Friedel-crafts heteroarylation of (Hetero)arenes: A facile entry to 4-(Hetero)aryl quinazolines and quinolines

Article abstract of DOI:10.1002/jhet.144

(Chemical Equation Presented) Anhydrous AlCl₃-mediated heteroarylation of various arenes and heteroarenes with 2,4-dichloro-quinazoline (1) and 4-chloroquinoline (4) afforded exclusively 4-aryl/ heteroarylquinazolines (3) and 4-aryl/heteroarylq

Full text of DOI:10.1002/jhet.144

748
Friedel-Crafts Heteroarylation of (Hetero)arenes: A Facile Entry
to 4-(Hetero)aryl Quinazolines and Quinolines
Vol 46
Shailesh Kumar and Devi Prasad Sahu*
Medicinal and Process Chemistry Division, Central Drug Research Institute,
Lucknow 226001, India
*E-mail: dpsahuin@yahoo.com (or) dp_sahu@cdri.res.in
Received February 28, 2009
DOI 10.1002/jhet.144
Published online 14 July 2009 in Wiley InterScience (www.interscience.wiley.com).
Anhydrous AlCl3-mediated heteroarylation of various arenes and heteroarenes with 2,4-dichloro-quin-
azoline (1) and 4-chloroquinoline (4) afforded exclusively 4-aryl/heteroarylquinazolines (3) and 4-aryl/
heteroarylquinolines (5), respectively. Compared with the available synthetic protocols, aluminum chlo-
ride induced CAC bond formation is direct and convenient to access bis-(hetero)aryl quinazolines and
quinolines. The products were obtained in good to excellent yields by this method.
J. Heterocyclic Chem., 46, 748 (2009).
INTRODUCTION
which include palladium-catalyzed Suzuki-Miyaura
cross coupling [13] between organoboronic acid and hal-
ides, nickel- or palladium-catalyzed Negishi coupling
[14] of organozinc compounds with various halides, or
Stille coupling [15] between stannanes and halides.
These synthetic protocols require multistep reactions
involving either pyrophoric organolithium reagents or
toxic and expensive catalysts. Alternately, anhydrous
AlCl3-mediated heteroarylation of arenes [16] and heter-
oarenes could be a cheap, convenient, and straightfor-
ward synthetic methodology to access the bis-heteroaryls
1-(2-chloroquinazolin-4-yl)-naphthalen-2-ol (3b) and 2-
chloro-4-(1H-indol-3-yl)quinazoline (3g), which are
structurally similar to quinazolinap and meridianins,
respectively. As a part of our ongoing program devoted
to the diversity-oriented synthesis (DOS), we had
reported synthesis and biological activity of some azahe-
terocycles and coumarine derivatives. In the continua-
tion of our studies [17], herein we report a facile and
direct synthesis of 4-aryl/heteroaryl quinazolines and 4-
aryl/heteroaryl quinolines by AlCl3-mediated direct
CAC bond forming reactions.
Biaryls and biheteroaryls are significant building
blocks in a large number of natural products [1] and are
also an important structural motif in a variety of biologi-
cally active compounds [2]. Pyrazinopyridine biheteroar-
yls have been reported as potent VEGFR-2 inhibitors
[3]. The meridianins and related psammopemmin marine
alkaloids
containing
3-(2-aminopyrimidine)-indole
motifs are potent protein kinase inhibitors [4] and pos-
sess antitumor activity [5]. The biheteroaryls have
drawn a great attention in advanced materials including
conductive polymers [6], liquid crystals [7], supramole-
cules [8], and molecular electronics [9]. Quinazolines
and quinolines are of considerable interest because of
their synthetic and therapeutic utility [10]. Biheteroaryls
containing these scaffolds may have interesting biologi-
cal and physicochemical properties. Important class of
atropisomeric biaryl ligands with axial chirality, quina-
zolinap [11], and related ligands [12] containing nitro-
gen in one of the aryl rings have been used in various
asymmetric reactions. These important biheteroaryls
were earlier synthesized by metal-catalyzed reactions,
C
V
2009 HeteroCorporation

July 2009
Friedel-Crafts Heteroarylation of (Hetero)arenes: A Facile Entry to 4-(Hetero)aryl
Quinazolines and Quinolines
749
RESULTS AND DISCUSSION
NOESY experiment of compound. A number of nitro-
gen-containing heteroarenes, e.g., pyrrole (entry 11),
indoles (entries 7–10), and indolizines (entries 12–15)
were used in the AlCl3-induced reaction.
The heteroarylation of arenes and heteroarenes with
2,4-dichloroquinazoline [18] was explored under Friedel-
Crafts reaction conditions. When one equivalent of arene/
heteroarene was reacted with one equivalent of 2,4-
dichloroquinazoline in the presence of 1.2 equiv of anhy-
drous aluminum chloride using dichloroethane as solvent,
4-(hetero)aryl-substituted-2-chloroquinazolines were
formed exclusively in good to excellent yields. The results
are summarized in Table 1. Alternatively, on carrying out
reactions at relatively lower temperature (40–45ꢀC) for a
longer duration of time (8–10 h), similar yield of the
arylated and heteroarylated products could be obtained.
