Organic solvent-free, enantio- and diastereoselective, direct Mannich reaction in the presence of water

Article abstract of DOI:10.1021/ol702489k

An organocatalyst-mediated, asymmetric Mannich reaction in the presence of water without using organic solvents has been developed. A highly reactive siloxytetrazole hybrid catalyst has been developed for the reaction of dimethoxyacetaldehyde, while the s

Full text of DOI:10.1021/ol702489k

ORGANIC
LETTERS
2008
Vol. 10, No. 1
21-24
Organic Solvent-Free, Enantio- and
Diastereoselective, Direct Mannich
Reaction in the Presence of Water
Yujiro Hayashi,* Tatsuya Urushima, Seiji Aratake, Tsubasa Okano, and
Kazuki Obi
Department of Industrial Chemistry, Faculty of Engineering, Tokyo UniVersity of
Science, Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan
hayashi@ci.kagu.tus.ac.jp
Received October 11, 2007
ABSTRACT
An organocatalyst-mediated, asymmetric Mannich reaction in the presence of water without using organic solvents has been developed. A
highly reactive siloxytetrazole hybrid catalyst has been developed for the reaction of dimethoxyacetaldehyde, while the sodium salt of siloxyproline
is an effective catalyst of
r-imino glyoxylate. Excellent enantioselectivity can be realized, and the usage of organic solvents can be reduced
compared to the conventional reactions in organic solvents.
The development of reactions in the presence of water1
without using organic solvents is one of the important topics
in current chemistry.2 The catalytic, asymmetric Mannich
reaction is one of the most powerful methods for the
construction of chiral nitrogen-containing molecules.3 Thus,
there is an endeavor to realize the enantioselective Mannich
reaction in the presence of water. Although there are several
aqueous non-enantioselective Mannich reactions of silyl enol
ether,4 there is only one asymmetric catalytic reaction in the
presence of water catalyzed by an organometallic reagent
so far as we are aware: Kobayashi and co-workers reported
the asymmetric Mannich-type reaction of acylhydrazone and
silyl enol ether in aqueous organic solvent using a diamine-
ZnF2-surfactant system.5
Organocatalysis-mediated, direct, enantioselective Man-
nich reactions6-9 have been developed over the past few years
that proceed in polar organic solvents such as DMSO and
NMP. Although there is a proline-mediated Mannich reaction
in aqueous media,8e,f the reaction in the presence of water
without using an organic solvent had not been reported until
recently.
(1) (a) Hayashi, Y. Angew. Chem., Int. Ed. 2006, 45, 8103. (b) Brogan,
A. P.; Dickerson, T. J.; Janda, K. D. Angew. Chem., Int. Ed. 2006, 45,
8100.
(2) (a) Organic Synthesis in Water; Grieco, P. A., Ed.; Blackie A & P:
London, 1998. (b) Lindstrom, U. M. Chem. ReV. 2002, 102, 2751. (c)
Blackmond, D. G.; Armstrong, A.; Coombe, V.; Wells, A. Angew. Chem.,
Int. Ed. 2007, 46, 3798. (d) Organic Reactions in Water; Lindstrom, U. M,
Ed.; Blackwell Publishing: Oxford, 2007.
(3) (a) Kobayashi, S.; Ishitani, H. Chem. ReV. 1999, 99, 1069. (b)
Denmark, S. E.; Nicaise, O. J.-C. In ComprehensiVe Asymmetric Catalysis;
Jacobsen, E. N., Ed.; Springer: Berlin, 1999; p 923. (c) Arend, M.;
Westermann, B.; Risch, N. Angew. Chem., Int. Ed. 1998, 37, 1044. (d)
EnantioselectiVe Synthesis of R-Amino Acids; Juaristi, E., Ed.; VCH:
Weinheim, Germany, 1997. (e) Kleinman, E. F. In ComprehensiVe Organic
Synthesis; Trost, B. M., Ed.; Pergamon Press: Oxford, 1991; Chapter 2.3,
Vol. 2, p 893. (f) Marques, M. M. B. Angew. Chem., Int. Ed. 2006, 45,
348.
(4) For aqueous Mannich reaction of silyl enol ether, see: (a) Loh, T.
P.; Wei, L. L. Tetrahedron Lett. 1998, 39, 323. (b) Manabe, K.; Kobayashi,
S. Org. Lett. 1999, 1, 1965. (c) Akiyama, T.; Takaya, J.; Kagoshima, H.
Synlett 1999, 1426. (d) Manabe, K.; Mori, Y.; Kobayashi, S. Tetrahedron
2001, 57, 2537. (e) Akiyama, T.; Itoh, J.; Fuchibe, K. Synlett 2002, 1269.
