Enantioselective aza-Morita-Baylis-Hillman reactions of acrylonitrile catalyzed by palladium(II) pincer complexes having C2-symmetric chiral bis(imidazoline) ligands

Article abstract of DOI:10.1002/anie.201204891

Simple and efficient: The first highly enantioselective aza-Morita-Baylis-Hillman reaction between acrylonitrile and imines has been developed. Excellent yields and enantioselectivities were observed for the reaction of various imines using chiral phebim/Pd^II complexes (1; see scheme). This process offers a simple and efficient route for the synthesis of functionalized α-methylene-β-aminonitriles and their derivatives. Copyright

Full text of DOI:10.1002/anie.201204891

Angewandte
Chemie
DOI: 10.1002/anie.201204891
Asymmetric Synthesis
Enantioselective Aza-Morita–Baylis–Hillman Reactions of
Acrylonitrile Catalyzed by Palladium(II) Pincer Complexes having
C2-Symmetric Chiral Bis(imidazoline) Ligands**
Kengo Hyodo, Shuichi Nakamura,* and Norio Shibata*
The enantioselective aza-Morita–Baylis–Hillman (aza-MBH)
reaction of a,b-unsaturated carbonyl compounds or nitriles
with imines is a powerful method for the preparation of
synthetically useful chiral a-methylidene-b-amino carbonyl
compounds or nitriles. Therefore, there are many reports on
the catalytic enantioselective aza-MBH reaction for
a,b-unsaturated carbonyl compounds.[1] However, the cata-
lytic enantioselective aza-MBH reaction with acrylonitriles is
still not fruitful,[2] even though the obtained b-amino nitriles
are chiral precursors to b-amino carboxylic acids and
1,3-diamines.[3,4] The first enantioselective aza-MBH reaction
of acrylonitrile with imines was reported by Shi and co-
workers.[5] They reported that using organocatalysts derived
from cinchona alkaloids for the reaction of imines with
acrylonitrile afforded a-methylidene-b-aminonitriles in mod-
erate yield (32–40%) with up to 68% ee. Adolfsson and Balan
reported the three-component aza-MBH reaction between
benzaldehyde, tosylamide, and acrylonitrile with 15 mol% of
the same organocatalyst and 2 mol% of Ti(OiPr)4 to give the
product in 45% yield with 53% ee.[6] Despite the pioneering
results achieved for the enantioselective aza-MBH reaction of
acrylonitrile with imines, a more efficient catalytic system
with regards to reactivity and selectivity is still highly
desirable. However, the enantioselective aza-MBH reaction
of acrylonitrile with imines is not a trivial task because of the
low reactivity and high polymerization ability of acrylonitrile
in comparison with a,b-unsaturated carbonyl compounds.
Therefore, the enhancement of the electrophilicity of acryl-
onitrile by coordination of transition metal catalysts to the
cyano group has become an attractive approach for the
activation of acrylonitrile. Although there are many reports
for the enantioselective aza-MBH reaction using chiral Lewis
bases, to the best of our knowledge, there is only one report
for the catalytic enantioselective aza-MBH reaction using
chiral Lewis acids together with achiral Lewis bases. In 2010,
Shibasaki and co-workers reported a highly enantioselective
aza-MBH reaction of acrylates using La(OiPr)3/linked-binol
complexes in combination with an achiral nucleophilic Lewis
base.[7] On the other hand, we recently developed a highly
enantioselective reaction of a-cyano carbanions with imines
catalyzed by chiral bis(imidazoline)/palladium(II) pincer
complexes.[8–10] In this catalyst system, palladium pincer
complexes enhance the acidity of the a-protons of alkylni-
triles to give palladium ketenimides, which react with imines
(Scheme 1). We expected that the bis(imidazoline)/palladium
system can be applied to the aza-MBH reaction of acryloni-
Scheme 1. Palladium pincer complexes activate alkylnitriles and acryl-
onitrile.
trile with imines; the chiral palladium pincer complexes
should coordinate to acrylonitrile, thus increasing its electro-
philicity, then an achiral Lewis base would attack the
b-position of acrylonitrile. The generated palladium keteni-
mide should react with imines to give chiral a-methylene-b-
amino nitriles. We herein report the first highly enantiose-
lective aza-MBH reaction of acrylonitrile and imines with
palladium(II) pincer complexes with chiral bis(imidazoline)
ligands as chiral Lewis acid catalysts.