The heteroarylation proceeded well in the presence of
various aryl and heteroaryl reactants. Arenes activated
with electron donating groups were found to be effective
for heteroarylation (entries 1–6). With 1,3,5-trimethoxy-
benzene as reactant, an excellent yield (85%) of the
product 3e was obtained in a short time (entry 5). Free
phenolic hydroxyl groups were found to be well toler-
ated during the reaction and heteroarylation occurred at
the ring carbon rather than oxygen (entries 1, 2, 3, and
6). With 2-hydroxynaphthalene (entry 2), a trace of 2,4-
diarylquinazoline was formed along with the product
3b. The structures of the products synthesized were
established by analytical and spectroscopic data. The
regioselectivity of the product 3a–d were confirmed by
NOESY experiment (Figure 1). In the 1H NMR spec-
trum of compound 3a, the signals at d 3.49, 6.46, 7.01,
and 7.68 were assigned for H-19, H-15, H-17, and H-4,
which in 13C NMR were appeared at d 55.25, 104.00,
116.21, and 128.65, respectively.
The reactivity toward indole and pyrrole derivatives
(entries 7–15) were somewhat more than those of naph-
thyl derivatives which might be due to differences in
their nucleophilicity. Similarly, with 1,3-dimethoxyben-
zene and sym-trimethoxybenzene, the arylation was com-
pleted within 2 h at 65–70ꢀC, and the products were iso-
lated in excellent yields (entries 4 and 5). The reaction of
2,4-dichloroquinazoline with various indolizines (fused
pyrroles) (entries 12–15) were completed at 40–45ꢀC
within a few minutes. Imidazoles (entries 16 and 17), sur-
prisingly, did not react under similar conditions. This is
perhaps due to the formation of a metal-ionic complex
with imidazole (pKa ¼ 7.1) resulting in a decrease of
nucleophilicity. Thus, unlike pyrrole derivatives, the
more basic imidazole system having an additional nitro-
gen atom deactivates the ring for arylation to occur.
The arylation of 4-chloroquinoline derivatives with
arenes and heteroarenes under similar conditions fur-
nished 4-(hetero)aryl-substituted quinolines. The results
are shown in Table 2. In the case of 4-chloro-2,8-bis(tri-
fluoromethyl)quinoline, the reaction occurred in 72–80%
yield at 60–65ꢀC in 45–50 min for 1,3-dimethoxy-ben-
zene and 1,3,5-trimethoxybenzene as nucleophiles. How-
ever, unsubstituted 4-chloroquinoline and 8-hydroxy
quinoline failed to undergo arylation with arenes and
heteroarenes.
The proposed mechanism is shown in Figure 2. The
two chlorine atoms in 2,4-dichloroquinazoline are in dif-
ferent electronic environments, the chlorine at C-4
becomes more labile due to a greater electron withdraw-
ing effect involving both the N atoms through meso-
meric effects and hence can be easily replaced by a suit-
able nucleophile to give the regioselective product. A
similar mechanism in the case of 4-chloro-2,8-bis(tri-
fluoromethyl)quinoline may be invoked. Trifluoromethyl
groups in the quinoline derivative make the reaction
more facile by participating in decreasing the electron
density at C-4 and thereby making this position more
electrophilic for the nucleophilic attack.
The existence of correlations in the NOESY experi-
ment of 3a between the protons signals of H-19 and H-
15, between the protons signals of H-19 and H-17 and
the protons signals of H-15 and H-4 suggested that there
is no substitution at C-15 and C-17, which is the con-
firmatory evidence of structure for the compound 3a.
Similarly, the connectivity in compound 3d was con-
firmed from correlation between the proton signals at d
6.61 (H-4) and d 3.71 (H-7), between the protons signals
of d 6.67 (H-2) and d 3.90 (H-8) and between the pro-
tons signals of d 6.61 (H-4) and d 3.90 (H-8) in the
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

750
S. Kumar and D. P. Sahu
Vol 46
Table 1
Regioselective AlCl3-mediated synthesis of 4-(hetero)arylquinazolines.a
Substrate 2;
Ar(Het)-H
Product 3;
Ar(Het) ¼
Entry
Temp. (ꢀC)
75–80
Time
3 h
Yieldb (%)
70
m.p. (ꢀC)
1
2
3
173–175
168–170
155–157
75–80
75–80
3 h
64
65
3 h
4
65–70
2 h
83
140–142
5
65–70
1.5 h
85
200–202
6
75–80
3 h
60
>250
7
75–80
3 h
77
175–177
(Continued)
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Table 1
(Continued)
Substrate 2;
Ar(Het)-H
Product 3;
Ar(Het) ¼
Entry
8
Temp. (ꢀC)
75–80
Time
2.5 h
Yieldb (%)
80
m.p. (ꢀC)
142–144
9
75–80
75–80
2.5 h
57
50
>250
10
2.5 h
260–262
11
12
75–80
40–45
2.5 h
85
80
107–109
192–194
15 min
13
14
15
40–45
40–45
40–45
15 min
10 min
10 min
85
85
80
218–220
190–192
146–148
16
17
75–80
75–80
4 h
No reaction
4 h
No reaction
a Reaction stoichiometries: 1 (1.0 equiv), 2a–2q (1.0 equiv), AlCl3 (1.2 equiv).
b Isolated yield.

752
S. Kumar and D. P. Sahu
Vol 46
thyl)quinoline could be arylated regioselectively to fur-
nish 4-arylquinolines. Similarly, arylation of 2,4-dichlor-
oquinazoline leads to the formation 4-aryl and 4-hetero-
aryl quinazolines which are of biological importance.
The biheteroaryls with ortho substituent are obtained in
their racemic form, which after resolution could be sep-
arated into atropisomers, providing an easy route to
access the P, N ligands. Surprisingly, demethylation and
debromination of the product were not observed in any
case in the presence of anhydrous aluminum chloride
under the comparatively mild conditions.
Figure 1. NOESY correlations in 3a and 3d.
