Magnesium(II)-binaphtholate as a practical chiral catalyst for the enantioselective direct mannich-type reaction with malonates

Article abstract of DOI:10.1021/ol101353r

(Equation Presented). A highly enantioselective direct Mannich-type reaction of aldimines with dialkyl malonates was developed with the use of a Mg(II)-BINOLate salt, which was designed as a cooperative acid-base catalyst that can activate both aldimines and malonates. Optically active β-aminoesters and α-halo-β-aminoesters could be synthesized in high yields and with high enantioselectivities. This inexpensive and practical Mg(II)-BINOLate salt could be used in gram-scale catalysis.

Full text of DOI:10.1021/ol101353r

ORGANIC
LETTERS
2010
Vol. 12, No. 15
3502-3505
Magnesium(II)-Binaphtholate as a
Practical Chiral Catalyst for the
Enantioselective Direct Mannich-Type
Reaction with Malonates
Manabu Hatano,† Takahiro Horibe,† and Kazuaki Ishihara*,†,‡
Graduate School of Engineering, Nagoya UniVersity, and Japan Science and
Technology Agency (JST), CREST, Furo-cho, Chikusa, Nagoya, 464-8603, Japan
ishihara@cc.nagoya-u.ac.jp
Received June 12, 2010
ABSTRACT
A highly enantioselective direct Mannich-type reaction of aldimines with dialkyl malonates was developed with the use of a Mg(II)-BINOLate
salt, which was designed as a cooperative acidsbase catalyst that can activate both aldimines and malonates. Optically active ꢀ-aminoesters
and r-halo-ꢀ-aminoesters could be synthesized in high yields and with high enantioselectivities. This inexpensive and practical Mg(II)-BINOLate
salt could be used in gram-scale catalysis.
A catalytic enantioselective direct Mannich-type reaction be-
tween aldimines and carbonyl compounds is highly useful for
the synthesis of chiral building blocks of ꢀ-amino carbonyl
compounds.1 As a result of the importance of these enantio-
enriched derivatives, particularly in biological and pharmaceuti-
cal chemistry, over the past decade considerable effort has been
devoted to establishing a methodology for the direct Mannich-
type reaction with chiral metal catalysts2 or organocatalysts.3
In this regard, we have recently developed chiral Li(I)-
BINOLate [BINOL ) 1,1′-bi-2-naphthol] salts4 as effective
acidsbase catalysts5 for the direct Mannich-type reaction with
1,3-diketone, 1,3-ketoester, 1,3-ketolactone, 1,3-ketothioester,
and 1,3-ketoamide (eq 1).6 However, less-reactive malonates
could not be used in the Li(I)-catalysis, unlike other favored
1,3-dicarbonyl compounds.
† Graduate School of Engineering.
‡ Japan Science and Technology Agency (JST).
Among 1,3-dicarbonyl compounds, the inherent difficulty
of the direct Mannich-type reaction with malonates2a,d,e,3c-f,i,l
is due to their weak acidity7 and stronger chelation to the
metal center without the generation of an activated metal-
(1) For reviews in direct Mannich-type reactions, see: (a) Co´rdova, A.
Acc. Chem. Res. 2004, 37, 102. (b) Friestad, G. K.; Mathies, A. K.
Tetrahedron 2007, 63, 2541. (c) Ting, A.; Schaus, S. E. Eur. J. Org. Chem.
2007, 5797. (d) Verkade, J. M. M.; van Hemert, L. J. C.; Quaedflieg,
P. J. L. M.; Rutjes, F. P. J. T. Chem. Soc. ReV. 2008, 37, 29.
10.1021/ol101353r  2010 American Chemical Society
Published on Web 07/07/2010

catalysts and organocatalysts, we report here that the
extremely simple and inexpensive Mg(II)-BINOLate salt is
highly effective for the catalytic enantioselective direct
Mannich-type reaction of aldimines with dialkyl malonates.
