Copper-catalyzed 1,4-addition of organoboronates to alkylidene cyanoacetates: Mechanistic insight and application to asymmetric catalysis

Article abstract of DOI:10.1002/anie.201008196

In addition: A copper/N-heterocyclic carbene(NHC)-catalyzed 1,4-addition of organoboronates to alkylidene cyanoacetates was developed, in which the catalytic cycle is proposed to consist of a transmetalation/insertion/ligand exchange. An effective asymmetric variant has also been achieved by the use of a chiral NHC ligand (see scheme). Copyright

Full text of DOI:10.1002/anie.201008196

Communications
DOI: 10.1002/anie.201008196
Homogeneous Catalysis
Copper-Catalyzed 1,4-Addition of Organoboronates to Alkylidene
Cyanoacetates: Mechanistic Insight and Application to Asymmetric
Catalysis**
Keishi Takatsu, Ryo Shintani,* and Tamio Hayashi*
Table 1: Copper-catalyzed 1,4-addition of phenylboronate 2 to electron-
deficient olefins 1.
The copper-catalyzed 1,4-addition of organometallic reagents
to a,b-unsaturated compounds is a powerful method for the
efficient construction of carbon–carbon bonds.[1] Highly
reactive nucleophiles such as Grignard reagents,[1a–c,2] dior-
ganozinc compounds,[1d,e,3] and triorganoaluminum com-
pounds[1d–f,4] are widely employed in these reactions, but the
use of milder nucleophiles has been much less studied; in fact
there has been only one such study reported, wherein Lee and
Hoveyda used organo(trifluoro)silanes as nucleophiles in the
presence of a fluoride additive.[5] In contrast, although the use
of organoboronic acids and their derivatives would be highly
attractive in view of their availability, stability, and ease of
handling, there has been no such report to date as far as we
are aware.[6–8] In this context, we herein describe a 1,4-
addition of aryl boronic acid esters to alkylidene cyanoace-
tates catalyzed by a copper/N-heterocyclic carbene complex.
We also describe the mechanistic details of the reaction and
also demonstrate that the use of a chiral N-heterocyclic
carbene ligand leads to an effective asymmetric variant of this
process.[9]
Entry
Substrate (Z1, Z2)
Product
Yield [%][a]
1
2
3
4
1a (CO2tBu, H)
1b (CN, H)
1c (CO2tBu, CO2tBu)
1d (CN, CN)
1e (CO2tBu, CN)
1e
3a
3b
3c
3d
3e
3e
3e
0[b]
0[b]
30[b]
67
5
92
6[c]
7[d]
89
1e
8[b]
[a] Yield of isolated product. [b] Determined by 1H NMR spectroscopy
with an internal standard (MeNO2). [c] The reaction was conducted in
THF. [d] The reaction was conducted in the absence of KOtBu.
In an initial investigation we attempted a reaction of tert-
butyl cinnamate (1a) with phenylboronic acid neopentylgly-
col ester (2) in the presence of [Cu(OtBu)(IPr)][10] (5 mol%)
and KOtBu (2.0 equiv) in dioxane at 308C, but no 1,4-
addition product was observed under these conditions
(Table 1, entry 1). The use of cinnamonitrile (1b) was also
unproductive (Table 1, entry 2), but more-electron-deficient
substrates such as di-tert-butyl benzylidenemalonate (1c) and
benzylidenemalononitrile (1d) led to the formation of 1,4-
adducts in moderate yield (30% yield and 67% yield; Table 1,
entries 3 and 4, respectively). We subsequently found that
tert-butyl benzylidenecyanoacetate (1e) reacted more
smoothly under the same conditions to give 1,4-adduct 3e in
92% yield after aqueous workup (Table 1, entry 5). A
similarly high yield was achieved for the reaction in THF
(Table 1, entry 6), but the reaction became very sluggish in
the absence of KOtBu (Table 1, entry 7).
