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Synlett 2007(18): 2815-2818  
DOI: 10.1055/s-2007-991093
LETTER
© Georg Thieme Verlag Stuttgart · New York

Novel and Facile Transformation of N,N-Disubstituted Glycylamides into Corresponding Cyanamides by Using Pentavalent Iodine Reagents in Combination with Tetraethylammonium Bromide

Kiran H. Chaudhari, Ulhas S. Mahajan, Dinesh S. Bhalerao, Krishnacharya G. Akamanchi*
Department of Pharmaceutical Sciences & Technology, Institute of Chemical Technology, Matunga, Mumbai 400 019, India
Fax: +91(22)24145614; e-Mail: kgap@rediffmail.com;
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Publication History

Received 4 June 2007
Publication Date:
12 October 2007 (online)

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Abstract

Novel and facile transformation of N,N-disubstituted glycylamides into corresponding cyanamides using pentavalent ­iodine reagents and tetraethylammonium bromide is discussed. The advantages of this system are use of non toxic reagents, shorter ­reaction times and moderate to good yields.

Key words

pentavalent iodine reagents - o-iodoxybenzoic acid - Dess-Martin periodinane - tetraethylammonium bromide - glycyl­amides - cyanamides

14

Preparation of N,N-Disubstituted Glycylamides 1 - Procedure for 2-[4-(3-Trifluoromethylphenyl)piperi-zine-1-yl] Acetamide (1e): To a stirred solution of 4-(3-trifluoromethylphenyl)piperi-zine (3 g, 13 mmol) in EtOH (50 mL) were added K2CO3 (1.77 g, 13 mmol), 2-chloroacetamide (1.46 g, 15.6 mmol) and a catalytic amount of NaI (0.1 g). The resultant reaction mixture was refluxed for 6 h. After completion of reaction (monitoring by TLC) the reaction mixture was cooled, filtered, and the filtrate was evaporated under reduced pressure. The resultant residue was dissolved in EtOAc (200 mL) and washed with H2O (2 × 50 mL), brine, dried over anhyd Na2SO4, filtered, and concentrated under reduced pressure. The residue obtained was crystallized from MeOH-H2O to give the product as a white solid.
