A domino three-component condensation of ortho-haloacetophenones with urea or amines: a novel one-pot synthesis of halogen-substituted quinolines

Article abstract of DOI:10.1016/j.tet.2008.12.039

Halogen-substituted quinolines have been synthesized in good yields by the condensation and cyclization of two molecules of ortho-haloacetophenones with urea or primary amines. The formation of halogen-substituted quinolines takes place through the unexpe

Full text of DOI:10.1016/j.tet.2008.12.039

Tetrahedron 65 (2009) 1316–1320
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A domino three-component condensation of ortho-haloacetophenones with
urea or amines: a novel one-pot synthesis of halogen-substituted quinolines
*
Chuanmei Qi, Qingwei Zheng, Ruimao Hua
Department of Chemistry, Tsinghua University, Innovative Catalysis Program, Key Laboratory of Organic Optoelectronics & Molecular Engineering of Ministry of Education,
Beijing 100084, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 6 August 2008
Received in revised form 9 December 2008
Accepted 12 December 2008
Available online 24 December 2008
Halogen-substituted quinolines have been synthesized in good yields by the condensation and cycliza-
tion of two molecules of ortho-haloacetophenones with urea or primary amines. The formation of
halogen-substituted quinolines takes place through the unexpected catalyst-free cleavage of C(sp2)–X
(X¼Cl, Br),
a
-C(sp3)–H bonds and formation of C–C, C–N bonds in a selective manner. The attractive
features of the present synthetic method for halogen-substituted quinolines include catalyst-free, one-
pot process, easy availability of starting materials, and introduction of halogen on the quinoline ring for
further transformation.
Keywords:
Amine
Condensation
o-Haloacetophenone
Quinoline
Ó 2008 Elsevier Ltd. All rights reserved.
Urea
1. Introduction
with n-propylamine in the presence of ReBr(CO)5. However, heat-
ing a solution of 1a, n-propylamine (2 equiv), and ReBr(CO)5
Development of the efficient methods for the synthesis of
nitrogen heterocycles is one of the most important research topics
in synthetic chemistry.1 Quinoline derivatives have attracted con-
siderable attention owing to their biological properties,2 occur-
rence in many natural products,3 and applications in the synthesis
of pharmaceuticals and biological active molecules.4 Therefore,
designing the synthetic method for constructing quinoline ring has
become interesting topic to many organic and medicinal chemists.5
In this paper, we report an one-pot synthesis of quinoline
derivatives from the condensation of two molecules of o-hal-
oacetophenones with urea or primary amines via the domino
(3 mol %) in toluene in a sealed tube at 120 ꢀC for 48 h did not
produce the desired N-arylated product. Instead, the formation of
the corresponding ketimine and a new compound with the
molecular weight of 253 was observed by GC–MS analysis of the
reaction mixture (Scheme 1). The structure of the new compound
was assigned as 2-(20-chlorophenyl)-4-methylquinoline (2a),
which was isolated in 21% yield and characterized by its 1H, 13C
NMR, GC–MS, elemental analysis, and further unambiguously
confirmed by X-ray crystallography (Fig. 1).7 It is apparent that the
formation of 2a was resulted from the domino three-component
condensation of two molecules of 1a and one molecule of
non-catalytic cleavage of C(sp2)–X (X¼Cl, Br),
a
-C(sp3)–H bonds
and formation of C–C, C–N bonds.
2. Results and discussion
NH
N
Cl
O
The purpose of our initial work was to examine the catalytic
activity of low-valent rhenium complexes in the N-arylation of
electron-deficient aryl chlorides with primary amines, since rhe-
nium complexes have been recently employed as both transition
metal and Lewis acid catalysts in diverse organic transformations.6
Thus we investigated the reaction of o-chloroacetophenone (1a)
ReBr(CO)5 (3 mol%)
n-C3H7NH2
+
toluene (sealed tube)
120 °C, 48 h
Cl
1a
N
2a
M+ = 253
* Corresponding author. Fax: þ86 10 62771149.
Scheme 1. Reaction of o-chloroacetophenone (1a) with n-propylamine affording
quinoline derivative 2a.
E-mail address: ruimao@mail.tsinghua.edu.cn (R. Hua).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.12.039

C. Qi et al. / Tetrahedron 65 (2009) 1316–1320
1317
Table 2
Reactions of o-haloacetophenones with ureaa
Entry
Haloacetophenone
Cl
Product
Yieldb (%)
O
Cl
1
69
N
Cl
2b
Cl
1b
Cl
Cl
O
Cl
Cl
Cl
2
3
68
N
Figure 1. Molecular structure of 2a. All hydrogen atoms are omitted for clarity.