Smooth conversion was established within 3-4 h at -20
°C with the use of a smaller amount of catalyst loading
(2.5-5 mol %) of the Mg(II)-BINOLate salt compared to
the reactions with many previous catalysts, which often
needed a catalyst loading of 10-20 mol % and/or a longer
reaction time (sometimes >12 h).2a,d,e,3c-f,i,l
Figure 1. Expected Mg(II)-malonate BINOLate salt in situ.
enolate. To overcome these problems, we designed a
cooperative acidsbase catalyst with divalent group II ele-
ments. In particular, an uncommon but easily prepared chiral
Mg(II)-BINOLate salt8,9 is attractive because it should have
enough Brønsted basicity to generate Mg(II)-enolate in situ
without the release of BINOL (Figure 1). Therefore, when
this cooperative acidsbase Mg(II)-salt catalyst activates both
aldimine and malonate, a diValent Mg(II) center would be
firmly bound to both BINOL and malonate through ionic
and coordinate bonds. In sharp contrast to previous metal
First, we examined the enantioselective direct Mannich-type
reaction of aldimine 1a with dimethyl malonate (2a) (Table 1).
Table 1. Screening of Catalysts
yield
(%)
ee
(%)
(2) (a) Marigo, M.; Kjærsgaard, A.; Juhl, K.; Gathergood, N.; Jørgensen,
K. A. Chem.sEur. J. 2003, 9, 2359. (b) Hamashima, Y.; Sasamoto, N.;
Hotta, D.; Somei, H.; Umebayashi, N.; Sodeoka, M. Angew. Chem., Int.
Ed. 2005, 44, 1525. (c) Sasamoto, N.; Dubs, C.; Hamashima, Y.; Sodeoka,
M. J. Am. Chem. Soc. 2006, 128, 14010. (d) Chen, Z.; Morimoto, H.;
Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc. 2008, 130, 2170. (e)
Poisson, T.; Tsubogo, T.; Yamashita, Y.; Kobayashi, S. J. Org. Chem. 2010,
75, 963. (f) Hatano, M.; Moriyama, K.; Maki, T.; Ishihara, K. Angew. Chem.,
entry
MX (mol %)
conditions
1a
2
rt, 24 h
-40 °C, 6 h
-40 °C, 6 h
-40 °C, 6 h
0
<3
98
>99
99
14
n-BuLi (5)
n-BuLi (5) + t-BuOH (10)
n-BuLi (10)
3b
4
0
28
0
5b
6
n-BuLi (10) + t-BuOH (20) -40 °C, 6 h
Int. Ed. 2010, 49, 3819
.
(3) (a) Uraguchi, D.; Terada, M. J. Am. Chem. Soc. 2004, 126, 5356.
(b) Lou, S.; Taoka, B. M.; Ting, A.; Schaus, S. E. J. Am. Chem. Soc. 2005,
127, 11256. (c) Tillman, A. L.; Ye, J.; Dixon, D. J. Chem. Commun. 2006,
1191. (d) Song, J.; Wang, Y.; Deng, L. J. Am. Chem. Soc. 2006, 128, 6048.
(e) Fini, F.; Bernardi, L.; Herrera, R. P.; Pettersen, D.; Ricci, A.; Sgarzani,
V. AdV. Synth. Catal. 2006, 348, 2043. (f) Song, J.; Shih, H.-W.; Deng, L.
Org. Lett. 2007, 9, 603. (g) Yamaoka, Y.; Miyabe, H.; Yasui, Y.; Takemoto,
Y. Synthesis 2007, 2571. (h) Hatano, M.; Maki, T.; Moriyama, K.; Arinobe,
M.; Ishihara, K. J. Am. Chem. Soc. 2008, 130, 16858. (i) Takada, K.; Tanaka,
S.; Nagasawa, K. Synlett 2009, 1643. (j) Han, X.; Kwiatkowski, J.; Xue,
F.; Huang, K.-W.; Lu, Y. Angew. Chem., Int. Ed. 2009, 48, 7604. (k) Pan,
Y.; Zhao, Y.; Ma, T.; Yang, Y.; Liu, H.; Jiang, Z.; Tan, C.-H. Chem.sEur.
n-Bu2Mg (2.5)
n-Bu2Mg (5)
n-Bu2Mg (10)
-40 °C, 6 h
-40 °C, 6 h
-40 °C, 6 h
7
8
98
97
92
80
a 5 mol % of (R)-BINOL was used without a metal complex. b In the
absence of MgSO4.
