Highly enantioselective intramolecular Michael reactions by d-camphor-derived triazolium salts

Article abstract of DOI:10.1039/b914805a

Camphor-derived chiral triazolium salts have been found to be highly efficient for asymmetric intramolecular Michael reactions. With 1-5 mol% of the catalyst, the desired products were obtained in excellent yields, with up to 99% ee.

Full text of DOI:10.1039/b914805a

View Article Online / Journal Homepage / Table of Contents for this issue
COMMUNICATION
www.rsc.org/chemcomm | ChemComm
Highly enantioselective intramolecular Michael reactions
by D-camphor-derived triazolium saltsw
Yi Li, Xue-Qiang Wang, Chao Zheng and Shu-Li You*
Received (in Cambridge, UK) 22nd July 2009, Accepted 22nd August 2009
First published as an Advance Article on the web 8th September 2009
DOI: 10.1039/b914805a
Camphor-derived chiral triazolium salts have been found to
be highly efficient for asymmetric intramolecular Michael
reactions. With 1–5 mol% of the catalyst, the desired products
were obtained in excellent yields, with up to 99% ee.
Fig. 2 Chiral triazolium salts derived from camphor.
Inversion of the normal reactivity (umpolung) of aldehydes by
chiral N-heterocyclic carbenes (NHCs) has received increasing
attention recently, providing an unconventional access to
versatile asymmetric organic transformations.1,2 The design
of chiral NHC catalysts based on new backbones is critical for
the success of enantioselective control.3 Among the chiral
NHCs that have been previously reported (Fig. 1), chiral
triazolium salts based on an aminoindanol-backbone initiated
by Rovis et al. and Bode et al. were found to be very successful
in several NHC-catalyzed asymmetric reactions.4a–c In
addition, there are several other successful chiral triazolium
salts such as those derived from tert-leucine by Enders et al.,
and the ones derived from phenylalanine by Scheidt et al.4d,e
Recently, You and coworkers developed chiral bis-bicyclic
triazolium salts that have been proved to be very efficient for
the asymmetric benzoin reaction.4f Notably, the chiral NHCs
developed by the Ye group, the Enders group and the Smith
group were also highly efficient nucleophilic catalysts.2j,o–q,u
Despite these successes, there are only a handful of scaffolds,
and many of them suffer from relatively expensive enantiopure
starting materials. The development of novel NHC catalysts
from readily available chiral sources and the expansion of their
application to various asymmetric organic transformations are
still in great demand.
Camphor exists extensively in nature and has been widely
used for chiral auxiliaries and catalysts.5 Recently, we
designed chiral triazolium salts based on a camphor backbone
and demonstrated that they are efficient catalysts for enantio-
selective intramolecular crossed aldehyde–ketone benzoin
reactions (Fig. 2).6
Recently, Scheidt and coworkers reported for the first time
that NHCs are suitable catalysts for an intramolecular
Michael reaction by generating activated nucleophiles through
b-protonation of the extended umpolung intermediate.7 The
chiral triazolium salt based on an aminoindanol backbone was
found the most efficient catalyst, with up to 99% ee obtained
in the presence of 10 mol% of the catalyst. As part of our
ongoing efforts towards NHC catalysis,6,8 we recently found
that camphor-derived NHC is a highly efficient catalyst for
this reaction. With only 1–5 mol% of the catalyst, the
products were obtained with excellent enantioselectivities up
to 99% ee. Herein, we report the preliminary results.
We first evaluated different camphor-derived triazolium
salts in the intramolecular Michael reaction of 1a. It was
found that a promising result (85% ee) was obtained by
employing 10 mol% of triazolium salt A and DIEA (entry 1,
Table 1). A slightly lower ee resulted by replacing the N-phenyl
substituent with an N-(p-methoxyphenyl) group (entry 2,
Table 1 Screening of the triazolium salts derived from camphora
Entry
Catalyst
Yield (%)b
ee (%)c
Fig. 1 Selected successful chiral triazolium salts.
