Chiral calcium iodide for asymmetric mannich-type reactions of malonates with imines providing β-aminocarbonyl compounds

Full text of DOI:10.1002/asia.201300102

COMMUNICATION
DOI: 10.1002/asia.201300102
Chiral Calcium Iodide for Asymmetric Mannich-type Reactions of Malonates
with Imines Providing b-Aminocarbonyl Compounds
[
a]
Tetsu Tsubogo, Shota Shimizu, and Sh u¯ Kobayashi*
The use of ubiquitously occurring elements is of current
interest because of the scarcity of precious metals. Calcium
ever, substrates have been limited to aromatic imines in
most cases. For aliphatic imines, there are only a few suc-
cessful examples, while some organocatalysts, sometimes
with relatively high loadings, have recently been employed
(
Ca) is one of the most promising elements; it is the fifth
[1]
most abundant element in the earthꢀs crust, and is nontox-
ic and inexpensive. In the periodic table, it belongs to
group 2 and has a unique character compared with the
group 1 and 3 elements; it has both Brønsted basicity and
Lewis acidity. In organic synthesis, however, uses of Ca as
either reagent or catalyst have been very limited. Recently,
[8a,b]
in those reactions.
We focused on chiral Ca halides as
potential chiral catalysts of asymmetric Mannich-type reac-
tions and found that chiral CaI catalysts were effective for
2
[2]
the reactions.
[1]
First, we investigated the Mannich-type reaction of the
imine 1a derived from benzaldehyde with benzyl malonate.
An initial trial was conducted using calcium triflate, a typical
Lewis acid, and pybox 3a (pybox=2,6-bis(2-oxazolinyl)pyri-
dine), and a moderate yield with moderate enantioselectivi-
ty was obtained (Table 1, entry 1). After screening several
Ca salts, such as Ca halides, nitrate, carbonate, etc., it was
we and other groups have shown the use of chiral Ca cata-
[1]
lysts in asymmetric CÀC bond-forming reactions. For ex-
ample, we have developed chiral Ca alkoxides and phenox-
ides in asymmetric 1,4-additions and [3+2]-cycloaddition re-
actions of glycine Schiff bases with a,b-unsaturated carbonyl
[3]
compounds. In these reactions, the Brønsted basicity of
the Ca catalysts plays a key role. On the other hand, we
have been interested in Ca halides and the use of their
[10,11]
found that calcium iodide (CaI2)
gave the best enantio-
selectivity (entry 2). Conducting the reaction at higher tem-
perature decreased the enantioselectivity because of a nonca-
talyzed reaction (entry 3). We then examined other solvents.
While lower enantiomeric excesses were obtained using di-
chloromethane (DCM), tetrahydrofuran (THF), and aceto-
nitrile (entries 4, 5, and 7), diethyl ether provided good
enantioselectivity (90.5:9.5 e.r., entry 6). After screening
[4]
Lewis acidity in asymmetric catalysis. Herein, we describe
for the first time a chiral calcium iodide (CaI ) catalyst and
2
its use in asymmetric Mannich-type reactions of malonates
with imines affording b-aminocarbonyl compounds.
Catalytic asymmetric Mannich-type reactions provide b-
[5]
amino acid derivatives, which are biologically important
compounds in peptide synthesis and other reactions. To
obtain b-amino acid derivatives, diastereoselective ap-
equivalents of CaI , pybox, and triethylamine, it was found
2
that 10 mol% CaI , 15 mol% pybox, and 60 mol% triethyla-
2
[6]
proaches starting from chiral a-amino acids have conven-
tionally been employed. In catalytic asymmetric reactions,
Mannich-type reactions of imines with enolate equivalents
mine gave the best enantioselectivity, and the product was
obtained in 96:4 e.r. (entry 10). Further optimizations ena-
bled the asymmetric reaction to be conducted using 5 mol%
of the catalyst and slow addition of the imine without signif-
icant decrease in the product yield and enantioselectivity
(entry 11). Furthermore, the reaction proceeded under air
without any significant loss of yield and enantioselectivity
(entry 12). We then conducted the reaction of the aliphatic
imine 1b derived from pentanal. The reaction proceeded
smoothly under the conditions to afford the desired product
in 72% yield with 82.5:17.5 e.r. (entry 13). To improve the
enantioselectivity, several pybox ligands were screened, and
[7]
such as silicon enolates are well established with chiral
metal complexes or organocatalysts. More recently, asym-
[8]
metric Mannich-type reactions of malonates with imines
have been studied. In these reactions, malonates have an ad-
vantage over enolate equivalents in terms of availability,
and give the corresponding b-aminocarbonyl compounds,
which can be readily converted into free b-amino acids in
[9]
a few steps. However, successful examples of asymmetric
[8]
[8m]
Mannich-type reactions of malonates are limited. Ni,
[
8l,n]
[8o]
[3e]
Pd,
Mg, and Ca catalysts have been reported; how-
it was found that anti-Ph - and anti-MePh-pybox ligands (3d
2
and 3e, respectively) resulted in better enantioselectivities
of up to 91:9 e.r. (entries 16 and 17). Finally, the desired
product was obtained in higher enantioselectivity using anti-
MePh-pybox (3e) in diethyl ether (entry 18).
