An efficient, catalyst- and solvent-free, four-component, and one-pot synthesis of polyhydroquinolines on grinding

Article abstract of DOI:10.1016/j.tet.2007.11.008

An efficient synthesis of polyhydroquinolines is achieved via a four-component reaction of aldehydes, dimedone, active methylene compounds, and ammonium acetate in one-pot under solvent-free conditions at room temperature on grinding. The present method does not involve any hazardous organic solvent or catalyst. The key advantages are the short reaction time, high yields, simple workup, and purification of products by non-chromatographic methods, i.e., by simple recrystallization from ethanol.

Full text of DOI:10.1016/j.tet.2007.11.008

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 536e542
www.elsevier.com/locate/tet
An efficient, catalyst- and solvent-free, four-component, and one-pot
synthesis of polyhydroquinolines on grinding
a
a
a,
b
Satish Kumar , Poonam Sharma , Kamal K. Kapoor *, Maninder Singh Hundal
a
Department of Chemistry, University of Jammu, Jammu 180 006, India
Department of Chemistry, Guru Nanak Dev University, Amritsar 143 005, India
b
Received 13 August 2007; received in revised form 19 October 2007; accepted 1 November 2007
Available online 6 November 2007
Abstract
An efficient synthesis of polyhydroquinolines is achieved via a four-component reaction of aldehydes, dimedone, active methylene
compounds, and ammonium acetate in one-pot under solvent-free conditions at room temperature on grinding. The present method does not
involve any hazardous organic solvent or catalyst. The key advantages are the short reaction time, high yields, simple workup, and purification
of products by non-chromatographic methods, i.e., by simple recrystallization from ethanol.
Ó 2007 Elsevier Ltd. All rights reserved.
Keywords: Hantzsch condensation; One-pot synthesis; Polyhydroquinolines; Grinding; Solvent-free; Catalyst-free
1
. Introduction
-Substituted 1,4-dihydropyridines (1,4-DHPs) constitute
In view of the biological importance of polyhydroquino-
lines, several methods for their synthesis have been reported.
The classical method involves the three-component coupling
of an aldehyde with ethyl acetoacetate and ammonia in acetic
4
2
þ
an important class of Ca channel blockers and have proved
valuable as one of the most important class of drugs for the
treatment of cardiovascular diseases, including hypertension.
1
ties, such as vasodilator, bronchodilator, antiatherosclerotic,
antitumor, geroprotective, hepatoprotective, and antidiabetic
agents. Recent studies have revealed that 1,4-DHPs exhibit
5
e7
acid or refluxing alcohol.
However, these methods suffer
1
from drawbacks of a long reaction time, usage of an excess
of organic solvent, and lower yields of the products. Several
alternate and more efficient methods have been developed
for the synthesis of polyhydroquinoline derivatives by using
,4-Dihydropyridines possess a variety of biological activi-
2
8
9
10
11
microwaves, ionic liquids, TMSCleNaI, metal triflates,
12
3
13
14
several medicinal applications, which include neuroprotectant
I , ceric ammonium nitrate, polymers, and organo-cata-
2
1
5
and platelet anti-aggregatory activity, in addition to cerebral
antiischemic activity in the treatment of Alzheimer’s disease
and as chemo sensitizer in tumor therapy. Quinolines having
a 1,4-dihydropyridine nucleus are very important compounds
because of their pharmacological properties. Members of
this family are being used as antimalarial, antiinflammatory,
antiasthamatic, antibacterial, and tyrosine kinase inhibiting
lyst. However, the use of high temperatures, expensive metal
precursors, catalysts that are harmful to environment, and
longer reaction times limit the use of these methods. There-
fore, the search for a better method for the synthesis of poly-
hydroquinoline derivatives is still the need of the day.
In recent times, the progress in the field of solvent-free re-
actions is gaining significance because of their high efficiency,
operational simplicity and environmentally benign processes.
Solventless organic reactions based on grinding of two macro-
4
agents.
