K. Ito et al. / Tetrahedron Letters 48 (2007) 6147–6149
6149
Table 2. Enantioselective aza-Morita–Baylis–Hillman reaction using
1c as a catalysta
References and notes
TsHN
R
1. For reviews: (a) Comprehensive Asymmetric Catalysis;
Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.;
Springer: Berlin, 1999; (b) Catalytic Asymmetric Synthesis;
2nd ed.; Ojima, I., Ed., Wiley-VCH: New York, 2000.
2. For reviews: (a) Schreiner, P. R. Chem. Soc. Rev. 2003, 32,
289–296; (b) Pihko, P. M. Angew. Chem., Int. Ed. 2004, 43,
2062–2064; (c) Akiyama, T.; Itoh, J.; Fuchibe, K. Adv.
Synth. Catal. 2006, 348, 999–1010; (d) Taylor, M. S.;
Jacobsen, E. N. Angew. Chem., Int. Ed. 2006, 45, 1520–
1543.
3. Examples of bidentate or bifunctional metallic Lewis
acids, see: (a) Maruoka, K. Catal. Today 2001, 66, 33–45;
(b) Maruoka, K. Pure Appl. Chem. 2002, 74, 123–128; (c)
Shibasaki, M.; Kanai, M.; Funabashi, K. Chem. Commun.
2002, 1989–1999, and references cited therein.
4. For reviews: (a) Wong, C.-H.; Halcomb, R. H.; Ichikawa,
Y.; Kajimoto, T. Angew. Chem., Int. Ed. 1995, 34, 412–
432; (b) Machajewski, T. D.; Wong, C.-H. Angew. Chem.,
Int. Ed. 2000, 39, 1352–1374.
5. Reviews for the Morita–Baylis–Hillman reaction, see: (a)
Iwabuchi, Y.; Hatakeyama, S. J. Synth. Org. Chem. Jpn.
2002, 60, 2–14; (b) Basavaiah, D.; Rao, A. J.; Satyanara-
yana, T. Chem. Rev. 2003, 103, 811–892; (c) Masson, G.;
Housseman, C.; Zhu, J. Angew. Chem., Int. Ed. 2007, 46,
4614–4628.
6. (a) Shi, M.; Xu, Y.-M. Angew. Chem., Int. Ed. 2002, 41,
4507–4510; (b) Shi, M.; Chen, L. H. Chem. Commun. 2003,
1310–1311; (c) Kawahara, S.; Nakano, A.; Esumi, T.;
Iwabuchi, Y.; Hatakeyama, S. Org. Lett. 2003, 5, 3103–
3105; (d) Balan, D.; Adolfsson, H. Tetrahedron Lett. 2003,
44, 2521–2524; (e) Matsui, K.; Takizawa, S.; Sasai, H. J.
Am. Chem. Soc. 2005, 127, 3680–3681; (f) Shi, M.; Chen,
L. H.; Li, C.-Q. J. Am. Chem. Soc. 2005, 127, 3790–3800;
(g) Shi, M.; Xu, Y.-M.; Shi, Y.-L. Chem. Eur. J. 2005, 11,
1794–1802; (h) Shi, M.; Li, C.-Q. Tetrahedron: Asymmetry
2005, 16, 1385–1391; (i) Rahhem, I. T.; Jacobsen, E. N.
Adv. Synth. Catal. 2005, 347, 1701–1705; (j) Matsui, K.;
Tanaka, K.; Horii, A.; Takizawa, S.; Sasai, H. Tetra-
hedron: Asymmetry 2006, 17, 578–583; (k) Matsui, K.;
Takizawa, S.; Sasai, H. Synlett 2006, 761–765; (l) Liu,
Y.-H.; Chen, L.-H.; Shi, M. Adv. Synth. Catal. 2006, 348,
973–979.