CONCLUSIONS
EXPERIMENTAL
In conclusion, we have explored for the first time the
scope and limitation of AlCl3-mediated arylation and
heteroarylation of mono and dichloroazarenes through a
direct CAC bond forming reaction with arenes and het-
eroarenes. Suitably substituted chloroazarenes with sin-
gle nitrogen atom such as 4-chloro-2,8-bis(trifluorome-
General methods. All the reactions were performed under
nitrogen atmosphere in oven-dried glass wares. The nucleo-
philic substrates 2a–q used were either commercially available
or prepared in laboratory. Aluminum chloride used was of
commercial grade. A commercial grade dichloroethane stored
Table 2
AlCl3-mediated synthesis of 4-(hetero)arylquinolines.a
Entry
1
Substrate Ar(Het)-H
Time
Product 5; Ar(Het)¼
Yieldb (%)
80
m.p. (ꢀC)
105–107
45 min
2
50 min
72
133–135
3
2.5 h
68
141–143
a Reaction stoichiometries: 4 (1.0 equiv), 2d, 2e, and 2g (1.0 equiv), AlCl3 (1.2 equiv).
b Isolated yield.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2009
Friedel-Crafts Heteroarylation of (Hetero)arenes: A Facile Entry to 4-(Hetero)aryl
Quinazolines and Quinolines
753
1-(2-Chloroquinazolin-4-yl)-7-methoxynaphthalen-2-ol (3a).
Yield 70%; m.p.: 173–175ꢀC; IR (potassium bromide): 3450,
1
1597, 1351, 1183 cmꢂ1; H NMR (300 MHz, CDCl3): d 3.49
(s, 3H), 6.46 (d, 1H, J ¼ 2.2 Hz), 7.01 (dd, 1H, J ¼ 8.9, 2.3
Hz), 7.14 (d, 1H, J ¼ 8.8 Hz), 7.44–7.49 (m, 1H), 7.68 (d,
1H, J ¼ 8.3 Hz), 7.72 (d, 1H, J ¼ 8.9 Hz), 7.81 (d, 1H, J ¼
8.9 Hz), 7.89–7.95 (m, 1H), 8.05 (d, 1H, J ¼ 8.4 Hz); 13C
NMR (75 MHz, CDCl3): d 55.25 (CH3), 104.00 (CH), 113.8,
116.21 (CH), 116.44 (CH), 122.92, 124.34, 128.05 (CH),
128.25 (CH), 128.65 (CH), 130.18 (CH), 132.90 (CH), 133.98,
135.86 (CH), 153.00, 154.64, 156.70, 158.87, 170.13; ES-MS
(m/z): [MþH]þ 337; HRMS -EI: found: 336.0665, calculated:
336.0666. Anal. Calcd. for C19H13ClN2O2: C, 67.76; H, 3.89;
N, 8.32. Found: C, 67.61; H, 3.78; N, 8.23.
Figure 2. Proposed mechanism for the regioselective substitution in
quinazoline.
over calcium chloride was used. Reaction progress was moni-
1
tored by TLC aluminum sheets silica gel 60 F254. H NMR and
13C NMR spectra were recorded on Bruker Supercon Magnet
DPX-200 or DRX-300 spectrometers (operating at 200 and 300
MHz, respectively, for 1H; 50 and 75 MHz, respectively, for
13C) using CDCl3 and DMSO-d6 as solvent. Tetramethylsilane
(d 0.00 ppm) served as an internal standard in 1H NMR and
CDCl3 (d 77.23 ppm) in 13C NMR. Splitting patterns are
described as singlet (s), broad singlet (brs), doublet (d), triplet
(t), and multiplet (m). Electrospray mass spectra (ES-MS) were
recorded on a Micromass Quattro II triple quadruple mass spec-
trometer. High-resolution electron impact mass spectra
(HREIMS) were obtained on JEOL MS route 600H instrument.
Elemental analysis was performed on Vario EL-III C H N S an-
alyzer. Column chromatography was performed over Merck
silica gel (particle size: 60–120 mesh) obtained from Qualigens
(India), or flash silica gel (particle size: 230–400 mesh).
General method for the preparation of 2,4-dichloroquin-
azoline 1
1-(2-Chloroquinazolin-4-yl)naphthalen-2-ol
(3b). Yield
64%; m.p.: 168–170ꢀC; IR (potassium bromide): 3455, 1580
cmꢂ1
;
1H NMR (300 MHz, CDCl3): d 7.17 (d, 1H, J ¼ 8.3
Hz), 7.26–7.32 (m, 2H), 7.34–7.39 (m, 1H), 7.42–7.48 (m,
1H), 7.61 (d, 1H, J ¼ 8.1 Hz), 7.85 (d, 1H, J ¼ 7.7 Hz),
7.90–7.96 (m, 2H), 8.09 (d, 1H, J ¼ 8.4 Hz); 13C NMR (75
MHz, CDCl3): d 115.17, 118.69, 123.48, 123.89, 124.09,
127.24, 127.80, 127.97, 128.15, 128.26, 128.44, 131.78,
133.04, 135.27, 152.50, 153.28, 157.18, 171.31; ES-MS (m/z):
[MþH]þ 307; HRMS-EI: found: 306.0550, calculated:
306.0560. Anal. Calcd. for C18H11ClN2O: C, 70.48; H, 3.61;
N, 9.13. Found: C, 70.16; H, 3.70; N, 8.93.
