Direct catalytic asymmetric aldol reaction of β-keto esters with formaldehyde promoted by a dinuclear Ni2-Schiff base complex

Article abstract of DOI:10.1039/b912380f

A homodinuclear Ni₂-Schiff base 1 complex (0.1-1 mol%) promoted the direct catalytic asymmetric aldol reaction of β-keto esters with formaldehyde, giving hydroxymethylated adducts in 94-66% ee. The Royal Society of Chemistry 2009.

Full text of DOI:10.1039/b912380f

View Article Online / Journal Homepage / Table of Contents for this issue
This article was published as part of the
2009 ‘Catalysis in Organic
Synthesis’ web theme issue
Showcasing high quality research in organic chemistry
Please see our website
(http://www.rsc.org/chemcomm/organicwebtheme2009)
to access the other papers in this issue.

COMMUNICATION
www.rsc.org/chemcomm | ChemComm
Direct catalytic asymmetric aldol reaction of b-keto esters with
formaldehyde promoted by a dinuclear Ni2-Schiff base complexwz
Shinsuke Mouri, Zhihua Chen, Shigeki Matsunaga* and Masakatsu Shibasaki*
Received (in College Park, MD, USA) 23rd June 2009, Accepted 7th July 2009
First published as an Advance Article on the web 24th July 2009
DOI: 10.1039/b912380f
A homodinuclear Ni2-Schiff base 1 complex (0.1–1 mol%)
promoted the direct catalytic asymmetric aldol reaction of
b-keto esters with formaldehyde, giving hydroxymethylated
adducts in 94–66% ee.
aldol reaction with formalin. As a part of our ongoing studies
of bifunctional Lewis acid/Brønsted base catalysis,7 we recently
reported the utility of dinuclear Schiff base complexes.8–12
Homodinuclear transition metal–Schiff base 1 complexes8–10
are bench-stable and can be used without regard to their
exposure to air and moisture. Thus, we expected that the
bimetallic Schiff base complexes would be suitable for a direct
aldol reaction with formalin. Initial optimization studies using
b-keto ester 2a and formalin are summarized in Table 1.
Among the homodinuclear Schiff base complexes screened,
the Ni2-1 catalyst8 gave promising results. The reaction of
b-keto ester 2a with 1.2 equiv. of formalin in i-Pr2O at 40 1C
completed within 0.5 h, giving product 3a in 81% yield and
77% ee (entry 1). The reaction also proceeded smoothly in
other solvents, but enantioselectivity was less satisfactory
(entries 2–7). Other metal complexes, such as Co,9 Mn,10 Zn,
and Pd, gave much less satisfactory enantioselectivity (entries
8–11, 1–30% ee). In entry 12, enantioselectivity decreased
when the reaction time was prolonged (12 h, 63% ee).
The results of entries 1 and 12 suggested that an undesirable
retro-aldol reaction would proceed under the reaction condi-
tions, resulting in lower enantiomeric excess after 12 h than
after 0.5 h. In addition, the reaction proceeded at 40 1C, even
in the absence of catalysts in i-Pr2O (0.2 M), giving product 3a
in 43% yield after 0.5 h (entry 13). To suppress the undesirable
The direct catalytic asymmetric aldol reaction is a powerful
and atom-economical method for synthesizing chiral b-hydroxy
carbonyl compounds.1,2 To date, many chiral metal and
organocatalysts have been developed for reactions of various
donors with aldehydes.2 The use of formaldehyde as a useful
C1 unit in direct catalytic asymmetric aldol reactions, however,
has been relatively limited,3–5 possibly due to its high reactivity.
Highly enantioselective chiral catalysts for indirect aldol
reactions of formaldehyde with preformed silyl enolates have
been developed,6 but for direct aldol reactions, there remains
room for improvement in catalyst loading, catalyst reactivity,
formaldehyde amount, and substrate scope. Herein, we report
a homodinuclear Ni2-Schiff base 1 complex-catalyzed direct
asymmetric aldol reaction of b-keto esters with formaldehyde.
Ni2-1 (0.1–1 mol%; Fig. 1) gave the hydroxymethylated
products in 66–94% ee.
Aqueous formaldehyde solution (i.e., formalin) is the most
convenient source of formaldehyde. A moisture-tolerant chiral
catalyst is required to realize the direct catalytic asymmetric
Table 1 Optimization of reaction conditionsa
Entry
M
x
Solvent Conc./M Time/h % Yield % ee
1
2
3
4
5
6
7
8
Ni
Ni
Ni
Ni
Ni
Ni
Ni
10
10
10
10
10
10
10
iPr2O
THF
Et2O
EtOH
AcOEt 0.2
CH2Cl2 0.2
Toluene 0.2
iPr2O
iPr2O
iPr2O
iPr2O
iPr2O
iPr2O
0.2
0.2
0.2
0.2
0.5
0.5
0.5
0.5
0.5
0.5
0.5
1
1
1
1
12
0.5
1
81
87
87
90
89
82
84
82
75
70
61
78
43
94
77
65
60
2
19
37
20
22
30
9
Fig. 1 Structures of dinucleating Schiff base 1 and homodinuclear
M2-Schiff base 1 complexes.
Graduate School of Pharmaceutical Sciences, The University of
Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan.
E-mail: mshibasa@mol.f.u-tokyo.ac.jp, smatsuna@mol.f.u-tokyo.ac.jp;
Fax: +81-3-5684-5206; Tel: +81-3-5841-4830
Co(OAc) 10
Mn(OAc) 10
Zn
Pd
Ni
None
Ni
0.2
0.2
0.2
0.2
0.2
0.2
0.02
9
10
11
12
13
14
10
10
10
0
1
w This article is part of a ChemComm ‘Catalysis in Organic Synthesis’
web-theme issue showcasing high quality research in organic chem-
istry. Please see our website (http://www.rsc.org/chemcomm/organic
webtheme2009) to access the other papers in this issue.
z Electronic supplementary information (ESI) available: General
experimental information, spectral data of new compounds, and
copies of NMR spectral data. See DOI: 10.1039/b912380f
63
—
93
0.1 iPr2O
a
Formalin (37% in water) was used in all entries. 1.2 equiv. of formalin
were used in entries 1–13, while 1.1 equiv. were used in entry 14.
ꢀc
This journal is The Royal Society of Chemistry 2009
5138 | Chem. Commun., 2009, 5138–5140

