R. Almansa et al. / Tetrahedron: Asymmetry 19 (2008) 603–606
605
of the asymmetric carbon atom of the major diastereoiso-
Acknowledgements
mer 2 or 3 could be determined. The enantiomeric ratios
of the free primary amines were determined by benzoyla-
tion of the nitrogen atom and analysis of the benzamides
obtained by HPLC using a ChiralCel OD-H column under
the same elution conditions as for the diastereoisomers
2 and 3 (see below). In every case, the enantiomeric ratio
of the free primary amine was equal to the corresponding
2:3 diastereomeric ratio as determined by HPLC.12
´
This work was generously supported by the Direccion Gen-
eral de Ensenanza Superior (DGES) of the current Spanish
Ministerio de Educacion y Ciencia (MEC; Grant No.
CONSOLIDER INGENIO 2010, CSD2007-00006) and
the Generalitat Valenciana (GV/2007/036). R.A. thanks
the Spanish Ministerio de Educacion y Ciencia for a
˜
´
´
predoctoral fellowship. We also thank MEDALCHEMY
S.L. for a gift of chemicals.
As has been described above, the reaction of triorganozin-
cates with N-(tert-butanesulfinyl)imine 1 is a very efficient
procedure to effect the diastereoselective addition of alkyl
groups to the imine carbon atom. Further efforts to extend
the substrate scope and to elucidate the mechanism of the
reaction are currently underway in our laboratories.
References
1. For reviews, see: (a) Davis, F. A.; Chen, B.-C. Chem. Soc.
Rev. 1998, 27, 13–18; (b) Ellman, J. A.; Owens, T. D.; Tang,
T. P. Acc. Chem. Res. 2002, 35, 984–995; (c) Ellman, J. A.
Pure Appl. Chem. 2003, 75, 39–46; (d) Zhou, P.; Chen, B.-C.;
Davis, F. A. Tetrahedron 2004, 60, 8003–8030; (e) Morton,
D.; Stockman, R. A. Tetrahedron 2006, 62, 8869–8905.
2. See, for instance: (a) Kosciolowicz, A.; Rozwadowska, M. D.
Tetrahedron: Asymmetry 2006, 17, 1444–1448; (b) Denolf, B.;
Mangelinckx, S.; Toernroos, K. W.; De Kimpe, N. Org. Lett.
2006, 8, 3129–3132; (c) Sun, X.; Wang, S.; Sun, S.; Zhu, J.;
Deng, J. Synlett 2005, 2776–2780.
3. (a) Knochel, P. In Comprehensive Organic Synthesis; Trost, B.
M., Fleming, I., Shreiber, S. L., Eds.; Pergamon Press:
Oxford, 1991; Vol. 1, Chapter 1.7; (b) Erdik, E. Organozinc
Reagents in Organic Synthesis; CRC Press: Boca Raton, 1996;
(c) Knochel, P. Sci. Synth. 2004, 3, 5–90.
4. Most R2Zn and RZnX reagents react sluggishly with alde-
hydes and not at all with ketones. See, for instance: (a)
Noyori, R.; Kitamura, M. Angew. Chem., Int. Ed. Engl. 1991,
30, 49–69; (b) Lee, V. J. In Comprehensive Organic Synthesis;
Trost, B. M., Fleming, I., Semmelhack, M. F., Eds.;
Pergamon Press: Oxford, 1991; Vol. 4, Section 1.2.2.1.4.
5. See, for instance: (a) Musser, C. A.; Richey, H. G., Jr. J. Org.
Chem. 2000, 65, 7750–7756; (b) Hatano, M.; Suzuki, S.;
Ishihara, K. J. Am. Chem. Soc. 2006, 128, 9998–9999; (c)
Gosselin, F.; Britton, R. A.; Mowat, J.; O’Shea, P. D.;
Davies, I. W. Synlett 2007, 2193–2196.