1
2
3
4
5
A
B
C
D
E
61
54
—
91
—
85
82
—
99
—
State Key Laboratory of Organometallic Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences,
345 Linglin Lu, Shanghai 200032, P. R. China.
E-mail: slyou@mail.sioc.ac.cn; Fax: (+86) 21-54925087
w Electronic supplementary information (ESI) available: Experimental
procedures and analysis data for new compounds. CCDC 740338. For
ESI and crystallographic data of 3 in CIF or other electronic format
see DOI: 10.1039/b914805a
a
Reaction conditions: 1a (0.1 mmol), cat (10 mol%), DIEA (10 mol%)
in CH2Cl2 (2 mL) at 45 1C. After completion of the reaction, MeOH
(5 mL) was added and the mixture was stirred at rt overnight.
b
c
Isolated yields. Determined by chiral HPLC (Chiralpak AD-H).
ꢀc
This journal is The Royal Society of Chemistry 2009
Chem. Commun., 2009, 5823–5825 | 5823

View Article Online
Table 2 Examination of solvents and catalyst loadingsa
Table 3 Substrate scope for the intramolecular Michael reactiona
Yield ee
(%)b
(%)c
Entry
x
Solvent
Yield (%)b
ee (%)c
Entry Substrate
Product
x
1
2
3
4
5
6
7
8
9
10
10
10
10
10
10
10
5
CH2Cl2
THF
Dioxane
t-BuOH
Toluene
Ether
DMF
CH2Cl2
CH2Cl2
91
70
85
46
83
71
41
99
93
99
99
99
98
98
97
94
99
99
1
2
3
4
5
6
7
8
9
10
R1 = Ph, R2 = H
2a
2a
2b
2c
2d
5
1
1
5
5
5
5
5
5
5
99
93
93
85
85
96
52
80
71
80
99
99
95
99
99
99
98
98
98
99
R1 = Ph, R2 = H
R1 = Me, R2 = H
R1 = t-Bu, R2 = H
R1 = p-ClC6H4, R2 = H
R1 = p-MeOC6H4, R2 = H 2e
R1 = p-NO2C6H4, R2 = H 2f
R1 = H, R2 = H
R1 = Ph, R2 = 4-F
R1 = Ph,
2g
2h
2i
1
a
Reaction conditions: 1a (0.1 mmol), D (x mol%), DIEA (10 mol%) in
solvent (2 mL) at 45 1C. After completion of the reaction, MeOH
(5 mL) was added and the mixture was stirred at rt overnight.
R2 = 4,5-CH2OCH2
a
Reaction conditions: 1a (0.1 mmol), D (x mol%), DIEA (10 mol%) in
solvent (2 mL) at 45 1C. After completion of the reaction, MeOH
(5 mL) was added and the mixture was stirred at rt overnight.
b
c
Isolated yields. Determined by chiral HPLC (Chiralpak AD-H).
b
c
Isolated yields. Determined by chiral HPLC.
Table 1). Whereas triazolium salt C, the most efficient catalyst
for the asymmetric intramolecular crossed aldehyde–ketone
benzoin reaction,6 failed to promote the reaction (entry 3,
Table 1), to our delight, precatalyst D bearing an N-mesityl
substituent gave 2a in 91% yield with 99% ee (entry 4,
Table 1).
Different solvents and catalyst loadings were also examined.
As shown in Table 2, with 10 mol% precatalyst D, common
organic solvents such as THF, dioxane, t-BuOH, toluene and
ether all resulted in excellent ees (97–99%) (entries 2–6,
Table 2). However, the reaction in DMF was not as efficient
as in other solvents and provided the product in only 41%
yield with 94% ee (entry 7, Table 2). Notably, we were pleased
to find that an excellent enantioselectivity (99% ee) was
obtained in CH2Cl2, even when the catalyst loading was down
to 1 mol% (entry 9, Table 2).
The scope of the NHC-catalyzed intramolecular Michael
reaction was further explored by testing a wide range of
substrates under the optimized conditions. As listed in
Table 3, the NHC generated from D and DIEA proved to
be highly efficient for a wide range of substrates (up to 99%
yield, 99% ee). Both electron-withdrawing and electron-
donating groups on the enone moiety were well tolerated,
resulting in good yields and excellent ees (entries 5–7, Table 3).
Besides the aromatic substituents on the enone moiety, alkyl
substituents, such as methyl and tert-butyl, also went well in
all cases (entries 3–4, Table 3). The bisaldehyde 1g was also
well tolerated, providing the desymmetrization product in
80% yield with 98% ee (entry 8, Table 3). To our delight,
substrates bearing either electron-withdrawing or electron-
donating groups (R2) on the aromatic moiety were also
tolerated (entries 9–10, Table 3).
