Enantioselective synthesis of imidazolines with quaternary stereocenters by organocatalytic reaction of N-(heteroarenesulfonyl)imines with isocyanoacetates

Article abstract of DOI:10.1021/ol301256q

An organocatalytic enantioselective Mannich-type reaction of isocyanoacetate with N-sulfonylimines catalyzed by chiral thioureas derived from quinine yielded 2-imidazolines with high diastereo- and enantioselectivities (up to >99:1 dr. and 96% ee). This reaction provided a convenient route to access various imidazolines and related α,β-diamino acids having a quaternary carbon center in high enantiomeric purities.

Full text of DOI:10.1021/ol301256q

ORGANIC
LETTERS
2012
Vol. 14, No. 12
2960–2963
Enantioselective Synthesis of Imidazolines
with Quaternary Stereocenters
by Organocatalytic Reaction
of N-(Heteroarenesulfonyl)imines
with Isocyanoacetates
Shuichi Nakamura,* Yuri Maeno, Mutsuyo Ohara, Akiko Yamamura,
Yasuhiro Funahashi, and Norio Shibata*
Department of Frontier Materials, Graduate School of Engineering, Nagoya Institute
of Technology, Gokiso, Showa-ku, Nagoya 466-8555, Japan
snakamur@nitech.ac.jp; nozshiba@nitech.ac.jp
Received April 6, 2012
ABSTRACT
An organocatalytic enantioselective Mannich-type reaction of isocyanoacetate with N-sulfonylimines catalyzed by chiral thioureas derived from
quinine yielded 2-imidazolines with high diastereo- and enantioselectivities (up to >99:1 dr. and 96% ee). This reaction provided a convenient route
to access various imidazolines and related R,β-diamino acids having a quaternary carbon center in high enantiomeric purities.
The construction of optically active 2-imidazolines has
received considerable attention because of their wide ap-
plications in the synthesis of biologically active compounds1
and also their synthetic importance.2 Furthermore, chiral
imidazoline derivatives can be readily hydrolyzed to chiral
2,3-diamines, which are a constituent of several antibiotics
as well as other biologically active compounds.3 There-
fore, their broad utility has prompted considerable interest
to develop asymmetric methods for the preparation of im-
idazolines. One of the most efficient methods for the synth-
esis of chiral imidazolines is the catalytic enantioselective
Mannich-type condensation of imines with isocyanides
containing an electron-withdrawing group (EWG) at the
R-carbon (Scheme 1).4À6
Scheme 1. Construction of Imidazolines through the Reaction
of Imines with Isocyanoacetates
(1) (a) Betschart, C.; Hegedus, L. S. J. Am. Chem. Soc. 1992, 114,
5010–5017. (b) Rondu, F.; Bihan, G. L.; Godfroid, J. J. J. Med. Chem.
1997, 40, 3793–3803. (c) Haiao, Y.; Hegedus, L. S. J. Org. Chem. 1997,
62, 3586–3591.
The first enantioselective reaction of sulfonylimines with
isocyanoacetates was reported by Lin and co-workers
(2) For a review, see: (a) Liu, H.; Du, D.-M. Adv. Synth. Catal. 2009,
351, 489–519 and references therein. See also: (b) Dalko, P. I.; Langlois,
Y. Chem. Commun. 1998, 331–332.
(4) (a) Zhou, X.-T.; Lin, Y.-R.; Dai, L.-X.; Sun, J.; Xia, L.-J.; Tang,
ꢀ
M.-H. J. Org. Chem. 1999, 64, 1331–1334. (b) Aydin, J.; Ryden, A.;
(3) For reviews, see: (a) Viso, A.; de la Pradilla, R. F.; Garcia, A.;
ꢀ
ꢀ
Szabo, K. J. Tetrahedron: Asymmetry 2008, 19, 1867–1870. (c) Zhang,
Z.-W.; Lu, G.; Chen, M.-M.; Lin, N.; Li, Y.-B.; Hayashi, T.; Chan,
Flores, A. Chem. Rev. 2005, 105, 3167–3196. (b) Arrayas, R. G.;
Carretero, J. C. Chem. Soc. Rev. 2009, 38, 1940–1948. (c) Viso, A.; de
la Pradilla, R. F.; Tortosa, M.; Garca, A.; Flores, A. Chem. Rev. 2011,
111, PR1–PR42 and references therein. See also: (d) Lu, G.; Yoshino,
T.; Morimoto, H.; Matsunaga, S.; Shibasaki, M. Angew. Chem., Int. Ed.
