Mannich-Type Reactions Catalyzed by Neutral Salts in Water

Article abstract of DOI:10.1002/adsc.200303106

Mannich-type reactions of imines with silicon enolates were found to be catalyzed by neutral salts such as sodium triflate in water as a suspension medium. Unusual kinetic behavior indicates that the presence of the Mannich adduct facilitates the rate of

Full text of DOI:10.1002/adsc.200303106

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Mannich-Type Reactions Catalyzed by Neutral Salts in Water
Catherine Loncaric, Kei Manabe, Shu≈ Kobayashi*
Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113 0033, Japan
Fax: ‡ 81-35684-0634, e-mail: skobayas@mol.f.u-tokyo.ac.jp
Received: June 4, 2003; Accepted: August 5, 2003
First, we investigated the effect of added salts in a
model reaction of N-benzylideneaniline with the silicon
enolate (1)[6] derived from phenyl propionate in water as
a suspension medium. The results are summarized in
Table 1. As shown in entry 1, the reaction did not
proceed without catalysts. On the other hand, neutral
salts such as NaOTf and NaI effectively promoted the
reaction to give the corresponding Mannich adduct in
good yields (entries 2 and 3). It is intriguing that the
reaction was catalyzed without using acid catalysts,
which have been used in the previous examples of the
Mannich-type reactions in water. Sodium dodecyl
sulfate (SDS) was less effective (entry 4). The reaction
in the presence of tetrabutylammonium iodide did not
Abstract: Mannich-type reactions of imines with
silicon enolates were found to be catalyzed by
neutral salts such as sodium triflate in water as a
suspension medium. Unusual kinetic behavior indi-
cates that the presence of the Mannich adduct
facilitates the rate of its formation.
Keywords: b-amino acid; aqueous media; imine;
ketene silyl acetal; Mannich reaction
Mannich-type reactions are useful methods to synthe- afford 2 (entry 5), suggesting that the metal cation plays
size various b-amino carbonyl compounds, which con- a pivotal role in the present catalysis. The effect of the
stitute many natural products, biologically active com- neutral salts was also observed in a two-solvent system
pounds, and other functional materials.[1] Among the where an organic solvent such as dichloromethane was
Mannich-type reactions, addition of silicon enolates to used as a cosolvent (entry 6). The reaction was
imines has been developed to afford the adducts under completely inhibited by 10 mol % [2.2.2]cryptand (3)
mild conditions.[2] Generally, Lewis acids or Brfnsted (entry 7), suggesting again the importance of sodium
acids are used to promote these reactions. Recently, cation for the catalysis.
organic reactions in aqueous media have attracted a
We next applied this catalytic system to three-
great deal of attention,[3] not only because these component reactions of various aldehydes, amines, and
reactions eliminate the necessity of vigorous drying of silicon enolates in water. A merit of the three-compo-
solvents and substrates, but also because unique reac- nent reactions is that the reactions can be done without a
tivity and selectivity are often observed in aqueous separate step for imine preparation prior to the Man-
reactions. Safety and low cost of water are also regarded nich-type reactions,[7] and that adducts from unstable
as beneficial aspects. Along these lines, Mannich-type imines such as those derived from aliphatic aldehydes
reactions in aqueous media have been investigated, and are obtained in high yields. As shown in Table 2, not only
several acid catalysts which work well in water have aromatic aldehydes but also a,b-unsaturated and ali-
emerged.[4] On the other hand, we have found, quite phatic aldehydes gave the corresponding adducts in
recently, that aza-Diels Alder reactions of imines with good yields (entries 1 7). As for amines, substituted
Danishefsky×s diene are effectively catalyzed by neutral anilines could also be used (entries 8 and 9). When the
salts such as sodium trifluoromethanesulfonate (NaOTf) silicon enolate derived from methyl isobutyrate was
in water as a suspension medium.[5] The reactions did not used, NaOTf gave the adduct in modest yield (entry 10),
require the use of acid catalysts and proceeded smoothly but the yield was improved by replacing NaOTf with
under mild conditions to give the desired dihydro-4- SDS (entry 11).
pyridones in good yields. These results prompted us to
To elucidate the mechanism of the present catalytic
investigate neutral salt-catalyzed Mannich-type reac- reactions, we carried out kinetic studies. However, the
tions of imines with silicon enolates derived from esters reaction was found to be more complicated than
in water. These reactions would provide a unique and expected. Fig. 1 shows the reaction profile of the
useful method for the construction of b-amino acid NaOTf-catalyzed Mannich-type reaction of N-benzyli-
skeletons. Here we report that this type of reactions deneaniline with 1 in water. To our surprise, the yield of 2
indeed proceeds in the presence of a neutral salt in drastically increased after 300 min, indicating that
water, and that kinetic studies have revealed the effect formation of 2 was further accelerated as the reaction
of the Mannich adducts to accelerate the reactions.
proceeded. From this result, we assumed that the
Adv. Synth. Catal. 2003, 345, 1187 1189
DOI: 10.1002/adsc.200303106
¹ 2003 WILEY-VCHVerlag GmbH& Co. KGaA, Weinheim
1187

