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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
J Heterocycl Chem. Author manuscript; available in PMC 2010 August 17.
Published in final edited form as:
J Heterocycl Chem. 2006 May 1; 43(3): 709–718.
doi:  10.1002/jhet.5570430327
PMCID: PMC2922769
NIHMSID: NIHMS204655

Synthesis of 1-(Substituted Phenylcarbonyl/sulfonylamino)-1,2,3,6-tetrahydropyridine-5-carboxylic acid diethylamides as Potential Anti-inflammatory Agents

Abstract

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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.

Introduction

Nonsteroidal anti-inflammatory drugs are a nonhomogeneous 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 [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).

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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 [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-diethylcarbamoyl 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).

Scheme 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,
Scheme 2
R = 4-tert-butyl-C6H5, 3,4,5-tri-methoxy-C6H5, 2-thiophene, 2-furan

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-diethylcarbamoyl)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.

Table 1
Pyridinium Ylides 6a-6k and 14a-14d Synthetic data
Table 2
1,2,3,6-Tetrahydropyridines 7a-7k and 15a-15d Synthetic Data

1,2,3,6-Tetrahydropyridines 7 and 15 show typical 1H NMR absorption at approximately δ 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 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 δ 2.41 when compared to C2-protons. On the other hand, C6-protons generally absorb at δ 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 δ 3.71 was assigned to C6-protons, which have very weak coupling with C4-proton. The peak at δ 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.

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 (δ 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, 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.

General Procedure A

3-[(Diethylamino)carbonyl]-1-[(3-pyridylcarbonyl)imino]pyridinium 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 × 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 °.

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 (2.5 × 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): ν 1644, 1591 (C=O) cm-1; 1H nmr (CDCl3): δ 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.

3-[(Diethylamino)carbonyl]-1-[(4-pyridylcarbonyl)imino]pyridinium Ylide (6b)

The compound 6b was obtained following General Procedure A has yellow color solid, 2.6 g (65.4%), mp115-117°; ir (potassium bromide): ν 1630, 1597 (C=O) cm-1; 1H nmr (CDCl3): δ 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): ν 1636, 1625 (C=O) cm-1; 1H nmr (CDCl3): δ 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 Hz, C4-H), 8.82 (tt, 1H, J= 1.2, 1.5 Hz, C6-H), 9.01 (s, 1H, C2-H).

Anal

Calcd. for C17H19N3O2: C, 68.67; H, 6.44; N, 14.13. Found: C, 68.76; H, 6.54; N, 13.95.

3-[(Diethylamino)carbonyl]-1-[(4-methylbenzoyl)imino]pyridinium Ylide (6d)

The compound 6d was obtained following General Procedure A to furnish (6d) has yellow crystals in 79.5 % (2.6 g) yield, mp 99-100°; ir (potassium bromide): ν 1625, 1615 (C=O) cm-1; 1H nmr (CDCl3): δ 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 C18H21N3O2: C, 69.43; H, 6.80; N, 13.49. Found: C, 69.34; H, 6.87; N, 13.60.

3-Diethylaminocarbonyl-1-(4-fluorobenzoylimino)pyridinium Ylide (6e)

The compound 6e was obtained following General Procedure A has a brownish semi-solid (1.6 g, 64.3 %), ir (potassium bromide): ν 1628, 1618 (C=O) cm-1; 1H nmr (CDCl3): δ 1.24 (t, 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).

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]pyridinium 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): ν 1635, 1628 (C=O) cm-1; 1H nmr (CDCl3): δ 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).

Anal

Calcd. for C17H18ClN3O2: C, 61.54; H, 5.47; N, 12.66. Found: C, 61.42; H, 5.54; N, 12.74.

1-[(3-Bromobenzoyl)imino]-3-[(diethylamino)carbonyl]pyridinium Ylide (6g)

The compound 6g was obtained following General Procedure A has shiny yellow color solid in 61.7% (3.0 g) yield, mp 97-98°, ir (potassium bromide): ν 1628, 1616 (C=O) cm-1; 1H nmr (CDCl3): δ 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 C17H18BrN3O2: C, 54.27; H, 4.82; N, 11.17. Found: C, 54.36; H, 4.90; N, 11.20.

1-(4-Aminobenzoylimino)-3-diethylcarbamoyl-pyridinium Ylide (6h)

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): ν 1630, 1617 (C=O), 3236 (NH2) cm-1; 1H nmr (CDCl3): δ 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]pyridinium 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): ν 1644 (C=O), 1284 and 1138 (SO2) cm-1; 1H nmr (CDCl3): δ 1.08 (t, 3H, J = 7.0 Hz, -CH2-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.

3-[(Diethylamino)carbonyl]-1-[(4-methylphenylsulfonyl)imino]-pyridinium Ylide (6j)

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): ν 1636 (C=O) and 1285, 1137 (SO2) cm-1; 1H nmr (CDCl3): δ 1.08 (t, 3H, J = 7.0 Hz, -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-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)

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): ν 1634 (C=O) and 1287, 1145 (SO2) cm-1; 1H NMR (CDCl3): δ 1.10 (t, 3H, J = 7.0 Hz, -CH2-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).

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

3-Diethylcarbamoyl-1-(3,4,5-trimethoxybenzoylimino)pyridinium Ylide (14a)

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 × 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 × 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): ν 1630, 1610 (C=O) cm-1; 1H nmr (CDCl3): δ 1.04 (t, 3H, J = 6.3 Hz, -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.

1-(4-tert-Butylbenzoylimino)-3-diethylcarbamoylpyridinium Ylide (14b)

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): ν 1635, 1620 (C=O) cm-1; 1H nmr (CDCl3): δ 1.18 (t, 6H, J = 6.3 Hz, -CH2-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).