2011, 50, 4382–4385.
A. S. C. Tetrahedron: Asymmetry 2010, 21, 1715–1721.
(5) For organocatalytic enantioselective reactions of imines with
isocyanides giving 5-aminooxazoles, see: Yue, T.; Wang, M.-X.; Wang,
D.-X.; Masson, G.; Zhu, J. Angew. Chem., Int. Ed. 2009, 48, 6717–6721.
r
10.1021/ol301256q
Published on Web 06/01/2012
2012 American Chemical Society

using Me2SAuCl and a ferrocene-derived diphosphine
ligand to afford imidazolines with up to 88% ee.4a Szabo
stereocenter from the reaction of N-(heteroarenesulfonyl)
imines with R-substituted isocyanoacetates using bifunc-
tional organocatalysts.
ꢀ
and co-workers also reported the asymmetric synthesis of
imidazolines using a chiral palladium-pincer complex in
98% yield with 86% ee for the cis isomer.4b Although
pioneering work on the enantioselective formation of
imidazolines using chiral transition metal catalysts has
been done, there is only one report on the organocatalytic
asymmetric reaction of imines with isocyanoacetates.4c
Chan and co-workers reported that the reaction of methyl
isocyanoacetate with N-(toluenesulfonyl)imines in the pre-
sence of 20 mol % of cinchona alkaloid catalysts afforded
products with up to 70% ee. On the other hand, the
construction of a stereogenic quaternary carbon center
by the reaction of imines with R-substituted isocyanoace-
tates is highly desirable; however, the synthesis of optically
active 2-imidazolines having a quaternary stereocenter has
not been reported. Recently, we developed a highly enan-
tioselective reaction using N-sulfonylimines having hetero-
arenesulfonyl groups, which act as highly functionalized
activating groups, with various nucleophiles using bifunc-
tional organocatalysts.7 Herein, we report an efficient asym-
metric synthesis of 2-imidazolines having a quaternary
First, we examined the reaction of various N-(arenesulfonyl)-
imines 1aÀc with isocyanoacetates 2aÀc in the presence of
various chiral organocatalysts 4À7 (Figure 1). The results
are shown in Table 1.
Figure 1. Structures of organocatalysts.
(6) For a review on the enantioselective reaction of isocyanides, see:
(a) Gulevich, A. V.; Zhdanko, A. G.; Orru, R. V. A.; Nenajdenko, V. G.
Chem. Rev. 2010, 110, 5235–5331. For organocatalytic enantioselective
reactions of aldehydes with isocyanides, see: (b) Xue, M.-X.; Guo,
C.; Gong, L.-Z. Synlett 2009, 2191–2197. For organocatalytic enantio-
selective reactions of R,β-unsaturated carbonyl compounds with
R-substituted isocyanides, see: (c) Bai, J.-F.; Wang, L.-L.; Peng, L.; Guo,
Y.-L.; Jai, L.-N.; Tian, F.; He, G.-Y.; Xu, X.-Y.; Wang,
L.-X. J. Org. Chem. 2012, 77, 2947–2953. (d) Wang, L.-L.; Bai, J.-F.;
Peng, L.; Qi, L.-W.; Jia, L.-N.; Guo, Y.-L.; Luo, X.-Y.; Xu, X.; Wang,
L.-X. Chem. Commun. 2012, 48, 5175–5177. For organocatalytic
enantioselective reaction of nitroolefins with isocyanide, see: (e) Guo,
C.; Xue, M.-X.; Zhu, M.-K.; Gong, L.-Z. Angew. Chem., Int. Ed. 2008,
47, 3414–3417. For enantioselective reaction of aldehydes with iso-
cyanides using chiral metal catalysts, see: (f) Ito, Y.; Sawamura, M.;
Hayashi, T. J. Am. Chem. Soc. 1986, 108, 6405–6406. (g) Ito, Y.;
Sawamura, M.; Hayashi, T. Tetrahedron Lett. 1987, 28, 6215–6218.
(h) Pastor, S. T..; Togni, A. J. Am. Chem. Soc. 1989, 111, 2333–2334.