Yield 80%; mp 98-99 °C. 1H NMR (60 MHz, CDCl3): δ = 3.29-3.31 (t, J = 3 Hz, 4 H), 3.41-3.43 (t, J = 3 Hz, 4 H), 5.778 (br s, 1 H), 7.06-7.42 (m, 4 H) ppm. IR (KBr): νmax = 1598, 1610, 1674, 3281 cm-1. MS: m/z (%) = 243 (100), 287 [M+].
Compounds 1a-d,i,j were prepared by the same procedure. The remaining compounds were prepared by standard literature procedure (see ref. 13).
2-(Piperidine-1-yl)acetamide (1a) White solid; mp 110-112 °C [lit. 13b: 111 °C]. 1H NMR (60 MHz, CDCl3): δ = 1.56-1.68 (m, 5 H), 2.48-2.54 (t, J = 4.2 Hz, 4 H), 3.02 (s, 2 H), 5.63 (br s, 1 H), 7.33 (br s, 1 H) ppm. IR (KBr): νmax = 1656, 3200, 3321 cm-1.
2-(4-Benzylpiperidine-1-yl)acetamide (1b)
White solid; mp 156-157 °C. 1H NMR (60 MHz, CDCl3): δ = 1.35-1.68 (m, 5 H), 2.12-2.20 (d, J = 4.8 Hz, 2 H), 2.53-2.61 (t, J = 2.4 Hz, 4 H), 2.95 (s, 2 H), 5.63 (br s,1 H), 7.20-7.33 (m, 5 H) ppm. IR (KBr): νmax = 1656, 3191, 3398 cm-1. MS: m/z (%) = 188 (100), 232 [M+].
2-Morpholinoacetamide (1c) White solid; mp 122-123 °C [lit.13c 122-125 °C]. 1H NMR (60 MHz, CDCl3): δ = 2.48-2.63 (t, J = 4.1 Hz, 4 H), 3.01 (s, 2 H), 3.66-3.80 (t, J = 4.1 Hz, 4 H), 5.77 (br s, 1 H), 6.93 (br s, 1 H) ppm. IR (KBr): νmax = 1654, 3177, 3347 cm-1.
2-(2,6-Dimethylmorpholino)acetamide (1d)
White solid; mp 104-105 °C. 1H NMR (60 MHz, CDCl3): δ = 1.20 (d, J = 4.1 Hz, 6 H), 2.20-2.55 (m, 2 H), 3.01 (s, 2 H), 3.65-3.78 (t, J = 4.1 Hz, 4 H), 5.77 (br s, 1 H), 6.93 (br s, 1 H) ppm. IR (KBr): νmax = 1656, 3172, 3349 cm-1. MS: m/z (%) = 128 (100), 172 [M+].
2-( N -Cyclohexyl- N -methylamino)acetamide (1g)
White solid; mp 83-84 °C [lit.13a 84-85 °C]. 1H NMR (60 MHz, CDCl3): δ = 1.15-1.83 (m, 11 H), 2.30 (s, 3 H), 3.04 (s, 2 H), 5.57 (br s, 1 H), 7.26 (s, 1 H) ppm. IR (KBr): νmax = 1658, 3180, 3372 cm-1.
2-[ N -(3-Chlorophenyl)- N -methylamino]acetamide (1i) White solid; mp 185-187 °C. 1H NMR (60 MHz, CDCl3): δ = 3.06 (s, 3 H), 3.90 (s, 2 H), 6.55-7.29 (m, 5 H). IR (KBr): νmax = 1651, 1599, 3167, 3330 cm-1. MS: m/z (%) = 154 (100), 198 [M+].
2-( N -Methyl- N - o -tolylamino)acetamide (1j)
White solid; mp 114-115 °C [lit.13a 114-115 °C]. 1H NMR (60 MHz, CDCl3): δ = 2.43 (s, 3 H), 2.81 (s, 3 H), 3.64 (s, 2 H), 5.82 (br s, 1 H), 7.21-7.59 (m, 5 H) ppm. IR (KBr): νmax = 1658, 3180, 3378 cm-1.

