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. Author manuscript; available in PMC: 2010 Jun 3.
Published in final edited form as: J Heterocycl Chem. 2009 May 1;46(2):309–316. doi: 10.1002/jhet.62

Synthesis of Substituted N-[4(5-Methyl/phenyl-1,3,4-oxadiazol-2-yl)-3,6-dihydropyridin-1(2H)-yl]benzamide/benzene Sulfonamides as Anti-Inflammatory and Anti-Cancer Agents

Madhavi Gangapuram 1, Kinfe K Redda 1,*
PMCID: PMC2880475  NIHMSID: NIHMS204659  PMID: 20526413

Abstract

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Fourteen novel substituted N-[4(5-methyl/phenyl-1,3,4-oxadiazol-2-yl)-3,6-dihydropyridin-1(2H)-y1] benzamide/benzene sulfonamides (11a–n) were synthesized in fair to good yields via sodium borohydride reduction of the corresponding substituted N-(benzoylimino)-4-(5-methyl/5-phenyl-1,3,4-oxadiazol-2yl) pyridinium ylide (10a–n) in absolute ethanol.

INTRODUCTION

Non steroidal anti-inflammatory drugs (NSAIDs) are of huge therapeutic benefit in the treatment of rheumatoid arthritis and anti-inflammatory, analgesic, and antipyretic activities and are widely used to treat acute and chronic inflammatory disorders [1,2]. NSAIDs are not only useful in the treatment of inflammatory diseases but they can also reduce the risk of Alzheimer's disease [3,4]. Although NSAIDs are the most widely used drugs, their long-term clinical employment is associated with significant side effects and the steady use determines the onset of gastrointestinal lesions, bleeding, and nephrotoxicity [5,6]. Therefore, the discovery of new safer anti-inflammatory drugs represents a challenging goal for such a research area. Functionalized tetrahydropyridine (THP) ring systems are widely found in biologically active natural products and pharmaceuticals [7–12]. The anti-inflammatory activities of compounds consisting of reduced pyridine systems have been investigated [13–18]. The chemistry of substituted 1,3,4-oxadiazoles and their derivatives received considerable attention during the last decade as potential antimicrobial, antifungal, anti-inflammatory, analgesic, CNS-stimulating, anticonvulsive, anti-cancer, diuretic, and antihypertensive agents [19–30]. The electro-philic cyclization of iminium ions (Mannich cyclization) to generate unsaturated azacyclic systems [31] and the synthesis of tetrahydropyridine derivatives by partial reduction of N-ylides constitute some of the most important methods for preparing tetrahydropyridines. From our previous research, Redda and coworkers reported the synthesis and anti-inflammatory activity profiles of a few 1,2,3,6-terahydropyrines [32]. The results showed the pharmacological activites of the derivatives of THP depended on the nature of the substituents on the THP ring system (Fig. 1). This investigation is a continuation of synthesis of 1,2,3,6-tetrahydropyridine designed to modify the tetrahydropyridine ring and phenyl moieties by introducing groups with various electronic properties. Incorporation of the 1,3,4-oxadiazole moiety might enhance biological activity of the tetrahydropyridine derivatives. Hence, it was thought worthwhile to synthesize 1,3,4-oxadizol-2-yl tetrahydropyridines and study their anti-inflammatory and anti-cancer activities.

Figure 1.

Figure 1

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General structure of the target compounds. R = —CH3, C6H5; R1 = C6H5, 4-OCH3—C6H4, 4-F—C6H4, 4-Br—C6H4, 4-tert-butyl-C6H4, X = CO, SO2.

In the current investigation, we have synthesized many analogs maintaining the 1,3,4-oxadiazole-2-yl-1,2,3,6-tetrahydropyridine ring and having modifications on the oxadiazole, phenyl ring, and interchanging the sulfonyl/carbonyl groups at position X to compare their biological activities. We expect that these structural modifications would affect the compounds electron density, lipophilicity, and the compounds steric configurations.

Chemistry

The starting compound was 4-(5-methyl/phenyl-1,3,4-oxadiazol-2-yl)pyridine (3) obtained by the reaction of isonicotinic acid hydrazide and triethyl orthoacetate/triethylorthobenzoate, which was heated under reflux for 24 h [33] as outlined in Scheme 1. Substituted N-[4(5-methyl/phenyl-1,3,4-oxadiazol-2-yl)-3,6-dihydropyridin-1(2H)-yl]benzamide/benzenesulfonamides (11a–n) were prepared via partial reduction of N-ylides with a mild reducing agent, as outlined in Scheme 2. The ylides were prepared by coupling N-aminopyridinum salt (8) with appropriate acyl chlorides or sulfonyl chlorides. O-mesitylene sulfonyl hydroxylamine (MSH) (7) was used to prepare the N-amino salt as an aminating agent [34]. Reaction of N-aminopyridinium derivatives with substituted acylating agents like acyl chlorides and sulfonyl chlorides, followed by treatment with a base afforded N-ylides (10) as stable crystalline solids. Sodium borohyride reduction of (10a–n) in absolute ethanol furnished the target compounds substituted N-[4(5-methyl/phenyl-1,3,4-oxadiazol-2-yl)-3,6-dihydropyridin-1(2H)-yl] benzamide/benzene sulfonamides (11a–n).

Scheme 1.

Scheme 1

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Scheme 2.