(i) Hayashi, T.; Uozumi, Y.; Yamazaki, A.; Sawamura, M.; Hamashima,
H.; Ito, Y. Tetrahedron Lett. 1991, 32, 2799–2802. (j) Hayashi, T.;
Sawamura, M.; Ito, Y. Tetrahedron Lett. 1992, 48, 1999–2012.
(k) Soloshonok, A. V.; Kacharov, D. A.; Hayashi, T. Tetrahedron 1996,
52, 245–254. (l) Longmire, J. M.; Zhang, X.; Shang, M. Organometallics
1998, 17, 4374–4379. (m) Motoyama, Y.; Shimozono, K.; Aoki, K.;
Nishiyama, H. Organometallics 2002, 21, 1684–1696. (n) Motoyama, Y.;
Kawakami, H.; Shimozono, K.; Aoki, K.; Nishiyama, H. Oganometallics
2002, 21, 3408–3416. (o) Gosiewska, S.; in‘t Veld, M. H.; de Pater, J. J. M.;
Bruijnincx, P. C. A.; Lutz, M.;Spek, A. L.;vanKotena, G.;Gebbinka, R. J.
M. K. Tetrahedron: Asymmetry 2006, 17, 674–686. (p) Yoon, S. M.;
Ramesh, R.; Kim, J.; Ryu, D.; Ahn, H. K. J. Organomet. Chem. 2006,
691, 5927–5934. (q) Wang, S.; Wang, M.-X.; Wang, D.-X.; Zhu, J. Eur. J.
Org. Chem. 2007, 4076–7080. (r) Wang, S.-X.; Wang, M.-X.; Wang, D.-X.;
Zhu, J. Org. Lett. 2007, 9, 3615–3618. (s) Gosiewska, S.; Herreras, S. M.;
Lutz, M.; Spek, A. L.; Havenith, R. W. A.; van Klink, G. P. M.; van Koten,
G.; Gebbink, R. J. M. K. Organometallics 2008, 27, 2549–2559. (t) Wang,
S.-X.; Wang, M.-X.; Wang, D.-X.; Zhu, J. Angew. Chem., Int. Ed. 2008, 47,
388–391. (u) Yue, T.; Wang, M.-X.; Wang, D.-X.; Zhu, J. Angew. Chem.,
Int. Ed. 2008, 47, 9454–9457. (v) Mihara, H.; Xu, Y.; Shepherd, N. E.;
Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc. 2009, 131, 8384–8385. (w)
Kim, H. Y.; Oh, K. Org. Lett. 2011, 13, 1306–1309. (x) Sladojevich, F.;
Trabocchi, A.;Guarna, A.;Dixon, D. J.J. Am. Chem. Soc. 2011, 133, 1710–
1713. For enantioselective reactions of R,β-unsaturated carbonyl com-
pounds with R-substituted isocyanides using chiral metal catalysts, see:
(y) Song, J.;Guo, C.; Chen, P.-H.; Yu, J.;Luo, S.-W.;Gong, L.-Z.Chem.;
Eur. J. 2011, 17, 7786–7790. (z) Padilla, S.; Adrio, J.; Carretero, J. C. J. Org.
Chem. 2012, 77, 4161–4166. For enantioselective reaction of nitroolefins
Table 1. Enantioselective Reaction of Imines and R-Substituted
Isocyanoacetates Using Various Organocatalysts
time
(h)
yield
(%)
dra
er
(%)b
run
1
2
catalyst
trans/cis
1
1a
1b
1c
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2c
2c
2c
2c
4a
4a
4a
4b
4c
4d
5a
5b
6
0.5
1
99
84
86
94
85
87
99
96
87
À
71:29
77:23
82:18
74:26
69:31
72:28
80:20
53:47
52:48
À
59:41
83:17
78:22
81:19
22:78
22:78
60:40
53:47
70:30
À
2
3
1
4
1
5
1
6
1
7
1
8
0.5
0.5
16
0.5
0.5
0.5
0.5
1
9
10
11
12
13c
14c,d
15c,d
7
4a
4a
4a
4a
4a
96
86
98
98
95
79:21
91: 9
85:15
99: 1
99: 1
87:13
86:14
91:9
91:9
79:21
a Diastereomer ratio (dr) was determined by 1H NMR analysis.
b Enantiomer ratio (er) for major diastereomer was determined by
ꢀ
with isocyanide using chiral metal catalysts, see: (aa) Arroniz, C.;
HPLC analysis using a chiral column. c At À20 °C. d MS 4 A was added.
