A stable homodinuclear biscobalt(III)-Schiff base complex for catalytic asymmetric 1,4-addition reactions of β-keto esters to alkynones

Article abstract of DOI:10.1002/anie.200805967

(Chemical Equation Presented) Two metal cooperation: A homodinuclear Co²-Schiff base complex Co²(OAc)²-1 promoted the asymmetric 1,4-addition of β-keto esters to alkynones under solvent-free conditions in air (see scheme).

Full text of DOI:10.1002/anie.200805967

Communications
DOI: 10.1002/anie.200805967
Asymmetric Synthesis
A Stable Homodinuclear Biscobalt(III)–Schiff Base Complex for
Catalytic Asymmetric 1,4-Addition Reactions of b-Keto Esters to
Alkynones**
Zhihua Chen, Makoto Furutachi, Yuko Kato, Shigeki Matsunaga,* and Masakatsu Shibasaki*
Bifunctional cooperative asymmetric catalysis is currently a
popular research topic in organic synthesis. Various bifunc-
tional metal and organocatalysts have been reported during
the last decade.[1] As part of our ongoing research into this
issue, we recently reported the utility of cooperative bimet-
allic complexes of the Schiff base 1 (Scheme 1),[2–5] the
catalytic properties of which differed from those of well-
established monometallic salen complexes.[6] Combined com-
plexes of Cu/Sm,[2] Pd/La,[3] and Ni/Ni[4] were utilized for
enantioselective 1,2-addition reactions, such as nitro-Man-
nich[2,4] and nitroaldol reactions.[3] Herein, we report studies
on the further expansion of the scope of bimetallic Schiff base
catalysis to 1,4-addition reactions with electron-deficient
alkynes. In contrast to 1,4-addition reactions to electron-
deficient alkenes,[7] catalytic enantioselective a-alkenylation
reactions by addition to electron-deficient alkynes are rare.[8]
À
The utility of products with a C C double bond that can be
further functionalized makes the development of catalytic
asymmetric 1,4-addition reactions to alkynes highly desirable.
Jørgensen[8a] and Maruoka[8b] reported enantioselective 1,4-
addition reactions of 1,3-diketones to alkynones and a-
cyanoacetates to an alkynoate moiety. However, the asym-
Scheme 1. Structures of dinucleating Schiff base H4–1, salen ligands
2a–2c, and di- and mononuclear Schiff base complexes.
metric 1,4-addition of b-keto esters to alkynones has not been
reported to date. A new homodinuclear complex CoIII
-
2
(OAc)2–1 (Scheme 1) was suitable for the 1,4-addition of b-
keto esters to alkynones. Reactions performed with 2.5–0.25
mol% catalyst loading at ambient temperature afforded
products with high enantioselectivity (up to 99% ee).
To find a suitable metal combination for the 1,4-addition
reaction of b-keto ester 4, we selected alkynone 3a as a model
substrate. The catalyst screening results are summarized in
Table 1. A Ni2–1 complex (Scheme 1),[4] which was suitable
for 1,2-addition to imines, gave moderate enantioselectivity
(entry 3, 32% ee), while rare-earth-metal complexes gave
poor enantioselectivity (Table 1, entries 1 and 2). Among
other metals screened (Table 1, entries 4–6), the CoIII
-
2
(OAc)2–1 complex[9] gave product 5aa in 52% ee (entry 6).
By changing the ester moiety of the b-keto ester to a tert-butyl
group (Table 1, entry 7, 4b) and the solvent to iPr2O (entry 8),
the enantioselectivity improved to 97% ee, albeit in a modest
E/Z ratio. It is noteworthy that the reaction proceeded
without difficulty even under solvent-free conditions at room
temperature, to give product 5ab in 97% ee after 1 h
(entry 9). In Table 1, entries 8 and 9, high enantioselectivity
was observed both for the E isomer and Z isomer. Because
the absolute configurations of the E isomer and the Z isomer
were the same, we investigated a one-pot sequential asym-
metric 1,4-addition/isomerization process to obtain the prod-
uct 5ab in both a high E/Z ratio and with high enantiose-
lectivity. As shown in Table 1, entry 10, the first 1,4-addition
proceeded smoothly with 2.5 mol% catalyst under solvent-
free conditions within 4 h. Ph2MeP (30 mol%) was added to
the reaction mixture for isomerization after completion of the
1,4-addition reaction, to predominantly afford the E adduct
5ab in greater than 95% yield (calculated from the 1H NMR
spectrum) and with 96% ee.
