Trifluoroacetic acid: a more effective and efficient reagent for the synthesis of 3-arylmethylene-3,4-dihydro-1H-quinolin-2-ones and 3-arylmethyl-2-amino-quinolines from Baylis-Hillman derivatives via Claisen rearrangement

Article abstract of DOI:10.1016/j.tet.2006.10.053

Trifluoroacetic acid has been discovered to be a highly effective and efficient reagent for the tandem Claisen rearrangement and cyclization reaction to yield 3-arylmethylene-3,4-dihydro-1H-quinolin-2-ones from compounds obtained from the S_N2 r

Full text of DOI:10.1016/j.tet.2006.10.053

Tetrahedron 63 (2007) 451–460
Trifluoroacetic acid: a more effective and efficient reagent for
the synthesis of 3-arylmethylene-3,4-dihydro-1H-quinolin-2-ones
and 3-arylmethyl-2-amino-quinolines from Baylis–Hillman
derivatives via Claisen rearrangement*
*
Richa Pathak, Sudharshan Madapa and Sanjay Batra
Medicinal and Process Chemistry Division, Central Drug Research Institute, PO Box 173, Chattar Manzil Palace,
Lucknow 226001, Uttar Pradesh, India
Received 3 August 2006; revised 6 October 2006; accepted 19 October 2006
Available online 9 November 2006
Abstract—Trifluoroacetic acid has been discovered to be a highly effective and efficient reagent for the tandem Claisen rearrangement and
cyclization reaction to yield 3-arylmethylene-3,4-dihydro-1H-quinolin-2-ones from compounds obtained from the SN2 reaction between
anilines and acetyl derivatives of Baylis–Hillman adducts of acrylates in the presence of DABCO. In contrast, similar compounds obtained
from the acetyl derivatives of Baylis–Hillman adduct of acrylonitrile on treatment with trifluoroacetic acid directly furnish 3-arylmethyl-2-
amino-quinoline via tandem Claisen rearrangement, cyclization and isomerization.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
Recently, the compound R207910 (Fig. 1) from Johnson and
Johnson has been described to have significant activity
against the drug sensitive and drug-resistant Mycobacterium
tuberculosis.1 This compound has been reported to elicit the
anti-tubercular activity via a novel mechanistic pathway.2
Figure 1. Structure of 207910.
The starting substrate for the synthesis of compound
R207910, i.e., 3-arylmethyl-2-chloro-quinoline, is afforded
by the reaction between aniline and substituted benzenepro-
were unsuccessful in obtaining quinoline derivatives when
pionyl chloride followed by heating of the product with
POCl3.3 During our studies toward the exploitation of Bay-
the aniline substrate containing the electron-donating groups
such as methoxy or methyl was used. Gratifyingly we
lis–Hillman chemistry for achieving the synthesis of valued
have discovered that in the presence of TFA, the Claisen
intermediates, it occurred to us that 3-arylmethyl-2-chloro-
rearrangement proceeds smoothly irrespective of the nature
quinolines can be readily synthesized from Baylis–Hillman
of functional groups present in the aniline and can be
adducts. Indeed recently, Kim et al. have described elegant
performed on large scales. The subsequent isomerization
was accomplished in the presence of potassium carbonate
synthesis of 3-arylmethylene-3,4-dihydro-1H-quinolin-2-
one, the precursor for 3-arylmethyl-2-chloro-quinoline,
in acetone. Interestingly the use of these reagents eliminates
from the acetates of Baylis–Hillman adducts via PPA-medi-
ated Claisen rearrangement.4 Although, the yields reported
the need for column chromatography. We describe herein
our results on the efficient synthesis of 3-arylmethylene-
3,4-dihydro-1H-quinolin-2-one and 3-arylmethyl-2-amino-
quinolines.
for the sequence were high, problems in handling PPA, par-
ticularly on large scale runs, prompted the development of
a more convenient yet efficient route. Besides, Kim et al.
*
CDRI communication no. 7071.
Keywords: Baylis–Hillman; TFA; Claisen rearrangement; 3-Arylmethyl-
3,4-dihydro-1H-quinolin-2-one; 3-Arylmethyl-2-amino-quinoline.
* Corresponding author. Tel.: +91 522 2262411–18x4368; fax: +91 522
2623405/938; e-mail: batra_san@yahoo.co.uk
2. Results and discussion
Synthesis of the title compound is outlined in Scheme 1. In
the initial step the Baylis–Hillman adducts 1 from several
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.10.053

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R. Pathak et al. / Tetrahedron 63 (2007) 451–460
Scheme 1. Reagents and conditions: (a) AcCl, pyridine, CH2Cl2, rt, 3 h; (b) substituted anilines, DABCO, THF/H2O (1:1), rt, 3 h; (c) TFA, 60 ꢀC, 8–14 h;
(d) K2CO3, acetone, 60 ꢀC, 10–15 min; (e) POCl3, toluene, 120 ꢀC, 30 min; (f) NaOMe, MeOH, reflux, 15 min. (For R and R1 refer to Table 1.)
aldehydes were prepared via DABCO-promoted Baylis–
Hillman reactions in the absence of solvent. These adducts
were acetylated with acetyl chloride in the presence of
pyridine in dichloromethane to yield the acetates 2. Nucleo-
philic substitution on the acetyl derivatives with anilines in
the presence of DABCO led to products 3 in 3 h. Treatment
of compounds 3 with neat trifluoroacetic acid at reflux
temperature for 8–14 h yielded the 3-arylmethylene-3,4-
dihydro-1H-quinolin-2-one in good yields. The workup pro-
cedure was simple since the evaporation of TFA in vacuo
followed by treatment of the residue with saturated sodium
bicarbonate gave the products as solids without the need
for column chromatography. Subsequent treatment of a few
of these compounds with potassium carbonate in acetone at
reflux temperature for 10–15 min furnished the isomerized
quinolines in almost quantitative yields. During the study
several compounds with different ester group were exam-
ined and this reaction sequence was found to be general in
nature as evident from Table 1. Even the anilines containing
methyl or methoxy substitution undergo this reaction, though
the yields of the resulting quinolinones were slightly lower.
At this stage it occurred to us that a one-pot procedure for
the generation of 3-arylmethyl-1H-quinolin-2-one might be
possible. Accordingly, in a representative reaction instead
of treating the reaction mixture obtained after TFA-pro-
moted Claisen rearrangement with sodium bicarbonate, the
residue was taken up in acetone and to it was added excess
of potassium carbonate and the mixture was heated at reflux
temperature for 10 min. Filtration of the inorganic salts
followed by evaporation of excess solvent furnished the
pure products as solids. However, the overall yield afforded
through this one-pot method was significantly less than that
obtained during two-step procedure. Treatment of 3-aryl-
methyl-1H-quinolin-2-one 5 with POCl3 yielded the 3-aryl-
methyl-2-chloro-quinolines in excellent yield. During this
investigation we found that the treatment of 3-arylmethy-
lene-3,4-dihydro-1H-quinolin-2-ones 4 with POCl3 led to
a tandem isomerization and chlorination though here also
the yields were less than the two-step process. Unlike the lit-
erature report,3 the reaction of 3-arylmethyl-2-chloro-quino-
lines with sodium methoxide was complete within 15 min to
yield the 3-arylmethyl-2-methoxy-quinolines 7–9 in excel-
lent yield, compound 7 being the starting substrate for
207910.
Table 1. Structure and yields of quinolines produced according to Scheme 1
Entry
R1
R
R
R
R1
R1
R1
HN
N
O
N
H
O
EWG
N
Cl
H
R
6
5
4
3
R
R1
EWG
Yield
R
R1
Yield
R
R1
H
Yield
99
R
R1
Yield
1
2
3
4
5
6
7
8
C6H5
H
H
H
4-Cl
4-Cl
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
85
80
82
76
81
80
77
77
86
64
85
65
55
C6H5
H
H
H
6-Cl
6-Cl
88
71
80
88
79
85
93
70
76
79
36
C6H5
C6H5
(2-Cl)C6H4
(4-Br)C6H4
H
H
H
66a
71a
85a
(2-Cl)C6H4
(4-Br)C6H4
C6H5
(2-F)C6H4
(4-Br)C6H4 4-Cl
C6H5 4-F
(2-Cl)C6H4 4-F
(4-Br)C6H4 4-F
C6H5
C6H5
C6H5
Pyrid-2-yl
C6H5
(2-Cl)C6H4 4-Cl
(2-F)C6H4
(2-F)C6H4
(2-F)C6H4
(2-F)C6H4
(2-F)C6H4
(2-Cl)C6H4
(4-Br)C6H4
C6H5
(2-F)C6H4
(4-Br)C6H4 6-Cl
C6H5 6-F
(2-Cl)C6H4 6-F
(4-Br)C6H4 6-F
C6H5
C6H5
C6H5
Pyridy-2-yl 6-F
C6H5
(2-Cl)C6H4 6-Cl
(2-F)C6H4
6-Cl 100
(2-F)C6H4 6-Cl 97
(4-Br)C6H4 6-Cl 82
(2-Cl)C6H4 6-F
(4-Br)C6H4 6-F
C6H5
(2-Cl)C6H4 6-F
(4-Br)C6H4 6-F
C6H5
68a
89
9
100
6-Br 100
10
11
12
13
14
15
16
17
18
19
20
4-Br
2-Me
6-Br
8-Me
5,6,7-(OMe)3 63
6-Br 97
3,4,5-(OMe)3 CO2Et
4-F
4-Me
CO2Et
68
78
70
73
53
85
85
77
CO2Me 86
CO2Me 82
CO2Me 88
CO2But 86
CO2But 81
CO2But 81
CO2But 63
6-Me
C6H5 6-Me 100
(2-Cl)C6H4 6-Cl 100
(2-F)C6H4
H
H
(2-F)C6H4
(2-F)C6H4
(2-F)C6H4
(2-F)C6H4
(2-F)C6H4
H
H
H
100
4-Cl
4-F
4-OMe
6-Cl
6-F
6-OMe
(2-F)C6H4
6-F
100
(2-F)C6H4
6-F
81
a
Yields of product directly obtained from compound 4.

R. Pathak et al. / Tetrahedron 63 (2007) 451–460
453
Having demonstrated the utility of TFA for Claisen rear-
4.2. General procedure for the preparation
of compounds 3 and 12
rangement for the Baylis–Hillman derivatives of acrylates,
we turned our attention to compounds 12 derived from acryl-
onitrile. It was envisaged that herein the Claisen rearrange-
ment would lead to an intermediate with a free aromatic
amino group, which may then attack the cyano group to yield
2-amino quinoline derivatives in a single step. Hence com-
pounds 12 were prepared via the reaction of substituted an-
ilines with the acetates 11 (Scheme 2). Unlike compounds 2,
the nucleophilic substitution reaction takes more than 48 h
for completion. Similar treatment of these compounds 12
with TFA led to isolation of a product, which was established
to be 2-amino-3-benzyl-quinoline 13 on the basis of spectral
analysis. It was interesting to note here that the Claisen rear-
rangement, cyclization and isomerization occurred in one
step. This reaction was found to be general in nature.
