Synthesis of 1-(substituted phenylcarbonyl/sulfonylamino)-1,2,3,6- tetrahydropyridine-5-carboxylic acid diethylamides as potential anti-inflammatory agents

Article abstract of DOI:10.1002/jhet.5570430327

Fifteen novel 1-(substituted phenylcarbonyl/sulfonylamino)-1,2,3,6- tetrahydro- pyridine-5-carboxylic acid diethylamide (7, 15) were synthesized in fair to good yields via sodium borohydride reduction of the corresponding 1-(substituted phenylcarbonyl/ su

Full text of DOI:10.1002/jhet.5570430327

May-Jun 2006
709
Synthesis of 1-(Substituted Phenylcarbonyl/sulfonylamino)-1,2,3,6-
tetrahydropyridine-5-carboxylic acid diethylamides as Potential Anti-
inflammatory Agents
Madhavi Gangapuram and Kinfe K. Redda*
College of Pharmacy and Pharmaceutical Sciences,
Florida A&M University, Tallahassee, FL 32307, USA
Received September 29, 2005
O
O
Cl
N(C2H5)2
NO2
N(C2H5)2
N
N
1. Acetone, reflux
+
2. R-X-NH-NH2, Et3N, MeOH
3. p-Dioxane:H2O, reflux
N
X
R
NO2
O
N(C2H5)2
N
NaBH4
EtOH, 0 oC
NH
X
R
Fifteen novel 1-(substituted phenylcarbonyl/sulfonylamino)-1,2,3,6-tetrahydro- pyridine-5-carboxylic
acid diethylamide (7, 15) were synthesized in fair to good yields via sodium borohydride reduction of the
corresponding 1-(substituted phenylcarbonyl/ sulfonylimino)-3-diethylcarbamoyl pyridinium ylides (6, 14)
in absolute ethanol.
J. Heterocyclic Chem., 43, 709 (2006).
Introduction.
[14,15]. It became evident that the pharmacological
activities of the THP derivatives depended greatly on the
position and nature of the substitutents on the THP ring
structure [12,16,17]. Our research interest has focused on
the anti-inflammatory activities of several THP ring
containing compounds 1. In literature survey some of
these compounds showed hypotensive, analgesic,
antipyretic and anti-inflammatory activities with no
observed toxicity even at very high dose levels [6,16,18-
24]. All of these compounds contained a carbonyl or
sulfonyl group in their structure at position (X).
Nonsteroidal anti-inflammatory drugs are a nonhom-
ogeneous family of pharmacologically active compounds
used in the treatment of acute and chronic inflammation,
pain, and fever. Functionalized tetrahydropyridine (THPs)
ring systems are widely found in biologically active
natural products and pharmaceuticals [1-7]. 1,2,3,4-
Tetrahydroisoquinolines and tetrahydropyridines are
found in nature as alkaloids of a large number of plant
species. These compounds exhibit a wide rage of
physiological activities and they act as precursors for
many other groups of alkaloids such as morphinans,
aporphines and protoberberines. Synthetically prepared 1-
methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a
potent neurotoxic substance which causes chronic
Parkinsonism in humans when used intraveneously. Fries
et al., indicated that MPTP and its analogs have less or no
toxicity when alkyl groups were introduced on the
tetrahydropyridine ring [8-11]. Earlier work [12,13] by
Knaus and co-workers indicated the synthesis of a series
of N-(carbonylamino)-1,2,3,6-tetrahydropyridines (THPs)
which showed anti-inflammatory, analgesic and
hyperglycemic activities with no observed toxicities.
Tetrahydropyridines are also important starting materials
for the synthesis of benzomorphans, compounds with an
analgesic activity similar to that of the morphinans
N(C2H5)2
O
H
N
N
X
R
1
R = C6H5, 4-CH3-C6H5, 4-OCH3-C6H5, 4-F-C6H5, 4-Cl-C6H5, 3-Br-C6H5, 4-NH2-C6H5,
4-pyridyl, 3-pyridyl, 3,4,5-trimethoxy-C6H5, 4-tert-butyl-C6H5, 2-thiophene, 2-furan
X = Carbonyl, Sulfonyl
In a recent approach, the carbonyl group of the THPs
was replaced with a sulfonyl group producing new
derivatives
with
significantly
enhanced
anti-
inflammatory activities [25]. Our previous reports
indicated that alkyl groups on the THP ring system
possessed reasonably higher anti-inflammatory activity

710
M. Gangapuram and K. K. Redda
Vol 43
[16,17,19]. In the current report, we have synthesized
compounds maintaining the 1,2,3,6-tetrahydropyridine-
5-carboxylic acid diethylamide ring and having
modifications on the phenyl ring and interchanging the
sulfonyl/carbonyl group at position (X). These groups
were chosen on the expectation that they would exert
appropriate lipophilic, steric and electronic effects on
the molecule. The compounds will be subject to
biological testing to establish their anti-inflammatory,
and analgesic activities.
The synthesis of the target compounds (7) is shown
in Scheme 1 and the synthesis of the target compounds
(15) is shown in Scheme 2. In Scheme 1, 1-chloro-2,4-
dinitrobenzene (3) was reacted with N,N-diethyl
nicotinamide (2) in acetone under reflux for 12 hours.
This nucleophilic aromatic substitution reaction gave
the salt, 3-diethylcarbamoyl-1-(2,4-dinitrophenyl)
pyridinium chloride (4). Nucleophilic attack of pyridyl or
substituted benzoyl hydrazides or sulfonyl hydrazides
on the pyridinium chloride (4) in methanol containing
triethylamine at room temperature for 12 hours resulted
in the formation of 2,4-dinitroanilinoderivatives (5).
Hydrolysis of the product (5) with water: p-dioxane (1:4
v/v) mixture under reflux for 12 hours furnished the N-
(substituted phenyl carbonyl/sulfonylimino)-3-diethyl-
carbamoyl pyridinium ylides (6). Sodium borohyride
reduction of ylides (6) in absolute ethanol at 0 °C for 7
hours afforded then N-(substituted phenylcarbonyl/
sufonylamino)-1,2,3,6-tetrahydropyridine-5-carboxylic
acid diethylamide (7).
In Scheme 2, O-mesitylene sulfonyl hydroxylamine
(MSH) (11) was used to prepare the N-amino salt as
an aminating agent [26]. Mesitelene sulfonly chloride
(9) was added with stirring to
a solution of
ethylacetohydroxymate (8) and triethylamine in
dimethylformamide at 0 °C. After 1 hour, the reaction
mixture was poured onto ice/water to give ethyl O-
mesitylene sulfonylacetohydroxamate (10) in 88.0 %
yield. Stirring the mixture of (10) in p-dioxane with 70%
perchloric acid and allowing them to react for 40 min,
gave a white solid of MSH (11) in 63.2% yeild. N,N-
Diethylnicotinamide (2) was reacted with MSH (11) in
dichloromethane to produce 1-amino-(3-diethyl-
carbamoyl)pyridine mesitylenesulfonate (12). Reaction of
(12) with substituted acid chlorides (13) in anhydrous
tetrahydrofuran at 70 °C gave stable ylides (14a-14d).
Sodium borohydride reduction of (14a-14d) in absolute
ethanol furnished the target compounds 1-(substituted
phenylcarbonylamino)-1,2,3,6-tetrahydropyridne-5-
carboxlic acid diethylamides (15a-15d).
Results and Discussion.
The results of the synthesis of the pyridinium ylides (6
and 14) and corresponding 1,2,3,6-tetrahydropyridines (7
and 15) are presented in Table 1 and Table 2.
