Mono Alkylation of α-Isocyano Acetamide to its Higher Homologues

Abstract

Alkylation of α-isocyano acetamide (2) with alkyl halide in MeCN at 0 °C in the presence of cesium hydroxide afforded the mono-alkylated product 1 in good to excellent yield.

cesium hydroxide - isonitrile - isocyano acetamide - monoalkylation

References and Notes

1a Hulme C. Gore V. Curr. Med. Chem.  2003,  10:  51 

1b Orru RVA. De Greef M. Synthesis  2003,  1471 

1c Nair V. Rajesh C. Vinod AU. Bindu S. Sreekanth AR. Mathen JS. Balagopal L. Acc. Chem. Res.  2003,  36:  899 

1d Zhu J. Eur. J. Org. Chem.  2003,  1133 

1e Dömling A. Chem. Rev.  2006,  106:  17 

2 Banfi L. Riva R. Organic Reactions.   Vol. 65:  Charette AB. John Wiley and Sons Inc.; New York: 2005.  p.1-140  

3 Multicomponent Reaction   Zhu J. Bienaymé H. Wiley-VCH; Weinheim: 2005. 

4a Marcaccini S. Torroba T. Org. Prep. Proced. Int.  1993,  25:  141 

For a recent example, see

4b Bon RS. Van Vliet B. Sprenkels NE. Schmitz RF. De Kanter FJJ. Stevens CV. Swart M. Bickelhaupt FM. Groen MB. Orru RVA. J. Org. Chem.  2005,  70:  3542 ; and references cited therein

5 Van Leusen D. Van Leusen AM. Organic Reactions   Vol. 57:  Oveman LE. John Wiley and Sons Inc.; New York: 2001.  p.417-666  

6a

See reference 4a. For representative examples, see:

6b Chupp JP. Leschinsky KL. J. Heterocycl. Chem.  1980,  17:  711 

6c Ito Y. Sawamura M. Hayashi T. J. Am. Chem. Soc.  1986,  108:  6405 

6d Bossio R. Marcaccini S. Pepino R. Polo C. Torroba T. Heterocycles  1989,  29:  1829 

6e Barton DHR. Kervagoret J. Zard SZ. Tetrahedron  1990,  46:  7587 

6f Zhou XT. Lin YR. Dai LX. Sun J. Tetrahedron  1998,  54:  12445 

7a Sun X. Janvier P. Zhao G. Bienaymé H. Zhu J. Org. Lett.  2001,  3:  877 

7b González-Zamora E. Fayol A. Bois-Choussy M. Chiaroni A. Zhu J. Chem. Commun.  2001,  1684 

7c Janvier P. Sun X. Bienaymé H. Zhu J. J. Am. Chem. Soc.  2002,  124:  2560 

7d Gámez-Montaño R. Zhu J. Chem. Commun.  2002,  2448 

7e Fayol A. Zhu J. Angew. Chem. Int. Ed.  2002,  41:  3633 

7f Janvier P. Bienaymé H. Zhu J. Angew. Chem. Int. Ed.  2002,  41:  4291 

7g Gámez-Montaño R. González-Zamora E. Potier P. Zhu J. Tetrahedron  2002,  58:  6351 

7h Cuny G. Gámez-Montaño R. Zhu J. Tetradedron  2004,  60:  4879 

7i Fayol A. Zhu J. Org. Lett.  2005,  7:  239 

7j Bonne D. Dekhane M. Zhu J. Org. Lett.  2005,  7:  5285 

8a Xia Q. Ganem B. Org. Lett.  2002,  4:  1631 

8b Wang Q. Xia Q. Ganem B. Tetradedron Lett.  2003,  44:  6825 

8c Wang Q. Ganem B. Tetradedron Lett.  2003,  44:  6829 

9a Zhao G. Sun X. Bienaymé H. Zhu J. J. Am. Chem. Soc.  2001,  123:  6700 

9b Janvier P. Bois-Choussy M. Bienaymé H. Zhu J. Angew. Chem. Int. Ed.  2003,  42:  811 