Table 2 Direct catalytic asymmetric aldol reaction of b-keto esters 2 with formaldehydea
Entry
1
2
Ni2-1 (x mol%)
HCHO (y equiv.)
Time/h
1
% Yieldb
% eec
0.1
1.1
94
93
2
3
1
1.1
1.1
12
12
91
81
85
66
0.1
4
0.1
1.1
10
5
28
48
79
32
79
43
84
40
81
79
89
75
90
89
5
1
6d
0.1
20
7
1
3
120
72
8d
0.1
5
9
1
1.1
120
10d
0.1
5
120
22
94
a
b
Formalin (37% in water) was used in entries 1–5, 7 and 9. Isolated yield after purification by silica gel column chromatography. Determined
c
d
by HPLC analysis. Paraformaldehyde (HCHO)n was used.
racemic pathway, we performed the reaction under diluted
conditions (0.02 M) to keep the formaldehyde concentration
low. Furthermore, we performed the reaction with reduced
catalyst loading (0.1 mol%) to avoid the undesirable retro-
aldol reaction and to obtain the aldol adduct under kinetic
control. The reaction proceeded smoothly even with 0.1 mol%
of Ni2-1, giving the product in 94% yield and 93% ee after 1 h
(entry 14).13
The substrate scope of the reaction is summarized in
Table 2. Because the reactivity of b-keto esters 2 depends on
ꢀc
This journal is The Royal Society of Chemistry 2009
Chem. Commun., 2009, 5138–5140 | 5139

the structure, the reaction conditions, such as catalyst loading,
reaction time, and the amount of formalin required, were
optimized for each b-keto ester to achieve the highest enantio-
selectivity under kinetic control. The best results for each
substrate are summarized in Table 2. The reactivity of b-keto
ester 2b with a six-membered ring was lower than that of
b-keto ester 2a, and product 3b was obtained in 91% yield and
85% ee with 1 mol% catalyst after 12 h (entry 2). With the
seven-membered ring b-keto ester 2c, the reaction proceeded
smoothly with 0.1 mol% catalyst, but enantioselectivity was
modest (entry 3, 66% ee). Ni2-1 was also applicable to acyclic
b-keto esters 2d–2g. The reaction of 2d with a methyl sub-
stituent gave product 3d in 79% yield and 81% ee using
0.1 mol% catalyst after 28 h (entry 4). b-Keto esters 2e and
2f with bulkier substituents, however, were much less reactive,
giving products in only 32–43% yield after 48–120 h (entries 5
and 7). For 2e and 2f, the use of paraformaldehyde instead
of formalin effectively improved both yield and enantio-
selectivity. The reaction with 5 equiv. of paraformaldehyde
proceeded well and products 3e and 3f were obtained in good
yield and enantioselectivity using 0.1 mol% catalyst (entry 6,
79% yield, 89% ee; entry 8, 84% yield, 90% ee). With phenyl
ketone 2g, good enantioselectivity was obtained (entries 9–10,
89–94% ee); however, it was difficult to improve the reactivity,
even with paraformaldehyde.
2004, 45, 6117; (c) M. Fujii, Y. Sato, T. Aida and M. Yoshihara,
Chem. Express, 1992, 7, 309.
4 With a Rh-catalyst: (a) R. Kuwano, H. Miyazaki and Y. Ito,
Chem. Commun., 1998, 71; (b) R. Kuwano, H. Miyazaki and
Y. Ito, J. Organomet. Chem., 2000, 603, 18.
5 With a Pd-catalyst: I. Fukuchi, Y. Hamashima and M. Sodeoka,
Adv. Synth. Catal., 2007, 349, 509.
6 (a) S. Ishikawa, T. Hamada, K. Manabe and S. Kobayashi, J. Am.
Chem. Soc., 2004, 126, 12236; (b) S. Kobayashi, T. Ogino,
H. Shimizu, S. Ishikawa, T. Hamada and K. Manabe, Org. Lett.,
2005, 7, 4729; (c) M. Kokubo, C. Ogawa and S. Kobayashi,
Angew. Chem., Int. Ed., 2008, 47, 6909. For early work, see also:
(d) N. Ozawa, M. Wadamoto, K. Ishihara and H. Yamamoto,
Synlett, 2003, 2219.
7 Recent reviews on bifunctional asymmetric metal catalysis:
(a) M. Shibasaki, S. Matsunaga and N. Kumagai, Synlett, 2008,
1583; (b) S. Matsunaga and M. Shibasaki, Bull. Chem. Soc. Jpn.,
2008, 81, 60. For selected examples of chiral catalysts for direct
aldol reactions developed in our group, see: (c) N. Yoshikawa,
Y. M. A. Yamada, J. Das, H. Sasai and M. Shibasaki, J. Am.
Chem. Soc., 1999, 121, 4168; (d) N. Kumagai, S. Matsunaga,
T. Kinoshita, S. Harada, S. Okada, S. Sakamoto, K. Yamaguchi
and M. Shibasaki, J. Am. Chem. Soc., 2003, 125, 2169 and
references therein.
8 Ni2-1 catalyst: (a) Z. Chen, H. Morimoto, S. Matsunaga and
M. Shibasaki, J. Am. Chem. Soc., 2008, 130, 2170; (b) Z.
Chen, K. Yakura, S. Matsunaga and M. Shibasaki, Org.
Lett., 2008, 10, 3239; (c) Y. Xu, G. Lu, S. Matsunaga and
M. Shibasaki, Angew. Chem., Int. Ed., 2009, 48, 3353;
