this study, it was found that regular ketones, such as p-methyl
acetophenone (1a, Figure 1) did not undergo a Mukaiyama
conditions for silyl enol ether formation from ketones. With
1 mol % IAd (3),12 the reaction between p-methyl aceto-
phenone (1a) and trimethylsilyl ketene acetal 2 in THF
reached 99% molar conversion within 2.5 h (entry 1, Table
1). Reactions using 0.5 mol % or even 0.1 mol % IAd
Table 1. Defining Reaction Conditions
Figure 1. Unexpected silyl enol ether formation
aldol reaction with trimethylsilyl ketene acetal 2 under NHC
catalysis in THF. The starting ketone was always recovered
from these reactions after aqueous workup. Later, careful
molar convn (%)a
starting
loading
assay yield
(%)b
materials NHC (mol %) 2.5 h 8.5 h 24 h
1
1
2
3
4
5
6
7
8
9
1a + 2
1a + 2
1a + 2
1a + 2
1a + 2
1b + 6
1b + 6
1a + 2
1b + 6
IAd
IAd
IAd
ItBu
IMes
IAd
IAd
no
1
99
98
74
82
44
66
50
-
-
99
96
96
70
85
71
-
-
-
98
98
97
95
91
92
84
-
analysis of the recovered ketone by H NMR revealed that
0.5
0.1
0.5
0.5
1
0.5
-
-
a very small amount of the unexpected silyl enol ether 5a
was present, indicating that silyl transfer from the silyl ketene
acetal 2 to ketone 1a occurred during these experiments.
We report in this letter that silyl enol ethers11 can be
cleanly formed from reactions between enolizable ketones
and silyl ketene acetals in good to excellent yields under
the catalysis of only 0.1-5 mol % NHC.
99
99
96
95
87
NR
NR
no
-
-
-
Following our initial lead shown in Figure 1, a series of
experiments were carried out to define the optimal reaction
a Molar conversion by HPLC. b Assay yield by HPLC.
(3) (a) Grasa, G. A.; Guveli, T.; Singh, R.; Nolan, S. P. J. Org. Chem.
2003, 68, 2812. (b) Singh, R.; Kissling, R. M.; Letellier, M.-A.; Nolan, S.
P. J. Org. Chem. 2004, 69, 209. (c) Grasa, G. A.; Kissling, R. M.; Nolan,
S. P. Org. Lett. 2002, 4, 3583. (d) Nyce, G. W.; Lamboy, J. A.; Connor, E.
F.; Waymouth, R. M.; Hedrick, J. L. Org. Lett. 2002, 4, 3587. (e) Nyce, G.
W.; Glauser, T.; Connor, E. F.; Mock, A.; Waymouth, R. M.; Hedrick, J.
L. J. Am. Chem. Soc. 2003, 125, 3046. (f) Connor, E. F.; Nyce, G. W.;
Myers, M.; Mock, A.; Hedrick, J. L. J. Am. Chem. Soc. 2002, 124, 914. (g)
Kano, T.; Sasaki, K.; Maruoka, K. Org. Lett. 2005, 7, 1347. (h) Singh, R.;
Nolan, S. P. Chem. Commun. 2005, 43, 5456. (i) Suzuki, Y.; Yamauchi,
K.; Muramatsu K.; Sato, M. Chem. Commun. 2004, 2770.
(4) Movassaghi, M.; Schmidt, M. A. Org. Lett. 2005, 7, 2453.
(5) Song, J. J.; Tan, Z.; Reeves, J. T.; Gallou, F.; Yee, N.; Senanayake,
C. H. Org. Lett. 2005, 7, 2193.
(6) Song, J. J.; Gallou, F.; Reeves, J. T.; Tan, Z.; Yee, N. K.; Senanayake,
C. H. J. Org. Chem. 2006, 71, 1273.
(7) (a) Fukuda, Y.; Maeda, Y.; Ishii, S.; Kondo, K.; Aoyama, T. Synthesis
2006, 589. (b) Fukuda, Y.; Maeda, Y.; Kondo, K.; Aoyama, T. Chem.
Pharm. Bull. 2006, 54, 397. (c) Fukuda, Y.; Maeda, Y.; Kondo, K.; Aoyama,
T. Synthesis 2006, 1937. (d) Fukuda, Y.; Kondo, K.; Aoyama, T. Synthesis
2006, 2649. (e) Suzuki, Y.; Abu Bakar, M. D.; Muramatsu, K.; Sato, M.
