LETTER
Transformation of N,N-Disubstituted Glycylamides into Cyanamides
2817
(12) Bhalerao, D. S.; Mahajan, U. S.; Chaudhari, K. H.;
(entry 2) the benzylic position remains unaffected,
showing chemoselectivity of the method.16
Akamanchi, K. G. J. Org. Chem. 2007, 72, 662.
(13) (a) Seki, C.; Ishizawa, S.; Koiwa, A.; Ogura, T.; Takaha, M.;
Uchiyama, M. EP 714885, 1996. (b) Kimura, I.; Muraoka,
Y. JP 06 279 407, 1993. (c) Henry, R. A.; Dehn, W. M. J.
Am. Chem. Soc. 1950, 72, 2804.
(14) Preparation of N,N-Disubstituted Glycylamides 1 –
Procedure for 2-[4-(3-Trifluoromethylphenyl)piperi-
zine-1-yl] Acetamide (1e):
The combination of DMP/TEAB was also used for this
transformation and found to be equally applicable. This
system also requires 3:3 equivalents of an equimolar ratio
of DMP and TEAB and reactions were found to be equally
fast and gave nearly the same yields (Table 3).
In conclusion a new reaction system using pentavalent io-
dine reagents, IBX or DMP with TEAB has been devel-
oped for transformation of various N,N-disubstituted
glycylamides into their corresponding cyanamides. The
advantages of the method are fast reactions, mild condi-
tions, nontoxic, and less expensive reagent systems.
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.
Acknowledgment
We sincerely thank the University Grants Commission (UGC) of
India for financial support.
Yield 80%; mp 98–99 °C. 1H NMR (60 MHz, CDCl3):
d = 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):
References and Notes
n
max = 1598, 1610, 1674, 3281 cm–1. MS: m/z (%) = 243
(1) (a) Sandler, S. R.; Karo, W. Organic Functional Group
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Goodman and Gilman’s The Pharmacological Basis of
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Chem. 1972, 37, 2969. (e) Hughes, T. V.; Hammond, S. D.;
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Tetrahedron Lett. 1973, 23, 2121. (b) Mai, K.; Patil, G.
Synth. Commun. 1986, 16, 1823. (c) Hu, N. X.; Aso, Y.;
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Lett. 1984, 1913.
(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): d = 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): nmax = 1656, 3200, 3321 cm–1.
2-(4-Benzylpiperidine-1-yl)acetamide (1b)
White solid; mp 156–157 °C. 1H NMR (60 MHz, CDCl3):
d = 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): nmax = 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): d = 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): nmax = 1654, 3177, 3347 cm–1.
2-(2,6-Dimethylmorpholino)acetamide (1d)
White solid; mp 104–105 °C. 1H NMR (60 MHz, CDCl3):
d = 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): nmax = 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): d = 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):
n
max = 1658, 3180, 3372 cm–1.
(8) Bakunov, S. A.; Rukavishnikov, A. V.; Tkachev, A. V.
2-[N-(3-Chlorophenyl)-N-methylamino]acetamide (1i)
White solid; mp 185–187 °C. 1H NMR (60 MHz, CDCl3):
d = 3.06 (s, 3 H), 3.90 (s, 2 H), 6.55–7.29 (m, 5 H). IR (KBr):
Synthesis 2000, 1148.
(9) Kamijo, S.; Tienan, J.; Yamamoto, Y. J. Am. Chem. Soc.
2001, 123, 9453; and references cited therein.
(10) (a) Zhdankin, V. V.; Stang, P. J. Chem. Rev. 2002, 102,
2523. (b) Zhdankin, V. V. Curr. Org. Synth. 2005, 2, 121.
(c) Wirth, T. Angew. Chem. Int. Ed. 2005, 44, 3656.
(11) (a) Shukla, V. G.; Salgaonkar, P. D.; Akamanchi, K. G. J.
Org. Chem. 2003, 67, 5422. (b) Chaudhari, S. S.;
Akamanchi, K. G. Synthesis 1999, 760. (c) Shukla, V. G.;
Salgaonkar, P. D.; Akmanchi, K. G. Synlett 2005, 1483.
n
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): d = 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):
n
max = 1658, 3180, 3378 cm–1.
Synlett 2007, No. 18, 2815–2818 © Thieme Stuttgart · New York