The enantioselective reaction of acrylonitrile 2 (3.0 equiv)
with N-(4-methylbenzylidene)-4-methybenzenesulfonamide
1a (1.0 equiv) was carried out by using 5 mol% of palladium
catalysts 4a–f and 5 mol% of AgOAc (Table 1). Although the
reaction using only 4a and AgOAc did not afford product 3a,
the addition of 20 mol% of DABCO, as a Lewis base,
enhanced the reactivity of acrylonitrile to give product 3a in
good yield with moderate enantioselectivity (Table 1,
entries 1 and 2).[11] The reaction without AgOAc resulted in
decreased enantioselectivity of the product (Table 1,
entry 3).[12] To improve enantioselectivity, we optimized the
structure of the bis(imidazoline)/palladium catalysts 4b–f
(Table 1, entries 4–8). When catalyst 4 f, having acetyl (R1)
[*] K. Hyodo, Prof. S. Nakamura, Prof. N. Shibata
Department of Frontier Materials, Graduate School of Engineering
Nagoya Institute of Technology
Gokiso, Showa-ku, Nagoya 466-8555 (Japan)
E-mail: snakamur@nitech.ac.jp
nozshiba@nitech.ac.jp
[**] This work was supported by Teijin Pharma Award in Synthetic
Organic Chemistry (Japan) and a Sasagawa Scientific Research
Grant from the Japan Science Society.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201204891.
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Table 1: Optimization of reaction conditions.
Table 2: The aza-MBH reaction of acrylonitrile with various imines 1a–o
catalyzed by 4 f.
Entry
4
Ar
R1
DABCO
[mol%]
Solvent
Yield[a]
[%]
ee
[%]
Entry
1
R1
3
t
[h]
Yield[b]
[%]
ee
[%]
1
2
4a
4a
4a
4b
4c
4d
4e
4 f
4e
4 f
4 f
4 f
4e
4 f
4 f
Ph
Ph
Ph
Ph
Ph
Ph
Ac
0
20
20
20
20
20
20
20
20
20
5
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
iPrCN
iPrCN
iPrCN
iPrCN
iPrCN
–
–
1
1a
1b
1c
1d
1e
1 f
1g
1h
1i
1j
1k
1l
1m
1n
1o
Ph
3a
3b
3c
3d
3e
3 f
3g
3h
3i
3j
3k
3l
3m
3n
3o
48
72
24
24
24
96
36
168
84
72
72
72
72
96
72
93
84
97
89
87
97
98
75
96
89
98
88
87
93
88
94
91
93
76
90
90
95
77
93
97
91
94
96
90
98
Ac
Ac
Bz
Ms
Ts
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
83
81
82
74
79
74
81
92
91
99
93
58
97
91
66
49
57
62
62
65
76
85
87
92
94
93
92
89
2[a]
3
4-FC6H4
3-FC6H4
2-FC6H4
3,5-FC6H4
4-ClC6H4
3-ClC6H4
4-MeOC6H4
3-MeOC6H4
1-C10H7
3[b]
4
4
5
5
6
7
8
6[a]
7
Mes
1-Nap
Mes
1-Nap
1-Nap
1-Nap
Mes
8[a]
9
9
10
11
12[c,d]
13[c,e]
14[f]
15[g,h]
10
11[a]
12
13
14
15
2-C10H7
5
5
2.5
1
2-C4H3O
3-C4H3O
2-C4H3S
3-C4H3S
1-Nap
1-Nap
iPrCN
iPrCN
[a] Yield of the isolated product. [b] Without AgOAc. [c] The reaction was
carried out at À108C. [d] Reaction time is 48 h. [e] 96 h. [f] 2.5 mol% of
4 f and AgOAc was used. [g] 1 mol% of 4 f and AgOAc was used.
