Chiral-Zn(NTf2)2-complex-catalyzed diastereo- and enantioselective direct conjugate addition of arylacetonitriles to alkylidene malonates

Article abstract of DOI:10.1002/chem.201302122

Chiral N,N′-dioxide/Zn(NTf₂)₂ complexes were demonstrated to be highly effective in the direct asymmetric conjugate addition of arylacetonitriles to alkylidene malonates under mild conditions. A wide range of substrates were tolerated to afford their corresponding products in moderate-to-good yields with high diastereoselectivities (82:18->99:1 d.r.) and enantioselectivities (81-99 % ee). The reactions performed well, owing to the high Lewis acidity of the metal triflimidate and a ligand-acceleration effect. The N,N′-dioxide also benefited the deprotonation process as a Bronsted base. The catalytic reaction could be performed on the gram-scale with retention of yield, diastereoselectivity, and enantioselectivity. The products that contained functional groups were ready for further manipulation. In addition, a possible catalytic model was proposed to explain the origin of the asymmetric induction. Copyright

Full text of DOI:10.1002/chem.201302122

DOI: 10.1002/chem.201302122
Chiral-ZnACHTUNGTRENNUNG(NTf2)2-Complex-Catalyzed Diastereo- and Enantioselective Direct
Conjugate Addition of Arylacetonitriles to Alkylidene Malonates
Jingjing Yao, Xiaohua Liu,* Peng He, Yin Zhu, Xiangjin Lian, Lili Lin, and
Xiaoming Feng*[a]
Abstract:
A
Chiral
N,N’-dioxide/Zn-
enantioselectivities (81–99% ee). The
reactions performed well, owing to the
high Lewis acidity of the metal triflimi-
date and a ligand-acceleration effect.
The N,N’-dioxide also benefited the de-
protonation process as a Brønsted
base. The catalytic reaction could be
performed on the gram-scale with re-
tention of yield, diastereoselectivity,
and enantioselectivity. The products
that contained functional groups were
ready for further manipulation. In ad-
dition, a possible catalytic model was
proposed to explain the origin of the
asymmetric induction.
to be highly effective in the direct
asymmetric conjugate addition of aryl-
ACHTUNGTRENNUNGacetonitriles to alkylidene malonates
under mild conditions. A wide range of
substrates were tolerated to afford
their corresponding products in moder-
ate-to-good yields with high diastereo-
selectivities (82:18–>99:1 d.r.) and
Keywords: asymmetric catalysis
·
conjugate addition · enantioselectiv-
ity · ligand effects · zinc
Introduction
The addition reaction of carbanions that are stabilized by
electron-withdrawing nitrile groups is a useful method for
À
the formation of carbon carbon bonds. Moreover, this reac-
tion efficiently introduces nitrile groups, which are common
functional groups in various bioactive natural products and
pharmaceuticals.[1,2] The nitrile group could also undergo
transformation into other functional groups, such as amines,
amides, and carboxylic acids. Therefore, remarkable atten-
tion has been devoted to pursuing efficient methods for the
construction of various optically active cyano-containing
compounds. Nitrile-stabilized carbanions that are derived
from active methylene compounds that contain two elec-
tron-withdrawing groups, such as cyanoacetate esters,[3] ma-
lononitrile,[4] and cyano ketones,[5] have been extensively in-
vestigated in asymmetric nucleophilic addition reactions
(Scheme 1a). Comparatively, much less progress has been
made in the direct addition of aryl-substituted acetonitriles,
owing to the relatively weak acidity and coordination ability
of phenylacetonitrile.[6,8a] Strong bases or elevated tempera-
tures are required to grab the a protons.[7] One variant is the
incorporation of electron-poor aryl groups onto phenylace-
tonitrile, which increases the acidity of the a protons,[8,9]
Scheme 1. Representative strategies for the direct conjugate-addition re-
action of acetonitrile derivatives. EWG=electron-withdrawing group.
thereby allowing the direct nucleophilic addition reaction to
proceed under milder reaction conditions (Scheme 1b).
