syn-selective catalytic asymmetric nitro-Mannich reactions using a heterobimetallic Cu-Sm-Schiff base complex

Article abstract of DOI:10.1021/ja0701560

syn-Selective catalytic asymmetric nitro-Mannich reactions using a heterobimetallic Cu/Sm/Schiff base complex are described. The present method is complementary to the previously reported methods, and products were obtained in high syn-selectivity (>20:1)

Full text of DOI:10.1021/ja0701560

Published on Web 03/30/2007
syn-Selective Catalytic Asymmetric Nitro-Mannich Reactions Using a
Heterobimetallic Cu-Sm-Schiff Base Complex
Shinya Handa, Vijay Gnanadesikan, Shigeki Matsunaga,* and Masakatsu Shibasaki*
Graduate School of Pharmaceutical Sciences, The UniVersity of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Received January 9, 2007; E-mail: mshibasa@mol.f.u-tokyo.ac.jp; smatsuna@mol.f.u-tokyo.ac.jp
Scheme 1 . Dinucleating Schiff Base Ligand 3 and Proposed
Structure of Heterobimetallic Cu/Sm/3 Complex with ArOH
Additive
The nitro-Mannich (aza-Henry) reaction provides synthetically
versatile â-nitroamines (eqs 1 and 2) that can be converted to 1,2-
diamines, R-aminocarbonyl compounds, and others. Tremendous
effort has been devoted to develop catalytic enantioselective variants
over the past decade.1 Since our reports using heterobimetallic
metal-BINOLate complexes,2 diastereo- and enantioselective reac-
tions with various nitroalkanes have been realized using metal
complexes2b,3 and organocatalysts,4 such as thioureas,4a,b a chiral
proton catalyst,4c and cinchona alkaloids.4d,5 Although those
catalysts2-4 gave anti-1 in good yield and high stereoselectivity
(eq 1),6 there are no reports of a syn-selective catalytic asymmetric
nitro-Mannich reaction (eq 2).6 Herein, we report the utility of a
heterobimetallic Cu-Sm-Schiff base 3 catalyst to realize a syn-
selective nitro-Mannich reaction, giving syn-2 in high syn-selectivity
(>20:1 dr) and enantioselectivity (up to 98% ee). The present
system complements the previously reported methods.2b,3,4
Table 1. Optimization of Reaction Conditions
metal
M1a
sources
M2b
M1/M2/3
yield
(%)
drc
(syn/anti) (syn)
% ee
entry
ratio
additive
1
2
3
4
5
6
7
8
9
Cu(II)
Cu(II)
Cu(II)
Cu(II)
Cu(II)
Zn(II)
Mg(II) Sm
Ni(II)
Rh(II)
La
Pr
Sm
Eu
Dy
Sm
1:1:1
1:1:1
1:1:1
1:1:1
1:1:1
1:1:1
1:1:1
1:1:1
1:1:1
1:0:1
1:0:1
1:0:1
0:1:1
none
none
none
none
none
none
none
none
none
none
73 3:1
82 1:1
5
9
96 >20:1 80
93 >20:1 64
89 7:1
48
-
-
-
1d
-
-
1g
29g
3
0
0
0
-
-
-
Sm
Sm
-
-
-
Sm
Sm
Sm
Sm
Sm
Sm
90 1:3
As a part of our continuing project on asymmetric bifunctional
catalysis, we developed various heterobimetallic complexes using
BINOL derivatives as ligands.7 None of the metal-BINOLate
complexes screened, however, were suitable to realize a syn-
selective nitro-Mannich reaction. Therefore, we screened other chiral
scaffolds that can incorporate two different metals and found that
the dinucleating Schiff base ligand 3 (Scheme 1) was a promising
candidate.8 The initial optimization studies with N-Boc imine 4a
and nitroethane 5a are summarized in Table 1.9,10 The combination
of Cu(OAc)2 and La(O-iPr)3 with ligand 3 afforded product 2aa
slightly in favor of the syn-isomer (entry 1, syn/anti ) 3:1), despite
poor enantioselectivity (5% ee). Rare earth metals affected both
syn-selectivity and enantioselectivity (entries 1-5), and Sm(O-iPr)3
gave the best selectivity (entry 3, syn/anti ) >20:1, 80% ee). Cu-