Scheme 2

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Reaction conditions: (i) DMF, Et3N, 0°C, 45 min; (ii) 70% HC1O4, p-dioxane, 0°C, 45 min; (iii) 4-substituted pyridine, CH2C12, 0°C, 3 h; (iv) 4-substituted acyl/sulfonyl chloride, dry THF, 70°C; (v) NaBH4, abs. EtOH, 7 h, X = CO, SO2. R1 = C6H5, 4-OCH3—C6H4, 4-F—C6H4, 4-Br—C6H4, 4-tert-C4H9—C6H4.

RESULTS AND DISCUSSION

The results of synthesis of the pyridinium ylides (10a–n) and corresponding tetrahydropyridines (11a–n) are summarized in Table 1 and Table 2. The tetrahydropyridines are thermally stable and soluble in chloroform, dichloromethane, and other polar solvents. Analytical data of these compounds 10a–n and 11a–n are presented in Tables 3 and 4. The pharmacological evaluations of the compounds for anti-inflammatory and anti cancer activities are underway.

Table 1.

Pyridinium ylides synthetic data (10a–n).

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Compound R R1 X M.W. Mp (°C) Yield (%)
10a CH3 C6H5 CO 280.28 273–275 34.4
10b CH3 4-OCH3—C6H4 CO 319.32 253–254 50.6
10c CH3 4-F—C6H4 CO 307.28 283–284 51.3
10d CH3 4-Br—C6H4 CO 375.4 290–291 61.9
10e CH3 4-tert-C4H9—C6H4 CO 340.9 246–248 24.6
10f CH3 C6H5 SO2 316.34 268–269 47.8
10g CH3 4-OCH3—C6H4 SO2 346.36 218–220 56.2
10h C6H5 C6H5 CO 342.35 262–263 39.6
10i C6H5 4-OCH3—C6H4 CO 372.38 277–278 48.5
10j C6H5 4-F—C6H4 CO 360.34 296–297 50.5
10k C6H5 4-tert-C4H9—C6H4 CO 398.46 271–272 82.5
10l C6H5 C6H5 SO2 378.4 211–213 43.6
10m C6H5 4-OCH3—C6H4 SO2 408.43 259–261 37.5
10n C6H5 4-tert-C4H9—C6H4 SO2 434.51 242–244 74.2
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Table 2.

Tetrahydropyridines synthetic data (11a–n).

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Compound R R1 X M.W. Mp (°C) Yield (%)
11a CH3 C6H5 CO 284.31 208–210 61.0
11b CH3 4-OCH3—C6H4 CO 314.34 238–240 54.3
11c CH3 4-F—C6H4 CO 302.30 215–217 68.7
11d CH3 4-Br—C6H4 CO 363.21 215–217 33.8
11e CH3 4-tert-C4H9—C6H4 CO 340.42 211–213 65.4
11f CH3 C6H5 SO2 320.37 208–210 48.2
11g CH3 4-OCH3—C6H4 SO2 350.39 150–152 54.4
11h C6H5 C6H5 CO 366.21 203–204 30.4
11i C6H5 4-OCH3—C6H4 CO 376.41 217–218 44.8
11j C6H5 4-F—C6H4 CO 364.37 213–215 51.4
11k C6H5 4-tert-C4H9—C6H4 CO 402.49 209–211 32.5
11l C6H5 C6H5 SO2 382.44 162–163 33.6
11m C6H5 4-OCH3—C6H4 SO2 412.46 135–136 42.5
11n C6H5 4-tert-C4H9—C6H4 SO2 438.54 163–164 48.5
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Table 3.

Elemental analysis of pyridinium ylides (10a–z).

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Analysis % Cacld/Found
Compound R R1 X Molecular formula M.W. C H N
10a CH3 C6H5 CO C15H12N4O2 280.28 64.28 4.32 19.99
64.11 4.30 19.83
10b CH3 4-OCH3—C6H4 CO C16H14N4O3 0.5 H2O 319.32 60.18 4.73 17.55
60.43 4.57 17.40
10c CH3 4-F—C6H4 CO C15H11FN4O2 0.9 H2O 307.28 58.63 3.77 18.23
58.69 3.79 18.04
10d CH3 4-Br—C6H4 CO C15H11BrN4O2 0.9 H2O 375.4 47.99 3.44 14.92
48.27 3.11 14.61
10e CH3 4-tert-C4H9—C6H4 CO C19H20N4O2 0.25 H2O 340.9 66.07 5.98 16.22
66.03 6.06 15.99
10f CH3 C6H5 SO2 C14H12N4O3S 316.34 54.16 3.82 17.71
53.97 3.76 17.56
10g CH3 4-OCH3—C6H4 SO2 C15H14N4O4S 346.36 52.02 4.07 16.18
51.53 4.27 16.30
10h C6H5 C6H5 CO C20H14N4O2 342.35 67.02 3.94 15.63
67.31 4.19 15.78
10i C6H5 4-OCH3—C6H4 CO C21H16N4O3 372.38 67.73 4.33 15.05
67.57 4.61 14.66
10j C6H5 4-F—C6H4 CO C20H13FN4O2 360.34 66.66 3.64 15.55
67.04 3.47 15.60
10k C6H5 4-tert-C4H9—C6H4 CO C24H22N4O2 398.46 72.34 5.57 14.06
72.39 5.38 13.82
10l C6H5 C6H5 SO2 C19H14N4O3S 378.4 60.31 3.73 14.81
60.71 3.53 14.44
10m C6H5 4-OCH3—C6H4 SO2 C20H16N4O4S 408.43 62.06 3.47 16.08
61.93 3.25 16.01
10n C6H5 4-tert-C4H9—C6H4 SO2 C23H22N4O3S 434.51 63.58 5.10 12.89
63.32 5.14 12.42
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Table 4.