The pioneering work in the direct asymmetric conjugate-
addition reaction of nitrophenylacetonitriles to a,b-unsatu-
rated aldehydes was reported by Ruano and co-workers, by
using prolinol ethers as organocatalysts.[10] Up to 90% ee
values and moderate diastereoselectivities were achieved.
Subsequently, the Kim group achieved the corresponding re-
actions between a,b-unsaturated ketones and cinnamalde-
hyde in moderate diastereo- and enantioselectivities.[11]
However, efficient catalyst systems to expand the scope of
electrophiles and enhance the stereoselectivity are still desir-
able and challenging. Benzylidene malonates are classic Mi-
chael acceptors. Nevertheless, in the presence of a strong
base, the reaction of alkylidene malonates with electron-de-
ficient phenylacetonitriles resulted in the formation of a-cy-
anostilbene derivatives, instead of the desired adducts.[7c]
Herein, we report a direct asymmetric conjugate-addition
reaction of arylacetonitriles to a variety of alkylidene malo-
nates. The combination of a chiral N,N’-dioxide and zinc(II)
triflimidate exhibited high reactivity and stereoinduction,
[a] J. Yao, Prof. Dr. X. Liu, P. He, Y. Zhu, X. Lian, Dr. L. Lin,
Prof. Dr. X. Feng
Key Laboratory of Green Chemistry and Technology
Ministry of Education, College of Chemistry
Sichuan University, Chengdu 610064 (P.R. China)
Fax : (+86)28-8541-8249
E-mail: liuxh@scu.edu.cn
xmfeng@scu.edu.cn
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201302122.
16424
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Chem. Eur. J. 2013, 19, 16424 – 16430

FULL PAPER
thereby generating the targeted adducts in good yields (up
to 98%), with excellent diastereoselectivities (up to >99:1
d.r.) and enantioselectivities (up to 99% ee). Notably, excess
N,N’-dioxide was used as a proton scavenger instead of
a basic additive in most cases. The triflimidate counterion
outperformed triflate and basic ions,[12] which provides an in-
teresting perspective on the use of chiral metal-triflimidate
complexes in asymmetric reactions.
ingly, the introduction of a triflimidate counterion, which
was highly delocalized and positive charged, appeared to en-
hance the Lewis acidity of the zinc(II) cation. The L1/Zn-
AHCTUNTGRENGUN(N NTf2)2 catalyst afforded an improved yield of 50%, with
slightly lower stereoselectivity (87:13 d.r., 71% ee; Table 1,
entry 8). To improve the reactivity and enantioselectivity of
this reaction, various chiral N,N’-dioxide ligands were sur-
veyed (Figure 1) on coordination with ZnACHTNURTGNEUNG(NTf2)2. Notably,
Results and Discussion
Initially, our investigation was based on the model reaction
between 4-nitrophenylacetonitrile (1a, pKa =12.3)[8b] and di-
ethyl benzylidene malonate (2a), with various N,N’-dioxide/
metal complexes as catalysts.[13] A screening of various
metals[14] indicated that few metals worked well with l-rami-
pril-derived ligand L1 in CH2Cl2 at 358C (Table 1, entries 1–
Figure 1. Chiral ligands that were used in the study.
8). For example, the complexes of Sc
ACHUTGTNERN(NGU OTf)3, YCAHTUNGTERN(NUGN OTf)3, and
Co(acac)2 gave low yields. Although the complex of Ni-
G
bulky substituents at the ortho position of the aniline moiety
in the ligands had a significant effect on the stereoselectivity
and reactivity of the conjugate-addition reaction (Table 1,
entries 9–11). Ligands L2 and L3, which contained less-steri-
cally hindered substituents at the phenyl rings, afforded ex-
tremely low yields and stereoselectivities (Table 1, entries 9
and 10), whereas ligand L4, which was decorated with tert-
butyl groups, and ligand L5, which contained isopropyl
groups and a two-carbonic linkage, gave trace amounts of
the product with opposite diastereoselectivities (Table 1, en-
tries 11 and 12). With respect to the chiral backbone of the
ligands, l-ramipril-derived ligand L1 exhibited advantages in
terms of higher yield and enantioselectivity compared with
both ligand L6, which was derived from l-proline, and li-
gands L7 and L8, which were derived from l-pipecolic acid.