We then surveyed the substrate scope of these chiral CaI2-
catalyzed asymmetric Mannich-type reactions. First, aromat-
ic imine substrates were investigated (Table 2). When we in-
vestigated the substitution positions of the benzene ring of
[
a] Dr. T. Tsubogo, S. Shimizu, Prof. Dr. S. Kobayashi
Department of Chemistry, School of Science
The University of Tokyo
Hongo 7-3-1, Bunkyo-ku, Tokyo, 113-0033 (Japan)
Fax : (+81)3-5684-0634
E-mail: shu_kobayashi@chem.s.u-tokyo.ac.jp
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201300102.
Chem. Asian J. 2013, 8, 872 – 876
872
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.chemasianj.org
Sh u¯ Kobayashi et al.
Table 1. Optimization of reaction conditions.
Table 2. Substrate scope for aryl imines.
Entry
Ar
Product
Yield [%]
e.r.
Entry
1
Conditions
x
y
Product Yield [%] e.r.
[
a]
1
2
3
4
5
6
7
8
9
1
1
1
1
Ph
o-MeC
4a
4c
4d
4e
4 f
4g
4h
4h
4i
89
86
91
89
71
66
87
90
88
91
82
84
95
96:4
92:8
94:6
96:4
90.5:9.5
92:8
96.5:3.5
95:5
[
a]
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
Tol, 3a
Tol, 3a
Tol, 3a
DCM, 3a
THF, 3a
10 10 4a
10 10 4a
10 10 4a
10 10 4a
10 10 4a
10 10 4a
10 10 4a
10 10 4a
10 10 4a
10 60 4a
5
5
5
5
5
5
5
5
57
78
85
82
87
50
81
81
81
79
89
84
72
77
72
76
62
62
71:29
[a,b]
[a]
6
H
4
94.5:5.5
88.5:11.5
84.5:15.5
56.5:43.5
90.5:9.5
77.5:22.5
75.5:24.5
94:6
96:4
96:4
96:4
82.5:17.5
76:24
m-MeC
p-MeC
p-MeOC
3,4-(OCH
p-ClC
p-ClC
p-FC
m-CF
p-CF
2-naphthyl
2-naphthyl
6
H
4
[
b]
[a]
6
H
4
[c]
6
H
4
[a]
2
6 3
O)C H
Et
2
O, 3a
[c]
[
[
[
b]
c]
d]
6
H
H
4
MeCN, 3a
Tol, 3a
Tol, 3a
Tol, 3a
Tol, 3a
Tol, 3a
[c,d]
[c]
6
4
6
H
4
96:4
[a]
0
1
2
3
3
C
6
H
4
4j
4k
4l
94.5:5.5
95.5:4.5
97:3
0
1
2
3
4
5
6
7
8
[c]
[
[
[
[
[
[
[
[
e]
f]
3
C
6
H
4
30 4a
30 4a
30 4b
30 4b
30 4b
30 4b
30 4b
30 4b
[e]
[e,f]
[g]
4l
98:2 (98.5:1.5)
e]
e]
e]
e]
g]
h]
1b Tol, 3a
1b Tol, 3b
1b Tol, 3c
1b Tol, 3d
1b Tol, 3e
[g]
(
88)
[a]
[a]
1
1
4
5
2-furyl
2-thienyl
4m
4n
99
76
96:4
93:7
74:26
90:10
91:9
94:6
[a] Slow addition of imine over 14 h. [b] Diethyl ether was used. [c] Slow
addition of imine over 7 h. [d] Catalyst (2 mol%). [e] Slow addition of
imine over 6 h. [f] Gram scale (1.51 g was obtained). [g] After recrystalli-
zation.
1b Et
(OTf)
e] Slow addition of imine over 14 h. [f] Slow addition of imine over 14 h.
2
O, 3e
[
[
a] Ca
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
2
. [b] À408C. [c] 10 mol% of pybox. [d] 20 mol% of pybox.