(d) Y. Kato, Z. Chen, S. Matsunaga and M. Shibasaki, Synlett,
2009, 1635.
9 Co2(OAc)2-1 catalyst: Z. Chen, M. Furutachi, Y. Kato,
S. Matsunaga and M. Shibasaki, Angew. Chem., Int. Ed., 2009,
48, 2218.
In summary, we developed a homodinuclear Ni2-Schiff
base-catalyzed enantioselective hydroxymethylation of b-keto
esters. The reaction proceeded with 0.1–1 mol% catalyst, and
hydroxymethylated products were obtained in 66–94% ee and
22–94% yield (TON = up to 940). Further trials to expand the
nucleophile scope are ongoing.
10 Mn2(OAc)2-1 catalyst: Y. Kato, M. Furutachi, Z. Chen,
H. Mitsunuma, S. Matsunaga and M. Shibasaki, J. Am. Chem.
Soc., 2009, 131, 9168.
11 Heterobimetallic transition metal–rare earth metal Schiff base
catalysts: (a) S. Handa, V. Gnanadesikan, S. Matsunaga and
M. Shibasaki, J. Am. Chem. Soc., 2007, 129, 4900; (b) S. Handa,
K. Nagawa, Y. Sohtome, S. Matsunaga and M. Shibasaki, Angew.
Chem., Int. Ed., 2008, 47, 3230; (c) H. Mihara, Y. Xu,
N. E. Shepherd, S. Matsunaga and M. Shibasaki, J. Am. Chem.
Soc., 2009, 131, 8384.
This work was supported by Grant-in-Aid for Scientific
Research (S), for Scientific Research on Priority Areas
(No. 20037010, Chemistry of Concerto Catalysis for SM),
and for Young Scientists (A) from JSPS and MEXT.
12 For selected examples of related bifunctional bimetallic Schiff base
complexes in asymmetric catalysis, see: (a) V. Annamalai,
E. F. DiMauro, P. J. Carroll and M. C. Kozlowski, J. Org. Chem.,
2003, 68, 1973 and references therein; (b) G. M. Sammis, H. Danjo
and E. N. Jacobsen, J. Am. Chem. Soc., 2004, 126, 9928;
(c) M. Yang, C. Zhu, F. Yuan, Y. Huang and Y. Pan, Org. Lett.,
2005, 7, 1927; (d) J. Gao, F. R. Woolley and R. A. Zingaro, Org.
Biomol. Chem., 2005, 3, 2126; (e) W. Li, S. S. Thakur, S.-W. Chen,
C.-K. Shin, R. B. Kawthekar and G.-J. Kim, Tetrahedron Lett.,
2006, 47, 3453; (f) W. Hirahata, R. M. Thomas, E. B. Lobkovsky
and G. W. Coates, J. Am. Chem. Soc., 2008, 130, 17658. For
related early studies with dinuclear Ni2-Schiff base complexes as
epoxidation catalysts, see also: (g) T. Oda, R. Irie, T. Katsuki and
H. Okawa, Synlett, 1992, 641.
Notes and references
1 For
a general review on asymmetric aldol reactions, see:
(a) L. M. Geary and P. G. Hultin, Tetrahedron: Asymmetry,
2009, 20, 131; (b) Modern Aldol Reactions, ed. R. Mahrwald,
Wiley-VCH, Weinheim, 2004.
2 Reviews on direct catalytic asymmetric aldol reactions:
(a) B. Alcaide and P. Almendros, Eur. J. Org. Chem., 2002,
1595. With organocatalysts, see: (b) S. Mukherjee, J. W. Yang,
S. Hoffmann and B. List, Chem. Rev., 2007, 107, 5471; (c) W. Notz,
F. Tanaka and C. F. Barbas, III, Acc. Chem. Res., 2004, 37, 580.
3 With organocatalysts: (a) H. Torii, M. Nakadai, K. Ishihara,
S. Saito and H. Yamamoto, Angew. Chem., Int. Ed., 2004, 43,
1983; (b) J. Casas, H. Sunden and A. Cordova, Tetrahedron Lett.,
13 The absolute configuration of 3a was determined by comparing the
sign of optical rotation with literature data in ref. 5.
ꢀc
This journal is The Royal Society of Chemistry 2009
5140 | Chem. Commun., 2009, 5138–5140