In addition, these latter two ligands generated the products
with reversed enantioselectivity (Table 1, entries 13–15).
ACHTUNGTRENNUNG(acac)2, which contained a basic counterion (this might be
helpful for the a-deprotonation of arylacetonitrile 1a),[9]
provided the desired product (3a) with satisfactory reactivi-
ty, albeit with poor enantioselectivity (Table 1, entry 4).
Chiral complex L1/Zn
ACHTUNGRTEN(NUNG OTf)2 afforded higher stereoselectiv-
ity than L1/Mg(OTf)2, albeit a lower yield of the product
ACHTUNGTRENNUNG
(3a; Table 1, entry 6 versus entry 5) was obtained. Interest-
Table 1. Screening of various central metals and ligands in the asymmet-
ric conjugate addition of compound 1a to compound 2a.
Entry[a] Ligand
Metal
Sc(OTf)3
(OTf)3
Co(acac)2
Ni(acac)2
Mg(OTf)2
Zn(OTf)2
(ClO4)2·6H2O
Zn(NTf2)2
Zn(NTf2)2
Zn(NTf2)2
Zn(NTf2)2
Zn(NTf2)2
Zn(NTf2)2
Zn(NTf2)2
Zn(NTf2)2
Zn(NTf2)2
Zn(NTf2)2
Yield [%][b] d.r.[c]
ee [%][c]
n.r.[d]
13
–
–
Moreover, the L8/ZnACHTUNRGTNEUNG(NTf2)2 complex promoted the reaction
1
L1
L1
L1
L1
L1
L1
L1
L1
L2
L3
L4
L5
L6
L7
L8
L1
L1
G
2
3
4
5
6
7
8
9
Y
R
40:60 11
in 40% yield, 96:4 d.r., and 69% ee (Table 1, entry 15). To
further improve the yield, the concentration of the reaction
mixture was investigated. To our delight, the yield was dra-
matically increased to 99%, with retention of stereoselectiv-
ity, on decreasing the volume of solvent (Table 1, entry 16).
However, under solvent-free conditions, both the yield and
G
trace
61
90:10
87:13
9
9
ACHTUNGTRENNUNG
G
51
75:25 41
G
34
15
95:5
95:5
73
74
Zn
N
E
50
87:13 71
E
15
86:14
–
34:66 63
38:62 39
9
–
enantioselectivity
deteriorated
significantly
(Table 1,
10
11
12
13
14
15
16[f]
17[g]
E
n.r.[d]
trace
trace
12
entry 16). Thus, the L1/ZnAHCTUGNRT(EUNNNG NTf2)2 complex and 1.0m of com-
R
pound 2a were chosen to assess other reaction parameters.
The reaction temperature and solvent were found to nota-
bly affect the enantioselectivity of this reaction (Table 2).