(5) (a) Hamada, T.; Manabe, K.; Kobayashi, S. J. Am. Chem. Soc. 2004,
126, 7768. (b) Hamada, T.; Manabe, K.; Kobayashi, S. Chem.sEur. J. 2006,
12, 1205.
10.1021/ol702489k CCC: $40.75
© 2008 American Chemical Society
Published on Web 12/04/2007

As for the aldol reaction, Barbas’ group10 and ours11-13
independently developed asymmetric aldol reactions cata-
lyzed by organocatalysts in the presence of water. While
Barbas and co-workers used a diamine with a long alkyl
chain in the presence of acid, we employed siloxyproline11
and a combined proline-surfactant organocatalyst.12 Fol-
lowing these reports, several organocatalysts have been
developed for the enantioselective aldol reaction in the
presence of water,14 and recently, a threonine-derived orga-
nocatalyst was applied to the Mannich reaction in the
presence of water, in which only alkoxyacetone was inves-
tigated.15 During the application of siloxyproline to the
asymmetric Mannich reaction in the presence of water, we
found effective Mannich catalysts, affording adducts with
excellent enantioselectivity, which will be disclosed in this
communication.
First, the three-component Mannich reaction of dimethoxy-
acetaldehyde, p-anisidine, and cyclohexanone was selected
as a model. Dimethoxyacetaldehyde is commercially avail-
able as aqueous solution; therefore, this reaction must be
performed in the presence of water. Moreover, the Mannich
product obtained is a synthetically useful polyfunctionalized
compound. The reaction was performed as follows: Mixing
anisidine, an aqueous solution of aldehyde (60 wt %
solution), and water (total volume of water is 18 equiv) for
0.5 h in the presence of the catalyst generated an oily material
that separated from the water. To this mixture we added 2
equiv of ketone, and the reaction proceeded in a biphase
system. Organocatalysts (Figure 1) were screened, with the
(6) For our contributions in the Mannich reaction, see: (a) Hayashi, Y.;
Tsuboi, W.; Shoji, M.; Suzuki, N. J. Am. Chem. Soc. 2003, 125, 11208. (b)
Hayashi, Y.; Tsuboi, W.; Ashimine, I.; Urushima, T.; Shoji, M.; Sakai, K.
Angew. Chem., Int. Ed. 2003, 42, 3677. (c) Hayashi, Y.; Urushima, T.;
Shoji, M.; Uchimaru, T.; Shiina, I. AdV. Synth. Catal. 2005, 347, 1595. (d)
Hayashi, Y.; Urushima, T.; Shin, M.; Shoji, M. Tetrahedron 2005, 61,
11393. (e) Hayashi, Y.; Urushima, T.; Tsuboi, W.; Shoji, M. Nat. Protocols
2007, 2, 113.
Figure 1. The organocatalysts examined in this study.
(7) For recent selected papers of direct enantioselective Mannich
reactions, see: (a) Trost, B. M.; Jaratjaroonphong, J.; Reutrakul, V. J. Am.
Chem. Soc. 2006, 128, 2778. (b) Song, J.; Wang, Y.; Deng, L. J. Am. Chem.
Soc. 2006, 128, 6048. (c) Shibasaki, M.; Matsunaga, S. J. Organomet. Chem.
2006, 691, 2089. (d) Cordova, A. Acc. Chem. Res. 2004, 37, 102.
(8) For representative papers of Mannich reactions catalyzed by orga-
nocatalysis, see: (a) List, B. J. Am. Chem. Soc. 2000, 122, 9336. (b) List,
B.; Pojarliev, P.; Biller, W. T.; Martin, H. J. J. Am. Chem. Soc. 2002, 124,
827. (c) Cordova, A.; Notz, W.; Zhong, G.; Betancort, J. M.; Barbas, C.
F., III. J. Am. Chem. Soc. 2002, 124, 1842. (d) Cordova, A.; Watanabe, S.;
Tanaka, F.; Notz, W.; Barbas, C. F., III. J. Am. Chem. Soc. 2002, 124,
1866. (e) Cordova, A.; Barbas, C. F., III. Tetrahedron Lett. 2003, 44, 1923.
(f) Notz, W.; Tanaka, F.; Watanabe, S.; Chawdari, N. S.; Turner, J. M.;
Thayumanavan, R.; Barbas, C. F., III. J. Org. Chem. 2003, 68, 9624. (g)
Akiyama, T.; Itoh, J.; Yokota, K.; Fuchibe, K. Angew. Chem., Int. Ed. 2004,
43, 1566. (h) Uraguchi, D.; Terada, M. J. Am. Chem. Soc. 2004, 126, 5356.