3. Conclusions
In conclusion, organozincates have been shown to be very
useful nucleophiles for the diastereoselective addition to
N-(tert-butanesulfinyl)imines. Reactions are fast and pro-
vide the expected sulfinamide products in good yields and
with very high diastereomeric ratios with all the alkyl
groups that were transferred, except for methyl. Due to
the low transfer ability of the methyl group, it can be used
as a non-transferable group in mixed triorganozincates.
Since the N-sulfinyl group can be easily removed, this
methodology represents a new and very efficient procedure
for the asymmetric synthesis of primary amines.
4. Experimental
4.1. Typical experimental procedure (Table 1, entry 7)
EtMgBr (0.75 mmol, 0.75 mL of a 1.0 M solution in THF)
was added to Me2Zn (0.86 mmol, 0.43 mL of a 2.0 M solu-
tion in toluene) under argon at room temperature and the
mixture was stirred for 15 min. The resulting solution of
the organozincate was then transferred dropwise via syr-
inge to a solution of the sulfinylimine 1 (105 mg, 0.5 mmol)
in anhydrous THF (3 mL) under argon at ꢀ78 °C and the
mixture was stirred for 1 h at the same temperature. The
reaction was hydrolysed with an aqueous saturated solu-
tion of NH4Cl (2 mL). Water (5 mL) was added and the
mixture was extracted with diethyl ether (3 ꢁ 5 mL). The
combined organic layers were washed with brine (5 mL)
and then dried over Na2SO4. After filtration and evapora-
tion of the solvents, pure tert-butanesulfinamides 2a and 3a
were obtained in 85% combined yield. This mixture was
analyzed by HPLC on a ChiralCel OD-H column using a
254 nm UV detector, 10% i-PrOH in hexane as eluent
and a flow rate of 0.5 mL/min. The retention times were
8.7 (2a) and 10.8 (3a).13 The diastereomeric ratio was
98:2 (2a:3a). The absolute configuration of the asymmetric
carbon atom of the major diastereoisomer was determined
by treatment of the mixture of products with HCl in meth-
anol and comparison of the sign of the specific rotation of
the obtained free amine with the reported data.14–17
6. Harada, T.; Katsuhira, T.; Hara, D.; Kotani, Y.; Maejima,
K.; Kaji, R.; Oku, A. J. Org. Chem. 1993, 58, 4897–4907.
7. (a) Alvaro, G.; Pacioni, P.; Savoia, D. Chem. Eur. J. 1997, 3,
726–731; (b) Alvaro, G.; Martelli, G.; Savoia, D. J. Chem.
Soc., Perkin Trans. 1 1998, 775–784.
8. (a) Almansa, R.; Guijarro, D.; Yus, M. Tetrahedron 2007, 63,
1167–1174; (b) Almansa, R.; Guijarro, D.; Yus, M. Tetrahe-
dron: Asymmetry 2007, 18, 896–899; (c) Almansa, R.;
Guijarro, D.; Yus, M. Tetrahedron: Asymmetry 2007, 18,
2828–2840.
9. See, for instance: (a) Tuckmantel, W.; Oshima, K.; Nozaki,
H. Chem. Ber. 1986, 119, 1581–1593; (b) See also Ref. 5c.
10. The low transfer ability of the methyl group from triorgano-
zincates has been shown in other addition reactions. For
instance, see Refs. 3c and 4b.
11. This formula indicates only the composition of the organo-
metallic mixture and implies neither the molecular formula
nor the dominant species in solution. For a study regarding
the possible reactive species in a reaction between Et3ZnLi
and di-tert-butyl ketone, see: Maclin, K. M.; Richey, H. G.,
Jr. J. Org. Chem. 2002, 67, 4602–4604.
12. A referee suggested that the determination of the relative
proportion of 2 and 3 by HPLC using UV detection is an
estimate unless it has been proven that both diastereoisomers
have the same UV response. The fact that the enantiomeric