Under air. [g] Slow addition of imine over 14 h. The opposite enantiomer
was obtained. [h] Slow addition of imine over 14 h. The opposite enantio-
mer was obtained after 48 h.
loading. In the presence of 2 mol% of the catalyst, the cor-
responding product was obtained in high yield with 95:5 e.r.
(
entry 8).
Next, we investigated imines derived from aliphatic alde-
hydes, and the results are summarized in Table 3. We tested
several n-alkyl aldehyde-derived imines, and the products
were obtained in moderate to good yields with high enantio-
Table 3. Substrate scope for aliphatic imines.
the benzaldehyde-derived imines, high yields and high enan-
tioselectivities were observed in all cases; in particular, the
para-tolylaldehyde-derived substrate gave the best enantio-
selectivity (entries 2–4). Then, we investigated imines de-
rived from benzaldehyde derivatives bearing electron-donat-
ing and -withdrawing substituents. Aryl imines with elec-
tron-rich substituents gave good to high yields with high
enantioselectivities (entries 2–6). When para-halogenated
benzaldehyde-derived imines were employed, the enantiose-
lectivities of the products were also high (entries 7 and 9).
We further examined trifluoromethyl benzaldehyde-derived
imines, which resulted in high enantioselectivities as well
Entry
R
Conditions
Product
Yield [%]
e.r.
1
2
3
4
5
6
Et
nPr
nBu
nPentyl
Ph
Tol, 3d
4o
4p
4b
4q
4r
64
48
62
53
53
57
95.5:4.5
94.5:5.5
94:6
[a]
Et
Et
Et
Et
Et
2
O, 3e
2
O, 3e
2
O, 3e
2
O, 3e
2
O, 3e
[b]
[a]
[
[
a]
a]
93.5:6.5
[
a]
A
H
U
G
R
N
U
(CH
2
)
2
91:9
96.5:3.5
iBu
4s
[
a] The opposite enantiomer was observed. [b] 48 h.
(
entries 10 and 11). The 2-naphthylaldehyde-derived imine
gave the best enantioselectivities (entries 12 and 13). It is
noted that a gram-scale experiment was also performed, and
the desired product was obtained in high yield with high
enantioselectivity (entry 13). The imines derived from heter-
oaromatic aldehydes were also investigated. In the case of
the 2-furylaldehyde-derived imine, the enantioselectivity
was high (entry 14). When we used the 2-thienylaldehyde-
derived imine, the enantioselectivity of the product was still
high (entry 15). Finally, we attempted to reduce the catalyst
selectivities (entries 1–4). Interestingly, the propionalde-
hyde-derived imine, one of the most difficult substrates be-
cause of side reactions, gave the second highest enantiose-
lectivity among the aliphatic substrates tested (entry 1). The
imine derived from 3-phenylpropanal could be applied to
the Mannich-type reaction, affording the corresponding
adduct in 53% yield with 91:9 e.r. (entry 5). In the case of
Chem. Asian J. 2013, 8, 872 – 876
873
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

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Sh u¯ Kobayashi et al.
a b-branched imine, the imine derived from isovaleralde-
hyde, the desired b-amino carbonyl product was obtained in
the Ca/pybox/malonate (1:1:1) complex ((pybox)·CaI ·2
2
(D)). It is noted that both the 1:1 complex (A) and the 1:2
complex (B) were converted into only one complex (D)
after the addition of malonate 2. This assumption corre-
sponds to the experimental results that both 15 mol% and
20 mol% of pybox afforded the same results (Table 1, en-
tries 2 and 9). The new resonances derived from the Ca/
pybox/malonate (1:1:1) complex were also observed in tolu-
ene-d8 (see the Supporting Information). We then added
96.5:3.5 e.r. (entry 6). Thus, we could establish a wide sub-
strate scope of chiral CaI -catalyzed asymmetric Mannich-
2
type reactions.
NMR studies were conducted to obtain information on
the CaI –pybox catalyst. For the NMR studies, acetonitrile-
2
d was used as a solvent instead of toluene-d because of the
3
8
1
13
solubility of the Ca catalysts. H and C NMR resonances of
the Ca complexes in toluene-d were weak; however, they
Et N (1 equiv) to the solution and recorded the NMR spec-
3
8
almost corresponded to those in acetonitrile-d . NMR charts
trum. The resonances of enolate complex E appeared; how-
ever, complex D still remained. The addition of an excess
3
of several ratios of CaI to pybox are shown in the Support-
2
ing Information. When a 1:1 ratio of CaI to pybox was
amount of Et N to the solution provided almost one species
2
3
used, (pybox)·CaI (A), in which two iodides, pybox, and
(see the Supporting Information), which was assigned as the
Ca/pybox/enolate complex ((pybox)·CaI·(2) (E)). These
2
[12]
À
acetonitrile-d3 are ligands,
might be formed (Figure 1).
observations also correspond to the experimental results
that an excess amount of Et N was necessary for high per-
3
formance of the catalyst (Table 1, entry 10).
