher, J.; Hartmann, H.
Synthesis 1979, 241
65. Gupton, J. T.; Banner, E. J.; Sartin, M. D.; Coppock, M. B.; Hempel, J. E.;Kharlamova, A.; Fisher, D. C.; Giglio, B. C.; Smith, K. L.; Keough, M. J.; Smith, T. M.; Kanters, R. P. F.; Dominey, R. N.; Sikorski, J. A. Tetrahedron 2008, 64, 5246. 66. Pfefferkorn, J. A.; Bowles, D. M.;
Kissel, W.; Boyles, D. C.; Choi, C.; Larsen, S. D.; Song, Y.; Sun, K. L.; Miller, S. R.; Trivedi, B. K. Tetrahedron, 2007, 63, 8124. 67. Cho, T. P.; Jun, F.; Li, H.; Zhe, X.;
Ling, C.; Xu, Z.; Lei, Z.; Bing, H.
Bioorg. Med. Chem. Lett.
2009,19, 6437.
68. Xiang, D.; Yang, Y.; Zhang, R.; Liang, Y.; Pan, W.; Huang, J. and Dong, D. J. Org. Chem. 2007, 72, 8593.
69. Pan, W.; Dong, D.; Wang, K.; Zhang, J.; Wu, R.; Xiang, D. and Liu, Q. Org. Lett. 2007, 9, 12, 2421.
70. Jones, G. Comprehensive
Heterocylclic Chemistry II;
Mckillop.A; Ed: pergamon press: Oxford,1996, Vol.5, P.167. 71. Jaysinghe, L.; Abbas, H. K.; Jacob,
M. R.; Herath, W.H.M.W.;
Nanayakkara, N. P. D. J. Nat. Prod. 2006, 69, 439.
72.Asokan, C. V.; Anabha , E. R.; Thomas, A. D.; Jose, A. M.; Lethesh, K. C.;Prasanth, M. and Krishanraj, K. U. Tetrahedron Letters 2007, 48, 5641.
73. Tabuchi, Y.; Ando, Y.; Kanemura, H.; Kawasaki, I.; Ohishi, T.; Koida, M.; Fukuyama, R.; Nakamuta, H.; Ohta, S.; Nishide, K.; Ohishi, Y. Bioorg. Med. Chem. 2009, 17, 3959.
74.Quiroga, J.; Trilleras, J.; Insuasty, B.; Abonia, R.; Nogueras, M.; Marchal, A.Cobo, J. Tetrahedron Lett. 2008, 49, 3257
75. ArunaKumar, D. B.; Prakash, G.
K.; kumaraswamy, M. N.;
Nandeshwarappa, B. P.;
Sherigara, B. S. and Mahadevan , K. M. Indian J. Chem. 2007, 46B, 336.
76.Elgemeie, G. H. and Metwally, N. H. J. Chem. Res(5), 1999, 6, 384.
77.Goudarshivannanavar, B. C.;
Jayadevappa H. and Mahadevan, K. M. Indian J. Chem. 2009, 48B, 1419.
78. Damljanovic, I.; Vukicevic, M.; Radulovic, N.; Palic, R.; Ellmerer, E.; Ratkovic, Z.; Joksovic, M. D.; Vukicevic, R. D. Bioorg. Med. Chem. Lett. 2009, 19, 1093 79.Joksovic, M.; Ratkovic, Z.;
Vukicevic, M. Vukicevic, R. D. Synlett 2006, 2581.
80.Vera-DiVaio, M. A. F.; Freitas
A.C.C.; Castro, H. C.;
Albuquerque, S. D.; Cabral, L. M.; Rodrigues, C. R.; Albuquerque, M. G.; Martins R. C. A.; Henriques, M. G. M. O.; Dias, L. R. S. Bioorg. Med. Chem. 2009, 17, 295.
81. Some, S.; Ray, J. K.; Barwell,
M.G. and Jones, M. T.
Tetrahedron Lett. 2007,48,
3609.
82.Banwell, M. G.; Lupton, D. W.; Ma, X.; Renner, J.; Sydnes, M. O.; Org. Lett. 2004, 6, 2741.
IJPCBS 2012, 3(1), 25-43 Rajputet al. ISSN: 2249-9504
A.; Dattolo, G.;Gia, O.; Via, L. D. and Cirrincione, G. Bioorg. Med. Chem. Lett. 2007, 17, 2342. 84. Popowycz, F.; et al, Tetrahedron
2007, 63, 1031.
