Chiral bicycle imidazole nucleophilic catalysts: Rational design, facile synthesis, and successful application in asymmetric Steglich rearrangement

Article abstract of DOI:10.1021/ja109069k

A new type of chiral bicycle imidazole nucleophilic catalyst was rationally designed, facilely synthesized, and successfully applied in an asymmetric Steglich rearrangement with good to excellent yield and enantioselectivity at ambient temperature. Moreov

Full text of DOI:10.1021/ja109069k

Published on Web 10/26/2010
Chiral Bicycle Imidazole Nucleophilic Catalysts: Rational Design, Facile
Synthesis, and Successful Application in Asymmetric Steglich Rearrangement
Zhenfeng Zhang, Fang Xie, Jia Jia, and Wanbin Zhang*
School of Chemistry and Chemical Engineering, Shanghai Jiao Tong UniVersity, Shanghai 200240, China
Received October 8, 2010; E-mail: wanbin@sjtu.edu.cn
influence to activity, we designed a rigid bicyclic structure of 6,7-
Abstract: A new type of chiral bicycle imidazole nucleophilic
dihydro-5H-pyrrolo[1,2-a]imidazole (abbreviated as DPI) with a
catalyst was rationally designed, facilely synthesized, and suc-
cessfully applied in an asymmetric Steglich rearrangement with
good to excellent yield and enantioselectivity at ambient temper-
ature. Moreover, it can be easily recycled with almost no reduction
of catalytic efficiency. This is the first example for the successful
chiral imidazole nucleophilic catalyst without H-bonding assistance.
much larger ∠R as the skeleton of our catalysts (Figure 1).
Therefore, good stereocontrol would be expected since the stereo-
control group R designed at the 7-position of DPI is nearby to the
catalytic active site and allowed to be efficiently adjustable. Here
we want to describe the first successful result regarding its synthesis
and application in asymmetric Steglich rearrangement.
In recent years, a number of chiral nonenzymatic nucleophilic
Scheme 1. Synthesis of (R)-2a
catalysts have been introduced for enantioselective acyl transfer and
offered useful levels of enantioselectivity in kinetic resolution (KR),
asymmetric desymmetrization (AD), and related transformations.1 For
asymmetric Steglich rearrangement of O-acylated azlactones to their
C-acylated isomers,2-6 which is one of a few methods for producing
a quaternary stereocenter,7 Fu’s planar-chiral 4-dimethylamino-pyridine
(DMAP) catalyst,2 Vedejs’ chiral phosphine catalyst and central chiral
a Conditions: (a) acrolein, AcOH, dioxane, reflux, 81%; (b) (+)-tartaric
acid, MeOH, 11% (99.9% ee), or preparative HPLC, 47% (99.9% ee); (c)
DMAP catalyst,3 and Birman’s amidine catalyst4 served as the most
efficient ones. However, there are still some limitations for practical
applications of these catalysts, such as expensive reagents and multistep
sequences in their synthesis and/or harsh conditions in asymmetric
catalysis. Developing new classes of chiral nucleophilic catalysts
remains an important challenge.
(R)-2a: NaH, THF, rt; then MeI, rt, 42%; (R)-2b: NaH, THF, rt; then EtBr,
reflux, 91%; (R)-2c: NaH, THF, rt; then BnBr, reflux, 73%; (R)-2d: NaH,
DMF, rt; then 1-chloromethyl naphthalene (NmCl), rt, 54%.
The catalysts were synthesized from facile starting materials of
imidazole and acrolein with ease in three steps (Scheme 1). First,
the key intermediate 1 was obtained in 81% yield with a modifica-
tion of the literature procedure.15 Then, the enantiomers of 1 were
N-Methylimidazole (NMI), which bears an electron-donating sp2-N
atom and a π-electron conjugated system, has already been proven to
be a good nucleophilic catalyst,8 but only a few types of chiral NMI
nucleophilic catalysts were reported9,10 compared with chiral pyridine
and amidine nucleophilic catalysts. Moreover, their stereocontrol groups
are mostly placed at the 5-position of imidazole,9 which makes it
difficult to control the chiral environment due to the far distance away
from the nucleophilic sp2-N atom. Therefore, a secondary interaction
such as H-bonding is essential for these catalysts to improve enanti-
oselectivity, which results in the limitation of the application scope.
