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

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.

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

References and Notes

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<A NAME="RD17507ST-14">14</A>

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): ν_max = 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): ν_max = 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): ν_max = 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): ν_max = 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): ν_max = 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): ν_max = 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): ν_max = 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): ν_max = 1658, 3180, 3378 cm^-1.

<A NAME="RD17507ST-15">15</A>

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 1}H 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): ν_max = 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): ν_max = 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 1}H 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): ν_max = 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): ν_max = 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): ν_max = 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 1}H NMR (60 MHz, CDCl₃): δ = 2.32 (s, 6 H) ppm. IR (neat): ν_max = 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): ν_max = 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 1}H 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): ν_max = 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): ν_max = 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): ν_max = 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.

<A NAME="RD17507ST-16">16</A> Nicolaou KC. Baran PS. Zhong YL. J. Am. Chem. Soc.  2001,  123:  3183 

<A NAME="RD17507ST-17A">17a</A> Jonczyk A. Ochal Z. Makosza M. Synthesis  1978,  882 

<A NAME="RD17507ST-17B">17b</A> Baker JA. inventors; DE  2106167.