85. Barraja, P.; Diana, P.;
Montalbano, A.; Carbone, A.;
Cirrincione, G.; Viola, G.;
Salvador, A.; Vedaldi, D.;
Dallacqua, F. Bioorg. Med. Chem. 2008, 16, 9668.
86. Xiang-Ying Tang and Min shi, J. Org. Chem. 2008, 73, 8317.
87. Damodiran, M.; Panneer,
Selvam. and Perumal, P.T. Tetrahedron Lett. 2009, 50, 5474
88. Wang, B. D.; Yang, Z.Y.; Qin, D. D.; Chen, Z. N. J. Photochem. Photobiol. A Chem. 2008,194, 49.
89. Herbivo, C.; Comel, A.; Kirsch, G.; Raposo, M. M. M. Tetrahedron 2009, 65, 2079.
90. Bhatti, H. S. and Seshadri, S. Dyes and Pigments 2004, 62, 83. 91. Mogilaiah, K.; Prasad, R. S. and Kumar, K. S. Indian J. Chem. 2010, 49B, 1417
92. Dutta, B.; Some, S. and Ray, J. K. Tetrahedron Lett. 2006, 47, 377. 93. Becker, C.; Roshchupkina, G.;
Rybalova, T.; Gatilov, Y. and Reznikov, V. Tetrahedron 2008, 64, 9191.
94. Singh, I. P.; Bharate, S. B. Nat. Prod. Rep. 2006, 23, 558.
95. Bharate, S. B.; Khan, S. I.; Yunus, N. A. M.; Chauthe, S. K.; Jacob, M. R.;Tekwani, B. L.; Khan, I. A. and Singh, I. P. Bioorg. Med. Chem. 2007, 15, 87.
96. Gandhi, V.; Thompson, M. L. and Lash, T. D. Tetrahedron 2010, 66, 1787.
97. Banerji, S.; Hyland, M. A. and Bruckner, C. Tetrahedron Lett. 2010, 51, 4505.
98. Bera, R.; Swamy, N. K.;
Dhananjaya, G.; Babu, J. M.; Kumar, P. R.; MukkantiK. and Pal, M. Tetrahedron 2007, 63, 13018.
99.Bubenyak, M.; Palfi, M.; Takacs, M.; Beni, S.; Szoko, E.; Noszal, B.; Kokosi, J. Tetrahedron Lett. 2008, 49, 4937.
100.(a) Park, M.; Lee, J.; Choi, J. Bioorg. Med. Chem. Lett. 1996, 6, 1297.(b) Moreia, A. L.; Corral, L. G.; Ye, W.; Johnson, B. A.; Stirling, D.; Muller, G. W.; Freedman, V. H.; Kaplan, G. AIDS Res. Hum. Retoviruses 1997, 13, 857. 101.Burzynski, S. R. Adv. Exp. Clin.
Chemother. 1988, 6, 45.
102.Tsuda, H.; Sugihara, S.; Nishida, H.; Hara, H.; Eriguchi, N.; Ishii, K.; Sasaki, K.; Yoshimura, S.; Tanaka, N. Jpn. J. Cancer Res. 1992, 86, 527
103.Victory, P.; Borrell, J. I. Trends Heterocycl. Chem. 1993, 3, 235.
104. Oesterle, T.; Simchen, G.
Synthesis 1985, 403.
105.Chang, M. Y.; Chen, C. Y.; Chen, S. T.; Chang, N. C. Tetrahedron 2003, 59, 7547.
106.Chang, M. Y.; Chen, C. Y.; Chen, S. T.; Chang, N. C. Tetrahedron Lett.2000,41,10273
107.Chen, C. Y.; Chang, M. Y.; Hsu, R. T.; Chen, S. T.; Chang, N. C. Tetrahedron Lett. 2003, 44, 8627.
108.Aitken, R. A.; Buchanan, G. M.; Karodia, N.; Massil, T.; Young, R. J. Tetrahedron Lett. 2001, 42, 141.
109.Kiyota, H.; Shimizu, Y.; Oritani, T. Tetrahedron Lett. 2000, 41, 5887.
110.Popovic Dordevic, J. B.; Ivanovic,
M. D.; Kiricojevic, V. D.
Tetrahedron Lett. 2005, 46, 2611.
111.Chang, B. R.; Chen, C. Y.; Chang, N. C. Tetrahedron Lett. 2002, 43, 3233.