15

General Procedure for Cyanamides 2 To a stirred suspension of IBX (4.2 g, 15 mmol) in MeCN (50 mL) was added TEAB (3.15 g, 15 mmol) and the was mixture allowed to stir for 5 min. A yellow suspension was observed, to which N,N-disubstituted glycylamide (5 mmol) was added in one portion. The reaction mixture was heated to 60 °C and held at this temperature until complete consumption of starting material (TLC). The reaction mixture was cooled and MeCN was removed under reduced pressure. The resultant residue was extracted with EtOAc (2 × 50 mL) and the organic layer was washed (1 × 30 mL) with 10% NaHSO3 solution, sat. Na2CO3, brine, dried over anhyd Na2SO4, filtered, and concentrated under reduced pressure to give crude cyanamide. Pure cyanamide was obtained after column chromatography (silica gel, mesh size 60-120; eluent EtOAc-hexane, 1:99).
Piperidine-1-carbonitrile (2a)
Oil.17a 1H NMR (60 MHz,CDCl3): δ = 1.12-1.27 (m, 6 H), 2.94-3.18 (t, J = 4.2 Hz, 4 H) ppm. IR (neat): νmax = 2210 cm-1.
4-Benzylpiperidine-1-carbonitrile (2b) Yellowish oil. 1H NMR (300 MHz, CDCl3): δ = 1.25-1.56 (q, 4 H), 1.77 (m, 1 H), 2.50 (d, 2 H), 2.92-3.09 (t, J = 3.6 Hz, 4 H), 7.10-7.31 (m, 5 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 29.69, 30.77, 42.89, 49.74, 118.62 (CN), 126.25, 128.34, 129.06, 139.35 ppm. IR (CHCl3): νmax = 2207 cm-1. Anal. Calcd for C13H16N2: C, 79.24; H, 7.54; N, 13.20. Found: C, 79.25. H, 7.56; N, 13.22.
Morpholine-4-carbonitrile (2c) Oil.17b 1H NMR (60 MHz, CDCl3): δ = 3.12-3.26 (t, J = 4.2 Hz, 4 H), 3.63-3.77 (t, J = 4.2 Hz, 4 H). IR (neat): νmax = 2215 cm-1.
2,6-Dimethylmorpholine-4-carbonitrile (2d) Oil. 1H NMR (60 MHz, CDCl3): δ = 2.82-3.23 (m, 4 H), 3.78-3.89 (m, 2 H), 1.21 (d, J = 6.0 Hz, 6 H) ppm. IR (neat): νmax = 2212 cm-1. Anal. Calcd for C7H12N2O: C, 59.98; H, 8.63; N, 18.41. Found: C, 60.01; H, 8.62; N, 18.40. 4-(3-Trifluoromethylphenyl)piperizine-1-carbonitrile (2e)
Yellowish oil. 1H NMR (300 MHz, CDCl3): δ = 3.29-3.31 (t, J = 3.0 Hz, 4 H), 3.41-3.43 (t, J = 3.0 Hz, 4 H), 7.06-7.42 (m, 4 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 48.44, 48.92, 113.39, 117.26 (CN), 119.92, 122.27 (CF3), 131.50, 150.92 ppm. IR (KBr): νmax = 2214 cm-1. Anal. Calcd for C12H12F3N3: C, 56.47; H, 4.70; N, 16.47. Found: C, 56.49; H, 4.72; N, 16.49.
N , N -Dimethylcyanamide (2f)
Oil.17a 1H NMR (60 MHz, CDCl3): δ = 2.32 (s, 6 H) ppm. IR (neat): νmax = 2207 cm-1.
N -Cyclohexyl- N -methylcyanamide (2g)
Liquid. 1H NMR (60 MHz, CDCl3): δ = 1.20-2.23 (m, 10 H), 2.78 (s, 3 H), 2.80 (m, 1 H) ppm. IR (neat): νmax = 2214 cm-1. Anal. Calcd for C8H14N2: C, 69.06; H, 10.79; N, 20.14. Found: C, 69.08; H, 10.80; N, 20.16.
N , N -Diethylcyanamide (2h) Oil.17a 1H NMR (60 MHz, CDCl3): δ = 0.92-1.16 (t, J = 7.1 Hz, 6 H), 2.40-2.76 (q, J = 7.1 Hz, 4 H) ppm. IR (neat): νmax = 2200 cm-1.
N -(3-Chlorophenyl)methylcyanamide (2i)
Pale yellow solid; mp 139-140 °C. 1H NMR (60 MHz, CDCl3): δ = 3.33 (s, 3 H), 6.78-7.64 (m, 4 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 37.08, 112.90, 114.71, 116.28, 116.59 (CN), 128.96, 134.41, 135.77 ppm. IR (KBr): νmax = 2226 cm-1. Anal. Calcd for C8H7ClN2: C, 62.95; H, 4.59; N, 9.18. Found: C, 62.97; H, 4.60; N, 9.20.
N -Methyl N - o -Tolyl Cyanamide (2j)
Oil. 1H NMR (60 MHz CDCl3): δ = 2.31 (s, 3 H), 2.76 (s, 3 H), 7.15-7.40 (m, 4 H) ppm. IR (neat): νmax = 2219 cm-1. Anal. Calcd for C9H10N2: C, 73.97; H, 6.84; N, 19.17. Found: C, 73.99; H, 6.87; N, 19.20.