As expected, the exclusive use of (R)-BINOL without a metal
precursor did not promote the reaction, even at room temper-
ature for 24 h (entry 1). Unlike in the reaction with diketones,
ketoesters, etc.,6 lithium salts of (R)-BINOL (5 mol %) in the
presence of t-BuOH (10-20 mol %) showed low enantiose-
lectivity for 3a despite high reactivity at -40 °C for 6 h (entries
3 and 5). However, a dry dilithium salt of (R)-BINOL (5 mol
%) in the absence of t-BuOH improved the enantioselectivity
up to 28% ee (entry 4), whereas a corresponding monolithium
salt scarcely provided 3a (entry 2).10 In sharp contrast, dry
magnesium salts of (R)-BINOL greatly improved the enanti-
oselectivity of 3a. After optimization of the amount of n-Bu2Mg
(entries 6- 8), (R)-3a was obtained in 98% yield with 92% ee
when 5 mol % each of (R)-BINOL and n-Bu2Mg were used in
the presence of MgSO411 (entry 7). Interestingly, modification
of the skeleton of (R)-BINOL (e.g., substitution at the 3,3′-
positions, etc.) gave 3a in low reactivity and/or low enantiose-
lectivity. Therefore, to our delight, we selected simple and
inexpensive nonmodified (R)-BINOL for subsequent experi-
ments.
J. 2010, 16, 779. (l) Lee, J. H.; Kim, D. Y. Synthesis 2010, 1860
.
(4) Chiral Li(I)-BINOLate catalyses: (a) Schiffers, R.; Kagan, H. B.
Synlett 1997, 1175. (b) Loog, O.; Ma¨eorg, U. Tetrahedron: Asymmetry 1999,
10, 2411. (c) Holmes, I. P.; Kagan, H. B. Tetrahedron Lett. 2000, 41, 7453.
(d) Nakajima, M.; Orito, Y.; Ishizuka, T.; Hashimoto, S. Org. Lett. 2004,
6, 3763. (e) Hatano, M.; Ikeno, T.; Miyamoto, T.; Ishihara, K. J. Am. Chem.
Soc. 2005, 127, 10776. (f) Ichibakase, T.; Orito, Y.; Nakajima, M.
Tetrahedron Lett. 2008, 49, 4427. (g) Tanaka, K.; Ueda, T.; Ichibakase,
T.; Nakajima, M. Tetrahedron Lett. 2010, 51, 2168
(5) For reviews in acidsbase chemistry, see: (a) Kanai, M.; Kato, N.;
Ichikawa, E.; Shibasaki, M. Synlett 2005, 1491. (b) Ishihara, K.; Sakakura,
.
A.; Hatano, M. Synlett 2007, 686
.
(6) Hatano, M.; Horibe, T.; Ishihara, K. J. Am. Chem. Soc. 2010, 132,
56.
(7) The pKa values for 1,3-dicarbonyl compounds: (a) Olmstead, W. N.;
Bordwell, F. G. J. Org. Chem. 1980, 45, 3299. (b) Mori, K.; Oshiba, M.;
Hara, T.; Mizugaki, T.; Ebitani, K.; Kaneda, K. Tetrahedron Lett. 2005,
46, 4283
.
(8) Mg(II)-BINOLates have received little attention in asymmetric
catalysis. For pioneering reports, see: (a) Noyori, R.; Suga, S.; Kawai, K.;
Okada, S.; Kitamura, M. Pure Appl. Chem. 1988, 60, 1597. (b) Charette,
A. B.; Gagnon, A. Tetrahedron: Asymmetry 1999, 10, 1961. (c) Bolm, C.;
Beckmann, O.; Cosp, A.; Palazzi, C. Synlett 2001, 1461. (d) Weinert, C. S.;
Fanwick, P. E.; Rothwell, I. P. Organometallics 2002, 21, 484. (e) Du, H.;
Zhang, X.; Wang, Z.; Bao, H.; You, T.; Ding, K. Eur. J. Org. Chem. 2008,
2248
.
