Facile iodine(III)-mediated approach for the regioselective chlorination of 2-aryl-2,3-dihydro-4(1H)-quinolones

Article abstract of DOI:10.1080/00397910802413865

Oxidation of 2-aryl-2,3-dihydro-4(1H)-quinolones (1) with 1.5 equivalents of (dichloroiodo)benzene in dichloromethane at room temperature leads to regioselective chlorination, thereby offering an efficient method for the synthesis of new 2-aryl-6-chloro-2

Full text of DOI:10.1080/00397910802413865

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Facile Iodine(III)-Mediated
Approach for the
Regioselective Chlorination
of 2-Aryl-2,3-dihydro-4(1H)-
quinolones
Deepak Sharma a , Pooja Ranjan a & Om Prakash a
a Department of Chemistry , Kurukshetra University ,
Kurukshetra, Haryana, India
Published online: 28 Jan 2009.
To cite this article: Deepak Sharma , Pooja Ranjan & Om Prakash (2009) Facile
Iodine(III)-Mediated Approach for the Regioselective Chlorination of 2-Aryl-2,3-
dihydro-4(1H)-quinolones, Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic Chemistry, 39:4, 596-603, DOI:
10.1080/00397910802413865
To link to this article: http://dx.doi.org/10.1080/00397910802413865
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Synthetic Communications1, 39: 596–603, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802413865
Facile Iodine(III)-Mediated Approach for the
Regioselective Chlorination of 2-Aryl-2,3-
dihydro-4(1H)-quinolones
Deepak Sharma, Pooja Ranjan, and Om Prakash
Department of Chemistry, Kurukshetra University, Kurukshetra,
Haryana, India
Abstract: Oxidation of 2-aryl-2,3-dihydro-4(1H)-quinolones (1) with 1.5 equivalents
of (dichloroiodo)benzene in dichloromethane at room temperature leads to
regioselective chlorination, thereby offering an efficient method for the synthesis
of new 2-aryl-6-chloro-2,3-dihydro-4(1H)-quinolones (3).
Keywords: 2-Aryl-2,3-dihydro-4(1H)-quinolones, (dichloroiodo)benzene, regio-
selective chlorination
INTRODUCTION
The introduction of chlorine into an aromatic ring is a commonly used
reaction in organic synthesis and medicinal chemistry. Several methods
for chlorination have been reported in literature.[1–3] However, most of
these still suffer from serious shortcomings such as the formation of
by-products and poor selectivity of the reaction. Among several chlorinat-
ing agents, we directed our attention to (dichloroiodo)benzene because of
its low toxicity, easy handling, and relatively benign nature.[4] Moreover,
the use of (dichloroiodo)benzene for large-scale monochlorination of
4-aminoacetophenone has been previously described.[5] As a part of our
ongoing interest in the development of iodine(III)-mediated methods
Received June 9, 2008.
Address correspondence to Om Prakash, Department of Chemistry,
Kurukshetra University, Kurukshetra, Haryana, 136119, India. E-mail:
dromprakash50@rediffmail.com
596