To a stirred solution of the required acetate (4.0 mmol)
(1.0 equiv) in THF/H2O (10 mL, 50:50, v/v) was added
DABCO (6.0 mmol) (1.5 equiv) at room temperature. After
15 min the appropriate aniline (4.8 mmol) was added to the
reaction and it was continued for 3 h (48 h when EWG is
CN). The solvent was removed in vacuo and the residue
was extracted with ethyl acetate (3ꢁ50 mL) and water
(70 mL). The organic fractions were combined, washed
with brine (50 mL), dried (Na2SO4), and evaporated to yield
the crude product, which was purified via silica gel column
chromatography using hexanes/ethyl acetate (90–85:10–15,
v/v) to afford pure compounds.
4.2.1. 2-(Phenyl-phenylamino-methyl)-acrylic acid ethyl
ester (Table 1, 3, entry 1). Yield: 0.57 g, 85%, as a brown
oil; Rf (20% EtOAc/hexane): 0.65; nmax (Neat): 1712
(CO), 3402 (NH) cmꢂ1 1H NMR (200 MHz, CDCl3):
;
d 1.21 (t, 3H, J¼7.1 Hz, CH3), 4.15 (q, 2H, J¼7.1 Hz,
CO2CH2), 5.41 (s, 1H, CH), 5.94 (s, 1H, ]CH2), 6.39 (s,
1H, ]CH2), 6.58 (d, 2H, J¼7.6 Hz, ArH), 6.72 (t, 1H,
J¼7.3 Hz, ArH), 7.16 (t, 2H, J¼7.4 Hz, ArH), 7.25–7.36
(m, 5H, ArH); mass (ES+): m/z 281.9 (M++1). Anal. Calcd.
for C18H19NO2 requires: C, 76.84; H, 6.81; N, 4.98. Found:
C, 76.65; H, 6.71; N, 5.09.
Scheme 2. Reagents and conditions: (a) AcCl, pyridine, rt, 3 h; (b)
substituted aniline, DABCO, THF/H2O (1:1), rt, 48 h; (c) TFA, reflux,
24 h. (For key to R and R1 refer to Table 2.)
Table 2. Structure and yields of quinolines produced according to Scheme 2
4.2.2. 2-[(2-Chlorophenyl)-phenylamino-methyl]-acrylic
acid ethyl ester (Table 1, 3, entry 2). Yield: 0.90 g, 80%,
as a white solid; mp 107–109 ꢀC; Rf (20% EtOAc/hexane):
Entry
R1
R
R1
HN
1
0.48; nmax (KBr): 1699 (CO), 3382 (NH) cmꢂ1; H NMR
CN
12
N
NH2
R
(200 MHz, CDCl3): d 1.21 (t, 3H, J¼7.2 Hz, CH3), 4.17
(q, 2H, J¼7.2 Hz, CO2CH2), 5.78 (s, 1H, CH), 5.85 (s, 1H,
]CH2), 6.42 (s, 1H, ]CH2), 6.55–6.59 (m, 2H, ArH),
6.68–6.75 (m, 1H, ArH), 7.11–7.23 (m, 4H, ArH), 7.37–
7.41 (m, 2H, ArH); 13C NMR (50 MHz, CDCl3): d 14.5,
55.9, 61.4, 113.7, 118.5, 127.5, 127.6, 128.8, 129.4, 129.6,
130.4, 134.5, 138.5, 140.3, 147.0, 166.5; mass (ES+):
m/z 316.0 (M++1). Anal. Calcd. for C18H18ClNO2
requires: C, 68.46; H, 5.75; N, 4.44. Found: C, 68.11; H,
5.96; N, 4.49.
13
R
R1
Yield
R
R1
Yield
1
2
3
4
C6H5
4-Cl 82
4-Cl 68
C6H5
2-F-C6H4
2,4-(Cl)2-C6H3 46
2,4-(Cl)2-C6H3 6-Cl 53
6-Cl 28
6-Cl 48
H
2-F-C6H4
2,4-(Cl)2-C6H3
2,4-(Cl)2-C6H3 4-Cl 62
H
73
3. Conclusions
4.2.3. 2-[(4-Bromophenyl)-phenylamino-methyl]-acrylic
acid ethyl ester (Table 1, 3, entry 3). Yield: 1.81 g, 82%,
as a brown oil; Rf (20% EtOAc/hexane): 0.5; nmax (Neat):
In summary we have demonstrated that trifluoroacetic acid
is an effective and efficient reagent for the synthesis of
3-arylmethylene-3,4-dihydro-1H-quinolin-2-onesand3-aryl-
methyl-2-amino-quinolines from the derivatives of Baylis–
Hillman adducts via tandem Claisen rearrangement followed
by cyclization.
1747 (CO), 3398 (NH) cmꢂ1
;
1H NMR (300 MHz,
CDCl3): d 1.25 (t, 3H, J¼7.2 Hz, CH3), 4.18 (q, 2H,
J¼7.2 Hz, CO2CH2), 5.39 (s, 1H, CH), 5.92 (s, 1H,
]CH2), 6.40 (s, 1H, ]CH2), 6.59 (d, 2H, J¼7.8 Hz,
ArH), 6.75 (d, 2H, J¼7.3 Hz, ArH), 7.18 (d, 2H,
J¼7.6 Hz, ArH), 7.28 (d, 2H, J¼3.9 Hz, ArH), 7.48 (d,
2H, J¼8.5 Hz, ArH); mass (ES+): m/z 359.9 (M++1), 361.9
(M++3). Anal. Calcd. for C18H18BrNO2 requires: C, 60.01;
H, 5.04; N, 3.89. Found: C, 60.08; H, 4.89; N, 3.90.
4. Experimental
4.1. General
Melting points were recorded on a hot stage melting point
apparatus and are uncorrected. The IR spectra were recorded
on a FTIR spectrophotometer. The 1H and 13C NMR spectra
were recorded on 200 MHz or 300 MHz spectrometer using
TMS as internal standard. The mass spectra were recorded as
FAB or LCMS having ES probe. The HRMS spectra were
recorded as EI-HRMS.
4.2.4. 2-[(4-Chloro-phenylamino)-phenyl-methyl]-acrylic
acid ethyl ester (Table 1, 3, entry 4). Yield: 1.45 g 76%, as
a light yellow oil; Rf (15% EtOAc/hexane): 0.42; nmax (Neat):
1715 (CO), 3413 (NH) cmꢂ1; 1H NMR (200 MHz, CDCl3):
d 1.21 (t, 3H, J¼7.1 Hz, CH3), 4.15 (q, 2H, J¼7.1 Hz,
CO2CH2), 5.36 (s, 1H, CH), 5.89 (s, 1H, ]CH2), 6.38
(s, 1H, ]CH2), 6.49 (d, 2H, J¼4.6 Hz, ArH), 7.10 (d, 2H,

454
R. Pathak et al. / Tetrahedron 63 (2007) 451–460
J¼4.6 Hz, ArH), 7.28–7.37 (m, 5H, ArH); 13C NMR
(75 MHz, CDCl3): d 12.8, 57.8, 59.6, 113.3, 121.2, 124.8,
126.2, 126.6, 127.5, 127.7, 138.8, 139.0, 144.0, 164.8;
mass (ES+): m/z 316.0 (M++1). Anal. Calcd. for
C18H18ClNO2 requires: C, 68.46; H, 5.75; N, 4.44. Found:
C, 68.60; H, 5.66; N, 4.30.
Yield: 1.9 g, 86%, as a brown oil; Rf (20% EtOAc/hexane):
1
0.53; nmax (Neat): 1707 (CO), 3419 (NH) cmꢂ1; H NMR
(200 MHz, CDCl3): d 1.25 (t, 3H, J¼7.1 Hz, CH3), 4.18
(q, 2H, J¼7.1 Hz, CH2), 5.31 (s, 1H, CH), 5.90 (s, 1H,
]CH2), 6.40 (s, 1H, ]CH2), 6.49–6.54 (m, 2H, ArH),
6.88 (t, 2H, J¼6.4 Hz, ArH), 7.27 (d, 2H, J¼7.3 Hz, ArH),
7.48 (d, 2H, J¼6.6 Hz, ArH); mass (ES+): m/z 377.9
(M++1), 379.9 (M++3); HR-EIMS calculated for
C18H17BrFNO2: 377.0427. Found: 377.0431.
4.2.5. 2-[(4-Chloro-phenylamino)-(2-fluorophenyl)-
methyl]-acrylic acid ethyl ester (Table 1, 3, entry 5).
Yield: 1.0 g, 81%, as a brown oil; Rf (15% EtOAc/hexane):
1
0.53; nmax (Neat): 1721 (CO), 3433 (NH) cmꢂ1; H NMR
4.2.10. 2-[(4-Bromo-phenylamino)-phenyl-methyl]-
acrylic acid ethyl ester (Table 1, 3, entry 10). Yield:
1.50 g, 75%, as a light yellow oil; Rf (20% EtOAc/hexane):
(200 MHz, CDCl3): d 1.21 (t, 3H, J¼7.2 Hz, CH3), 4.20
(q, 2H, J¼7.2 Hz, CO2CH2), 4.27 (br s, 1H, NH), 5.67 (s,
1H, CH), 5.84 (s, 1H, ]CH2), 6.40 (s, 1H, ]CH2), 6.50
(d, 2H, J¼6.6 Hz, ArH), 7.05–7.14 (m, 4H, ArH), 7.23–
7.33 (m, 2H, ArH); mass (ES+): m/z 333.9 (M++1), 335.9
(M++3); HR-EIMS calculated for C18H17ClFNO2:
333.0932. Found: 333.0924.
1
0.8; nmax (Neat): 1709 (CO), 3398 (NH) cmꢂ1; H NMR
(300 MHz, CDCl3): d 1.23 (t, 3H, J¼7.1 Hz, CH3), 4.17
(q, 2H, J¼7.1 Hz, CO2CH2), 5.38 (s, 1H, CH), 5.92 (s, 1H,
]CH2), 6.40 (s, 1H, ]CH2), 6.46–6.50 (m, 2H, ArH),
7.23–7.26 (m, 3H, ArH), 7.28–7.32 (m, 4H, ArH); 13C
NMR (50 MHz, CDCl3): d 13.0, 58.0, 59.9, 108.5, 114.0,
125.0, 126.4, 126.9, 127.7, 128.7, 130.8, 139.0, 139.2,
144.7, 165.0; mass (ES+): m/z 359.9 (M++1), 361.9
(M++3); HR-EIMS calculated for C18H18BrNO2:
359.0521. Found: 359.0527.
4.2.6. 2-[(4-Bromophenyl)-(4-chloro-phenylamino)-
methyl]-acrylic acid ethyl ester (Table 1, 3, entry 6).
Yield: 1.2 g, 80%, as a brown oil; Rf (20% EtOAc/hexane):
1
0.70; nmax (Neat): 1710 (CO), 3421 (NH) cmꢂ1; H NMR
(200 MHz, CDCl3): d 1.24 (t, 3H, J¼7.2 Hz, CH2CH3),
4.16 (q, 2H, J¼7.2 Hz, CH2CH3), 5.35 (s, 1H, CH), 5.87
(s, 1H, ]CH2), 6.39 (s, 1H, ]CH2), 6.48 (d, 2H,
J¼8.9 Hz, ArH), 7.10 (d, 2H, J¼8.8 Hz, ArH), 7.24 (d,
2H, J¼8.5 Hz, ArH), 7.47 (d, 2H, J¼8.5 Hz, ArH); mass
(ES+): m/z 393.9 (M++1), 395.9 (M++3). Anal. Calcd. for
C18H17BrClNO2 requires: C, 54.78; H, 4.34; N, 3.55. Found:
C, 54.71; H, 4.38; N, 3.59.