4-(2-Chloroquinazolin-4-yl)naphthalen-1-ol
(3c). Yield
65%; m.p.: 155–157ꢀC; IR (potassium bromide): 3445, 1587
cmꢂ1
;
1H NMR (300 MHz, CDCl3): d 6.95 (d, 1H, J ¼ 9.1
Step 1. A mixture of anthranilic acid (50 g, 0.36 mol) and
urea (109 g, 1.82 mol) was heated [18a] in neat at 135–140ꢀC
using an air condenser for 3 h. The product mixture was
poured into crushed ice (500 mL) with continuous stirring for
30 min. Quinazoline-2,4-dione thus obtained as solid was fil-
tered, washed with water and used as such in the next step.
Yield 74%; m.p. > 250ꢀC.
Step 2. A mixture of quinazoline-2,4-dione (20 g, 0.12 mol)
as obtained earlier and POCl3 (98 g, 0.64 mol) was refluxed in
the presence of N,N-dimethylaniline (8.5 g, 0.07 mol) for 5 h
[18b]. The reaction mixture was allowed to cool to room tem-
perature and poured cautiously into crushed ice (500 mL) with
continuous stirring for 20 min. The precipitate obtained was
filtered, washed with water, and finally purified column chro-
matography using 30% ethyl acetate/hexane as eluent. Yield
73%; m.p.: 115–116ꢀC (116–117ꢀC) [18b].
General method for the preparation of 4-(hetero)aryl
quinazolines 3a–o. To the solution of 2,4-dichloroquinazoline
1 (1 mmol, 0.198 g) in 10 mL of dichloroethane under stirring,
AlCl3 (1.2 mmol, 0.158 g) was added and allowed to stir for
2–5 min. Nucleophilic substrate 2a–q (1 mmol) (Table 1) were
added and allowed to stir for completion of the reaction (see
Table 1 for time and temperature). Reaction was monitored by
TLC using 30% of ethyl acetate-hexane mixture. The reaction
mixture was cooled to room temperature and poured into
crushed ice (100 mL) with continuous stirring for 15–20 min.
The products were obtained either by filtration through suction
pump (3b, 3g) or extracted with dichloromethane (3 ꢁ
30 mL). The organic layers were combined, washed with
brine, and concentrated under reduced pressure after drying
over Na2SO4. The crude products obtained were further puri-
fied by silica gel column chromatography using ethyl acetate-
hexane as eluent.
Hz), 7.26–7.40 (m, 4H), 7.47 (d, 1H, J ¼ 9.0 Hz), 7.66 (d,
1H, J ¼ 6.1 Hz), 7.78–7.83 (m, 1H), 7.93 (d, 1H, J ¼ 6.0 Hz),
8.28 (d, 1H, J ¼ 9.0 Hz), 9.95 (s, 1H); 13C NMR (75 MHz,
CDCl3þDMSO-d6): d 106.27, 121.53, 122.12, 122.46, 123.50,
123.76, 125.95, 126.36, 126.45, 126.79, 128.64, 131.28,
133.72, 151.25, 154.48, 155.53, 171.47; ES-MS (m/z):
[MþH]þ 307; HRMS-EI: found: 306.0558, calculated:
306.0559. Anal. Calcd. for C18H11ClN2O: C, 70.48; H, 3.61;
N, 9.13. Found: C, 70.17; H, 3.66; N, 9.01.
2-Chloro-4-(2,4-dimethoxyphenyl)quinazoline (3d). Yield
83%; m.p.: 140–142ꢀC; IR (potassium bromide): 1611, 1209,
1
1161 cmꢂ1; H NMR (300 MHz, CDCl3): d 3.71 (s, 3H), 3.90
(s, 3H), 6.61 (d, 1H, J ¼ 2.2 Hz), 6.67 (dd, 1H, J ¼ 8.4, 2.3
Hz), 7.41 (d, 1H, J ¼ 8.4 Hz), 7.49–7.55 (m, 1H), 7.77 (dd,
1H, J ¼ 8.0, 0.8 Hz), 7.85–7.90 (m, 1H), 7.99 (d, 1H, J ¼ 8.4
Hz); 13C NMR (75 MHz, CDCl3): d 55.89, 56.01, 99.23,
105.64, 123.45, 127.70, 128.03, 128.65, 132.68, 135.00,
152.52, 158.66, 163.26, 171.21; FAB (m/z): 300, [MþH]þ
301; HRMS-EI: found: 300.0663, calculated: 300.0666. Anal.
Calcd. for C16H13ClN2O2: C, 63.90; H, 4.36; N, 9.31. Found:
C, 63.95; H, 4.39; N, 9.29.
2-Chloro-4-(2,4,6-trimethoxyphenyl)quinazoline (3e). Yield
85%; m.p.: 200–202ꢀC; IR (potassium bromide): 1610, 1215
;
cmꢂ1 1H NMR (300 MHz, CDCl3): d 3.64 (s, 6H), 3.89 (s,
3H), 6.25 (s, 2H), 7.47–7.53 (m, 1H), 7.66 (dd, 1H, J ¼ 7.9,
0.6 Hz), 7.83–7.89 (m, 1H), 7.99 (d, 1H, J ¼ 8.46 Hz); 13C
NMR (75 MHz, CDCl3): d 55.68 (OCH3), 55.95 (OCH3),
90.99, 106.72, 124.48, 127.59, 127.72, 134.70, 152.19, 157.22,
159.17, 163.07, 169.66. ES-MS (m/z): [MþH]þ 331; HRMS-
EI: found: 330.0769, calculated: 330.0771. Anal. Calcd. for
C17H15ClN2O3: C, 61.73; H, 4.57; N, 8.47. Found: C, 61.49;
H, 4.42; N, 8.15.