Anal

Calcd. for C21H27N3O2: C, 71.36; H, 7.70; N, 11.89. Found: C, 71.45; H, 7.79; N, 12.09.

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): ν 1631, 1615 (C=O) cm-1; 1H nmr (CDCl3): δ 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 C15H17N3O2S: C, 59.38; H, 5.65; N, 13.85. Found: C, 59.47; H, 5.76; N, 13.99.

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): ν 1628, 1618 (C=O) cm-1; 1H nmr (CDCl3): δ 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 C15H17N3O3: C, 62.71; H, 5.96; N, 14.63. Found: C, 62.87; H, 6.06; N, 14.88.

General procedure C

1-(3-Pyridylcarbonylamino)-1,2,3,6-tetrahydropyridine-5-carboxylic acid diethylamide (7a)

3-[(Diethylamino)carbonyl]-1-[(3-pyridylcarbonyl)imino]pyridinium 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 × 100 ml) and water (2 × 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): ν 3235(NH), 1662 and 1604 (C=O) cm-1; 1H nmr (CDCl3): δ 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 C16H22N4O2: C, 63.55; H, 7.33; N, 18.53. Found: C, 63.20; H, 7.38; N, 18.34.

1-(4-Pyridylcarbonylamino)-1,2,3,6-tetrahydropyridine-5-carboxylic acid diethylamide (7b)

The compound 7b was obtained following General Procedure C has white solid 50.4% (0.51 g) yield, mp 124-126°; ir (potassium bromide): ν 3233 (NH), 1660 and 1608 (C=O) cm-1; 1H nmr (CDCl3): δ 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).

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)

The compound 7c was obtained following General Procedure C has white solid 53.1% (0.85 g) yield, mp 48-50°; ir (potassium bromide): ν 3238 (NH), 1670, 1604 (C=O) cm-1; 1H nmr (CDCl3): δ 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).

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-carboxylic acid diethylamide (7d)

The compound 7d was obtained following General Procedure C has white crystals in 38.4% (0.78 g) yield, mp 120-122°; ir (potassium bromide): ν 3240 (NH), 1657, 1608 (C=O) cm-1; 1H nmr (CDCl3): δ 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).

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-carboxylic 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 (potassium bromide): ν 3224 (NH), 1660, 1608 (C=O) cm-1; 1H nmr (CDCl3): δ 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-carboxylic acid diethylamide (7f)

The compound 7f was obtained following General Procedure C has white crystals in 48.6% (0.49 g) yield, mp 137-139 °; ir (potassium bromide): ν 3226 (NH), 1660, 1608 (C=O) cm-1; 1H nmr (CDCl3): δ 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.

1-(3-Bromo-benzoylamino)-1,2,3,6-tetrahydropyridine-5-carboxylic acid diethylamide (7g)

The compound 7g was obtained following General Procedure C has white solid 55.3% (0.57 g) yield, mp 53-55°; ir (potassium bromide): ν 3238 (NH), 1665, 1604 (C=O) cm-1; 1H nmr (CDCl3): δ 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 C17H22BrN3O2: C, 53.69; H, 5.83; N, 11.05. Found: C, 53.78; H, 5.94; N, 11.20.

1-(4-Amino-benzoylamino)-1,2,3,6-tetrahydropyridine-5-carboxylic 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): ν 3239 (NH2), 3225 (NH), 1660, 1608 (C=O) cm-1; 1H NMR (CDCl3): δ 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.

1-Benzenesulfonylamino-1,2,3,6-tetrahydropyridine-5-carboxylic acid diethylamide (7i)

The compound 7i was obtained following General Procedure C has white granules 42.3% (0.43 g) yield, mp 132-134°; ir (potassium bromide): ν 3197 (NH), 1607 (C=O), and 1340, 1167 (SO2) cm-1; 1H nmr (CDCl3): δ 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, -CH2-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 C16H23N3O3S: C, 56.95; H, 6.87; N, 12.45. Found: C, 57.10; H, 6.96; N, 12.56.

1-(4-Methyl-benzenesulfonylamino)-1,2,3,6-tetrahydropyridine-5-carboxylic acid diethylamide (7j)

The compound 7j was obtained following General Procedure C has white crystals 58.0% (0.25 g) yield, mp 148-150°; ir (potassium bromide): ν 3116 (NH), 1602 (C=O), and 1289, 1167 (SO2) cm-1; 1H nmr (CDCl3): δ 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, 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-(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): ν 3118 (NH), 1600 (C=O), and 1333, 1163 (SO2) cm-1; 1H nmr (CDCl3): δ 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, -CH2-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).

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)

The compound 15a was obtained following General Procedure C has white solid 40.7% (0.41 g) yield, mp 151-152°; ir (potassium bromide): ν 3239 (NH), 1654, 1602 (C=O) cm-1; 1H nmr (CDCl3): δ 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).

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-carboxylic 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 (potassium bromide): ν 3240 (NH), 1656, 1606 (C=O) cm-1; 1H nmr (CDCl3): δ 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).

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)

The compound 15c was obtained following General Procedure C has white solid 38.4% (0.41 g) yield, mp 48-50°; ir (potassium bromide): ν 3226 (NH), 1660, 1608 (C=O) cm-1; 1H nmr (CDCl3): δ 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).

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.

1-[(Furan-2-carbonyl)-amino]-1,2,3,6-tetrahydropyridine-5-carboxylic 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 (potassium bromide): ν 3238 (NH), 1665, 1604 (C=O) cm-1; 1H nmr (CDCl3): δ 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.

Table 3
Elemental Analysis of the Pyridinium ylides (6a-6k and 14a-14d)
Table 4
Elemental Analysis of the Tetrahydropyridines (7a-7k and 15a-15d)

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.

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