A series of stoichiometric reactions were then conducted
to gain some insight into the catalytic cycle for the reaction of
substrate 1e with phenylboronate 2 described above:[6d,k] The
reaction of [Cu(OtBu)(IPr)] with 2 proceeded smoothly in
dioxane at 308C to give [CuPh(IPr)] (4) in 64% yield after
recrystallization [Eq. (1) and Figure 1a]. Complex 4 thus
obtained underwent insertion of 1e in [D8]THF at 308C to
give copper enolate 5 almost quantitatively [Eq. (2) and
Figure 1b]. The identity of 5 was confirmed by 1H and
13C NMR spectroscopy as well as by HRMS.[11] Protonolysis
of 5 produced 1,4-adduct 3e cleanly in 84% yield of the
isolated product. To the best of our knowledge, this represents
the first example of the direct observation of a copper enolate
in the context of a 1,4-addition of an organocopper species to
an electron-deficient olefin.[12] Treatment of compound 5 with
1.0 equivalent of KOtBu in [D8]THF at 308C gave a clean
1H NMR spectrum consisting of signals that correspond to
[Cu(OtBu)(IPr)] and potassium enolate 6 [Eq. (3) and Fig-
ure 1c]. The signals assigned to compound 6 matched with the
ones that formed on treatment of the isolated compound 3e
with 1.0 equivalent of KOtBu in [D8]THF, thereby confirming
its identity as a potassium enolate of the 1,4-adduct. In
addition to these stoichiometric reactions, we also made the
following observations: Copper enolate 5 remained intact and
[*] K. Takatsu, Dr. R. Shintani, Prof. Dr. T. Hayashi
Department of Chemistry
Graduate School of Science, Kyoto University
Sakyo, Kyoto 606-8502 (Japan)
Fax: (+81)75-753-3988
E-mail: shintani@kuchem.kyoto-u.ac.jp
thayashi@kuchem.kyoto-u.ac.jp
[**] Support has been provided in part by a Grant-in-Aid for Young
Scientists (B), the Ministry of Education, Culture, Sports, Science,
and Technology (Japan), and in part by Mitsubishi Tanabe Pharma
Corporation. K.T. thanks the JSPS for a fellowship.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201008196.
5548
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Angew. Chem. Int. Ed. 2011, 50, 5548 –5552

Figure 1. 1H NMR spectra in [D8]THF of: a) [CuPh(IPr)] (4), b) copper enolate 5 obtained from the reaction of 4 with 1e, and c) [Cu(OtBu)(IPr)]
and potassium enolate 6 obtained from the reaction of 5 with KOtBu.
did not undergo direct transmetalation with phenylboronate 2
in [D8]THF at 308C; phenylcopper complex 4 did not show
any detectable interactions with KOtBu or phenylboronate 2
in [D8]THF at 308C; and the rate of reaction of 1e with
phenylcopper 4 was unaffected by the addition of KOtBu and/
or phenylboronate 2.
On the basis of these results, a proposed catalytic cycle for
the reaction depicted in Table 1, entry 5 is illustrated in
Scheme 1.[6d,k] Thus, [Cu(OtBu)(IPr)] undergoes transmetala-
tion with phenylboronate 2 to give phenylcopper species 4.
Insertion of 1e into 4 then gives copper enolate 5, which
reacts with KOtBu to regenerate [Cu(OtBu)(IPr)] along with
potassium enolate 6. The final product 3e is obtained from 6
after aqueous workup. This proposed mechanism involving
only copper(I) species throughout the cycle is in stark contrast
to the reported reaction mechanisms for the copper-catalyzed
1,4-addition of organomagnesium or organozinc reagents to
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5549

Communications
tether derived from 1-amino-2-indanols ((S,R)-7d, 68% ee
and (S,S)-7e, 76% ee; Table 2, entries 4 and 5, respectively).
We subsequently found that changing the 2,6-dimethylphenyl
group on the other nitrogen atom of (S,S)-7e for a 9-anthryl
group ((S,S)-7 f) led to the formation of 3 f with 88% ee
(Table 2, entry 6), and the use of CuBr instead of CuCl as a
catalyst precursor turned out to be optimal (92% ee; Table 2,
entry 7). The absolute configuration at the b position of 3 f
thus obtained was determined to be R by X-ray crystallo-
graphic analysis after de-esterification.[18]
Scheme 1. Proposed catalytic cycle for the copper-catalyzed 1,4-addi-
tion of phenylboronate 2 to 1e ([Cu]=Cu(IPr)).
A combination of CuBr and (S,S)-7 f resulted in the
triethylmethyl ester 8a giving a slightly higher enantioselec-
tivity than tert-butyl ester 1 f (Table 3, entry 1 versus Table 2,
a,b-unsaturated carbonyl compounds. In these latter cases,
the active organocopper(I) species is tightly associated with
magnesium or zinc salts to facilitate the oxidative addition of
a,b-unsaturated compounds. The resulting copper(III) inter-
mediate then undergoes reductive elimination with formation
of a carbon–carbon bond.[13,14]
Table 3: Copper-catalyzed asymmetric 1,4-addition of organoboronates
to 8: Scope.