(i) Westermann, B.; Neuhaus, C. Angew. Chem., Int. Ed. 2005, 44, 4077.
(j) Enders, D.; Grondal, C.; Vrettou, M.; Raabe, G. Angew. Chem., Int. Ed.
2005, 44, 4079. (k) Kano, T.; Yamaguchi, Y.; Tokuda, O.; Maruoka, K. J.
Am. Chem. Soc. 2005, 127, 16408. (l) Paulsen, T. B.; Alemparte, C.; Saaby,
S.; Bella, M.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2005, 44, 2896.
(m) Lou, S.; Taoka, B. M.; Ting, A.; Schaus, S. E. J. Am. Chem. Soc. 2005,
127, 11256. (n) Mitsumori, S.; Zhang, H.; Cheong, P. H.; Houk, K. N.;
Tanaka, F.; Barbas, C. F., III. J. Am. Chem. Soc. 2006, 128, 1040. (o) Zhang,
H.; Mifsud, M.; Tanaka, F.; Barbas, C. F., III. J. Am. Chem. Soc. 2006,
128, 9630. (p) Ramasastry, S. S. V.; Zhang, H.; Tanaka, F.; Barbas, C. F.,
III. J. Am. Chem. Soc. 2007, 129, 288. (q) Liu, T.-Y.; Cui, H.-L.; Long, J.;
Li, B.-J.; Wu, Y.; Ding, L.-S.; Chen, Y.-C. J. Am. Chem. Soc. 2007, 129,
1878. (r) Yang, J. W.; Stadler, M.; List, B. Angew. Chem., Int. Ed. 2007,
46, 609. (s) Hashimoto, T.; Maruoka, K. J. Am. Chem. Soc. 2007, 129,
10054 and the references cited therein.
(9) For reviews of organocatalysis, see: (a) Berkssel, A.; Groger, H.
Asymmetric Organocatalysis; Wiley-VCH: Weinheim, Germany, 2005. (b)
Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2004, 43, 5138. (c) Hayashi,
Y. J. Synth. Org. Chem. Jpn. 2005, 63, 464. (d) List, B. Chem. Commun.
2006, 819. (e) Marigo, M.; Jørgensen, K. A. Chem. Commun. 2006, 2001.
(f) Lelais, G.; MacMillan, D. W. C. Aldrichimica Acta 2006, 39, 79. (g)
Gaunt, M. J.; Johnsson, C. C. C.; McNally, A.; Vo, N. T. Drug DiscoVery
Today 2007, 12, 8. (h) EnantioselectiVe Organocatalysis; Dalko, P. I., Ed.;
Wiley-VCH: Weinheim, Germany, 2007.
(10) Mase, N.; Nakai, Y.; Ohara, N.; Yoda, H.; Takabe, K.; Tanaka, F.;
Barbas, C. F., III. J. Am. Chem. Soc. 2006, 128, 734.
(11) (a) Hayashi, Y.; Sumiya, T.; Takahashi, J.; Gotoh, H.; Urushima,
T.; Shoji, M. Angew. Chem., Int. Ed. 2006, 45, 958. (b) Aratake, S.; Itoh,
T.; Okano, T.; Nagae, N.; Sumiya, T.; Shoji, M.; Hayashi, Y. Chem.sEur.
J. 2007, DOI: 10.1002/chem.200700363.
results summarized in Table 1. Low yield and enantioselec-
tivity were obtained in the reactions with proline (1) and
4-hydroxyproline (2). Tetrazole catalyst 316 gave 50% ee,
and a moderate ee (72%) was observed with siloxyproline
4.11,17 Among other catalysts, siloxytetrazole hybrid catalyst
5 afforded the adduct not only in excellent yield but also
with very high enantioselectivity. By lowering the reaction
temperature, higher diastereoselectivity and enantioselectivity
were realized. As for the diastereoselectivity, although proline
(1) and siloxyproline 4 gave anti-isomer predominantly, syn-
isomer was obtained selectively when tetrazolesiloxy hybrid
catalyst 5 was employed. It should be noted that tetrazole
catalyst 3 and siloxyproline 4, both of which are active
catalysts in several transformations, are not suitable, but the
combination of a siloxy and tetrazole moiety in a pyrrolidine
scaffold created a highly efficient Mannich catalyst 5. The
reaction also proceeds in good yield with excellent enantio-
selectivity in the presence of a large excess (100 equiv) of
water (entry 7). Practically, the amount of water should be
reduced, and the reaction was found to proceed efficiently
without the additional amount of water.