Facile Iodine(III)-Mediated Approach
597
especially for the synthesis of heterocyclic compounds,[6–12] we now
became interested in the scope of (dichloroiodo)benzene-mediated
nuclear chlorination. In this context, the opportunity was taken to
examine the reaction of 2-aryl-2,3-dihydro-4(1H)-quinolones (1) with
(dichloroiodo)benzene in dichloromethane at room temperature. The
reagent, in principle, could chlorinate C(3), C(6) (para to –NH), and
C(8) (ortho to –NH) of 2-aryl-2,3-dihydro-4(1H)-quinolone (1). In
addition, we also considered the possibility that the initially formed
C(3)-chloro product could undergo elimination of one molecule of HCl
to give quinolone of the type 2.
To determine the feasibility of such possibilities, we first carried out
the reaction of 1a with 1.5 equivalents of (dichloroiodo)benzene in
dichloromethane at room temperature. Interestingly, the reaction
afforded a solid product, which was characterized as 6-chloro-2,3-
dihydro-2-phenyl-4(1H)-quinolone (3a) on the basis of physical and
spectral data. The IR spectrum displayed carbonyl stretch and –NH
1
stretch at 1657 and 3347 cmꢀ1 respectively. The H NMR spectrum of
3a showed a characteristic doublet at 7.77 ppm with a coupling constant
of 2.4 Hz that can be ascribed to the C5-proton. A doublet with meta
interaction clearly confirmed the presence of a chloro group at the sixth
position. Mass spectrum showed Mþ and Mþ þ 2 peaks in relative
abundance, 3:1, clearly confirming the presence of one chlorine atom in
the structure of product. The regioselective chlorination that occurred
in this reaction is a significant result, as the compounds of type 3 are
unknown in the literature. The generality of this facile transformation
was established by treating other 2,3-dihydro-4(1H)-quinolones (1b–f)
with (dichloroiodo)benzene under similar conditions which provided
2-aryl-6-chloro-2,3-dihydro-4(1H)-quinolones (3b–f) in good yields
(53–76%) (Scheme 1).[13]
The mechanism of the reaction is not clear. A plausible pathway for
transformation 1 ! 3 is outlined in Scheme 2. The transformation
probably involves the formation of N-I(III) intermediate 4 by ligand
exchange between –NH group and (dichloroiodo)benzene. The N-I(III)

598
D. Sharma, P. Ranjan, and O. Prakash
Scheme 1. Regioselective chlorination of 2-aryl-2,3-dihydro-4(1H)-quinolones
using PhICl2.
Scheme 2. Mechanistic pathway for chlorination.

Facile Iodine(III)-Mediated Approach
599
intermediate 4 might give the product by nucleophilic attack of chloride
ion with simultaneous reductive elimination of iodobenzene.
To determine whether the reaction proceeds through the in situ
generation of chlorine from (dichloroiodo)benzene, we performed chlori-
nation of a representative case 1e with chlorine gas. In this experiment,
the chlorine gas was passed through solution of 1e in dichloro-
methane for 2 h. Surprisingly, the reaction afforded a polysubstitution
product, 2-(40-bromophenyl)-5,6,7,8-tetrachloro-4-hydroxyquinoline (5e)
[Eq. (1)].
This experiment clearly indicated that regioselective chlorination occur-
ring with (dichloroiodo)benzene does not proceed through the in situ
generation of chlorine from the reagent.
The iodine(III)-mediated conversion 1 ! 3, a new application of
(dichloroiodo)benzene, is significant for the following reasons:
1. The method involves mild conditions and simple experimentation.
2. The reaction offers an easy and efficient way for selective nuclear
monochlorination of 2-aryl-2,3-dihydro-4(1H)-quinolones at the sixth
position.
3. All the chlorodihydroquinolones 3a-3f, synthesized in this study, are
new compounds.
EXPERIMENTAL
Melting points were taken in open capillaries and are uncorrected. IR
spectra were recorded on Perkin-Elmer IR 1800 spectrophotometer.
1
The H NMR spectra were recorded on Brucker 300-MHz instrument.
2-Aryl-2,3-dihydro-4(1H)-quinolones (1) were synthesized according to
literature procedures.[14–16]