9c Bughin C. Zhao G. Bienaymé H. Zhu J. Chem. Eur. J.  2006,  12:  1174 

10 Fayol A. Housseman C. Sun X. Janvier P. Bienaymé H. Zhu J. Synthesis  2005,  161 

11 Matsumoto K. Suzuki M. Yoneda N. Miyoshi M. Synthesis  1977,  249 

12a Hoppe D. Angew. Chem., Int. Ed. Engl.  1974,  13:  789 

12b Schöllkopf U. Angew. Chem., Int. Ed. Engl.  1977,  16:  339 

Schöllkopf reported that it is possible to perform monoalkylation of tert-butyl α-isocyano acetate, see:

13a Schöllkopf U. Hoppe D. Jentsch R. Angew. Chem., Int. Ed. Engl.  1971,  10:  331 

13b Schöllkopf U. Hoppe D. Jentsch R. Chem. Ber.  1975,  108:  1580 

14a Bonne D. Dehkane M. Zhu J. Org. Lett.  2004,  6:  4771 

14b Bonne D. Dehkane M. Zhu J. J. Am. Chem. Soc.  2005,  127:  6926 

15

Synthesis of Compound 2a.
To a solution of methyl α-isocyanoacetate (4.4 mmol) in dry MeOH (3.0 mL) was added morpholine (10.3 mmol, 2.3 equiv) and the reaction mixture was stirred at r.t. for 18 h. The volatile was removed under reduced pressure and the crude material was purified by flash chromatography (SiO₂, EtOAc-heptane = 2:1) to afford 2a in 85% yield, mp 77-78 °C. IR (CHCl₃): 2163, 1658, 1462, 1422, 1274, 1236, 1111, 992 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 4.31 (s, 2 H), 3.63 (m, 4 H), 3.54 (m, 2 H), 3.30 (m, 2 H). ¹³C NMR (75 MHz, CDCl₃): δ = 161.3, 160.7, 66.5, 66.1, 45.6, 44.3, 42.6. MS (ES, positive mode): m/z = 177.1 [M + Na]⁺.
Synthesis of Compound 2d.
To a suspension of potassium salt of α-isocyano acetic acid (4.4 mmol) in dry CH₂Cl₂ (22 mL) were added Et₃N (5.7 mmol), EDCI (5.3 mmol) and hydrochloride salt of MeNH(OMe) (4.8 mmol). After being stirred at r.t. for 20 h, the reaction mixture was quenched with H₂O (2 mL) and extracted with CH₂Cl₂. The combined organic layers were washed with brine, dried and evaporated under reduced pressure. The crude material was purified by flash chromatography (Al₂O₃, EtOAc-heptane = 2:1) to afford 2d as a brown solid (69%), mp 72-73 °C. IR (CHCl₃): 2162, 1681, 1410, 1317, 1179, 963 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 4.39 (s, 2 H), 3.69 (s, 3 H), 3.19 (s, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 163.9, 160.7 (141.9), (62.3) 61.7, (52.3) 43.8, (40.7) 32.7. MS (ES, positive mode): m/z = 151.1 [M + Na]⁺.

16

Monoalkylation of α-Isocyanoacetamide - A General Procedure.
To a dry test tube containing CsOH·H₂O (0.34 mmol, 1.7 equiv) were added, under argon atmosphere, a solution of isocyano acetamide (0.20 mmol) in MeCN (1.0 mL) and alkylating agent (0.21 mmol) at 0 °C. The resulting reaction mixture was stirred at 0 °C. When the reaction was deemed complete by TLC analysis (typically 24 h), the volatile was removed under reduced pressure. Purification of the crude product by either preparative TLC (silica gel) or flash chromatography (silica gel) afforded the desired product.
Compound 1a: yield 94%. IR (CHCl₃): 2928, 2863, 2142, 1668, 1496, 1456, 1116 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 7.26-7.36 (m, 5 H), 4.54 (dd, J = 7.7, 7.0 Hz, 1 H), 3.20-3.69 (m, 10 H). ¹³C NMR (62.5 MHz, CDCl₃): δ = 163.5, 159.8, 135.0, 129.4 (2 C), 128.8 (2 C), 127.7, 66.4, 65.9, 55.0, 46.2, 42.9, 39.1. MS (EI): m/z = 244 [M]⁺. Anal. Calcd for C₁₄H₁₆N₂O₂ (%): C, 68.83; H, 6.60; N, 11.47. Found: C, 68.71; H, 6.60; N, 11.47.

17a Friedman L. Schechter H. J. Org. Chem.  1960,  25:  877 

17b Beugelmans R. Bigot R. Bois-Choussy M. Zhu J. J. Org. Chem.  1996,  61:  771