Having established the viability of the copper-catalyzed
1,4-addition of organoboronates to alkylidene cyanoacetates,
we turned our attention to the development of its asymmetric
variant by employing chiral N-heterocyclic carbene (NHC)
ligands.[15,16] As a starting point, we carried out the reaction of
tert-butyl 4-chlorobenzylidenecyanoacetate (1 f) with phenyl-
boronate 2 in the presence of CuCl (5 mol%) and the chiral
NHC salt (S)-7a,[6k,17] which has a tert-leucinol-derived tether
(5.5 mol%), in dioxane at 308C. Under these conditions, 1,4-
adduct 3 f was obtained in 85% yield, but the enantioselec-
tivity was only moderate (47% ee; Table 2, entry 1). Chang-
ing the substitutent on the ligand tether from tert-butyl to
isopropyl ((S)-7b, 62% ee; Table 2, entry 2) or phenyl ((S)-
7c, 65% ee; Table 2, entry 3) gave somewhat higher enantio-
selectivity, and further improvement was observed by using a
Entry
8
R’
Product
Yield [%][a]
ee [%][b]
1
2
3
4
5
6
7
8a
8b
8c
8d
8e
8 f
8g
8h
8i
8i
8i
8i
8i
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
(R)-9a
(R)-9b
(R)-9c
(R)-9d
(R)-9e
(R)-9 f
(R)-9g
(S)-9h
(S)-9a
(S)-9c
(S)-9d
(S)-9e
(S)-9i
(R)-9h
(S)-9j
(R)-9k
93
92
88
82
87
79
78
57
84
87
81
87
95
88
70[d]
91
94
87
91
92
88
91
94
90
88
94
92
91
89
73
77
95
8[c]
9
4-ClC6H4
4-MeC6H4
4-MeOC6H4
3-MeC6H4
2-naphthyl
1-cyclohexenyl
Me
10
11
12
13
14
15[c]
16
8i
8i
8a
Table 2: Copper-catalyzed asymmetric 1,4-addition of phenylboronate 2
to 1 f: Ligand effect.
4-MeC6H4
[a] Yield of isolated product. [b] Determined by HPLC on a chiral
stationary phase with hexane/2-propanol after de-esterification. [c] The
reaction was conducted with 3.0 equiv of the organoboronate and
3.0 equiv of KOtBu in the presence of 10 mol% catalyst. [d] Determined
by 1H NMR spectroscopy after chromatographic purification on silica
gel.
Entry
Ligand salt
Yield [%][a]
ee [%][b]
1
2
3
4
(S)-7a
(S)-7b
(S)-7c
(S,R)-7d
(S,S)-7e
(S,S)-7 f
(S,S)-7 f
85
85
84
81
86
82
86
47 (R)
62 (R)
65 (R)
68 (R)
76 (R)
88 (R)
92 (R)
entry 7).[19] Furthermore, not only 8a but also several other
aryl-, heteroaryl-, and alkenyl-substituted methylidenecya-
noacetates (8b–h) can be used in the reaction with phenyl-
boronate to give 1,4-adducts 9 with high enantioselectivity
(57–93% yield, 87–94% ee; Table 3, entries 1–8). Various aryl
groups can be incorporated effectively from the nucleophilic
component into benzylidenecyanoacetate 8i with a similarly
high efficiency (81–95% yield, 88–94% ee; Table 3, entries 9–
13). In addition to these aryl boronates, 1-cyclohexenyl- and
methylboronates can also be used, although the ee values
become somewhat lower (70 and 88% yield, 73 and 77% ee;
Table 3, entries 14 and 15, respectively). Furthermore, 1,1-
diaryl methylcyanoacetates having substituents on both of the
5
6
7[c]
[a] Yield of isolated product. [b] Determined by HPLC on a chiral
stationary phase (Chiralpak AD-H column) with hexane/2-propanol=
95:5 after de-esterification. [c] The reaction was conducted with CuBr
instead of CuCl.
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[4] For recent examples, see a) X. Tang, A. J. Blake, W. Lewis, S.
Woodward, Tetrahedron: Asymmetry 2009, 20, 1881; b) D.
Mꢈller, C. Hawner, M. Tissot, L. Palais, A. Alexakis, Synlett
2010, 1694; c) M. Tissot, D. Mꢈller, S. Belot, A. Alexakis, Org.