600
D. Sharma, P. Ranjan, and O. Prakash
Preparation of 6-Chloro-2-aryl-2,3-dihydro-4(1H)-quinolones (3)
According to Scheme 1
(Dichloroiodo)benzene (0.825 g, 0.003 mol) was added to a solution
of 2-phenyl-2,3-dihydro-4(1H)-quinolone 1a (0.446 g, 0.002 mol) in
dichloromethane (20 ml), in portions and the resulting mixture was
allowed to stir for 2 h at room temperature. The reaction mixture was
concentrated on a water bath. The residue was purified by column chro-
matography on silica gel (100–200 mesh) using petroleum ether–ethyl
acetate as eluent to give 0.380 g of 3a. Other derivatives 3b–3f were pre-
pared in a similar manner.
Data
6-Chloro-2-phenyl-2,3-dihydro-4(1H)-quinolone (3a)
Yield 74%, mp 156–58 ꢁC; IR (vmax, in KBr): 1657, 3347 cmꢀ1; 1H NMR
(CDCl3, 300 MHz, d): 2.68–2.86 (m, 2H), 4.4–4.5 (bp, 1H, NH), 4.67
(dd, 1H, C2-H, J ¼ 13.2 Hz, 4.5 Hz), 6.60 (d, 1H, J ¼ 8.7 Hz), 7.22–7.39
(m, 6H), 7.77 (d, 1H, C5-H, J ¼ 2.4 Hz). Elemental analysis: found C,
69.5%; H, 4.5%; N, 5.2%; requires C, 70%; H, 4.7%; N, 5.4%. Mass: 257
(Mþ), 259 (Mþ þ 2).
6-Chloro-2-(40-methoxyphenyl)-2,3-dihydro-4(1H)-quinolone (3b)
Yield 68%, mp 98–100 ꢁC; IR (nmax, in KBr): 1658, 3348 cmꢀ1; 1H NMR
(CDCl3, 300 MHz, d): 2.7–2.9 (m, 2H), 3.76 (s, 3H, –OCH3), 4.65 (dd, 1H,
C2-H, J ¼ 13.2 Hz, 4.5 Hz), 4.9–5.0 (bp, 1H, NH), 6.86–6.89 (m, 2H),
7.22–7.37 (m, 4H), 7.71 (d, 1H, C5-H, J ¼ 2.4 Hz). Elemental analysis:
found C, 65.8%; H, 4.6%; N 4.2%; requires C, 66.9%; H, 4.9%; N
4.9%. Mass: 287 (Mþ), 289 (Mþ þ 2).
6-Chloro-2-(20-methoxyphenyl)-2,3-dihydro-4(1H)-quinolone (3c)
Yield 53%, mp 88–90 C; IR (vmax, in KBr): 1660, 3345 cmꢀ1; 1H NMR
ꢁ
(CDCl3, 300 MHz, d): 2.79–3.00 (m, 2H), 3.76 (s, 3H, –OCH3), 4.5–4.7
(bp, 1H, NH), 5.15 (dd, 1H, C2-H, J ¼ 13.2 Hz, 4.5 Hz), 6.8–7.0 (m, 2H),
7.25–7.30 (m, 1H), 7.34–7.40 (m, 1H), 7.55–7.65 (m, 2H), 7.70 (d, 1H, C5-
H, J ¼ 2.4 Hz). Elemental analysis: found C, 65.2%; H, 4.3%; N, 4.4%;
requires C, 66.9%, H, 4.9%; N, 4.9%. Mass: 287 (Mþ), 289 (Mþ þ 2).