(II) was also essential to realize high selectivity and good reactivity
(entry 3 vs entries 6-9). Neither Cu(OAc)2 nor Sm(O-iPr)3 alone
gave good results (entries 10 and 13). Cu(II)-Lewis acid in the
presence of amine base resulted in poor reactivity (entry 11, 20
mol % of amine, 0% yield) and selectivity (entry 12, 1 equiv of
amine, 24% yield, 1% ee, syn/anti ) 2/1), implying the importance
of Sm(O-iPr)3. The ratio of Cu/Sm/ligand 3 was also critical for
good selectivity (entry 3 vs entries 14 and 15). To further improve
the enantioselectivity, achiral additives were screened, and phenol
showed positive effects (entry 16, 85% ee). Further screening of
phenolic additives revealed that 4-tBu-phenol gave the best results
10 Cu(II)
11 Cu(II)
12 Cu(II)
0
0
-
-
iPr2NEte
iPr2NEtf
none
24 2:1
14 2:1
14 16:1
90 7:1
13
-
14 Cu(II)
15 Cu(II)
16 Cu(II)
17 Cu(II)
18 Cu(II)
1:0.5:1 none
1:2:1
1:1:1
1:1:1
1:1:1
none
3
phenolh
81 >20:1 85
2,6-(tBu)2-phenolh 91 >20:1 76
4-tBu-phenolh
96 >20:1 94
a M1(OAc)2 was used. b M2(O-iPr)3 was used. c Diastereomeric ratio was
determined by 1H NMR analysis. d Enantiomeric excess of anti-isomer.e 20
mol % of iPr2NEt was used. f 100 mol % of iPr2NEt was used. g (S,S)-
Enantiomer was major. h 10 mol % of ArOH was used.
(entries 16-18).9 Under the optimized conditions, 2aa was obtained
in 96% yield, syn/anti ) >20:1, and 94% ee (entry 18).
The heterobimetallic Cu/Sm/3 complex with a 4-tBu-phenol
additive was applicable to various N-Boc imines (Table 2).10 Aryl
imines with either an electron-donating substituent or an electron-
withdrawing substituent, as well as heteroaryl imine 4g, afforded
the products in high syn-selectivity and ee (entries 3-7).11 Readily
isomerizable alkyl Boc imine 4h12 was also applicable, giving the
product in good ee (entry 7). High syn-selectivity was also achieved
with nitropropane 5b (entries 9-11). Catalyst loading was suc-
cessfully reduced to 5 and 2.5 mol % without any loss of
stereoselectivity. With 2.5 mol % of catalyst, nitro-Mannich adduct
2aa was obtained in 99% yield, syn:anti ) >20:1, and 97% ee
9
4900
J. AM. CHEM. SOC. 2007, 129, 4900-4901
10.1021/ja0701560 CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Table 2. syn-Selective Catalytic Asymmetric Nitro-Mannich
Reactions with Various N-Boc Imines 4a
Cu and Sm metals were essential to realize high syn-selectivity.
Further mechanistic studies as well as applications of the present
heterobimetallic catalyst to other asymmetric reactions are in
progress.
Acknowledgment. This work was supported by Grant-in-Aid
for Specially Promoted Research and Grant-in-Aid for Encourage-
ments for Young Scientists from JSPS and MEXT. We thank Dr.
T. Ohshima for his advice at the initial stage of this work.
time yieldb
drc
% ee
entry
imine (R)
nitroalkane product
(h)
(%)
(syn/anti) (syn)
1
C6H5- (4a)
5a
5a
5a
5a
5a
5a
5a
5a
5b
5b
5b
5a
5a
2aa
2ba
2ca
2da
2ea
2fa
2ga
2ha
2ab
2cb
2eb
2aa
2aa
23
48
48
48
48
48
48
48
44
48
48
44
72
96
87
90
77
87
81
71
62
84
68
64
92
99
>20:1 94
>20:1 93
>20:1 98
>20:1 96
>20:1 94
>20:1 90
>20:1 91
>20:1 83
>20:1 88
>20:1 95
>20:1 91
>20:1 96
>20:1 97
Supporting Information Available: Experimental procedures,
spectra data of the new compounds, determination of relative and
absolute configurations, and ESI-MS data. This material is available
free of charge via the Internet at http://pubs.acs.org.