1
6
scopic particles together mostly involve the formation of a
liquid phase prior to reaction, i.e., formation of a eutectic
melt of uniform distribution where the reacting components
*
Corresponding author. Tel.: þ91 191 245 3969; fax: þ91 191 245 3079.
E-mail address: k2kapoor@yahoo.com (K.K. Kapoor).
0040-4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.11.008

S. Kumar et al. / Tetrahedron 64 (2008) 536e542
537
O
R
O
O
R'
O
O
NH4OAc,
O
R
CHO
+
+
R'
Grinding, rt,
Solvent-free
O
N
H
O
1
2
3
4
R = aryl, R' = Me, Ethyl
Scheme 1. Synthesis of hexahydroquinoline derivatives from aldehyde, dimedone, b-ketoesters, and ammonium acetate on grinding.
O
O
R
NH OAc
EWG
4
R
CHO
+
+
NC
EWG
grinding, rt,
solvent-free
O
N
H
NH2
1
5
2
6
EWG = CN or CO R'
2
Scheme 2. Synthesis of 2-amino-hexahydroquinoline derivatives from aldehyde, dimedone, malononitrile/a-cyanoesters, and ammonium acetate on grinding.
being in close proximity are poised to react in a controlled
way. The grinding mode for the solid-state reactions has
electron deficient aldehydes as well as heterocyclic systems
such as thiophene-2-carboxaldehyde, reacted smoothly with
b-ketoesters (methyl and ethyl acetoacetate) to produce high
yields of products. However, with aliphatic aldehydes, lower
yields of the products were witnessed (entry 16). All the prod-
ucts were characterized by comparison of their analytical data
(IR, NMR, and MS) with those of authentic samples. The
structure of product 4q (entry 17) was further confirmed by
the crystal structure analysis. The structure solution reveals
that both the six membered rings of the polyhydroquinoline
derivative 4q adopt half chair conformation. Figure 1 shows
the ORTEP diagram of 4q. The structure is stabilized by one
intermolecular H-bonding interaction with neighboring trans-
lation equivalent (xꢀ1, y, z) molecule (Fig. 2). The proton
attached to nitrogen N1 forms a H-bond with the oxygen O6
1
earlier been reported for Grignard reaction, Reformatsky
7
1
reaction, Aldol condensation, Dieckmann condensation,
8
19
20
2
1
22
23
Knoevenagel condensation, reduction, and others. Most
of these reactions are carried out at room temperature in abso-
lutely solvent-free environment using only a mortar and pestle.
All these facts have strengthened our resolve to find newer
2
4,25
eco-friendly methods
and prompted us to employ grinding
at room temperature for the multicomponent synthesis of
polyhydroquinoline in solvent-free environment (Schemes 1
and 2).
2
. Results and discussion
˚
In an initial endeavor, 1 equiv each of benzaldehyde 1a, di-
such that the N1eH1/O6 distance is 2.057(2) A. The mole-
medone 2, ethyl acetoacetate 3, and ammonium acetate were
heated under reflux in ethanol. After 4 h, only 55% of the ex-
pected product 4a was obtained after workup and recrystalliza-
tion from ethanol. In an attempt to improve the yields of the
cule linked through H-bonds thus form a linear chain parallel
to the ‘a’ axis of the unit cell.
In order to check the versatility of the procedure, b-ketoest-
ers were replaced with other active methylene compounds
such as malononitrile and ethyl cyanoacetate and the re-
actions were observed to follow the expected routes to yield
2-amino-4-aryl-3-cyano-7,7-dimethyl-5-oxo-1,4,5,6,7,8-hexa-
hydroquinolines and 2-amino-7,7-dimethyl-5-oxo-4-phenyl-
1,4,5,6,7,8-hexahydroquinoline-3-carboxylic acid ethyl ester,
respectively, in good to excellent yields (Scheme 2). The
results with different aldehydes are depicted in Table 2.