4.2.11. 2-(Phenyl-o-tolylamino-methyl)-acrylic acid ethyl
ester (Table 1, 3, entry 11). Yield: 0.4 g, 85%, as brown oil;
Rf (20% EtOAc/hexane): 0.66; nmax (Neat): 1705 (CO), 3429
1
(NH) cmꢂ1; H NMR (200 MHz, CDCl3): d 1.21 (t, 3H,
J¼7.2 Hz, CH3), 2.15 (s, 3H, CH3), 4.04–4.20 (q merged
with br s, 3H, CO2CH2, and NH), 5.47 (s, 1H, CH), 5.90
(s, 1H, ]CH2), 6.38 (s, 1H, ]CH2), 6.50 (d, 1H,
J¼8.2 Hz, ArH), 6.71 (t, 1H, J¼7.0 Hz, ArH), 7.06 (d,
2H, J¼7.1 Hz), 7.31–7.38 (m, 5H, ArH); mass (ES+):
m/z 296.0 (M++1). Anal. Calcd. for C19H21NO2
requires: C, 77.26; H, 7.17; N, 4.74. Found: C, 77.14; H,
7.26; N, 4.91.
4.2.7. 2-[(4-Fluoro-phenylamino)-phenyl-methyl]-acrylic
acid ethyl ester (Table 1, 3, entry 7). Yield: 1.12 g, 77%, as
a brown oil; Rf (20% EtOAc/hexane): 0.58; nmax (Neat):
1712 (CO), 3401 (NH) cmꢂ1
;
1H NMR (300 MHz,
CDCl3): d 1.24 (t, 3H, J¼7.1 Hz, CH3), 4.17 (q, 2H,
J¼7.1 Hz, CO2CH2), 5.36 (s, 1H, CH), 5.92 (t, 1H,
J¼1.0 Hz, ]CH2), 6.40 (s, 1H, ]CH2), 6.51–6.56 (m,
2H, ArH), 6.88 (t, 2H, J¼8.6 Hz, ArH), 7.30–7.40 (m, 5H,
ArH); 13C NMR (50 MHz, CDCl3): d 14.4, 60.0, 61.3,
114.7, 114.8, 115.8, 116.2, 126.4, 127.9, 128.2, 129.1,
140.8, 141.0, 143.5, 154.1, 158.8, 166.6; mass (ES+): m/z
299.9 (M++1); HR-EIMS calculated for C18H18FNO2:
299.1322. Found: 299.1328.
4.2.12. 2-[Phenyl-(3,4,5-trimethoxy-phenylamino)-
methyl]-acrylic acid ethyl ester (Table 1, 3, entry 12).
Yield: 1.95 g, 65%, as a brown oil; Rf (20% EtOAc/hexane):
1
0.41; nmax (Neat): 1713 (CO), 3383 (NH) cmꢂ1; H NMR
(300 MHz, CDCl3): d 1.24 (t, 3H, J¼7.1 Hz, CH3), 3.77
(s, 3H, OCH3), 3.78 (s, 6H, 2ꢁOCH3), 4.17 (q, 2H,
J¼3.9 Hz, CO2CH2), 5.40 (s, 1H, CH), 5.85 (s, 2H, ArH),
5.97 (s, 1H, ]CH2), 6.41 (s, 1H, ]CH2), 7.28–7.38 (m,
5H, ArH); 13C NMR (CDCl3, 75 MHz): d 12.8, 54.6, 58.1,
59.6, 59.8, 89.9, 124.7, 126.1, 126.5, 127.5, 129.1, 139.3,
139.4, 142.3, 152.5, 165.0; mass (ES+): m/z 371.9 (M++1).
Anal. Calcd. for C21H25NO5 requires: C, 67.91; H, 6.78;
N, 3.77. Found: C, 68.12; H, 6.89; N, 3.59.
4.2.8. 2-[(2-Chlorophenyl)-(4-fluoro-phenylamino)-
methyl]-acrylic acid ethyl ester (Table 1, 3, entry 8).
Yield: 0.68 g, 77%, as a brown oil; Rf (20% EtOAc/hexane):
1
0.58; nmax (Neat): 1714 (CO), 3400 (NH) cmꢂ1; H NMR
(300 MHz, CDCl3): d 1.24 (t, 3H, J¼7.2 Hz, CH3), 4.13
(br s, 1H, NH), 4.20 (q, 2H, J¼7.2 Hz, CO2CH2), 5.78 (s,
1H, CH), 5.81 (s, 1H, ]CH2), 6.45 (s, 1H, ]CH2), 6.49–
6.55 (m, 2H, ArH), 6.85–6.90 (m, 2H, ArH), 7.23–7.28
(m, 2H, ArH), 7.39–7.45 (m, 2H, ArH); 13C NMR
(75 MHz, CDCl3): d 12.7, 54.8, 59.7, 112.9, 114.2, 114.5,
125.8, 126.0, 127.0, 127.7, 128.7, 132.8, 136.6, 138.5,
141.7, 153.3, 156.4, 164.7; mass (ES+): m/z 334.1 (M++1);
HR-EIMS calculated for C18H17ClFNO2: 333.0932. Found:
333.0930.
4.2.13. 2-[(4-Fluoro-phenylamino)-pyridin-3-yl-methyl]-
acrylic acid ethyl ester (Table 1, 3, entry 13). Yield:
1.38 g, 55%, as a brown oil; Rf (30% EtOAc/hexane):
1
0.54; nmax (Neat): 1707 (CO), 3407 (NH) cmꢂ1; H NMR
(200 MHz, CDCl3): d 1.23 (t, 3H, J¼7.1 Hz, CH3), 4.16
(q, 2H, J¼7.1 Hz, CH2), 5.37 (d, 1H, J¼3.7 Hz, CH), 5.95
(s, 1H, ]CH2), 6.44 (s, 1H, ]CH2), 6.49–6.56 (m, 2H,
ArH), 6.88 (t, 2H, J¼8.7 Hz, ArH), 7.29–7.32 (m, 1H,
ArH), 7.71 (d, 1H, J¼7.8 Hz, ArH), 8.55 (d, 1H,
J¼3.9 Hz, ArH), 8.65 (s, 1H, ArH); mass (ES+): m/z 301.1
(M++1); HR-EIMS calculated for C17H17FN2O2:
300.1274. Found: 300.1266.
4.2.9. 2-[(4-Bromophenyl)-(4-fluoro-phenylamino)-
methyl]-acrylic acid ethyl ester (Table 1, 3, entry 9).

R. Pathak et al. / Tetrahedron 63 (2007) 451–460
455
4.2.14. 2-(Phenyl-p-tolylamino-methyl)-acrylic acid
methyl ester (Table 1, 3, entry 14). Yield: 3.1 g, 86%, as
a brown oil; Rf (20% EtOAc/hexane): 0.69; nmax (Neat):
128.2, 139.6, 143.9, 157.6, 160.9, 163.9; mass (ES+): m/z
361.9 (M++1); HR-EIMS calculated for C20H21ClFNO2:
361.1245. Found: 361.1243.
1719 (CO), 3402 (NH) cmꢂ1
;
1H NMR (200 MHz,
CDCl3): d 2.23 (s, 3H, CH3), 3.70 (s, 3H, CH3), 4.04 (br s,
1H, NH), 5.37 (s, 1H, CH), 5.97 (s, 1H, ]CH2), 6.38 (s,
1H, ]CH2), 6.50 (d, 2H, J¼8.4 Hz, ArH), 6.97 (d, 2H,
J¼8.4 Hz, ArH), 7.26–7.39 (m, 5H, ArH); mass (ES+): m/z
282.2 (M++1). Anal. Calcd. for C18H19NO2 requires: C,
76.84; H, 6.81; N, 4.98. Found: C, 76.60; H, 6.75; N, 5.10.
4.2.19. 2-[(2-Fluorophenyl)-(4-fluoro-phenylamino)-
methyl]-acrylic acid tert-butyl ester (Table 1, 3, entry
19). Yield: 2.1 g, 81%, as a yellow solid; mp 82–84 ꢀC; Rf
(15% EtOAc/hexane): 0.74; nmax (KBr): 1696 (CO), 3398
1
(NH) cmꢂ1; H NMR (CDCl3, 300 MHz): d 1.40 (s, 9H,
3ꢁCH3), 5.64 (s, 1H, CH), 5.77 (s, 1H, ]CH2), 6.34 (s,
1H, ]CH2), 6.54–6.57 (m, 2H, ArH), 6.85–6.91 (m, 2H,
ArH), 7.05–7.15 (m, 2H, ArH), 7.25–7.38 (m, 2H, ArH);
13C NMR (75 MHz, CDCl3): d 26.6, 51.7, 80.2, 112.9,
113.0, 114.2, 114.5, 123.0, 124.3, 126.7, 127.2, 128.1, 139.8,
141.7, 153.2, 156.4, 157.6, 160.9, 164.0; mass (ES+): m/z
345.9 (M++1); HR-EIMS calculated for C20H21F2NO2:
345.1540. Found: 345.1544.
4.2.15. 2-[(2-Chlorophenyl)-(4-chloro-phenylamino)-
methyl]-acrylic acid methyl ester (Table 1, 3, entry 15).
Yield: 1.90 g, 82%, as a brown oil; Rf (20% EtOAc/hexane):
1
0.70; nmax (Neat): 1718 (CO), 3408 (NH) cmꢂ1; H NMR
(300 MHz, CDCl3): d 3.76 (s, 3H, CH3), 4.21 (br s, 1H,
NH), 5.78 (s, 1H, ]CH2), 5.81 (d, 1H, J¼5.2 Hz, CH),
6.44 (s, 1H, ]CH2), 6.50 (d, 2H, J¼8.8 Hz, ArH), 7.10 (d,
2H, J¼8.8 Hz, ArH), 7.22–7.28 (m, 2H, ArH), 7.36–7.46
(m, 2H, ArH); 13C NMR (75 MHz, CDCl3): d 50.9, 54.3,
113.12, 121.4, 125.8, 126.4, 126.9, 127.8, 128.8, 132.8,
136.1, 138.0, 143.8, 165.1; mass (ES+): m/z 335.9 (M++1),
337.9 (M++3). Anal. Calcd. for C17H15Cl2NO2 requires: C,
60.73; H, 4.50; N, 4.17. Found: C, 60.50; H, 4.66; N, 3.98.
4.2.20. 2-[(2-Fluorophenyl)-(4-methoxy-phenylamino)-
methyl)]-acrylic acid tert-butyl ester (Table 1, 3, entry
20). Yield: 1.10 g, 63%, as a brown oil; Rf (20% EtOAc/hex-
1
ane): 0.71; nmax (Neat): 1711 (CO), 3419 (NH) cmꢂ1; H
NMR (300 MHz, CDCl3): d 1.39 (s, 9H, 3ꢁCH3), 3.75 (s,
3H, OCH3), 5.63 (s, 1H, CH), 5.79 (s, 1H, ]CH2), 6.33
(s, 1H, ]CH2), 6.58 (d, 2H, J¼8.9 Hz, ArH), 6.77 (d, 2H,
J¼8.9 Hz, ArH), 7.06–7.15 (m, 2H, ArH), 7.23–7.41 (m,
2H, ArH); mass (ES+): m/z 358.9 (M++1). Anal. Calcd. for
C21H24FNO3 requires: C, 70.57; H, 6.77; N, 3.92. Found:
C, 70.48; H, 6.59; N, 4.11.