˚
ꢀ
Gil-Gonzalez, A.; Semak, V.; Escolano, C.; Sosch, J.; Amat, M. Eur. J.
Org. Chem. 2011, 3755–3760.
Org. Lett., Vol. 14, No. 12, 2012
2961

Chiral thiourea 4a derived from quinine can activate the
reaction of 1a with 2a to give product 3aa in high yield but
with low diastereo- and enantioselectivity (entry 1).8 The
reaction of imines 1b,c having heteroarenesulfonyl groups,
such as a 2-pyridinesulfonyl- or 8-quinolinesulfonyl group,
with 2a afforded products 3ba, 3ca with good diastereos-
electivity and moderate enantioselectivity (entries 2 and 3).9
To improve the stereoselectivity, we next optimized the
structure of organocatalysts. The reaction of 1b with 2a
using variouschiralthioureas4bÀd, cinchonaalkaloids5a,
b, and squaramide 6 afforded product 3ba with lower
enantioselectivity than that using 4a (entry 2 vs 4À9).
Our previous studies on the FriedelÀCrafts alkylation
reaction of N-(2-pyridinesulfonyl)imines with pyrroles or
indole showed that chiral phosphoric acid 7 is an effective
organocatalyst;7b however the reaction of 1b with 2a using
7 did not give the product 3ba (entry 10). Therefore, the
chiral thiourea 4a finally proved to be the catalyst of
choice. We next examined the reaction using several alkyl
or aryl 2-phenyl-1-isocyanoacetates 2b,c. The reaction
using a phenyl ester or 2,4,6-trimethylphenyl ester of
isocyanoacetates 2b,c afforded products 3bb, 3bc in high
yields with high diastereo- and enantioselectivities (entries
11 and 12). When the reaction was carried out at lower
temperature, the enantioselectivity improved slightly more
than that at room temperature (entry 13). The addition of
first example of the enantioselective synthesis of imidazo-
line having a quaternary stereocenter through the reaction
of R-substituted isocyanoacetates with imines.
With these optimized conditions, the reaction of a series
of N-(2-pyridinesulfonyl)imines 1bÀm and R-substituted
isocyanoacetates 2cÀi using 4a was examined (Table 2).
Table 2. Enantioselective Formation of 2-Imidazolines Using
Various Imines 1bÀm and R-Substituted Isocyanoacetates 2cÀi
dr
prod- yield trans/
er
(%)a
entry
Ar
R
uct
(%)
cis
1
Ph
4-MeC6H4
Ph
Ph
3bc
8
98
83
90
87
87
99
86
83
91
87
71
96
84
90
79
85
À
99:1
95:5
97:3
98:2
98:2
99:1
99:1
99:1
99:1
98:2
81:19
98:2
91:9
83:17
99:1
73:27
À
91:9
92:8
91:9
94:6
94:6
98:2
92:8
95:5
94:6
94:6
87:13
93:7
91:9
89:11
90:10
94:6
À
2
3
4-MeOC6H4 Ph
9
4
4-BrC6H4
4-ClC6H4
4-NO2C6H4
2-BrC6H4
3-BrC6H4
1-Naphthyl
2-Naphthyl
2-Thienyl
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
10
11
12
13
14
15
16
17
18
19
20
21
22
23
5
6
7
8
9
˚
10
11
12
13b
14c
15
16c
17c
4 A molecular sieves improved the diastereoselectivity of
the reaction without a loss of enantioselectivity (entry 14).
We examined the reaction of 1a under the best reaction
conditions to give the product 3ac but with low enantio-
selectivity (entry15). This result provides evidence of the
clear superiority of the 2-pyridinesulfonyl group as a
stereocontrolling auxiliary. To our knowledge, this is the
p-ClPh
p-FPh
Me
Ph
Ph
Ph
CH2Ph
iBu
Ph
Ph
iPr
a Enantiomer ratio for major diastereomer was determined by HPLC
(7) (a) Nakamura, S.; Nakashima, H.; Yamamura, A.; Shibata, N.;
Toru, T. Adv. Synth. Catal. 2008, 350, 1209–1212. (b) Nakamura, S.;
Sakurai, Y.; Nakashima, H.; Shibata, N.; Toru, T. Synlett 2009, 1639–
1642. (c) Nakamura, S.; Shibata, N.; Toru, T. J. Synth. Org. Chem. Jpn.