(9) For reviews in asymmetric catalysis with Mg(II) complexes: (a)
Motoyama, Y.; Nishiyama, H. In Lewis Acids in Organic Synthesis;
Yamamoto, H., Ed.; Wiley-VCH: Weinheim, Germany, 2000; Vol. 1,
Chapter 3. (b) Hatano, M.; Ishihara, K. In Acid Catalysis in Modern Organic
Synthesis; Yamamoto, H., Ishihara, K., Eds.; Wiley-VCH: Weinheim,
Germany, 2008; Vol. 1, Chapter 4.
(10) During the preliminary investigation with lithium salt catalysts, we
found that previously optimized 3,3′-(3,4,5-F3C6H2)2-BINOL did not promote
the reaction between 1a and 2a at -78 to -20 °C. Also see ref 6.
(11) MgSO4 was not an actual source of the catalyst. While it was not
essential, it was used as a drying agent to remove adventitious water in
situ. Powdered MS 4Å was also effective in place of MgSO4.
Org. Lett., Vol. 12, No. 15, 2010
3503

Table 2. Direct Mannich-Type Reaction with N-Boc Aldimines and Dimethyl Malonate
entry
1
Ar
R1
3
yield (%)
ee (%)
92
81
93
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
1g
1h
1i
Ph
Ph
CO2t-Bu (Boc)
CO2Bn (Cbz)
Boc
3a
3b
3c
3d
3e
3f
3g
3h
3i
>99
98
98
4-ClC6H4
3-MeC6H4
3,4-(MeO)2C6H3
2-furyl
3-thienyl
3-pyridyl
Boc
Boc
Boc
Boc
Boc
Boc
94
87
55, [91]a
>99
>99
>99
98
87, [90]a
90
95
89
88
1-naphthyl
a 5 mol % of (R)-BINOL and 7.5 mol % of n-Bu2Mg were used.
We further found that the reactions proceeded at -20 °C
for 3 h without any loss of enantioselectivity (Table 2). With
regard to the protecting group in the N-moiety of aldimines,
tert-butoxycarbonyl (Boc) showed better enantioselectivity
than benzyoxycarbonyl (Cbz) (entries 1 and 2). A variety of
aryl aldimines with an electron-withdrawing or electron-
donating group and heteroaryl aldimines could be applied,
and the desired products 3c-i were obtained in high yields
and with high enantioselectivities (entries 3-9).12 For 1e
with a 3,4-(MeO)2C6H3 moiety, an optimal 1/1 ratio of (R)-
BINOL/n-Bu2Mg (5 mol % each) provided 3g in moderate
yield (55%) (entry 5). Interestingly, however, a slight excess
of n-Bu2Mg (7.5 mol %) to (R)-BINOL (5 mol %) improved
the yield and enantioselectivity (91% with 90% ee) (entry
5, data in brackets). A chelatable moiety such as an
o-dimethoxy group may partially ligate the Mg(II) center,
and this may prevent the generation of the active catalyst.
We next explored the scope of malonates (Figure 2). Not
only dimethyl malonate (2a) but also di(n-propyl) malonate,
dibenzyl malonate, and diallyl malonate were applied success-
fully, and the corresponding products were obtained from 1a
in almost quantitative yields with 88-92% ee (see 3j-l). The
reaction of dimethyl R-halomalonates was also examined.13
Although dimethyl 2-fluoromalonate gave the corresponding
adduct (3m) with moderate enantioselectivity (50% ee), the
reaction of dimethyl 2-chloromalonate and dimethyl 2-bromo-
malonate proceeded smoothly with the formation of a chiral
quaternary carbon center, and the desired R-halo-ꢀ-aminoesters
(3n and 3o) were obtained in high yields (92->99%) and with
high enantioselectivities (96-97% ee). The reaction proceeded
smoothly even in the presence of 2.5 mol % of (R)-BINOL
and 3.75 mol % of n-Bu2Mg,14 and 3o was obtained in 87%
yield with 94% ee.
To evaluate the tolerance of this catalyst, a 2-g-scale (5
mmol) synthesis of 3o was examined in the reaction of 1a
with dimethyl 2-bromomalonate (Scheme 1). The reaction
proceeded smoothly with the use of 5 mol % each of (R)-
BINOL and n-Bu2Mg in toluene at -20 °C for 4 h, and the
desired product (3o) was obtained in quantitative yield
(>99%) with 99% ee.