O
NTs
O
1c (1 mol%)
THF, 0 °C
+
R
H
Entry R in N-tosyl imine Time Yield % eeb Confign.c
(h)
(%)
1
2
3
4
5
6
7
Phenyl
17
17
10
84
100
98
96
95
94
96
95
95
87
S
S
S
S
S
S
S
4-Fluorophenyl
4-Nitrophenyl
4-Methylphenyl
4-Methoxyphenyl
2-Naphthyl
35
99
76
97
17
164
100
71
(E)-Cinnamyl
a All reactions were carried out at 0 °C in THF with molar ratio of
imine/enone/1c = 1:3:0.01.
b Determined by HPLC analysis using chiral stationary phase column
according to the literature (Refs. 6e,f).
c Determined by comparison of elution order of HPLC with the
reported value (Refs. 6e,f).
2). The most optimal result was obtained with 1c, where
the reaction was completed after 1.5 h with a high enantio-
selectivity of 95% ee (entry 3).11 Although 1d exhibited
higher catalytic activity than 1c, the enantioselectivity
was somewhat decreased (entry 4). The high catalytic
activity of 1c allowed the reaction to be carried out at
lower catalyst loading. To our delight, the catalyst load-
ing could be reduced to 1 mol % without diminishing
enantioselectivity (entry 5). The loading could be further
reduced to 0.5 mol %, but the reaction was very slow
(entry 6). Lowering the reaction temperature to À15 °C
considerably retarded the reaction and no enhancement
of the enantioselectivity was observed (entry 7).
Under the optimized conditions, we next examined the
reactions of several other N-tosylimines (Table 2).
Equally high enantioselectivities were obtained irrespec-
tive of the electronic nature of the aryl substituent, while
the reaction rate was found to be dependent on the elec-
tronic nature such that the presence of an electron-
donating group retarded the reaction (entries 4 and 5).
The reaction of cinnamyl N-tosylimine was slow, and
the enantioselectivity was decreased to 87% ee, although
this is still good (entry 7).
7. Uozumi, Y.; Tanahashi, A.; Lee, S. Y.; Hayashi, T. J. Org.
Chem. 1993, 58, 1945–1948.
8. Mitsunobu, O. Synthesis 1981, 1.
9. Matsunaga, S.; Das, J.; Roels, J.; Vogl, E. M.; Yamamoto,
N.; Iida, T.; Yamaguchi, K.; Shibasaki, M. J. Am. Chem.
Soc. 2000, 122, 2252–2260.
10. Coumbe, T.; Lawrence, N. J.; Muhammad, F. Tetrahe-
dron Lett. 1994, 35, 625–628.
In conclusion, we have demonstrated that newly devel-
oped phosphino-bisphenol 1c is an efficient organocata-
lyst for the aza-MBH reaction. To the best of our
knowledge, 1c is the most active organocatalyst so far
developed for the aza-MBH reaction. Further studies on
the scope of the reaction and clarification of the reaction
mechanism are currently under way in our laboratory.
11. Typical experimental procedure is exemplified by aza-
MBH of N-(4-chlorobenzylidene)-4-methylbenzenesulf-
onamide with methyl vinyl ketone (MVK): To a solution
of N-(4-chlorobenzylidene)-4-methylbenzenesulfonamide
(58.8 mg, 0.2 mmol) and 1c (1.2 mg, 2.0 lmol) in THF
(0.4 ml), MVK (48.7 ll, 0.6 mmol) was added at 0 °C.
After stirring for 14 h at 0 °C, the mixture was directly
subjected to silica gel chromatography (hexane/ethyl
acetate = 90:10–70:30), giving the desired product
(70.0 mg, 96%). Enantiomeric excess of the product was
determined to be 95% by HPLC using a chiral stationary
phase column (Ref. 6e).
Acknowledgments
The authors thank Dr. H. Furuno, Institute for
Materials Chemistry and Engineering (IMCE), Kyushu
University for measurement of NMR and HRMS.