Microwave-assisted regioselective one-pot synthesis of trisubstituted pyridine scaffolds using K5CoW12O40.3H 2O under solvent free conditions

Article abstract of DOI:10.1002/jhet.5570450424

(Chemical Equation Presented) A highly efficient, microwave-assisted, regioselective synthesis of 2,3-disubstituted-6-arylpyridines and new series of 7,7-dimethyl-2-aryl-5,6,7,8-tetrahydroquinoline-5-ones from enaminones in the presence of K₅CoW₁₂O₄₀.3H₂O (1.0 mol %) as heterogeneous catalyst under solvent free conditions is reported.

Full text of DOI:10.1002/jhet.5570450424

Jul-Aug 2008
Microwave-Assisted Regioselective One-Pot Synthesis of
1099
Trisubstituted Pyridine Scaffolds using K CoW O .3H O under
5
12 40
2
Solvent Free Conditions
Srinivas Kantevari,* Mahankhali Venu Chary, Srinivasu V.N. Vuppalapati,
N. Lingaiah
Organic Chemistry Division – II, Indian Institute of Chemical Technology, Tarnaka, Hyderabad, 500 007,
India.
E-mail: kantevari@yahoo.com
Received September 22, 2007
O
O
O
NMe
2
O
R'
CH3
CH
CH
3
3
R'
O
O
CH3
CH3
NH OAc, K CoW12O 3H O,
R
N
CH
R
N
NH OAc, K CoW12O 3H O,
4
5
40.
2
R
O
4
5
40.
2
3
MW, 3-6 min
MW, 3-6 min
A highly efficient, microwave-assisted, regioselective synthesis of 2,3-disubstituted-6-arylpyridines and
new series of 7,7-dimethyl-2-aryl-5,6,7,8-tetrahydroquinoline-5-ones from enaminones in the presence of
K CoW O .3H O (1.0 mol %) as heterogeneous catalyst under solvent free conditions is reported.
5
12 40
2
J. Heterocyclic Chem., 45, 1099 (2008).
INTRODUCTION
temperatures, long reaction times; has difficulty in
isolation and unsatisfactory yields.
Synthesis of pyridine ring system and its derivatives
1] occupy an important place in the realm of natural
[
RESULTS AND DISCUSSION
and synthetic organic chemistry. Because of their
therapeutic and pharmacological properties, they have
emerged as integral backbones of over 7000 existing
drugs [2] and are ideal scaffolds to make libraries of
inhibitors of HIV-1 protease [3,4]. Enaminoketones are
readily available versatile intermediates and play an
important role in the synthesis of a number of
heterocyclic compounds [5]. 6-Aryl-2-methylnicotinates
are synthesized by the condensation of 3-amino-
Microwave mediated [13] multicomponent reactions
(MCRs) leading to heterocycles under solvent free [14]
conditions are efficient, in terms of energy used, enhanced
reaction rates and provides improved yields with often only
water as waste. Over recent years potassium dodecatungsto-
cobaltate trihydrate [15] (K CoW12O40.3H O) and hetero
5 2
poly acid mediated reactions have attracted tremendous
interest throughout the scientific communities due to their
Scheme 1.
O
O
O
NMe
2
R'
O
CH
CH3
3
O
2a, 2b
CH
3
O
R'
CH
2
c
CH3
CH3
NH OAc, K CoW12O 3H O,
R
N
R
N
NH OAc, K CoW12O 3H O,
4
5
40.
2
R
O
4
5
40.
2
3
MW, 3-6 min
MW, 3-6 min
5
1
3
4
R' = OC H5
2
R' = CH3
crotonate with acetophenone Mannich base
hydrochlorides in refluxing ethanol [6,7], with
acetylenic ketones [8] at higher temperatures, from
oxazolidines in refluxing acetonitrile in the presence of
acetic acid [9] and its microwave modification [10] in
DMSO. Recently these compounds are prepared by the
condensation of enaminoketones, ꢀ-dicarbonyl
compounds and ammonium acetate in refluxing acetic
acid [11], and later by montmorillonite K10 in refluxing
isopropanol [12]. However many of these methods
involve the use of stochiometric amounts of catalysts,
more polar solvents like AcOH, DMSO, reflux
low toxicity, ease of handling, low cost, stability,
reusability, water and organic solvent tolerant nature of the
reagent. In continuation of our efforts towards the synthesis
and development of new methodologies in organic synthesis
[16], we herein describe a general and practical route for the
synthesis of 2,3-disubstituted-6-aryl pyridines and 7,7-
dimethyl-2-aryl-5,6,7,8-tetra-hydroquinoline-5-ones using
K CoW O .3H O (1.0 mol%) as the catalyst under solvent
5
12 40
2
free microwave assisted reaction conditions (Scheme 1). To
the best of our knowledge, the generality and applicability
of K CoW O .3H O in the preparation of substituted
5
12 40
2
pyridines is not known.

