Asymmetric Mannich reaction of malonates with imines catalyzed by a chiral calcium complex

Article abstract of DOI:10.1021/jo902383b

(Chemical Equation Presented) Achiral calcium complex was found to be effective for the Mannich reactions of malonates with N-Boc imines. The desired adducts were obtained in excellent yields (up to 95%) with moderate to good enantioselectivities (up to 77% ee).

Full text of DOI:10.1021/jo902383b

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report of the use of alkaline earth metals in asymmetric aldol
Asymmetric Mannich Reaction of Malonates with
Imines Catalyzed by a Chiral Calcium Complex
reactions,3 chiral alkaline earth metal catalysts have been
intensively investigated; however, successful examples were
limited.2,4
Thomas Poisson, Tetsu Tsubogo, Yasuhiro Yamashita, and
Shu Kobayashi*
The Mannich reaction of malonates with imines represents
one of the most attractive ways to provide β-aminocarbonyl
compounds, which are interesting building blocks in synthetic
organic chemistry as well as medicinal chemistry.5 In these
reactions, no preformation of enolates or naked enolates is
required to access to the Mannich adducts. Despite organo-
catalytic pathways receiving much attention,6 the asymmetric
addition of malonates to imines catalyzed by a chiral metal
complex has been under development.7 Herein we disclose the
Mannich reaction of malonates with N-Boc imines catalyzed
by a chiral calcium complex prepared from a calcium salt and a
neutral coordinative ligand (Scheme 1).8
Department of Chemistry, School of Science and Graduate
School of Pharmaceutical Sciences, The University of Tokyo,
The HFRE Division, ERATO, Japan Science and Technology
Agency (JST), Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
shu_kobayashi@chem.s.u-tokyo.ac.jp
Received November 6, 2009
SCHEME 1. Asymmetric Mannich Reaction with Chiral Ca
Complexes
A chiral calcium complex was found to be effective for the
Mannich reactions of malonates with N-Boc imines. The
desired adducts were obtained in excellent yields (up to
95%) with moderate to good enantioselectivities (up to
77% ee).
Group 2 alkaline earth metals (calcium, strontium, and
barium) are now of great interest because of the abundance
and specific properties of these metals such as low electron
negativity and various coordination sites.1 The use of these
metals in organic synthesis, especially as a catalyst,2 is also
beneficial from an environmental viewpoint. Since the first
In the course of our investigation to expand use of alkaline
earth metal complexes in organic synthesis, we studied
the addition of dimethyl malonate (2a, R2=Me, R3=H) to
N-Boc imine 1a (R1=Ph) derived from benzaldehyde in the
presence of a catalytic amount of calcium isopropoxide and a
(1) Basic Inorganic Chemistry, 3rd ed.; Cotton, F. A., Wilkinson, G.,
Gaus, P. L., Eds.; Wiley: New York, 1995.
(2) Selected examples of nonenantioselective reactions with alkaline earth
metal complexes as catalysts: (a) Crimmin, M. R.; Casely, I. J.; Hill, M. S.
J. Am. Chem. Soc. 2005, 2042. (b) Crimmin, M. R.; Barrett, A. G. M.; Hill,
M. S.; Hitchcock, P. B.; Procopiou, P. A. Organometallics 2007, 2953. (c)
Crimmin, M. R.; Barrett, A. G. M.; Hill, M. S.; Procopiou, P. A. Org. Lett.
2007, 331. (d) Buch, F.; Bettar, J.; Harder, S. Angew. Chem., Int. Ed. 2006,
2741. (e) Vanden Eynden, M. J.; Stambuli, J. P. Org. Lett. 2008, 5289.
(3) Yamada, Y. M. A.; Shibasaki, M. Tetrahedron Lett. 1998, 39, 5561.
(4) Selected examples of enantioselective reactions with chiral alkaline
earth metal complexes: Ca catalysts: (a) Suzuki, T.; Yamagiwa, N.; Matsuo,
Y.; Sakamoto, S.; Yamaguchi, K.; Shibasaki, M.; Noyori, R. Tetrahedron
Lett. 2001, 42, 4669. (b) Kumaraswamy, G.; Sastry, M. N. V.; Jena, N.
Tetrahedron Lett. 2001, 42, 8515. (c) Kumaraswamy, G.; Jena, N.; Sastry, M.
N. V.; Padmaja, M.; Markondaiah, B. Adv. Synth. Catal. 2005, 347, 867. (d)
Saito, S.; Tsubogo, T.; Kobayashi, S. J. Am. Chem. Soc. 2007, 129, 5364. (e)
Tsubogo, T.; Saito, S.; Seki, K.; Yamashita, Y.; Kobayashi, S. J. Am. Chem.