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754
S. Kumar and D. P. Sahu
Vol 46
(m, 1H), 7.26–7.28 (m, 1H), 7.79–7.64 (m, 1H), 7.83–7.88 (m,
1H), 7.92 (dd, 4H, J ¼ 8.3, 0.9 Hz), 8.53 (d, 1H, J ¼ 8.5 Hz),
10.13 (s, NH); 13C NMR (75 MHz, CDCl3): d 112.59, 117.33,
119.68, 123.99, 126.21, 127.85, 127.97, 128.34, 134.47,
153.26, 156.75, 159.41; ES-MS (m/z): [MþH]þ 230; HRMS-
EI: found: 229.0357, calculated: 229.0407. Anal. Calcd. for
C12H8ClN3: C, 62.76; H, 3.51; N, 18.30. Found: C, 62.41; H,
3.67; N, 18.54.
4-(2-Chloroquinazolin-4-yl)naphthalene-1,7-diol (3fY).ield
60%; m.p.: >250ꢀC; IR (potassium bromide): 3452, 1585,
1
1352, 761 cmꢂ1; H NMR (200 MHz, DMSO-d6): d 6.77–6.86
(m, 2H), 7.10 (d, 1H, J ¼ 7.7 Hz), 7.27 (d, 1H, J ¼ 9.1 Hz),
7.35 (d, 1H, J ¼ 2.3 Hz), 7.45–7.58 (m, 2H), 7.88–7.89 (m,
2H), 9.6 (brs, 1H), 10.39 (brs, 1H); 13C NMR (50 MHz,
DMSO-d6): d 104.43, 107.64, 119.96, 123.45, 123.63, 126.57,
127.09, 127.72, 128.12, 128.73, 135.90, 152.52, 154.39,
155.24, 156.35, 172.96, 175.22; ES-MS (m/z): [MþH]þ 323;
HRMS-EI: found: 322.0507, calculated: 322.0509. Anal.
Calcd. for C18H11ClN2O2: C, 66.99; H, 3.44; N, 8.68. Found:
C, 66.79; H, 3.41; N, 8.61.
2-Chloro-4-(2-phenylindolizin-3-yl)quinazoline (3l). Yield
80%; m.p.: 192–194ꢀC; IR (potassium bromide): 2366, 1598,
;
1350, 767 cmꢂ1 1H NMR (300 MHz, CDCl3): d 6.72–6.77
(m, 1H), 6.78 (s, 1H), 6.98–7.08 (m, 2H), 7.10–7.15 (m, 5H),
7.53–7.59 (m, 2H), 7.63–7.68 (m, 1H), 7.87 (d, 1H, J ¼ 8.49
Hz), 8.99 (d, 1H, J ¼ 7.2 Hz); 13C NMR (75 MHz, CDCl3): d
101.55, 111.23, 114.25, 117.69, 119.95, 120.45, 123.43,
125.49, 125.70, 125.90, 127.24, 127.76, 133.15, 134.13,
134.22, 135.39, 151.99, 155.59, 161.36; ES-MS (m/z):
[MþH]þ 356; HRMS-EI: found: 355.0876, calculated:
355.0876. Anal. Calcd. for C22H14ClN3: C, 74.26; H, 3.97; N,
11.81. Found: C, 73.95; H, 4.13; N, 11.49.
2-Chloro-4-(1H-indol-3-yl)quinazoline (3g). Yield 77%;
m.p.: 175–177ꢀC; IR (potassium bromide): 1521, 1487, 1340
cmꢂ1
;
1H NMR (300 MHz, CDCl3þDMSO-d6): d 7.27–7.30
(m, 2H), 7.54–7.57 (m, 1H), 7.61–7.67 (m, 1H), 7.88–7.94 (m,
1H), 7.97–8.02 (m, 2H), 8.26–8.29 (m, 1H), 8.45 (dd, 1H, J ¼
8.1, 0.6 Hz), 11.57 (NH); 13C NMR (75 MHz,
CDCl3þDMSO-d6): d 111.91, 112.23, 121.12, 121.27, 121.40,
122.94, 126.03, 127.05, 127.25, 130.80, 133.98, 136.81,
152.17, 156.63, 166.35; FAB (m/z): 279, [MþH]þ 280;
HRMS-EI: found: 279.0494, calculated: 279.0485. Anal.
Calcd. for C16H10ClN3: C, 68.70; H, 3.60; N, 15.02. Found: C,
68.79; H, 3.68; N, 15.21.
2-Chloro-4-[2-(4-chlorophenyl)indolizin-3-yl]quinazoline (3m).
Yield 85%; m.p.: 218–220ꢀC; IR (potassium bromide): 1597,
1
1349, 773 cmꢂ1; H NMR (300 MHz, CDCl3): d 6.69–6.74 (m,
2H), 6.96–7.13 (m, 6H), 7.51 (d, 1H, J ¼ 8.9 Hz), 7.53 (dd, 1H,
J ¼ 8.6, 0.6 Hz), 7.66–7.71 (m, 1H), 7.87 (d, 1H J ¼ 8.5 Hz),
8.91 (dd, 1H, J ¼ 7.2, 0.6 Hz); 13C NMR (75 MHz, CDCl3): d
102.87, 112.90, 115.55, 119.18, 121.32, 122.07, 124.86, 127.29,
127.56, 128.41, 128.91, 130.32, 133.22, 134.04, 134.21, 134.89,
136.81, 153.53, 157.09, 162.54; ES-MS (m/z): [MþH]þ 390;
HRMS-EI: found: 389.0492, calcuated: 389.0487. Anal. Calcd.
for C22H13Cl2N3: C, 67.71; H, 3.36; N, 10.77. Found: C, 67.46;
H, 3.42; N, 10.63.