Table 1. Optimization Studiesa
Entry
Substrate
Solvent
T (°C)
Yield (%)b
Ee (%)c
1
2
3
4
5
6
7
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3b
3c
MeCN
DCM
20
20
20
20
20
20
20
20
20
0
38
60
33
30
31
30
12
29
29
14
52
68
46
74
83
71
88
92
93
69
93
94
94
91
86
98
t-AA
THF
Et2O
Toluene
Hexane
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Figure 1. Design of Catalyst DPI.
d
8
e
As far as we know, only one type of ortho-substituted chiral
DMAP nucleophilic catalyst was reported11 because of the low
activity of this kind of catalyst caused by steric hindrance from
the ortho stereocontrol group.12 Although the activity of the ortho-
substituted chiral NMI nucleophilic catalyst is higher10 due to its
larger ∠R than that of ortho-substituted chiral DMAP,13 it is still
unsatisfactory for some reactions with bulky substrates and reagents
(Figure 1).14 In order to reduce or even avoid the ortho group’s
9
e,f
10
e
40
20
20
11
e
12
e
13
a Conditions: 0.05 M 3, 10 mol % (R)-2c, 1.0 mL of solvent, 24 h.
b Yields are calculated from 1H NMR spectroscopy. c Ee’s are
determined by HPLC analysis. d The concentration of 3a is 0.10 M.
e Addition of 4 Å MS. f The reaction time is 48 h.
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J. AM. CHEM. SOC. 2010, 132, 15939–15941 15939

C O M M U N I C A T I O N S
separated by optical resolution or preparative HPLC and simply
derived to give (R)-2 in high yields.16
higher yield and ee could be achieved by increasing the loading of
catalyst (entries 3, 5, 6) or extending the reaction time (entries 3,
7, 8). Using (R)-2c and (R)-2d as the optimized catalysts, the six
primary alkyl-substituted substrates 3a and 3d-h at C4 were
asymmetrically rearranged to corresponding products at 20 °C with
excellent yields and ee’s (entries 8-19). Remarkably, the most
commonly used substrate 3a was rearranged by (R)-2c with 95%
ee (entry 8), which is the best result to the best of our knowledge.2-5
Additionally, these catalysts were also effective for secondary alkyl-
and aryl-substituted substrates 3i-k (entries 20-23).
Lastly, we examined the possibility of catalyst recycling and
found that this kind of nucleophilic catalyst could be easily
recovered and reused in this rearrangement reaction five times with
little loss in quantity and almost no reduction of catalytic efficiency
(for details please see Supporting Information).
In conclusion, a new type of chiral bicycle imidazole nucleophilic
catalyst (R)-2 was rationally designed, facilely synthesized, and
successfully applied in an asymmetric Steglich rearrangement with
good to excellent yield and enantioselectivity at ambient temper-
ature. Moreover, it can be easily recycled with almost no reduction
of catalytic efficiency. This is the first example of a successful chiral
imidazole nucleophilic catalyst without H-bonding assistance.
Further studies on its application in other reactions are underway.
Then, (R)-2 was applied in the asymmetric Steglich rearrange-
ment of O-acylated azlactones to their C-acylated isomers. Initial
study on the solvent effect showed that low-polar solvents gave
higher ee’s but lower yields in the asymmetric rearrangement of
3a (Table 1, entries 1-7). Toluene as the preferred solvent gave
the highest ee (entry 6), but hexane gave the lowest ee probably
due to its poor solubility for both catalyst and substrate (entry 7).
To further improve the yield and ee, we optimized the reaction
conditions. First, we increased the concentration of 3a from 0.05
to 0.10 M, but there was almost no effect (entry 8 vs 6). Then, we
found that the addition of a 4 Å molecular sieve could slightly
improve the ee (entry 9 vs 6). And raising the reaction temperature
could increase the yield but decrease the ee (entries 9-11). A great
increase of yield was observed by changing R1 from Bn to Ph,
though the ee dropped to 86% (entry 12). And the highest ee of
98% was achieved when R1 was changed to be CMe2CCl3 (entry
13).