Fig. 3 Postulated model of transition states. The hydrogen atoms on
the NHC catalyst are omitted for clarity.
Interestingly, the reaction of 3 under the optimized condi-
tions led to the formation of Michael addition product 4 as a
minor product in only 18% yield with 31% ee (eqn (1)).
g-Butyrolactone 5 was isolated in 55% yield, likely through
NHC-catalyzed annulations of enal and ketone.
ð1Þ
The current reaction was also applied to construct a chiral
quaternary carbon center. Substrate 3 with a trifluoromethyl
substituent on the b-position of the enone moiety was
synthesized and its structure was confirmed through the
X-ray analysis.w
A postulated model of transition state is depicted in Fig. 3.
The exceptional enantioselectivity is rationalized by the high
preference for the favored transition state where the enone lies
on the bottom to avoid the steric collision with camphor
backbone in the unfavored transition state.
ꢀc
This journal is The Royal Society of Chemistry 2009
5824 | Chem. Commun., 2009, 5823–5825

View Article Online
In conclusion, camphor-derived chiral triazolium salts have
been found to be highly efficient for asymmetric intramolecular
Michael reaction. With 1–5 mol% of the NHC catalyst, the
desired products were obtained in excellent yields and ees.
Further application of these camphor-derived triazolium salts
in asymmetric catalysis, and improvement of the chemo- and
enantioselectivity of the chiral quaternary carbon formation
reaction are currently under way.
E. Suresh, Org. Lett., 2009, 11, 2507; For recent examples on
NHC as nucleophilic catalysts: (o) Y.-R. Zhang, L. He, X. Wu,
P.-L. Shao and S. Ye, Org. Lett., 2008, 10, 277; (p) Y.-R. Zhang,
H. Lv, D. Zhou and S. Ye, Chem.–Eur. J., 2008, 14, 8473;
(q) N. Duguet, C. D. Campbell, A. M. Z. Slawin and
A. D. Smith, Org. Biomol. Chem., 2008, 6, 1108;
(r) C. D. Campbell, N. Duguet, K. A. Gallagher, J. E. Thomson,
A. G. Lindsay, A. C. O’Donoghue and A. D. Smith, Chem.
Commun., 2008, 3528; (s) J. E. Thomson, C. D. Campbell,
C. Concellon, N. Duguet, K. Rix, A. M. Z. Slawin and
A. D. Smith, J. Org. Chem., 2008, 73, 2784; (t) J. E. Thomson,
A. F. Kyle, K. A. Gallagher, P. Lenden, C. Concellon,
L. C. Morrill, A. J. Miller, C. Joannesse, A. M. Z. Slawin and
A. D. Smith, Synthesis, 2008, 17, 2805; (u) X.-L. Huang, L. He,
P.-L. Shao and S. Ye, Angew. Chem., Int. Ed., 2009, 48, 192.
3 Comprehensive Asymmetric Synthesis, ed. E. N. Jacobsen, A. Pfaltz
and H. Yamamoto, Springer, Berlin, 1999, vol. I, II, and III.
4 (a) M. S. Kerr, J. Read de Alaniz and T. Rovis, J. Org. Chem., 2005,
70, 5725; (b) M. He, J. R. Struble and J. W. Bode, J. Am. Chem.
Soc., 2006, 128, 8418; (c) J. R. Struble, J. Kaeobamrung and
J. W. Bode, Org. Lett., 2008, 10, 957; (d) D. Enders and
U. Kallfass, Angew. Chem., Int. Ed., 2002, 41, 1743;
(e) M. Wadamoto, E. M. Phillips, T. E. Reynolds and
K. A. Scheidt, J. Am. Chem. Soc., 2007, 129, 10098; (f) Y.-J. Ma,
S.-P. Wei, J. Wu, F. Yang, B. Liu, J.-B. Lan, S.-Y. Yang and
J.-S. You, Adv. Synth. Catal., 2008, 350, 2645.
We gratefully acknowledge the National Natural Science
Foundation of China (20872159, 20732006), National Basic
Research Program of China (973 Program 2009CB825300),
and the Chinese Academy of Sciences for generous financial
support.