Catherine Loncaric et al.
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Figure 1. Reaction profile of the Mannich-type reaction in
water. Conditions: benzylideneaniline:1 ˆ 1:1.5 in H2O at
308C in the presence of NaOTf (10 mol %).
To confirm this hypothesis, the reaction in the
presence of the Mannich adduct itself as an additive
was carried out as shown in Equation (1). Toluene was
used as a cosolvent to ensure dissolution of the additive.
Under these conditions, the yield was improved in the
presence of 10 mol % Mannich adduct 2 (21% vs. 9%
yield). Adduct 4 as an additive also promoted the
reaction. On the other hand, 2 alone without NaOTf did
not give the product. These results indicate that NaOTf
and the adduct cooperatively work to promote the
formation of the adduct itself. While the precise
mechanism is still unclear, this cooperative effect is a
characteristic feature of the present catalysis.[8]
ꢀ1†
presence of a catalytic amount of the Mannich adduct
wouldimprove the rate of the NaOTf-catalyzed reaction In conclusion, we have found that neutral salts such as
at the early stage. NaOTf and SDS effectively catalyzed Mannich-type
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Adv. Synth. Catal. 2003, 345, 1187 1189

Mannich-Type Reactions Catalyzed by Neutral Salts in Water
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Tetrahedron 1990, 46, 703; d) E. F. Kleinnmann, in Com-
prehensive Organic Synthesis, (Ed.: B. M. Trost), Perga-
mon Press, New York, 1991, Vol. 2, Chapter 4.1; e) M.
Arend, B. Westermann, N. Risch, Angew. Chem. Int. Ed.
1998, 37, 1044; f) S. Kobayashi, H. Ishitani, Chem. Rev.
1999, 99, 1019.
reactions of imines with silicon enolates in water. In
contrast to the previous examples of Mannich-type
reactions in water, the present system does not need
acidic materials as catalysts. In addition, the unique
kinetic behavior indicates that the product itself is
involved in the catalytic system to promote the neutral
salt-catalyzed reaction. The catalysis by the neutral salts
described here will open a new avenue for efficient
catalytic processes in water.
[2] For early examples, see: a) I. Ojima, S.-I. Inaba, K.
Yoshida, Tetrahedron Lett. 1977, 3643; b) J.-E. Dubois,
G. Axiotis, Tetrahedron Lett. 1983, 24, 3643; c) K. Ikeda,
K. Achiwa, M. Sekiya, Tetrahedron Lett. 1983, 24, 4707;
d) T. Mukaiyama, K. Kashiwagi, S. Matsui, Chem. Lett.
1989, 1397.
[3] a) Organic Synthesis in Water; (Ed.: P. A. Grieco), Blackie
Academic and Professional, London, 1998; b) C.-J. Li, T.-
H. Chan, Organic Reactions in Aqueous Media, John
Wiley & Sons, New York, 1997; c) K. Manabe, S.
Kobayashi, Chem. Eur. J. 2002, 8, 4094.
[4] a) K. Manabe, Y. Mori, T. Wakabayashi, S. Nagayama, S.
Kobayashi, J. Am. Chem. Soc. 2000, 122, 7202; b) K.
Manabe, Y. Mori, S. Kobayashi, Synlett 1999, 1401; c) K.
Manabe, Y. Mori, S. Kobayashi, Tetrahedron 2001, 57,
2537; d) T. Akiyama, J. Takaya, H. Kagoshima, Synlett
1999, 1426; e) T. Akiyama, J. Takaya, H. Kagoshima, Adv.
Catal. Synth. 2002, 344, 338; f) T.-P. Loh, S. B. K. Liung,
K.-L. Tan, L.-L. Wei, Tetrahedron 2000, 56, 3227; g) M. T.
Reetz, D. Giebel, Angew. Chem. Int. Ed. 2000, 39, 2498;
h) W. Gu, W.-J. Zhou, D. L. Gin, Chem. Mater. 2001, 13,
1949.
Experimental Section
General Procedure for the Three-Component
Mannich-Type Reactions
To
a mixture of an amine (0.30 mmol), an aldehyde
(0.30 mmol), and NaOTf (0.030 mmol) in H2O (0.60 mL) was
added a silicon enolate (0.45 mmol). After stirring for 7 h at
208C, the reaction mixture was diluted with CH2Cl2, and the
organic materials were extracted. The organic phases were
combined and dried over Na2SO4. The crude mixture was
purified by preparative TLC (silica gel) affording the corre-
sponding Mannich adduct.
Acknowledgements
[5] C. Loncaric, K. Manabe, S. Kobayashi, Chem. Commun.
2003, 574.
This work was partially supported by CREST and SORST,
Japan Corporation of Science and Technology and by a Grant-
in-Aid for Scientific Research from Japan Society of the
Promotion of Science (JSPS).
[6] E/Z ˆ 96:4.
[7] S. Kobayashi, M. Araki, M. Yasuda, Tetrahedron Lett.
1995, 36, 5773.
[8] Hosomi and co-workers have reported amine-catalyzed
Mannich-type reactions: K. Miura, K. Tamaki, T. Naka-
gawa, A. Hosomi, Angew. Chem. Int. Ed. 2000, 39, 1958.
References and Notes
[1] a) F. F. Blicke, Org. React. 1942, 1, 303; b) M. Tramontini,
Synthesis 1973, 703; c) M. Tramontini, L. Angiolini,
Adv. Synth. Catal. 2003, 345, 1187 1189
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