LETTER
Mannich-type Reaction Catalyzed by HBF4 in Water
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Table 3 Results of the Three-component Mannich-type Reactions
NH2
p-MeOC6H4
HBF4
Me
Me
OTMS
OMe
RCHO
+
NH
O
+
R
OMe
H2O
OMe
Protocol A
2a
3
Protocol B
HBF4 (10 mol%)
SDS (1 mol%)
Ketene silyl acetal (1.2 equiv)
HBF4 (30 mol%)
Ketene silyl acetal (1.5 equiv)
Protocol A
Protocol B
Entry
Aldehyde
C6H5CHO
Product
Reaction time (h)
Yield (%)
Reaction time (h)
Yield (%)
1
2
3a
3j
0.4
3
87
92
5
5
74
73
Me
CHO
3
3k
1
90
5
96
CHO
O
4
5
6
PhCOCHOa
3l
5
3
3
86
73
53
5
5
5
89
84
86
BnOCH2CHO
3m
3n
PhCH2CH2CHO
a PhCOCHO H2O was employed.
(4) Selected examples of Mannich-type reactions, see:
(a) Ojima, I.; Inaba, S.; Yoshida, K. Tetrahedron Lett. 1977,
3643. (b) Pilli, R. A.; Russowsky, D. J. Chem. Soc., Chem.
Commun. 1987, 1053. (c) Guanti, G.; Narisano, E.; Banfi, L.
Tetrahedron Lett. 1987, 28, 4331. (d) Mukaiyama, T.;
Kashiwagi, K.; Matsui, S. Chem. Lett. 1989, 1397.
(e) Mukaiyama, T.; Akamatsu, H.; Han, J. S. Chem. Lett.
1990, 889. (f) Onaka, M.; Ohno, R.; Yanagiya, N.; Izumi, Y.
Synlett 1993, 141. (g) Ishihara, K.; Funahashi, K.; Hanaki,
N.; Miyata, M.; Yamamoto, H. Synlett 1994, 963.
(h) Ishihara, K.; Miyata, M.; Hattori, K.; Tada, T.;
Yamamoto, H. J. Am. Chem. Soc. 1994, 116, 10520.
(i) Miura, K.; Nakagawa, T.; Hosomi, A. J. Am. Chem. Soc.
2002, 124, 536.
(5) Examples of three-component Mannich-type reactions, see:
(a) Kobayashi, S.; Ishitani, H. Chem. Commun. 1995, 1379.
(b) Kobayashi, S.; Busujima, T.; Nagayama, S. Chem.
Commun. 1998, 19. (c) Kobayashi, S.; Busujima, T.;
Nagayama, S. Synlett 1999, 545. (d) Manabe, K.; Mori, Y.;
Kobayashi, S. Synlett 1999, 1401. (e) Loh, T.-P.; Wei, L.-L.
Tetrahedron Lett. 1998, 39, 323. (f) Loh, T.-P.; Liung, S. B.
K. W.; Tan, K.-L.; Wei, L.-L. Tetrahedron 2000, 56, 3227.
(g) Shimizu, M.; Itohara, S. Synlett 2000, 1828.
(7) (a) Akiyama, T.; Takaya, J.; Kagoshima, H. Chem. Lett.
1999, 947. (b) Akiyama, T.; Takaya, J.; Kagoshima, H.
Synlett 1999, 1045.
(8) (a) Akiyama, T.; Takaya, J.; Kagoshima, H. Synlett 1999,
1426. (b) Akiyama, T.; Takaya, J.; Kagoshima, H.
Tetrahedron Lett. 2001, 42, 4025. (c) Akiyama, T.; Takaya,
J.; Kagoshima, H. Adv. Synth. Catal. 2002, 344, 338.
(9) Akiyama, T.; Takaya, J.; Kagoshima, H. Tetrahedron Lett.
1999, 40, 7831.
(10) We optimized the loading of SDS by use of a silyl enol ether
as a substrate in ref.8
(11) Recent examples of synthetic reactions in water in the co-
existence of surfactant, see: (a) Kobayashi, S.;
Wakabayashi, T.; Nagayama, S.; Oyamada, H. Tetrahedron
Lett. 1997, 38, 4559. (b) Manabe, K.; Mori, Y.; Kobayashi,
S. Synlett 1999, 1401. (c) Yonehara, K.; Ohe, K.; Uemura,
S. J. Org. Chem. 1999, 64, 9381. (d) Yonehara, K.;
Hashizume, T.; Mori, K.; Ohe, K.; Uemura, S. J. Org. Chem.
1999, 64, 5593. (e) Manabe, K.; Mori, Y.; Kobayashi, S.
Tetrahedron 2001, 57, 2537. (f) Lautens, M.; Roy, A.;
Fukuoka, K.; Fagnou, K.; Martin-Matute, B. J. Am. Chem.
Soc. 2001, 123, 5358.
(12) General Experimental Procedure for Protocol A (entry 3
of Table 1). Aq solution of HBF4 (8 L, 0.0080 mmol,
1.3598 mol/L) was added to a mixture of N-benzylidene-p-
anisidine(1) (17 mg, 0.0805 mmol), ketene silyl acetal(2a)
(48 L, 0.241 mmol), SDS (8 L, 0.0080 mmol, 0.10027
mol/L solution) in H2O (0.5 mL) at r.t. After being stirred at
the temperature for 0.5 h, the reaction was quenched by
addition of sat. NaHCO3 and CH2Cl2. The aq layer was
extracted with CH2Cl2 and the combined organic layers were
washed with brine, dried over anhyd Na2SO4, and
concentrated to dryness. Purification of the crude mixture by
(h) Shimizu, M.; Itohara, S.; Hase, E. Chem. Commun. 2001,
2318.
(6) Recent examples of asymmetric synthesis, see: (a) List, B.
J. Am. Chem. Soc. 2000, 122, 9336. (b) Juhl, K.;
Gathergood, N.; Jørgensen, K. A. Angew. Chem. Int. Ed.
2001, 40, 2995. (c) Gastner, T.; Ishitani, H.; Akiyama, R.;
Kobayashi, S. Angew. Chem. Int. Ed. 2001, 40, 1896.
(d) Xue, S.; Yu, S.; Deng, Y.; Wulff, W. D. Angew. Chem.
Int. Ed. 2001, 41, 2271; see also references cited therein.
Synlett 2002, No. 8, 1269–1272 ISSN 0936-5214 © Thieme Stuttgart · New York