2c
1c
Cl
Br
n-propylamine, in which the C–Cl, C–H bonds of 1a and C–N bond
of n-propylamine were cleaved and the new C–C, C–N bonds were
created to form an quinoline ring, and n-propylamine was the only
source of nitrogen. Surprisingly, our further studies disclosed that
2a could be also obtained in a comparable yield without ReBr(CO)5.
Therefore, we investigated the effects of temperature, solvent, and
the source of nitrogen for the formation of 2a to optimize the
reaction conditions to develop a practical one-pot process for the
synthesis of quinolines as summarized in Table 1.
To improve the yield of 2a, we first repeated the reaction of 1a
with n-propylamine (2.0 equiv) at an elevated temperature
(150 ꢀC), and the yield of 2a was slightly increased to 35% (entry 1).
The use of much more excess amount of n-propylamine (4 equiv)
led to the unexpected decrease of the yield to 16% (entry 2), in-
dicating that the use of the excess amount of n-propylamine was
unfavorable for 2a formation. Indeed, when 1.0 equiv of n-propyl-
amine was employed, the yield of 2a was similar to that in the case
of 2.0 equiv of n-propylamine used (entry 3 vs entry 1), and a good
yield of 2a was achieved when 0.5 equiv of n-propylamine was used
under the similar reaction conditions (entry 4). It was also found
that the yield of 2a depended on the reaction temperature and the
nature of amines. For example, repeating the reaction in entry 4 at
O
Br
75 (83)
N
1d
2d
Br
Br
O
Br
Br
Br
4
63
N
2e
1e
a
Reactions were carried out using 2.0 mmol of 1 and 14.0 mmol of urea in 0.5 mL
of toluene at 150 ꢀC for 60 h in a sealed tube.
Isolated yield, number in parenthesis is 1H NMR yield.
b
120 ꢀC resulted in the significant decrease of the yield (entry 5 vs
entry 4), and when benzyl and cyclohexylamines (0.5 equiv) were
used as sources of nitrogen, 2a was formed in fair yields only
(entries 6 and 7).
Urea is a cheap chemical reagent, and its thermal decomposition
in the presence of water to eliminate ammonia was a known pro-
cess.8 We believed that under this reaction conditions, even if the
additional water was not added, ammonia should be produced by
the thermal decomposition of urea because of the presence of trace
amount of water in organic starting materials, which were used
without further purification. Once the reaction is initiated, the re-
action should proceed smoothly due to in situ generation of water
(vide infra). Therefore we examined the reaction of 1a with urea. As
shown in Table 1, the amount of urea used greatly affected the yield
of 2a (entries 8–12). When 3.5 equiv of urea was used, the yield of
2a reached 74% (NMR yield, entry 12). However, more excess
amount of urea did not improve the yield further. In addition, we
used DMSO and DMF instead of toluene as solvents, the isolated
yields of 2a were comparable (entries 13 and 14). Decreasing the
reaction temperature to 130 ꢀC resulted in a significant decrease of
the yield (entry 15). Fortunately, a prolonged reaction time (from
48 h to 60 h) improved the yields considerably, giving the desired
product in 81% NMR yield (entry 16 vs entry 12).
We applied similar conditions of entry 16 in Table 1 for the
condensation of other o-halogen-substituted acetophenones with
urea. As summarized in Table 2,9 the reactions of 2,4-dichloro-
acetophenone (1b) and 2,5-dichloroacetophenone (1c) with urea
afforded the corresponding quinoline derivatives 2b and 2c in 69%
and 68% isolated yields, respectively (entries 1 and 2). These results
indicated that the introduction of one more chloro group on the
aromatic ring had little effect for the formation of quinoline de-
rivatives. When the analogue of chloro-substituted acetophenones
such as o-bromoacetophenone (1d) and 2,5-dibromoacetophene
(1e) were employed, as expected, the corresponding quinoline
derivatives were isolated in good yields (entries 3 and 4).