1
100
S. Kantevari, M. V. Chary, S. V. N. Vuppalapati, N. Lingaiah
Vol 45
Table-1
K
5
CoW12
O
40.3H
2
O Catalyzed synthesis of 2,3-disubstiuted-6-aryl pyridines 3a–d, 4a-d and 7,7-dimethyl-2-aryl-5,6,7,8-
tetrahydroquuinoline-5-ones 5a-e.
Entry
R
Product
Reaction time
Yield [b]
(%)
Mp
Ref.
°
[a] (minutes)
( C)
1
2
3
4
5
6
7
8
9
C
6
H
5
3a
3b
3c
3d
4a
4b
4c
4d
5a
5b
5c
5d
5e
5
3
4
5
4
3
6
6
3
5
4
6
6
90
45
142
75
[12]
p-NO
p-BrC
1-Naphthyl
2
C
6
H
4
97
[12]
6
H
4
95
92
[12]
-
oil
p-NO
p-BrC
p-CH
2
C
6
H
4
4
4
95
94
131
78
-
-
6
H
4
3
C
6
H
91
89
84
-
C
6
H
5
110
182
67
[12]
p-NO
2
C
6
H
98, 95, 90 [c]
-
-
-
-
-
1
1
1
1
0
1
2
3
C
6
H
5
90
93
83
90
p-BrC
p-OCH
1-Naphthyl
6
H
4
132
125
oil
3
6 4
C H
[
a] All the reactions were carried out in a domestic microwave oven at 540W. [b] Yield of the corresponding isolated and purified
st
rd
th
product. All compounds were fully characterized by IR, NMR and mass spectroscopy. [c] The yields obtained after 1 , 3 , and 5
successive reuse of catalyst.
In a typical general experimental procedure a mixture
be introduced with high efficiency and are produced with
high yields of products in high purity (ꢀ 95 % by 1H
NMR). However the nature of the functional group on the
aromatic ring of the enaminoketones exerted a strong
influence on the reaction time. An increase of the reaction
rate was observed with enaminoketones bearing an
electron withdrawing group in the p-position 5a in
comparison to the unsubstituted 5b enaminoketone. The
presence of an electron donating methoxy group 5d
decreased both the rate of reaction and yield of product.
Acid sensitive ꢀ-dicarbonyl compounds such as ethyl
acetoacetate, acetylacetone and dimedone worked well
without formation of any side products with variety of
structurally and electronically divergent enaminoketones.
Use of just 1 mol % of K CoW O .3H O is sufficient to
of enaminoketones 1, ꢀ-dicarbonyl compounds (ethyl
acetoacetate 2a, acetylacetone 2b, or dimedone 2c) and
ammonium acetate in the presence of catalytic amount of
K CoW O .3H O (1.0 mol %) were subjected to
5
12 40
2
microwave irradiation under solvent free conditions to get
substituted pyridines 3, and or substituted
4
tetrahydroquinoline-5-ones 5 in excellent yields. In order
to improve the yields we performed reactions using
different quantities of reagents and varying microwave
power settings and exposure times. The best results were
obtained with 0.01:1:1:2.5 ratios of K CoW O .3H O,
5
12 40
2
enaminoketone,
1,3-dicarbonyl
compounds
and
ammonium acetate respectively in a domestic microwave
oven at 540W for 3 to 6 min. After completion of reaction
as indicated by TLC the reaction mixture was cooled to
room temperature, methanol was added and catalyst was
filtered off. The filtrate was quenched with crushed ice
and precipitated solid was filtered to get substituted
pyridines or substituted tetrahydroquinoline-5-one
derivatives. To study the generality of this process several
examples illustrating this novel and general method for
the synthesis of 2,3-disubstiuted-6-aryl pyridines and 7,7-
dimethyl-2-aryl-5,6,7,8-tetrahydroquinoline-5-ones were
studied and are summarized in Table 1. More over the
catalyst could be quantitatively recovered from the
reaction mixture and could be reused after thermal
activation (80 °C, for 2h). For example the catalyst was
reused in the preparation of 7,7-dimethyl-2-(4-nitro-
phenyl)-5,6,7,8-tetrahydroquinoline-5-one 5a more than
five times without loss of activity.
