JOURNAL OF DISPERSION SCIENCE AND TECHNOLOGY

Vol. 25, No. 1, pp. 1721, 2004

Vilsmeier Haack Acetylation in Micellar Media: An Efficient One Pot

Synthesis of 2-Chloro-3-acetyl Quinolines
K. C. Rajanna,1, * M. Moazzam Ali,2 S. Sana,2 Tasneem,2 and P. K. Saiprakash3
1

Post Graduate College, Osmania University, Mirzapur (SGD), India

Nawab Shah Alam Khan, Centre for P.G. Studies and Research, Anwar-Ul-Uloom College, Hyderabad, India
3
Department of Chemistry, Osmania University, Hyderabad, India

ABSTRACT
Vilsmeier Haack (VH) acetylations of aromatic hydrocarbons have been carried out by
using an N,N-dimethyl acetamide (DMA)-POCl3 system to afford the corresponding
acetophenones in good yield with high regioselectivity. These acetylations are
dramatically accelerated in micellar media. Further it is of interest to note that
cyclizations in micellar media under VH conditions are obtained to afford 2-chloro-3acetyl quinoline derivatives in good yield. This procedure works efficiently in CTAB
(cetyltrimethyl ammonium bromide), SDS (sodium dodecyl sulphate), and TX (TritonX100) media under reflux conditions (particularly for deactivated acetanilides).
Key Words: Vilsmeier Haack acetylation; Aromatic hydrocarbons; (DMA)-POCl3;
Quinolines.

the corresponding iminium species.[2] The cyclization of

iminium species under Vilsmeier Haack conditions is an
important synthetic tool of organic chemistry, and
provides a facile entry into large numbers of heterocyclic
systems.[3a g] Despite the fact that a large number of
publications describing Vilsmeier Haack formylation are
available, Vilsmeier Haack acetylation has remained
almost unexplored. We are currently focusing our
attention on exploiting the use of micelles as catalysts
in various organic reactions.[4] Micellar mediated

INTRODUCTION
The Vilsmeier Haack reaction (VHR) is one of the
most versatile reactions in organic synthesis. The
reactive intermediates involved in the VHR are the
halomethyleniminium salts derived from the action of
acid chloride on N,N-disubstituted formamides.[1a c] The
Vilsmeier Haack reaction under classical conditions
involves electrophilic substitution of an activated
aromatic ring with a halomethyleniminium salt to yield

*Correspondence: K. C. Rajanna, Post Graduate College, Osmania University, Mirzapur (SGD) 502 249, India; E-mail: kcrajanna@
satyamonline.com.
17
DOI: 10.1081/DIS-120027663
Copyright # 2004 by Marcel Dekker, Inc.

0193-2691 (Print); 1532-2351 (Online)

www.dekker.com

18

Rajanna et al.

organic reactions are of great interest because of the

relationship in close parallelism with enzyme processes.[5a c] It has been very well documented in the
literature that rate and selectivity of catalytic reactions
can be enhanced by micelles acting as kinds of microreactors. On account of their solubilization capability
micelles may increase the reactant concentration with the
hydrophilic or hydrophobic areas and cause a favorable
orientation of the reactants by polarity gradients.
Quinolines[6a g] are an important group of heterocyclic compounds. Several derivatives of this class of
compounds have been found to possess useful biological
activities such as bactericidal,[7a,b] antitumor,[8] antimalarial,[9] antiinflamatory,[10] etc. Among quinolines,
2-chloro-3-acetyl quinolines occupy a prominent position, as they are key intermediates for the synthesis of
dihydrothieno [2,3-b] quinolines.[11] The synthesis of
2-chloro-3-acyl quinolines from acetanilides requires
several steps. In the first step it proceeds via Vilsmeier
Haack formylation to give 2-chloro-3-formyl quinolines,
which on Grignard reaction with RMgX afford secondary
alcohols. These secondary alcohols on subsequent
oxidation with PCC give the desired 2-chloro-3-acyl
quinolines. In continuation of our efforts in this area we
wish to report Vilsmeier Haack acetylation of aromatic
compounds by employing POCl3/DMA as acetylating
reagent in the presence of micelles and application of this
methodology for the one pot synthesis of 2-chloro-3acetyl quinolines from acetanilides (Sch. 1). Earlier, the
use of POCl3/DMA has been reported for the synthesis
of benzoxazoles from 2-hydroxy acetophenone oximes,
under Vilsmeier Haack reaction conditions.[12]

(10 ml of 0.05 mol) in acetonitrile and refluxed for

45 min. After completion of reaction as indicated by
TLC, the acetonitrile was evaporated and the reaction
mixture was dissolved in dichloromethane and quenched
with sodium thiosulphate solution; the organic layer was
separated, dried over Na2SO4 and evaporated under
vacuum, purified with column chromatography using
ethyl acetate: hexane (3:7) as eluent to get pure product,
4-hydroxy acetophenone (2d) in 90% yield; m.p. 108
1108C (lit. 109 1118C).