Finally, we transformed the obtained Mannich product
[15]
(
4a) to a b-amino acid derivative (Scheme 1).
b-Amino
acid derivatives are important in the synthesis of drugs and
Figure 1. Assumed catalyst species.
Scheme 1. Transformations of a Mannich product.
Judging from the NMR spectrum, the formation of A was
incomplete, and this corresponds to the lower enantioselec-
tivity in the experiment (see Table 1, entry 8). In addition,
other resonances were observed in the chart, and we as-
sumed the formation of dinuclear complex C under equilib-
peptides, including the well-known taxol derivatives bearing
b-amino acid skeletons, which have hydroxy groups at the
a-position. We therefore focused on the synthesis of a-hy-
droxy b-amino acid derivatives from the Mannich product
(4a). Some transformations of Mannich adducts derived
[13]
rium conditions. On the other hand, only the 1:2 complex,
pybox) ·CaI (B), was obtained when 1:2 and 1:3 ratios of
[9]
(
from malonates have already been reported; however,
2
2
CaI to pybox were combined (see the Supporting Informa-
tion). Complex B has eight coordination sites occupied by
transformations to a-hydroxy b-amino acids have not been
discussed. We succeeded in introducing a hydroxy group
2
[16]
two iodides and two pybox. A complex containing one calci-
at the a-position of the malonate derivative 4a using Davis
[17]
um perchlorate and two pybox ((pybox) ·Ca
cently been reported and characterized by X-ray crystallo-
A
H
U
G
R
N
U
G
oxaziridine,
thereby affording the desired product 5 in
2
4 2
[14]
high yield without any loss of enantioselectivity. After this
transformation, deprotection, decarboxylation, and esterifi-
cation were conducted to afford the desired a-hydroxy b-
amino acid derivative 6 in good yield (three steps) with high
enantioselectivity.
graphic analysis. When a 1:1.5 ratio of CaI to pybox was
2
used, two complexes, (pybox)·CaI (A) and (pybox) ·CaI
2
2
2
(
B), were observed (see the Supporting Information). We
have already shown that the 1:1.5 ratio of CaI to pybox was
2
important for obtaining high enantioselectivity (Table 1,
entry 2). We then added malonate 2 to this solution and re-
corded the NMR spectrum (see the Supporting Informa-
tion), which showed one species, which might be assigned as
In conclusion, we have developed a novel chiral calcium
iodide catalyst prepared from CaI and pybox that is stable
2
under moisture and oxygen. This catalyst was applied to cat-
alytic asymmetric Mannich-type reactions of malonates with
Chem. Asian J. 2013, 8, 872 – 876
874
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.chemasianj.org
Sh u¯ Kobayashi et al.
both N-Boc-protected aromatic and aliphatic imines, and
gave moderate to high yields with high enantioselectivities.
To the best of our knowledge, this is the first example of
highly enantioselective metal-catalyzed asymmetric Man-
nich-type reactions of malonates with N-Boc-protected ali-
phatic imines. The Mannich adduct was successfully convert-
ed into an a-hydroxy b-amino acid derivative. We have also
shown the unique structure of the chiral Ca complexes with
malonates. Further investigations of other reactions using
these types of calcium catalysts are now in progress.
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[
1
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[
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[
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(
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2
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1
0
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.9m toluene solution) were added successively. After the reaction mix-
ture was heated at 808C for 0.5 h, it was cooled to À788C; subsequently,
an imine solution (1a, 0.30 mmol, 0.70 mL of 0.43m toluene solution) was
slowly added over 14 h. After the addition, the mixture was stirred for
another 10 h at the same temperature and then quenched with saturated
[
ammonium chloride (NH
added, and the organic layer was separated. The aqueous layer was ex-
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4
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1
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2
2
2
4
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2
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Acknowledgements
This work was partially supported by a Grant-in-Aid for Scientific Re-
search from the Japan Society for the Promotion of Science (JSPS) and
the Japan Science and Technology Agency (JST).
Keywords: air-stable catalysts · alkaline earth metals ·
calcium iodide · CÀC bond formation · Mannich-type
2
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[
[
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