5
12 40
2
push the reaction forward. No additive or protic\Lewis
acid is necessary in the procedure. Another important
aspect of this procedure is survival of variety of functional
groups, NO , Br, OCH and various ꢀ-dicarbonyl
2
3
compounds and the catalyst is reusable under the reaction
condition employed.
In conclusion we described herein the regioselective
one-pot three component synthesis of trisubstituted
pyridines and 7,7-dimethyl-2-aryl-5,6,7,8-tetrahydroquin-
oline-5-ones by a reusable potassium dodecatungsto-
cobaltate trihydrate under solvent free microwave
irradiation conditions. Moreover this method offers
several advantages including high yields, short reaction
times, and a simple workup procedure and it also has the
ability to tolerate a wide variety of substitution in the
components and reaction conditions. Furthermore, the
present procedure is readily amenable to parallel synthesis
and generation of combinatorial 2,3,6-trisubstituted
Many of the pharmacologically relevant substitution
patterns on the aromatic ring of the enaminoketones could

Jul-Aug 2008
Microwave-Assisted Regioselective One-Pot Synthesis of Trisubstituted Pyridine Scaffolds
1101
pyridines and 7,7-dimethyl-2-aryl-5,6,7,8-tetrahydro
quinoline-5-ones libraries.
(300MHz, CDCl
, TMS): ꢁ 1.45 (t, J = 7.0 Hz, 3H), 2.98 (s, 3H),
3
3
.82 (s, 3H), 4.35 (q, J =7.0 Hz, 2H), 7.42 to 7.65 (m, 5H), 7.82
+
to 8.15 (m, 3H), 8.32 (d, J =8.5 Hz, 1H); ms: m/z 291 (M ,
1
7
1%), 263 (43), 219 (20), 128 (40), 113 (13), 105 (80), 86 (11),
7 (65), 58 (222), 44 (100); (Found: C, 78.32; H, 5.88; N, 4.80.
EXPERIMENTAL
Anal. Calcd for C H NO ; C, 78.32; H, 5.88; N, 4.80) (Found:
MH , 291.3479; C H NO requires MH, 291.3483).
19 17 2
1
9
17
2
+
General procedure for the preparation of 2,3,6-
trisubstituted pyridines (3a-d, 4a-d) and 7,7-dimethyl-2-aryl-
3
-Acetyl-2-methyl-6-(p-nitrophenyphenyl)pyridine (4a).
5
,6,7,8-tetrahydroquinoline-5-ones (5a-e). Enaminoketone 1 (2
mmol), ꢀ-dicarbonyl compound 2 (2 mmol) ammonium acetate
5 mmol) and K CoW O .3H O (0.064g, 0.02 mmol, 1 mol%)
Pale yellow solid (95 %), mp 131 °C; ir (KBr): 2925, 2851,
-1
1
1
719, 1682, 1581, 1517, 1428, 1341, 1261, 830, 739 cm ; H
(
5
12 40
2
nmr (300MHz, CDCl , TMS): ꢁ 2.62 (s, 3H), 2.82 (s, 3H), 7.72
3
was charged into a 15 mL open glass vial with a 20 mm
diameter. The mixture was stirred gently with a spatula for a few
seconds and was subjected to microwave irradiation (Kenstar-
(
d, J = 7.5 Hz, 1H), 8.08 (d, J =7.5 Hz, 1H), 8.25 (d, J =9.0 Hz,
1
3
2
1
1
1
H), 8.30 (d. J =9.0 Hz, 2H); C nmr (200 MHz, CDCl ): ꢁ
3
99.7,158.7, 155.6, 148.4, 144.0, 137.9, 131.9, 128.0, 123.9,
+
3
D Power OM-34ECR) at 540W for 3 to 6 min. After
17.9, 29.3, 25.0; ms: m/z 256 (M , 7%), 241 (25), 167 (8),
completion of reaction (monitered by TLC) the crude mixture
was cooled to 30 °C, hot methanol (5 mL) was added and
catalyst was filtered and cake was washed with hot MeOH (2ꢀ2
mL). Filtrate was cooled and triturated with crushed ice (1 g)
and precipitated solid was filtered to get pure products (single
spot on TLC). They were further purified by column
chromatography on silica gel using petroleum ether/EtOAc, 9:1
as the eluent to give trisubstituted pyridines 3a-d, 4a-d and
tetrahydroquinoline-5-ones 5a-e in 83-98% yields. The filtered
catalyst was reactivated by heating in oven at 80 °C for 2h and
reused at least for five times without loss of activity.