General Procedure for the Synthesis of

2-Chloro-3-acetyl Quinolines
A Vilsmeier Haack adduct prepared from POCl3
(9.3 ml, 100 mmol) and DMA (9.29 ml, 100 mmol) at
258C was slowly added to a solution of acetanilide (1g)
(6.75 gr, 50 mmol) in acetonitrile and refluxed for
45 min. After completion of reaction as indicated by
TLC, the acetonitrile was evaporated and the reaction
mixture was dissolved in dichloromethane and quenched
with sodium thiosulphate solution. The organic layer was
separated, dried over Na2SO4 and evaporated under
vacuum, purified with column chromatography using
ehtylacetate: hexane (3:7) as eluent to get pure product 2chloro-3-acetyl quinoline (2g) in 80% yield; m.p. 74
768C (lit. 75 768C); 1H-NMR (CDCl3) d 2.70 (s, 3H,
COCH3); 7.0 8.25 (m, 5H, aromatic); mass 205,
IR cm211705 (C55O).

RESULTS AND DISCUSSION

PROCEDURES
General Procedure for Acetylation of
Aromatic Compounds
A Vilsmeier Haack adduct prepared from POCl3
(9.3 ml, 100 mmol) and DMA (9.29 ml, 100 mmol) at
258C was slowly added to a solution of phenol (1d)
(50 mmol) in acetonitrile containing a solution of CTAB

Aromatic compounds when treated with POCl3/

DMA in the presence of cetyltrimethyl ammonium
bromide (CTAB), sodium dodecyl sulphate (SDS), and
Triton-X100 in CH3CN under reflux condition for 45
90 min afforded the corresponding acetophenones in
good yields. In the same way, this method of Vilsmeier
Haack acetylation, by employing POCl3/DMA, is
extended for the synthesis of 2-chloro-3-acetylquinolines
(Table 1)a from acetanilides via cyclization.
a

Scheme 1. Reagents and conditions: (i) POCl3 DMA,

CTAB, CH3CN, reflux, 45 90 min; (ii) POCl3 DMA, SDS,
CH3CN, reflux, 45 90 min; (iii) POCl3 DMA, TX-100,
CH3CN, reflux, 45 90 min.

Selected spectral data. 6-Bromo-2-chloro-3-acetyl quinoline

(1h): M.P. 1228C, 1H-NMR (CDCl3) d 2.1 (s, 3H, COCH3)
7.0 7.4 (m, 4H, Aromatic): IR (KBr), 1590 (C N), 1670
(C O); Mass: 283 (M). 2,8-dichloro-3-acetyl quinoline (1i):
M.P. 828 C, 1H-NMR (CDCl3) d2.2 (s, 3H, COCH3), 7.0 8.4
(m,4H, Aromatic), IR (KBr), 1590 (C N), 1670 (C O);
Mass: 239 (M). 6-Nitro-2-chloro-3-acetyl-quinoline (1o).
M.P. 1308C, 1H-NMR (CDCl3), d 2.3 (s, 3H, COCH3), 7.0 7.4
(m, 4H, Aromatic), IR (KBr) 1590 (C N). 1670 (C O);
Mass: 250 (M).

2-Acetonapthone
9-Acetyl anthracene
4-Methyl acetophenone
4-Mydroxy acetophenone
4-Chloro acetophenone
2-Acetyl naphthol
2-Chloro-3-acetyl quinoline
6-Bromo-2-chloro-3-acetyl quinoline
2,8-Dichloro-3-acetyl quinoline
2,6-Dichloro-3-acetyl quinoline
6-Methyl-2-chloro-3-acetyl quinoline
8-Ethyl-2-chloro-3-acetyl-quinoline
8-Nitro-2-chloro-3-acetyl-quinoline
7-Nitro-2-chloro-3-acetyl-quinoline
6-Nitro-2-chloro-3-acetyl-quinoline
6-Methoxy-2-chloro-3-acetyl-quinoline

Product

45
45
50
50
90
80
90
90
90
85
60
45
90
90
90
60

Reaction
time/min

CTAB

90
90
86
88
80
84
82
80
84
90
90
88
74
72
78
88

Yield
(%)b
45
45
60
55
80
85
90
85
90
90
60
45
90
90
90
60

Reaction
time/min

SDS

90
88
84
86
82
84
88
86
88
86
90
86
74
74
76
84

Yield
(%)b

Vilsmeier Haack acetylation under micellar conditions.