2010, 68, 1017–1027. For related recent studies from our group, see: (d)
Nakamura, S.; Nakashima, H.; Sugimoto, H.; Sano, H.; Hattori, M.;
Shibata, N.; Toru, T. Chem.;Eur. J. 2008, 14, 2145–2152. (e) Naka-
mura, S.; Hara, N.; Nakashima, H.; Kubo, K.; Shibata, N.; Toru, T.
Chem.;Eur. J. 2008, 14, 8079–8081. (f) Hara, N.; Nakamura, S.;
Shibata, N.; Toru, T. Chem.;Eur. J. 2009, 15, 6790–6793. (g) Naka-
mura, S.; Hayashi, M.; Hiramatsu, Y.; Shibata, N.; Funahashi, Y.;
Toru, T. J. Am. Chem. Soc. 2009, 131, 18240–18241. (h) Nakamura, S.;
Ohara, M.; Nakamura, Y.; Shibata, N.; Toru, T. Chem.;Eur. J. 2010,
16, 2360–2362. (i) Nakamura, S.; Hayashi, M.; Kamada, Y.; Sasaki, R.;
Hiramatsu, Y.; Shibata, N.; Toru, T. Tetrahedron Lett. 2010, 51, 3820–
3823. Selected examples for related recent studies from other groups,
analysis using a chiral column. b At À40 °C. c At rt.
The reaction with both electron-donating and -with-
drawing imines 1dÀj gave products 8À14 in high yield
with high stereoselectivity (entries 2À8). The reaction of
imines having a 1- or 2-naphthyl group or heteroaryl group
also resulted in high enantioselectivity (entries 9À11). The
absolute configuration of a major diastereomer of 10
(Ar = p-BrC6H4) was determined to be a (4R,5S)-isomer
by X-ray crystallography analysis (see Supporting
Information), and the stereochemistry of other products
was tentatively assumed by analogy. The reaction of 1b
and various R-substituted isocyanoacetates 2dÀh using 4a
affordedproducts 18À22in good yield withhighdiastereo-
and enantioselectivity (entries 12À16). However, the reac-
tion with isocyanide 2i having a bulky isopropyl group did
not afford the product (entry 17).
ꢀ
ꢀ
see: (j) Gonzalez, A. S.; Arrayas, R. G.; Carretero, J. C. Org. Lett. 2006,
ꢀ
8, 2977–2980. (k) Esquivias, J.; Arrayas, R. G.; Carretero, J. C. J. Am.
Chem. Soc. 2007, 129, 1480–1481. (l) Morimoto, H.; Lu, G.; Aoyama,
N.; Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc. 2007, 129, 9588–
9589. (m) Lu, G.; Morimoto, H.; Matsunaga, S.; Shibasaki, M. Angew.
ꢀ
ꢀ
Chem., Int. Ed. 2008, 47, 6847–6850. (n) Hernandez-Toribio, J.; Arrayas,
R. G.; Carretero, J. C. J. Am. Chem. Soc. 2008, 130, 16150–16151. (o)
ꢀ
ꢀ
Gonzalez, A. S.; Arrayas, R. G.; Rivero, M. R.; Carretero, J. C. Org.
Lett. 2008, 10, 4335–4337. (p) Zajac, M.; Peters, R. Chem.;Eur. J. 2009,
ꢀ
ꢀ
15, 8204–8222. (q) Hernandez-Toribio, J.; Arrayas, R. G.; Carretero,
We next examined the deprotection of the pyridinesulfonyl
group from the imidazoline product and the transformation of
imidazoline to a chiral diamine. The recrystallization of
product 10 afforded a diastereo- and enantiomerically pure
compound. The pyridinesulfonyl group in 10 can be removed
by magnesium in MeOH to give nonprotected 2-imidazoline
24 without a loss of diastereo- and enantiopurity (Scheme 2).
J. C. Chem.;Eur. J. 2010, 16, 1153–1157.
(8) For selected reviews for thiourea catalysts, see: (a) Takemoto, Y.