Decreasing the reaction temperature led to higher enantio-
selectivities and diastereoselectivities (up to 84% ee and
92:8 d.r.), but lower yields (Table 2, entries 1–3). Taking the
influence of temperature on the activity and enantioselectiv-
ity into consideration, 158C was selected as the optimum
temperature. Next, various solvents were tested in the pres-
AHCTUNGTRENNUNG
N
>99:1
23
G
35
40
92:8
93:7
57[e]
69[e]
N
U
99
80
87:13 71
85:15 37
N
[a] Unless otherwise stated, the reactions were carried out with a N,N’-di-
oxide/metal catalyst (1:1, 10 mol%), compound 1a (0.1 mmol), and com-
pound 2a (0.1 mmol) in CH2Cl2 (0.5 mL) at 358C for 2 days; [b] yield of
the isolated product; [c] determined by HPLC analysis; the ee value
refers to the syn isomer; [d] no reaction; [e] with reversed enantioselec-
tivity; [f] 0.1 mL of the solvent was used; [g] the reaction was performed
under solvent-free conditions; acac=acetylacetonate, Tf=trifluorome-
thanesulfonate.
ence of the L1/ZnACTHUNTRGNE(UNG NTf2)2 catalyst at 158C. Aprotic solvents,
such as CH2Cl2 and toluene, afforded the products in accept-
able yields and selectivities (Table 2, entries 1–4). Oxygen-
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X. Liu, X. Feng et al.
Table 2. Effects of temperature and solvent on the asymmetric conju-
gate-addition reaction.
ther increasing the ratio of the ligand to the metal resulted
in lower yields (Table 3, entry 1). When ZnACTHUNRTGNEUNG(NTf2)2 was pres-
ent in small excess, the reaction was completely suppressed
(Table 3, entry 5). If Et3N was subjected to the above
system, the yield recovered with good diastereo- and enan-
tioselectivities (Table 3, entry 6). These results implied that
the N,N’-dioxide ligand could assist the deprotonation pro-
Entry[a]
T [8C]
Solvent
Yield [%][b]
d.r.[c]
ee [%][c]
cess as a Brønsted base. In addition, neither ZnACTHUNTRGNE(UNG NTf2)2 or
1
2
3
4
35
15
0
CH2Cl2
CH2Cl2
CH2Cl2
toluene
Et2O
THF
MeOH
DMF
CHCl3
99
95
40
87:13
92:8
92:8
92:8
n.d.
71
82
84
ligand L1 alone could promote the reaction, which indicated
the operation of a ligand-acceleration phenomenon (Table 3,
entry 6). Thus, the best results were obtained by using the
L1/ZnACHTNUTGRNEUG(N NTf2)2 complex (1.5:1, 10 mol%), 4-nitrophenylace-
tonitrile (1a, 0.2 mmol), and diethyl benzylidene malonate
(2a, 0.1 mmol) in CHCl2CHCl2 (0.1 mL) at 158C.
Under the optimized conditions, an exploration of the
scope of the Michael acceptor revealed that a considerable
number of alkylidene malonates were well-tolerated. As
shown in Table 4, alkylidene malonates with either electron-
withdrawing or electron-donating substituents on the aro-
15
15
15
15
15
15
15
15
15
66
78
5[d]
6[d]
7[d]
8
trace
trace
trace
20
61
66
n.d.
n.d.
n.d.
0
88
85
n.d.
n.d.
76:24
94:6
92:8
94:6
95:5
9
10
11
12
CH2ClCH2Cl
CHCl2CH2Cl
CHCl2CHCl2
70
60
87
92
[a] Reaction conditions: N,N’-dioxide-L1/ZnACHTNURTGNE(UNG NTf2)2 (1:1, 10 mol%), com-
pound 1a (0.2 mmol), and compound 2a (0.1 mmol) were stirred in
solvent (0.1 mL) for 2 days; [b] yield of the isolated product; [c] deter-
mined by HPLC analysis; the ee value refers to the major isomer; [d] not
detected.
Table 4. Scope of the alkylidene malonate in the asymmetric conjuga-
tion-addition reaction of compound 1a.
containing solvents, such as Et2O, THF, and MeOH, gave
trace amounts of the product (Table 2, entries 5–8). Accord-
ingly, a detailed screen of various haloalkane solvents was
conducted (Table 2, entries 9–12). Pleasingly, CHCl2CHCl2
could further improve the enantioselectivity to 92% ee, al-
though the yield was somewhat decreased (60% yield;
Table 2, entry 12).