Elemental analysis of tetrahydropyridines (11a–z).

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Analysis % Cacld/Found
Compound R R1 X Molecular formula M.W. C H N
11a CH3 C6H5 CO C15H16N4O2 284.31 63.37 5.67 19.71
63.34 5.73 19.62
11b CH3 4-OCH3—C6H4 CO C16H18N4O3 314.34 61.13 5.77 17.82
61.11 5.83 17.65
11c CH3 4-F—C6H4 CO C15H15FN4O2 302.30 59.60 5.00 18.53
59.45 5.05 18.37
11d CH3 4-Br—C6H4 CO C15H15BrN4O2 363.21 49.60 4.16 15.43
49.51 4.38 15.15
11e CH3 4-tert-C4H9—C6H4 CO C19H24N4O2 340.42 67.04 7.11 16.46
67.4 7.15 16.26
11f CH3 C6H5 SO2 C14H16N4O3S 320.37 52.49 5.03 17.49
52.74 5.11 17.65
11g CH3 4-OCH3—C6H4 SO2 C15H18N4O4S 350.39 51.42 5.18 15.99
51.70 5.30 15.79
11h C6H5 C6H5 CO C20H18N4021.1H2O 342.35 65.60 4.95 15.30
65.58 5.04 15.01
11i C6H5 4-OCH3—C6H4 CO C21H20N4O3 376.41 67.01 5.59 15.55
66.81 5.40 14.59
11j C6H5 4-F—C6H4 CO C20H17FN4O2 364.37 65.93 4.70 15.38
65.92 4.75 15.18
11k C6H5 4-tert-C4H9—C6H4 CO C24H26N4O2 402.49 71.62 6.51 13.92
71.78 6.56 13.79
11l C6H5 C6H5 SO2 C19H18N4O3S 382.44 59.67 4.74 14.65
59.38 4.78 14.34
11m C6H5 4-OCH3—C6H4 SO2 C20H20N4O4S 412.46 58.24 4.89 13.58
58.26 4.96 13.47
11n C6H5 4-tert-C4H9—C6H4 SO2 C23H26N4O3S 438.54 62.99 5.98 12.78
62.89 5.91 12.45
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EXPERIMENTAL

The structures of the products described were confirmed by IR, 1H NMR, and elemental analysis data. 1H NMR spectra were determined on a Varian Gemini HX 300 MHz spectrometer using CDCl3 as solvent unless otherwise specified. Chemical shifts (δ) are reported in parts per million (ppm) downfield from TMS as an internal standard. Infrared spectra were run with KBr pellets on a Perkin–Elmer 1430 FT spectrometer. Elemental analyses were performed by Galbraith Laboratories (Knoxville, TN). 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 (Milwaukee, WI), Fisher Scientific Company (Suwannee, GA). Separations on column chromatography were performed on silica gel (200–425 mesh). All reactions and purification procedures were monitored by TLC on What-man AL SIL g/UV, 250 lm layer flexible plates, with visualization under UV light.

General procedure-1

Synthesis of 4-(5-methyl-1,3,4-oxadiazol-2-yl)pyridine (3)

To a solution of isonicotinic acid hydrazide 25 g (182.3 mmol) in triethyl orthoacetate (135 mL) was added and refluxed for 24 h. The excess triethyl orthoacetate was distilled under reduced pressure, and the residue was washed with cold ethanol. The residue was recrystallized from ethanol and obtained as brown crystals, yield 24 g (81.7%); Mp 148–150°C; 1H NMR (CDCl3): δ 2.66 (s, 3H, —CH3); 7.88 (dd, J = 1.8, 1.5 Hz, 2H, C3, C5—H); 8.81 (dd, J = 1.8, 1.5 Hz; 2 H, C2, C6—H).

Synthesis of 4-(5-phenyl-1,3,4-oxadiazol-2-yl)pyridine (3)

To a solution of isonicotinic acid hydrazide 20 g (145.6 mmol) in triethyl orthobenzoate (135 mL) was added and refluxed for 24 h. The excess triethyl orthobenzoate was distilled under reduced pressure, and the residue was washed with cold ethanol. The residue was recrystallized from ethanol and obtained as light yellow color solid, yield 29.17 g (89.8%); Mp 160–161°C. 1H NMR (CDCl3): δ 7.51–7.61 (m. 3H, C3′, C4′C5′—H); 7.98 (d, J = 5.1 Hz, 2H, C2′, C6′—H); 8.12 (dd, J = 1.8, 1.5 Hz; 2 H, C3, C5—H), 8.84 (d, J = 6.9 Hz, 2H, C2, C6—H).