48(9), 115 (8), 105 (100), 91 (32), 77 (80), 51 (44), 43 (54);
(Found: C, 65.61; H, 4.71; N, 10.92. Anal. Calcd for
+
C H N O ; C, 65.61; H, 4.71; N, 10.93) (Found: MH ,
2
1
4
12
2
3
56.2589; C H N O requires MH, 256.2598).
14 12 2 3
3
-Acetyl-2-methyl-6-(p-bromophenylpyridine (4b). Pale
yellow solid (94 %), mp 76-78 °C; ir (KBr): 2925, 1678, 1576,
1
-1
1
485, 1430, 1352, 1256, 1005, 952, 816, 762 cm ; H NMR
(300MHz, CDCl , TMS): ꢁ 2.62 (s, 3H), 2.86 (s, 3H), 7.62 (m,
3
1
3
3
1
1
H), 7.96 to 8.10 (m, 3H); C NMR (200 MHz, CDCl ): ꢁ
3
99.6,158.4, 157.1, 137.8, 137.0, 131.8, 130.8, 128.6, 124.2,
+
16.8, 29.1, 25.1; ms: m/z 289 (M , 20%), 273 (35), 247 (100),
Ethyl (2-methyl-6-phenyl)nicotinate (3a). Pale yellow
solid (90 %), mp 43-45 °C (lit [12] 43-45 °C); ir (KBr):
221 (17), 182 (15), 167 (57), 141 (37), 101 (61), 75 (88), 43
(83); (Found: C, 57.95; H, 4.16; N, 4.82. Anal. Calcd for
-
1
1
+
2
991, 2928, 1715, 1581, 1451, 1269, 1088, 758, 691 cm ; H
C H BrNO; C, 57.95; H, 4.16; N, 4.82) (Found: MH ,
1
4
12
nmr (300MHz, CDCl , TMS): ꢁ 1.42 (t, J=7.1 Hz, 3H), 2.92
290.1379; C H BrNO requires MH, 290.1588).
3
14 12
(
s, 3H), 4.38 (q, J=7.1 Hz, 2H) 7.42 (m, 3H), 7.60 (d, J=8.1
3-Acetyl-2-methyl-6-(p-methylphenyl)pyridine (4c). Pale
yellow solid (91 %), mp 82-84 °C; ir (KBr): 2921, 1681, 1578,
1
3
Hz, 1H), 8.05 (m, 2H), 8.22 (d, J=8.3 Hz, 1H); C nmr (50
MHz, CDCl ): ꢁ 14.1, 25.1, 60.9, 117.1, 123.5, 127.2, 128.6,
1
1
-1 1
3
1451, 1260, 1184, 818, 788, 763 cm ; H nmr (300MHz, CDCl ,
3
+
29.5, 138.4, 139.1, 158.9, 159.8, 166.5; ms: m/z 241 (M ,
00%), 213 (26), 196 (93), 169 (32), 155 (12), 141 (57), 128
TMS): ꢁ 2.45 (s, 3H), 2.60 (s, 3H), 2.85, (s, 3H), 7.28 (d, J = 7.8
1
3
Hz, 2H), 7.60 (d, J =7.8 Hz, 1H), 7.95 to 8.05 (m, 3H); C nmr
(
26), 115 (70), 98 (22), 84 (20), 77 (26), 57 (12), 51 (15).