2-Chloro-4-(1-methyl-1H-indol-3-yl)quinazoline (3h). Yield
80%; m.p.: 142–144ꢀC; IR (potassium bromide): 1563, 1347,
1
735 cmꢂ1; H NMR (300 MHz, CDCl3): d 3.93 (s, 3H), 7.28–
7.36 (m, 2H), 7.38–7.43 (m, 1H), 7.55–7.61 (m, 1H), 7.78 (s,
1H), 7.84–7.89 (m, 1H), 7.97 (dd, 1H, J ¼ 8.3, 0.7 Hz), 8.17–
8.20 (m, 1H), 8.41 (dd, 1H, J ¼ 8.6, 0.7 Hz); 13C NMR (75
MHz, CDCl3): d 33.68 (CH3), 109.96 (CH), 112.19 (C),
121.53 (C), 122.04 (CH), 122.12 (CH), 123.52 (CH), 127.00
(C), 127.29 (CH), 127.46 (CH), 128.05 (CH), 133.93 (CH),
134.33 (CH), 137.65 (C), 152.90 (C), 157.37 (C), 166.15 (C);
ES-MS (m/z): [MþH]þ 294; HRMS-EI: found: 293.0689, calc-
uated: 293.0719. Anal. Calcd. for C17H12ClN3: C, 69.51; H,
4.12; N, 14.30. Found: C, 69.45; H, 4.10; N, 14.19.
4-[2-(4-Bromophenyl)indolizin-3-yl]-2-chloroquinazoline
(3n). Yield 85%; m.p.: 190–192ꢀC; IR (potassium bromide):
1597, 1348, 772cmꢂ1 1H NMR (300 MHz, CDCl3): d 6.70–
;
6.75 (m, 2H), 6.97–7.02 (m, 3H), 7.09–7.15 (m, 1H), 7.22–
7.25 (m, 2H), 7.50–7.55 (m, 2H), 7.67–7.73 (m, 1H), 7.88 (d,
1H, J ¼ 8.3 Hz), 8.91 (dd, 1H, J ¼ 7.1, 0.5 Hz); 13C NMR
(75 MHz, CDCl3): d 102.83, 112.94, 115.55, 119.22, 121.38,
121.45, 122.08, 124.90, 127.35, 127.64, 128.42, 130.66,
131.90, 134.05, 134.72, 134.94, 136.85, 157.15, 162.58; ES-
MS (m/z): [MþH]þ 434 (Br78), 436(Br80); HRMS-EI: found:
2-Chloro-4-(2-methyl-1H-indol-3-yl)quinazoline (3i). Yield
57%; m.p.: >250ꢀC; IR (potassium bromide): 1519, 1485,
1352 cmꢂ1
;
1H NMR (200 MHz, CDCl3þDMSO-d6): d 2.60
(s, 3H), 7.05–7.21 (m, 2H), 7.42–7.45 (m, 2H), 7.51–7.58 (m,
1H), 7.87–8.01 (m, 2H), 8.12 (d, 1H, J ¼ 8.3 Hz), 10.95 (brs,
1H); 13C NMR (50 MHz, CDCl3þDMSO-d6): d 13.67, 111.52,
119.62, 120.96, 122.18, 122.79, 127.26, 127.91, 128.18,
128.93, 134.88, 136.06, 139.67, 153.01, 157.41, 168.56; ES-
MS (m/z): [MþH]þ 294; HRMS-EI: found: 293.0718, calcu-
lated: 293.0719. Anal. Calcd. for C17H12ClN3: C, 69.51; H,
4.12; N, 14.30. Found: C, 69.35; H, 4.22; N, 14.22.
432.9950,
calcuated:
432.9981.
Anal.
Calcd.
for
C22H13BrClN3: C, 60.78; H, 3.01; N, 9.67. Found: C, 60.59;
H, 3.29; N, 9.43.
4-(2-Benzofuran-2-yl-indolizin-3-yl)-2-chloroquinazoline
(3o). Yield 80%; m.p.: 146–148ꢀC; IR (potassium bromide):
1596, 1350 1172, 765 cmꢂ1 1H NMR (300 MHz, CDCl3): d
;
2-Chloro-4-(2-phenyl-1H-indol-3-yl)quinazoline (3j). Yield
50%; m.p.: 260–262ꢀC; IR (potassium bromide): 3223, 1598,
6.49 (s, 1H), 6.67–6.71 (m, 1H), 6.94–6.99 (m, 1H), 7.02–7.12
(m, 4H), 7.17–7.22 (m, 1H), 7.36–7.39 (m, 1H), 7.52 (d, 1H,
J ¼ 8.9 Hz), 7.72–7.79 (m, 2H), 7.99 (d, 1H, J ¼ 8.3 Hz), 8.68
(d, 1H, J ¼ 7.2 Hz); 13C NMR (75 MHz, CDCl3): d 99.79,
103.04, 109.49, 111.60, 113.77, 117.96, 119.38, 120.36, 121.16,
121.49, 122.17, 122.87, 123.14, 126.27, 126.35, 127.39, 133.58,
135.01, 149.88, 151.95, 153.21, 155.61, 161.43; ES-MS (m/z):
[MþH]þ 396; HRMS-EI: found: 395.0831, calculated:
395.0825. Anal. Calcd. for C24H14ClN3O: C, 72.82; H, 3.56; N,
10.62. Found: C, 72.53; H, 3.70; N, 10.45.
1345, 747 cmꢂ1
;
1H NMR (300 MHz, CDCl3þDMSO-d6): d
7.09–7.15 (m, 1H), 7.23–7.28 (m, 4H), 7.32–7.39 (m, 3H),
7.55–7.82 (m, 2H), 7.73 (d, 1H, J ¼ 8.2 Hz), 7.84–7.93 (m,
2H); 13C NMR (75 MHz, CDCl3þDMSO-d6): d 106.57,
110.20, 117.70, 119.13, 120.14, 121.12, 125.47, 125.71,
126.32, 126.69, 126.96, 129.81, 133.24, 134.71, 138.15,
150.58, 154.79, 166.49; FAB (m/z): 355, [MþH]þ 356. Anal.