[h] 168 h. Bz=benzoyl, DABCO=1,4-diazabicyclo[2.2.2]octane,
Mes=2,4,6-trimethylphenyl, Ms=methanesulfonyl, M.S.=molecular
sieves, Nap=naphthyl, Ts=p-toluenesulfonyl.
[a] The reaction was carried out using 5 mol% of 4e and 20 mol%
DABCO at À208C. [b] Yield of the isolated product.
3j–o with high enantioselectivity (entries 10–15).[13] The
absolute stereochemistry of product 3a was assigned to be S
by comparison with the value of the specific rotation reported
in the literature.[5c] To the best of our knowledge, the levels of
enantioselectivity and substrate generality reported herein
are the highest among those previously reported.
We next examined the transformation of product 3a to
amide, tetrahydroisoindoline, and pyrroline derivatives
(Scheme 2). Hydrolysis of 3a using Pd(OAc)2, PPh3, and
=
CH3CH NOH in aqueous EtOH, heated to reflux, gave a-
and 1-naphthyl groups (Ar), was used as the catalyst, to our
delight, good enantioselectivity was obtained (Table 1,
entry 8). When the reaction was carried out with 5 mol% of
DABCO in isobutyronitrile (iPrCN) as a solvent, the
enantioselectivity improved slightly (Table 1, entries 9–11).
The best enantioselectivity was obtained when the reaction
was carried out at À108C in iPrCN using 4 f (Table 1,
entry 12). The reaction with 2.5 mol% of 4 f and DABCO
worked efficiently, and the reaction with 1 mol% of 4 f and
DABCO gave the product with slightly lower enantioselec-
tivity and yield (Table 1, entries 14 and 15).
methylidene-b-amino amide 6 in high yield.[14] In addition, the
reaction of 3a with (E)-5-bromopenta-1,3-diene in the
presence of K2CO3 gave the N-alkylated product. A subse-
We next examined the reaction of 2 with various imines
1a–o in the presence of 4 f, AgOAc, and DABCO (Table 2).
The reaction of various imines 1a–o gave products 3a–o in
high yield with high enantioselectivity (Table 1, entries 1–15),
although the reaction of ortho-substituted imine 1d pro-
ceeded with relatively lower enantioselectivity (Table 1,
entry 4). For the reactions of para-substituted imines 1b, 1 f,
1h, and 1k, higher enantioselectivity could be achieved with
2,4,6-trimethylphenyl-substituted phebim/palladium complex
4e instead of 4 f (entries 2, 6, 8, and 11; see also the
Supporting Information). Imines with naphthyl- and hetero-
atom-containing substituents (1j–o) also afforded products
Scheme 2. Transformation of a-methylidene-b-aminonitriles.
DMF=N,N’-dimethylformamide, DMSO=dimethylsulfoxide.
2
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quent intramolecular Diels–Alder reaction using BCl3
afforded the corresponding 1-aryl-substituted tetrahydro-
isoindoline derivative 7 without loss of enantiopurity.[15]
Furthermore, the reaction of 3a with allyl bromide using
K2CO3 gave N-allylated product. Then, ring-closing meta-
thesis of the N-allylated product in the presence of 5 mol% of
Grubbs II type catalyst in CH2Cl2 afforded pyrroline 8 in high
yield.
The proposed catalytic cycle for the reaction of acryloni-
trile with imines is shown in Scheme 3. The addition of
AgOAc causes the exchange reaction of bromide in 4 to
Scheme 4. Aza-MBH reactions of 1c with acrylonitrile and ethyl
acrylate.
acrylonitrile in the presence of catalyst is at least 10 times
faster than that for the reaction with ethyl acrylate. These
results indicate that the palladium/pincer complex selectively
coordinates to the cyano group and that it activates acryloni-
trile.