Table 2. Interaction between Catalysts and Substratesa
Acknowledgment. This work was supported by the National
Natural Science Foundation of China and Nippon Chemical
Industrial Co., Ltd.
Supporting Information Available: Experimental procedures,
spectroscopic data, chromatographic data and crystallographic data of
(R)-1 (cif). This material is available free of charge via the Internet at
http://pubs.acs.org.
References
(1) For reviews, see: (a) France, S.; Guerin, D. J.; Miller, S. J.; Lectka, T.
Chem. ReV. 2003, 103, 2985. (b) Spivey, A. C.; McDaid, P. In Enantiose-
lectiVe Organocatalysis; Dalko, P. I., Ed.; Wiley-VCH: Weinheim, 2007;
p 287.
(2) Ruble, J. C.; Fu, G. C. J. Am. Chem. Soc. 1998, 120, 11532.
(3) (a) Shaw, S. A.; Aleman, P.; Vedejs, E. J. Am. Chem. Soc. 2003, 125,
13368. (b) Shaw, S. A.; Aleman, P.; Christy, J.; Kampf, J. W.; Va, P.;
Vedejs, E. J. Am. Chem. Soc. 2006, 128, 925.
(4) (a) Joannesse, C.; Johnston, C. P.; Concello´n, C.; Simal, C.; Philp, D.;
Smith, A. D. Angew. Chem., Int. Ed. 2009, 48, 8914. The amidine catalysts
were previously developed by Birman: (b) Birman, V. B.; Uffman, E. W.;
Jiang, H.; Li, X.; Kilbane, C. J. J. Am. Chem. Soc. 2004, 126, 12226. (c)
Birman, V. B.; Li, X. Org. Lett. 2008, 10, 1115. (d) Zhang, Y.; Birman,
V. B. AdV. Synth. Catal. 2009, 351, 2525.
(5) For other examples, see: (a) Seitzberg, J. G.; Dissing, C.; Søtofte, I.; Norrby,
P.; Johannsen, M. J. Org. Chem. 2005, 70, 8332. (b) Busto, E.; Gotor-
Ferna´ndez, V.; Gotor, V. AdV. Synth. Catal. 2006, 348, 2626. (c) Nguyen,
H. V.; Butler, D. C. D.; Richards, C. J. Org. Lett. 2006, 8, 769. (d) Dietz,
F. R.; Gro¨ger, H. Synlett 2008, 663. (e) A new report was published during
our submission: Uraguchi, D.; Koshimoto, K.; Miyake, S.; Ooi, T. Angew.
Chem., Int. Ed. 2010, 49, 5567.
Entry
Substrate
Catalyst
t (d)
Yield (%)b
Ee (%)c
1
2
3
3a
3a
3a
3a
3a
3a
3a
3a
3a
3d
3d
3e
3e
3f
(R)-2a
(R)-2b
(R)-2c
(R)-2d
(R)-2c
(R)-2c
(R)-2c
(R)-2c
(R)-2d
(R)-2c
(R)-2d
(R)-2c
(R)-2d
(R)-2c
(R)-2d
(R)-2c
(R)-2d
(R)-2c
(R)-2d
(R)-2c
(R)-2c
(R)-2c
(R)-2d
1
1
1
1
1
1
4
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
18
21
29
26
17
39
75
81
83
96
96
61
63
94
93
93
96
50
58
35
75
99
99
90
91
94
95
93
94
94
95
95
94
93
94
93
95
93
93
93
95
87
84
78
59
58
4
5d
6e
7
8
9
10
11
12
13
14
15
16
17
18
19
20f
21f
22
23
3f
3g
3g
3h
3h
3i
3j
3k
3k
(6) For analogous asymmetric rearrangements, see: (a) Hills, I. D.; Fu, G. C.
Angew. Chem., Int. Ed. 2003, 42, 3921. (b) Mermerian, A. H.; Fu, G. C.
