LETTER
Mono Alkylation of a-Isocyano Acetamide
1779
(12) (a) Hoppe, D. Angew. Chem., Int. Ed. Engl. 1974, 13, 789.
(b) Schöllkopf, U. Angew. Chem., Int. Ed. Engl. 1977, 16,
339.
(13) Schöllkopf reported that it is possible to perform
monoalkylation of tert-butyl a-isocyano acetate, see:
(a) Schöllkopf, U.; Hoppe, D.; Jentsch, R. Angew. Chem.,
Int. Ed. Engl. 1971, 10, 331. (b) Schöllkopf, U.; Hoppe, D.;
Jentsch, R. Chem. Ber. 1975, 108, 1580.
Acknowledgment
We thank CNRS and this institute for financial support. C.H. thanks
‘Ministère de l’Enseignement Supérieur et de la Recherche’ for a
doctoral fellowship.
References and Notes
(14) (a) Bonne, D.; Dehkane, M.; Zhu, J. Org. Lett. 2004, 6,
4771. (b) Bonne, D.; Dehkane, M.; Zhu, J. J. Am. Chem. Soc.
2005, 127, 6926.
(1) (a) Hulme, C.; Gore, V. Curr. Med. Chem. 2003, 10, 51.
(b) Orru, R. V. A.; De Greef, M. Synthesis 2003, 1471.
(c) Nair, V.; Rajesh, C.; Vinod, A. U.; Bindu, S.; Sreekanth,
A. R.; Mathen, J. S.; Balagopal, L. Acc. Chem. Res. 2003, 36,
899. (d) Zhu, J. Eur. J. Org. Chem. 2003, 1133.
(15) Synthesis of Compound 2a.
To a solution of methyl a-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): d = 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): d = 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.
(e) Dömling, A. Chem. Rev. 2006, 106, 17.
(2) Banfi, L.; Riva, R. Organic Reactions., Vol. 65; Charette, A.
B., Ed.; John Wiley and Sons Inc.: New York, 2005, 1–140.
(3) Multicomponent Reaction; Zhu, J.; Bienaymé, H., Eds.;
Wiley-VCH: Weinheim, 2005.
(4) (a) Marcaccini, S.; Torroba, T. Org. Prep. Proced. Int. 1993,
25, 141 . For a recent example, see (b) Bon, R. S.; Van
Vliet, B.; Sprenkels, N. E.; Schmitz, R. F.; De Kanter, F. J.
J.; Stevens, C. V.; Swart, M.; Bickelhaupt, F. M.; Groen, M.
B.; Orru, R. V. A. J. Org. Chem. 2005, 70, 3542; and
references cited therein.
To a suspension of potassium salt of a-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,
(5) Van Leusen, D.; Van Leusen, A. M. Organic Reactions, Vol.
57; Oveman, L. E., Ed.; John Wiley and Sons Inc.: New
York, 2001, 417–666.
(6) (a) See reference 4a. For representative examples, see:
(b) Chupp, J. P.; Leschinsky, K. L. J. Heterocycl. Chem.
1980, 17, 711. (c) Ito, Y.; Sawamura, M.; Hayashi, T. J. Am.
Chem. Soc. 1986, 108, 6405. (d) Bossio, R.; Marcaccini, S.;
Pepino, R.; Polo, C.; Torroba, T. Heterocycles 1989, 29,
1829. (e) Barton, D. H. R.; Kervagoret, J.; Zard, S. Z.
Tetrahedron 1990, 46, 7587. (f) Zhou, X. T.; Lin, Y. R.;
Dai, L. X.; Sun, J. Tetrahedron 1998, 54, 12445.
CDCl3): d = 4.39 (s, 2 H), 3.69 (s, 3 H), 3.19 (s, 3 H). 13
C
(7) (a) Sun, X.; Janvier, P.; Zhao, G.; Bienaymé, H.; Zhu, J. Org.
Lett. 2001, 3, 877. (b) González-Zamora, E.; Fayol, A.;
Bois-Choussy, M.; Chiaroni, A.; Zhu, J. Chem. Commun.
2001, 1684. (c) Janvier, P.; Sun, X.; Bienaymé, H.; Zhu, J. J.
Am. Chem. Soc. 2002, 124, 2560. (d) Gámez-Montaño, R.;
Zhu, J. Chem. Commun. 2002, 2448. (e) Fayol, A.; Zhu, J.
Angew. Chem. Int. Ed. 2002, 41, 3633. (f) Janvier, P.;
Bienaymé, H.; Zhu, J. Angew. Chem. Int. Ed. 2002, 41,
4291. (g) Gámez-Montaño, R.; González-Zamora, E.;
Potier, P.; Zhu, J. Tetrahedron 2002, 58, 6351. (h) Cuny,
G.; Gámez-Montaño, R.; Zhu, J. Tetradedron 2004, 60,
4879. (i) Fayol, A.; Zhu, J. Org. Lett. 2005, 7, 239.
(j) Bonne, D.; Dekhane, M.; Zhu, J. Org. Lett. 2005, 7, 5285.
(8) (a) Xia, Q.; Ganem, B. Org. Lett. 2002, 4, 1631. (b) Wang,
Q.; Xia, Q.; Ganem, B. Tetradedron Lett. 2003, 44, 6825.
(c) Wang, Q.; Ganem, B. Tetradedron Lett. 2003, 44, 6829.
(9) (a) Zhao, G.; Sun, X.; Bienaymé, H.; Zhu, J. J. Am. Chem.
Soc. 2001, 123, 6700. (b) Janvier, P.; Bois-Choussy, M.;
Bienaymé, H.; Zhu, J. Angew. Chem. Int. Ed. 2003, 42, 811.
(c) Bughin, C.; Zhao, G.; Bienaymé, H.; Zhu, J. Chem. Eur.
J. 2006, 12, 1174.
NMR (75 MHz, CDCl3): d = 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 a-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):
d = 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): d = 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.
(10) Fayol, A.; Housseman, C.; Sun, X.; Janvier, P.; Bienaymé,
H.; Zhu, J. Synthesis 2005, 161.
(17) (a) Friedman, L.; Schechter, H. J. Org. Chem. 1960, 25,
877. (b) Beugelmans, R.; Bigot, R.; Bois-Choussy, M.; Zhu,
J. J. Org. Chem. 1996, 61, 771.
(11) Matsumoto, K.; Suzuki, M.; Yoneda, N.; Miyoshi, M.
Synthesis 1977, 249.
Synlett 2006, No. 11, 1777–1779 © Thieme Stuttgart · New York