(200 MHz, CDCl ): ꢁ 199.773, 158.54, 138.01, 137.84, 129.46,
3
Anal. Calcd for C H NO : C, 74.67; H, 6.27; N, 5.81.
Found: C, 74.59; H, 6.31; N, 5.93.
128.30, 127.10, 126.76, 117.45, 116.74, 29.13, 25.28, 21.24; ms:
m/z 225 (M , 8%), 210 (7), 197 (46), 183 (100), 167 (19), 115
1
5
15
2
+
Ethyl (2-methyl-6-p-nitrophenyl)nicotinate (3b). Pale
yellow solid (97 %), mp 142 °C (lit. [12] 142-143 °C); ir (KBr):
(13), 91 (33), 39 (42); (Found: C, 79.949; H, 6.70; N, 6.21. Anal.
+
Calcd for C H NO; C, 79.95; H, 6.71; N, 6.22) (Found: MH ,
1
5
15
3
1
094, 2974, 2928, 2849, 1719, 1580, 1517, 1436, 1371, 1340,
225.1389; C H NO requires MH, 255.1395).
15 15
-1 1
260, 1160, 1087, 847, 791, 746 cm ; H nmr (300MHz, CDCl ,
3-Acetyl-2-methyl-6-phenylpyridine (4d). Pale yellow solid
(89 %), mp 110 °C (lit. [12] 110 °C); ir (KBr): 2930, 1679,
3
TMS): ꢁ 1.45 (t, J= 7.5 Hz, 3H), 2.92 (s, 3H), 4.42 (q, J= 7.5 Hz,
2
1
3
-1
1
H) 7.70 (d, J=8.3 Hz, 1H), 8.22 to 8.37 (m, 5H); C nmr (50
1575, 1422, 1351, 1254, 742, 689 cm ; H nmr (300MHz,
MHz, CDCl ): ꢁ; 14.2, 25.0, 61.3, 117.9, 123.8, 125.0, 127.9,
CDCl , TMS): ꢁ 2.58 (s, 3H), 2.82 (s, 3H) 7.36 to 7.50 (m, 3H),
7.62 (d, J = 8.3 Hz, 1H), 8.01 to 8.10 (m, 3H); C nmr (50 MHz,
3
3
+
13
1
1
39.5, 144.1, 148.4, 156.0, 160.2, 166.1; ms: m/z 286 (M ,
00%), 242 (88), 207 (55), 178 (27), 150 (91), 140 (26), 104
CDCl ): ꢁ 25.2, 29.1, 117.1, 127.2, 128.7, 129.6, 137.8, 138.3,
3
+
(
32), 75 (28), 43 (60). Anal. Calcd for C H N O ; C, 62.93; H,
158.4, 158.5, 199.8; ms: m/z 211 (M , 60%), 196 (100), 168
1
5
14
2
4
4
.93; N, 9.79. Found: C, 63.08; H, 4.86; N, 9.88.
Ethyl (2-methyl-6-p-bromophenyl)nicotinate (3c). (95 %),
mp 75 °C (lit. [12] 72-74 °C); ir (KBr): 2978, 2929, 1721, 1582,
(40), 153 (10), 141 (57), 115 (15), 77 (11), 43 (20). Anal. Calcd
for C H NO: C, 79.59; H, 6.20; N, 6.63. Found: 79.48; H, 6.19;
1
4
13
N, 6.71.
-1 1
1
451, 1369, 1267, 1089, 1009, 826, 779 cm ; H nmr (300MHz,
7,7-Dimethyl-5-oxo-2-(4-nitrophenyl)-5,6,7,8-tetrahydro
CDCl , TMS): ꢁ 1.44 (t, J= 6.8 Hz, 3H), 2.89 (s, 3H), 4.36 (q,
quinoline (5a): Yellow solid (98 %), mp 182 °C; ir (KBr):
3
-1
J=6.8 Hz, 2H) 7.55 (m, 3H), 7.93 (d, J=7.5 Hz, 2H), 8.20 (d, J=
3076, 2928, 2870, 1688, 1575, 1515, 1419, 1344, 835, 732 cm
;
+
1
8
.3 Hz, 1H); ms: m/z 319 (M , 96%), 317 (100), 275 (16), 275
H nmr (300MHz, CDCl , TMS): ꢁ 1.18 (s, 6H), 2.59 (s, 2H),
3
1
3
(
1
64), 274 (66), 249 (47), 247 (54), 182 (25), 167 (77), 155 (21),
41 (41), 126 (11), 115 (9), 83 (13), 75 (15), 63 (11), 39 (14).