112.Wanner, M. J.; Koomen, G. J. Synthesis 1988, 325.
113.The Merk Index, 13th ed.; Merk & Co.: NJ, 2001.
115.Leonardi, A.; Barlocco, D.; Montesano, F.; Cignarella, G.; Motta, G.; Testa, R.; Poggesi, E.; Seeber, M.; De Benedetti, P. G.; Fanelli, F. J. Med. Chem. 2004, 47, 1900.
116.Paluchowska, M. H.; Bugno, R.; Duszynska, B.; Tatarczynska, E.; Nikiforuk,A.; Lenda, T. and Wojcik, E. C. Bioorg. Med. Chem. 2007, 15, 7116
117.Shaabani, A.; Soleimani, E.; Khavasi, H. R.; Hoffmann, R. D.; Rodewald, U. C. and Pottgen, R. Tetrahedron Lett. 2006, 47, 5493.
118.Kiyota, H.; Shimizu, Y. and Oritani, T. Tetrahedron Lett. 2000, 41, 5887
119. Sonoda, T.; Osada, H.; Uzawa, J.; Isono, K. J. Antibiot. 1991, 44, 160.
120.Isono, K.; Osada, H.; Sonoda, T. JPn Kokai Tokkyo Koho 1991
JPO3, 255, 082
(Chem.Abstr.1992, 116,
126985).
121. Fu, R.; Ye, J.; Dai, X.; Ruan, Y. and Huang, P. J. Org. Chem. 2010, 75, 4230.
122.Fu, R.; Du, Yu; Li, Z.-Y.; Xu, W.-X.; Huang, P.- Q. Tetrahedron 2009, 65, 9765.
123.Amat, M.; Brunaccini, E.; Checa, B.; Perez, M.; Llor, N.; Bosch, J. Org. Lett. 2009, 11, 4370.
124.Huang, C. G.; Chang B. R. and Chang, N. C. Tetrahedron Lett. 2002, 43, 2721.
125.Mederski Werner W. K. R.;
Baumgarth, M.; Germann, M.;
Kux, D. and Weitzel, T.
Tetrahedron Lett. 2003, 44, 2133.
126.Chen, B. F.; Tasi, M. R.; Yang, C. Y.; Chang J. K. and Chang, N. C. Tetrahedron 2004, 60, 10223. 127.Stout, D. M.; Meyers, A. Chem.
Rev. 1982, 82, 233.
128.Godfraid,T.; Miller, R.; Wibo, M. Pharmacol. Rev. 1986, 38, 321. 129.Gaudio, A. C.; Korolkovas, A.;
Takahata, Y. J. Pharm. Sci. 1994, 83, 1110.
130.Antman, E.; Muller, J.; Goldberg, S.; MacAlpin, R.; Rubenfire, M.; Tabatznik, B.; Liang, C.; Heupler, F.; Achuff, S.; Reichek, N.; Geltman, E.; Kerin, N. Z.; Neff, R. K.; Braunwald, E. N. Engl. J. Med. 1980, 302, 1269.
131.Guazzi, M.; Olivari, M. T.; Polese, A.; Fiorentini, C.; Margrini, F.; Moruzzi, P. Clin. Pharmacol. Ther. 1977, 22, 528
132.Soldatenkov, A. T.; Kolyadina, N.
M. and Shendrik, I. V.
Fundamentals of the Organic
Chemistry of Medicinal
Substances [in Russian], Khimia, Moscow 2001, 192 pp.
133.Moiseev, V. S. Klin. Farmakol. Ther. 2006, 15 (3), 45.
134.Kappe, C. O. Molecules 1998, 3, 1.
135. Suresh, T.; Swamy, S. K. and Reddy, V. M. Indian J. Chem. 2007, 46B, 115 .
136.Pattan, S. R.; Rasal, V. P.; Venkatramana, N. V.; Khade, A. B.; Butle, S. R.; Jadhav, S. G.; Desai, B. G. and Manvi,F. V. Indian J. Chem. 2007, 46B, 698. 137.Pattan, S. R.; Purohit, S. S.; Rasal,
V. P.; Mallya, S.; Marihal, S. C.; Khade, A. B. and Paschapur, M. S. Indian J. Chem. 2008, 47B, 626.
138.Arumugam, P. and Perumal, P. T. Indian J. Chem. 2008, 47B, 1084 .