2d 2-naphthyl- (4b)
3
4
5
6
4-Me-C6H4- (4c)
3-Me-C6H4- (4d)
4-MeO-C6H4- (4e)
4-Cl-C6H4- (4f)
7d 2-furyl (4g)
References
8d C6H5CH2CH2- (4h)
9d C6H5- (4a)
(1) A review of catalytic asymmetric nitro-Mannich reactions: Westermann,
B. Angew. Chem., Int. Ed. 2003, 42, 151.
10 4-Me-C6H4- (4c)
11 4-MeO-C6H4- (4e)
12e C6H5- (4a)
(2) With nitromethane: (a) Yamada, K.-I.; Harwood, S. J.; Gro¨ger, H.;
Shibasaki, M. Angew. Chem., Int. Ed. 1999, 38, 3504. With nitroalkanes:
(b) Yamada, K.-I.; Moll, G.; Shibasaki, M. Synlett 2001, 980.
(3) Nitro-Mannich reaction of R-imino esters with nitroalkanes: (a) Nishiwaki,
N.; Knudsen, K. R.; Gothelf, K. V.; Jørgensen, K. A. Angew. Chem., Int.
Ed. 2001, 40, 2992. With preformed silyl nitronates: (b) Knudsen, K.
R.; Risgaard, T.; Nishiwaki, N.; Gothelf, K. V.; Jørgensen, K. A. J. Am.
Chem. Soc. 2001, 123, 5843. (c) Anderson, J. C.; Howell, G. P.; Lawrence,
R. M.; Wilson, C. S. J. Org. Chem. 2005, 70, 5665. For a related example
using tert-butyl 2-nitropropanoate as a nucleophile, see: (d) Knudsen, K.
R.; Jørgensen, K. A. Org. Biomol. Chem. 2005, 3, 1362.
13f C6H5- (4a)
a Reaction was performed in THF (0.2 M on imines 4) at -40 °C using
10 mol % of Cu/Sm/3 complex and 10 mol % of 4-tBu-phenol unless
otherwise noted. b Isolated yield. c Diastereomeric ratio was determined by
1H NMR analysis. Minor anti-isomer was not detected on 1H NMR (>20:1
dr). d Reaction was run at -50 °C. e 5 mol % of Cu/Sm/3 complex was
used. f 2.5 mol % of Cu/Sm/3 complex and 5 mol % of 4-tBu-phenol were
used.
(4) Highly anti-selective catalytic asymmetric nitro-Mannich reactions with
thioureas: (a) Yoon, T. P.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2005,
44, 466. (b) Xu, X.; Furukawa, T.; Okino, T.; Miyabe, H.; Takemoto, Y.
Chem.sEur. J. 2006, 12, 466. With a chiral proton catalyst: (c) Nugent,
B. M.; Yoder, R. A.; Johnston, J. N. J. Am. Chem. Soc. 2004, 126, 3418.
With cinchona alkaloids: (d) Palomo, C.; Oiarbide, M.; Laso, A.; Lo´pez,
R. J. Am. Chem. Soc. 2005, 127, 17622.
Scheme 2 . Conversion to syn-1,2-Diaminea
(5) For other selected examples of enantioselective nitro-Mannich reactions
with nitromethane, see: (a) Okino, T.; Nakamura, S.; Furukawa, T.;
Takemoto, Y. Org. Lett. 2004, 6, 625. In ref 5a, nitroethane is also utilized
(one example). (b) Lee, A.; Kim, W.; Lee, J.; Hyeon, T.; Kim, B. M.
Tetrahedron: Asymmetry 2004, 15, 2595. (c) Fini, F.; Sgarzani, V.;
Pettersen, D.; Herrera, R. P.; Bernardi, L.; Ricci, A. Angew. Chem., Int.
Ed. 2005, 44, 7975. (d) Bernardi, L.; Fini, F.; Herrera, R. P.; Ricci, A.;
Sgarzani, V. Tetrahedron 2006, 62, 375. (e) Palomo, C.; Oiarbide, M.;
Halder, R.; Laso, A.; Lo´pez, R. Angew. Chem., Int. Ed. 2006, 45, 117. (f)
Gao, F.; Zhu, J.; Tang, Y.; Deng, M.; Qian, C. Chirality 2006, 18, 741.
(6) In this paper, we call â-nitroamine 1 as anti-isomer and 2 as syn-isomer.
(7) Reviews for bifunctional asymmetric catalysis using metal-BINOLate
complexes: (a) Shibasaki, M.; Yoshikawa, N. Chem. ReV. 2002, 102, 2187.
(b) Shibasaki, M.; Matsunaga, S. Chem. Soc. ReV. 2006, 35, 269.