Anal. Calcd for C H BrNO : C, 56.27; H, 4.41; N, 4.37. Found:
3.12 (s, 2H), 7.80 (d, J =8.3 Hz, 1H), 8.22 to 8.40 (m, 5H); C
NMR (200 MHz, CDCl ): ꢁ 197.3, 162.5, 158.0, 148.5, 144.0,
3
1
5
14
2
135.6, 129.1, 128.1, 126.4, 123.8, 119.3, 51.9, 46.5, 32.8, 28.1;
+
C, 56.31; H, 4.30; N, 4.31.
ms: m/z 296 (M , 2%), 240 (3), 150 (100), 141 (20), 104 (73),
Ethyl-(2-methyl-6-1-naphthyl)nicotinate (3d). Pale yellow
76 (31), 43 (100); (Found: C, 68.90; H, 5.44; N, 9.45. Anal.
+
oil (92%); ir (film): 3052, 2979, 2931, 1721, 1584, 1556, 1508,
Calcd for C H N O ; C, 68.90; H, 5.44; N, 9.45) (Found: MH ,
1
7
16
2
3
-1
1
1
445, 1390, 1269, 1148, 1081, 858, 782, 740 cm ; H nmr
296.3239; C H N O requires MH, 296.3244).
17 16 2 3

1
102
S. Kantevari, M. V. Chary, S. V. N. Vuppalapati, N. Lingaiah
Vol 45
7
,7-Dimethyl-5-oxo-2-(phenyl)-5,6,7,8-tetrahydroquinoline
5b). Pale yellow solid (90 %), mp 65-67 °C; ir (KBr): 3059,
950, 2867, 1678, 1581, 1446, 1395, 1304, 1186, 1122, 837, 778
Acknowledgement: Authors thankful to Dr. J. S. Yadav,
Director, IICT, and Head, Organic Chemistry Division-II, IICT
Hyderabad for their constant encouragement and support. M. V.
Chary and V. N. V. Srinivasu thank CSIR, New Delhi, for SRF
fellowships.
(
2
-
1 1
cm ; H nmr (300MHz, CDCl , TMS): ꢀ 1.15 (s, 6H), 2.02 (s,
3
2
(
H), 3.08 (s, 2H), 7.49 (m, 3H), 7.70 (d, J =7.5 Hz, 1H), 8.05
m, 2H), 8.26 (d, J =8.3 Hz, 1H); C nmr (200 MHz, CDCl ): ꢀ
13
3
1
1
97.3, 162.0, 160.6, 138.1, 136.7, 129.6, 128.5, 127.1, 125.2,
18.4, 51.7, 46.4, 32.6, 28.0, 25.2; ms: m/z 251 (M , 76%), 236
REFERENCES
+
(
12), 223 (23), 208 (7), 195 (100), 167 (28), 141 (23), 77 (10);
[
1] Weissberer, A.; Taylor, E. C. In Pyridine and its derivatives,
(Found: C, 81.24; H, 6.81; N, 5.57. Anal. Calcd for C H NO;
1
7
17
Newkome, G. R. Wiley, New York, 1984, Vol.14, part -5 pp 1-619.
[2] (a) Henry, G. D. Tetrahedron 2004, 60, 6043; (b) Bagley, M.
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Gilchrist, T. L. J. Chem. Soc. Perkin Trans. 1 2001, 2491.
+
C, 81.24; H, 6.81; N, 5.57) (Found: MH , 251.3269; C H NO
1
7
17
requires MH, 251.3273).
,7-Dimethyl-5-oxo-2-(4-bromophenyl)-5,6,7,8-tetrahydro-
quinoline (5c). Pale yellow solid (93 %), mp 132 °C; ir (KBr):
2
8
7
[3] (a) Bashford, K. E.; Burton, M. B.; Cameron, S.; Cooper, A.