1
1,2,3,6-Tetrahydropyridines 7 and 15 show typical H
NMR absorption at approximately ꢀ 3.11 observed as a
triplet, which corresponds to C2-protons coupled to the
C3-protons. Since C2-protons are directly connected to N-
atom of the tetrahydropyridine ring they are deshielded
Scheme 1
O
N(C2H5)2
Cl
O
NO2
N
Acetone, reflux
N(C2H5)2
Cl
+
NO2
N
H
NO2
R X N NH2
2
3
Et3N, MeOH
NO2
4
O
O
O
N(C2H5)2
N(C2H5)2
N(C2H5)2
N
NH NH
X R
N
N
X
R
N
NaBH4
p-Dioxane:H2O
NH
X
NO2
EtOH, 0°C
Reflux
R
7
6
NO2
5
R = C6H5, 4-CH3-C6H5, 4-OCH3-C6H5, 4-F-C6H5, 4-Cl-C6H5, 3-Br-C6H5, 4-NH2-C6H5,
4-pyridyl, 3-pyridyl,
X = CO, SO2

May-Jun 2006
Synthesis of 1-(Substituted Phenylcarbonyl/sulfonylamino)-1,2,3,6-
tetrahydropyridine-5-carboxylic acid diethylamides
711
Scheme 2
O
S
O
S
H3C
H3C
DMF, Et3N
00C, 45 min
NOH
+
N
O
Cl
O
O
O
O
9
8
10
70% HClO4,
p-dioxane
0°C, 45 min
O
O
O
S
N(C2H5)2
N(C2H5)2
CH2Cl2
H2N
O
+
N
00C, 3 hour
O
OMes
N
NH2
12
2
11
O
O
Anhydrous
THF
12 hour,
reflux
N(C2H5)2
R-CO-Cl
N(C2H5)2
13
N
N
O
NaBH4, EtOH (absolute)
00C, 7 hours
N
HN
O
O
R
R
-OMes = O
S
14
15
O
R = 4-tert-butyl-C6H5, 3,4,5-tri-methoxy-C6H5, 2-thiophene, 2-furan
Table 1
Pyridinium Ylides 6a-6k and 14a-14d Synthetic data
N(C2H5)2
O
N
N X R
R
X
M.W.
Mp
( °C)
Yield
%
Compound
6a
6b
6c
6d
3 -pyridyl
4 -pyridyl
phenyl
CO
CO
CO
CO
298.34
298.34
297.35
311.38
136-138
115-117
99-101
99-100
63.8
65.4
65.6
79.5
4-methylbenzyl
6e
4-flurobenzyl
CO
315.34
semi solid
64.3
6f
6g
4-chlorobenzyl
3-bromobenzyl
4-aminobenzyl
phenyl
CO
CO
CO
SO2
SO2
SO2
CO
CO
CO
CO
331.8
376.25
312.37
333.41
347.43
363.43
387.43
353.21
303.38
287.31
94-96
97-98
66.5
61.7
77.5
60.1
77.1
55.9
62.1
44.5
83.1
82.2
6h
6i
6j
163-165
145-147
140-142
125-127
51-52
4-methylbenzyl
4-methoxybenzyl
3,4,5-trimethoxybenzyl
4-tert-butylbenzyl
2-thiophenyl
6k
14a*
14b*
14c*
14d*
67-68
80-82
2-furanyl
132-133
* compounds 14a-14d is prepared in Scheme 2.

712
M. Gangapuram and K. K. Redda
Vol 43
Table 2
1,2,3,6-Tetrahydropyridines 7a-7k and 15a-15d Synthetic Data
N(C2H5)2
O
H
N
N
X
R
Compound
R
X
M.W.
Mp
( °C)
Yield
%
7a
7b
7c
7d
3 -pyridyl
CO
CO
CO
CO
CO
CO
CO
CO
SO2
SO2
SO2
CO
CO
CO
CO
302.37
302.37
301.38
315.41
319.37
335.83
380.28
316.4
337.44
351.46
367.46
391.46
357.49
307.41
291.35
127-129
124-126
48-50
38.5
50.4
53.1
38.4
43.3
48.6
55.3
34.4
42.3
58.0
49.4
40.7
30.8
38.4
48.2
4 -pyridyl
phenyl
4-methylbenzyl
4-flurobenzyl
4-chlorobenzyl
3-bromobenzyl
4-aminobenzyl
phenyl
120-122
125-126
137-139
53-55
7e
7f
7g
7h
7i
178-180
132-134
148-150
145-147
151-152
96-98
7j
4-methylbenzyl
4-methoxybenzyl
3,4,5-trimethoxybenzyl
4-tert-butylbenzyl
2-thiophene
7k
15a*
15b*
15c*
15d*
48-50
50-51
2-furan
* Compounds 15a-15d is prepared in Scheme 2.
Georgia. Separations on column chromatography were
performed on silica gel (Fisher Brand 200-425 mesh). All
reactions and purification procedures were monitored by TLC
on Whatmann AL SIL G/UV, 250μm layer flexible plates, with
visualization under UV light.
thus absorbing at a lower field than those of C3-protons,
which are farther away form the N-atom and C3-protons are
expected to absorb at around ꢀ 2.41 when compared to C2-
protons. On the other hand, C6-protons generally absorb at ꢀ
3.71 and are seen at slightly lower field than the C2-protoons
because they are near the double bond and N-atom
environment. The broad singlet at around ꢀ 3.71 was
assigned to C6-protons, which have very weak coupling with
C4-proton. The peak at ꢀ 5.84 is a unique indication of vinyl
proton of the terahydropyridines on the C4-proton. The
infrared (ir) spectrum confirmed the presence of structural
features in targeted compounds, which typically display
absorption approximately at 3200 (NH), 1660 (CO) cm-1.
The pharmacological evaluations of the compounds for anti-
inflammatory and analgesic activities are underway.
General Procedure A.
3-[(Diethylamino)carbonyl]-1-[(3-pyridylcarbonyl)imino]pyri-
dinium Ylide (6a).
N, N-Diethylnicotinamide (2) (10 g, 56.1 mmoles) was added
to a stirring solution of 1-chloro-2, 4-dinitrobenzene (3) (11.37
g, 56.1 mmoles) in acetone (150 ml) drop wise addition over a
period of 15 minutes and the reaction mixture was refluxed for
12 hours. The reaction mixture was cooled to room temperature
and filtered. The residue was washed with acetone (3 X 100 ml)
and dried in vacuo at room temperature. The crude product 3-
diethylcarbamoyl-1-(2,4-dinitrophenyl)pyridinium chloride salt
(4) was vacuum filtered and crystallized from ethyl
acetate:methanol (4:1 v/v 50 ml) to afford 12.34 g (57.76%) of
pale yellow crystals, mp 157-158 °.
EXPERIMENTAL
1H nmr spectra were determined on a Brucker HX 300 MHz
spectrometer using CDCl3 as a solvent and the chemical shifts
are reported in parts per million (ꢀ ppm) downfield from
tetramethylsilane as an internal standard. Infrared spectra
obtained on a Perkin-Elmer FTIR 1430 spectrometer, using KBr
pellets unless otherwise stated. Elemental analyses were
performed by Galbraith Laboratories, Inc., Knoxville, TN, USA.