Tetrahedron 2006, 62, 4227. (f) Kano, T.; Sasaki, K.; Konishi, T.; Mii, H.;
Maruoka, K. Tetrahedron Lett. 2006, 47, 4615.
(8) (a) Wu, J.; Sun, X.; Ye, S.; Sun, W. Tetrahedron Lett. 2006, 47,
4813. (b) For a related aziridine opening reaction with acid anhydride, see:
Sun, X.; Ye, S.; Wu, J. Eur. J. Org. Chem. 2006, 21, 4787.
(9) Bjerre, J.; Fenger, T. H.; Marinescu, L. G.; Bols, M. Eur. J. Org.
Chem. 2007, 704.
(10) Song, J. J.; Tan, Z.; Reeves, J. T.; Yee, N.; Senanayake, C. H. Org.
Lett. 2007, 9, 1013.
(11) For representative methods to prepare silyl enol ethers, see: (a)
Stork, G.; Hudrlik, P. F. J. Am. Chem. Soc. 1968, 90, 4462. (b) Kita, Y.;
Yasuda, H.; Haruta, J.; Segawa, J.; Tamura, Y. Synthesis 1982, 1089. (c)
Tanabe, Y.; Misaki, T.; Kurihara, M.; Iida, A.; Nishii, Y. Chem. Commun.
2002, 15, 1628. (d) Nakamura, E.; Murofushi, T.; Shimizu, M.; Kuwajima,
I. J. Am. Chem. Soc. 1976, 98, 2346. (e) Nakamura, E.; Hashimoto, K.;
Kuwajima, I. Bull. Chem. Soc. Jpn. 1981, 54, 805. (f) Sakurai, H.; Miyoshi,
K.; Nakadaira, Y. Tetrahedron Lett. 1977, 2671. (g) Nakamura, E.;
Hashimoto, K.; Kuwajima, I. Tetrahedron Lett. 1978, 2079. (h) Orban, J.;
Turner, J. V.; Twitchin, B. Tetrahedron Lett. 1984, 25, 5099. (i) Takai, K.;
Kataoka, Y.; Okazoe, T.; Utimoto, K. Tetrahedron Lett. 1988, 29, 1065.
(j) Davis, F. A.; Lal, G. S.; Wei, J. Tetrahedron Lett. 1988, 29, 4269.
proceeded smoothly to 99% molar conversions in 8.5 and
24 h, respectively (entries 2-3). ItBu-catalyzed reaction was
slightly slower, requiring 24 h to achieve 99% molar
conversion at 0.5 mol % catalyst level (entry 4). Reaction
using IMes (0.5 mol %) progressed to a 96% molar
conversion after 24 h (entry 5).
It was found that the much bulkier tert-butyldimethylsilyl
(TBS) enol ethers could also be formed in a similar manner.
Reaction between acetophenone (1b) and TBS ketene acetal
6 with 1 mol % IAd gave a 95% molar conversion after 24
h (entry 6). When 0.5 mol % IAd was employed, an 87%
molar conversion was achieved after 1 day at 23 °C (entry
7). Finally, control experiments showed that no reaction
occurred between 1a and 2 or 1b and 6 after 24 h at ambient
temperature in the absence of the carbene catalyst (entries
8-9).
The scope of the NHC-catalyzed silyl enol ether formation
was explored as summarized in Table 2. On the basis of the
results from Table 1, our standard conditions were defined
to involve the use of 1 mol % IAd (3) in THF at 23 °C,
except for two substrates (vide infra). After the reaction was
complete (judged by HPLC or GC), the volatiles were
directly removed by evaporation without the need for
aqueous workup. The residue was then distilled under
vacuum to give the desired silyl enol ethers.
In addition to compound 5a (entry 1, Table 2),13 the
trimethylsilyl enol ethers of R-tetralone and cyclododecanone
(12) IAd ) 1,3-di-(1-adamantyl)imidazol-2-ylidene; ItBu ) 1,3-di-tert-
butylimidazol-2-ylidene; IMes ) 1,3-di-mesitylimidazol-2-ylidene.
878
Org. Lett., Vol. 10, No. 5, 2008