The generality of the reaction was examined, with the
results summarized in Table 2. Both cyclohexanone and
(14) (a) Jiang, Z.; Liang, Z.; Wu, X.; Lu, Y. Chem. Commun. 2006, 2801.
(b) Wu, Y.; Zhang, Y.; Yu, M.; Zhao, G.; Wang, S. Org. Lett. 2006, 8,
4417. (c) Font, D.; Jimeno, C.; Pericas, M. A. Org. Lett. 2006, 8, 4653. (d)
Guillena, G.; Hita, M. C.; Najera, C. Tetrahedron: Asymmetry 2006, 17,
1493. (e) Wu, X.; Jiang, Z.; Shen, H.-M.; Lu, Y. AdV. Synth. Catal. 2007,
349, 812. (f) Maya, V.; Raj, M.; Singh, V. K. Org. Lett. 2007, 9, 2593.
(15) (a) Cheng, L.; Wu, X.; Lu, Y. Org. Biomol. Chem. 2007, 5, 1018.
(b) Cheng, L.; Han, X.; Huang, H.; Wong, M. W.; Lu, Y. Chem. Commun.
2007, 4143.
(16) (a) Torii, H.; Nakadai, M.; Ishihara, K.; Saito, S.; Yamamoto, H.
Angew. Chem., Int. Ed. 2004, 43, 1983. (b) Cobb, A. J. A.; Shaw, D. M.;
Longbottom, D. A.; Gold, J. B.; Ley, S. V. Org. Biomol. Chem. 2005, 3,
84. (c) Hartikka, A.; Arvidsson, P. I. Eur. J. Org. Chem. 2005, 4287.
(17) Hayashi, Y.; Yamaguchi, J.; Hibino, K.; Sumiya, T.; Urushima, T.;
Shoji, M.; Hashizume, D.; Koshino, K. AdV. Synth. Catal. 2004, 346, 1435.
(12) Hayashi, Y.; Aratake, S.; Okano, T.; Takahashi, J.; Sumiya, T.; Shoji,
M. Angew. Chem., Int. Ed. 2006, 45, 5527.
(13) (a) Hayashi, Y.; Aratake, S.; Itoh, T.; Okano, T.; Sumiya, T.; Shoji,
M. Chem. Commun. 2007, 957. (b) Aratake, S.; Itoh, T.; Okano, T.; Usui,
T.; Shoji, M.; Hayashi, Y. Chem. Commun. 2007, 2524.
22
Org. Lett., Vol. 10, No. 1, 2008

Table 1. Effect of Catalyst on the Mannich Reaction in the
Presence of Watera
Table 2. Asymmetric Mannich Reaction of
Dimethoxyacetaldehyde under Wet Conditionsa
entry
catalyst
time [h]
yield [%]b
syn:antic
ee [%]d
1
2
3
4
1
2
3
4
5
5
5
5
48
48
48
16
16
48
70
48
36
34
48
95
95
61
95
93
1:2.3
1:2.2
1:1.1
1:1.4
4.4:1
6.1:1
4.2:1
4.6:1
16
1
50
72
93
96
93
95
5
6e
7e,f
8e,g
a Unless otherwise shown, the reaction was conducted with 0.04 mmol
of catalyst, 60 µL of dimethoxyacetaldehyde solution (60 wt %, 0.4 mmol),
0.44 mmol of p-anisidine, 0.8 mmol of cyclohexanone, and water (102 µL)
at room temperature. b Isolated yield. c Determined by 1H NMR. d Enan-
tiomeric excess of syn-isomer. Determined by chiral HPLC (see Supporting
Information). e The reaction temperature is 0 °C. f The reaction was
performed in the presence of 100 equiv of water (0.72 mL). g The reaction
was performed without the additional water.
cycloheptanone are suitable nucleophiles to afford the
Mannich adduct with high diastereoselectivity and enantio-
selectivity. 2,2-Dimethyl-1,3-dioxa-5-one can be employed
successfully as the nucleophilic ketone, affording a poly-
oxyamine derivative with high enantioselectivity, which is
an important synthetic intermediate of aminosugars.8i,j Acy-
clic ketones such as 3-pentanone are also suitable nucleo-
philes.
a The reaction was conducted with 0.04 mmol of 5, 60 µL of dimethoxy-
acetaldehyde solution (60 wt %), 0.44 mmol of p-anisidine, and 0.8 mmol
of ketone at 0 °C. b Isolated yield. c Determined by 1H NMR. d Enantiomeric
excess of syn-isomer, which was determined by chiral HPLC analysis.
e Ketone (5 equiv) and water (18 equiv) were used.