J. Am. Chem. Soc. 2003, 125, 4050. (c) Mermerian, A. H.; Fu, G. C. J. Am.
Chem. Soc. 2005, 127, 5604. (d) Duffey, T. A.; Shaw, S. A.; Vedejs, E.
J. Am. Chem. Soc. 2009, 131, 14.
(7) (a) Douglas, C. J.; Overman, L. E. Proc. Natl. Acad. Sci. U.S.A. 2004,
101, 5363. (b) Christoffers, J.; Baro, A. AdV. Synth. Catal. 2005, 347, 1473.
(8) Connors, K. A.; Pandit, N. K. Anal. Chem. 1978, 50, 1542.
(9) (a) Miller, S. J.; Copeland, G. T.; Papaioannou, N.; Horstmann, T. E.; Ruel,
E. M. J. Am. Chem. Soc. 1998, 120, 1629. (b) Jarvo, E. R.; Copeland,
G. T.; Papaioannou, N.; Bonitatebus, P. J., Jr.; Miller, S. J. J. Am. Chem.
Soc. 1999, 121, 11638. (c) Ishihara, K.; Kosugi, Y.; Akakura, M. J. Am.
Chem. Soc. 2004, 126, 12212. (d) Davie, E. A. C.; Mennen, S. M.; Xu, Y.;
Miller, S. J. Chem. ReV. 2007, 107, 5759. (e) Mu¨ller, C. E.; Wanka, L.;
Jewell, K.; Schreiner, P. R. Angew. Chem., Int. Ed. 2008, 47, 6180. (f)
Geng, X.; Wang, J.; Li, G.; Chen, P.; Tian, S.; Qu, J. J. Org. Chem. 2008,
73, 8558. (g) Fowler, B. S.; Mikochik, P. J.; Miller, S. J. J. Am. Chem.
Soc. 2010, 132, 2870.
a Conditions: 0.05 M 3, 10 mol % (R)-2, 1.0 mL of toluene, 20 °C.
b Yields are calculated from 1H NMR spectroscopy. c Ee’s are
determined by HPLC analysis. d The loading of catalyst is 5 mol %.
e The loading of catalyst is 20 mol %. f The reaction temperature is 75
°C.
(10) For examples of ortho-substituted chiral NMI catalysts, see: (a) Horstmann,
T. E.; Guerin, D. J.; Miller, S. J. Angew. Chem., Int. Ed. 2000, 39, 3635.
(b) Guerin, D. J.; Miller, S. J. J. Am. Chem. Soc. 2002, 124, 2134. (c)
Zhao, Y.; Rodrigo, J.; Hoveyda, A. H.; Snapper, M. L. Nature 2006, 443,
Further studies on the interaction between catalysts and substrates
showed that (R)-2c and (R)-2d were the most effective catalysts
for the rearrangement of 3a to 4a (Table 2, entries 1-4). And a
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C O M M U N I C A T I O N S
67. (d) Zhao, Y.; Mitra, A. W.; Hoveyda, A. H.; Snapper, M. L. Angew.
Chem., Int. Ed. 2007, 46, 8471.
(11) Ruble, J. C.; Latham, H. A.; Fu, G. C. J. Am. Chem. Soc. 1997, 119, 1492.
(12) (a) Vedejs, E.; Chen, X. J. Am. Chem. Soc. 1996, 118, 1809. (b) Spivey,
A. C.; Maddaford, A.; Leese, D. P.; Redgrave, A. J. J. Chem. Soc., Perkin
Trans. 1 2001, 1785.
(14) Jones, G.; Richards, C. J. Organometallics 2001, 20, 1251.
(15) Weintraub, P. M.; Tiernan, P. L. J. Heterocyclic Chem. 1987, 24, 561.
(16) The absolute configuration of (R)-2 was deduced by X-ray diffraction
analysis of (R)-1; for details please see SI.
(13) ∠R was calculated by us from the stable conformation of relevant
compounds optimized by Gaussian 03W using the B3LYP/6-311+G(d,p)//
B3LYP/6-31G(d) level of theory.
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