Based on previous X-ray crystallographical analysis of the
palladium pincer complexes,[8a] and the absolute configura-
tion of the products, we propose the structure shown in
Figure 1 for palladium ketenimide intermediate and transi-
Figure 1. The structure of the complex and the assumed transition
state for the addition reaction of activated acrylonitrile with an imine
in the presence of 4a.
tion state of the enantioselective reaction of palladium
ketenimide with imine in the presence of 4a. We believe
imine 1 approaches from the opposite side to DABCO, thus
avoiding steric repulsion; the Re face of the imine reacts with
palladium ketenimide to give the S isomer. Further studies
are required to fully elucidate the mechanistic detail of the
aza-MBH reaction of acrylonitrile with imines.[16]
In conclusion, we have developed the first highly enan-
tioselective aza-MBH reaction of acrylonitrile with imines
using chiral pincer complexes of 1,3-bis(imidazolin-2-yl)ben-
zene bearing a bulky substituent and PdII. A range of imines
can be tolerated in this process. This process offers a simple
and efficient route for the synthesis of functionalized
a-methylene-b-aminonitriles and their derivatives. Further
experiments are in progress to study the scope of this process
and the potential application of the bis(imidazoline)/palla-
dium pincer catalyst to other reactions.
Scheme 3. Proposed reaction cycle of the aza-MBH reaction of acryl-
onitrile with imines catalyzed by 4.
acetate (A). Coordination of the cyano group in acrylonitrile
to the palladium atom of A affords cationic B, which was
observed by APCI–MS analysis of a 1:1:1 mixture of 4a,
AgOAc, and acrylonitrile (cation mode, calcd. for
C43H36N5O2Pd: 760.19, found: 760.19, see the Supporting
Information). DABCO attacks the b-position of acrylonitrile
in the B to give palladium ketenimide (C). Then the C reacts
with N-sulfonylimines to give D, which subsequently under-
goes deprotonation and decomplexation giving products 3
and regenerated A.
To clarify the activation ability of A, the reactions of
mixtures of acrylonitrile and ethyl acrylate to imine 1c with or
without 4 f and AgOAc were examined (Scheme 4). The
reaction without 4 f and AgOAc afforded both products 3c
and 5, and the reactions showed similar reactivity. On the
other hand, the aza-MBH reaction using 4 f and AgOAc
preferably afforded product 3c. The rate for the reaction with
Experimental Section
Typical procedure for aza-Morita–Baylis–Hillman reaction of acryl-
onitrile catalyzed by chiral phebim/PdII complexes: N-[(1S)-2-Cyano-
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1-phenylpropen-3-yl]-4-methylbenzenesulfonamide (3a): DABCO
(1.2 mg, 11.7 mmol), and 2 (46.5 mL, 0.504 mmol) were added to
a mixture of AgOAc (1.8 mg, 11.7 mmol), 4 f (12.6 mg, 11.7 mmol), and
molecular sieves (4 ꢀ; 90 mg) in iPrCN (0.75 mL) at À108C. Then,
N-sulfonylimine 1a (61.5 mg, 0.237 mmol) was added. After disap-
pearance of N-sulfonylimine in the reaction mixture, as monitored by
TLC, the crude mixture was filtered through a pad of silica gel and
washed with CH2Cl2 (10 mL). The solvent was removed under
reduced pressure to give a residue, which was purified by column
chromatography (benzene/CH3CN = 95:5) giving 3a (68.9 mg, 93%)
as a white solid.
11992, see also Ref. [6]; for the aza-MBH reaction using a chiral
Brønsted acid in combination with an achiral nucleophilic Lewis
base, see: b) I. T. Raheem, E. N. Jacobsen, Adv. Synth. Catal.
2005, 347, 1701 – 1708; for the MBH reaction using a chiral Lewis
acid in combination with an achiral nucleophilic Lewis base, see:
c) V. K. Aggarwal, G. J. Tarver, R. McCague, Chem. Commun.
1996, 2713 – 2714; d) V. K. Aggarwal, A. Mereu, G. J. Tarver, R.
McCague, J. Org. Chem. 1998, 63, 7183 – 7189; e) T. Iwama, S.
Tsujiyama, H. Kinoshita, K. Kanematsu, Y. Tsurukami, T.
Iwamura, S. Watanabe, T. Kataoka, Chem. Pharm. Bull. 1999,
47, 956 – 961; f) K.-S. Yang, W.-D. Lee, J.-F. Pan, K. Chen, J. Org.
Chem. 2003, 68, 915 – 919; g) K. Matsui, S. Takizawa, H. Sasai,
Tetrahedron Lett. 2005, 46, 1943 – 1946.