4.2.16. 2-[(2-Fluorophenyl)-phenylamino-methyl]-acrylic
acid methyl ester (Table 1, 3, entry 16). Yield: 1.50 g, 88%,
as a white solid; mp 89–91 ꢀC; Rf (20% EtOAc/hexane):
1
0.54; nmax (KBr): 1709 (CO), 3403 (NH) cmꢂ1; H NMR
(300 MHz, CDCl3): d 3.76 (s, 3H, CH3), 4.32 (br s, 1H,
NH), 5.83 (s, 1H, CH), 5.96 (s, 1H, ]CH2), 6.46 (s, 1H,
]CH2), 6.64–6.67 (m, 2H, ArH), 6.75–6.80 (m, 1H,
ArH), 7.08–7.23 (m, 4H, ArH), 7.27–7.35 (m, 1H, ArH),
7.39–7.45 (m, 1H, ArH); 13C NMR (75 MHz, CDCl3):
d 50.7, 51.2, 112.2, 114.4, 114.7, 116.9, 123.1, 125.6, 126.3,
127.4, 128.0, 128.2, 138.2, 145.2, 157.7, 161.2, 165.2; mass
(ES+): m/z 286.0 (M++1); HR-EIMS calculated for
C17H16FNO2: 285.1165. Found: 285.1158.
4.2.21. 2-[(4-Chloro-phenylamino)-phenyl-methyl]-acryl-
onitrile (Table 2, 12, entry 1). Yield: 1.45 g, 82%, as
a brown oil; Rf (20% EtOAc/hexane): 0.56; nmax (Neat):
2225 (CN), 3391 (NH) cmꢂ1
;
1H NMR (300 MHz,
CDCl3): d 4.15 (d, 1H, J¼3.9 Hz, NH) 5.02 (d, 1H,
J¼5.1 Hz, CH), 6.11 (s, 1H, ]CH2), 6.15 (s, 1H, ]CH2),
6.56 (d, 2H, J¼8.8 Hz, ArH), 7.17 (d, 2H, J¼8.8 Hz,
ArH), 7.42–7.48 (m, 5H, ArH); 13C NMR (75 MHz,
CDCl3): d 60.2, 113.5, 115.0, 116.0, 122.4, 122.8, 126.0,
127.7, 127.8, 128.1, 129.8, 136.5, 143.0; mass (ES+): m/z
268.0 (M+). Anal. Calcd. for C16H13ClN2 requires: C,
71.51; H, 4.88; N, 10.42. Found: C, 71.77; H, 5.02; N, 10.61.
4.2.17. 2-[(2-Fluorophenyl)-phenylamino-methyl]-acrylic
acid tert-butyl ester (Table 1, 3, entry 17). Yield: 2.4 g,
86%, as a white solid; mp 85–87 ꢀC; Rf (15% EtOAc/hex-
1
ane): 0.72; nmax (KBr): 1699 (CO), 3401 (NH) cmꢂ1; H
NMR (300 MHz, CDCl3): d 1.40 (s, 9H, 3ꢁCH3), 5.73 (s,
1H, CH), 5.81 (s, 1H, ]CH2), 6.35 (s, 1H, ]CH2), 6.63
(d, 2H, J¼7.7 Hz, ArH), 6.75 (t, 1H, J¼7.3 Hz), 7.06–7.22
(m, 4H, ArH), 7.26–7.33 (m, 2H, ArH); 13C NMR (CDCl3,
75 MHz): d 26.6, 51.1, 80.1, 112.1, 114.2, 114.5, 116.7,
123.0, 124.3, 126.7, 126.9, 127.9, 128.1, 139.9, 145.4,
157.6, 160.9, 164.0; mass (ES+): m/z 327.9 (M++1); HR-
EIMS calculated for C20H22FNO2: 327.1635. Found:
327.1644.
4.2.22. 2-[(4-Chloro-phenylamino)-(2-fluorophenyl)-
methyl]-acrylonitrile (Table 2, 12, entry 2). Yield: 1.1 g,
68%, as a brown oil; Rf (20% EtOAc/hexane): 0.51; nmax
1
(Neat): 2226 (CN), 3386 (NH) cmꢂ1; H NMR (200 MHz,
CDCl3): d 4.17 (d, 1H, J¼5.8 Hz, NH), 5.35 (d, 1H,
J¼5.8 Hz, CH), 6.08 (s, 1H, ]CH2), 6.13 (s, 1H, ]CH2),
6.57–6.63 (m, 3H, ArH), 7.08–7.19 (m, 3H, ArH), 7.35–
7.39 (m, 2H, ArH); mass (ES+): m/z 287.0 (M++1). Anal.
Calcd. for C16H12ClFN2 requires: C, 67.02; H, 4.22; N,
9.77. Found: C, 66.92; H, 4.09; N, 9.97.
4.2.18. 2-[(4-Chlorophenylamino)-(2-fluorophenyl)-
methyl]-acrylic acid tert-butyl ester (Table 1, 3, entry
18). Yield: 2.0 g, 81%, as a brown solid; mp 102–104 ꢀC;
Rf (15% EtOAc/hexane): 0.76; nmax (KBr): 1700 (CO),
4.2.23. 2-[(2,4-Dichlorophenyl)-phenylamino-methyl]-
acrylonitrile (Table 2, 12, entry 3). Yield: 1.6 g, 73%, as
a brown oil; Rf (20% EtOAc/hexane): 0.5; nmax (Neat):
1
3337 (NH) cmꢂ1; H NMR (300 MHz, CDCl3): d 1.40 (s,
2247 (CN), 3425 (NH) cmꢂ1 1H NMR (200 MHz,
;
9H, 3ꢁCH3), 4.23 (br s, 1H, NH), 5.67 (s, 1H, CH), 5.76
(s, 1H, ]CH2), 6.34 (s, 1H, ]CH2), 6.54 (d, 2H,
J¼8.7 Hz, ArH), 7.06–7.15 (m, 4H, ArH), 7.26–7.36 (m,
2H, ArH); 13C NMR (75 MHz, CDCl3): d 26.6, 51.3, 80.2,
113.0, 114.2, 114.5, 121.3, 123.0, 124.4, 126.5, 127.1, 127.8,
CDCl3): d 4.09 (d, 1H, J¼4.6 Hz, CHNH), 5.49 (d, 1H, J¼
5.0 Hz, CHNH), 6.07 (s, 1H, ]CH2), 6.16 (s, 1H, ]CH2),
6.55 (d, 2H, J¼7.4 Hz, ArH), 6.79 (t, 1H, J¼7.2 Hz, ArH),
7.15–7.32 (m, 3H, ArH), 7.39–7.48 (m, 2H, ArH); mass
(FAB+): m/z 303 (M++1). Anal. Calcd. for C16H12Cl2N2

456
R. Pathak et al. / Tetrahedron 63 (2007) 451–460
requires: C, 63.38; H, 3.99; N, 9.24. Found: C, 63.41; H,
4.19; N, 9.41.
requires: C, 61.17; H, 3.85; N, 4.46. Found: C, 61.15; H,
3.84; N, 4.41.
4.2.24. 2-[(4-Chloro-phenylamino)-(2,4-dichloro-phenyl-
methyl]-acrylonitrile (Table 2, 12, entry 4). Yield: 1.6 g,
62%, as a brown oil; Rf (20% EtOAc/hexane): 0.61; nmax
4.3.4. 3-Benzylidene-6-chloro-3,4-dihydro-1H-quinolin-
2-one (Table 1, 4, entry 4). Yield: 1.2 g, 88%, as a yellow
solid; mp 235–237 ꢀC; Rf (20% EtOAc/hexane): 0.36; nmax
1
1
(Neat): 2223 (CN), 3386 (NH) cmꢂ1; H NMR (200 MHz,
(KBr): 1668 (CO), 3415 (NH) cmꢂ1; H NMR (300 MHz,
CDCl3): d 4.08 (d, 1H, J¼4.8 Hz, NH), 5.01 (d, 1H,
J¼5.2 Hz, CH), 6.12 (s, 1H, ]CH2), 6.14 (s, 1H, ]CH2),
6.48–6.62 (m, 2H, ArH), 6.74–6.80 (m, 3H, ArH), 7.35 (d,
1H, J¼2.6 Hz, ArH), 7.58 (d, 1H, J¼2.6 Hz, ArH); mass
(ES+): m/z 337.2 (M++1), 339.2 (M++1). Anal. Calcd. for
C16H11Cl3N2 requires: C, 56.92; H, 3.28; N, 8.30. Found:
C, 56.94; H, 3.10; N, 8.14.
DMSO-d6): d 4.12 (d, 2H, J¼2.0 Hz, CH2), 6.89–6.92 (m,
1H, ArH), 7.17–7.20 (m, 1H, ArH), 7.30 (s, 1H, ArH),
7.41–7.55 (m, 5H, ArH), 7.65 (s, 1H, ]CH), 10.49 (s, 1H,
NH); mass (ES+): m/z 270.1 (M++1); HR-EIMS calculated
for C16H12ClNO: 269.0607. Found: 269.0595.
4.3.5. 6-Chloro-3-(2-fluorobenzylidene)-3,4-dihydro-1H-
quinolin-2-one (Table 1, 4, entry 5). Yield: 0.81 g, 79%,
as a yellow solid; mp 197–199 ꢀC; Rf (20% EtOAc/hexane):
4.3. General procedure for the preparation of
compounds 4 and 13
1
0.39; nmax (KBr): 1666 (CO), 3428 (NH) cmꢂ1; H NMR
(300 MHz, DMSO-d6): d 3.85 (s, 2H, CH2), 7.11–7.21 (m,
2H, ArH), 7.27–7.34 (m, 3H, ArH), 7.45–7.49 (m, 1H,
ArH), 7.56 (s, 1H, ArH), 7.72 (s, 1H, ]CH), 11.96 (s, 1H,
NH); 13C NMR (75 MHz, DMSO-d6): d 28.0, 114.3,
114.5, 115.8, 119.5, 123.6, 124.9, 125.6, 127.7, 128.6, 130.6,
132.2, 134.8, 135.8, 160.6; mass (ES+): m/z 288.2 (M++1);
HR-EIMS calculated for C16H11ClFNO: 287.0513. Found:
287.0502.
To a vessel containing the appropriate aniline (2.5 mmol)
was added TFA (5 mL) (amount of TFA was kept between
5 and 8 mL for all compounds in the range 1.0–3.0 g) and
the mixture was refluxed for 8–14 h. On completion (moni-
tored by TLC), the reaction mixture was poured into ice cold
water and neutralized with saturated NaHCO3 solution. The
suspension formed was filtered and washed with ethyl ace-
tate to afford the product 4 in 30–94% yield. However, for
compounds 13 the crude product obtained after usual
workup were purified via silica gel column chromatography
using hexane/ethyl acetate (35:65, v/v) as eluent.