Scheme 1. Catalytic Gram-Scale Synthesis of Mannich Adduct
Figure 2. Scope of malonates. The reactions were performed in
toluene at -20 °C for 3 h in the presence of 5 mol % each of
(R)-BINOL and n-Bu2Mg, unless otherwise noted. (a) Yield and
enantioselectivity when 10 mol % each of (R)-BINOL and n-Bu2Mg
were used. (b) Yield and enantioselectivity when 2.5 mol % of
(R)-BINOL and 3.75 mol % of n-Bu2Mg were used.
With regard to the utility of the resulting Mannich product,
we transformed 3a (92% ee) to the corresponding ꢀ-lactam
5 (Scheme 2).15,16 Without any loss of enantioselectivity
3504
Org. Lett., Vol. 12, No. 15, 2010

In summary, we have developed a catalytic enantioselec-
tive direct Mannich-type reaction of aldimines with dialkyl
malonates in the presence of a simple Mg(II)-BINOLate salt.
Smooth conversion was established within 3-4 h at -20
°C with 2.5-5 mol % catalyst loading of the Mg(II)-
BINOLate salt. This was in sharp contrast to the reactions
with previous catalysts, which often needed 5-10 mol %
loading and a longer reaction time. Although a mechanistic
investigation of the actual catalysts (Brønsted acidsBrønsted
base or Lewis acidsBrønsted base) will be necessary in the
future, this inexpensive and practical Mg(II)-BINOLate salt
catalyst should be highly attractive in academic and industrial
process chemistry. Further applications of BINOL-alkali and
alkaline earth metal (group I and II elements) complexes to
other catalytic enantioselective reactions are now underway.
Scheme 2. ꢀ-Lactam Synthesis
(92% ee), ꢀ-phenyl-substituted ꢀ-lactam 5 was obtained in
71% yield in three steps via the synthetically useful optically
active ꢀ-aminoester (4).
Acknowledgment. Financial support for this project was
partially provided by JSPS. KAKENHI (20245022), MEXT.
KAKENHI (21750094, 21200033), and the Global COE
Program of MEXT.
(12) The compatibility of this catalysis with aliphatic aldimines would
need further examinations due to their lower reactivity. However, we
examined the preliminary reaction of PMPNdCCO2Et (PMP ) p-
methoxyphenyl) as a non-aromatic aldimine with dimethyl 2-bromoma-
lonate, and the corresponding product was obtained in 81% yield with 60%
ee.
(13) Recently, some research groups have reported the catalytic asym-
metric direct Mannich-type reaction with 2-halo-1,3-dicarbonyl compounds.
See refs 2f and 3j-l
(14) Poor conversion (<5%) was observed when 2.5 mol % each of (R)-
BINOL and n-Bu2Mg were used, probably due to the incomplete formation
of Mg(II)-BINOLate salt.
Supporting Information Available: Experimental pro-
cedures, spectral data, and copies of NMR spectra. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL101353R
(15) For reviews in ꢀ-lactam synthesis. (a) Mukerjee, A. K.; Srivastava,
R. C. Synthesis 1973, 327. (b) Magriotis, P. A. Angew. Chem., Int. Ed.
2001, 40, 4377. (c) Palomo, C.; Aizpurua, J. M.; Ganboa, I.; Oiarbide, M.
Curr. Med. Chem. 2004, 11, 1837. (d) Aranda, M. T.; Perez-Faginas, P.;
Gonzalez-Muniz, R. Curr. Org. Chem. 2009, 6, 325.
(16) (a) Matsuyama, H.; Kurosawa, A.; Takei, T.; Ohira, N.; Yoshida,
M.; Iyoda, M. Chem. Lett. 2000, 29, 1105. (b) Nejman, M.; Sliwin´ska, A.;
Zwierzak, A. Tetrahedron 2005, 61, 8536. (c) Kano, T.; Yamaguchi, Y.;
Maruoka, K. Angew. Chem., Int. Ed. 2009, 48, 1838.
´
Org. Lett., Vol. 12, No. 15, 2010
3505