Soc. 2008, 130, 13321. (f) Kobayashi, S.; Tsubogo, T.; Saito, S.; Yamashita,
Y. Org. Lett. 2008, 10, 807. Sr catalysts: (g) Agostinho, M.; Kobayashi, S.
J. Am. Chem. Soc. 2008, 130, 2430. (h) Kobayashi, S.; Yamaguchi, M.;
Agostinho, M.; Schneider, U. Chem. Lett. 2009, 38, 296. Ba catalysts: (i)
Saito, S.; Kobayashi, S. J. Am. Chem. Soc. 2006, 128, 8704. (j) Yamaguchi,
A.; Aoyama, N.; Matsunaga, S.; Shibasaki, M. Org. Lett. 2007, 9, 3387. (k)
Yamatsugu, K.; Yin, L.; Kamijo, S.; Kimura, Y.; Kanai, M.; Shibasaki, M.
Angew. Chem., Int. Ed. 2009, 48, 1070.
(5) For reviews on Mannich and asymmetric Mannich reactions see: (a)
Kobayashi, S.; Ishitani, H. Chem. Rev. 1999, 99, 1069. (b) Arend, M.;
Westermann, B.; Risch, N. Angew. Chem., Int. Ed. 1998, 37, 1044. (c)
Denmark, S. E.; Nicaise, O. J.-C. In Comprehensive Asymmetric Catalysis;
Jacobsen, E. N., Pflatz, A., Yamamoto, H., Eds.; Springer: Berlin, Germany, 1999;
Vol. 2, p 923.
(6) Selected examples with organocatalysts in direct addition of malo-
nates to imines: (a) Song, J.; Wang, Y.; Deng, L. J. Am. Chem. Soc. 2006, 128,
6048. (b) Tillman, A. L.; Yeb, J.; Dixon, D. J. Chem. Commun. 2006, 1191. (c)
Yamaoka, U.; Miyabe, H.; Yasui, Y.; Takemoto, Y. Synthesis 2007, 22,
2571. (d) Fini, F.; Bernardi, L.; Herrera, R. P.; Pettersen, D.; Ricci, A.;
Sgarzanic, V. Adv. Synth. Catal. 2006, 348, 2043. (e) Marianacci, O.;
Micheletti, G.; Bernardi, L.; Fini, F.; Fochi, M.; Pettersen, D.; Sgarzani,
V.; Ricci, A. Chem.;Eur. J. 2007, 13, 8338. (f) Okada, A.; Shibuguchi, T.;
Ohshima, T.; Masu, H.; Yamaguchi, K.; Shibasaki, M. Angew. Chem., Int.
Ed. 2005, 44, 4564.
(7) (a) Marigo, M.; Kjorsgaard, A.; Juhl, K.; Gathergood, N.; Jorgensen,
K. A. Chem.;Eur. J. 2003, 9, 2359. Sasamoto, N.; Dubs, C.; Hamashima,
Y.; Sodeoka, M. J. Am. Chem. Soc. 2006, 128, 14010. (b) Chen, Z.;
Morimoto, H.; Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc. 2008, 130,
2170.
(8) Tsubogo, T.; Yamashita, Y.; Kobayashi, S. Angew. Chem., Int. Ed.
2009, 48, 9117.
DOI: 10.1021/jo902383b
r
Published on Web 01/08/2010
J. Org. Chem. 2010, 75, 963–965 963
2010 American Chemical Society

Poisson et al.
JOCNote
TABLE 1. Ligand Screeninga
TABLE 2. Optimization of the Reaction Conditionsa
entry
ligand
yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
4
5
85
79
85
89
86
94
98
99
-11
4d
6a
6b
6c
6d
6e
6f
28d
25d
40d
43d
0
entry
R2
x:y
1:1
1:1
1:1.5
1:1
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
temp (°C)
yield (%)b
ee (%)c
47d
aThe Mannich reaction of 1a (0.20 mmol) with 2a (0.24 mmol) was
performed in toluene at 0 °C for 24 h in the presence of a calcium
complex prepared from Ca(OiPr)2 (10 mol %), a ligand (10 mol %), and
1
2
3
4
5
Me (2a)
Me (2a)
Me (2a)
Me (2a)
Et (2b)
iPr (2c)
tBu (2d)
Bn (2e)
Bn (2e)
Bn (2e)
Bn (2e)
Bn (2e)
Bn (2e)
Bn (2e)
0
-20
-20
-40
-20
-20
-20
-20
-20
-20
-20
-20
-20
-20
99
83
99
83
95
95
92
91
82
75
83
88
90
89
47
50
55
40
54
51
43
68
69
69
69
65
73
73
molecular sieves 4A (10 mg/mmol). The concentration is 0.2 M. bIso-
˚
lated yield. cDetermined by HPLC analysis. dAbsolute configuration
was determined to be R according to the literature data.6b
6
7
8
chiral ligand (Table 1). When known anionic calcium com-
plexes derived from Bisoxazoline 44f and BINOL ligand 54c
were used, very low enantioselectivities were obtained (Table 1,
entries 1 and 2). After extensive screening of ligands, Ca-
Pyridinebisoxazoline (PyBox) 6a complex8 was found to be
more effective, and the Mannich adduct 3aa was obtained in
excellent yield with moderate enantioselectivity (28% ee,
entry 3). This promising result led us to screen several PyBox
ligands carefully. While PyBox 6b furnished the corresponding
β-aminodicarbonyl compound with similar selectivity (entry 4,
25% ee), the use of PyBox 6c and 6d provided significant
increase of selectivity (40% ee and 43% ee, respectively). Ph-
PyBox (6e) gave the Mannich adduct as a racemate, whereas
Bn-PyBox (6f) gave the product in 47% ee.