General procedure-2

Synthesis of 1-(benzoylimino)-4-(5-methyl-1,3,4-oxadiazol-2yl) pyridinium ylide (10a)

To an ice cooled solution of 4-(5-methyl-1,3,4-oxadiazol-2yl)pyridine (4.35 g, 26.99 mmol) in 15 mL of dry methylene chloride was added dropwise O-mesitylenesulfonylhydroxylamine (5.81 g, 26.99 mmol) in 10 mL of dry methylene chloride over 5 min with stirring. The reaction stirred at 0°C for 3 h at which time 60 mL of ether was added and the suspension filtered. The precipitate was recrystallized from ethyl acetate-methanol (5:1 v/v) to give 1-amino-4-(5-methyl-1,3,4,-oxadiazol-2-yl)pyridinium mesitylene sulfo-nate (7) in 57.5% yield. The N-aminopyridinium salt (2.0 g, 5.096 mmol) in 30 mL of anhydrous tetrahydrofuran (THF) containing triethylamine at 70°C was stirred for 5 min before benzoyl chloride (1.43 g, 10.19 mmol) was added. The mixture was allowed to proceed for 12 h at which time 70 mL of saturated sodium bicarbonate (NaHCO3) was used to arrest the reaction. The product 1-[(benzoylimino)-4-(5-methyl-1,3,4-oxadiazol-2yl)]pyridinium ylide (10a) was extracted with (2 × 100 mL) of chloroform and dried over anhydrous sodium sulfate. The solvent was removed in vacuo to give crude product, which was purified by column chromatography (2.5 × 22 cm) on silica gel (200–425 mesh) using ethyl acetate: methanol (9:1 v/v) as eluent. The resultant product (10a) was off-white solid obtained in 34.4% yield, Mp 273–275°C; IR (KBr): ν 1593 (C=O)/cm; 1H NMR (CDCl3): δ 2.71 (s, 3H, —CH3 of oxadiazol ring), 7.43 (m, 3H, C3′, C4′ and C5′—H), 8.18 (m, 4H, C3, C5 and C2′, C6′—H), 9.18 (d, J = 7.2 Hz, 2H, C2, C6—H).

Synthesis of 1-[(4-methoxy benzoyl)imino]-4-(5-methyl-1,3,4-oxadiazol-2-yl) pyridinium ylide (10b)

The compound 10b was obtained following general procedure 2 as yellow crystalline solid obtained in 50.6% yield, Mp 253–254°C; IR (KBr) ν 1605 (C=O)/cm; 1H NMR (CDCl3): † 2.70 (s, 3H, —CH3 of oxadiazol ring), 3.86 (s, 3H, —OCH3 group), 6.94 (d, J = 9.0 Hz, 2H, C3′,C5′—H), 8.16 (dd, J = 7.2, 8.7 Hz, 4H, C3,C5, and C2′,C6′—H), 9.18 (d, J = 7.5 Hz, 2H, C2,C6—H).

Synthesis of 1-[(4-fluorobenzoyl)imino]-4-(5-methyl-1,3,4-oxadiazol-2-yl) pyridinium ylide (10c)

The compound 10c was obtained following general procedure 2 as white solid obtained in 51.3% yield, Mp 283–284°C; IR (KBr): ν 1604 (C=O)/cm; 1H NMR (CDCl3): † 2.71 (s, 3H, —CH3 of oxadiazol ring), 7.09 (t, 2H, J = 9.0 Hz, C3′, C5′—H), 8.16 (d, 2H, J = 6.0 Hz, C2′, C6′—H), 8.21 (d, 2H, J = 7.2 Hz, C3, C5—H), 9.16 (d, 2H, J = 6.6 Hz, C2, C6—H).

Synthesis of 1-[(4-bromobenzoyl)imino]-4-(5-methyl-1,3,4-oxadiazol-2-yl) pyridinium ylide (10d)

The compound 10d was obtained following general procedure 2 as yellow color solid obtained in 61.9% yield, Mp 290–291°C; IR (KBr): ν 1601 (C=O)/cm; 1HNMR (CDCl3): † 2.69 (s, 3H, —CH3 of oxadiazol ring), 7.53 (d, 2H J = 8.4 Hz, C3′, C5′—H), 8.03 (d, 2H, J = 8.4 Hz, C2′, C6′—H), 8.20 (d, 2H, J = 7.2 Hz, C3, C5—H), 9.15 (d, 2H, J = 7.2 Hz, C2, C6—H).

Synthesis of 1-[(4-tert-butylbenzoyl)imino]-4-(5-methyl-1,3,4-oxadiazol-2-yl) pyridinium ylide (10e)

The compound 10e was obtained following general procedure 2 as yellow crystalline solid obtained in 24.6% yield, Mp 246–248°C; IR (KBr): ν 1604 (C=O)/cm; 1H NMR (CDCl3): δ 1.35 (s 9H, tert-butyl group), 2.70 (s, 3H, —CH3 of oxadiazol ring), 7.44 (d, 2H, J = 8.4 Hz, C3′, C5′—H), 8.09 (d, 2H, J = 8.1 Hz, C2′, C6′—H), 8.18 (d, 2H, J = 6.9 Hz, C3, C5—H), 9.18 (d, 2H, J = 7.2 Hz, C2, C6—H).

Synthesis of 4-(5-methyl-1,3,4-oxadiazol-2-yl)-1-[(phenylsulfonyl)amino]pyridinium ylide (10f)

The compound 10f was obtained following general procedure 2 as brown crystalline solid obtained in 47.8% yield, Mp 268–269°C; IR (KBr): ν 1332, 1205 (SO2)/cm; 1H NMR (CDCl3): δ 2.69 (s, 3H, —CH3 of oxadiazol ring), 7.37–7.45 (m, 3H, C3′, C4′ and C5′—H), 8.16 (ddd, 4H, J = 7.2, 1.7, and 2.3 Hz, C3, C5 and C2′, C6′—H), 9.16 (d, 2H, J = 7.2 Hz, C2, C6—H).