Lett. 2010, 12, 2770.
aryl groups can be prepared in a highly enantioselective
fashion (91% yield, 95% ee; Table 3, entry 16).
The utility of the present asymmetric catalysis is high-
lighted in the stereoselective and straightforward synthesis of
enantioenriched
3-(3,4-dichlorophenyl)-3-phenylpropio-
[5] K. Lee, A. H. Hoveyda, J. Org. Chem. 2009, 74, 4455.
[6] For examples of copper-catalyzed carbon–carbon bond-forming
reactions with organoboronic acid derivatives, see a) R. Wada,
K. Oisaki, M. Kanai, M. Shibasaki, J. Am. Chem. Soc. 2004, 126,
8910; b) R. Wada, T. Shibuguchi, S. Makino, K. Oisaki, M.
Kanai, M. Shibasaki, J. Am. Chem. Soc. 2006, 128, 7687; c) D.
Tomita, M. Kanai, M. Shibasaki, Chem. Asian J. 2006, 1, 161;
d) T. Ohishi, M. Nishiura, Z. Hou, Angew. Chem. 2008, 120,
5876; Angew. Chem. Int. Ed. 2008, 47, 5792; e) J. Takaya, S.
Tadami, K. Ukai, N. Iwasawa, Org. Lett. 2008, 10, 2697; f) Y.
Yamamoto, N. Kirai, Y. Harada, Chem. Commun. 2008, 2010;
g) Y. Yamamoto, N. Kirai, Org. Lett. 2008, 10, 5513; h) H. Zheng,
Q. Zhang, J. Chen, M. Liu, S. Cheng, J. Ding, H. Wu, W. Su, J.
Org. Chem. 2009, 74, 943; i) H. Ohmiya, U. Yokobori, Y. Makida,
M. Sawamura, J. Am. Chem. Soc. 2010, 132, 2895; j) A. M.
Whittaker, R. P. Rucker, G. Lalic, Org. Lett. 2010, 12, 3216; k) R.
Shintani, K. Takatsu, T. Hayashi, Chem. Commun. 2010, 46,
6822.
[7] For examples of copper-catalyzed 1,4-addition of diboron
compounds, see a) H. Ito, H. Yamanaka, J. Tateiwa, A.
Hosomi, Tetrahedron Lett. 2000, 41, 6821; b) K. Takahashi, T.
Ishiyama, N. Miyaura, Chem. Lett. 2000, 29, 982; c) K. Takaha-
shi, T. Ishiyama, N. Miyaura, J. Organomet. Chem. 2001, 625, 47;
d) S. Mun, J.-E. Lee, J. Yun, Org. Lett. 2006, 8, 4887; e) J.-E. Lee,
J. Yun, Angew. Chem. 2008, 120, 151; Angew. Chem. Int. Ed.
2008, 47, 145; f) X. Feng, J. Yun, Chem. Commun. 2009, 6577;
g) I.-H. Chen, L. Yin, W. Itano, M. Kanai, M. Shibasaki, J. Am.
Chem. Soc. 2009, 131, 11664; h) J. M. OꢉBrien, K. Lee, A. H.
Hoveyda, J. Am. Chem. Soc. 2010, 132, 10630.
nitrile (10; Scheme 2), which is a key intermediate in the
synthesis of the potent psychoactive (+)-indatraline.[20,21]
Scheme 2. Asymmetric synthesis of compound 10, an intermediate for
(+)-indatraline. Ts=toluene-4-sulfonyl.
In summary, we have developed a 1,4-addition of organo-
boronates to alkylidene cyanoacetates catalyzed by a copper/
N-heterocyclic carbene under mild conditions. The catalytic
cycle consisting of transmetalation/insertion/ligand exchange
has been proposed on the basis of a series of stoichiometric
reactions. Furthermore, an effective asymmetric variant has
also been achieved through the use of a newly synthesized
chiral N-heterocyclic carbene ligand.
[8] For examples of copper-catalyzed 1,4-addition of silylboronates,
see K. Lee, A. H. Hoveyda, J. Am. Chem. Soc. 2010, 132, 2898.
[9] Rhodium-catalyzed asymmetric 1,4-addition of aryl boronic
acids to alkylidene cyanoacetates with up to 99% ee has been
reported: S. Sꢄrgel, N. Tokunaga, K. Sasaki, K. Okamoto, T.
Hayashi, Org. Lett. 2008, 10, 589.
Received: December 27, 2010
Revised: March 29, 2011
Published online: April 28, 2011
[10] N. P. Mankad, D. S. Laitar, J. P. Sadighi, Organometallics 2004,
23, 3369.
