Doubly Stereocontrolled Asymmetric Aza-Henry Reaction
COMMUNICATIONS
amine (10 mmol) in dry ether (35 mL) at 08C. The reaction References
mixture was allowed to warm slowly to room temperature
over a period of 3 h and then was stirred for a further 12 h
at room temperature. After separation of the precipitated
thiourea by filtration, the solvent was removed under re-
duced pressure. After column chromatography on silica gel
eluted with 25% ethyl acetate in hexanes, the corresponding
isothiocyanate as a white solid was isolated in 92% yield.
Under an argon atmosphere, to a solution of the above
isothiocyanate (9.17 mmol) in dry dichloromethane (80 mL)
[1] For recent advances on this reaction, see: a) E. Mar-
quꢃs-Lꢄpez, P. Merino, T. Tejero, R. P. Herrera, Eur. J.
Org. Chem. 2009, DOI: 10.1002/ejoc.200801097; b) A.
Ting, S. E. Schaus, Eur. J. Org. Chem. 2007, 5797; c) B.
Westermann, Angew. Chem. 2003, 115, 161; Angew.
Chem. Int. Ed. 2003, 42, 151.
[2] a) D. Lucet, T. Le Gall, C. Mioskowski, Angew. Chem.
1998, 110, 2724; Angew. Chem. Int. Ed. 1998, 37, 2580;
b) H. Adams, J. C. Anderson, S. Peace, A. M. K. Pen-
nell, J. Org. Chem. 1998, 63, 9932.
[3] Selected recent reviews, see: a) M. Petrini, Chem. Rev.
2005, 105, 3949; b) R. Ballini, M. Petrini, Tetrahedron
2004, 60, 1017; c) E. Foresti, G. Palmieri, M. Petrini, R.
Profeta, Org. Biomol. Chem. 2003, 1, 4275.
[4] K.-i. Yamada, S. J. Harwood, H. Grçger, M. Shibasaki,
Angew. Chem. 1999, 111, 3713; Angew. Chem. Int. Ed.
1999, 38, 3504.
[5] a) S. Handa, V. Gnanadesikan, S. Matsunaga, M. Shiba-
saki, J. Am. Chem. Soc. 2007, 129, 4900; b) H. Zhou, D.
Peng, B. Qin, Z. Hou, X. Liu, X. Feng, J. Org. Chem.
2007, 72, 10302; c) B. M. Trost, D. W. Lupton, Org.
Lett. 2007, 9, 2023; d) C. Palomo, M. Oiarbide, R.
Halder, A. Laso, R. Lꢄpez, Angew. Chem. 2006, 118,
123; Angew. Chem. Int. Ed. 2006, 45, 117; e) F. Gao, J.
Zhu, J. Y. Tang, M. Deng, C. Qian, Chirality 2006, 18,
741; f) J. C. Anderson, A. J. Blake, G. P. Howell, C. J.
Wilson, J. Org. Chem. 2005, 70, 549; g) J. C. Anderson,
G. P. Howell, R. M. Lawrence, C. J. Wilson, J. Org.
Chem. 2005, 70, 5665; h) K. R. Knudsen, K. A. Jørgen-
sen, Org. Biomol. Chem. 2005, 3, 1362; i) A. Lee, W.
Kim, J. Lee, T. Hyeon, B. M. Kim, Tetrahedron: Asym-
metry 2004, 15, 2595; j) K. Yamada, G. Moll, M. Shiba-
saki, Synlett 2001, 980; k) K. R. Knudsen, T. Risgaard,
N. Nishiwaki, K. V. Gothelf, K. A. Jørgensen, J. Am.
Chem. Soc. 2001, 123, 5843; l) N. Nishiwaki, K. R.
Knudsen, K. V. Gothelf, K. A. Jørgensen, Angew.
Chem. 2001, 113, 3080; Angew. Chem. Int. Ed. 2001, 40,
2992.
[6] a) K. Takada, K. Nagasawa, Adv. Synth. Catal. 2009,
351, 345; b) C. J. Wang, X. Q. Dong, Z. H. Zhang, Z. Y.
Xue, H. L. Teng, J. Am. Chem. Soc. 2008, 130, 8606;
c) C. G. Wang, Z. H. Zhou, C. C. Tang, Org. Lett. 2008,
10, 1707; d) M. Rueping, A. P. Antonchick, Org. Lett.
2008, 10, 1731; e) C. Rampalakos, W. D. Wulff, Adv.
Synth. Catal. 2008, 350, 1785; f) A. Singh, R. A. Yoder,
B. Shen, J. N. Johnston, J. Am. Chem. Soc. 2007, 129,
3466; g) M. T. Robak, M. Trincado, J. A. Ellman, J.