Synthesis of 1-{[(4-methoxyphenyl)sulfonyl]imino}-4-(5-methyl-1,3,4-oxadiazol-2-yl) pyridinium ylide (10g)

The compound 10g was obtained following general procedure 2 as brown crystalline solid obtained in 56.2% yield, Mp 218–220°C; IR (KBr): ν 1280, 1137 (SO2)/cm; 1H NMR (CDCl3): δ 2.66 (s, 3H, —CH3 of oxadiazol ring), 3.81 (s, 3H, —OCH3 group), 6.87 (d, 2H, J = 8.8 Hz, C3′, C5′—H), 7.74(dd, 2H, J = 1.9, 5.0 Hz, C2′, C6′—H), 8.06 (d, 2H, J = 7.1 Hz, C3, C5—H), 8.63 (d, 2H, J = 7.1 Hz, C2, C6—H).

Synthesis of 1-(benzoylimino)-4-(5-phenyl-1,3,4-oxadiazol-2yl) pyridinium ylide (10h)

The compound 10h was obtained following general procedure 2 as white crystalline solid obtained in 39.6% yield, Mp 262–263°C; IR (KBr): ν 1548 (C=O)/cm; 1H NMR (CDCl3): δ 7.38–7.62 (complex multiplet, 6H, phenyl protons), 8.16 (ddd, 4H, J = 4.2, 1.5, 1.5 Hz, C2′, C6′ and C2″, C6″—H), 8.29 (d, 2H, J = 7.2 Hz, C3, C5—H), 9.21 (d, 2H, J = 7.2 Hz, C2, C6—H).

Synthesis of 1-[(4-methoxybenzoylimino)]-4-(5-phenyl-1,3,4-oxadiazol-2yl) pyridinium ylide (10i)

The compound 10i was obtained following general procedure 2 as yellow solid obtained in 48.5% yield, Mp 277–278°C; IR (KBr): ν 1593 (C=O)/cm; 1H NMR (CDCl3): δ 3.84 (s, 3H, OCH3), 6.92 (d, 2H, J = 8.7 Hz C3″, C5″0—H), 7.54–7.65 (m, 3H, C3′, C4′, C5′—H), 8.15(dd, 4H, J = 1.2, 8.7 Hz, C2′, C6′ and C2″, C6″—H), 8.28 (d, 2H, J = 7.2 Hz, C3, C5—H), 9.21 (d, 2H, J = 7.2 Hz, C2, C6—H).

Synthesis of 1-[(4-fluorobenzoylimino)]-4-(5-phenyl-1,3,4-oxadiazol-2yl) pyridinium ylide (10j)

The compound 10j was obtained following general procedure 2 as yellow solid obtained in 50.5% yield, Mp 296–297°C; IR (KBr): ν 1557 (C=O)/cm; 1H NMR (CDCl3): δ 7.38 (d, 2H, J = 8.7 Hz C3″, C5″—H), 7.55–7.63 (m, 3H, C3′, C4′, C5′—H), 8.19 (ddd, 4H, J = 5.4, 3.3, 2.4 Hz, C2′, C6′ and C2″, C6″—H), 8.34 (d, 2H, J = 6.6 Hz, C3, C5—H), 9.21 (d, 2H, J = 6.9 Hz, C2, C6—H).

Synthesis of 1-[(4-tert-butylbenzoyl)imino]-4-(5-phenyl-1,3,4-oxadiazol-2-yl) pyridinium ylide (10k)

The compound 10k was obtained following general procedure 2 as yellow shiny crystals obtained in 82.5% yield, Mp 271–272°C; IR (KBr): ν 1585 (C=O)/cm; 1H NMR (CDCl3): δ 1.33 (s, 9H, t-butyl group), 7.43 (d, 2H, J = 8.4 Hz, C3″, C5″—H), 7.53–7.64 (m, 3H, C3′, C4′, C5′—H), 8.09 (d, 2H, J = 8.4 Hz, C2′, C6′—H), 8.15 (dd, 2H, J = 1.2, 6.6 Hz, C2″, C6″—H), 8.28 (d, 2H, J = 7.2 Hz, C3, C5—H), 9.20 (d, 2H, J = 7.2 Hz, C2, C6—H).

Synthesis of 4-(5-Phenyl-1,3,4-oxadiazol-2-yl)-1-[(phenyl)-sulfonyl]imino] pyridinium Ylide (10l)

The compound 10l was obtained following general procedure 2 as yellow crystals obtained in 43.6% yield, Mp 211–213°C; IR (KBr): ν 1282, 1150 (SO2)/cm; 1H NMR (CDCl3): δ 7.37–7.64 (complex multiplet, 6H, phenyl protons), 7.80 (d, 2H, J = 6.9 Hz, C2′, C6′—H), 8.12 (d, 2H, J = 6.9 Hz, C2″, C6″—H), 8.20 (d, 2H, J = 6.3 Hz, C3, C5—H), 8.67 (d, 2H, J = 6.6 Hz, C2, C6—H).