[*] Z. Chen, M. Furutachi, Y. Kato, Dr. S. Matsunaga,
Prof. Dr. M. Shibasaki
Graduate School of Pharmaceutical Sciences
The University of Tokyo
Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan)
Fax: (+81)3-5684-5206
E-mail: smatsuna@mol.f.u-tokyo.ac.jp
mshibasa@mol.f.u-tokyo.ac.jp
Homepage: http://www.f.u-tokyo.ac.jp/~kanai/e_index.html
[**] This work was supported by a Grant-in-Aid for Scientific Research
(S) (to M.S.), for Scientific Research on Priority Areas (no.
20037010, Chemistry of Concerto Catalysis, to S.M.), and for
Encouragements for Young Scientists (A) (to S.M.) from JSPS and
MEXT.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200805967.
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Chemie
Table 1: Optimization of catalytic asymmetric 1,4-addition of b-keto ester 4 to alkynone 3a using
complexes of dinuclear Schiff base 1.
95% ee) under the optimized reac-
tion conditions. Both cyclic and
acyclic b-keto esters 4c–4g were
applicable to afford products in 99–
91% ee (Table 2, entries 7–11). The
catalyst loading could be success-
fully reduced to 0.25 mol%, while
maintaining high enantioselectivity
and reactivity (entry 12, 97% ee,
85% yield, 4 h).
Entry R, 4
M1
M2
Solvent Isomerization Cat.
t
E:Z[a] Yield ee
[mol%] [h]
[%][a] [%]
1
2
3
4
5
6
7
8
9
Me, 4a Cu
Me, 4a Pd
Me, 4a Ni
Me, 4a Zn
Me, 4a Cu
Me, 4a Co(OAc) Co(OAc) THF
tBu, 4b Co(OAc) Co(OAc) THF
tBu, 4b Co(OAc) Co(OAc) iPr2O
tBu, 4b Co(OAc) Co(OAc) neat
tBu, 4b Co(OAc) Co(OAc) neat
Sm(OiPr) THF
La(OiPr) THF
–
–
–
–
–
–
–
–
–
5
5
5
5
5
5
5
5
5
12 1:1
76
47
95
1[b]
A
preliminary investigation
12 1:1
12 3:1
12 n.d.
12 n.d.
12 3:1
12 2:1
12 3:1
14[b]
revealed that the bimetallic Co2-
(OAc)2–1 catalyst was also applica-
ble to an electron-deficient alke-
ne.[7c] As shown in Table 3, the
reaction of nitroalkene 6 with b-
keto ester 4a was successfully per-
formed with 2.5 mol% catalyst in
air and without solvent; high dia-
stereoselectivity and enantioselec-
tivity were achieved at room tem-
perature (Table 3, entry 1, drꢀ
30:1, 98% ee). Catalyst loading
Ni
Zn
Cu
THF
THF
THF
32[b]
trace n.d.
0
n.d.
>95 52[b]
>95 92[b]/89[c]
>95 97[b]/97[c]
>95 97[b]/97[c]
1
4
3:1
10
+(Ph2MeP)[d] 2.5
>30:1 >95 96[b]
[a] Yield and E/Z ratio were determined from the 1H NMR spectrum of the crude mixture.
[b] Enantioselectivity of the E isomer. [c] Enantioselectivity of the Z isomer. [d] After the 1,4-addition,
Ph2MeP (0.3 equiv) was added to the reaction mixture, which was then stirred for an additional 12 h at
RT for isomerization under solvent-free conditions.
The substrate scope of the one-pot sequential 1,4-addi-
tion/isomerization process is summarized in Table 2. Because
the bimetallic Co2(OAc)2–1 catalyst was stable towards air
and moisture, the catalyst that was stored in air at room
temperature for more than six months was used for the
procedures outlined in Table 2 without loss of reactivity and
enantioselectivity. In addition, the first 1,4-addition reaction
was successfully performed in air without solvent in all
entries.[10] Both alkyl–alkynyl ketones 3a and 3b (Table 2,
entries 1 and 2) and aryl–alkynyl ketones 3c–3 f (entries 3–6)
gave predominantly E adducts in high enantioselectivity (98–
was successfully reduced to 0.2–0.1 mol% at high concen-
trations (THF, 20m, Table 3, entries 2 and 3), while maintain-
ing high enantioselectivity. Pure 7a was isolated in 87% yield
and 99% ee only by recrystallization and without purification
by column chromatography (Table 3, entry 2).
The results of the control experiments in Table 4 implied
that two Co metal centers are essential for high enantiose-
lectivity and reactivity. The use of several different mono-
metallic CoIII(OAc)–salen complexes 2a–2c (Scheme 1)
resulted in poor yields and enantioselectivities of the prod-
ucts, which confirms the importance of the outer Co metal
Table 2: One-pot sequential catalytic asymmetric 1,4-addition/isomerization process with b-keto esters 4b–4g and alkynones 3a–3 f using
Co2(OAc)2–1.[a]
Entry
R1
3
4
Cat.