(8) For related attempts to develop bifunctional asymmetric catalysts using
heterobimetallic Schiff base complexes, see: (a) Annamalai, V.; DiMauro,
E. F.; Carroll, P. J.; Kozlowski, M. C. J. Org. Chem. 2003, 68, 1973 and
references therein. See also: (b) Sammis, G. M.; Danjo, H.; Jacobsen, E.
N. J. Am. Chem. Soc. 2004, 126, 9928. (c) Li, W.; Thakur, S. S.; Chen,
S.-W.; Shin, C.-K.; Kawthekar, R. B.; Kim, G.-J. Tetrahedron Lett. 2006,
47, 3453 and references therein.
(9) For more detailed results of optimization studies (metal effects, additive
effects, and M1/M2/ligand ratio effects), see Supporting Information. In
the initial screening, N-Boc imines gave better results than other imines
such as N-diphenylphosphinoyl imine and N-Ts imine.
(10) For determination of relative and absolute configurations of products in
Tables 1 and 2, see Supporting Information.
(11) When using aryl imine with an ortho-substituent (R ) 2-Me-C6H4), the
reaction did not proceed cleanly under the present reaction conditions.
Product was obtained in low yield (25% yield).
(12) Synthesis of aliphatic Boc imines: (a) Song, J.; Wang, Y.; Deng, L. J.
Am. Chem. Soc. 2006, 128, 6048. (b) Trost, B. M.; Jaratjaroonphong, J.;
Reutrakul, V. J. Am. Chem. Soc. 2006, 128, 2778. See also refs 4d and
5c.
(13) For more detailed results of ESI-MS analysis and discussion, see
Supporting Information.
(14) The structures of related heterobimetallic Cu-rare earth metal-Schiff
base complexes were unequivocally determined by X-ray crystallographic
analysis. See: (a) Koner, R.; Lee, G.-H.; Wang, Y.; Wei, H.-H.; Mohanta,
S. Eur. J. Inorg. Chem. 2005, 1500. (b) Benelli, C.; Guerriero, P.;
Tamburini, S.; Vigato, P. A. Mater. Chem. Phys. 1992, 31, 137 and
references therein. Inner N2O2 cavity of a dinucleating ligand is occupied
by Cu(II), while rare earth metal occupies the outer O2O2 position.
(15) Postulated reaction mechanism and transition state model for the syn-
isomer are described in Supporting Information.
a Reagents and conditions: (a) NaBH4, NiCl2‚6H2O, MeOH, 0 °C, 15
min, 99%; (b) Ac2O, Et3N, CH2Cl2, rt, 30 min, 98%.
(entry 13). To demonstrate the utility of â-nitroamine products, 2aa
was successfully converted into syn-1,2-diamine 6 in 99% yield
without epimerization using NaBH4 and NiCl2 (Scheme 2).
In the present reaction, both Cu(OAc)2 and Sm(O-iPr)3 were
essential for good reactivity and selectivity. The 1:1 ratio of Cu-
(II) and Sm was also crucial (Table 1),9 and the addition of 4-tBu-
phenol had beneficial effects on enantioselectivity. Sterically
hindered 2,6-(tBu)2-phenol was not effective as an additive (Table
1, entry 17), suggesting that 4-tBu-phenol would work not as a
simple proton source but as an achiral ligand. In ESI-MS analysis,13
peaks corresponding to a Cu/Sm/3 complex trimer and oligomers
were observed in the absence of 4-tBu-phenol. With 4-tBu-phenol,
a new peak corresponding to a monomeric Cu/Sm/3 ) 1:1:1
complex was observed. On the basis of the ESI-MS analysis, as
well as previous reports of related heterobimetallic Cu/rare earth
metal/Schiff base complexes,14 we assumed that a monomeric Cu/
Sm/3/4-tBu-phenol ) 1:1:1:1 complex (Scheme 1) would be the
active species. At the moment, we believe that the bimetallic Cu-
Sm system, aligned suitably in dinucleating ligand 3, would play a
key role for high stereoselectivity. Further mechanistic studies to
clarify the precise role of each metal, reaction mechanism, and
origin of syn-selectivity are ongoing.15
In summary, we achieved syn-selective catalytic asymmetric
nitro-Mannich reactions using a heterobimetallic Cu/Sm/Schiff base
ligand 3. The present method is complementary to the previously
reported methods, and products were obtained in high syn-selectivity
(>20:1), yield (99-62%), and enantioselectivity (98-83% ee). Both
JA0701560
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J. AM. CHEM. SOC. VOL. 129, NO. 16, 2007 4901