The molar ratio of ligand L1 to the central metal was an-
other important factor in determining the reactivity of the
reaction. As shown in Table 3, it was clear that a small
Entry[a]
R1
Product t [h] Yield [%][b] d.r.[c] ee
[%][c]
1
2
3
4
5
6
Ph
2-FC6H4
3-FC6H4
4-FC6H4
3a
3b
3c
3d
3e
3 f
3 f
3g
3h
3i
44
44
24
24
44
96
40
24
24
92
24
24
24
44
44
24
44
48
48
98
96
98
98
90
60
80
98
96
75
94
90
88
95
94
96
98
94
70
95:5
97:3
95:5
92:8
95:5
98:2
98:2
93:7
92:8
95:5
92
98
93
88
99
97
93
91
2,6-F2C6H3
2-ClC6H4
2-ClC6H4
3-ClC6H4
4-ClC6H4
2,4-Cl2C6H3
3,4-Cl2C6H3
3-BrC6H4
4-BrC6H4
3-MeC6H4
4-MeC6H4
3-CF3C6H4
4-CF3C6H4
3-MeOC6H4
4-MeOC6H4
excess of ligand L1 over Zn
the reaction rate. The optimal ratio of ligand L1 to Zn-
(NTf2)2 was confirmed to be 1.5:1, which gave the product
in 98% yield, 95:5 d.r., and 92% ee (Table 3, entry 2). Fur-
ACHTUNGTREN(NNUG NTf2)2 had a positive effect on
7[d]
8
9
ACHTUNGTRENNUNG
85
10
11
12
13
14
15
16
17
18
19
93 (1R,2R)
3j
89:11 88
3k
3l
94:6
93:7
94:6
95:5
92:8
94:6
95:5
97:3
93
85
93
92
87
85
91
91
Table 3. Effect of the L1/ZnACHTNUTRGNEUNG(NTf2)2 ratio on the asymmetric conjugate-
addition reaction.
3m
3n
3o
3p
3q
3r
Entry[a]
L1/Zn
(NTf2)2
Yield [%][b]
d.r.[c]
ee [%][c]
20
3s
48
90
94:6
93:7
81:19 81
83:17 81
83:17 98
88:12 92
92
92
1
2
3
4
2:1
1.5:1
1.2:1
1:1
0.9:1
0.9:1
–
90
98
90
96:4
95:5
95:5
95:5
–
92
92
92
92
–
21
2-naphthyl
2-thienyl
3-thienyl
cyclohexyl
iPr
3t
3u
3v
3w
3x
3y
48
48
48
40
40
60
96
80
85
82
70
55
22[e]
23[e]
24[f]
25[f]
26[f]
60
5
n.r.[d]
84
6[e]
7[f]
93:7
–
84
–
n.r.[d]
Et
94:6
97
[a] Reaction conditions, unless otherwise stated: N,N’-dioxide-L1/Zn-
(NTf2)2 (10 mol%), compound 1a (0.2 mmol), and compound 2a
[a] Reaction conditions, unless otherwise stated: N,N’-dioxide-L1/Zn-
(NTf2)2 (1.5:1, 10 mol%), compound 1a (0.2 mmol), and compound 2
N
ACHTUNGTRENNUNG
(0.1 mmol) were stirred in CHCl2CHCl2 (0.1 mL) at 158C for 2 days;
[b] yield of the isolated product; [c] determined by HPLC analysis; [d] no
reaction; [e] 358C, with Et3N (0.1 equiv) as an additive; [f] without chiral
(0.1 mmol) were stirred in CHCl2CHCl2 (0.1 mL) at 158C for 2 days;
[b] yield of the isolated product; [c] determined by HPLC analysis; the ee
value refers to the major isomer; [d] at 358C; [e] at 08C; [f] Et3N
(0.1 equiv) was used as an additive.
ligand L1 or ZnACHTUNGTRENNUNG(NTf2)2.