Melting points were determined on a Mel-Temp 3.0 melting
point apparatus and were uncorrected. Chemicals and solvents
were purchased from Sigma-Aldrich Chemical Company Inc.,
Milwaukee, Wisconsin, Fisher Scientific Company, Suwanee,
Compound (4) (3.00 g, 7.89 mmoles) was dissolved in
methanol (100 ml) and stirred at 0 °C for 10 minutes followed by
addition of (1.08 g, 7.89 mmoles) nicotinic acid hydrazide. To this
solution (1.0 ml) triethylamine was added and the mixture stirred
at 0° for 1 hour and continued to stir at room temperature for 12
hours. The brown precipitate that formed was filtered and washed
with 50 ml of hexane and 300 ml of water. The residue was
immediately refluxed in water: p-dioxane (80 ml, 1:4 v/v) for 12
hours to afford a clear solution. The reaction medium was
evaporated under reduced pressure and obtained the brownish
residue. The crude product was chromatographed on a column

May-Jun 2006
Synthesis of 1-(Substituted Phenylcarbonyl/sulfonylamino)-1,2,3,6-
tetrahydropyridine-5-carboxylic acid diethylamides
713
Table 3
Elemental Analysis of the Pyridinium ylides (6a-6k and 14a-14d)
N (C2H5)2
O
N N X R
Compound
R
Molecular Formula
MW
Analysis %
Calcd./Found
H
C
N
6a
6b
3-pyridyl
4-pyridyl
C16H18N4O2
C16H18N4O2
C17H19N3O2
C18H21N3O2
C17H18FN3O2
C17H18ClN3O2
C17H18BrN3O2
C17H20N4O2
C16H19N3O3S
C17H21N3O3S
C17H21N3O4S
C20H25N3O5
C21H27N3O2
C15H17N3O2S
C15H17N3O3
298.34
298.34
297.35
311.38
315.34
331.18
376.25
312.37
333.41
347.43
363.43
387.43
353.46
303.38
287.31
64.41
64.50
64.41
64.62
68.76
68.76
69.43
69.34
64.75
65.00
61.54
61.42
54.27
54.36
65.37
65.45
57.64
57.72
58.77
58.65
56.18
58.27
62.00
62.13
71.36
71.45
59.38
59.47
62.71
62.87
6.08
6.10
6.08
6.15
6.44
6.54
6.80
6.87
5.75
5.84
5.47
5.54
4.82
4.90
6.45
6.55
5.74
5.81
6.09
6.09
5.82
5.94
6.50
6.58
7.70
7.79
5.65
5.76
5.96
6.06
18.78
18.88
18.78
19.02
14.13
13.95
13.49
13.60
13.33
13.45
12.66
12.74
11.17
11.20
17.94
18.13
12.60
12.71
12.09
12.18
11.56
11.69
10.85
10.93
11.89
12.09
13.85
13.99
14.63
14.88
6c
phenyl
6d
4-methylbenzyl
4-flurobenzyl
4-chlorobenzyl
3-bromobenzyl
4-aminobenzyl
phenyl
6e
6f
6g
6h
6i
6j
4-methylbenzyl
4-methoxybenzyl
3,4,5-trimethoxybenzyl
4-tert-butylbenzyl
2-thiophenyl
6k
14a*
14b*
14c*
14d*
2-furanyl
* Compounds 14a-14d is prepared in Scheme 2.
(2.5 X 22 cm) of silica gel (200-425 mesh) using ethyl acetate:
methanol (3:2 v/v, 500 ml) as the eluent. The product was
recrystallized form ethyl acetate to afford 1.3 g (63.8%) of yellow
crystals, mp 136-138°. The other derivatives were similarly
prepared and purified. IR (potassium bromide): ꢀ 1644, 1591
(C=O) cm-1; 1H nmr (CDCl3): ꢀ 1.23 (t, 6H, J = 7 Hz, CH2-CH3),
3.41 (d, 2H, J = 6.1 Hz, CH2-CH3), 3.55 (d, 2H, J = 6.0 Hz, CH2-
CH3), 7.33 (dd, 1H, J = 4.8, 3.0 Hz, C5 -H), 7.73 (dd, 1H, J= 6.6,
0.9 Hz, C4 -H), 7.95 (tt, 1H, J = 1.5, 1.5 Hz, C5-H), 8.39 (tt, 1H, J
= 2.1, 2.1 Hz, C4-H), 8.64 (d, 1H, J = 3.9 Hz, C6 -H), 8.84 (tt, 1H, J
= 1.2, 1.5 Hz, C6-H), 9.01 (s, 1H, C2 -H), 9.34 (s, 1H, C2-H).
Anal. Calcd. for C16H18N4O2: C, 64.41; H, 6.08; N, 18.78.
Found: C, 64.50; H, 6.10; N, 18.88.
(potassium bromide): ꢀ 1630, 1597 (C=O) cm-1; 1H nmr
(CDCl3): ꢀ 1.25 (t, 6H, J = 7 Hz, CH2-CH3), 3.41 (d, 2H, J = 6.6
Hz, CH2-CH3), 3.56 (d, 2H, J = 6.0 Hz, CH2-CH3), 7.75 (dd, 1H,
J= 6.3, 0.9 Hz, C5-H), 7.96 (dd, 2H,J = 0.9, 2.1 Hz, C2 -H, C6 -
H), 7.98 (t, 1H, J = 1.5 Hz, C4-H), 8.69 (d, 2H, J = 4.8 Hz, C3 -H,
C5 -H), 8.82 (tt, 1H, J = 1.2, 1.2 Hz C6-H), 9.00 (s, 1H, C2-H).
Anal. Calcd. for C16H18N4O2: C, 64.41; H, 6.08; N, 18.78.
Found: C, 64.51; H, 6.15; N 19.02.
1-(Benzoylamino)-3-[(diethylamino)carbonyl]pyridinium Ylide
(6c).
The compound 6c was obtained following General Procedure
to furnish pail yellow color compound in (2.56 g) 65.6% yield,
mp 99-101°; ir (potassium bromide): ꢀ 1636, 1625 (C=O) cm-1;
1H nmr (CDCl3): ꢀ 1.24 (t, 6H, J = 6 Hz, CH2-CH3), 3.41 (d, 2H,
J = 6.3 Hz, CH2-CH3), 3.56 (d, 2H, J = 6.5 Hz, CH2-CH3), 7.40-
7.45 (m, 3H, C3 , C4 and C5 -H), 7.70 (dd, 2H, J = 6.3, 6.9 Hz, C2,
C6 -H ), 7.91 (tt, 1H, J = 1.2, 1.5 Hz, C5-H) 8.14 (t, 1H, J = 1.8
3-[(Diethylamino)carbonyl]-1-[(4-pyridylcarbonyl)imino]pyri-
dinium Ylide (6b).
The compound 6b was obtained following General Procedure
A has yellow color solid, 2.6 g (65.4%), mp115-117°; ir

714
M. Gangapuram and K. K. Redda
Vol 43
Table 4
Elemental Analysis of the Tetrahydropyridines (7a-7k and 15a-15d)
N (C2H5)2
O
H
N N X R
Compound
R
Molecular Formula
MW
Analysis %
Calcd./Found
H
C
N
7a
7b
7c
7d
7e
7f
3-pyridyl
4-pyridyl
phenyl
C16H22N4O2
C16H22N4O2
C17H23N3O2
C18H25N3O2
C17H22FN3O2
C17H22ClN3O2
C17H22BrN3O2
C17H24N4O2
C16H23N3O3S
C17H25N3O3S
C17H25N3O4S
C20H29N3O5
302.37
63.55
63.80
63.55
63.20
67.75
67.90
68.54
68.55
63.93
64.07
60.80
60.78
53.69
53.78
64.53
64.62
56.95
57.10
58.09
58.27
55.57
55.36
61.36
61.00
7.33
7.42
7.33
7.38
7.69
7.85
7.99
8.07
6.94
7.03
6.60
6.58
5.83
5.94
7.65
7.79
6.87
6.96
7.17
7.24
6.86
6.98
7.47
7.60
18.53
18.79
18.53
18.34
13.94
14.03
13.32
13.27
13.16
13.44
12.51
12.42
11.05
11.20
17.71
17.38
12.45
12.56
11.96
12.08
11.44
11.53
10.73
10.60
302.37
301.38
315.41
319.37
335.83
380.28
316.40
337.44
351.46
367.46
391.46
4-methylbenzyl
4-flurobenzyl
4-chlorobenzyl
3-bromobenzyl
4-aminobenzyl
phenyl
7g
7h
7i
7j
4-methylbenzyl
4-methoxybenzyl
3,4,5-trimethoxybenzyl
7k
15a*
15b*
15c*
4-tert-butylbenzyl
C21H31N3O2
357.49
311.56
70.55
70.74
57.83
57.92
8.74
8.83
6.87
7.11
11.75
11.99
13.49
13.13
2-thiophenyl
C15H21N3O2S.
0.115H2O
15d*
2-furanyl
C15H21N3O3
291.35
61.84
61.72
7.27
7.48
14.42
14.10
* Compounds 15a-15d is prepared in Scheme 2.
Hz, C4-H), 8.82 (tt, 1H, J= 1.2, 1.5 Hz, C6-H), 9.01 (s, 1H, C2-
H).
3-Diethylaminocarbonyl-1-(4-fluorobenzoylimino)pyridinium
Ylide (6e).
Anal. Calcd. for C17H19N3O2: C, 68.67; H, 6.44; N, 14.13.
Found: C, 68.76; H, 6.54; N, 13.95.
The compound 6e was obtained following General Procedure
A has a brownish semi-solid (1.6 g, 64.3 %), ir (potassium
1
bromide): ꢀ 1628, 1618 (C=O) cm-1; H nmr (CDCl3): ꢀ 1.24 (t,
3-[(Diethylamino)carbonyl]-1-[(4-methylbenzoyl)imino]pyri-
dinium Ylide (6d).