139. Das, P. J. and Baruah, A. Indian J. Chem. 2008, 47B, 1568.
140.Desai, B. G. and Sureja, D. Bioorg. Med. Chem. 2001, 9, 1993. 141.Mannhild, R.; Jabolanka, B.;
Voigelt, W.; Schoeuafinger, K. and Schravan, K. Eur. J. Med. Chem. 1992, 27, 229.
142.Subudhi, B. B.; Panda, P. K. and Bhatta, D. Indian J. Chem. 2009, 48B, 725.
143.Skrastyn'sh, I. P.; Kastron, V. V.; Dubur, G. Y. Mazheika, I. B. and
Liepin'sh, E. E. Khim.
IJPCBS 2012, 3(1), 25-43 Rajputet al. ISSN: 2249-9504
144. Skrastiņš, I.; Kastron, V.; Cekavičus, B.; Sausiņš, A.; Zolotoyabko, R. and Dubur, G. Khim. Geterotsikl. Soedin. 1991, 1230. [Chem. Heterocycl. Comp. 1991, 27, 989.].
145.Skrastinsh, I. P.; Kastron, V. V.; Vitolin’, R. O.; Dubur, G. Y.; Stivrinya, M. I. and Kaidaka, K. A. Khim.-Farm. Zh. 1989, 23, 1323. 146.Vovk, M. V.; Mel’nichenko, N. V.; Sukach, V. A.; Chubaruk, N. G. Chem.Heterocycl. Compd. 2004, 40, 1485.
147.Quiroga, J.; Trilleras, J.; Cobo, J.; Glidewell, C. Acta Crystallogr. Sect. C 2010, 66, 47.
148.Verdecia, Y.; Suarez, M.; Morales, A.; Rodriguez, E.; Ochoa, E.;
Gonzalez, L.; Martin, N.;
Quintero, M.; Seoane, C.; Soto, J. L. J. Chem. Soc. Perkin Trans. 1 1996, 947.
149.De la Torre, J. M.; Trilleras, J.; Cobo, J.; Glidewell, C. Acta Crystallogr. Sect. C 2009, 65, 281.
150.Trilleras, J.; Quiroga, J.; Low, J. N.; Cobo, J.; Glidewell, C. Acta Crystallogr. Sect. C 2008, 64, 341.
151.Zhu, D.-G.; Gunawardana, I. W.; Boyd, S. A.; Melcher, L. M. J. Heterocycl. Chem. 2008, 45, 91. 152.Kvitoko, I. Y.; Panfilova, E. A.
Khim. Geterotsikl. Soedin. 1973, 507, (Engl. Transl. P.467). Chem. Abstr. 1973, 79, 31775s.
153.Maddox, M. L.; Muchowski, J. M. J. Org. Chem. 1990, 55, 5793. 154.Quiroga, J.; Diaz,Y.; Insuasty, B.;
Abonia, R.; Nogueras, M. and Cobo, J. Tetrahedron Lett. 2010, 51, 2928.
155. A. P. Rajput, Asian J. Chem., 14, 2, 2002, 807.
156. A. P. Rajput, Asian J. Chem., 16, 3-4, 2004, 1374
157.A. P. Rajput and S. S. Rajput, Asian J. Chem., 19, 4, 2007, 3265. 158.A. P. Rajput and S. S. Rajput, Asian J. Chem., 19, 6, 2007, 4939.
159.A. P. Rajput and S. S. Rajput, Int. J. PharmTech Res., 1(4), 2009, 1605
160.Rajput A. P. and Bhadane S. J., Int. J. PharmTech Res., 4(2), 2012, 523.
161.A. P. Rajput and P. D. Girase Indian J. Heterocyclic Chem. 2010, Vol. 20, 87.
162.A. P. Rajput and P. D. Girase, Int.
J. Pharm. Pharm. Sci.,
2011,Volume-3, suppl 4, 214. 163.A. P. Rajput and P. D. Girase, Int.
J. Chem. Res., Vol.2, Issue 4, 2011, 38.
164.A. P. Rajput and P. D. Girase, Int. J. Pharm Tech Res. 2011, 3(4), 2111.
165.A. P. Rajput and P. D. Girase, Indian J. Heterocyclic Chem., Vol.21,Jan-March 2012, pp. 201-208.
166.A. P. Rajput and P. D. Girase, Int.
J. Chem Tech Res. .,
Vol.4,No2,April-June 2012,