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Chem. Eur. J. 2013, 19, 16424 – 16430

Conjugate Addition of Arylacetonitriles to Alkylidene Malonates
FULL PAPER
matic ring provided their corresponding products in good
yields and excellent diastereoselectivities and enantioselec-
tivities (up to 98:2 d.r. and up to 99% ee; Table 4, entries 1–
20). The reactions of substrates with para-electron-donating
substituents gave slightly higher enantioselectivities than
those with para-electron-withdrawing substituents (Table 3,
entries 15, 19, and 20 versus 4, 9, 13, and 17). The positions
of the substituents had a subtle influence on the enantio-
and diastereoselectivities: ortho substitution was the best,
followed by meta substitution (Table 4, entries 2–5, 6–11).
The yield dropped significantly on increasing the steric bulk
of the ortho substituents on the substrate, which could be
compensated for by raising the reaction temperature, at the
expense of slightly lower enantioselectivity (Table 1, en-
tries 6 and 7). Moreover, a fused-ring substrate was well-tol-
erated, thus providing the addition product (3t) in 96%
yield, with 93:7 d.r. and 92% ee (Table 4, entry 21). In addi-
tion, hetero-aryl-containing substrates were also competent
for the addition of compound 1a after lowering the reaction
temperature to 08C (Table 4, entries 22 and 23). Moreover,
the reactions of alkyl-substituted substrates were stimulated
by the addition of Et3N, with up to 82% yield, 95:5 d.r., and
98% ee (Table 4, entries 24–26 and Supporting Information),
as the result of the basicity of Et3N, which was helpful for
the deprotonation of the arylacetonitrile.
tween 3-nitrophenylacetonitrile (pKa =18.1)[8b] and para-sub-
stituted alkylidene malonate 2d gave a relatively higher ee
value (Table 3, entry 6 versus Table 2, entry 4). Moreover,
the reaction of 2-nitrophenylacetonitrile with compound 2
suffered from hindrance from the nitro group, thereby lead-
ing to moderate yields and enantioselectivities, but extreme-
ly high diastereoselectivities (Table 5, entries 7–9). We also
examined the direct conjugate-addition reaction of phenyl-
AHCTUNGTREGaNNNU cetonitrile to compound 2a. However, the desired product
was not obtained; thus, the activation of arylacetonitriles by
electron-withdrawing groups was necessary in this catalyst
system.
The absolute configuration of the major isomer, syn-3i,
was unambiguously determined to be R,R by single-crystal
X-ray crystallographic analysis (Figure 2).[15]
The scope of the arylacetonitrile was also explored to in-
vestigate the influence of electronic and steric effects of var-
ious substituents on the reactivity and stereoselectivity of
the reaction (Table 5). 4-Cyanophenylacetonitrile (pKa =
16.0)[8b] reacted in a similar manner to 4-nitrophenylacetoni-
trile, albeit in a lower yield (only up to 70%), because of its
higher pKa value than compound 1a (Table 5, entries 1–4).
The results demonstrated that the para substituent did not
affect the stereoselectivity of the reaction. The reaction be-
Figure 2. X-ray structure of product 3i.
We also tested the reaction between ethyl 2-benzylidene-
3-oxobutanoate and compound 1a.[14] The corresponding
product was generated in 38% yield, 57:43 d.r., and 82%
and 79% ee for the two diastereomers. NMR analysis indi-
cated that the b-nucleophilic addition reaction occurred in
a highly stereocontrolled manner, whereas the selectivity of
the proton-transfer process was low.
Table 5. Scope of the arylacetonitrile in the asymmetric conjugate addi-
To determine the synthetic potential of this catalytic
system, the reaction between diethyl benzylidene malonate
(2a) and compound 1a was performed on the gram scale
under the optimized reaction conditions. Thus, the corre-
sponding adduct (3a) was obtained without any loss of
yield, diastereoselectivity, or enantioselectivity (Scheme 2).