Table 3. Mannich Reaction of R-Imino Ethyl Glyoxylate in
Next, the catalyst was applied to the Mannich reaction of
R-imino ethyl glyoxylate. This reaction is synthetically
important for the formation of the R-amino acid. Its original
reaction in organic solvent catalyzed by proline was devel-
oped by Barbas and co-workers.8c,d While proline (1) and
tetrazole catalyst 3 were poor catalysts in the presence of
water, both siloxyproline 4 and siloxytetrazole hybrid catalyst
5 gave a complex mixture in the presence of water without
an organic solvent. This is contrary to the reaction of
dimethoxyacetaldehyde (eq 1, Table 1). The decomposition
of imine was observed, probably because of the instability
of imine in the presence of the acidity of the catalyst. After
several experiments, it was found that good yield and
excellent enantioselectivity were obtained when the reaction
was carried out in aqueous NaHCO3 solution instead of water
in the presence of siloxyproline 4 (Table 3). The same
excellent results were obtained when the isolated sodium salt
of 4 was used as the catalyst.18 Moreover, the lithium and
potassium salts of 4 also gave the same excellent diastereo-
selectivity and enantioselectivity. It should be noted that the
excellent diastereoselectivity is in marked contrast to the low
selectivity (syn/anti ) 3:1) reported when the reaction was
performed in dioxane and catalyzed by proline.8d Propanal,
n-butanal, and n-pentanal are suitable nucleophiles, affording
the adducts in good yield with excellent selectivities.
Aldehydes and ketones such as cyclohexanone react with
the Presence of Watera
time yield
ee
entry
R1, R2
Me, H
catalyst
solvent
[h] [%]b syn:antic [%]d
1
2
3
4
5
6
7
8
9
1
H2O
1
1
1
1
1
1
1
1
2
3
9
<5
<5
cm
cm
81
88
70
69
78
66
40
nd
nd
nd
nd
nd
97
95
95
97
98
97
95
Me, H
Me, H
Me, H
Me, H
Me, H
Me, H
Me, H
Et, H
3
4
5
4
H2O
nd
H2O
nd
H2O
nd
aq NaHCO3
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
Na salt 4 H2O
Li salt 4 H2O
4
4
4
5
aq KHCO3
aq NaHCO3
aq NaHCO3
H2O
10 n-Pr, H
11 -(CH2)4-
a The reaction was conducted with 0.03 mmol of catalyst, 0.3 mmol of
imine, and 0.6 mmol of carbonyl compound and water (49 µL, 9 equiv) at
room temperature; cm ) complex mixture; nd ) not determined. b Isolated
yield. c Determined by 1H NMR. d Determined by chiral HPLC (see
Supporting Information).
imine in the presence of siloxytetrazole hybrid 5 to afford
the product in moderate yield with excellent enantioselec-
tivity.
The same enantiomer was obtained selectively in the
reaction catalyzed by the sodium salt of 4 in the presence of
Org. Lett., Vol. 10, No. 1, 2008
23

water as that in the reaction using proline in organic solvent.
These results would indicate that sodium has the same role
in the transition state as the proton of the carboxylic acid of
proline does.8a,19
directly charged on silica gel for column chromatography,
organic solvents are not necessary for either the reaction or
the extraction. They are only required for column chroma-
tography.
In summary, we have developed an organocatalyst-
mediated, asymmetric Mannich reaction in the presence of
water without using organic solvents. Reactive siloxytetrazole
hybrid catalyst 5 has been developed for the reaction of
dimethoxyacetaldehyde, while the Na salt of siloxyproline
4 is an effective catalyst of R-imino glyoxylate. One of the
advantages of the organic solvent-free reaction is the
decreased amount of organic solvent compared with the
reaction in organic solvent. As the reaction mixture was
Acknowledgment. This work was partially supported by
Toray Science Foundation and a Grand-in-Aid for Scientific
Research from the Ministry of Education, Culture, Sports,
Science and Technology, Japan.
Supporting Information Available: Detailed experi-
1
mental procedures, full characterization, copies of H, 13C
NMR, and IR spectra of all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
(18) Yamaguchi and co-workers reported an excellent Michael reaction
using Pro-Rb; see: Yamaguchi, M.; Shiraishi, T.; Hirama, M. Angew. Chem.,
Int. Ed. Engl. 1993, 32, 1176.
(19) Bahmanyar, S.; Houk, K. N. Org. Lett. 2003, 5, 1249.
OL702489K
24
Org. Lett., Vol. 10, No. 1, 2008