1
7e23
reaction and acknowledging the benefits of grinding,
the same reaction was performed in solvent-free conditions
at room temperature. All the ingredients of the reaction were
taken in a mortar, mixed thoroughly and ground well at
room temperature. It was observed that the mixture which
was initially in a partial liquid state, solidified during the pro-
cess of grinding to a light yellow solid mass and thin layer
chromatography (TLC), at this moment, indicated the com-
plete conversion to the desired product. The solid mass was
washed with cold water to remove any unreacted ammonium
acetate, dried and recrystallized from ethanol to give 3-carb-
ethoxy-1,4,5,6,7,8-hexahydro-4-phenyl-2,7,7-trimethyl-5-oxo-
quinoline, 4a (95% yield). A possible explanation for the
better yield in solvent-free conditions is that the eutectic
mixture having uniform distribution of the reactants, brings
the reacting species in close proximity to react than in solvent.
A variety of substrates were submitted to this reaction con-
dition and the desired products were obtained in good to excel-
lent yields (Table 1). It is evident that electron rich and
3. Conclusions
In conclusion, we have developed a simple and efficient
method for the synthesis of polyhydroquinoline derivatives
via Hantzsch condensation under grinding the four reactants
at room temperature in solvent-free conditions. The mildness
of the conversion, experimental simplicity, compatibility
with various functional groups, efficient yields, short reaction
times, and the easy workup procedure, makes this procedure
attractive to synthesize a variety of these derivatives.

538
S. Kumar et al. / Tetrahedron 64 (2008) 536e542
Table 1
Synthesis of polyhydroquinolines 4 on grinding the four components 1, 2, 3, and ammonium acetate at room temperature in solvent-free conditions (Scheme 1)
0
ꢁ
Entry
R
R
Product
Time (min)
Yield (%)
Melting point ( C)
Observed
Reported
CHO
CHO
1
1
1
2
3
4
5
Et
Et
Et
Et
Et
4a
4b
4c
4d
4e
15
15
15
15
15
95
93
92
93
95
203e204
202e203
Cl
9a
209e211
258e259
255e257
250e251
208e210
260e261
257e259
245e246
CHO
1
1
9
1
1
a
H C
3
CHO
H CO
3
CHO
Cl
CHO
CHO
1
9
9
1
a
a
6
7
8
9
Et
Et
Et
4f
30
12
20
83
88
80
228e230
245e246
231e233
232e234
242e244
235e237
HO
4g
4h
O N
2
MeO
CHO
CHO
HO
Br
1
1
Et
Et
4i
4j
15
25
90
80
234e236
241e244
235
1
1
1
1
1
1
0
1
238e240
248e250
CHO
CHO
S
Et
Et
4k
4l
25
20
83
92
252e255
243e245
S
CHO
9
a
1
2
251e253
222e223
O
O
CHO
CHO
1
3
4
Me
Me
4m
4n
15
15
95
87
221e222
283e285
Cl
1
5
1
>280
H C
3
1
5
6
Me
Et
4o
4p
30
45
81
56
213e215
144e146
216e217
147e148
CHO
S
1
5
1
a
1
CHO
CHO
MeO
MeO
1
1
7
8
Me
Me
4q
4r
20
20
88
85
203e206
256e258
198e199
257e258
OMe
CHO
5
a
H3C
N
CH3

S. Kumar et al. / Tetrahedron 64 (2008) 536e542
539
was thoroughly mixed in a mortar followed by grinding till
the completion of reaction as indicated by TLC (10e
20 min). The resultant material was washed with water to re-
move any unreacted ammonium acetate and was air-dried to
afford the crude product. The pure product was obtained by
recrystallization from ethyl alcohol. The spectroscopic and
analytical data for selected compounds are presented below.