Calcd. for C22H14ClN3: C, 74.26; H, 3.97; N, 11.81. Found: C,
74.59; H, 3.89; N, 11.75.
General method for the preparation of 4-(hetero)aryl
quinolines 5a-c. 4-Chloro-2,8-bis(trifluoromethyl)quinoline 4
(1 mmol, 0.299 g) was added in 10 mL of dichloroethane.
Under stirring, to it was added AlCl3 (1.2 mmol, 0.158 g) and
2-Chloro-4-(1H-pyrrol-2-yl)quinazoline (3k). Yield 85ꢂ%1;
m.p.: 107–109ꢀC; IR (potassium bromide): 3220, 1550 cm
;
1H NMR (300 MHz, CDCl3): d 6.46–6.49 (m, 1H), 7.14–7.16
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2009
Friedel-Crafts Heteroarylation of (Hetero)arenes: A Facile Entry to 4-(Hetero)aryl
Quinazolines and Quinolines
755
2004, 14, 1703; (b) Butler, M. S.; Capon, R. J.; Lu, C. C. Aust J
Chem 1992, 45, 1871.
allowed to stirred for 2–5 min. Nucleophilic substrates 2d, 2e,
and 2g (1 mmol) (Table 2) were added and allowed to stirred
at 60–65ꢀC. The reaction mixture was cooled to room temper-
ature and poured into ice-cold water (100 mL) with continuous
stirring for 15–20 min. The products were obtained by extract-
ing with dichloromethane (3 ꢁ 30 mL). The organic layers
were combined, washed with brine and concentrated under
reduced pressure after drying over Na2SO4. The crude products
obtained further purified by silica gel column chromatography
using ethyl acetate-hexane mixture.
[5]
2007, 14, 1206.
[6] (a) Yamamoto, T.; Maruyama, T.; Zhou, Z.; Ito, T.;
Radwan, M. A. A.; El-Sherbiny, M. Bioorg Med Chem
Fukuda, T.; Yoneda, Y.; Begum, F.; lkeda, T.; Sasaki, S.; Takezoe, H.;
Fukada, A.; Kubota, K. J Am Chem Soc 1994, 116, 4832; (b) Schulz,
E.; Fahmi, K.; Lemaire, M. Acros Org Acta 1995, 1, 10; (c) Zhu, S.
S.; Swager, T. M. Adv Mater 1996, 8, 497; (d) Papillon, J.; Schulz,
E.; Gelinas, S.; Lessard, J.; Lemaire, M. Synth Met 1998, 96, 155.
[7] Manka, J. T.; Guo, F.; Huang, J.; Yin, H.; Farrar, J. M.; Sien-
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[8] Lehn, J. M., Ed. Supramolecular Chemistry, 1st ed.; VCH:
Weinheim, Germany, 1995; p 55.
4-(2,4-Dimethoxyphenyl)-2,8-bis-trifluoromethylquinoline
(5a). Yield 80%; m.p.: 105–107ꢀC; IR (potassium bromide):
1
1610, 1200, 1150 cmꢂ1; H NMR (200 MHz, CDCl3): d 3.69
(s, 3H), 3.91 (s, 3H), 6.64–6.69 (m, 2H), 7.19 (d, 1H, J ¼ 8.5
Hz), 7.54–7.62 (m, 1H), 7.72 (s, 1H), 7.92 (d, 1H, J ¼ 8.4 Hz),
8.13 (d, 1H, J ¼ 7.1 Hz). 13C NMR (75 MHz, CDCl3): d 55.70,
55.81, 99.23, 105.28, 118.33, 119.23, 126.61, 128.90, 128.97,
129.12, 131.21, 132.05, 144.16, 147.99, 148.45, 148.86, 157.97,
162.40; ES-MS (m/z): [MþH]þ 402; HRMS-EI: found:
401.0848, calcuated: 401.0850. Anal. Calcd. for C19H13F6NO2:
C, 56.87; H, 3.27; N, 3.49. Found: C, 57.02; H, 3.56; N, 3.24.
4-(2,4,6-Trimethoxyphenyl)-2,8-bis-trifluoromethylquinoline
(5b). Yield 72%; m.p.: 133–135ꢀC; IR (potassium bromide):
[9] (a) Monk, P. S. M., Ed. The Viologens; Wiley: Canada,
1999; p 32; (b) Stoddart, J. F. J Am Chem Soc 2000, 122, 164; (c)
Balzani, V.; Credi, A.; Raymo, F. M.; Stoddart, J. F. Angew Chem Int
Ed 2000, 39, 3348; (d) Stoddart, J. F. Acc Chem Res 2001, 34, 410;
(e) Benniston, A. C.; Harriman, A.; Li, P.; Rostron, J. P. Tetrahedron
Lett 2005, 46, 7291; (f) Branowska, D.; Rykowski, A.; Wysocki, W.