Notes and references
1 For reviews: (a) D. Enders and T. Balensiefer, Acc. Chem. Res.,
2004, 37, 534; (b) J. S. Johnson, Angew. Chem., Int. Ed., 2004, 43,
1326; (c) M. Christmann, Angew. Chem., Int. Ed., 2005, 44, 2632;
(d) K. Zeitler, Angew. Chem., Int. Ed., 2005, 44, 7506; (e) N. Marion,
S. Dez-Gonzalez and S. P. Nolan, Angew. Chem., Int. Ed., 2007, 46,
´
2988; (f) D. Enders, O. Niemeier and A. Henseler, Chem. Rev., 2007,
107, 5606; (g) V. Nair, S. Vellalath and B. P. Badu, Chem. Soc. Rev.,
2008, 37, 2691.
5 Selected examples: (a) S. Ye, Z.-Z. Huang, C.-A. Xia, Y. Tang and
L.-X. Dai, J. Am. Chem. Soc., 2002, 124, 2432; (b) M. Kitamura,
H. Oka, S. Suga and R. Noyori, Organic Synthesis, 2003, 79, 139;
2 For recent examples on NHC as umpolung catalysts:
(a) E. M. Phillips, T. E. Reynolds and K. A. Scheidt, J. Am. Chem.
Soc., 2008, 130, 2416; (b) J. Seayad, P. K. Patra, Y. Zhang and
J. Y. Ying, Org. Lett., 2008, 10, 953; (c) F. T. Wong, P. K. Patra,
J. Seayad, Y. Zhang and J. Y. Ying, Org. Lett., 2008, 10, 2333;
(d) M. He and J. W. Bode, J. Am. Chem. Soc., 2008, 130, 418;
(e) M. Rommel, T. Fukuzumi and J. W. Bode, J. Am. Chem. Soc.,
2008, 130, 17266; (f) M. He, B. J. Beahm and J. W. Bode, Org. Lett.,
2008, 10, 3817; (g) B. E. Maki and K. A. Scheidt, Org. Lett., 2008,
10, 4331; (h) A. Chan and K. A. Scheidt, J. Am. Chem. Soc., 2008,
130, 2740; (i) Q. Liu, S. Perreault and T. Rovis, J. Am. Chem. Soc.,
2008, 130, 14066; (j) D. Enders and J.-W. Han,
Tetrahedron: Asymmetry, 2008, 19, 1367; (k) E. M. Phillips,
M. Wadamoto, H. S. Roth, A. W. Ott and K. A. Scheidt,
Org. Lett., 2009, 11, 105; (l) L. Wang, K. Thai and M. Gravel,
Org. Lett., 2009, 11, 891; (m) L. Yang, B. Tan, F. Wang and
G.-F. Zhong, J. Org. Chem., 2009, 74, 1744; (n) V. Nair,
B. P. Babu, S. Vellalath, V. Varghese, A. E. Raveendran and
(c) H. Y. Kim, A. E. Lurain, P. Garcıa-Garcıa, P. J. Carroll and
´ ´
P. J. Walsh, J. Am. Chem. Soc., 2005, 127, 13138;
(d) R. J. Kloetzing, T. Thaler and P. Knochel, Org. Lett., 2006, 8,
1125; (e) X.-M. Deng, P. Cai, S. Ye, X.-L. Sun, W.-W. Liao, K. Li,
Y. Tang, Y.-D. Wu and L.-X. Dai, J. Am. Chem. Soc., 2006, 128,
9730.
6 Y. Li, Z. Feng and S.-L. You, Chem. Commun., 2008, 2263.
7 E. M. Phillips, M. Wadamoto, A. Chan and K. A. Scheidt, Angew.
Chem., Int. Ed., 2007, 46, 3107.
8 (a) G.-Q. Li, L.-X. Dai and S.-L. You, Chem. Commun., 2007, 852;
(b) G.-Q. Li, Y. Li, L.-X. Dai and S.-L. You, Org. Lett., 2007, 9,
3519; (c) G.-Q. Li, Y. Li, L.-X. Dai and S.-L. You, Adv. Synth.
Catal., 2008, 350, 1258; (d) Y. Li, Z.-A. Zhao, H. He and S.-L. You,
Adv. Synth. Catal., 2008, 350, 1885; (e) G.-Q. Li, L.-X. Dai and
S.-L. You, Org. Lett., 2009, 11, 1623; (f) Y. Li, F.-Q. Shi, Q.-L. He
and S.-L. You, Org. Lett., 2009, 11, 3182.
ꢀc
This journal is The Royal Society of Chemistry 2009
Chem. Commun., 2009, 5823–5825 | 5825