4.2.1. Ethyl-1,4,7,8-tetrahydro-2,7,7-trimethyl-4-
(
2-chlorolphenyl)-5(6H )-oxoquinolin-3-carboxylate (4b)
ꢁ
ꢀ1
Yellow solid, mp 207e208 C. IR (KBr) nmax/cm : 3063,
1
956, 1721, 1640, 1611, 1467, 1384,1227, 1021, 745; H
2
NMR (200 MHz, DMSO-d ): d 0.95 (s, 3H, CH ), 1.05 (s,
6
3
3
2
4
H, CH ), 1.20 (t, J¼7.2 Hz, 3H, CH ), 2.01e2.21 (m, 4H,
3
3
ꢂCH ), 2.40 (s, 3H, CH ), 4.05 (q, J¼7.2 Hz, 2H, CH ),
2 3 2
.60 (s, 1H, CH), 7.10e7.30 (m, 4H, ArH), 7.60 (s, 1H,
1
3
NH); C NMR (50 MHz, DMSO-d ): d 26.5, 29.1, 31.2,
Figure 1. Showing the ORTEP diagram of 4q. The H atoms have been omitted
for clarity.
6
32.3, 42.4, 46.8, 48.9, 50.5, 52.9, 55.1, 101.3, 109.2, 114.2,
125.9, 127.1, 128.7, 131.1, 132.3, 141.0, 167.5, 195.7;
þ
4
. Experimental section
MS (ESI): m/z 374.1 (MþH) . Anal. Calcd for C H NO Cl:
21
24
3
C, 67.56; H, 6.43; N, 3.75. Found: C, 67.52; H, 6.48;
N, 3.72.
4
.1. General procedures
Melting points were determined on a Buchi melting point
apparatus and are uncorrected. IR spectra were recorded in
4
.2.2. Ethyl-1,4,7,8-tetrahydro-2,7,7-trimethyl-4-
1
KBr discs on PerkineElmer FTIR spectrophotometer.
1
H
NMR and C NMR spectra were recorded on BrukerAC-200
(4-methoxylphenyl)-5(6H )-oxoquinolin-3-carboxylate (4d)
3
ꢁ
ꢀ
1
Yellow solid, mp 255e257 C. IR (KBr) nmax/cm : 3276,
1
956, 1703, 1648, 1606, 1496,1381, 1215, 1031, 765; H
(
(
200 and 50 MHz, respectively) spectrometer. Mass spectra
ESI) were recorded on JEOL SX-102 spectrometer. Elemen-
2
NMR (200 MHz, DMSO-d ): d 0.95 (s, 3H, CH ), 1.09 (s,
6
3
tal analysis was performed on Leco CHNS-932 Analyzer. TLC
was performed on 0.5 mm thick plates using BDH silica gel G
as adsorbent.
3
2
H, CH ), 1.21 (t, J¼7.2 Hz, 3H, CH ), 2.01e2.10 (m, 4H,
2 3 3
3
3
ꢂCH ), 2.30 (s, 3H, CH ), 3.70 (s, 3H, OCH ), 4.00 (q,
J¼7.2 Hz, 2H, CH ), 4.80 (s, 1H, CH), 6.65 (d, J¼7.3 Hz,
2
2
H, ArH), 7.10 (d, J¼7.3 Hz, 2H, ArH), 8.65 (s, 1H, NH);
1
3
4
.2. General procedure for the synthesis of 1,4,7,8-
C NMR (50 MHz, DMSO-d ): d 14.1, 18.2, 26.4, 29.1,
6
tetrahydro-2,7,7-trimethyl-4-aryl-5(6H )-oxoquinolin-3-
carboxylic acid alkyl ester (4aek)
32.1, 34.7, 50.2, 50.5, 54.8, 58.9, 103.2, 110.1, 113.0, 113.1,
128.2, 128.3, 139.8, 144.6, 149.1, 157.2, 166.9, 194.2;
þ
MS (ESI): m/z 370.2 (MþH) . Anal. Calcd for C H NO :
2
2
27
4
A mixture of aldehyde 1 (2 mmol), dimedone 2 (2 mmol),
b-ketoester 3 (2 mmol), and ammonium acetate (3 mmol)
C, 71.54; H, 7.31; N, 3.79. Found: C, 71.59; H, 7.35;
N, 3.84.
Figure 2. Showing the formation of a chain due to H-bonding interactions.