Tetrahedron Lett 2005, 46, 6223; (g) Coe, B. J.; Harris, J. A.;
Brunschwig, B. S.; Garin, J.; Orduna, J. J Am Chem Soc 2005, 127,
3284; (h) Dichtel, W. R.; Miljanic, O. S.; Spruell, J. M.; Heath, J. R.;
Stoddart, J. F. J Am Chem Soc 2006, 128, 10388; (i) Badjic, J. D.;
Ronconi, C. M.; Stoddart, J. F.; Balzani, V.; Silvi, S.; Credi, A. J Am
Chem Soc 2006, 128, 1489.
1
1613, 1194, 1143 cmꢂ1; H NMR (200 MHz, CDCl3): d 3.64
(s, 6H), 3.89 (s, 3H), 6.24 (s, 2H), 7.10 (d, 1H, J ¼ 8.2 Hz),
7.23 (s, 1H), 7.53–7.62 (m, 1H), 7.89 (d, 1H, J ¼ 8.3); 13C
NMR (75 MHz, CDCl3): d 55.67, 55.98, 91.10, 106.70,
118.36, 119.21, 126.58, 128.87, 128.89, 130.99, 132.01,
144.12, 147.95, 148.39, 148.84, 159.10, 168.90; ES-MS (m/z):
[MþH]þ 432; HRMS-EI: found: 431.0955, calcuated:
431.0955. Anal. Calcd. for C20H15F6NO3: C, 55.69; H, 3.51;
N, 3.25. Found: C, 55.51; H, 3.58; N, 2.97.
[10] (a) Connolly, D. J.; Cusack, D.; O’sullivan, T. P.; Guiry, P.
J. Tetrahedron 2005, 61, 10153; (b) Mhaske, S. B.; Argade, N. P. Tet-
rahedron 2006, 62, 9787; (c) Fekner, T.; Bunz, H. M.; Guiry, P. J. Org
Lett 2006, 8, 5109; (d) Xu, G. F.; Song, B. A.; Bhadury, P. S.; Yang,
S.; Zhang, P. Q.; Jin, L. H.; Xue, W.; Hu, D. Y.; Lu, P. Bioorg Med
Chem 2007, 15, 3768; (e) Sunduru, N.; Agarwal, A.; Katiyar, S. B.;
Nishi, N.; Goyal, N.; Gupta, S.; Chauhan, P. M. S. Bioorg Med Chem
2006, 14, 7706.
4-(1H-Indol-3-yl)-2,8-bis-trifluoromethylquinoline (5c). Yield
66%; m.p.: 145–147ꢀC; IR (potassium bromide): 1611, 1522,
[11] (a) Flanagan, S. P.; Goddard, R.; Guiry, P. J. Tetrahedron
2005, 61, 9808; (b) Connolly, D. J.; Lacey, P. M.; McCarthy, M.;
Saunders, C. P.; Carroll, A.-M.; Goddard, R.; Guiry, P. J. J Org Chem
2004, 69, 6572; (c) McCarthy, M.; Hooper, M. W.; Guiry, P. J. Chem
Commun 2000, 14, 1333; (d) McCarthy, M.; Guiry, P. J. Polyhedron
2000, 19, 541; (e) Lacey, P. M.; McDonnell, C. M.; Guiry, P. J. Tetra-
hedron Lett 2000, 41, 2475; (f) McCarthy, M.; Goddard, R.; Guiry, P.
J. Tetrahedron: Asymmetry 1999, 10, 2797.
1403, 778 cmꢂ1 1H NMR (300 MHz, CDCl3): d 7.21–7.27
;
(m, 2H), 7.52–7.58 (m, 2H), 8.01–8.13 (m, 1H), 8.26 (m, 1H),
8.27–8.29 (m, 1H), 8.39 (s, 1H), 11.53 (brs, 1H, NH); 13C
NMR (75 MHz, CDCl3): d 111.89, 112.30, 118.21, 119.03,
120.99, 121.19, 121.31, 123.01, 126.11, 127.25, 128.63,
128.96, 130.99, 131.93, 136.71, 145.62, 147.89, 148.36,
148.67; ES-MS (m/z): [MþH]þ 381; HRMS-EI: found:
380.0739, calculated: 380.0746. Anal. Calcd. for C19H10F6N2:
C, 60.01; H, 2.65; N, 7.37. Found: C, 59.73; H, 2.55; N, 7.26.
[12] Alcock, N. W.; Brown, J. M.; Hulmes, D. I. Tetrahedron:
Asymmetry 1993, 4, 743.
[13] (a) Liu, W. J.; Xie, Y. X.; Liang, Y.; Li, J. H. Synthesis
2006, 860; (b) Marion, N.; Navarro, O.; Mei, J.; Stevens, E. D.; Scott,
N. M.; Nolan, S. P. J Am Chem Soc 2006, 128, 4101 (Suzuki-Miyaura
cross coupling).
Acknowledgments. S.K is thankful to the University Grants
Commission, New Delhi, for the financial support and the Sophis-
ticated Analytical Instrument Facility, CDRI, Lucknow, for pro-
viding spectroscopic data.
[14]
Lu¨tzen, A.; Hapke, M. Eur J Org Chem 2002, 2292
(Negishi coupling).
[15] Mee, S. P. H.; Lee, V.; Baldwin, J. E. Angew Chem 2004,
116, 1152 (Stille coupling).
[16] (a) Knopfel, T. F.; Aschwanden, P.; Ichikawa, T.; Wata-
nabe, T.; Carreira, E. M. Angew Chem Int Ed 2004, 43, 5971; (b) Pal,
M.; Batchu, V. R.; Parasuraman, K.; Yeleswarapu, K. R. J Org Chem
2003, 68, 6806.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet