5706
S. Okamoto et al. / Tetrahedron Letters 51 (2010) 5704–5707
Table 3
Results of the stoichiometric reactions of 3a with 1b (2 equiv) and n-BuMgCl (3.1–6.7 equiv)a
Run
Grignardb–(equiv as an anion source)c
Reagent typesd (equiv)
h
Conversion (%) (4a:5a)e
1
2
3
4
3.1 Equiv (1.1 equiv)
4.9 Equiv (2.9 equiv)
6.7 Equiv (4.7 equiv)
1.5 Equiv with 5 mol % of 1b [catalytic condition]
I (0.9) + II (1.1)
II (1.1) + III (0.9)
III (1.3) + IV (0.7)
44
44
10
28
No reaction
96 (65:35)
97 (27:73)
97% (2:98)
a
b
c
Substrate (1.0 mmol), n-BuMgCl (3.1–8.2 mmol, 0.94 M in THF), 1b (2.0 mmol) in THF (7 mL) at room temperature.
The Grignard reagent was titrated prior to use.
Equivalent for deprotonation of 1b was deducted.
d
e
Postulated considering the reagent stoichiometry and the mechanism depicted in Scheme 2.
Determined by 1H NMR analysis of the crude mixture.
ing salts 1 and 2 can be classified in the following order of donor
strength: 2c > 2a > 2b > 2d > 2e ꢁ 1c > 1d > 1a > 1b. This is in good
agreement with the order of the rate of the reaction with each salt.
Increasing
r-donating ability of NHC might enhance the nucleo-
philicity of NHC-magnesium complexes.
Scheme 3 depicts the preliminary results of the asymmetric
allylic substitution reaction13 using enantiomerically pure imi-
dazolium salts 1e and 2f. The reaction of 3d with n-C6H13MgCl in
the presence of 5 mol % of 2f at ꢀ20 °C afforded the corresponding
SN20 product with a high yield and high regioselectivity, but with
moderate enantiomeric excess (34% ee).14 Ee was reduced with
phosphate 3i or E substrate 3j, the later of which demonstrated
an opposite enantioselectivity to Z isomer 3d.
We demonstrated that N-heterocyclic carbenes (NHCs), imida-
zol-2-ylidenes, and imidazolium-4-ylidenes, catalyzed a
c-selec-
Scheme 3. Preliminary study on asymmetric reactions.
tive Grignard substitution reaction of -substituted allyl
c
chlorides and phosphates, in which magnesium ate complexes
(NHC-MgR3)ꢀ(MgX)+ were postulated as the active species. It is
possible to apply this reaction to an asymmetric reaction catalyzed
by a chiral imidazol-4-ylidene. Further investigations, which in-
clude improvement of enantioselectivity, are still being conducted.
salt 1 or 2 was deprotonated by the reaction with a Grignard re-
agent to generate the corresponding carbene, imidazol-2-ylidene
or imidazol-4-ylidene, respectively, and yield the corresponding
NHC-MgX2 (I) complexes. Under catalytic conditions, subsequent
substitution and complexation of the resulting NHC-MgX2 complex
with the Grignard reagents might yield NHC-MgRX (II), NHC-MgR2
(III),10 an ate complex (NHC-MgR3)ꢀ(MgX)+ (IV),11 and their sol-
vated derivatives.
Supplementary data
To confirm the active intermediate(s) among these schemes, the
stoichiometric reactions were investigated (Table 3). Thus, to a
mixture of imidazolium salt 1b (2.0 equiv) in THF was added drop-
wise a THF solution of n-BuMgCl (equiv indicated in the table) at
0 °C. After being stirred for 1 h at room temperature, a solution
of 3a (1.0 equiv) in THF was added. An analysis of the hypothetical
mechanisms illustrated in Scheme 2 and the reagent stoichiometry
suggests that the use of 3.1, 4.8, 6.6, and 8.2 equiv of the Grignard
reagent, respectively, would generate the following combinations of
the reagents: NHC-MgX2/NHC-MgXR [I (0.9 equiv) + II (1.1 equiv)]
(run 1), NHC-MgXR/NHC-MgR2 [II (1.1 equiv) + III (0.9 equiv)]
(run 2), NHC-MgR2/[(NHC-MgR3)ꢀ(MgX)+] [III (1.3 equiv) + IV
(0.7 equiv)] (run 3), because 2 equiv of the Grignard reagent (1 equiv
to 1b) were consumed in the deprotonation of 1b. The reaction mix-
ture comprising I and II did not react with 3a (run 1). The reaction
with reagent III (a mixture with II) afforded 4a and 5a in good yield,
butthe reactionwas slow and yielded SN2 product4a predominantly
(run 2). Contrastingly, the reactions involving reagent IV proceeded
much faster (run 3) and demonstrated SN20 selectivity. These results
suggest that the reaction under catalytic conditions may involve
(NHC)(trialkyl)magnesium ate complex [(NHC-MgR3)ꢀ(MgX)+] (IV)
as a rapid, active species.
Supplementary data associated with this article can be found, in
References and notes
1. (a) Ehlers, A. W.; van Klink, G. P. M.; van Eis, M. J.; Bickelhaupt, F.; Nederkoorn,
P. H. J.; Lammertsma, K. J. Mol. Model. 2000, 6, 186; (b) Kneisel, F. F.; Dochnahl,
M.; Knochel, P. Angew. Chem., Int. Ed. 2004, 43, 1017; (c) Gong, L.-Z.; Knochel, P.
Synlett 2005, 267; (d) Kneisel, F. F.; Leuser, H.; Knochel, P. Synthesis 2005, 2625;
(e) Ren, H.; Krasovskiy, A.; Knochel, P. Org. Lett. 2004, 6, 4215; (f) Liu, C.-Y.;
Knochel, P. Org. Lett. 2005, 7, 2543; (g) Liu, C.-Y.; Ren, H.; Knochel, P. Org. Lett.
2006, 8, 617; (h) Boudet, N.; Lachs, J. R.; Knochel, P. Org. Lett. 2007, 9, 5525; (i)
Shi, L.; Chu, Y.; Knochel, P.; Mayr, H. J. Org. Chem. 2009, 74, 2760; (j) Shi, L.; Chu,
Y.; Knochel, P.; Mayr, H. Org. Lett. 2009, 11, 3502.
2. (a) Apsimon, J.; Colier, T. L. Tetrahedron 1986, 42, 5157; (b) Tomioka, K.
Synthesis 1990, 541; (c) Akiyama, T.; Shimizu, M.; Mukaiyama, T. Chem. Lett.
1984, 611; (d) Nakajima, M.; Tomioka, T.; Koga, K. Tetrahedron 1993, 49, 9735;
(e) Nakajima, M.; Tomioka, K.; Koga, K. Tetrahedron 1993, 49, 9751; (f) Noyori,
R.; Kitamura, M. Angew. Chem., Int. Ed. Engl. 1991, 30, 49.
3. Denmark, S. E.; Beutner, G. L.; Wynn, T.; Eastgate, M. D. J. Am. Chem. Soc. 2005,
127, 3774.
4. (a) Chelucci, G.; Thummel, R. P. Chem. Rev. 2002, 102, 3129; (b) Denmark, S. E.;
Fu, J. Chem. Rev. 2003, 103, 2763.
5. (a) Arduengo, A. J. Acc. Chem. Res. 1999, 32, 913; (b) Bourissou, D.; Guerret, O.;
Gabbaï, F. P.; Bertrand, G. Chem. Rev. 2000, 100, 39; (c) Herrmann, W. A. Angew.
Chem., Int. Ed. 2002, 41, 1290; (d)Carbene Chemistry. From Fleeting Intermediates
to Powerful Reagents; Bertrand, G., Ed.; Dekker: New York, 2002; (e) Enders, D.;
Balensiefer, T. Acc. Chem. Res. 2004, 37, 534; (f) Peris, E.; Crabtree, R. H. Coord.
Chem. Rev. 2004, 248, 2239; (g) Scott, N. M.; Nolan, S. P. Eur. J. Inorg. Chem. 2005,
1815; (h) Hahn, F. E. Angew. Chem., Int. Ed. 2006, 45, 1348; (i)N-Heterocyclic
Carbenes in Synthesis; Nolan, S. P., Ed.; Wiley-VCH: Weinheim, Germany, 2006;
(j) Hahn, F. E.; Jahnke, M. C. Angew. Chem., Int. Ed. 2008, 47, 3122.
6. Lee, Y.; Hoveyda, A. H. J. Am. Chem. Soc. 2006, 128, 15604.
The
r-donative nature of the ligating imidazolylidenes in NHC-
magnesium complexes might have a significant effect on the reac-
tion rate and selectivity. Recently, efforts have been devoted to the
evaluation of the
r
-donating ability of NHC ligands.12 Based on the
currently available data for the C2- and C4-bound carbenes (imida-
zol-2- and -4-ylidenes), the carbenes derived from the correspond-
7. Kobayashi, K.; Ueno, M.; Naka, H.; Kondo, Y. Chem. Commun. 2008, 3780; See
also, Ueno, M.; Wheatley, A. E. H.; Kondo, Y. Chem. Commun. 2006, 3549.