[mol%]
t
[h]
5
E/Z[b]
Yield[c]
[%]
ee[d]
[%]
1
2
3
4
5
6
7
8
Me
cyclohexyl
Ph
4-ClC6H4
4-MeOC6H4
3-thienyl
Ph
Ph
Ph
Me
Me
3a
3b
3c
3d
3e
3 f
3c
3c
3c
3a
3a
3a
4b
4b
4b
4b
4b
4b
4c
4d
4e
4 f
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
0.25
4
4
4
4
4
4
4
9
9
9
9
4
5ab
5bb
5cb
5db
5eb
5 fb
5cc
5cd
5ce
5af
>30:1
>30:1
>30:1
>30:1
>30:1
>30:1
>30:1
>30:1
>30:1
>30:1
>30:1
>30:1
92
92
93
91
93
96
95
83
94
75
92
85
96
95
95
96
98
95
91
96
99
97
96
97
9
10
11
12
4g
4b
5ag
5ab
Me
[a] 1,4-Addition reactions were performed under solvent-free conditions at room temperature (24–288C) in air with 1.1 equiv of 4. After the indicated
time for the 1,4-addition, Ph2MeP (0.3 equiv) was added to the reaction mixture, which was stirred for 4–12 h at RT under Ar. The absolute
configuration of 5cb was determined by comparing the sign of the optical rotation with the data reported in Ref. [8d]. [b] The E/Z ratio was determined
by 1H NMR spectroscopy. [c] Yield of isolated product after purification by column chromatography. [d] Enantioselectivity of the E isomer.
Angew. Chem. Int. Ed. 2009, 48, 2218 –2220
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Communications
Table 3: Catalytic asymmetric 1,4-addition of b-keto ester 4a to nitro-
Keywords: asymmetric catalysis · asymmetric synthesis · cobalt ·
conjugate addition · Schiff bases
.
alkene 6 using Co2(OAc)2–1.[a]
[1] For recent reviews on bifunctional asymmetric catalysis, see:
a) S. Matsunaga, M. Shibasaki, Bull. Chem. Soc. Jpn. 2008, 81,
60; b) S. Mukherjee, J. W. Yang, S. Hoffmann, B. List, Chem.
Rev. 2007, 107, 5471; c) M. S. Taylor, E. N. Jacobsen, Angew.
Chem. 2006, 118, 1550; Angew. Chem. Int. Ed. 2006, 45, 1520;
d) H. Yamamoto, K. Futatsugi, Angew. Chem. 2005, 117, 1958;
Angew. Chem. Int. Ed. 2005, 44, 1924.
Entry
Cat.
[mol%]
Solvent
t
[h]
d.r.[b]
Yield
[%]
ee
[%]
1
2
3
2.5
0.2
0.1
neat
THF (20m)
THF (20m)
6
24
48
>30:1
>30:1
16:1
94[c]
87[d]
98[c]
98
99
95
[2] S. Handa, V. Gnanadesikan, S. Matsunaga, M. Shibasaki, J. Am.
Chem. Soc. 2007, 129, 4900.
[3] a) S. Handa, K. Nagawa, Y. Sohtome, S. Matsunaga, M.
Shibasaki, Angew. Chem. 2008, 120, 3274; Angew. Chem. Int.
Ed. 2008, 47, 3230; b) Y. Sohtome, Y. Kato, S. Handa, N.
Aoyama, K. Nagawa, S. Matsunaga, M. Shibasaki, Org. Lett.
2008, 10, 2231.
[4] a) Z. Chen, H. Morimoto, S. Matsunaga, M. Shibasaki, J. Am.
Chem. Soc. 2008, 130, 2170; b) Z. Chen, K. Yakura, S.
Matsunaga, M. Shibasaki, Org. Lett. 2008, 10, 3239.
[5] For selected examples of related bifunctional bimetallic Schiff
base complexes in asymmetric catalysis, see: a) V. Annamalai,
E. F. DiMauro, P. J. Carroll, M. C. Kozlowski, J. Org. Chem.
2003, 68, 1973, and references therein; b) G. M. Sammis, H.
Danjo, E. N. Jacobsen, J. Am. Chem. Soc. 2004, 126, 9928; c) J.
Gao, F. R. Woolley, R. A. Zingaro, Org. Biomol. Chem. 2005, 3,
2126; d) W. Li, S. S. Thakur, S.-W. Chen, C.-K. Shin, R. B.
Kawthekar, G.-J. Kim, Tetrahedron Lett. 2006, 47, 3453.