4.3.6. 3-(4-Bromobenzylidene)-6-chloro-3,4-dihydro-1H-
quinolin-2-one (Table 1, 4, entry 6). Yield: 0.45 g, 85%, as
a pale yellow solid; mp 240–242 ꢀC; Rf (20% EtOAc/hex-
1
ane): 0.36; nmax (KBr): 1674 (CO), 3408 (NH) cmꢂ1; H
4.3.1. 3-Benzylidene-3,4-dihydro-1H-quinolin-2-one
(Table 1, 4, entry 1). Yield: 1.2 g, 88%, as a white solid; mp
177–179 ꢀC; Rf (25% EtOAc/hexane): 0.42; nmax (KBr):
1669 (CO), 3444 (NH) cmꢂ1; 1H NMR (300 MHz, DMSO-
d6): d 4.08 (s, 2H, CH2), 6.86–6.93 (m, 2H, ArH), 7.09–
7.17 (m, 2H, ArH), 7.36–7.54 (m, 5H, ArH), 7.66 (s,
1H, ]CH), 10.35 (s, 1H, NH); 13C NMR (75 MHz,
DMSO-d6): d 29.1, 114.0, 120.0, 121.2, 126.3, 127.1, 127.2,
127.7, 129.1, 134.3, 134.4, 135.9, 163.2; mass (FAB+): m/z
236 (M++1). Anal. Calcd. for C16H13NO requires: C, 81.68;
H, 5.57; N, 5.95. Found: C, 81.82; H, 5.69; N, 5.63.
NMR (300 MHz, DMSO-d6): d 3.80 (s, 2H, CH2), 7.23–
7.31 (m, 4H, ArH), 7.46–7.49 (m, 2H, ArH), 7.68–7.72
(m, 2H, ]CH, ArH), 11.92 (s, 1H, NH); 13C NMR
(50 MHz, DMSO-d6): d 34.1, 121.8, 121.9, 127.1, 130.3,
130.4, 130.7, 133.2, 133.3, 133.4, 133.8, 135.3, 138.0, 155.1,
158.2; mass (ES+): m/z 349 (M++1). Anal. Calcd. for
C16H11BrClNO requires: C, 55.12; H, 3.18; N, 4.02. Found:
C, 55.10; H, 3.15; N, 4.00.
4.3.7. 3-Benzylidene-6-fluoro-3,4-dihydro-1H-quinolin-
2-one (Table 1, 4, entry 7). Yield: 0.95 g, 93%, as a light
yellow solid; mp 220–222 ꢀC; Rf (25% EtOAc/hexane):
1
4.3.2. 3-(2-Chlorobenzylidene)-3,4-dihydro-1H-quinolin-
2-one (Table 1, 4, entry 2). Yield: 0.48 g, 71%, as a white
solid; mp 196–198 ꢀC; Rf (20% EtOAc/hexane): 0.4; nmax
0.43; nmax (KBr): 1668 (CO), 3433 (NH) cmꢂ1; H NMR
(300 MHz, DMSO-d6): d 4.11 (d, 2H, J¼1.5 Hz, CH2),
6.89–6.98 (m, 2H, ArH), 7.07–7.11 (m, 1H, ArH), 7.38–
7.54 (m, 5H, ArH), 7.65 (t, 1H, J¼2.1 Hz, ]CH), 10.38
(s, 1H, NH); 13C NMR (75 MHz, DMSO-d6): d 29.0,
112.7, 113.0, 113.8, 114.1, 115.1, 121.9, 126.3, 127.8, 129.1,
132.4, 134.1, 134.6, 155.1, 158.2, 162.8; mass (FAB+): m/z
254 (M++1); HR-EIMS calculated for C16H12FNO:
253.0903. Found: 253.0896.
1
(KBr): 1672 (CO), 3428 (NH) cmꢂ1; H NMR (200 MHz,
DMSO-d6): d 3.96 (s, 2H, CH2), 6.88–6.96 (m, 2H, ArH),
7.13–7.23 (m, 2H, ArH), 7.38–7.51 (m, 2H, ArH), 7.57–
7.60 (m, 2H, ArH), 7.67 (s, 1H, ]CH), 10.50 (s, 1H, NH);
mass (ES+): m/z 270.2 (M++1); HR-EIMS calculated for
C16H12ClNO: 269.0607. Found: 269.0604.
4.3.3. 3-(4-Bromobenzylidene)-3,4-dihydro-1H-quinolin-
2-one (Table 1, 4, entry 3). Yield: 1.04 g, 80%, as a pale yel-
low solid; mp 238–240 ꢀC; Rf (20% EtOAc/hexane): 0.38;
4.3.8. 3-(2-Chlorobenzylidene)-6-fluoro-3,4-dihydro-1H-
quinolin-2-one (Table 1, 4, entry 8). Yield: 0.60 g, 70%,
as a white solid; mp 185–187 ꢀC; Rf (25% EtOAc/hexane):
1
nmax (KBr): 1676 (CO), 3407 (NH) cmꢂ1
;
1H NMR
0.37; nmax (KBr): 1674 (CO), 3426 (NH) cmꢂ1; H NMR
(300 MHz, DMSO-d6): d 4.06 (d, 2H, J¼1.8 Hz, CH2),
6.88–6.93 (m, 2H, ArH), 7.10–7.19 (m, 2H, ArH), 7.46–
7.52 (m, 2H, ArH), 7.59 (s, 1H, ]CH), 7.66–7.74 (m, 2H,
ArH), 10.38 (s, 1H, NH); 13C NMR (50 MHz, DMSO-d6):
d 35.4, 120.4, 126.2, 127.5, 127.7, 132.7, 133.7, 134.4,
136.7, 137.1, 137.5, 139.5, 139.9, 142.2, 169.3; mass
(FAB+): m/z 314 (M++1). Anal. Calcd. for C16H12BrNO
(200 MHz, CDCl3): d 3.91 (s, 2H, CH2), 6.80–6.88 (m,
3H, ArH), 7.35 (br s, 3H, ArH), 7.46–7.49 (m, 1H, ArH),
7.93 (s, 1H, ArH), 8.68 (s, 1H, NH); 13C NMR (75 MHz,
DMSO-d6): d 28.8, 112.8, 113.1, 113.7, 114.1, 115.3, 122.0,
126.4, 128.7, 129.5, 130.0, 131.1, 132.4, 155.1, 158.3,
162.6; mass (ES+): m/z 288.2 (M++1); HR-EIMS calculated
for C16H11ClFNO: 287.0513. Found: 287.0514.

R. Pathak et al. / Tetrahedron 63 (2007) 451–460
457
4.3.9. 3-(4-Bromobenzylidene)-6-fluoro-3,4-dihydro-1H-
quinolin-2-one (Table 1, 4, entry 9). Yield: 1.0 g, 76%, as
an off white solid; mp 215–217 ꢀC; Rf (20% EtOAc/hexane):
a yellow solid; mp 215–217 ꢀC; Rf (20% EtOAc/hexane):
1
0.28; nmax (KBr): 1669 (CO), 3431 (NH) cmꢂ1; H NMR
(200 MHz, DMSO-d6): d 2.49 (s, 3H, CH3), 4.04 (s, 2H,
CH2), 6.77 (d, 1H, J¼7.9 Hz, ArH), 6.91–6.97 (t, 2H,
J¼7.8 Hz, ArH), 7.39–7.54 (m, 5H, ArH), 7.61 (s, 1H,
]CH), 10.28 (s, 1H, NH); 13C NMR (75 MHz, DMSO-
d6): d 19.5, 29.1, 98.7, 113.9, 119.8, 126.7, 127.0, 127.3,
127.7, 129.1, 130.1, 133.4, 134.2, 134.3, 163.1; mass
(ES+): m/z 250.2 (M++1). Anal. Calcd. for C17H15NO
requires: C, 81.90; H, 6.06; N, 5.62. Found: C, 82.05;
H, 6.01; N, 5.51.
1
0.39; nmax (KBr): 1670 (CO), 3436 (NH) cmꢂ1; H NMR
(300 MHz, DMSO-d6): d 4.07 (s, 2H, CH2), 6.87–7.01 (m,
2H, ArH), 7.05–7.09 (m, 1H, ArH), 7.22–7.34 (m, 2H,
ArH), 7.45–7.49 (m, 3H, ArH), 7.59 (s, 1H, ]CH), 7.65
(d, 2H, J¼8.3 Hz, ArH), 10.44 (s, 1H, NH); mass (ES+):
m/z 332.1 (M+1), 334.1 (M+1); HR-EIMS calculated for
C16H11BrFNO: 331.0008. Found: 331.0007.
4.3.10. 3-Benzylidene-6-bromo-3,4-dihydro-1H-quino-
lin-2-one (Table 1, 4, entry 10). Yield: 0.52 g, 79%, as
a white solid; mp 221–223 ꢀC; Rf (20% EtOAc/hexane):
4.3.15. 6-Chloro-3-(2-chlorobenzylidene)-3,4-dihydro-
1H-quinolin-2-one (Table 1, 4, entry 15). Yield: 1.40 g,
70%, as a white solid; mp 215–217 ꢀC; Rf (20% EtOAc/hex-
1
0.31; nmax (KBr): 1670 (CO), 3404 (NH) cmꢂ1; H NMR
1
(300 MHz, DMSO-d6): d 3.81 (s, 2H, CH2), 7.15–7.27 (m,
5H, ArH), 7.52–7.56 (m, 1H, ArH), 7.62 (s, 1H, ArH),
7.78 (d, 1H, J¼1.7 Hz, ]CH); 13C NMR (75 MHz,
DMSO-d6): d 39.5, 117.2, 120.8, 125.0, 130.1, 132.3,
132.8, 133.2, 135.9, 138.5, 139.5, 140.9, 143.3, 165.5;
mass (ES+): m/z 314.1 (M++1), 316.1 (M++3); HR-EIMS
calculated for C16H12BrNO: 313.0102. Found: 313.0106.
ane): 0.37; nmax (KBr): 1674 (CO), 3406 (NH) cmꢂ1; H
NMR (300 MHz, CDCl3): d 3.94 (s, 2H, CH2), 7.29–7.34
(m, 4H, ArH), 7.43–7.49 (m, 3H, ArH), 7.69 (d, 1H,
J¼1.7 Hz); 13C NMR (75 MHz, CDCl3): d 37.2, 120.6,
124.3, 129.6, 130.4, 131.2, 132.3, 133.3, 133.4, 135.3,
136.7, 137.3, 139.4, 140.3, 140.5, 165.4; mass (ES+): m/z
304.2 (M++1), 306.2 (M++3). Anal. Calcd. for C16H11Cl2NO
requires: C, 63.18; H, 3.65; N, 4.60. Found: C, 62.93; H,
3.88; N, 4.48.
4.3.11. 3-Benzylidene-8-methyl-3,4-dihydro-1H-quino-
lin-2-one (Table 1, 4, entry 11). Yield: 0.45 g, 36%, as
a pale yellow solid; mp 172–174 ꢀC; Rf (20% EtOAc/
4.3.16. 3-(2-Fluorobenzylidene)-3,4-dihydro-1H-quino-
lin-2-one (Table 1, 4, entry 16). Yield: 0.52 g, 73%, as
a light yellow solid; mp 182–183 ꢀC; Rf (20% EtOAc/hex-
hexane): 0.31; nmax (KBr): 1624 (CO), 3422 (NH) cmꢂ1
;
1H NMR (200 MHz, CDCl3): d 2.28 (s, 3H, CH3), 4.09 (s,
2H, CH2), 6.84–7.00 (m, 3H, ArH), 7.15–7.44 (m, 4H,
ArH), 7.79–7.84 (m, 2H, ]CH, ArH); 13C NMR
(50 MHz, CDCl3): d 17.1, 31.0, 121.5, 123.0, 126.5, 127.5,
128.3, 128.9, 129.4, 130.3, 132.2, 134.7, 135.8, 137.8,
166.1; mass (ES+): m/z 250.2 (M++1). Anal. Calcd. for
C17H15NO requires: C, 81.90; H, 6.06; N, 5.62. Found: C,
81.92; H, 6.08; N, 5.66.