540
S. Kumar et al. / Tetrahedron 64 (2008) 536e542
Table 2
Synthesis of polyhydroquinoline derivatives 6 on grinding the four components 1, 2, 5, and ammonium acetate at room temperature in solvent-free conditions
Scheme 2)
(
ꢁ
Entry
R
EWG
Product
Time (min)
Yield (%)
Melting point ( C)
8
c
Observed
Reported
CHO
1
2
3
CN
CN
CN
6a
6b
6c
15
15
15
88
82
87
275e277
280e281
288e289
290e291
CHO
289e293
287e288
H CO
3
CHO
Cl
CHO
4
H3C
CN
6d
25
75
>300
>300
N
CH3
Br
CHO
5
6
CN
CN
6e
6f
20
20
88
75
293e294
273e276
295e296
Cl
CHO
d
CHO
7
8
CN
CN
6g
6h
15
20
80
74
294e295
253e255
>300
H C
3
256e257
CHO
CHO
S
9
CN
6i
25
20
25
77
72
70
265e267
150e155
122e125
269e270
O
O
CHO
1
0
1
CO
2
Et
Et
6j
6k
d
d
CHO
1
CO
2
H CO
3
CHO
CHO
1
1
2
3
CO
2
Et
Et
6l
18
15
65
75
135e137
174e176
d
d
H C
3
CO
2
6m
Cl
CHO
14
H3C
2
CO Et
6n
25
77
115e120
d
N
CH3
4
.2.3. Ethyl-1,4,7,8-tetrahydro-2,7,7-trimethyl-4-
J¼7.2 Hz, 2H, CH ), 4.80 (s, 1H, CH), 6.60 (s 2H, ArH),
2
(4-hydroxy-3-methoxylphenyl)-5(6H )-oxoquinolin-3-
carboxylate (4h)
Yellow solid, mp 231e233 C. IR (KBr) nmax/cm : 3388,
2
NMR (200 MHz, DMSO-d ): d 0.95 (s, 3H, CH ), 1.09 (s,
6.82 (s, 1H, ArH), 7.69 (s, OH), 8.49 (s, 1H, NH);
C NMR (50 MHz, DMSO-d ): d 14.2, 18.2, 26.3, 29.2,
1
3
6
ꢁ
ꢀ1
32.1, 35.0, 50.2, 55.4, 58.9, 104.0, 110.1, 112.0, 114.9,
119.3, 119.5, 139.0, 144.3, 144.5, 146.7, 149.2, 167.0,
1
953, 1700, 1643, 1589, 1482, 1385, 1218, 1029, 782; H
þ
194.3; MS (ESI): m/z 386.2 (MþH) . Anal. Calcd for
6
3
3
2
H, CH ), 1.25 (t, J¼7.2 Hz, 3H, CH ), 2.02e2.20 (m, 4H,
C H NO : C, 68.57; H, 7.06; N, 3.64. Found: C, 68.52; H,
5
3
3
22 27
ꢂCH ), 2.30 (s, 3H, CH ), 3.80 (s, 3H, OCH ), 4.05 (q,
7.10; N, 3.68.