Keywords: 1,4-addition · asymmetric catalysis · copper ·
N-heterocyclic carbenes · organoboronates
.
[11] Analytical data for 5: 1H NMR ([D8]THF): d = 7.57 (s, 2H), 7.52
(t, J = 7.8 Hz, 2H), 7.36 (d, J = 7.8 Hz, 4H), 7.01–6.96 (m, 8H),
6.96–6.91 (m, 2H), 4.87 (s, 1H), 2.57 (sept, J = 6.8 Hz, 4H), 1.26–
1.19 ppm (m, 33H); 13C NMR ([D8]THF): d = 171.6, 148.0,
146.5, 135.6, 131.3, 129.4, 129.0, 128.0, 125.3, 125.2, 125.0, 75.2,
51.3, 47.8, 29.6, 29.3, 25.2, 24.0 ppm; HRMS (ESI-TOF) calcd for
C47H57CuN3O2 (M + H+): 758.3741, found: 758.3739.
[1] For reviews, see a) S.-Y. Wang, T.-P. Loh, Chem. Commun. 2010,
46, 8694; b) S. R. Harutyunyan, T. den Hartog, K. Geurts, A. J.
Minnaard, B. L. Feringa, Chem. Rev. 2008, 108, 2824; c) F.
Lꢀpez, A. J. Minnaard, B. L. Feringa, Acc. Chem. Res. 2007, 40,
179; d) A. Alexakis, J. E. Bꢁckvall, N. Krause, O. Pꢂmies, M.
Diꢃguez, Chem. Rev. 2008, 108, 2796; e) J. Christoffers, G.
Koripelly, A. Rꢄsiak, M. Rossle, Synthesis 2007, 1279; f) P.
von Zezschwitz, Synthesis 2008, 1809.
[2] For recent examples, see a) P. H. Bos, A. J. Minnaard, B. L.
Feringa, Org. Lett. 2008, 10, 4219; b) T. den Hartog, A. Rudolph,
B. Maciꢅ, A. J. Minnaard, B. L. Feringa, J. Am. Chem. Soc. 2010,
132, 14349; c) J. C. H. Lee, D. G. Hall, J. Am. Chem. Soc. 2010,
132, 5544.
[3] For recent examples, see a) A. Wilsily, T. Lou, E. Fillion,
Synthesis 2009, 2066; b) P. H. Bos, B. Maciꢅ, M. ꢆ. Fernꢅndez-
Ibꢅꢇez, A. J. Minnaard, B. L. Feringa, Org. Biomol. Chem. 2010,
8, 47; c) L. Palais, L. Babel, A. Quintard, S. Belot, A. Alexakis,
Org. Lett. 2010, 12, 1988; d) K. Endo, M. Ogawa, T. Shibata,
Angew. Chem. 2010, 122, 2460; Angew. Chem. Int. Ed. 2010, 49,
2410.
[12] For examples of NMR spectroscopic studies on 1,4-addition of
organocuprates, see a) B. Christenson, T. Olsson, C. Ullenius,
Tetrahedron 1989, 45, 523; b) S. H. Bertz, R. A. Smith, J. Am.
Chem. Soc. 1989, 111, 8276; c) S. H. Bertz, M. K. Carlin, D. A.
Deadwyler, M. Murphy, C. A. Ogle, P. H. A. Seagle, J. Am.
Chem. Soc. 2002, 124, 13650; see also: d) K. Nilsson, C. Ullenius,
N. Krause, J. Am. Chem. Soc. 1996, 118, 4194.
[13] a) S. R. Harutyunyan, F. Lopꢃz, W. R. Browne, A. Correa, D.
Peꢇa, R. Badorrey, A. Meetsma, A. J. Minnaard, B. L. Feringa, J.
Am. Chem. Soc. 2006, 128, 9103; b) A. Alexakis, C. Benhaim, S.
Rosset, M. Humam, J. Am. Chem. Soc. 2002, 124, 5262; see also:
c) K. Nakano, Y. Bessho, M. Kitamura, Chem. Lett. 2003, 32, 224.
[14] For relevant theoretical studies, see a) E. Nakamura, S. Mori, K.
Morokuma, J. Am. Chem. Soc. 1997, 119, 4900; b) E. Nakamura,
M. Yamanaka, S. Mori, J. Am. Chem. Soc. 2000, 122, 1826; c) M.
Yamanaka, E. Nakamura, Organometallics 2001, 20, 5675; d) M.