Synthesis of 1-{[(4-methoxyphenyl)sulfonyl]imino}-4-(5-phenyl-1,3,4-oxadiazol-2-yl)-pyridinium Ylide (10m)

The compound 10m was obtained following general procedure 2 as yellow solid obtained in 37.5% yield, Mp 259–261°C; IR (KBr): ν 1280, 1134 (SO2)/cm; 1H NMR (CDCl3): δ 3.81 (s, —OCH3), 6.88 (d, 2H, J = 8.7 Hz, C3″, C5″—H), 7.54–7.65 (m, 3H, C3′, C4′, C5′—H), 7.76 (d, 2H, J = 8.7 Hz, C2′ C6′—H), 8.12 (d, 2H, J = 6.9 Hz, C2″, C6″—H), 8.19 (d, 2H, J = 6.6 Hz, C3, C5—H), 8.70 (d, 2H, J = 6.3 Hz, C2, C6—H).

Synthesis of 1-{[(4-tert-butylphenyl)sulfonyl]imino}-4-(5-phenyl-1,3,4-oxadiazol-2-yl) pyridinium ylide (10n)

The compound 10n was obtained following general procedure 2 as yellow solid obtained in 74.2% yield, Mp 242–244°C; IR (KBr): ν 1296, 1136 (SO2)/cm; 1H NMR (CDCl3): δ 1.28 (s, 9H, t-butyl group), 7.41 (d, 2H, J = 8.4 Hz, C3″, C5″—H), 7.52–7.64 (m, 3H, C3′, C4′, C5′—H), 7.74 (d, 2H, J = 8.4 Hz, C2′, C6′—H), 8.11 (dd, 2H, J = 1.5, 6.9 Hz, C2″, C6″—H), 8.19 (d, 2H, J = 6.6 Hz, C3, C5—H), 8.70 (d, 2H, J = 6.3 Hz, C2, C6—H).

General procedure-3

N-[4[(5-Methyl-1,3,4-oxadiazol-2-yl)-3,6-dihydropyridin-1(2H)-yl] benzamide (11a)

A solution of 1-(Benzoylimino)-4-(5-methyl-1,3,4-oxadiazol-2yl) pyridinium ylide 10a (0.25 g, 0.79 mmol) in dichloromethane: ethanol (1:1 v/v, 40 mL) was added dropwise to a stirred suspension of sodium borohydride (0.12 g, 3.16 mmol) in 10 mL of absolute ethanol over a period or 30 min. The resulting solution was stirred for 4 h at 0°C and then overnight for a total of 24 h. The excess sodium borohyride was treated with 50 mL distilled water. It was then extracted with dichloromethane (200 mL) and dried over anhydrous sodium sulfate. The dichloromethane filtrate was evaporated in vacuo and the product chromatographed on a column of silica gel using ethyl acetate: methanol (9:1 v/v) as an eluent. The solid obtained was further crystallized from dichlormethane: ethylacetate (3:2 v/v) and furnished 11a as a white flakes (61.0% yield), Mp 208–210°C; IR (KBr): ν 3213 (NH), 1638 (C=O)/cm; 1H NMR (CDCl3): δ 2.54 (s, 3H, —CH3 of oxadiazol ring), 2.86 (m, 2H, C3—H), 3.34 (t, J = 5.7 Hz, 2H, C2—H), 3.84 (m, 2H, C6—H), 6.65 (m, 1H, C5—H olefinic proton), 7.17 (brs, 1H, —NH D2O exchange), 7.48 (m, 3H, C3′,C4′ and C5′—H), 7.74 (d, J = 7.5 Hz, 2H, C2′,C6′—H).

4-Methoxy-N-[4-(5-methyl-1,3,4-oxadiazol-2-yl)-3,6-dihydropyridin-1(2H)-yl]-benzamide (11b)

The compound 11b was obtained following general procedure 3 as off-white solid 54.3% yield, Mp 238–240°C; IR (KBr): ν 3138 (NH), 1625 (C=O)/cm; 1H NMR (CDCI3): δ 2.54 (s, 3H, CH3), 2.85 (m, 2H, C3—H), 3.32 (t, 2H, J = 6.0 Hz, C2—H), 3.82 (brs, 2H, C6—H), 3.84 (s, —OCH3 group), 6.64 (m, C5—H, olefinic), 6.92 (d, 2H, J = 8.7 Hz, C3′,C5′—H), 7.14 (brs, —NH, D2O exchange), 7.72 (d,2H, J = 8.4 Hz, C2′, C6‰—H).

4-Fluoro-N-[4-(5-methyl-1,3,4-oxadiazol-2-yl)-3,6-dihydropyridin-1(2H)-yl]-benzamide (11c)

The compound 11c was obtained following general procedure 3 as white granules 68.7% yield, Mp 215–217°C; IR (KBr): ν 3190 (NH), 1636 (C=O)/cm; 1H NMR (CDCI3): δ 2.52 (s, 3H, CH3 of oxadiazol ring), 2.84 (m, 2H, C3—H), 3.30 (t, 2H, J = 6.2 Hz, C2—H), 3.81 (brs, 2H, C6—H), 6.62 (m, 1H, C5—H, olefinic proton), 7.71 (t, 2H, J = 8.6 Hz, C3′, C5′—H), 7.15 (brs, 1H, NH proton, D2O exchange), 7.75 (d, 2H, J = 8.4 Hz, C2′ C6′—H).