6H, J = 6.7 Hz, CH2-CH3), 3.35 (d, 2H, J = 6 Hz, CH2-CH3),
3.55 (d, 2H, J = 5.8 Hz, CH2-CH3), 7.47 (d, 2H, J = 8.4 Hz, C3 -
H C5 -H), 7.97 (dd, 2H, J = 7.1, 7.8 Hz, C2 -H, C6 -H), 8.23 (d,
1H, J = 8.5 Hz, C5-H), 8.34 (d, 1H, J = 6.7 Hz, C4-H), 8.99 (s,
1H, C2-H), 9.23 (d, 1H, J = 5.9 Hz, C6-H).
The compound 6d was obtained following General Procedure
A to furnish (6d) has yellow crystals in 79.5 % (2.6 g) yield, mp
1
99-100°; ir (potassium bromide): ꢀ 1625, 1615 (C=O) cm-1; H
nmr (CDCl3): ꢀ 1.21 (t, 6H, J = 6.9 Hz, CH2-CH3), 2.37 (s, 3H,
CH3 group of phenyl), 3.37 (d, 2H, J = 5.9 Hz, CH2-CH3), 3.54
(d, 2H, J = 5.7 Hz, CH2-CH3), 7.19 (d, 2H, J = 8.1 Hz, C3 -H, C5
-H), 7.62 (dd, 1H, J = 6.6, 6.3 Hz, C5-H), 7.89 (tt, 1H, J = 1.2,
1.2 Hz, C4-H) 8.00 (d, 2H, J = 8.1 Hz, C2 ,C6 -H), 8.77 (tt, 1H, J
= 1.2, 1.2 Hz, C6-H), 8.95 (s, 1H, C2-H).
Anal. Calcd. For C17H18FN3O2: C, 64.75; H, 5.75; N, 13.33.
Found: C, 65.00; H, 5.84; N, 13.45.
1-[(4-Chlorobenzoyl)imino]-3-[(diethylamino)carbonyl]pyri-
dinium Ylide (6f).
The compound 6f was obtained following General Procedure
A has a yellow color solid in 66.5% (2.9 g) yield, mp 94-96 °; ir
(potassium bromide): ꢀ 1635, 1628 (C=O) cm-1; 1H nmr
Anal. Calcd. for C18H21N3O2: C, 69.43; H, 6.80; N, 13.49.
Found: C, 69.34; H, 6.87; N, 13.60.

May-Jun 2006
Synthesis of 1-(Substituted Phenylcarbonyl/sulfonylamino)-1,2,3,6-
tetrahydropyridine-5-carboxylic acid diethylamides
715
(CDCl3): ꢀ 1.23 (t, 6H, J = 6.9 Hz, CH2-CH3), 3.43 (d, 2H, J =
5.9 Hz, CH2-CH3), 3.55 (d, 2H, J = 5.7 Hz, CH2-CH3), 7.47 (d,
2H, J = 8.4 Hz, C3 -H C5 -H), 7.97 (dd, 2H, J = 7.2, 8.7 Hz, C2 -
H, C6 -H), 8.23 (d, 1H, J = 8.4 Hz, C5-H), 8.33 (tt, 1H, J = 1.2,
1.2 Hz, C4-H) 8.99 (tt, , 1H, J = 1.2, 1.2 Hz, C6-H), 9.04 (s, 1H,
C2-H).
H), 7.95 (tt, 1H, J = 1.5, 1.2 Hz, C4-H), 8.44 (tt, 1H, J = 1.2, 1.2
Hz, C6-H), 8.48 (s, 1H, C2-H).
Anal. Calcd. for C17H21N3O3S: C, 58.77; H, 6.09; N, 12.09.
Found: C, 58.65: H, 6.09: N, 12.18.
3-[(Diethylamino)carbonyl]-1-[(4-methoxyphenylsulfonyl)imino]-
pyridinium Ylide (6k).
Anal. Calcd. for C17H18ClN3O2: C, 61.54; H, 5.47; N, 12.66.
Found: C, 61.42; H, 5.54; N, 12.74.
The compound 6k was obtained following General Procedure
A to furnish off-white color solid in 55.9% (2.6 g) yield, mp
125-127°, ir (potassium bromide): ꢀ 1634 (C=O) and 1287, 1145
1-[(3-Bromobenzoyl)imino]-3-[(diethylamino)carbonyl]pyri-
dinium Ylide (6g).
1
(SO2) cm-1; H NMR (CDCl3): ꢀ 1.10 (t, 3H, J = 7.0 Hz, -CH2-
The compound 6g was obtained following General Procedure
A has shiny yellow color solid in 61.7% (3.0 g) yield, mp 97-
CH3), 1.20 (t, 3H, J = 7.5 Hz, -CH2-CH3), 3.17 (d, 2H, J = 6.0
Hz, -CH2-CH3), 3.51 (d, 2H, J = 6.0 Hz, -CH2-CH3), 3.79 (s, 3H,
-OCH3 of phenyl ring), 6.84 (dd, 2H, J = 3.0, 3.0 Hz, C3 , C5 -H),
7.57 (dd, 1H, J = 6.3, 6.3 Hz, C5-H), 7.66 (tt, 2H, J = 2.7, 2.1 Hz,
C2 , C6 -H), 7.94 (tt, 1H, J = 1.2, 1.2 Hz, C4-H), 8.44 (tt, 1H, J
=1.2, 1.5 Hz, C6-H), 8.50 (s, 1H, C2-H).
1
98°, ir (potassium bromide): ꢀ 1628, 1616 (C=O) cm-1; H nmr
(CDCl3): ꢀ 1.25 (t, 6H, J = 6.7 Hz, CH2-CH3), 3.34 (d, 2H, J = 6
Hz, CH2-CH3), 3.54 (d, 2H, J = 5.8 Hz, CH2-CH3), 7.27 (d, 1H, J
= 7.7 Hz, C5 -H), 7.54 (d, 1H, J = 7.8 Hz, C4 -H), 7.71 (t, 1H, J =
6.6 Hz, C6 -H) 7.94 (d, 1H, J = 7.8 Hz, C2 -H), 8.05 (d, 1H, J=
7.7 Hz, C5-H ), 8.28 (t, 1H, J = 1.7 Hz, C4-H) 8.78 (d, 1H, J =
6.3 Hz, C6-H), 8.96 (s, 1H, C2-H).
Anal. Calcd. for C17H21N3O4S: C, 56.18; H, 5.82; N, 11.56.
Found: C, 58.27; H, 5.94; N, 11.69.
General Procedure B.
Anal. Calcd. for C17H18BrN3O2: C, 54.27; H, 4.82; N, 11.17.
Found: C, 54.36; H, 4.90; N, 11.20.
3-Diethylcarbamoyl-1-(3,4,5-trimethoxybenzoylimino)pyri-
dinium Ylide (14a).
1-(4-Aminobenzoylimino)-3-diethylcarbamoyl-pyridinium Ylide
(6h).
1-Amino-3-diethylcarbamoyl pyridinium mesitylene-
sulfonates (12) were synthesized by the method described earlier
by Tamura et al [26]. To an ice-cold solution of (12) (5.0 g,
12.71 mmoles) in anhydrous tetrahydrofuran (80 ml) was added
3,4,5-trimethoxy benzenesulfonyl chloride (13a) (5.86 g, 25.42
mmoles) drop wise. The reaction was allowed to reflux for 12
hours at 70°. After cooling to room temperature, the reaction
was quenched by adding 40 ml of a saturated aqueous sodium
bicarbonate solution. The mixture was shaken repeatedly in a
separatory funnel and allowed to stand for a few minutes. The
solution was extracted with chloroform (3 x 100 ml), drying
over anhydrous sodium sulfate, filtration and solvent was
removed in vacuo gave the crude product, which was purified by
column chromatography (2.5 x 22 cm) on silica gel (200-425
mesh) using ethyl acetate:methanol (9:1v/v) as eluent. The
resultant product (14a) was white crystalline solid obtained in
62.1% (3.1 g) yield, mp 51-52°; ir (potassium bromide): ꢀ 1630,
The compound 6h was obtained following General Procedure
A to furnish 6h has a yellow crystals in 77.5% (1.9 g) yield, mp
163-165°, ir (potassium bromide): ꢀ 1630, 1617 (C=O), 3236
1
(NH2) cm-1; H nmr (CDCl3): ꢀ 1.12 (t, 6H, J = 7.0 Hz, CH2-
CH3), 2.50 (brs, 2H, -NH2), 3.40 (q, 4H, J = 6.5, 6.6 Hz, CH2-
CH3), 6.67 (dd, 2H, J = 6.5, 6.6 Hz, C3 -H C5 -H), 7.66 (dd, 2H, J
= 6.3, 7.2 Hz, C2 -H, C6 -H), 7.88 (d, 1H, J= 8.5 Hz, C5-H), 7.97
(t, 1H, J = 6.9 Hz, C4-H), 8.81 (dd, 1H, J= 0.9, 1.2 Hz, C6-H) ,
8.98 (s, 1H, C2-H).