Facile Iodine(III)-Mediated Approach
601
6-Chloro-2-(40-chlorophenyl)-2,3-dihydro-4(1H)-quinolone (3d)
Yield 70%, mp 177–178 ꢁC; IR (nmax, in KBr): 1658, 3343 cmꢀ1; 1H NMR
(CDCl3, 300 MHz, d): 2.71–2.81 (m, 2H), 4.4–4.5 (bp, 1H, NH), 4.66
(dd, 1H, C2-H, J ¼ 13.2 Hz, 4.5 Hz), 6.60 (d, 1H, J ¼ 8.7 Hz), 7.20–7.24
(m, 1H), 7.32–7.39 (m, 4H), 7.76 (d, 1H, C5-H, J ¼ 2.4 Hz). Elemental
analysis: found C, 60.8%; H, 3.3%; N, 4.4%; requires C, 61.8%; H,
3.8%, N, 4.8%. Mass: 291 (Mþ), 293 (Mþ þ 2), 295 (Mþ þ 4).
6-Chloro-2-(40-bromophenyl)-2,3-dihydro-4(1H)-quinolone (3e)
Yield 76%, mp 180–81 ꢁC; IR (nmax, in KBr): 1658, 3343 cmꢀ1; 1H NMR
(CDCl3, 300 MHz, d): 2.75–2.89 (m, 2H), 4.3–4.5 (bp, 1H, NH), 4.73
(dd, 1H, C2-H, J ¼ 13.2 Hz, 4.5 Hz), 6.70 (d, 1H, J ¼ 8.7 Hz), 7.27–7.36
(m, 3H), 7.54–7.57 (m, 2H), 7.85 (d, 1H, C5-H, J ¼ 2.4 Hz); Elemental
analysis: found C, 52.9%; H 3.6%; N 3.28%; Requires C 53.5%, H,
3.3%; N, 4.2%; Mass: 335 (Mþ), 337 (Mþ þ 2), 339 (Mþþ 4).
6-Chloro-2-(40-nitrophenyl)-2,3-dihydro-4(1H)-quinolone (3f)
Yield 66%, mp 188–90 ꢁC; IR (nmax, in KBr): 1348, 1545, 1661, 3349 cmꢀ1;
1H NMR (CDCl3, 300 MHz, d): 2.76–2.79 (m, 2H), 4.3–4.5 (bp, 1H, NH),
4.69 (dd, 1H, C2-H, J ¼ 13.2 Hz, 4.5 Hz), 6.6–6.7 (m, 1H), 7.25–7.30
(m, 1H), 7.56–7.61 (m, 2H), 7.78 (d, 1H, C5-H, J ¼ 2.4 Hz), 8.19–8.22
(m, 2H). Elemental analysis: found C, 58.8%; H, 3.6%; N, 8.8%; requires
C, 59.6%; H 3.6%; N, 9.3%. Mass: 302 (Mþ), 304 (Mþ þ 2).
Preparation of 2-(40-Bromophenyl)-5,6,7,8-tetrachloro-4-hydroxyquino-
line (5e)
Forty mL dry dichloromethane and 2-(40-bromophenyl)-2,3-dihydro-
4(1H)-quinolone 1e (0.604 g, 0.002 mol) were placed in a 100-mL, two-
necked, round-bottom flask with an inlet tube for the introduction of
chlorine gas and an exit tube carrying calcium chloride guard tube.
The flask was cooled in an ice–salt mixture, and dry chlorine gas was
passed through a stirred solution of 1e in dichloromethane for 2 h. The
reaction mixture was concentrated on a water bath. The residue was
purified by column chromatography on silica gel (100–200 mesh) using
petroleum ether–ethyl acetate as eluent.
1
Yield 71%, mp 204–206 ꢁC; IR (nmax, in KBr): 3243 cmꢀ1; H NMR
(CDCl3, 300 MHz, d): 7.58 (d, 2H, J ¼ 8.8 Hz), 7.76 (d, 2H, J ¼ 8.8 Hz),

602
D. Sharma, P. Ranjan, and O. Prakash
7.84 (s, 1H), 8.4 (bp, 1H, ꢀOH). Elemental analysis: found C, 40.8%; H
1.32%; N, 2.9%; requires C, 41.09%; H, 1.37%; N, 3.2%; Mass: 435 (Mþ),
437 (Mþ þ 2), 439 (Mþ þ 4), 441 (Mþ þ 6).
ACKNOWLEDGMENTS
We are thankful to Kurukshetra University, Kurukshetra, for a Univer-
sity Research Fellowship to Deepak Sharma and to Council for Scientific
and Industrial Research (CSIR), New Delhi, for the award of a junior
research fellowship to Pooja Ranjan for financial support of this
work. We are also thankful to Defense Research & Development Orga-
nization (DRDO), New Delhi (Grant No ERIP/ER/0303447/M/01),
for support.
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