Received: June 22, 2012
Published online: && &&, &&&&
[8] a) K. Hyodo, S. Nakamura, K. Tuji, T. Ogawa, Y. Funahashi, N.
Shibata, Adv. Synth. Catal. 2011, 353, 3385 – 3390. See also our
related research for chiral bis(imidazoline)catalysts: b) S. Naka-
mura, K. Hyodo, Y. Nakamura, N. Shibata, T. Toru, Adv. Synth.
Catal. 2008, 350, 1443 – 1448; c) S. Nakamura, M. Ohara, Y.
Nakamura, N. Shibata, T. Toru, Chem. Eur. J. 2010, 16, 2360 –
2362; d) M. Ohara, S. Nakamura, N. Shibata, Adv. Synth. Catal.
2011, 353, 3285 – 3289.
Keywords: asymmetric synthesis · homogeneous catalysis ·
.
imidazolines · Lewis acids · pincer complex
[1] For reviews, see: a) D. Basavaiah, A. J. Rao, T. Satyanarayana,
Chem. Rev. 2003, 103, 811 – 891; b) Y.-L. Shi, M. Shi, Eur. J. Org.
Chem. 2007, 2905 – 2916; c) G. Masson, C. Housseman, J. Zhu,
Angew. Chem. 2007, 119, 4698 – 4712; Angew. Chem. Int. Ed.
2007, 46, 4614 – 4628; d) V. Declerck, J. Martinez, F. Lamaty,
Chem. Rev. 2009, 109, 1 – 48; e) D. Basavaiah, B. S. Reddy, S. S.
Badsara, Chem. Rev. 2010, 110, 5447 – 5674; f) Chiral Amine
Synthesis (Ed.: T. C. Nugent), Wiley-VCH, New York, 2010.
[2] For the racemic aza-MBH reaction for acrylonitriles, see: a) D.
Balan, H. Adolfsson, J. Org. Chem. 2001, 66, 6498 – 6501; b) D.
Balan, H. Adolfsson, J. Org. Chem. 2002, 67, 2329 – 2334; c) M.
Shi, G.-L. Zhao, Tetrahedron Lett. 2002, 43, 4499 – 4499; d) X.
Liu, J. Zhao, G. Jin, G. Zhao, S. Zhu, S. Wang, Tetrahedron 2005,
61, 3841 – 3851; e) X. Mi, S. Luo, H. Xu, L. Zhang, J.-P. Cheng,
Tetrahedron 2006, 62, 2537 – 2544; f) A. Gajda, T. Gajda, J. Org.
Chem. 2008, 73, 8643 – 8646.
[9] For bis(imidazoline) ligands, see the review: a) H. Liu, D.-M. Du,
Adv. Synth. Catal. 2009, 351, 489 – 519, and references therein.
See also: b) T. Arai, T. Mizukami, A. Yanagisawa, Org. Lett.
2007, 9, 1145 – 1147; c) S. Jautze, P. Seiler, R. Peters, Chem. Eur.
J. 2008, 14, 1430 – 1444; d) H. Huang, R. Peters, Angew. Chem.
2009, 121, 612 – 615; Angew. Chem. Int. Ed. 2009, 48, 604 – 606;
e) S. Jautze, S. Diethelm, W. Frey, R. Peters, Organometallics
2009, 28, 2001 – 2004; f) L. Cheng, J. Dong, J. You, G. Gao, J. Lan,
Chem. Eur. J. 2010, 16, 6761 – 6765; g) M. Weber, S. Jautze, W.
Frey, R. Peters, J. Am. Chem. Soc. 2010, 132, 12222 – 12225; h) H.
Lin, D.-M. Du, Adv. Synth. Catal. 2010, 352, 1113 – 1118; i) D. C.
Braddock, T. Cailleau, G. Cansell, S. A. Hermitage, R. H.
Pouwer, J. M. Redmond, A. J. P. White, Tetrahedron: Asymmetry
2010, 21, 2911 – 2919; j) S.-M. Kim, K. Choi, Eur. J. Org. Chem.