1
ane): 0.31; nmax (KBr): 1667 (CO), 3422 (NH) cmꢂ1; H
NMR (300 MHz, DMSO-d6): d 3.97 (d, 2H, J¼1.4 Hz,
CH2), 6.89–6.94 (m, 2H, ArH), 7.10–7.15 (m, 2H, ArH),
7.29–7.34 (m, 2H, ArH), 7.45–7.47 (m, 1H, ArH), 7.54–
7.62 (m, 2H, ArH and ]CH), 10.38 (s, 1H, NH); 13C
NMR (75 MHz, DMSO-d6): d 29.1, 114.1, 114.7, 115.0,
119.9, 120.9, 123.7, 126.4, 126.5, 127.2, 129.5, 130.0,
135.9, 157.5, 160.8, 162.7; mass (ES+): m/z 254.2 (M++1);
HR-EIMS calculated for C16H12FNO: 253.0903. Found:
253.0902.
4.3.12. 3-Benzylidene-5,6,7-trimethoxy-3,4-dihydro-1H-
quinolin-2-one (Table 1, 4, entry 12). Yield: 0.55 g, 63%,
as a yellow solid; mp 134–136 ꢀC; Rf (20% EtOAc/hexane):
1
0.43; nmax (KBr): 1671 (CO), 3421 (NH) cmꢂ1; H NMR
4.3.17. 6-Fluoro-3-(2-fluorobenzylidene)-3,4-dihydro-
1H-quinolin-2-one (Table 1, 4, entry 19). Yield: 0.8 g
85%, as a white solid; mp 215–217 ꢀC; Rf (20% EtOAc/hex-
(300 MHz, CDCl3): d 3.82 (s, 3H, CH3), 3.85 (s, 3H,
CH3), 3.91 (s, 3H, CH3), 4.01 (d, 2H, J¼2.0 Hz CH2), 6.35
(s, 1H, ArH), 7.36–7.41 (m, 1H, ArH), 7.44–7.53 (m, 4H,
ArH), 7.94 (s, 1H, ]CH), 9.96 (s, 1H, NH); 13C NMR
(75 MHz, CDCl3): d 23.6, 54.8, 59.4, 59.7, 94.2, 105.3,
125.3, 127.3, 127.4, 128.8, 130.8, 134.2, 136.2, 136.4,
149.7, 151.6, 164.9; mass (FAB+): m/z 326 (M++1). Anal.
Calcd. for C19H19NO4 requires: C, 70.14; H, 5.89; N, 4.31.
Found: C, 69.88; H, 6.06; N, 4.52.
1
ane): 0.34; nmax (KBr): 1672 (CO), 3424 (NH) cmꢂ1; H
NMR (300 MHz, CDCl3): d 3.96 (d, J¼1.0 Hz, 2H, CH2),
6.84–6.91 (m, 3H, ArH), 7.15–7.28 (m, 2H, ArH), 7.37–
7.45 (m, 2H, ArH), 7.90 (s, 1H, ]CH), 9.40 (s, 1H, NH);
13C NMR (75 MHz, CDCl3): d 29.2, 112.8, 113.0, 113.4,
114.5, 114.8, 115.1, 121.7, 122.7, 127.4, 129.3, 129.6,
131.1, 157.5, 160.9, 164.1; mass (ES+): m/z 272.2 (M++1);
HR-EIMS calculated for C16H11F2NO: 271.0809. Found:
271.0811.
4.3.13. 6-Fluoro-3-pyridin-3-yl-methylene-3,4-dihydro-
1H-quinolin-2-one (Table 1, 4, entry 13). Yield: 0.52 g,
68%, as a pale yellow solid; mp 186–188 ꢀC; Rf (20%
EtOAc/hexane): 0.3; nmax (KBr): 1659 (CO), 3431 (NH)
4.3.18. 3-(2-Fluorobenzylidene)-6-methoxy-3,4-dihydro-
1H-quinolin-2-one (Table 1, 4, entry 20). Yield: 0.61 g,
77%, as a white solid; mp 180–182 ꢀC; Rf (20% EtOAc/hex-
cmꢂ1 1H NMR (300 MHz, DMSO-d6): d 3.86 (s, 2H,
;
1
CH2), 7.28–7.38 (m, 3H, ArH), 7.43–7.49 (m, 1H, ArH),
7.68–7.73 (m, 2H, ArH), 8.42 (d, 1H, J¼3.7 Hz, ArH),
8.54 (s, 1H, ]CH), 11.90 (s, 1H, NH); mass (FAB+): m/z
255 (M++1); HR-EIMS calculated for C15H11FN2O:
254.0855. Found: 254.0856.
ane): 0.34; nmax (KBr): 1658 (CO), 3419 (NH) cmꢂ1; H
NMR (300 MHz, CDCl3): d 3.72 (s, 3H, CH3), 3.90 (s,
2H, CH2), 6.62–6.67 (m, 2H, ArH), 6.82–6.85 (m, 1H,
ArH), 7.09–7.15 (m, 1H, ArH), 7.19–7.24 (m, 1H, ArH),
7.32–7.39 (m, 2H, ArH), 7.74 (s, 1H, ]CH), 9.88 (s, 1H,
CONH); 13C NMR (75 MHz, CDCl3): d 34.2, 59.0, 116.5,
119.6, 125.6, 126.7, 127.5, 132.5, 133.6, 133.8, 133.9,
134.0, 158.6, 162.2, 165.5, 168.0; mass (ES+): m/z 284.2
4.3.14. 3-Benzylidene-6-methyl-3,4-dihydro-1H-quino-
lin-2-one (Table 1, 4, entry 14). Yield: 2.07 g, 78%, as

458
R. Pathak et al. / Tetrahedron 63 (2007) 451–460
(M++1). Anal. Calcd. for C17H14FNO2 requires: C, 72.07; H,
4.98; N, 4.94. Found: C, 71.88; H, 5.16; N, 5.13.
mp 235–236 ꢀC; Rf (20% EtOAc/hexane): 0.37; nmax
1
(KBr): 1656 (CO), 3426 (NH) cmꢂ1; H NMR (300 MHz,
DMSO-d6): d 3.85 (s, 2H, CH2), 7.14–7.20 (m, 2H, ArH),
7.26–7.33 (m, 3H, ArH), 7.45–7.49 (m, 1H, ArH), 7.55 (s,
1H, ArH), 7.71 (d, 1H, J¼1.9 Hz, ArH), 11.95 (s, 1H,
NH); 13C NMR (75 MHz, DMSO-d6): d 27.9, 114.3, 114.5,
115.8, 119.5, 123.5, 124.8, 124.9, 125.6, 127.7, 128.6, 130.5,
132.1, 134.7, 135.8, 160.6; mass (ES+): m/z 288.2 (M++1),
290.2 (M++3); HR-EIMS calculated for C16H11ClFNO:
287.0513. Found: 287.0516.
4.3.19. 3-Benzyl-6-chloro-quinolin-2-ylamine (Table 2,
13, entry 1). Yield: 0.17 g, 28%, as a yellow solid; mp
157–159 ꢀC; Rf (30% EtOAc/hexane): 0.49; nmax (KBr):
3462 (NH2) cmꢂ1; 1H NMR (300 MHz, DMSO-d6): d 3.95
(s, 2H, CH2), 6.44 (s, 2H, NH2), 7.26–7.32 (m, 5H, ArH),
7.44 (t, 2H, J¼2.5 Hz, ArH), 7.59 (s, 1H, ArH), 7.66 (s,
1H, ArH); mass (ES+): m/z 368.2 (M++1), 370.2 (M++3).
Anal. Calcd. for C16H13ClN2 requires: C, 71.51; H, 4.88;
N, 10.42. Found: C, 71.66; H, 5.11; N, 10.13.
4.4.3. 3-(4-Bromobenzyl)-6-fluoro-1H-quinolin-2-one
(Table 1, 5, entry 9). Yield: 0.17 g, 100%, as a pale yellow
solid; mp >250 ꢀC; Rf (20% EtOAc/hexane): 0.37; nmax
4.3.20. 6-Chloro-3-(2-fluorobenzyl)-quinolin-2-ylamine
(Table 2, 13, entry 2). Yield: 0.43 g, 48%, as a yellow solid;
mp 204–206 ꢀC; Rf (20% EtOAc/hexane): 0.41; nmax (KBr):
1
(KBr): 1662 (CO), 3425 (NH) cmꢂ1; H NMR (300 MHz,
DMSO-d6): d 3.81 (s, 2H, CH2), 7.23 (d, 2H, J¼8.3 Hz,
ArH), 7.31–7.34 (m, 2H, ArH), 7.44–7.49 (m, 3H, ArH),
7.66 (s, 1H, ArH); 13C NMR (75 MHz, DMSO-d6): d 34.2,
111.2, 111.5, 115.8, 116.5, 116.8, 118.5, 119.1, 130.3, 133.3,
133.9, 135.2, 138.1, 154.6, 157.7, 160.6; mass (ES+): m/z
332.1 (M++1); HR-EIMS calculated for C16H11BrFNO:
331.0008. Found: 331.0012.
1
3430 (NH2) cmꢂ1; H NMR (300 MHz, CDCl3): d 3.97 (s,
2H, CH2), 4.57 (br s, 2H, NH2), 7.10–7.16 (m, 3H, ArH),
7.31–7.34 (m, 1H, ArH), 7.46–7.64 (m, 4H, ArH); mass
(ES+): m/z 287.3 (M++1). Anal. Calcd. for C16H12ClFN2 re-
quires: C, 67.02; H, 4.22; N, 9.77. Found: C, 67.10; H, 4.17;
N, 9.52.