Yamanaka, E. Nakamura, J. Am. Chem. Soc. 2005, 127, 4697.
Angew. Chem. Int. Ed. 2011, 50, 5548 –5552
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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[15] For reviews, see a) J. Wencel, M. Mauduit, H. Hꢃnon, S. Kehrli,
c) D. Martin, S. Kehrli, M. d’Augustin, H. Clavier, M. Mauduit,
A. Alexakis, J. Am. Chem. Soc. 2006, 128, 8416; d) S. Kehrli, D.
Martin, D. Rix, M. Mauduit, A. Alexakis, Chem. Eur. J. 2010, 16,
9890; See also: e) P. L. Arnold, M. Rodden, K. M. Davis, A. C.
Scarisbrick, A. J. Blake, C. Wilson, Chem. Commun. 2004, 1612.
[18] CCDC 804933 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.
cam.ac.uk/data_request/cif.
[19] a) The use of a substrate having a smaller ester group such as a
methyl ester gives the product with lower enantioselectivity
(e.g., 78% yield, 76% ee for the reaction of the methyl ester
variant of 8a with phenylboronate 2); b) the use of organo-
boronic acid pinacol esters instead of neopentylglycol esters
results in lower enantioselectivity by ca. 10%; c) essentially the
same result is obtained by conducting the reaction in the
presence of tBuOH (1.0 equiv) or by using NaOtBu as the base;
d) significantly lower reactivity is observed by using KOMe as
the base (e.g., 45% yield, 92% ee for the reaction of 8a with
phenylboronate 2), presumably because of the poor solubility of
KOMe in dioxane.
A. Alexakis, Aldrichimica Acta 2009, 42, 43; b) L. H. Gade, S.
Bellemin-Laponnaz, Coord. Chem. Rev. 2007, 251, 718; c) V.
Cꢃsar, S. Bellemin-Laponnaz, L. H. Gade, Chem. Soc. Rev. 2004,
33, 619; d) M. Perry, K. Burgess, Tetrahedron: Asymmetry 2003,
14, 951.
[16] For recent progress, see a) R. E. Giudici, A. H. Hoveyda, J. Am.
Chem. Soc. 2007, 129, 3824; b) T. L. May, M. K. Brown, A. H.
Hoveyda, Angew. Chem. 2008, 120, 7468; Angew. Chem. Int. Ed.
2008, 47, 7358; c) Y. Lee, H. Jang, A. H. Hoveyda, J. Am. Chem.
Soc. 2009, 131, 18234; d) K. Akiyama, F. Gao, A. H. Hoveyda,
Angew. Chem. 2010, 122, 429; Angew. Chem. Int. Ed. 2010, 49,
419; e) M. R. Chaulagain, G. J. Sormunen, J. Montgomery, J.
Am. Chem. Soc. 2007, 129, 9568; f) Y.-X. Jia, J. M. Hillgren, E. L.
Watson, S. P. Marsden, E. P. Kꢈndig, Chem. Commun. 2008,
4040; g) H. Hꢃnon, M. Mauduit, A. Alexakis, Angew. Chem.
2008, 120, 9262; Angew. Chem. Int. Ed. 2008, 47, 9122; h) T.
Uchida, T. Katsuki, Tetrahedron Lett. 2009, 50, 4741; i) K. B.
Selim, Y. Matsumoto, K. Yamada, K. Tomioka, Angew. Chem.
2009, 121, 8889; Angew. Chem. Int. Ed. 2009, 48, 8733; j) N.
Shibata, M. Okamoto, Y. Yamamoto, S. Sakaguchi, J. Org. Chem.
2010, 75, 5707.
[20] H. M. Davies, T. M. Gregg, Tetrahedron Lett. 2002, 43, 4951.
[21] a) K. P. Bogeso, A. V. Christensen, J. Hyttel, T. Liljefors, J. Med.
Chem. 1985, 28, 1817; b) J. Hyttel, J. J. Larsen, J. Neurochem.
1985, 44, 1615.
[17] For precedents of this family of chiral NHCs, see a) H. Clavier,
L. Coutable, J.-C. Guillemin, M. Mauduit, Tetrahedron: Asym-
metry 2005, 16, 921; b) H. Clavier, L. Coutable, L. Toupet, J.-C.
Guillemin, M. Mauduit, J. Organomet. Chem. 2005, 690, 5237;
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Angew. Chem. Int. Ed. 2011, 50, 5548 –5552