2
3
3

S. Kumar et al. / Tetrahedron 64 (2008) 536e542
541
4
.2.4. Methyl-1,4,7,8-tetrahydro-2,7,7-trimethyl-4-(3,4,5-
Table 3
Showing the crystal data and refinement details for 4q
trimethoxylphenyl)-5(6H )-oxoquinolin-3-carboxylate (4q)
ꢁ
ꢀ1
Yellow solid, mp 223e226 C. IR (KBr) nmax/cm : 3280,
185, 3058, 2931, 1686, 1644, 1603, 1490, 1382, 1333, 1227,
Identification code
Empirical formula
Formula weight
4q
23 6
C H29NO
3
1
3
2
1
415.47
295(2) K
˚
0.71073 A
114, 1004, 787; H NMR (200 MHz, DMSO-d ): d 0.94 (s,
6
Temperature
Wavelength
H, CH ), 1.03 (s, 3H, CH ), 2.00e2.51 (m, 4H, 2ꢂCH ),
3
3
2
.27 (s, 3H, CH ), 3.47 (s, 3H, CO Me), 3.59 (s, 3H,
3
Crystal system, space group
Unit cell dimensions
Monoclinic, P2 /n
2
1
˚
OMe), 3.67 (s, 6H, two OMe), 4.83 (s, 1H, CH), 6.41 (s,
2
a¼7.167(1) A
1
H, ArH), 8.39 (s, 1H, NH); C NMR (50 MHz, DMSO-
3
b¼20.095(1) A˚
˚
c¼15.157(1) A
d6): d 18.6, 26.7, 29.6, 32.5, 35.9, 50.6, 55.9, 60.2, 103.0,
ꢁ
b¼90.66(1)
1
1
04.7, 110.0, 136.1, 143.5, 145.4, 150.3, 152.7, 167.8,
þ
˚
2182.8(4) A
4, 1.264 mg/m
3
Volume
3
94.9; MS (ESI): m/z 416.0 (MþH) . Anal. Calcd for
Z, Calculated density
Absorption coefficient
F(000)
Theta range for data collection
Limiting indices
ꢀ
1
C H NO : C, 66.49; H, 7.04; N, 3.37. Found: C, 66.57;
29
0.091 mm
888
1.68e27.50
2
3
6
H, 7.11; N, 3.46.
0ꢃhꢃ9, 0ꢃkꢃ26, ꢀ19ꢃlꢃ19
5395/5009 [R(int)¼0.0244]
Full-matrix least-squares on F
5009/0/271
2
6
4
.3. X-ray crystallography
Reflections collected/unique
Refinement method
Data/restraints/parameters
2
The data were collected on a Siemens P4 single crystal dif-
fractometer using graphite monochromatized Mo Ka radiation
(l¼0.71073 A). Table 3 shows the unit cell parameters and other
crystallographic details. Data collection and cell refinement
2
Goodness-of-fit on F
1.069
R
Final R indices [I>2s(I )]
R indices (all data)
CCDC number
1
¼0.0700, wR ¼0.1750
2
2
˚
R ¼0.1470, wR ¼0.2201
1
656035
2
6a
were donewith XSCANS. The data was corrected for Lorentz
and polarization effects. Structure was solved by direct methods
and refined anisotropically by full-matrix least-squares method.
All the hydrogens were fixed geometrically as riding atoms with
a displacement parameter equal to 1.2 (CH, CH ) or 1.5 (CH )
0
4
1
.4.2. 2-Amino-4-(2 -thienyl)-3-cyano-7,7-dimethyl-5-oxo-
,4,5,6,7,8-hexahydroquinoline (6h)
ꢁ
ꢀ1
Yellow solid, mp 254e255 C. IR (KBr) nmax/cm : 3378,
2
3
1
319, 3286, 2198, 1679, 1607; H NMR (200 MHz, DMSO-
3
times that of the parent atoms. Data reduction, structure solu-
tions, refinement and molecular graphics were performed using
d ): d 0.92 (s, 3H, CH ), 1.01 (s, 3H, CH ), 2.06e2.29 (m,
), 4.51 (s, 1H, CH), 5.85 (s, 2H, NH ), 6.85e
2 2
7.12 (m, 3H, ArH), 8.98 (s, 1H, NH); MS (ESI): m/z 300.2
6
3
3
2
6b
26c
SHELXLTL-PC and WINGX. Torsion angles and least-
4H, 2ꢂCH
2
square planes were calculated by using PARST. CCDC num-
5d
þ
(
MþH) . Anal. Calcd for C H N OS: C, 64.19; H, 5.72;
1
6 17 3
ber for compounds 4q is CCDC 656035.
N, 14.04. Found: C, 64.15; H, 5.68; N, 13.99.