To evaluate the versatility of the functional groups in the
product, several transformations started from product 3a
were carried out. The nitro group could be reduced into an
amino group with almost complete conversion and retention
of the stereoselectivity.[1b] The hydrolysis of the cyano group
performed smoothly to afford an amide group in a solution
of concentrated sulfuric acid in absolute EtOH.[16]
To gain insight into the reaction mechanism, the relation-
ship between the enantiomeric excess of ligand L7 and that
of product 3a was investigated (Figure 3).[14] A slightly posi-
tive nonlinear effect[17] was observed in either the presence
or absence of an amine. The positive nonlinear effect
became more obvious at a ligand-to-metal ratio of 1.5:1.
These results suggested that minor oligomeric aggregates ex-
isted in the reaction system. The catalytic composition was
tion of compound 1 to compound 2.
Entry[a]
R1
Ph
R2
Product Yield [%][b] d.r.[c]
ee [%][c]
1
2
3
4
4-CN
4a
4b
4c
4d
4e
4 f
4g
4h
4i
64
46
70
60
64
50
51
61
93:7
>99:1
93:7
94
98
91
87
2-FC6H4 4-CN
3-FC6H4 4-CN
4-FC6H4 4-CN
Ph
4-FC6H4 3-NO2
Ph 2-NO2
3-FC6H4 2-NO2
4-FC6H4 2-NO2
Ph
97:3
5[d,e]
6[d,e]
7[e]
8[e]
9[e]
10[e]
3-NO2
83:17 87
82:18 94
>99:1
85
85
81
–
>99:1
>99:1
–
60
H
n.r.[f]
[a] Reaction conditions, unless otherwise stated: N,N’-dioxide-L1/Zn-
ACHTUNGTRENNUNG(NTf2)2 (1.5:1, 10 mol%), compound 1 (0.2 mmol), and compound 2
(0.1 mmol) were stirred in CHCl2CHCl2 (0.1 mL) at 158C for 90 h;
[b] yield of the isolated product; [c] determined by HPLC analysis;
[d] ligand L8 was used instead of ligand L1; [e] at 358C, in the presence
of 4 ꢁ molecular sieves (10.0 mg); [f] no reaction.
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X. Liu, X. Feng et al.
Figure 4. ESI-MS spectrum of the L1/ZnACHTNURTGNE(UNG NTf2)2 catalyst.
Scheme 2. Gram-scale synthesis of compound 3a and its functional trans-
formations: a) H2 (6 MPa), PtO2·xH2O, HCl/EtOH, then K2CO3 (pH 9);
b) enthanol, conc. H2SO4, then aqueous NaHCO3.
Scheme 3. Proposed catalytic model.
the Re face of Michael acceptor 2i, thereby generating the
observed product, (R,R)-3i.
Figure 3. Nonlinear effects in the L7/ZnACTHNUTRGNEUNG(NTf2)2-catalyzed reaction be-
&
tween compounds 1a and 2a: L7/ZnACTHNUTRGENNUG(NTf2)2 =1:1 ( ); L7/ZnCAHUTNGTREN(NUGN NTf2)2 =1:1
~
*
(
) with 0.05 equiv of Et3N; L7/ZnACHTUNGRETNNU(G NTf2)2 =1.5:1 ( ).
Conclusion
also investigated by using ESI-MS. The spectrum of a mix-
ture of ligand L1 and Zn(NTf2)2 in a 1.5:1 ratio in
In summary, we have reported a direct asymmetric conju-
gate-addition reaction between arylacetonitriles and alkyli-
dene malonates under mild reaction conditions. A chiral
N,N’-dioxide/zinc(II)-triflimidate complex was found to be
efficient for this reaction and the corresponding adducts
were afforded in good yields, with high levels of diastereo-
and enantioselectivities. The N,N’-dioxide also worked as
a Brønsted base to activate the arylacetonitriles, thereby
providing their corresponding nitrile-stabilized carbanions.