2011, 4747 – 4750; k) X. Du, H. Liu, D.-M. Du, Eur. J. Org.
Chem. 2011, 786 – 793; l) M. Weber, W. Frey, R. Peters, Adv.
Synth. Catal. 2012, 354, 1443 – 1449; for tris(imdazorine) ligands,
see: m) K. Murai, S. Fukushima, S. Hayashi, Y. Takahara, H.
Fujioka, Org. Lett. 2010, 12, 964 – 966; n) K. Murai, T. Matsush-
ita, A. Nakamura, S. Fukushima, M. Shimura, H. Fujioka,
Angew. Chem. 2010, 122, 9360 – 9363; Angew. Chem. Int. Ed.
2010, 49, 9174 – 9177; o) K. Murai, S. Fukushima, A. Nakamura,
M. Shimura, H. Fujioka, Tetrahedron 2011, 67, 4862 – 4868; p) T.
Arai, K. Sakagami, Eur. J. Org. Chem. 2012, 1097 – 1100; q) K.
Murai, A. Nakamura, T. Matsushita, M. Shimura, H. Fujioka,
Chem. Eur. J. 2012, 18, 8448 – 8453; for recent reviews of pincer-
type transition metal catalysts havinging bis(oxazolyl)phenyl
ligands (Phebox), see: r) H. Nishiyama, Chem. Soc. Rev. 2007,
36, 1133 – 1141; s) H. Nishiyama, J. Ito, Chem. Rec. 2007, 7, 159 –
166; t) H. Nishiyama, J. Ito, Chem. Commun. 2010, 46, 203 – 212.
[10] For palladium pincer complexes with bis(imidazoline) ligands,
see: a) X.-Q. Hao, J.-F. Gong, C.-X. Du, L.-Y. Wu, Y.-J. Wu, M.-
P. Song, Tetrahedron Lett. 2006, 47, 5033 – 5036; b) L.-Y. Wu, X.-
Q. Hao, Y.-X. Xu, M.-Q. Jia, Y.-N. Wang, J.-F. Gong, M.-P. Song,
Organometallics 2009, 28, 3369 – 3380; c) J.-L. Niu, X.-Q. Hao, J.-
F. Gong, M.-P. Song, Dalton Trans. 2011, 40, 5135 – 5150; d) M.-J.
Yang, Y.-J. Liu, J.-F. Gong, M.-P. Song, Organometallics 2011, 30,
3793 – 3803; for platinum pincer complexes with bis(imidazo-
line) ligands, see: e) X.-Q. Hao, Y.-X. Xu, M.-J. Yang, L. Wang,
J.-L. Niu, J.-F. Gong, M.-P. Song, Organometallics 2012, 31, 835 –
846.
[3] For chiral diamines, see: a) D. Lucet, T. L. Gall, C. Mioskowski,
Angew. Chem. 1998, 110, 2724 – 2772; Angew. Chem. Int. Ed.
1998, 37, 2580 – 2627; b) J.-C. Kizirian, Chem. Rev. 2008, 108,
140 – 205; for biologically active chiral vicinal diamines, see:
c) S. R. S. S. Kotti, C. Timmons, G. Li, Chem. Biol. Drug Des.
2006, 67, 101 – 114; for b-amino acids, see: d) Enantioselective
Synthesis of b-Amino Acids (Ed.: E. Juaristi, V. A. Soloshonok),
Wiley-VCH, New York, 2005; e) E. F. Kleinmann in Compre-
hensive Organic Synthesis, Vol. 2 (Eds.: B. M. Trost, I. Flem-
ming), Pergamon, New York, 1991, Chapter 4.1; f) T. Hinter-
mann, D. Seebach, Chimia 1997, 50, 244 – 247; g) D. Seebach,
J. L. Matthews, Chem. Commun. 1997, 2015 – 2022; h) U. Koert,
Angew. Chem. 1997, 109, 1922 – 1923; Angew. Chem. Int. Ed.
Engl. 1997, 36, 1836 – 1837; i) S. H. Gellman, Acc. Chem. Res.
1998, 31, 173 – 180.