Anal. Calcd. For C17H20N4O2: C, 65.37; H, 6.45; N, 17.94.
Found: C, 65.45; H, 6.55; N, 18.13.
3-[(Diethylamino)carbonyl]-1-[(phenylsulfonyl)imino]pyri-
dinium Ylide (6i).
The compound 6i was obtained following General Procedure
A to furnish 6i has yellow crystals in 60.1% (3.1 g) yield, mp
145-147°, ir (potassium bromide): ꢀ 1644 (C=O), 1284 and 1138
1
1610 (C=O) cm-1; H nmr (CDCl3): ꢁ 1.04 (t, 3H, J = 6.3 Hz, -
1
(SO2) cm-1; H nmr (CDCl3): ꢀ 1.08 (t, 3H, J = 7.0 Hz, -CH2-
CH2-CH3), 1.18 (t, 3H, J = 6.3 Hz, -CH2-CH3), 2.24 (s, 3H, p-
OCH3), 2.64 (s, 6H, m-OCH3), 3.21 (d, 2H, J = 6.6 Hz, -CH2-
CH3), 3.47 (d, 2H, J = 6.6 Hz, -CH2-CH3), 6.84 (s, 2H, -C2 , C6 -
H), 7.69 (dd, 1H, J = 6.3, 6.3 Hz, C5-H), 7.87 (t, 1H, J = 6.9 Hz,
C4-H), 9.0 (s, 1H, C6-H), 9.17 (d, 1H, J = 6.6 Hz, C2-H).
Anal. Cacld. for C20H25N3O5: C, 62.00; H, 6.50: N, 10.85.
Found: C, 62.13; H, 6.58; N, 10.93.
CH3), 1.21 (t, 3H, J = 7.5 Hz, -CH2-CH3), 3.15 (d, 2H, J = 6.0
Hz, -CH2-CH3), 3.49 (d, 2H, J = 6.0 Hz, -CH2-CH3), 7.33-7.40
(m, 3 H, C3 , C4 and C5 -H), 7.60 (dd, 1H, J = 1.5, 1.5 Hz, C5-H),
7.71 (tt, 2H, J = 1.5, 1.8 Hz, C2 , C6 -H), 7.97 (tt, 1H, J = 1.2, 1.2
Hz, C4-H), 8.44 (d, 1H, J = 6.3 Hz, C6-H), 8.47 (s, 1H, C2-H).
Anal. Calcd. for C16H19N3O3S: C, 57.64; H, 5.74; N, 12.60.
Found: C, 57.72; H, 5.81; N, 12.71.
1-(4-tert-Butylbenzoylimino)-3-diethylcarbamoylpyridinium
Ylide (14b).
3-[(Diethylamino)carbonyl]-1-[(4-methylphenylsulfonyl)imino]-
pyridinium Ylide (6j).
The compound 14b was obtained following General
Procedure B to furnish 14b has white solid obtained in 44.5%
(1.0 g) yield, mp 67-68°; ir (potassium bromide): ꢀ 1635, 1620
The compound 6j was obtained following General Procedure
A to furnish 6j has yellow color solid in 77.1% (3.5 g) yield, mp
140-142 °, ir (potassium bromide): ꢀ 1636 (C=O) and 1285,
1
(C=O) cm-1; H nmr (CDCl3): ꢁ 1.18 (t, 6H, J = 6.3 Hz, -CH2-
1
1137 (SO2) cm-1; H nmr (CDCl3): ꢀ 1.08 (t, 3H, J = 7.0 Hz, -
CH3), 1.21 (s, 9H, -t-butyl group), 3.21 (d, 2H, J = 6.6 Hz, -CH2-
CH3), 3.47 (d, 2H, J = 6.6 Hz, -CH2-CH3), 7.37 (d, 2H, J = 9.0
Hz, C3 , C5 - H), 7.64 (dd, 2H, J = 7.2, 7.5 Hz, C2 , C6 -H), 7.87
(d, 1H, J = 7.5 Hz, C5-H), 8.01(d, 1H, J = 8.7 Hz, C4-H), 8.77 (d,
1H, J = 6.6 Hz, C6-H), 8.93 (s, 1H, C2-H).
CH2-CH3), 1.21 (t, 3H, J = 6.9 Hz, -CH2-CH3), 2.33 (s, 3H, -CH3
of phenyl ring), 3.16 (d, 2H, J = 5.8 Hz, -CH2-CH3), 3.50 (d, 2H,
J = 5.7 Hz, -CH2-CH3), 7.15 (d, 2H, J = 7.8 Hz, C3 , C5 -H), 7.56
(d, 2H, J = 7.8 Hz, C2 , C6 -H), 7.60 (dd, 1H, J = 1.5, 1.5 Hz, C5-

716
M. Gangapuram and K. K. Redda
Vol 43
1-(4-Pyridylcarbonylamino)-1,2,3,6-tetrahydropyridine-5-carbox-
ylic acid diethylamide (7b).
Anal. Calcd. for C21H27N3O2: C, 71.36; H, 7.70; N, 11.89.
Found: C, 71.45; H, 7.79; N, 12.09.
The compound 7b was obtained following General Procedure
C has white solid 50.4% (0.51 g) yield, mp 124-126°; ir
(potassium bromide): ꢀ 3233 (NH), 1660 and 1608 (C=O) cm-1;
1H nmr (CDCl3): ꢀ 1.11 (t, 6H, J = 6.7 Hz, -CH2-CH3), 2.40-2.43
(m, 2H, C3-H), 3.12 (t, 2H, J = 6.7 Hz, C2H), 3.44 (q, 4H, J =
6.9, 7.0 Hz, -CH2-CH3), 3.71 (d, 2H, J = 1.8 Hz, C6-H), 5.76-
5.81 (m, 1H, C4-H, olefinic), 7.65 (d, 2H, J = 5.9 Hz, C3 , C5 -H),
8.23 (s, 1H, -NH, D2O exchangeable), 8.69 (d, 2H, J = 5.8 Hz,
C2 , C6 -H).
3-Diethylcarbamoyl-1-[(thiophene-2-carbonyl)imino]pyridinium
Ylide (14c).
The compound 14c was obtained following General
Procedure B to furnish 14c has yellow needles obtained in
83.1% (2.5 g) yield, mp 80-82°; ir (potassium bromide): ꢀ 1631,
1
1615 (C=O) cm-1; H nmr (CDCl3): ꢁ 1.22 (t, 6H, J = 6.4 Hz, -
CH2-CH3), 3.24 (d, 2H, J = 6.6 Hz, -CH2-CH3), 3.47 (d, 2H, J =
6.6 Hz, -CH2-CH3), 6.41 (dd, 1H, J = 1.9, 1.8 Hz, -C3 -H), 7.10
(dd, 1H, J = 1.2, 2.4 Hz, -C4 -H), 7.50 (dd, 1H, J = 0.9, 1.2 Hz, -
C5 -H), 7.72 (dd, 1H, J= 1.5, 1.5 Hz, C5-H), 7.94 (tt, 1H, J= 1.5,
1.2 Hz, C4-H), 8.75 (tt, 1H, J = 1.2, 1.2 Hz, C6-H), 9.02 (s, 1H,
C2-H).