953, 2928, 2867, 1678, 1574, 1413, 1378, 1299, 1070, 1008, 828,
-1
1
L.; Hogg, R. D.; Kane, P. D.; Macmanus, D. A.; Matrunola, C. A.;
Moody, C. J.; Robertson, A. A. B.; Warne. M. R. Tetrahedron Lett.
003, 44, 1627; (b) Bouras, A.; Boggetto, N.; Benatalah, Z.; de Rosny,
E.; Sicsic, S.; Rebound-Ravaus, M. J. Med. Chem. 1999, 42, 957; (c)
Phillips, G.; Davey, D. D.; Eagen, K. A.; Koovakkat, S. E.; Liang, A.;
Ng, H. P.; Pinkerton, M.; Trinh, L.; Whitlow, M.; Beatty, A. M.;
Morrissy, M. M. J. Med. Chem. 1999, 42, 1749.
06, 743 cm ; H nmr (300MHz, CDCl , TMS): ꢀ 1.16 (s, 6H),
3
2
.52 (s, 2H), 3.08 (s, 2H), 7.59 (d, J = 9.0 Hz, 2H), 7.66 (d, J = 8.3
2
1
3
Hz, 1H), 7.95 (d, J = 8.3 Hz, 2H), 8.28 (d, J = 8.3 Hz, 1H);
nmr (200 MHz, CDCl ): ꢀ 197.5, 162.3, 159.5, 137.1, 135.3,
1
C
3
31.8, 129.6, 128.8, 125.6, 124.5, 118.3, 51.9, 46.5, 32.8, 28.1;
+
ms: m/z 329 (M , 96%), 300 (18), 273 (93), 191 (8), 166 (100),
1
4
39 (32), 102 (26), 75 (28) 39 (95); (Found: C, 61.83; H, 4.88; N,
[4] (a) Troschutz, R.; Dennestedt, T. Arch. Pharm. 1993, 327,
2
21; (b) Troschutz, R.; Zink, M.; Dennestedt, T. Arch. Pharm. 1995,
328, 535; (c) Troschutz, R.; Karger, A. J. Heterocycl. Chem. 1996, 33,
815.
.24. Anal. Calcd for C H BrNO; C, 61.83; H, 4.88; N, 4.24)
17
16
+
(Found: MH , 330.2230; C H BrNO requires MH, 330.2234).
17 16
1
7
,7-Dimethyl-5-oxo-2-(4-methoxyphenyl)-5,6,7,8-tetrahy-
[
5] (a) Omran, F. A.; Awadi, N. A.; Khair, A. A. E.; Elnagdi, M.
droquinoline (5d). Light yellow solid (83 %), mp 125 °C; ir
H. Org. Prep. Proced. Int. 1997, 29, 285; (b) Saleh, B. A.; Abdelkhalik,
M. M.; Enzy, A. A.; Elnagdi, M. H. J. Chem. Res. (S). 1999, 654; (c)
Abdel-Khalik, M. M.; Elnagdi, M. H. Synth. Commun. 2002, 32, 159.
[6] Bohlmann, F.; Rahtz, D. Chem. Ber. 1957, 90, 2265.
(KBr): 3071, 2959, 2932, 2840, 1676, 1580, 1510, 1447, 1307,
-1 1
1
254, 1173, 1028, 830, 809, 759 cm ; H nmr (300MHz, CDCl ,
3
TMS): ꢀ 1.15 (s, 6H), 2.52 (s, 2H), 3.05 (s, 2H), 3.90 (s, 3H),
.95 (d, J =8.7 Hz, 2H), 7.65 (d, J =8.0 Hz, 1H), 8.05 (d, J =8.7
[7] Graf, E.; Troschutz, R. Synthesis 1999, 1216.
6
13
[8] Bagley, M. C.; Bashford, K. E.; Hesketh, C. L.; Moody, C. J.
Hz, 2H), 8.25 (d, J =8.0 Hz, 1H); C nmr (200 MHz, CDCl ): ꢀ
3
J. Am. Chem. Soc. 2000, 122, 3301.
1
1
1
1
4
97.6, 162.2, 161.2, 135.0, 130.8, 130.4, 128.7, 124.8, 117.7,
[
9] Singh, K.; Singh, J.; Singh, H. Tetrahedron 1998, 54, 935.