[4] Hamada and co-workers reported the asymmetric allylic ami-
nation of MBH adducts with a nitrile group in the presence of
chiral diaminophosphine oxide (DIAPHOX)/Pd catalysts, see
a) T. Nemoto, T. Fukuyama, E. Yamamoto, S. Tamura, T.
Fukuda, T. Matsumoto, Y. Akimoto, Y. Hamada, Org. Lett.
2007, 9, 927 – 930. Recently, the group of Shibasaki and Kumagai
reported the enantioselective synthesis of a-methylene-b-amino
nitriles from the reaction of imines with allylcyanides, see: b) R.
Yazaki, T. Nitabaru, N. Kumagai, M. Shibasaki, J. Am. Chem.
Soc. 2008, 130, 14477 – 14479.
[5] a) M. Shi, Y.-M. Xu, Angew. Chem. 2002, 114, 4689 – 4692;
Angew. Chem. Int. Ed. 2002, 41, 4507 – 4510; b) M. Shi, Y.-M.
Xu, Adv. Synth. Catal. 2004, 346, 1205 – 1219; c) M. Shi, Y.-M.
Xu, Y.-L. Shi, Chem. Eur. J. 2005, 11, 1794 – 1802.
[6] D. Balan, H. Adolfsson, Tetrahedron Lett. 2003, 44, 2521 – 2524.
[7] a) T. Yukawa, B. Seelig, Y. Xu, H. Morimoto, S. Matsunaga, A.
Berkessel, M. Shibasaki, J. Am. Chem. Soc. 2010, 132, 11988 –
[11] We also examined the reaction using triphenylphosphine instead
of DABCO, but the reaction did not afford the desired product,
see: Y.-M. Xu, M. Shi, J. Org. Chem. 2004, 69, 417 – 425. See also,
Ref. [2c].
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Angewandte
Chemie
[12] We also examined other silver salts as an additive, such as
AgOTf, AgSbF6, AgBF4, and AgClO4; however, the reaction
afforded product 3a either in low yields or with low enantiose-
lectivity. We also examined the reactions of imines protected
with various groups, such as Boc, Cbz, and 2,4,6-trimethylben-
zensulfonyl groups. The highest enantioselectivity and reactivity
was obtained by the reaction with N-tosylimines, see the
Supporting Information.
[13] We also tried the aza-MBH reaction with aliphatic imines,
however the reaction did not afford the desired product.
[14] a) E. S. Kim, H. S. Kim, J. N. Kim, Tetrahedron Lett. 2009, 50,
2973 – 2975; b) E. S. Kim, H. S. Lee, J. N. Kim, Tetrahedron Lett.
2009, 50, 6286 – 6289; c) E. S. Kim, Y. M. Kim, J. N. Kim, Bull.
Korean Chem. Soc. 2010, 31, 700 – 703.
[15] K. N. Clary, M. Parvez, T. G. Back, J. Org. Chem. 2010, 75, 3751 –
3760.
[16] We also checked the primary kinetic isotope effect by compar-
ison of reaction of acrylonitrile with separate reactions of
a-deuterio-acrylonitrile. The weak kinetic isotope effect of the
reaction was observed in this reaction (kH/KD = 1.8). Therefore,
the possibility that dynamic kinetic resolution at the catalyst
turnover step from D to A cannot be strictly ruled out.
Angew. Chem. Int. Ed. 2012, 51, 1 – 6
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Angewandte
Communications
Communications
Asymmetric Synthesis
K. Hyodo, S. Nakamura,*
N. Shibata*
&&&& — &&&&
Enantioselective Aza-Morita–Baylis–
Hillman Reactions of Acrylonitrile
Catalyzed by Palladium(II) Pincer
Complexes havingC2-Symmetric Chiral
Bis(imidazoline) Ligands
Simple and efficient: The first highly
enantioselective aza-Morita–Baylis–Hill-
man reaction between acrylonitrile and
imines has been developed. Excellent
yields and enantioselectivities were
observed for the reaction of various
imines using chiral phebim/PdII com-
plexes (1; see scheme). This process
offers a simple and efficient route for the
synthesis of functionalized a-methylene-
b-aminonitriles and their derivatives.
6
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These are not the final page numbers!