Table 1
Synthesis of 2-(20-chlorophenyl)-4-methylquinolinea
Cl
O
Cl
N
R
NH2
+
sealed tube
1a
2a
Entry
RNH2 (equiv to 1a)
Solvent
Temp (ꢀC)/time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
C3H7NH2 (2)
C3H7NH2 (4)
C3H7NH2 (1)
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
DMSO
150/48
150/48
150/48
150/48
120/48
150/48
150/48
150/48
150/48
150/48
150/48
150/48
150/48
150/48
130/48
150/60
(35)c
(16)c
(36)c
(69)c
(7)c
C3H7NH2 (0.5)
C3H7NH2 (0.5)
C6H5CH2NH2 (0.5)
c-C6H11NH2 (0.5)
H2NCONH2 (0.25)
H2NCONH2 (0.5)
H2NCONH2 (1)
H2NCONH2 (2)
H2NCONH2 (3.5)
H2NCONH2 (3.5)
H2NCONH2 (3.5)
H2NCONH2 (3.5)
H2NCONH2 (3.5)
(39)c
(21)c
(<10)c
(22)c
(45)c
(62)d
62 (74)d
60.0
9
10
11
12
13
14
15
16
DMF
Toluene
Toluene
62.0
(25)d
75 (81)d
a
Reaction were carried out using 0.5–1.0 mmol of 1a in 0.5–1.0 mL of solvent in
sealed tube.
b
Isolated yield based on 1a used.
GC yield based on the less amount of substrate used with C16H34 as internal
c
standard material.
1H NMR yield based on 1a used with ferrocene as internal material.
d

1318
C. Qi et al. / Tetrahedron 65 (2009) 1316–1320
In order to further extend the present reaction in synthesis of
X
X
NHR'
X
O
X
NR'
H2O
1
R'NH2
H2O
the heterocycle containing two different heteroatoms, the reaction
of 2-acetyl-3-bromothiophene (1f) with urea was also examined.
As shown in Eq. 1, 2f was obtained in 32% isolated yield. In this case,
1f was recovered in 59% (Eq. 1).
In addition, the condensation of three different substrates of 1a,
acetophenone (3 equiv), and urea (7.0 equiv) was also briefly ex-
amined (Eq. 2). Heating the mixture at 150 ꢀC for 48 h resulted in
a complex mixture of products, and the real three-component
condensation products 2g, as well as 2a were isolated in 15% and
17% yields, respectively.
..
R
R
R
1
3
3'
R
R
electrocyclic
reaction
..
X
R'N
R'
X
X
N
R
R
4
5
R
X
+
R'
SN2
R'X
S
X
N
Br
O
Br
2
urea (7.0 equiv)
N
toluene, 150 °C, 60 h
in a sealed tube
ð1Þ
R
S
S
6
2f
1f
Scheme 2. Possible route for the formation of isoquinolines 2.
32% yield of 2f and recovered 59% of 1f
Cl
Cl
N
toluene (sealed tube)
O
ð3Þ
No 2a was formed
150 °C, 48 h
urea (7.0 mmol)
1a
+
3a
N
+
2a
N
toluene, 150 °C, 48 h
in a sealed tube
1.0 mmol
3.0 mmol
17%
2g 15%
ð2Þ
ð4Þ
toluene (sealed tube)
Cl
+
1a
2a
+
150 °C, 48 h
It should be noted that when 1-(2-chlorophenyl)-pentanone
(1g) and 2-chlorobenzoylacetonitrile (1h) were subjected to
thermal reaction under the same conditions, the formation of the
corresponding quinolines was not observed, indicating that instead
of acetyl, the sterically hindered acyl groups were unfavorable to
this cyclic coupling reaction.
Furthermore, 2-chloro-5-nitroacetophenone (1i), which is
a much more electron-deficient substrate, did not give the corre-
sponding quinoline derivative either. The reaction solution became
black immediately as soon as urea was added, and therefore the
reaction was not further examined. In the case of n-propylamine
used, the determinable product was 2-propylamino-5-nitro-
acetophenone, indicating that the nucleophilic substitution re-
action of C–Cl with n-propylamine occurred predominately.
3a
64%
Based on this proposed route, it is reasonable to explain why the
best result was achieved in the reaction of 1a with 0.5 equiv of
n-propylamine (Table 1, entry 4), since the formation of 2a is
resulted from the condensation of ketimine 3 with 1a in a 1:1 ratio.
Therefore, the use of excess amount of amine would only transfer
1a into 3a in an excess amount, leading to a decrease of the yield of
2a. In case of urea employed, it might require an excess amount of
urea to generate 3 to promote the condensation reaction.