4-Bromo-N-[4-(5-methyl-1,3,4-oxadiazol-2-yl)-3,6-dihydro pyridin-1(2H)-yl]-benzamide (11d)

The compound 11d was obtained following general procedure 3 as yellow solid 33.8% yield, Mp 216–217°C; IR (KBr): ν 3185 (NH), 1635 (C=O)/cm; 1H NMR (CDCl3): δ 2.53 (s, 3H, CH3 of oxadiazol ring), 2.85 (m, 2H, C3—H), 3.31 (t, 2H, J = 6.2 Hz, C2—H), 3.81 (brs, 2H, C6—H), 6.64 (m, 1H, C5—H, olefinic proton), 7.72 (t, 2H, J = 8.6 Hz, C3′, C5′—H), 7.13 (brs, NH proton, D2O exchange), 7.75 (d, 2H, J = 8.4 Hz, C2′, C6′—H).

4-tert-Butyl--N-[4-(5-methyl-1,3,4-oxadiazol-2-yl)-3,6-dihydropyridin-1(2H)-yl]-benzamide (11e)

The compound 11e was obtained following general procedure 3 as off-white solid 65.4% yield, Mp 211–213°C; IR (KBr): ν 3274 (NH), 1643 (C=O)/cm; 1H NMR (CDCl3): δ 1.31 (s 9H, tert-butyl group), 2.52 (s, 3H, —CH3 of oxadiazol ring), 2.84 (m, 2H, C3—H), 3.30 (t, 2H, J = 5.4 Hz, C2—H), 3.81 (brs, 2H, C6—H), 6.62 (m, 1H, C5—H, olefinic proton), 7.14 (brs, 1H, —NH proton, D2O exchange), 7.43 (d, 2H, J = 8.3 Hz, C3′, C5′,—H), 7.66 (d, 2H, J = 8.1 Hz, C2′, C6′—H).

N-[4-(5-Methyl-1,3,4-oxadiazol-2-yl)-3,6-dihydropyridin-1 (2H)-yl]-benzene sulfonamide (11f)

The compound 11f was obtained following general procedure 3 as white solid 48.2% yield, Mp 208–210°C; IR (KBr): ν 3069 (NH), and 1332, 1164 (SO2)/cm; 1H NMR (CDCl3): δ 2.53 (s, 3H, —CH3 of oxadiazol ring), 2.85 (m, 2H, C3—H), 3.31 (t, 2H, J = 5.8 Hz, C2—H), 3.82 (brs, 2H, C6—H), 6.63 (m, 1H, C5—H, olefinic proton), 7.16 (brs, —NH, D2O exchange), 7.40–7.54 (m 3H, C3′0, C4′, C5′—H), 7.73 (d, 2H, J = 7.3 Hz, C2′, C6′—H).

4-Methoxy-N-[4-(5-methyl-1,3,4-oxadiazol-2-yl)-3,6-dihydropyridin-1(2H)-yl]-benzene sulfonamide (11g)

The compound 11g was obtained following general procedure 3 as white granules 54.4% yield, Mp 150–152°C; IR (KBr): ν 3078 (NH), and 1331, 1163 (SO2)/cm; 1H NMR (CDCl3): δ 2.50 (s, 3H, —CH3 of oxadiazol ring), 2.49 (m, 2H, C3—H), 2.77 (t, 2H, J = 5.4 Hz, C2—H), 3.45 (d, 2H, J = 3 Hz, C6—H), 3.86 (s, 3H, —OCH3), 5.47 (s, 1H, —NH, D2O exchange), 6.46 (m, 1H, C5—H olefinic proton), 6.96 (d, 2H, J = 9.0 Hz, C3′, C5′—H), 7.86 (dd, 2H, J = 3.0, 6.9 Hz, C2′, C6′—H).

N-[4-(5-Phenyl-1,3,4-oxadiazol-2-yl)-3,6-dihydropyridin-1 (2H)-yl]benzamide (11h)

The compound 11h was obtained following general procedure 3 as white granules 30.4% yield, Mp 203–204°; IR (KBr): ν 3189 (NH), 1635 (C=O)/cm; 1H NMR (CDCl3: δ 2.93 (m, 2H, C3—H), 3.36 (t, 2H, J = Hz, C2—H), 3.88 (brs, 2H, C6—H), 6.79 (m, 1H, C5—H, olefinic proton), 7.21 (brs, 1H, —NH, D2O exchange), 7.40–7.53 (complex m, 6H, C3′, C4′, C5′ and C3″, C4″, C5″—H), 7.74 (d, 2H, J = 7.2 Hz, C2′, C6′—H), 8.05 (dd, 2H, J = 1.2, 6.0 Hz C2″, C6″—H,).

4-Methoxy-N-[4-(5-phenyl-1,3,4-oxadiazol-2-yl)-3,6-dihydropyridin-1(2H)-yl]-benzamide (11i)

The compound 11i was obtained following general procedure 3 as white solid 44.8% yield, Mp 217–21°C; IR (KBr): ν 3221 (NH), 1638 (C=O)/cm; 1H NMR (CDCl3): δ 2.91 (m, 2H, C3—H), 3.34 (t, 2H, J = 5.7 Hz, C2—H), 3.83 (s, 3H, —OCH3), 3.86 (brs, 2H, C6—H), 6.78 (m, 1H, C5—H, olefinic proton), 6.90 (d, 2H, J = 8.7 Hz, C3″, C5″—H), 7.15 (brs, 1H, —NH, D2O exchange), 7.45–7.54 (m, 3H, C3′, C4′, C5′—H), 7.71 (d, 2H, J = 7.8 Hz, C2″, C6″—H), 8.05 (dd, 2H, J = 1.5, 6.0 Hz, C2′, C6′—H).