Am. Chem. Soc. 2007, 129, 15110; h) X. N. Xu, T. Furu-
kawa, T. Okino, H. Miyabe, Y. Takemoto, Chem. Eur.
J. 2006, 12, 466; i) A. S. Hess, R. A. Yoder, J. N. John-
ston, Synlett 2006, 147; j) L. Bernardi, F. Fini, R. P. Her-
rera, A. Ricci, V. Sgarzani, Tetrahedron 2006, 62, 375;
k) T. P. Yoon, E. N. Jacobsen, Angew. Chem. 2005, 117,
470; Angew. Chem. Int. Ed. 2005, 44, 466; l) T. Okino,
A. Nakamura, T. Furukawa, Y. Takemoto, Org. Lett.
2004, 6, 625; m) B. M. Nugent, R. A. Yoder, J. N. John-
ston, J. Am. Chem. Soc. 2004, 126, 3418; n) B. M.
Nugent, R. A. Yoder, J. N. Johnston, J. Am. Chem. Soc.
2004, 126, 3418.
was
added
N,N-dimethyl-trans-diaminocyclohexane
(10 mmol). The reaction mixture was stirred for 12 h at
room temperature and was concentrated under vacuum.
After column chromatography on silica gel (ethyl acetate/
hexane=2/1 as eluent), the thiourea L1 as a white solid was
isolated in 83% yield.
1-[(1R,2R)-2-(Dimethylamino)cyclohexyl]-3-
{[(1R,4aS,10aR)-7-isopropyl-1,4a-dimethyl-1,2,3,4,4a,9,
10,10a-octahydrophenanthren-1-yl]methyl}thiourea (1R,2R)-
1
L2: [a]20: +2 (c 2.0, CHCl3); mp 828C. H NMR (300 MHz,
CDCl3)D: d=7.14–7.17 (d, J=8.1 Hz, 1H), 6.97–6.99 (m, 1H),
6.88 (s, 1H), 6.45 (br, 1H), 3.68–3.70 (m, 1H), 3.35 (m, 1H),
2.79–2.91 (m, 3H), 2.39–2.45 (m, 1H), 2.20–2.34 (m, 7H),
1.67–1.88 (m, 8H), 1.43–1.50 (m, 2H), 1.21–1.38 (m, 16H),
0.85–1.64 (m, 5H); 13C NMR (75 MHz, CDCl3): d=147.1,
145.7, 134.7, 126.8, 124.1, 123.8, 67.1, 56.3, 55.4, 45.6, 40.3,
38.3, 37.8, 37.4, 36.6, 33.4, 33.1, 30.0, 25.2, 25.1, 24.5, 24.0,
23.9, 22.1, 19.1, 18.6, 18.5; IR: n=3437, 3259, 3066, 2928,
2248, 2122, 1550, 1452, 1380, 1058, 1029, 913, 822, 759,
624 cmÀ1; ESI-MS: m/z=470 [M+]; HR-MS-ESI: m/z=
470.3573, calcd. for C29H47N3S [M+H]+: 470.3563.
Typical Procedure for the Asymmetric Aza-Henry
Reaction of Nitroalkanes to N-Boc-Imines Generated
in situ from a-Amido Sulfones
To
a
stirred solution of
G
ACHTUNGTRENUN(NG 1S,2S)-L2
(0.015 mmol, 7 mg), a-amido sulfone 2a (0.1 mmol, 34.7 mg)
in the biphasic solvent of CHCl3 (1.0 mL) and H2O
(1.0 mL), K2CO3 (0.1 mmol, 13.8 mg) was added. Subse-
quently, nitromethane (0.3 mmol, 16.1 mL) was added under
argon. The solution was stirred at 08C. After the reaction
was completed (the course of the reaction was monitored by
means of thin-layer chromatography, TLC), the mixture was
extracted with CHCl3 (10 mL ꢂ 4) and dried with sodium
sulfate. Concentration and flash chromatography on silica
gel (eluent, ethyl acetate/hexane 1:8) afforded the optical
active product (S)-3a; yield: 22.8 mg (86%) or (R)-3a; yield:
23.4 mg (88%). The enantiomeric purity of the product was
determined by using HPLC (Chiralpak AD column, l=
210 nm, i-PrOH/hexane 10:90, 0.6 mLminÀ1): (S)-3a ee=
93%, tmajor =16.88 min, tminor =17.91 min; (R)-3a ee=87%,
tminor =17.07 min, tmajor =17.91 min.
Acknowledgements
We are grateful for the grants from the National Natural Sci-
ence Foundation of China (Nos. 20525206, 20772052 and
20621091), the Chang Jiang Program of the Ministry of Edu-
cation of China for financial support.
Adv. Synth. Catal. 2009, 351, 2096 – 2100
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2099