3. Conclusions
We have established a novel and straightforward domino cata-
lyst-free process for the synthesis of halogen-substituted quino-
lines from the condensation of o-haloacetophenones with urea or
primary amines. This method has the advantages of simplicity and
readily accessible starting materials, without employing a catalyst
and good yields. To the best of our knowledge, the present report is
the first example on the catalyst-free cleavage of C(sp2)–X bond and
the formation of C–C bond. In addition, the obtained halogen-
substituted quinolines may potentially be applied to construct the
Cl
O
Cl
O
Cl
O
CN
1g
1h
1i
NO2
The reaction mechanism is proposed based on the following
results: (1) when ketimine 3a was subjected to the thermal reaction
conditions, the formation of 2a was not observed (Eq. 3); (2)
heating a mixture of 3a with 1 equiv of 1a under the same condi-
tions resulted in the formation of 2a in the comparable yield as
shown in entry 4 of Table 1, accompanied with the formation of
n-propyl chloride confirmed by GC–MS (Eq. 4); (3) the formation of
n-propyl, benzyl, and cyclohexyl chloride were observed in the
reactions of entries 4, 6, and 7 in Table 1 by careful GC and GC–MS
analyses of the reaction mixtures. Therefore, the proposed route
may involve: (1) first the formation of ketimine 3 by dehydration of
1 with amine or NH3; (2) intermolecular nucleophilic attack of 1 by
highly conjugated
p system with N-heteroaromatics, which have
attracted much attention as promising organic materials for elec-
tronic devices.
4. Experimental section
4.1. General methods
All organic starting materials are analytically pure and used
without further purification. 1H and 13C NMR spectra were recorded
on JOEL JNM-ECA300 spectrometers at 300 MHz and 75 MHz, re-
enamine carbon of 30 followed by dehydration to give
saturated imine 4; (3) electrocyclic reaction of 4 to form the in-
termediate 5; (4) elimination of Xꢁ and subsequent SN2 reaction of
5 to produce 2 (Scheme 2).
a,b-un-
spectively. 1H chemical shifts (
NMR chemical shifts (
nance. GC analyses of organic compounds were performed on an
d
) were referenced to TMS and 13C
d) were referenced to internal solvent reso-

C. Qi et al. / Tetrahedron 65 (2009) 1316–1320
1319
Agilent Technologies 1790 GC (with a TC-WAX capillary 25 m col-
umn) instrument. Mass spectra were obtained on a HEWLETT 5890
PACKARD SERIES II GC/MS spectrometer with a PEG-25M column.
Element analyses were obtained with a Flash EA 1112 Element An-
alyzer in the Institute of Chemistry, Chinese Academy of Sciences.
2.75 (s, 3H). 13C NMR (75 MHz, CDCl3)
d
158.5, 147.7, 144.1, 141.8,
133.3, 131.6, 130.3, 130.0, 129.5, 127.7, 127.3, 126.7, 123.8, 123.4,
122.0, 19.0. GC–MS m/z (% relative intensity): 299 (Mþ, 21), 297
(Mþ, 23), 218 (100), 203 (9), 189 (7), 109 (23). IR (KBr): 3062, 2961,
2926, 1601, 1589, 1557, 1500, 1097, 1042, 824 cmꢁ1. TLC Rf¼0.35
(silica, CH2Cl2). Anal. Calcd for C16H12BrN: C, 64.45; H, 4.06; N, 4.70.
Found: C, 64.64; H, 4.15; N, 4.68.
4.2. Typical experimental procedure for the formation of
quinoline 2a (Table 1, entry 16)
4.3.5. 6-Bromo-2-(20,50-dibromophenyl)-4-methylquinoline (2e)
Yellow solid, mp 162.0–162.5 ꢀC (recrystallization from a mix-
ture of solvents of n-hexane, CH2Cl2, and THF). 1H NMR (300 MHz,
In a thick-walled Pyrex screw-cap tube (10 mL) equipped with
a
magnetic stirring bar were placed o-chloroacetophenone
(309.0 mg, 2.0 mmol), urea (420.0 mg, 7.0 mmol), and toluene
(0.5 mL). The tube was capped and the mixture was stirred at 150 ꢀC
for 60 h. After the reaction mixture was cooled to room tempera-
ture, CH2Cl2 (10 mL) was added, and the insoluble materials were
filtrated off. The filtrate was then subjected to GC and GC–MS
analyses. Removal of solvent and volatiles under reduced pressure
afforded a viscous residue, which was dissolved in CDCl3 (2.0 mL),
and ferrocene (22.9 mg) was added as internal material for 1H NMR.