4
4
.4. General procedure for the synthesis of 2-amino-
-phenyl-3-cyano-7,7-dimethyl-5-oxo-1,4,5,6,7,8-
4
.4.3. 2-Amino-7,7-dimethyl-5-oxo-4-phenyl-1,4,5,6,7,8-
hexahydroquinoline-3-carboxylic acid ethyl ester (6j)
hexahydroquinoline (6aei)
ꢁ
ꢀ1
Light yellow solid, mp 150e155 C. IR (KBr) nmax/cm
1
:
426, 3315, 3203, 2177, 1657, 1603, 1495; H NMR
3
A mixture of aldehyde 1 (2 mmol), dimedone 2 (2 mmol),
malononitrile or ethyl cyanoacetate 5 (2 mmol), and ammo-
nium acetate (3 mmol) was mixed thoroughly in a mortar
with pestle followed by grinding till the completion of reaction
as indicated by TLC (10e20 min). The resultant material was
washed with water to remove any unreacted ammonium ace-
tate and was air-dried to afford the crude product. The pure
product was obtained by recrystallization from ethyl alcohol.
The spectroscopic and analytical data for selected compounds
are presented below.
(
200 MHz, DMSO-d ): d 0.88 (s, 3H, CH ), 1.02 (s, 3H,
6 3
CH ), 1.07 (t, J¼7.1 Hz, 3H, CH ) 1.99e2.49 (m, 4H,
3
3
2
5
ꢂCH ), 3.92 (q, J¼7.1 Hz, 2H, CH ), 4.48 (s, 1H, CH),
2
2
.73 (s, 2H, ArH), 7.07e7.19 (m, 5H, ArH), 7.52 (s, 2H,
þ
NH ). MS (ESI): m/z 341.2 (MþH) . Anal. Calcd for
2
C H N O : C, 70.56; H, 7.11; N, 8.23. Found: C, 70.48;
2
0 24 2 3
H, 7.17; N, 8.18.
0
4
1
.4.4. 2-Amino-7,7-dimethyl-5-oxo-4-(4 -methoxyphenyl)-
,4,5,6,7,8-hexahydroquinoline-3-carboxylic acid ethyl
ester (6k)
Light yellow solid, mp 122e125 C, IR (KBr) nmax/cm
ꢁ
ꢀ1
:
4
1
.4.1. 2-Amino-4-phenyl-3-cyano-7,7-dimethyl-5-oxo-
1
,4,5,6,7,8-hexahydroquinoline (6a)
Light yellow solid, mp 275e277 C. IR (KBr) nmax/cm
3410, 3323, 3198, 2976, 1679, 1619, 1507; H NMR
(200 MHz, DMSO-d ): d 0.90 (s, 3H, CH ), 1.02 (s, 3H,
ꢁ
ꢀ1
:
6
3
1
3
(
426, 3315, 3203, 2177, 1657, 1603, 1495; H NMR
200 MHz, DMSO-d ): d 0.91 (s, 3H, CH ), 1.02 (s, 3H, CH ),
CH ), 1.09 (t, 3H, J¼7.1 Hz, CH ), 2.07e2.54 (m, 4H,
2 2
3
3
2ꢂCH ), 3.76 (s, 3H, OMe), 3.98 (q, 2H, J¼7.1 Hz, CH ),
6
3
3
1.98e2.42 (m, 4H, 2ꢂCH ), 4.31 (s, 1H, CH), 5.73 (s, 2H,
ArH), 7.15e7.24 (m, 5H, ArH), 8.86 (s, 1H, NH); MS (ESI):
4.56 (s, 1H, CH), 6.82 (d, 2H, J¼8.0 Hz, ArH), 7.06 (d, 2H,
2
J¼8.0 Hz, ArH), 7.55 (s, 2H, NH ); MS (ESI): m/z 371.0
2
þ
þ
m/z 294.1 (MþH) . Anal. Calcd for C H N O: C, 73.69; H,
(MþH) . Anal. Calcd for C H N O : C, 68.09; H, 7.07;
21 26 2 4
1
8
19
3
6
.53; N, 14.32. Found: C, 73.73; H, 6.59; N, 14.35.