The high Lewis acidity of the metal triflimidate, combined
with the privileged chiral N,N’-dioxide catalysts, are expect-
ed to find diverse applications in asymmetric synthesis.
AHCTUNGTRENNUNG
CHCl2CHCl2 at 358C showed a signal at m/z 1044.3693,
À
which was assigned to the complex [L1+Zn2++NTf2 ]+ (m/z
calcd: 1044.3392; Figure 4). This major monomeric complex
would function as the most-active and -effective catalytic
intermediate.
Based on previous reports[13j,k] and on the absolute config-
uration of product 3i, a possible catalytic model is proposed
to explain the origin of the high diastereo- and enantioselec-
tivities. As outlined in Scheme 3, the steric hindrance be-
tween the aryl group of the arylacetonitrile and the b-sub-
stituent and the ester group of the alkylidene malonate re-
sulted in the predominant formation of the syn adduct. In
the asymmetric process, N,N’-dioxide L1 and alkylidene
Experimental Section
malonate 2i coordinated to ZnACHTNUGTRNEUNG(NTf2)2 to form a hexacoordi-
nate intermediate. Assisted by free N,N’-dioxide L1, a ben-
Typical procedure for the asymmetric conjugate addition of 4-nitrophe-
zylic carbon center was generated, which preferred to attack
nylacetonitrile (1a) to diethyl benzylidene malonate (2a): 4-Nitropheny-
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Chem. Eur. J. 2013, 19, 16424 – 16430

Conjugate Addition of Arylacetonitriles to Alkylidene Malonates
FULL PAPER
lacetonitrile (1a, 32.4 mg, 0.2 mmol), Zn
(NTf2)2 (6.3 mg, 0.01 mmol),
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5238.
N,N’-dioxide L1 (10.5 mg, 0.015 mmol), and CHCl2CHCl2 (0.1 mL) were
placed in a dry tube and the mixture was stirred at 358C under a N2 at-
mosphere for 0.5 h. Then, diethyl benzylidene malonate (2a, 24.8 mg,
0.1 mmol) was added and the reaction was stirred at 158C and monitored
by TLC. After compound 2a had been completely consumed, the reac-
tion mixture was purified by flash chromatography on silica gel (petrole-
um ether/EtOAc, 5:1) to afford the desired product (3a) as light-yellow
oil in 95% yield, 95:5 d.r., and 92% ee. The d.r. and ee values of com-
pound 3a were determined by chiral HPLC analysis on a Chiralcel AD-
H column. 1H NMR (400 MHz, CDCl3): d=8.01 (d, J=8.4 Hz, 2H), 7.15
(d, J=8.8 Hz, 3H), 7.10 (d, J=6.8 Hz, 2H), 6.90 (d, J=7.2 Hz, 2H), 4.80
(d, J=4.0 Hz, 1H), 4.28 (m, 2H), 4.20 (d, J=11.6 Hz, 1H), 3.88–3.75 (m,
2H), 3.68 (m, 1H), 1.29 (t, J=6.8 Hz, 3H), 0.81 ppm (t, J=7.0 Hz, 3H);
13C NMR (101 MHz, CDCl3): d=168.09, 166.50, 147.64, 140.83, 133.48,
129.11, 129.05, 128.64, 128.43, 123.78, 117.63, 62.61, 61.83, 54.71, 49.44,
40.81, 14.05, 13.55 ppm; HRMS (ESI): m/z calcd for C22H22N2O6:
433.1376 [M+Na]+]; found: 433.1378.
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Typical procedure for the scale-up reaction: 4-Nitrophenylacetonitrile
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We appreciate the financial support from the National Natural Science
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search Program of China (973 Program, 2011CB808600), and the Minis-
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Received: June 4, 2013
Revised: August 20, 2013
Published online: October 15, 2013
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