Compound 2a was isolated in 189.2 mg (0.748 mmol, 75%) as
colorless solid by column chromatography (silica gel, eluted with
petroleum ether/ethyl acetate¼100:0–100:20). Recrystallization of
2a in CH2Cl2 and n-hexane gave the suitable crystals for X-ray dif-
fraction analysis. 1H NMR analysis of the reaction mixture disclosed
that 2a was formed in 81% yield.
CDCl3)
158.4, 148.5, 144.6, 140.2, 135.7, 132.6, 132.4, 131.0, 130.3, 126.0,
d
8.34–7.46 (m, 7H), 2.74 (s, 3H). 13C NMR (75 MHz, CDCl3)
d
125.3, 123.8, 123.4, 123.3, 122.5, 18.9. GC–MS m/z (% relative in-
tensity): 459 (Mþ, 11), 457 (Mþ, 36), 455 (Mþ, 34), 453 (Mþ, 12), 376
(100), 297 (27), 216 (44), 189 (54), 108 (37). IR (KBr): 2954, 2922,
1600, 1578, 1552, 1493, 1092, 1031, 878 cmꢁ1. TLC Rf¼0.23 (silica,
CH2Cl2). Anal. Calcd for C16H10Br3N: C, 42.15; H, 2.21; N, 3.07.
Found: C, 42.27; H, 2.34; N, 2.99.
4.3.6. 5-(3-Bromo-thiophen-2-yl)-7-methyl-thieno[3,2-b]-
pyridine (2f)
Orange solid, mp 82.0–83.5 ꢀC (recrystallization from n-hexane
and CH2Cl2). 1H NMR (300 MHz, CDCl3)
d 7.99 (s, 1H), 7.74 (d, 1H,
J¼5.5 Hz), 7.60 (d, 1H, J¼5.5 Hz), 7.36 (d, 1H, J¼5.5 Hz), 7.08 (d, 1H,
J¼5.5 Hz), 2.66 (s, 3H). 13C NMR (75 MHz, CDCl3)
d 156.0, 149.6,
4.3. Characterization data for all products
141.8 (2C), 139.2, 132.4, 130.5, 127.2, 125.8, 117.6, 107.8, 20.5. GC–MS
m/z (% relative intensity): 311 (Mþ, 100), 309 (Mþ, 92), 308 (99), 230
(85), 215 (21), 186 (31), 115 (40). IR (KBr): 3048, 2977, 2910, 1564,
1518, 1443, 1365, 708 cmꢁ1. TLC Rf¼0.40 (silica, CH2Cl2). Anal. Calcd
for C12H8BrNS2: C, 46.60; H, 2.59; N, 4.53. Found: C, 46.37; H, 2.83;
N, 4.57.
4.3.1. 2-(20-Chlorophenyl)-4-methylquinoline (2a)
Colorless solid, mp 87.0–87.5 ꢀC (recrystallization from n-hex-
ane and CH2Cl2). 1H NMR (300 MHz, CDCl3)
d
8.18–7.35 (m, 9H),
2.75 (s, 3H). 13C NMR (75 MHz, CDCl3)
d 157.2, 147.9, 143.7, 139.8,
132.3,131.6,130.3,130.0,129.7,129.3,127.2,127.1,126.5,123.7,123.3,
18.9. GC–MS m/z (% relative intensity): 255 (Mþ, 19), 253 (Mþ, 62),
238 (19), 218 (100), 203 (7), 189 (7), 109 (22). IR (KBr): 3058, 2947,
2918, 1602, 1569, 1550, 1507, 1349, 1044, 754 cmꢁ1. TLC Rf¼0.50
(silica, CH2Cl2). Anal. Calcd for C16H12ClN: C, 75.74; H, 4.77; N, 5.52.
Found: C, 75.37; H, 4.85; N, 5.57.
4.3.7. 4-Methyl-2-phenylquinoline (2g)10
Colorless solid (recrystallization with n-hexane and CH2Cl2). 1H
NMR (300 MHz, CDCl3)
(75 MHz, CDCl3) 157.1,148.3,144.9,139.9,130.4,129.4,129.3,128.9,
d
8.18–7.42 (m, 10H), 2.71 (s, 3H). 13C NMR
d
127.6,127.4,126.1,123.7,119.9,19.1. GC–MS m/z (% relative intensity):
219 (Mþ, 100), 204 (70), 189 (6), 174 (24), 132 (22), 108 (19).