Anal. Calcd. for C16H22N4O2: C, 63.55; H, 7.33; N, 18.53.
Found: C, 63.20; H, 7.38; N, 18.34.
1-Benzoylamino-1,2,3,6-tetrahydropyridine-5-carboxylic acid
diethylamide (7c).
Anal. Calcd. for C15H17N3O2S: C, 59.38; H, 5.65; N, 13.85.
Found: C, 59.47; H, 5.76; N, 13.99.
The compound 7c was obtained following General Procedure
C has white solid 53.1% (0.85 g) yield, mp 48-50°; ir (potassium
bromide): ꢀ 3238 (NH), 1670, 1604 (C=O) cm-1; 1H nmr
(CDCl3): ꢀ 1.14 (t, 6H, J = 7.2 Hz, -CH2-CH3), 2.39-2.43 (m,
2H, C3-H), 3.15 (t, 2H, J = 6.0 Hz, C2-H), 3.41 (q, 4H, J = 6.9,
7.5 Hz, -CH2-CH3), 3.71 (d, 2H, J = 1.8 Hz, C6-H), 5.81-5.87
(m, 1H, C4-H, olefinic), 7.34 (s, 1H, -NH, D2O exchangeable),
7.41-7.45 (m, 3H, C3 , C4 and C5 -H), 7.75 (d, 2H, J = 6.9 Hz,
C2, C6 -H).
3-Diethylcarbamoyl-1-[(furan-2-carbonyl)-imino]pyridinium
Ylide (14d).
The compound 14d was prepared as outlined in General
Procedure B has a white solid 82.2% (3.1 g) yield, mp 132-133°;
ir (potassium bromide): ꢀ 1628, 1618 (C=O) cm-1; 1H nmr
(CDCl3): ꢁ 1.21 (t, 6H, J = 6.3 Hz, -CH2-CH3), 3.21 (d, 2H, J =
6.6 Hz, -CH2-CH3), 3.47 (d, 2H, J = 6.6 Hz, -CH2-CH3), 6.46
(dd, 1H, J = 1.8, 1.8 Hz, -C3 -H), 7.07 (dd, 1H, J = 0.9, 2.4 Hz, -
C4 -H), 7.49 (dd, 1H, J = 0.6, 0.9 Hz, -C5 -H), 7.70 (dd, 1H, J =
1.5, 1.5 Hz, C5-H), 7.93 (tt, 1H, J = 1.5, 1.2 Hz, C4-H), 8.79 (tt,
1H, J = 1.2, 1.2 Hz, C6-H), 9.01 (s, 1H, C2-H).
Anal. Calcd. for C17H23N3O2: C, 67.75; H, 7.69; N, 13.94.
Found: C, 67.90; H, 7.85; N, 14.03.
1-(4-Methyl-benzoylamino)-1,2,3,6-tetrahydropyridine-5-carbox-
ylic acid diethylamide (7d).
Anal. Calcd. for C15H17N3O3: C, 62.71; H, 5.96; N, 14.63.
Found: C, 62.87; H, 6.06; N, 14.88.
The compound 7d was obtained following General Procedure
C has white crystals in 38.4% (0.78 g) yield, mp 120-122°; ir
General procedure C.
1
(potassium bromide): ꢀ 3240 (NH), 1657, 1608 (C=O) cm-1; H
1-(3-Pyridylcarbonylamino)-1,2,3,6-tetrahydropyridine-5-carbox-
ylic acid diethylamide (7a).
nmr (CDCl3): ꢀ 1.12 (t, 6H, J = 7.0 Hz, -CH2-CH3), 2.36 (s, 3H,
-CH3 of phenyl), 2.37-2.42 (m, 2H, C3-H), 3.11 (t, 2H, J = 5.6
Hz, C2-H), 3.44 (q, 4H, J = 6.9, 7.0 Hz, -CH2-CH3), 3.67 (br s,
2H, C6-H), 5.79-5.84 (m, 1H, C4-H, olefinic), 7.19 (d, 2H, J =
7.9 Hz, C3 , C5 -H), 7.26 (s, 1H, -NH, D2O exchangeable), 7.63
(d, 2H, J = 7.9 Hz C2 , C6 -H).
3-[(Diethylamino)carbonyl]-1-[(3-pyridylcarbonyl)imino]pyri-
dinium ylide (6a) (1.0 g, 3.35 mmoles) was stirred in 80 mL of
absolute ethanol at 0° for 30 minutes. Sodium borohydride (0.51
g, 13.40 mmoles) was added and the reduction was carried out at
0°. The stirring proceeded for 7 hours and the reaction was
monitored by TLC. The reaction mixture was treated with 15 g
of ice and allowed to warm up to room temperature. The product
was extracted with methylene chloride (4 X 100 ml) and water
(2 X 100 ml) and washed with 60 ml of brine. The combined
methylene chloride extracts were dried over anhydrous sodium
sulfate, filtered and evaporated in vacuo. The residue was
chromatographed on a column of silica gel (200-425 mesh)
using ethyl acetate: methanol (3:2 v/v 500 ml) as an eluent and
afford (7a) as white solid which was recrystallized with ethyl
acetate:hexane (2:3 v/v, 50 ml) to produce a white crystalline
solid, 50.4% (0.51 g) yield, mp 127-128°; ir (potassium
bromide): ꢀ 3235(NH), 1662 and 1604 (C=O) cm-1; 1H nmr
(CDCl3): ꢀ 1.12 (t, 6H, J = 6.7 Hz, -CH2-CH3), 2.41-2.44 (m,
2H, C3-H), 3.13 (t, 2H, J = 6.7 Hz, C2H), 3.43 (q, 4H, J = 6.9,
7.0 Hz, -CH2-CH3), 3.73 (d, 2H, J = 1.8 Hz, C6-H), 5.76-5.80
(m, 1H, C4-H, olefinic), 7.52 (d, 2H, J = 5.9 Hz, C5 -H), 8.40 (d,
1H, J = 6.1 Hz, C6 -H), 8.70 (d, 2H, J = 5.9 Hz, C6 -H), 8.75 (s,
1H, -NH, D2O exchangeable).
Anal. Calcd. for C18H25N3O2: C, 68.54; H, 7.99; N, 13.32.
Found: C, 68.55; H, 8.07; N, 13.27.
1-(4-Fluoro-benzoylamino)-1,2,3,6-tetrahydropyridine-5-carbox-
ylic acid diethylamide (7e).
The compound 7e was obtained following General Procedure
C has white solid 43.3% (0.35 g) yield, mp 123-125 °; ir
1
(potassium bromide): ꢀ 3224 (NH), 1660, 1608 (C=O) cm-1; H
nmr (CDCl3): ꢀ 1.13 (t, 6H, J = 6.9 Hz, -CH2-CH3), 2.38-2.42
(m, 2H, C3-H), 3.14 (t, 2H, J = 5.4 Hz, C2-H), 3.40 (q, 4H, J =
7.0 & 7.2 Hz, -CH2-CH3), 3.71 (br s, 2H, C6-H), 5.79-5.83 (m,
1H, C4-H, olefinic), 7.08 (d, 2H, J = 9.0 Hz, C3 , C5 -H), 7.82
(d, 2H, J = 5.4 Hz C2 , C6 -H), 7.84 (s, 1H, -NH, D2O
exchangeable).
Anal. Calcd. for C17H22FN3O2: C, 63.93; H, 6.94; N, 13.16.
Found: C, 64.07; H, 7.03; N, 13.44.
1-(4-Chloro-benzoylamino)-1,2,3,6-tetrahydropyridine-5-carbox-
ylic acid diethylamide (7f).
Anal. Calcd. for C16H22N4O2: C, 63.55; H, 7.33; N, 18.53.
Found: C, 63.20; H, 7.38; N, 18.34.