4.3.21. 3-(2,4-Dichlorobenzyl)-quinolin-2-ylamine (Table
2, 13, entry 3). Yield: 0.21 g, 46%, as a yellow solid; mp
286–288 ꢀC; Rf (20% EtOAc/hexane): 0.3; nmax (KBr):
4.4.4. 3-Benzyl-6-bromo-1H-quinolin-2-one (Table 1, 5,
entry 10). Yield: 0.52 g, 100%, as a white solid; mp
>250 ꢀC; Rf (20% EtOAc/hexane): 0.3; nmax (KBr): 1670
1
1
3432 (NH) cmꢂ1; H NMR (300 MHz, DMSO-d6): d 3.98
(CO), 3399 (NH) cmꢂ1; H NMR (DMSO-d6, 300 MHz):
(s, 2H, CH2), 7.26–7.29 (m, 1H, ArH), 7.36 (d, 2H,
J¼6.2 Hz, ArH), 7.46 (s, 1H, ]CH), 7.58–7.61 (m, 1H,
ArH), 7.78 (d, 1H, J¼2.0 Hz, ArH), 7.88 (d, 1H,
J¼8.5 Hz, ArH); mass (FAB+): m/z 303 (M++1); HR-
EIMS calculated for C16H12Cl2N2: 302.0378. Found:
302.0366.
d 3.81 (s, 2H, CH2), 7.18–7.27 (m, 6H, ArH), 7.54–7.57
(m, 1H, ArH), 7.64 (s, 1H, ArH), 7.80 (d, 1H, J¼2.1 Hz,
ArH); 13C NMR (DMSO-d6, 75 MHz): d 35.5, 113.4,
116.9, 121.1, 126.2, 128.4, 128.9, 129.4, 132.0, 134.6,
135.7, 137.0, 139.4, 161.6; mass (ES+): m/z 314.1 (M++1),
316.1 (M++3); HR-EIMS calculated for C16H12BrNO:
313.0102. Found: 313.0102.
4.3.22. 6-Chloro-3-(2,4-dichlorobenzyl)-quinolin-2-yl-
amine (Table 2, 13, entry 4). Yield: 0.79 g, 53%, as a yellow
solid; mp 228–230 ꢀC; Rf (20% EtOAc/hexane): 0.45; nmax
4.4.5. 3-Benzyl-6-methyl-1H-quinolin-2-one (Table 1, 5,
entry 14). Yield: 0.50 g, 100%, as a white solid; mp 224–
225 ꢀC; Rf (20% EtOAc/hexane): 0.3; nmax (KBr): 1646
1
(KBr): 3442 (NH2) cmꢂ1; H NMR (300 MHz, DMSO-
1
d6): d 3.98 (s, 2H, CH2), 6.58 (br s, 2H, NH2), 7.21 (s, 1H,
ArH), 7.32–7.35 (m, 1H, ArH), 7.42–7.49 (m, 3H, ArH),
7.65 (d, 1H, J¼2.2 Hz, ArH), 7.67 (d, 1H, J¼2.1 Hz,
ArH); 13C NMR (75 MHz, DMSO-d6) d 32.8, 121.5, 123.0,
124.2, 125.0, 125.7, 126.8, 127.9, 128.1, 131.4, 131.9, 132.8,
133.8, 134.1, 144.4, 156.4; mass (ES+): m/z 337.3 (M++1).
Anal. Calcd. for C16H11Cl3N2 requires: C, 56.92; H, 3.28;
N, 8.30. Found: C, 60.21; H, 3.50; N, 8.12.
(CO), 3431 (NH) cmꢂ1; H NMR (DMSO-d6, 300 MHz):
d 2.31 (s, 3H, CH3), 3.82 (s, 2H, CH2), 7.18–7.35 (m, 8H,
ArH), 7.58 (s, 1H, ArH), 11.69 (s, 1H, NH); 13C NMR
(DMSO-d6, 75 MHz): d 24.3, 39.5, 118.6, 123.2, 130.0,
130.8, 132.2, 132.8, 134.6, 137.1, 139.9, 140.4, 143.7,
165.7; mass (ES+): m/z 250.2 (M++1). Anal. Calcd. for
C17H15NO requires: C, 81.90; H, 6.06; N, 5.62. Found: C,
82.16; H, 5.93; N, 5.69.
4.4. General procedure for the preparation of
compound 5
4.4.6. 6-Chloro-3-(2-chlorobenzyl)-1H-quinolin-2-one
(Table 1, 5, entry 15). Yield: 0.60 g, 100%, as a white solid;
mp 229–231 ꢀC; Rf (20% EtOAc/hexane): 0.35; nmax (KBr):
1662 (CO), 3429 (NH) cmꢂ1; 1H NMR (300 MHz, DMSO-
d6): d 3.93 (s, 2H, CH2), 7.28–7.37 (m, 4H, ArH), 7.41–7.48
(m, 3H, ArH), 7.68 (d, 1H, J¼2.1 Hz); 13C NMR (75 MHz,
DMSO-d6): d 32.4, 115.9, 119.5, 124.8, 125.6, 126.5, 127.6,
128.5, 130.6, 131.9, 132.6, 134.7, 135.5, 135.8, 160.7; mass
(ES+): m/z 304.2 (M++1), 306.1 (M++3). Anal. Calcd. for
C16H11Cl2NO requires: C, 63.18; H, 3.65; N, 4.60. Found:
C, 63.04; H, 3.89; N, 4.78.
To a solution of the appropriate 3-arylmethylene-3,4-di-
hydro-1H-quinolin-2-one (3.2 mmol) in acetone (10 mL)
was added anhydrous K2CO3 (0.9 g, 6.4 mmol) (2.0 equiv)
and the mixture refluxed for 15 min. Thereafter acetone
was removed under reduced pressure, the residue was
diluted with water, and the formed suspension was filtered
and dried under vacuum to yield the pure compound.
4.4.1. 3-Benzyl-1H-quinolin-2-one (Table 1, 5, entry 1).
See Ref. 4.
4.4.7. 3-(2-Fluorobenzyl)-1H-quinolin-2-one (Table 1, 5,
entry 16). Yield: 0.20 g, 100%, as a white solid; mp 197–
199 ꢀC; Rf (20% EtOAc/hexane): 0.3; nmax (KBr): 1662
4.4.2. 6-Chloro-3-(2-fluorobenzyl)-1H-quinolin-2-one
(Table 1, 5, entry 5). Yield: 0.5 g, 100%, as a white solid;
1
(CO), 3427 (NH) cmꢂ1; H NMR (300 MHz, DMSO-d6):

R. Pathak et al. / Tetrahedron 63 (2007) 451–460
459
d 4.07 (s, 2H, CH2), 7.06–7.35 (m, 5H, ArH), 7.39–7.49
(m, 4H, ArH), 11.49 (s, 1H, NH); 13C NMR (50 MHz,
DMSO-d6): d 29.1, 115.2, 115.8, 119.5, 122.1, 124.7,
126.2, 127.7, 128.8, 129.9, 131.8, 131.9, 137.0,
138.3, 162.0, 163.4; mass (ES+): m/z 254.1 (M++1);
HR-EIMS calculated for C16H12FNO: 253.0903. Found:
253.0902.
126.5, 127.0, 129.6, 128.5, 129.9, 130.4, 131.2, 133.3,
134.8, 136.5, 145.3, 150.1, 164.4; mass (ES+): m/z 288.3
(M++1), 290.2 (M+3). Anal. Calcd. for C16H11Cl2N
requires: C, 66.69; H, 3.85; N, 4.86. Found: C, 66.45;
H, 4.03; N, 4.99.
4.5.3. 3-(4-Bromobenzyl)-2-chloro-quinoline (Table 1, 6,
entry 3). Yield: 0.18 g, 85%, as a yellow solid; mp 144–
1
4.4.8. 6-Fluoro-3-(2-fluorobenzyl)-1H-quinolin-2-one
(Table 1, 5, entry 19). Yield: 1.0 g, 100%, as a white solid;
mp 219–221 ꢀC; Rf (20% EtOAc/hexane): 0.32; nmax (KBr):
1657 (CO), 3414 (NH) cmꢂ1; 1H NMR (300 MHz, DMSO-
d6): d 3.86 (s, 2H, CH2), 7.11–7.21 (m, 2H, ArH), 7.26–7.33
(m, 4H, ArH), 7.45–7.53 (m, 2H, ArH), 11.86 (br s, 1H, NH);
13C NMR (75 MHz, DMSO-d6): d 28.0, 111.5, 114.5, 115.8,
116.9, 119.0, 123.5, 125.0, 127.7, 130.6, 132.2, 133.8, 134.9,
157.7, 160.5, 161.4; mass (ES+): m/z 272.2 (M++1); HR-
EIMS calculated for C16H11F2NO: 271.0809. Found:
271.0805.
146 ꢀC; Rf (5% EtOAc/hexane): 0.61; H NMR (300 MHz,
CDCl3): d 4.19 (s, 2H, CH2), 7.13 (d, 2H, J¼8.3 Hz, ArH),
7.48 (d, 2H, J¼8.3 Hz, ArH), 7.52–7.57 (m, 1H, ArH),
7.69–7.75 (m, 2H, ArH), 7.81 (s, 1H, ArH), 8.03 (d, 1H,
J¼8.3 Hz, ArH); 13C NMR (75 MHz, DMSO-d6):
d 37.3, 119.4, 125.9, 126.1, 126.9, 128.8, 129.6, 130.6,
135.8, 136.9, 145.3, 150.0; mass (ES+): m/z 332.3
(M++1), 334.2 (M++3). Anal. Calcd. for C16H11BrClN
requires: C, 57.77; H, 3.33; N, 4.21. Found: C, 57.75; H,
3.31; N, 4.19.
4.5.4. 3-(4-Bromobenzyl)-2,6-dichloro-quinoline (Table
1, 6, entry 6). Yield: 0.15 g, 82%, as yellow solid; mp
4.5. General procedure for the preparation of
compound 6
1
151 ꢀC; Rf (5% EtOAc/hexane): 0.58; H NMR (300 MHz,
CDCl3): d 4.17 (s, 2H, CH2), 7.11 (d, 2H, J¼8.3 Hz, ArH),
7.48 (d, 2H, J¼8.3 Hz, ArH) 7.60–7.64 (m, 3H, ArH),
7.68–7.70 (m, 1H, ArH), 7.93 (d, 1H, J¼9.0 Hz, ArH); 13C
NMR (75 MHz, DMSO-d6): d 37.3, 119.6, 124.6, 126.7,
128.5, 129.6, 129.7, 130.7, 131.7, 132.4, 135.4, 135.8, 143.6,
150.3; mass (ES+): m/z 368.2 (M++1), 370.2 (M++3). Anal.
Calcd. for C16H10BrCl2N requires: C, 52.35; H, 2.75; N,
3.82. Found: C, 52.59; H, 2.97; N, 4.11.
To a round bottom flask containing 2-quinolone (3.2 mmol)
(1.0 equiv) was added POCl3 (5.8 mL, 63.9 mmol) and the
mixture refluxed for 30 min. After completion of the reac-
tion, reaction mixture was poured in ice cold water and ba-
sified with NaHCO3 solution to pH 8–8.5 and extracted
with ethyl acetate (3ꢁ50 mL). These organic fractions were
combined, washed with brine (50 mL), dried (Na2SO4), and
evaporated in vacuo to yield the crude product, which was
purified by silica gel column chromatography using hex-
anes/ethyl acetate (95–90:5–10, v/v) to furnish the pure
compounds in 82–97% yield.
4.5.5. 2-Chloro-3-(2-chlorobenzyl)-6-fluoro-quinoline
(Table 1, 6, entry 8). Yield: 0.19 g, 68%, as yellow solid;
1
mp 109–111 ꢀC; Rf (5% EtOAc/hexane): 0.67; H NMR
(300 MHz, CDCl3): d 4.35 (s, 2H, CH2), 7.19–7.22 (m,
1H, ArH), 7.28–7.33 (m, 3H, ArH), 7.43–7.50 (m, 2H,
ArH), 7.58 (s, 1H, ArH), 8.00–8.05 (m, 1H, ArH); 13C
NMR (75 MHz, CDCl3): d 35.5, 109.0, 109.3, 118.6,
118.9, 126.0, 127.4, 128.7, 129.4, 130.0, 131.2, 133.3,
134.3, 135.7, 157.7, 161.0; mass (ES+): m/z 306.2 (M++1),
308.2 (M+3); HR-EIMS calculated for C16H10Cl2FN:
305.0174. Found: 305.0175.
One-pot procedure from compound 4: to a vessel containing
the appropriate aniline (2.5 mmol) was added TFA (5 mL)
and this mixture was heated at reflux for 8–14 h. On comple-
tion (as monitored by TLC), the excess TFA was evaporated
in vacuo and the residue was taken in 10 mL of acetone. To
this solution K2CO3 (1.19 g, 8.62 mmol) was added and
the mixture was heated at reflux for 15 min. The solvent
was removed, water was added to the residue, and the
separated solid was filtered and dried to furnish the pure
products.