With ligand 6f in hand, we investigated the optimization of
reaction conditions and influence of the malonate moiety on
selectivity (Table 2). The first examination of reaction tem-
perature revealed that -20 °C was the optimum temperature
for the reaction. Indeed decrease of the temperature to -40 °C
induced a drop of enantioselectivity from 50% ee (at -20 °C)
to 40% ee (entry 4). This might be explained by partial
decomplexation of the Ca-PyBox complex; free calcium alk-
oxide could catalyze a racemic background reaction.9 A study
of the ratio of calcium vs. ligand at -20 °C revealed an
optimum of 1 to 1.5; in that case the selectivity increased to
55% ee (entry 3). On the other hand, we observed a significant
influence of the malonate part on selectivity. The reaction of
diethyl malonate (2b) provided almost the same enantioselec-
tivity (entry 5), whereas those of secondary and tertiary esters
(2c and 2d) gave lower selectivities (entries 6 and 7). Finally,
dibenzyl malonate 2e was found to be the most efficient
furnishing the product in 68% ee (entry 8). To improve the
enantioselectivity further, use of additives was investigated.
Unfortunately, use of molecular sieves was ineffective on the
selectivity (entries 9 and 10), and the same selectivity was
observed without addition of molecular sieves (entry 11).
Furthermore, solvent screening revealed that xylene was more
effective than toluene and mesitylene (entries 11 and 12,
respectively), providing the corresponding product in excellent
yield with 73% ee (entry 13).10 Interestingly, decrease of
concentration to 0.02 M led to similar results (entry 14).
9d
10e
11i
12f,i
13g,i
14g-i
aThe Mannich reaction of 1a (0.20 mmol) with 2 (R3 = H, 0.24 mmol)
was performed in toluene at 0.2 M for 2 h in the presence of a calcium
complex prepared from Ca(OiPr)2 (10x mol %) and 6f (10y mol %) and
molecular sieves 4 A (10 mg/mmol), unless otherwise noted. bIsolated
˚
c
yield. Determined by HPLC analysis. MS 3 A was used as additive,
d
˚
e
f
MS 5 A was used as additive, Mesitylene was used as a solvent, Xylene
g
˚
was used as a solvent. hThe concentration was 0.02 M. iReaction
˚
conducted without MS 4 A.
After these optimizations, we decided the use of 10 mol %
of Ca(OiPr)2 in the presence of 15 mol % of PyBox 6f in
xylene at -20 °C was the best system for the Mannich
reaction of the malonate with the N-Boc imine. With
this system in hand, the substrate scope of several N-Boc
imines11,12 and malonates was investigated (Table 3).
First, the R-substitution of dibenzylmalonate was exam-
ined, and it was found that this substitution was important
for obtaining good enantioselection. Indeed, methyl malo-
nate 2f (Table 3, entry 2) provided a significant loss of
selectivity, whereas the use of malonate 2g with a bulkier
benzyl group as a substituent provided a dramatic drop of
enantioselectivity (entry 3). We examined several substituted
imines with 2e as a nucleophile. It was revealed that sub-
stitution at the para position of the aromatic ring provided a
decrease of selectivity (entries 6, 9, and 10) except for the
fluoro analogue (entry 8), while a meta substitution did not
have any significant effect (entry 5). A methyl substitution at
the ortho position of the aromatic ring was found to have a
beneficial effect on enantioselectivity; 77% ee was obtained
as shown in entry 4. Unexpectedly, when the methyl sub-
stituent was replaced by a methoxy substitution (entry 7), the
selectivity decreased to 56%, probably due to the steric
hindrance of the methoxy group. The use of the N-Boc imine
derived from 1-naphthaldehyde revealed the same trend; the
selectivity also dropped to 66% (entry 11).