All the products were characterized by IR, 1H-NMR and mass spectra.
Isolated yields. NR no reaction.

Naphthalene
Anthracene
Toluene
Phenol
Chlorobenezene
a-Naphthol
Acetanilide
4-Bromo-acetanilide
2-Chloro-acetanilide
4-Chloro-acetanilide
4-Methyl-acetanilide
2-Ethyl-acetanilde
2-Nitro-acetanilide
3-Nitro-acetanilide
4-Nitro-acetanilide
4-Methoxy-acetanilide

1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
1o
1p

Sustrate

Entry

Table 1.

45
45
60
55
80
85
90
85
90
90
60
45
90
90
90
60

Reaction
time/min
90
86
88
84
82
86
80
88
86
84
86
84
78
74
76
84

Yield
(%)b

Triton-X100

6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6

Reaction
time/h

Thermal

34
35
30
40
32
40
22
30
NR
20
23
10
NR
NR
NR
23

Yield
(%)b

VH Acetylation in Micellar Media

19

20

The acetylation was carried out by refluxing the

aromatic compounds in acetonitrile with DMA/POCl3 in
the presence of micelles. These reactions could also be
conveniently carried out using dichloro methane (DCM)
or dichloro ethane (DCE) as solvents instead of
acetonitrile. But acetonitrile was found to be superior
over DCE and DCM. The reactions were completed in
45 90 min to afford the corresponding acetophenones in
good yields with high regio selectivity. To check the
generality of the reaction an array of substituted aromatic
compounds were acetylated under these reaction
conditions (1a-f). The yields of major products are
compiled in Table 1, although other isomers were also
detected in small amounts.
Encouraged by these promising results we tried to
synthesize 2-chloro-3-acetylquinoline in one pot via
cyclization of acetanilides (1g-p) in the presence of
CTAB, SDS, and Triton-X100. The reactions rapidly
afforded high yields of the corresponding 2-chloro-3acetyl quinoline derivatives. All the products were
characterized by IR, 1H-NMR, mass spectra, and
physical data with authentic samples and found to be
satisfactory.
It was observed that the aromatic compounds are
acetylated efficiently. Furthermore, these trends are also
seen in the case of cyclization of acetanilides where
activated as well as deactivated acetanilides are cyclized
to afford 2-chloro-3-acetylquinoline. It is believed that
micelles are acting as promoters in the acetylation of
aromatics as well as in the cyclization of acetanilides. It
is also observed that in the absence of micelles
(surfactant), reaction is very sluggish under thermal
conditions. Although mechanistic studies are beyond the
scope of the present work, we believe that micelles by
their solubilization capability increase the reactant
concentration within the hydrophilic or hydrophobic
micellar regions facilitating the reaction.
The results of the present method clearly indicate
that direct acetylation as well as cyclization could be
achieved successfully by employing CTAB, SDS, and
Triton-X100 as catalysts under Vilsmeier-Haack reaction
conditions, which is not possible under classical thermal
conditions.
In summary, we have demonstrated Vilsmeier
Haack acetylation of aromatic compounds in the
presence of CTAB, SDS, and Triton-X100. Furthermore,
this method has been extended for the one-pot synthesis
of 2-chloro-3-acetyl quinoline derivatives in good yields.
The present finding has advantages such as readily
available reagents, and the reaction occurs in very mild
conditions with simple work up. Thus, it is believed that
the present work is a major break through in the area of
synthesis of 2-chloro-3-acetyl quinolines with potential

Rajanna et al.

biological activity. Application of this new strategy for

various aromatic and heteroaromatic compounds is under
investigation and will be reported in due course.

ACKNOWLEDGMENTS
The authors thank Nawab Shah Alam Khan,
Chairman, and Nawab Mahboob Alam Khan, Secretary,
of Nawab Shah Alam Khan Centre for Post-Graduate
Studies and Research, Mallepally and Prof. T. Navaneeth
Rao (former Vice-Chancellor, Osmania University,
Hyderabad) for their constant encouragement.

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