4.3.2. 7-Chloro-2-(20,40-dichlorophenyl)-4-methylquinoline (2b)
White solid, mp 181.0–183.0 ꢀC (recrystallization from a mixture
of solvents of n-hexane, CH2Cl2, and THF). 1H NMR (300 MHz,
Acknowledgements
CDCl3)
157.1, 148.6, 144.5, 137.8, 135.6, 135.4, 133.2, 132.6, 130.0, 129.1,
d
8.16–7.37 (m, 7H), 2.74 (s, 3H). 13C NMR (75 MHz, CDCl3)
This project (20573061) was supported by National Natural
Science Foundation of China.
d
127.8, 127.6, 125.8, 125.2, 123.4, 18.9. GC–MS m/z (% relative in-
tensity): 327 (Mþ, 3), 325 (Mþ, 22), 323 (Mþ, 68), 321 (Mþ, 67), 286
(100), 251 (40), 216 (31), 189 (10), 108 (30). IR (KBr): 3062, 2961,
2926, 1601, 1557, 1542, 1500, 1097, 912, 824 cmꢁ1. TLC Rf¼0.35
(silica, CH2Cl2). Anal. Calcd for C16H10Cl3N: C, 59.57; H, 3.12; N, 4.34.
Found: C, 59.31; H, 3.18; N, 4.25.
Supplementary data
Copies of 1H, 13C NMR and MS charts for all products and the full
X-ray structural details for 2a are concluded in Supplementary data.
Supplementary data associated with this article can be found in the
online version, at doi:10.1016/j.tet.2008.12.039.
4.3.3. 6-Chloro-2-(20,50-dichlorophenyl)-4-methylquinoline (2c)
White solid, mp 188.0–188.5 ꢀC (recrystallization from a mix-
ture of solvents of n-hexane, CH2Cl2, and THF). 1H NMR (300 MHz,
References and notes
CDCl3)
156.1, 146.3, 143.7, 140.7, 133.2, 132.8, 131.9, 131.6, 131.3, 130.7,
d
8.11–7.32 (m, 7H), 2.73 (s, 3H). 13C NMR (75 MHz, CDCl3)
1. Selected reviews on the synthesis and application of N-heterocyclic com-
pounds, see: (a) Bergstrom, F. W. Chem. Rev. 1944, 35, 77–277; (b) Shawali, A. S.
Chem. Rev. 1993, 93, 2731–2777; (c) Nefzi, A.; Ostresh, J. M.; Houghten, R. A.
Chem. Rev. 1997, 97, 449–472; (d) Zeni, G.; Larock, R. C. Chem. Rev. 2004, 104,
2285–2309; (e) Bur, S. K.; Padwa, A. Chem. Rev. 2004, 104, 2401–2432; (f) Ku¨ hl,
O. Coord. Chem. Rev. 2004, 248, 411–427; (g) Watson, I. D. G.; Yu, L.; Yudin, A. K.
Acc. Chem. Res. 2006, 39, 194–206.
2. Selected reports, see: (a) Giardina, G. A. M.; Sarau, H. M.; Farina, C.; Medhurst,
A. D.; Grugni, M.; Raveglia, L. F.; Schmidt, D. B.; Rigolio, R.; Luttmann, M.;
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Monga, V.; Malde, A.; Coutinho, E.; Jain, R. Bioorg. Med. Chem. 2007, 15, 626–
640; (c) Ilovich, O.; Jacobson, O.; Aviv, Y.; Litchi, A.; Chisin, R.; Mishani, E. Bioorg.
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d
130.6, 130.0, 128.1, 123.8, 122.9, 18.9. GC–MS m/z (% relative in-
tensity): 327 (Mþ, 4), 325 (Mþ, 23), 323 (Mþ, 73), 321 (Mþ, 67), 286
(100), 251 (36), 216 (33), 189 (9), 107 (25). IR (KBr): 3074, 2957,
2923, 1598, 1542, 1490, 1096, 1041, 803 cmꢁ1. TLC Rf¼0.36 (silica,
CH2Cl2). Anal. Calcd for C16H10Cl3N: C, 59.57; H, 3.12; N, 4.34.
Found: C, 59.53; H, 3.18; N, 4.23.
4.3.4. 2-(20-Bromophenyl)-4-methylquinoline (2d)
Pale yellow solid, mp 85.0–86.0 ꢀC (recrystallization from n-
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d 8.20–7.24 (m, 9H),

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C. Qi et al. / Tetrahedron 65 (2009) 1316–1320
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´
´
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