4.5.6. 3-(4-Bromobenzyl)-2-chloro-6-fluoro-quinoline
(Table 1, 6, entry 9). Yield: 0.14 g, 89%, as a yellow solid;
1
mp 138–140 ꢀC; Rf (5% EtOAc/hexane): 0.62; H NMR
4.5.1. 3-Benzyl-2-chloro-quinoline (Table 1, 6, entry 1).
Yield: 0.035 g, 66%, as a yellow solid; mp 156–158 ꢀC; Rf
(10% EtOAc/hexane): 0.81; H NMR (200 MHz, CDCl3):
d 4.11 (s, 2H, CH2), 6.84 (d, 2H, J¼7.6 Hz, ArH), 6.97 (t,
1H, J¼7.2 Hz, ArH), 7.17 (d, 2H, J¼8.8 Hz, ArH), 7.45
(s, 4H, ArH), 7.88 (s, 1H, ArH), 8.68 (s, 1H, ArH); mass
(ES+): m/z 254.2 (M++1). Anal. Calcd. for C16H12ClN
requires: C, 75.74; H, 4.77; N, 5.52. Found: C, 75.72;
H, 4.73; N, 5.49.
(300 MHz, CDCl3): d 4.20 (s, 2H, CH2), 7.13 (d, 2H,
J¼8.2 Hz, ArH), 7.34–7.38 (m, 1H, ArH), 7.44–7.50 (m,
3H, ArH), 7.75 (s, 1H, ]CH), 7.99–8.01 (m, 1H, ArH);
13C NMR (50 MHz, CDCl3): d 38.9, 110.5, 111.0, 120.3,
120.8, 121.2, 128.4, 131.1, 132.3, 133.8, 147.1, 137.7,
144.0, 151.0, 158.6, 163.6; mass (ES+): m/z 350.2 (M++1),
352.2 (M++3); HR-EIMS calculated for C16H10BrClFN:
348.9669. Found: 348.9676.
1
4.5.7. 3-Benzyl-6-bromo-2-chloro-quinoline (Table 1, 6,
entry 10). Yield: 0.51 g, 97%, as a white solid; mp 111–
4.5.2. 2-Chloro-3-(2-chlorobenzyl)-quinoline (Table 1, 6,
entry 2). Yield: 0.20 g, 71%, as a yellow solid; mp 107–
109 ꢀC; Rf (15% EtOAc/hexane): 0.61; 1H NMR
(300 MHz, CDCl3): d 4.36 (s, 2H, CH2), 7.18–7.21 (m,
1H, ArH), 7.23–7.32 (m, 3H, ArH), 7.46–7.55 (m, 2H,
ArH), 7.66–7.73 (m, 3H, ArH), 8.04 (d, 1H, J¼9.0 Hz,
ArH); 13C NMR (75 MHz, CDCl3): d 36.8, 115.4, 123.0,
1
112 ꢀC; Rf (5% EtOAc/hexane): 0.51; H NMR (300 MHz,
CDCl3): d 4.23 (s, 2H, CH2), 7.24–7.28 (m, 2H, ArH),
7.31–7.41 (m, 3H, ArH), 7.66 (s, 1H, ArH), 7.72–7.75 (m,
1H, ArH), 7.84–7.88 (m, 2H, ArH); 13C NMR (75 MHz,
CDCl3): d 37.8, 119.6, 125.7, 127.2, 127.6, 128.0, 128.5,
132.0, 133.1, 135.6, 136.3, 143.7, 150.7; mass (ES+): m/z

460
R. Pathak et al. / Tetrahedron 63 (2007) 451–460
332.2 (M++1), 334.2 (M++3); HR-EIMS calculated for
C16H11BrClN: 330.9763. Found: 330.9769.
4.6.2. 6-Chloro-3-(2-fluorobenzyl)-2-methoxy-quinoline
(8). Yield: 0.34 g, 87%, as a white solid; mp 87–89 ꢀC; Rf
(2% EtOAc/hexane): 0.63; H NMR (300 MHz, CDCl3):
1
4.5.8. 2,6-Dichloro-3-(2-fluorobenzyl)-quinoline (Table 1,
6, entry 18). Yield: 0.31 g, 97%, as a white solid; mp 93–
d 4.08 (s, 2H, CH2), 4.11 (s, 3H, CH3), 7.07–7.14 (m, 2H,
ArH), 7.22–7.31 (m, 2H, ArH), 7.49–7.53 (m, 2H, ArH),
7.61 (d, 1H, J¼2.3 Hz, ArH), 7.77 (d, 1H, J¼8.8 Hz,
ArH); 13C NMR (75 MHz, CDCl3): d 28.0, 52.4, 114.0,
114.3, 122.9, 124.3, 124.6, 124.8, 127.1, 127.5, 128.0,
130.1, 134.5, 142.6, 158.4, 159.7, 161.6; mass (ES+): m/z
302.2 (M++1), 304.2 (M++3); HR-EIMS calculated for
C17H13ClFNO: 301.0670. Found: 301.0673.
1
94 ꢀC; Rf (5% EtOAc/hexane): 0.5; H NMR (300 MHz,
CDCl3): d 4.25 (s, 2H, CH2), 7.10–7.17 (m, 2H, ArH),
7.20–7.33 (m, 2H, ArH), 7.60–7.63 (m, 1H, ArH), 7.70 (s,
2H, ArH), 7.94 (d, 1H, J¼9.0 Hz, ArH); 13C NMR (75 MHz,
CDCl3): d 31.1, 114.2, 114.6, 123.2, 124.7, 126.7, 127.8,
128.4, 129.6, 130.0, 130.1, 131.5, 1355.6, 150.3, 158.3,
161.5; mass (ES+): m/z 306.3 (M++1), 308.3 (M++3); HR-
EIMS calculated for C16H10Cl2FNO: 305.0174. Found:
305.0178.
4.6.3. 6-Fluoro-3-(2-fluorobenzyl)-2-methoxy-quinoline
(9). Yield: 0.20 g, 81%, as a white solid; mp 91–93 ꢀC; Rf
(2% EtOAc/hexane): 0.43; H NMR (300 MHz, CDCl3):
1
4.5.9. 2-Chloro-6-fluoro-3-(2-fluorobenzyl)-quinoline
(Table 1, 6, entry 19). Yield: 0.33 g, 81%, as a white solid;
mp 85–87 ꢀC; Rf (5% EtOAc/hexane): 0.5; 1H NMR
(300 MHz, CDCl3): d 4.26 (s, 2H, CH2), 7.12–7.17 (m,
2H, ArH), 7.22–7.36 (m, 3H, ArH), 7.45–7.48 (m, 1H,
ArH), 7.75 (s, 1H, ArH), 7.99–8.03 (m, 1H, ArH); 13C
NMR (75 MHz, CDCl3): d 31.2, 52.4, 115.8, 125.2, 125.4,
125.8, 127.3, 127.8, 128.0, 130.6, 133.2, 134.5, 137.6,
142.9, 159.9, 161.5; mass (ES+): m/z 290.3 (M++1), 292.3
(M++3); HR-EIMS calculated for C16H10ClF2N: 289.0470.
Found: 289.0460.
d 4.08 (s, 2H, CH2), 4.11 (s, 3H, CH3), 7.07–7.14 (m, 2H,
ArH), 7.22–7.37 (m, 4H, ArH), 7.57 (s, 1H, ArH), 7.80–
7.84 (m, 1H, ArH); 13C NMR (75 MHz, CDCl3): d 28.0,
52.3, 109.1, 114.3, 117.1, 122.9, 124.1, 124.7, 127.1, 127.5,
130.1, 134.7, 141.0, 158.4, 159.4, 161.6; mass (ES+): m/z
2863 (M++1); HR-EIMS calculated for C17H13F2NO:
285.0965. Found: 285.0966.
Acknowledgements
Two of the authors (R.P. and S.M.) acknowledge the finan-
cial support from CSIR, N. Delhi in the form of fellowship.
This work was supported by the financial grant from DST,
N. Delhi.
4.6. General procedure for the preparation
of compounds 7–9
To a solution of the appropriate 2-chloro-quinoline
(1.0 equiv) in dry methanol (10 mL) was added 50%
NaOMe (w/v, 10 mL) in methanol and refluxed for 15 min.
The solvent was removed in vacuo and the residue was
extracted with ethyl acetate (3ꢁ50 mL) and water (50 mL).
These combined organic fractions were washed with brine
(50 mL), dried over Na2SO4, and evaporated. The crude
product was purified by silica gel column chromatography
using hexanes/ethyl acetate (98–95:2–5, v/v) to furnish the
pure compounds in 81–97% yield.
References and notes
1. (a) Cole, S. T.; Alzari, P. M. Science 2005, 306–307; (b)
Rubin, E. J. N. Engl. J. Med. 2005, 352, 933–934; (c) Ji,
B.; Jarlier, V. Antimicrob. Agents Chemother. 2006, 50,
1558–1560.
2. Andries, K.; Verhasselt, P.; Guillemont, J.; Gohlmann, H. W. H.;
Neefs, J.-M.; Winkler, H.; Gestel, J. V.; Timmerman, P.; Zhu,
M.; Lee, E.; Williams, P.; de Chaffoy, D.; Huitric, E.; Hoffner,
S.; Cambau, E.; Truffot-Pernot, C.; Lounis, N.; Jarlier, V.
Science 2005, 307, 223–227.
3. (a) Andries, K. J.; Van Gestel, J. F. E. WO 2005117875, 2005;
(b) Van Gestel, J. F. E.; Guillemont, J. E. G.; Venet, M. G.;
Poignet, H. J. J.; Decrane, L. F. B.; Vernier, D. F. J.; Odds, F. C.
U.S. 2005148581 A1, 2005.
4. Lee, C. G.; Lee, K. Y.; Lee, S.; Kim, J. N. Tetrahedron 2005, 61,
1493–1499. For other references pertaining to the synthesis of
quinoline derivatives from Baylis–Hillman chemistry refer to:
Madapa, S.; Singh, V.; Batra, S. Tetrahedron 2006, 62, 8740–
8747 and references cited therein.
4.6.1. 3-Benzyl-6-bromo-2-methoxy-quinoline (7). Yield:
0.51 g, 97%, as a white solid; mp 82–83 ꢀC (lit. 82 ꢀC)3;
Rf (2% EtOAc/hexane): 0.45; 1H NMR (300 MHz,
CDCl3): d 4.05 (s, 2H, CH2), 4.11 (s, 3H, CH3), 7.25–7.30
(m, 3H, ArH), 7.33–7.37 (m, 2H, ArH), 7.50 (s, 1H, ArH),
7.61–7.76 (m, 3H, ArH); 13C NMR (75 MHz, CDCl3):
d 34.8, 52.4, 115.8, 125.2, 125.4, 125.8, 127.3, 127.8,
128.0, 130.6, 133.2, 134.5, 137.6, 142.9, 159.9; mass
(ES+): m/z 328.2 (M++1), 330.2 (M++3); HR-EIMS calcu-
lated for C17H14BrNO: 327.0259. Found: 327.0260.