Org. Biomol. Chem. 2005, 3, 4299–4306. (b) Miyabe, H.; Takemoto, Y.
Bull. Chem. Soc. Jpn. 2008, 81, 785–795. (c) Yu, X.; Wang, W. Chem.;
Asian. J. 2008, 3, 516–532. (d) Connon, S. J. Chem. Commun. 2008,
2499–2510. (e) Zhang, Z.; Schreiner, P. R. Chem. Soc. Rev. 2009, 38,
1187–1198.
(9) We also tried the reaction of Boc-imine, however the product
could not be obtained.
2962
Org. Lett., Vol. 14, No. 12, 2012

Scheme 2. Synthesis of N-Nonsubstituted Imidazoline 10
The hydrolysis of imidazoline 10 using 6 N HCl afforded
chiral diamine 25 without a loss of stereoselectivity (Scheme 3).
Figure 3. Proposed transition state for the reaction of N-(2-
pyridinesulfonyl)imines 1b with isocyanoacetate 2b. H-atoms
have been omitted for clarity.
Scheme 3. Transformation of 10 to R,β-Diaminoacid 25
gens for pyridine and imine in N-(2-pyridinesulfonyl)-
imines coordinate to hydrogen in protonated 4a. In this
structure, the pyridylgroup in1bplaysanimportantrolein
stabilizing the hydrogen bonding. The addition of the
R-carbanion of isocyanoacetate to the imine in the coordi-
nation sphere of chiral thiourea led to a chiral product.
From the above consideration and the absolute stereo-
chemistry of the product, the proposed transition state for the
enantioselective reaction of R-substituted isocyanoacetates
with N-(2-pyridinesulfonyl)imines 1b is shown in Figure 3.
The Z-geometry of 1b is preferred due to the steric repulsion
between the quinuclidine ring in 4a and phenyl group in 1b.
The enolate of isocyanoacetate approaches N-(2-pyridin-
esulfonyl)imines avoiding steric repulsion with the quinucli-
dine group; therefore the (4R,5S)-isomer is preferably
formed. Therefore, the chiral thiourea 4a would act as a dual
activating organocatalyst. Further studies are required to
fully elucidate the mechanistic detail of the reaction.
Figure 2. Proposed reaction mechanism for the reaction of N-(2-
pyridinesulfonyl)imines with isocyanoacetates.
In conclusion, we developed the first highly enantio-
selective reaction of N-(heteroarenesulfonyl)imines with
R-substituted isocyanoacetates. The obtained products
can be converted to chiral nonprotected imidazolines. This
process offers a simple and efficient route for synthesis of
functionalized 2-imidazolines. Further studies are in pro-
gress to study the potential of N-(heteroarenesulfonyl)-
imines for other process.
On the basis of the obtained results, we envisioned that
catalyst 4a could act in a bifunctional fashion, as pre-
viously proposed in the literature for chiral thiourea
catalysts. The capacity to activate both substrates by
a bifunctional catalyst in a cooperative manner would
result in high catalytic activity and stereoselectivity. The
proposed activating mechanism for the reaction of N-(2-
pyridinesulfonyl)imines with isocyanoacetates using a
chiral thiourea catalyst is shown in Figure 2. Thiourea
functionalities in catalyst 4a coordinates to the isocyano
group in isocyanoacetate by hydrogen bonding to enhance
the acidity of the R-proton on isocyanide.10 Then, a basic
site in catalyst 4a deprotonates the acidic R-proton of
isocyanide. Next, the generated R-isocyano carbanion
converts to a more stable ester enolate.11 Then, two nitro-
Acknowledgment. This work was partly supported by a
Grant-in-Aid for Young Scientists B (20750074) from JSPS.
Supporting Information Available. Representative ex-
perimental procedures and NMR spectra of the products.
This material is available free of charge via Internet at
http://pubs.acs.org.
(11) The possibility that the direct reaction between the generated
R-isocyano carbainons and 1b cannot be ruled out. This reaction path-
way also affords the product with the same stereochemistry.
(10) For strong hydrogen bonding to carbon in isocyanide, see:
Schleyer, P. V. R.; Allerhand, A. J. Am. Chem. Soc. 1962, 84, 1322–
1323. Recently, the enhancement for acidity of isocyanoacetates by
coordinating with achiral thiourea catalysts has been reported; see
ref 6u.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 12, 2012
2963