N, 7.56. Found: C, 68.13; H, 7.02; N, 7.54.

5
42
S. Kumar et al. / Tetrahedron 64 (2008) 536e542
7. Margarita, S.; Yamila, V.; Estael, M.; Nazario, M.; Roberto, M.; Margaria,
0
.4.5. 2-Amino-7,7-dimethyl-5-oxo-4-(4 -chlorophenyl)-1,4,5,
,7,8-hexahydroquinoline-3-carboxylic acid ethyl ester (6k)
4
6
Q.; Carlos, S.; Jose, S.; Hector, L. N.; Norbert, B.; Oswald, M.; Camiel, D.
J. Heterocycl. Chem. 2000, 37, 735.
ꢁ
ꢀ1
:
Light yellow solid, mp 174e176 C. IR (KBr) nmax/cm
8
. (a) Ohberg, L.; Westman, J. Synlett 2001, 1296; (b) Agarwal, A.; Chauhan,
P. M. S. Tetrahedron Lett. 2005, 46, 1345e1348; (c) Tu, S.; Zhang, J.;
Zhu, X.; Zhang, Y.; Wang, Q.; Xu, J.; Jiang, B.; Jia, R.; Zhang, J.;
Shi, F. J. Heterocycl. Chem. 2006, 43, 985e989.
3
1
465, 3329, 2995, 1726, 1595, 1507, 1365, 1272, 1208,
1
198, 1094, 1020, 816, 762; H NMR (200 MHz, CDCl ):
3
d 0.96 (s, 3H, CH ), 1.09 (s, 3H, CH ), 1.15 (t, 3H,
3
3
9
. (a) Ji, S.-J.; Jiang, Z.-Q.; Lu, J.; Loh, T.-P. Synlett 2004, 831e835; (b)
Sridhar, R.; Perumal, P. T. Tetrahedron 2005, 61, 2465e2470.
J¼7.1 Hz, CH ), 2.22 (m, 2H, CH ), 2.42 (m, 2H, CH ),
3
2
2
4
.04 (q, 2H, J¼7.1 Hz, CH ), 4.66 (s, 1H, CH), 6.17 (s, 2H,
2
1
0. Sabitha, G.; Reddy, G. S. K. K.; Reddy, C. S.; Yadav, J. S. Tetrahedron
Lett. 2003, 44, 4129e4131.
11. Wang, L.-M.; Sheng, J.; Zhang, L.; Han, J.-W.; Fan, Z.; Tian, H.; Qian,
NH ), 7.23 (m, 4H, ArH), 7.26 (s, 1H, NH); MS (ESI): m/z
3
C H ClN O : C, 64.08; H, 6.18; N, 7.47. Found: C, 64.03;
2
þ
74.1 (100), 376.1 (30) (MþH) . Anal. Calcd for
C.-T. Tetrahedron 2005, 61, 1539e1543.
2
0
23
2 3
1
2. Ko, S.; Sastry, M. N. V.; Lin, C.; Yao, C.-F. Tetrahedron Lett. 2005, 46,
771e5774.
3. Ko, S.; Yao, C.-F. Tetrahedron 2006, 62, 7293e7299.
H, 6.12; N, 7.44.
5
1
Acknowledgements
1
4. (a) Legeay, J. C.; Goujon, J. Y.; Eynde, J. J. V.; Toufet, L.; Bazureau, J. P.
J. Comb. Chem. 2006, 8, 829e833; (b) Dondoni, A.; Massi, A.; Minghini,
E.; Bertolasi, V. Tetrahedron 2004, 60, 2311e2326.
One of the authors, S.K. is thankful to CSIR, New Delhi for
financial assistance in the form of SRF.
1
5. Kumar, A.; Maurya, R. A. Tetrahedron 2007, 63, 1946e1952.
6. Rothenberg, G.; Downie, A. P.; Raston, C. L.; Scott, J. L. J. Am. Chem.
Soc. 2002, 123, 8701e8708.
1
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6
1