[6] For reviews, see: a) T. Katsuki, Chem. Soc. Rev. 2004, 33, 437;
b) P. G. Cozzi, Chem. Soc. Rev. 2004, 33, 410; c) E. N. Jacobsen,
Acc. Chem. Res. 2000, 33, 421.
[a] 1,4-Addition reactions were performed under solvent-free conditions
at room temperature (24–288C) in air with 1.1 equiv of 4a. [b] The d.r.
value was determined by 1H NMR analysis. [c] Yield of isolated product
after purification by column chromatography. [d] 7a was obtained in pure
form by recrystallization of the crude product without purification by
column chromatography.
Table 4: Control experiments using mononuclear complexes CoIII(OAc)–
salen 2a–2c and heterodinuclear complex 1.[a]
Entry
Schiff base
M1
M2
Yield
[%]
ee
[%]
1
2
3
4
5
2a
2b
2c
1
Co(OAc)
Co(OAc)
Co(OAc)
Cu
none
none
none
Co(OAc)
Co(OAc)
0
56
0
66
67
n.d.
36
n.d.
10
[7] For reviews on asymmetric 1,4-addition to electron-deficient
alkenes with metal catalysis, see: a) J. Christoffers, G. Koripelly,
A. Rosiak, M. Rꢀssle, Synthesis 2007, 1279; with organocatalysis:
b) S. B. Tsogoeva, Eur. J. Org. Chem. 2007, 1701; for a review on
asymmetric 1,4-addition to nitroalkenes, see: c) O. M. Berner, L.
Tedeschi, D. Enders, Eur. J. Org. Chem. 2002, 1877.
[8] For the addition of 1,3-diketones to alkynones, see: a) M. Bella,
K. A. Jørgensen, J. Am. Chem. Soc. 2004, 126, 5672; for the
addition of a-cyanoacetates to an alkynoate, see: b) X. Wang, M.
Kitamura, K. Maruoka, J. Am. Chem. Soc. 2007, 129, 1038. For
other related work, see also c) R. Shintani, G. C. Fu, J. Am.
Chem. Soc. 2003, 125, 10778; for a-alkenylation by vinylic
substitution using vinyl halides, see d) T. B. Poulsen, L. Bernardi,
M. Bell, K. A. Jørgensen, Angew. Chem. 2006, 118, 6701; Angew.
Chem. Int. Ed. 2006, 45, 6551.
1
Pd
8
[a] 1,4-Addition reactions were performed under solvent-free conditions
at room temperature (24–288C) with 1.1 equiv of 4b. After 4 h for 1,4-
addition, Ph2MeP (0.3 equiv) was added to the reaction mixture, which
was then stirred for 12 h at RT.
center (Table 4, entries 1–3). In addition, heterobimetallic
Cu/Co(OAc)–1 (entry 4) and Pd/Co(OAc)–1 (entry 5) com-
plexes showed moderate reactivity and poor enantioselectiv-
ity, which suggests the importance of inner Co metal center
for good enantioselectivity. We believe that cooperative
functions of two Co metal centers are important;[11,12] further
mechanistic studies to clarify the functions of two Co metal
centers are underway.
In summary, we have developed a stable homodinuclear
Co2(OAc)2–Schiff base complex that expands the scope of
bimetallic cooperative Schiff base catalysis. The complex
Co2–1 was suitable for the 1,4-addition of b-keto esters to
alkynones and a nitroalkene. The reactions proceeded in high
yields and with high enantioselectivities at room temperature
under highly concentrated conditions (neat–20m) using 0.1–
2.5 mol% catalyst loading without air or moisture sensitiv-
ity.[10] Further mechanistic studies[12] as well as full details on
the substrate scope and limitations of electron-deficient
alkenes will be reported in due course.
[9] CoIII2(OAc)2–1 was synthesized from CoII(OAc)2 and Schiff base
H4–1 in EtOH at reflux in air. The structure was assigned to be
CoIII2(OAc)2–1·2H2O based on elemental analysis results.
[10] If necessary, the reactions reported in this manuscript can also be
performed in iPr2O (reactions in Table 2), and THF under dry
Ar (reactions in Table 3), to give products in comparable yields
and stereoselectivities.
[11] For intermolecular cooperative mechanism of monometallic Co–
salen complexes, see Ref. [6c] and references therein.
[12] Preliminary mechanistic studies showed a linear relationship
between the enantiomeric excess of Co2(OAc)2–1 catalyst and
product 5ab. An initial rate kinetic study using nitroalkene 6 and
b-keto ester 3a showed first-order dependency on the bimetallic
Co2(OAc)2–1 catalyst.
Received: December 8, 2008
Published online: February 9, 2009
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