The compound 7f was obtained following General Procedure
C has white crystals in 48.6% (0.49 g) yield, mp 137-139 °; ir

May-Jun 2006
Synthesis of 1-(Substituted Phenylcarbonyl/sulfonylamino)-1,2,3,6-
tetrahydropyridine-5-carboxylic acid diethylamides
717
(potassium bromide): ꢀ 3226 (NH), 1660, 1608 (C=O) cm-1; H
nmr (CDCl3): ꢀ 1.14 (t, 6H, J = 6.9 Hz, -CH2-CH3), 2.40-2.43
(m, 2H, C3-H), 3.13 (t, 2H, J = 5.4 Hz, C2-H), 3.40 (q, 4H, J =
6.3, 7.2 Hz, -CH2-CH3), 3.70 (br s, 2H, C6-H), 5.81-5.84 (m, 1H,
C4-H, olefinic), 7.39 (d, 2H, J= 8.4 Hz, C3 , C5 -H), 7.53 (s, 1H, -
NH, D2O exchangeable), 7.72 (d, 2H, J = 8.4 Hz C2 , C6 -H).
Anal. Calcd. for C17H22ClN3O2: C, 60.80; H, 6.60; N, 12.51.
Found: C, 60.78; H, 6.58; N, 12.42.
D2O exchangeable), 5.74-5.78 (m, 1H, C4-H, olefinic), 7.28 (d,
2H, J = 8.0 Hz, C3 , C5 -H), 7.82 (d, 2H, J = 8.2 Hz C2 , C6 -H).
Anal. Calcd. for C17H25N3O3S: C, 58.09; H, 7.17; N, 11.96.
Found: C, 58.27; H, 7.24; N, 12.08.
1
1-(4-Methoxy-benzensulfonylamino)-1,2,3,6-tetrahydropyridine-
5-carboxylic acid diethylamide (7k).
The compound 7k was obtained following General Procedure
C has white granules 49.4% (0.43 g) yield, mp 145-147°; ir
(potassium bromide): ꢀ 3118 (NH), 1600 (C=O), and 1333, 1163
1-(3-Bromo-benzoylamino)-1,2,3,6-tetrahydropyridine-5-carbox-
ylic acid diethylamide (7g).
1
(SO2) cm-1; H nmr (CDCl3): ꢀ 1.07 (t, 6H, J = 7.2 Hz, -CH2-
CH3), 2.18-2.22 (m, 2H, C3-H), 2.82 (t, 2H, J = 5.8 Hz, C2-H),
3.25 (d, 2H, J = 2.0 Hz, C6-H), 3.31 (q, 4H, J = 6.5, 6.9 Hz, -CH-
2-CH3), 3.85 (s, 3H, -OCH3 of phenyl ring) 5.54 (s, 1H, -NH,
D2O exchangeable), 5.75-5.78 (m, 1H, C4-H, olefinic), 6.95 (dd,
2H, J = 2.1, 2.0 Hz, C3 , C5 -H), 7.87 (dd, 2H, J = 2.2, 2.0 Hz, C2 ,
C6 -H).
The compound 7g was obtained following General Procedure
C has white solid 55.3% (0.57 g) yield, mp 53-55°; ir (potassium
bromide): ꢀ 3238 (NH), 1665, 1604 (C=O) cm-1; 1H nmr
(CDCl3): ꢀ 1.12 (t, 6H, J = 6.7 Hz, -CH2-CH3), 2.39-2.41 (m,
2H, C3-H), 3.12 (t, 2H, J = 5.2 Hz, C2-H), 3.41 (q, 4H, J = 6.9,
7.2 Hz, -CH2-CH3), 3.68 (br s, 2H, C6-H), 5.81-5.85 (m, 1H, C4-
H, olefinic), 7.29 (d, 1H, J = 7.5 Hz, C5 -H), 7.45 (s, 1H, -NH,
D2O exchangeable), 7.60 (d, 1H, J = 8.1 Hz, C4 -H ), 7.66 (d,
1H, C6 -H), 7.89 (s, 1H, C2 -H).
Anal. Calcd. for C17H25N3O4S: C 55.57, H 6.86, N 11.44;
found: C 55.36, H 6.98, N 11.53.
1-(3,4,5-Trimethoxy-benzoylamino)-1,2,3,6-tetrahydropyridine-
5-carboxylic acid diethylamide (15a).
Anal. Calcd. for C17H22BrN3O2: C, 53.69; H, 5.83; N, 11.05.
Found: C, 53.78; H, 5.94; N, 11.20.
The compound 15a was obtained following General
Procedure C has white solid 40.7% (0.41 g) yield, mp 151-152°;
ir (potassium bromide): ꢀ 3239 (NH), 1654, 1602 (C=O) cm-1;
1H nmr (CDCl3): ꢀ 1.13 (t, 6H, J = 6.9 Hz, -CH2-CH3), 2.38-2.42
(m, 2H, C3-H), 3.14 (t, 2H, J = 5.4 Hz, C2-H), 3.40 (q, 4H, J =
6.6, 6.9 Hz, -CH2-CH3), 3.71 (brs, 1H, C6-H), 3.86 (s, 3H, -m-
OCH3 of phenyl ring), 3.89 (s, 6H, p-OCH3 of phenyl ring),
5.82-5.86 (m, 1H, C4-H, olefinic), 6.98 (s, 2H, C2 , C6 -H), 7.41
(s, 1H, -NH, D2O exchangeable).
1-(4-Amino-benzoylamino)-1,2,3,6-tetrahydropyridine-5-carbox-
ylic acid diethylamide (7h).
The compound 7h was obtained following General Procedure
C has white solid 34.4% (0.28 g) yield, mp 178-180°; ir
(potassium bromide): ꢀ 3239 (NH2), 3225 (NH), 1660, 1608
1
(C=O) cm-1; H NMR (CDCl3): ꢀ 1.13 (t, 6H, J = 6.9 Hz, -CH2-
CH3), 2.39-2.42 (m, 2H, C3-H), 2.52 (br s, -NH2 of phenyl ring),
3.14 (t, 2H, J = 5.4 Hz, C2-H), 3.40 (q, 4H, J = 6.9, 7.2 Hz, -
CH2-CH3), 3.70 (br s, 2H, C6-H), 5.82-5.86 (m, 1H, C4-H,
olefinic), 6.66 (d, 2H, J = 8.1 Hz, C3 , C5 -H), 7.39 (s, 1H, -NH,
D2O exchangeable), 7.60 (d, 2H, J = 7.8 Hz C2 , C6 -H).
Anal. Calcd. for C17H24N4O2: C, 64.53; H, 7.65; N, 17.71.
Found: C, 64.62; H, 7.79N, 17.38.
Anal. Calcd. for C20H29N3O5: C, 61.36; H, 7.47; N, 10.73.
Found: C, 61.00; H, 7.60; N 10.60.
1-(4-tert-Butyl-benzoylamino)1,2,3,6-tetrahydropyridine-5-carbox-
ylic acid diethyl- amide (15b).
The compound 15b was obtained following General
Procedure C has white solid 30.8% (0.25 g) yield, mp 96-98°; ir
1-Benzenesulfonylamino-1,2,3,6-tetrahydropyridine-5-carbox-
ylic acid diethylamide (7i).
1
(potassium bromide): ꢀ 3240 (NH), 1656, 1606 (C=O) cm-1; H
nmr (CDCl3): ꢀ 1.12 (t, 6H, J = 6.9 Hz, -CH2-CH3), 1.30 (s, 9H,
-t-butyl group), 2.39-2.42 (m, 2H, C3-H), 3.11 (t, 2H, J = 5.6 Hz,
C2-H), 3.39 (q, 4H, J = 6.6, 6.9 Hz, -CH2-CH3), 3.67 (br s, 2H,
C6-H), 5.82-5.85 (m, 1H, C4-H, olefinic), 7.26 (s, 1H, -NH, D2O
exchangeable),7.41 (d, 2H, J = 8.4 Hz, C3 , C5 -H), 7.67 (d, 2H,
J = 8.3 Hz, C2 , C6 -H).
The compound 7i was obtained following General Procedure
C has white granules 42.3% (0.43 g) yield, mp 132-134°; ir
(potassium bromide): ꢀ 3197 (NH), 1607 (C=O), and 1340, 1167
1
(SO2) cm-1; H nmr (CDCl3): ꢀ 1.08 (t, 6H, J = 6.9 Hz, -CH2-
CH3), 2.19-2.24 (m, 2H, C3-H), 2.84 (t, 2H, J = 6.0 Hz, C2-H),
3.25 (d, 2H, J = 2.1 Hz, C6-H), 3.30 (q, 4H, J = 7.5, 6.9 Hz, -CH-
2-CH3), 5.72 (s, 1H, -NH, D2O exchangeable), 5.75-5.79 (m, 1H,
C4-H, olefinic), 7.48-7.60 (complex multiplet, 3H, C3 , C4 and C5
-H), 7.97 (dd, 2H, J = 1.5, 2.1 Hz C2 , C6 -H).