10] (a) Bagley, M. C.; Glover, C.; Merritt, E.A. SynLett, 2007,
459. (b) Bagley, M. C.; Glover, C.; Chevis, D. SynLett, 2005, 649. (c)
+
14.1, 113.5, 55.2, 51.9, 46.6, 32.8, 28.2; ms: m/z 281 (M ,
[
00%), 267 (6), 254 (8), 239 (8), 226 (61), 183 (11), 151 (28),
36 (95), 128 (22), 109 (10), 105 (10), 89 (35), 77 (44), 52 (35),
2
Bagley, M. C.; Bashford, K. E.; Hesketh, C. L.; Moody, C. J. J. Am.
Chem. Soc. 2000, 122, 3301. (d) Bagley, M.C.; Lunn. R.; Xiong, X.
Tetrahedron Lett. 2002, 43, 8331.
11] Al-Saleh, B.; Abdelkhalik, M. M.; Eltoukhy, A. M.; Elnagdy,
M. H. J. Heterocycl. Chem. 2002, 39, 1035.
12] Reddy, G. J.; Latha, D.; Thirupathaiah, C.; Rao, K. S.
Tetrahedron Lett. 2005, 46, 301.
13] (a) Kappe, C. O.; Kallinger, D. Nature Rev. Drug Discovery
2006, 5, 51; (b) Kappe, C. O. Angew. Chem. Int. Ed. 2004, 43, 6250; (c)
Crouch, R. D.; Howard, J. L.; Zile. J. L.; Barker, K. H. J. Cem. Edu.
2006, 83, 1658.
14] Rao. M. L. N.; Awasthi. D. K.; Banerjee. D. Tetrahedron
Lett. 2007, 48, 431.
2 (55); (Found: C, 76.84; H, 6.80; N, 4.98. Anal. Calcd for
+
C H NO ; C, 76.84; H, 6.80; N, 4.97) (Found: MH , 281.3528;
C H NO requires MH, 281.3531).
18
19
2
[
18
19
2
7
,7-Dimethyl-5-oxo-2-(1-naphthyl)-5,6,7,8-tetrahydroquin-
[
oline (5e). Pale yellow oil (90%); ir (film): 3053, 2956, 2870,
1
7
2
729, 1686, 1581, 1560, 1508, 1396, 1305, 1115, 848, 801, 778,
[
-1
1
41, 663 cm ; H nmr (300MHz, CDCl , TMS): ꢀ 1.20 (s, 6H),
3
.60 (s, 2H), 3.15 (s, 2H), 3.15 (s, 2H), 7.45 to 7.65 (m, 5H) 7.85
1
3
to 7.95 (m, 2H), 8.10 (m, 1H), 835 (d, J =8.3 Hz, 1H); C nmr
200 MHz, CDCl ): ꢀ 197.8, 163.3, 162.1, 137.5, 134.8, 133.9,
[
(
3
1
1
1
30.7, 129.5, 128.4, 127.7, 126.6, 125.9, 125.4, 125.2, 125.1,
+
[15] (a) Habibi, M. H.; Tangestaninejad, S.; Mirkhani, V.;
Yadollahi, B. Tetrahedron 2001, 57, 8333; (b) Bose, D. S.; Chary. M.
V.; Mereyala, H. B. Heterocycles 2006, 68, 1217.
23.5, 52.0, 46.5, 32.9, 28.2; ms: m/z 301 (M , 38%), 217 (11),
71 (16), 156 (50), 138 (11), 128 (71), 118 (57), 106 (46), 89
(27), 66 (51), 64 (93), 42 (100); (Found: C, 83.68; H, 6.35; N,
[
16] Nagarapu. L.; Kantevari, S.; Mahankhali, V. C.; Apuri, S.
4
.64. Anal. Calcd for C H NO; C, 83.69; H, 6.35; N, 4.64)
Catal. Commun. 2007, 8, 1173; (b) Mereyala, H. B.; Chary, M. V.;
Kantevari, S. Synthesis 2007, 187.
2
1
19
+
(Found: MH , 301.3869; C H NO requires MH, 301.3871).
21 19