Heteroaromatic substitutions were also investigated. Impress-
ively, the N-Boc imine derived from furfural provided a good
selectivity (76% ee, entry 12), whereas 2-thienyl-N-Boc-imine
(9) The calcium-PyBox complex might exist in equilibrium with the
ligand and free Ca(OiPr)2, and the decrease of temperature led to a displace-
ment of this equilibrium in favor of free Ca(OiPr)2, which was found to be
efficient as catalyst in the direct addition of malonates to N-Boc imines.
(10) Previous optimizations revealed that aromatic solvents were the
most efficient.
(11) For an efficient preparation of N-Boc imines, see: Wenzel, A. G.;
Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124, 12964 and ref 6a.
(12) Boc was found to be the most efficient N-protecting group under
conditions described in Table 2, entry 11. The N-Cbz analogue of 1a
furnished the corresponding product in 54% ee.
964 J. Org. Chem. Vol. 75, No. 3, 2010

Poisson et al.
JOCNote
TABLE 3. Substrates Scopea
(up to 77% ee). This work could expand the use of alkaline
earth metals in organic synthesis.
Experimental Section
Representative Procedure (Entry 13 in Table 2). In a flame-
dried glass tube, a suspension of Ca(OiPr)2 (3.1 mg, 0.020 mmol)
and PyBox 6f (12 mg, 0.030 mmol) in dry xylene (0.5 mL) was
heated at 80 °C for 2 h. Dibenzylmalonate 2e (neat, 58 μL, 0.24
mmol) was then added, and the resulting solution was stirred at the
same temperature for 0.5 h. The reaction solution was cooled to
-20 °C, and the corresponding imine (0.20 mmol) was added as a
solution of xylene (0.5 mL). After 2 h, the reaction was quenched
with aq NH4Cl (saturated, 3 mL). After addition of DCM, the
organic layer was separated and the aqueous layer was extracted
with DCM (three times). The combined organic layers were dried
over anhydrous Na2SO4 and concentrated under reduced pres-
sure. The residue was purified by preparative thin-layer chroma-
tography (PTLC, hexane-Et2O = 4:1) to afford the desired
product (88 mg, 90% yield). HPLC analysis of the product
(Daicel Chiralpak AS-H, hexane/iPrOH=40/1, 1.0 mL/min, 254
nm, tR = 24.1 min (major isomer) and tR = 30.9 min (minor
isomer)) indicated that the optical purity was 73% ee.
entry
R1
R3
yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Ph (1a)
Ph (1a)
Ph (1a)
H (2e)
Me (2f)
Bn (2g)
H (2e)
H (2e)
H (2e)
H (2e)
H (2e)
H (2e)
H (2e)
H (2e)
H (2e)
H (2e)
H (2e)
90
84
95
90
93
75
92
91
82
92
73
95
89
80
73c
62
16
77
71
66
56
72
61
67
66
76
54
5
o-MeC6H4 (1b)
m-MeC6H4 (1c)
p-MeOC6H4 (1d)
o-MeOC6H4 (1e)
p-FC6H4 (1f)
p-ClC6H4 (1g)
3,4-(OCH2O)C6H3 (1h)
1-naphthyl (1i)
2-furyl (1j)
2-thienyl (1k)
C6H11 (1l)
aThe Mannich reaction of 1 (0.20 mmol) with 2 (0.24 mmol) was
performed in xylene at 0.2 M at -20 °C for 2 h in the presence of a
calcium complex prepared from Ca(OiPr)2 (10 mol %) and 6f (15 mol
%), unless otherwise noted. bIsolated yield. cDetermined by HPLC
analysis. Absolute configuration was determined to be R according to
the literature data.6e
Acknowledgment. This work was partially supported by a
Grant-in-Aid for Science Research from the Japan Society
for the Promotion of Science (JSPS) and Global COE
Program (Chemistry Innovation through Cooperation of
Science and Engineering), The University of Tokyo, MEXT,
Japan. T.P. thanks the JSPS Postdoctoral Fellowship for
Foreign Researchers, and T.T. thanks the JSPS Research
Fellowship for Young Scientists.
gave the Mannich adduct in 54% ee (entry 13). Finally, aliphatic
N-Boc imine derived from cyclohexanecarboxaldehyde was
engaged in the Mannich reaction. Unfortunately, our catalytic
system was found to be ineffective for this substrate furnishing
the corresponding aminodicarbonyl compound with only 5% ee
despite an acceptable yield (entry 14).
In summary, we have shown the first use of the chiral Ca-
PyBox complex in the Mannich reaction of malonates with
N-Boc imines. The corresponding adducts were obtained with-
in 2 h in high yields with good to moderate enantioselectivities
Supporting Information Available: Proposed catalytic cycle,
general experimental procedure, characterization data of the
products including new compounds, separation conditions of
each enantiomer of the products in HPLC analysis, and 1H and
13C NMR charts of the new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 75, No. 3, 2010 965