Anal. Calcd. for C21H31N3O2: C, 70.55; H, 8.74; N, 11.75.
Found: C, 70.74; H, 8.83; N, 11.99.
1-[(Thiophene-2-carbonyl)-amino]-1,2,3,6-tetrahydropyridine-5-
carboxylic acid diethylamide (15c).
Anal. Calcd. for C16H23N3O3S: C, 56.95; H, 6.87; N, 12.45.
Found: C, 57.10; H, 6.96; N, 12.56.
The compound 15c was obtained following General
Procedure C has white solid 38.4% (0.41 g) yield, mp 48-50°; ir
1-(4-Methyl-benzenesulfonylamino)-1,2,3,6-tetrahydropyridine-
5-carboxylic acid diethylamide (7j).
1
(potassium bromide): ꢀ 3226 (NH), 1660, 1608 (C=O) cm-1; H
nmr (CDCl3): ꢀ 1.13 (t, 6H, J = 6.9 Hz, -CH2-CH3), 2.39-2.42
(m, 2H, C3-H), 3.13 (t, 2H, J = 6.1 Hz, C2-H), 3.42 (q, 4H, J =
6.9, 7.2 Hz, -CH2-CH3), 3.67 (br s, 2H, C6-H), 5.81-5.85 (m, 1H,
C4-H, olefinic), 6.45-6.49 (m, 1H, C3 -H), 7.19 (d, 2H, J = 2.7
Hz, C4 -H), 7.46 (d, 1H, J = 7.5 Hz, C5 -H), 7.49 (s, 1H, -NH,
D2O exchangeable).
The compound 7j was obtained following General Procedure
C has white crystals 58.0% (0.25 g) yield, mp 148-150°; ir
(potassium bromide): ꢀ 3116 (NH), 1602 (C=O), and 1289, 1167
1
(SO2) cm-1; H nmr (CDCl3): ꢀ 1.07 (t, 6H, J = 7.0 Hz, -CH2-
CH3), 2.18-2.22 (m, 2H, C3-H), 2.40 (s, 3H, -CH3 of phenyl
ring), 2.83 (t, 2H, J = 5.8 Hz, C2-H), 3.23 (d, 2H, J = 2.0 Hz, C6-
H), 3.30 (q, 4H, J = 7.5, 6.9 Hz, -CH2-CH3), 5.74 (s, 1H, -NH,
Anal. Calcd. for C15H21N3O2S.0.115H2O(311.56): C, 57.83;
H, 6.87; N, 13.49. Found: C, 57.92; H, 7.11; N, 13.13.

718
M. Gangapuram and K. K. Redda
Vol 43
[6] K. K. Redda, K. Rao, A.S. Heiman and H. Melles, J. Pharm.
Sci., 81(5), 463 (1992).
[7] N. N. Mateeva, L. L. Winfield and K.K. Redda, Curr. Med.
Chem., 12, 551 (2005).
[8] G. J. Meuzelaar, L. Maat and R. A. Sheldon, Tetrahedron,
55, 4481 (1999).
[9] R. Lewin, Science, 224, 1083 (1984).
[10] R. E. Heikkaila, A. Hess, and R. C. Duvoisin, Science, 224,
1451 (1984).
[11] D. S. Fries, J. D. Varies, B. Hazelhoff and A. S. Horn, J.
Med. Chem., 29, 424 (1986).
[12] K. K. Redda, L. A. Corleto and E. E. Knaus, J. Med. Chem.,
22, 1079 (1979).
1-[(Furan-2-carbonyl)-amino]-1,2,3,6-tetrahydropyridine-5-carbox-
ylic acid diethyl- amide (15d).
The compound 15d was obtained following General
Procedure C has white solid 48.2% (0.49 g) yield, mp 50-51 °; ir
1
(potassium bromide): ꢀ 3238 (NH), 1665, 1604 (C=O) cm-1; H
nmr (CDCl3): ꢀ 1.14 (t, 6H, J = 6.9 Hz, -CH2-CH3), 2.39-2.43
(m, 2H, C3-H), 3.12 (t, 2H, J = 5.4 Hz, C2-H), 3.40 (q, 4H, J =
6.9, 7.2 Hz, -CH2-CH3), 3.66 (br s, 2H, C6-H), 5.85-5.88 (m, 1H,
C4-H, olefinic), 6.45-6.49 (m, 1H, C3 -H), 7.16 (d, 2H, J = 2.7
Hz, C4 -H), 7.44 (d, 1H, J = 7.5 Hz, C5 -H), 7.47 (s, 1H, -NH,
D2O exchangeable).
Anal. Calcd. for C15H21N3O3: C, 61.84; H, 7.27; N, 14.42.
Found: C, 61.72; H, 7.48; N, 14.10.
[13] J. M. Young, L. A. Corleto and E. E. Knaus, J. Med. Chem.,
25, 720 (1982).
[14] E. L. May, and E. M. Fry, J. Org. Chem., 22, 1366 (1957).
[15] D. C. Palmer and M. J. Strauss, Chem. Rev., 77, 1 (1977).
[16] K. K. Redda, N. R. Kode, A. S. Heiman, F. Y. Onayemi and
J. B. Clark, Chem. Pharm. Bull., 39, 786 (1991).
[17] N. Kode, K. K. Redda, F. Y. Onayemi, H. Melles and J.
Choi, J. Heterocyclic Chem., 32, 307 (1995).
[18] T. Wilson, U. Onubogu, R. Kode, and K. Redda, Drugs
Exptl. Clin. Res., 24, 165 (1998).
[19] K. K. Redda, H. Melles, and R. N. Kode, J. Heterocyclic
Chem., 27, 1041 (1990).
Acknowledgments.
We are grateful to the National Institute of Health, the
National Institute of General Medical Sciences, Minority
Biomedical Research Support research funding program, NIH
No.08111 and the Research center at Minority Institutions Grant
(RCMI) RR 03020. We are also grateful to Dr. Thomas Gedris,
Chemistry Department, NMR unit, Florida State University,
Tallahassee, Florida, for recording all the NMR spectra of our
compounds.
[20] C. J. Pelle, C. O. Okoro, T. L. Wilson, U. C. Onubogu, K. J.
Yoon and K. K. Redda, Synthetic Comm., 26(14), 2703 (1996).
[21] C. O. Okoro, T. L. Wilson, J. O. Choi, and K. K. Redda,
Med. Chem. Res., 7(1), 1 (1997).
REFERENCES
[22] K. Yoon, T. Wilson, S. William, and K. Redda, Drugs Exptl.
Clin. Res., 26, 73 (2000).
[23] T. L. Wilson,and K. K. Redda, Med Chem. Res., 12(2), 69
(2003).
[24] B. Mochona, T. Wilson, and K. Redda, Drugs Exptl. Clin.
Res., 29(4), 131 (2003).
[1] A. R. Pinder, Nat. Prod. Rep., 9, 491 (1992).
[2] P. S., Watson, B. Jiang, B. Scott, Org. Lett., 2, 3679 (2000).
[3] R.T. Coutts and A.F. Casay, Pyridine and Reduced Pyridines
of Pharmacological Interest, Vol 14, R.A. Abramovich, ed, Interscience
publishers, New York, NY, 1975, p 445.
[4] W. Gessner, A. Brossi, R. S. Shen and C. W. Abell, J. Med.
Chem., 28, 311 (1985).
[5] E. E. Knaus and K.K. Redda, J. Heterocyclic Chem., 13,
1237 (1976).
[25] J. Choi, T. L. Wilson, A. M. Ly, C. O. Okoro, U. C. Onubogu
and K. K. Redda, Med. Chem. Res., 5, 281 (1995).
[26] Y. Tamura, J. Minamikawa, Y. Miki, S. Matsigashita and M.
Ikeda, Tetrahedron Letters, 40, 4133 (1972).