4-Fluoro-N-[4-(5-phenyl-1,3,4-oxadiazol-2-yl)-3,6-dihydropyridin-1(2H)-yl]-benzamide (11j)

The compound 11j was obtained following general procedure 3 as white solid 51.4% yield, Mp 213–215°C; IR (KBr): ν 3185 (NH), 1637 (C=O)/cm; 1H NMR (CDCl3): δ 2.92 (m, 2H, C3—H), 3.34 (t, 2H, J = 5.8 Hz, C2—H), 3.86 (brs, 2H, C6—H), 6.78 (m, 1H, C5—H, olefinic proton), 7.10 (t, 2H, J = 8.7 Hz, C3″, C5″—H), 7.25 (brs, 1H, —NH, D2O exchange), 7.45–7.55 (m, 3H, C3′, C4′, C5′—H), 7.71 (d, 2H, J = 7.8 Hz, C2′, C6′—H), 8.05 (dd, 2H, J = 0.9, 6.3 Hz, C2″, C6″—H).

4-tert-Butyl-N-[4-(5-methyl-1,3,4-oxadiazol-2-yl)-3,6-dihydropyridin-1(2H)-yl]benzamide (11k)

The compound 11k was obtained following general procedure 3 as white solid 32.5% yield, Mp 209–211°C; IR (KBr): ν 3211 (NH), 1638 (C=O)/cm; 1H NMR (CDCl3): δ 1.31 (s, 9H, t-butyl group), 2.94 (m, 2H, C3—H), 3.40 (t, 2H, J = 5.7 Hz, C2—H), 3.92 (d, 2H, J = 2.4 Hz, C6—H), 6.78 (m, 1H, C5—H, olefinic proton), 7.39 (brs, 1H, —NH, D2O exchange), 7.43–7.53 (m, 5H, phenyl protons), 7.69 (d, 2H, J = 8.1 Hz, C3″, C5″—H), 8.05 (d, 2H, J = 8.1 Hz, C2″, C6″—H).

N-[4-(5-Phenyl-1,3,4-oxadiazol-2-yl)-3,6-dihydropyridin-1(2H)-yl]-benzene sulfonamide (11l)

The compound 11l was obtained following general procedure 3 as white granules 33.6% yield, Mp 162–163°C; IR (KBr): ν 3106 (NH), 13323, 1168 (SO2)/cm; 1H NMR (CDCl3): δ 2.65 (m, 2H, C3—H), 2.81 (t, 2H, J = 5.7 Hz, C2—H), 3.03 (brs, 2H, C6—H), 5.72 (brs, 1H, —NH, D2O exchange), 6.62 (m, 1H, C5—H, olefinic proton), 7.44–7.64 (complex m, 6H, C3′, C4′, C5′ and C3″, C4″, C5″—H), 7.96 (dd, 2H, J = 1.2 and 7.2 Hz, C2′, C6′—H), 8.01 (dd, 2H, J = 1.5, 6.0 Hz, C2″, C6″—H).

4-Methoxy-N-[4-(5-phenyl-1,3,4-oxadiazol-2-yl)-3,6-dihydropyridin-1(2H)-yl]-benzene-sulfonamide (11m)

The compound 11m was obtained following general procedure 3 as white solid 42.5% yield, Mp 135–136°C; IR (KBr): ν 3089 (NH), 1330, 1154 (SO2)/cm; 1H NMR (CDCl3): δ 2.67 (m, 2H, C3—H), 2.81 (t, 2H, J = 5.4 Hz, C2—H), 3.51 (d, 2H, J = 3.0 Hz, C6—H), 3.87 (s, 3H, —OCH3), 5.45 (s, 1H, —NH, D2O exchange), 6.63 (m, 1H, C5—H, olefinic proton), 6.98 (d, 2H, J = 9.0 Hz, C3″, C5″—H), 7.45–7.54 (m, 3H, C3′, C4′, C5′—H), 7.88 (d, 2H, J = 9.0 Hz, C2′, C6′—H), 8.02 (dd, 2H, J = 1.2, 6.6 Hz, C2″, C6″—H).

4-tert-butyl-N-[4-(5-phenyl-1,3,4-oxadiazol-2-yl)-3,6-dihydropyridin-1(2H)-yl]benzene sulfonamide (11n)

The compound 11n was obtained following general procedure 3 as white solid 48.5% yield, Mp 163–134°C; IR (KBr): ν 3088 (NH), 1335, 1152 (SO2)/cm; 1H NMR (CDCl3): δ 1.33 (s, 9H, t-butyl group), 2.67 (m, 2H, C3—H), 2.81 (t, 2H, J = 5.4 Hz, C2—H), 3.52 (d, 2H, J = 2.4 Hz, C6—H), 5.55 (brs, 1H, —NH, D2O exchange), 6.64 (m, 1H, C5—H, olefinic proton), 6.98 (d, 2H, J = 9.0 Hz, C3″, C5″—H), 7.45–7.54 (m, 3H, C3′, C4′, C5′—H), 7.88 (d, 2H, J = 9.0 Hz, C2′, C6′—H), 8.02 (dd, 2H, J = 1.2, 6.6 Hz, C2″, C6″—H).

Acknowledgment

The authors are grateful to the National Institute of Health, the National Institute of General Medical Sciences, MBRS Program (GM 08111), Research Center at Minority Institutions Grant (RCMI) RR 03020, and Pharmaceutical Research Center NIH/NCRR Grant 1 C06RR12512-01.

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