C. H. Cheon, H. Yamamoto / Tetrahedron Letters 50 (2009) 3555–3558
3557
Table 3
reaction mixture, protodesilylation of 3a still took place and fi-
nally the di-silylated squaramide (TMS)2-2 was generated
(Scheme 2). When the in situ generated silylated Brønsted acid,
TMS-2 or (TMS)-2, was used as a catalyst, aldol reaction still
proceeded. However, the yields of the reactions with these sily-
lated Brønsted acids were much lower than those with Brønsted
acid 2 itself (entries 1–3). Furthermore, when reactions were car-
Mukaiyama Michael reaction of a,b-unsaturated ketones with silyl enol ether
R2
O
OPMDS
O
R1
O
2 (1 mol %)
R1
R3
Ph
Ph
R3
R2
7a-e
CH3CN, rt, time (h)
3bb
6a-e
Entry
1c
Enone
Time (h)
% Yielda
O
ried out with 2,6-di-t-butylpyridine (DTBP),
a Brønsted acid
3
2
65
98
scanvenger,17 the yields of aldol reactions were dramatically de-
creased (entries 4–6). Although we cannot exclude the Lewis
acid-catalyzed aldol reaction by the silylated Brønsted acid, at
this moment it is more reasonable that the aldol reaction may
proceed through Brønsted acid catalysis rather than through sily-
lated Lewis acid catalysis.
Ph
Me
2
O
3
4
5
6
2
95
45
98
91
42
In conclusion, we have developed a new strong Brønsted acid
based on squaric acid scaffold. This new Brønsted acid 2 is bench
stable and no special care is required for its handling. Compound
2 was applied to Mukaiyama aldol reactions of aldehydes and ke-
tones with silyl enol ether. The corresponding products of alde-
hydes were obtained in quantitative yields, whereas the products
of ketones were obtained in moderate yields with limited substrate
scope. The utility of 2 was further expanded to Mukaiyama Michael
Me
O
Ph
2
O
O
2
reaction of a,b-unsaturated ketones. Remarkably, the catalyst load-
2
ing was as low as 1 mol % for all Mukaiyama reactions and could be
decreased below this level. Mechanistic studies implied that the
Mukaiyama aldol reaction might proceed through Brønsted acid
catalysis, rather than through Lewis acid catalysis by silylated
Brønsted acid. Further applications of this Brønsted acid to other
organic reactions are underway in our laboratory, and will be
reported in due course.
Me
Ph
O
7
12
Ph
a
Isolated yields after chromatographic purification.
Compound 3b is pentamethyldisilyl (PMDS) enol ether.
TMS-silyl enol ether 3a was used.
b
c
Acknowledgments
may proceed through either a real Brønsted acid catalyst or a Le-
wis acid catalyst11 with silylated squaramide in situ generated
by proton-silyl group exchange reaction between 2 and 3a. To
distinguish these two possible pathways, we carried out several
controlled experiments (Table 4). On addition of the stoichiome-
tric 3a to 2, 3a was immediately hydrolyzed to the correspond-
ing ketone and mono-silylated squaramide TMS-2 was
generated. When another 1 equiv of 3a was added to the same
We would like to thank Toyata company for financial support
and Dr. V.H. Rawal for his kind discussion for this project.
References and notes
1. For a review of enantioselective organocatalysis, see: Pihko, P. M. Angew. Chem.,
Int. Ed. 2004, 43, 2062–2064.
2. For a review of hydrogen bond organic catalysis, see: Doyle, A. G.; Jacobsen, E.
N. Chem. Rev. 2007, 107, 5713–5743.
3. Huang, Y.; Unni, A. K.; Thadani, A. N.; Rawal, V. H. Nature 2003, 424, 146.
4. For reviews of chiral phosphoric acid catalysis, see: (a) Akiyama, T. Chem. Rev.
2007, 107, 5744–5758; (b) Terada, M. Chem. Commun. 2008, 4097.
5. The pKa1 of squaric acid is 1.5 and pKa2 is 3.5, see: West, R.; Powell, D. L. J. Am.
Chem. Soc. 1963, 85, 2577–2579.
6. Malerich, J. P.; Hagihara, K.; Rawal, V. H. J. Am. Chem. Soc. 2008, 130, 14416–
14417.
7. (a) Ishihara, K.; Hasegawa, A.; Yamamoto, H. Angew. Chem., Int. Ed. 2001, 40,
4077–4079; (b) Hasegawa, A.; Ishikawa, T.; Ishihara, K.; Yamamoto, H. Bull.
Chem. Soc. Jpn. 2005, 78, 1401–1410.
8. (a) Nakashima, D.; Yamamoto, H. J. Am. Chem. Soc. 2006, 128, 9626–9627; (b)
Jiao, P.; Nakashima, D.; Yamamoto, H. Angew. Chem., Int. Ed. 2008, 47, 2411–
2413; (c) Cheon, C. H.; Yamamoto, H. J. Am. Chem. Soc. 2008, 130, 9246–9247.
9. For a review of Mukaiyama aldol reaction, see: Palomo, C.; Oiarbide, M.; Garcia,
J. M. Chem. Eur. J. 2002, 8, 37–44.
10. (a) Zhuang, W.; Poulsen, T. B.; Jorgensen, K. A. Org. Biomol. Chem. 2005, 3, 3284–
3289; (b) Gondi, V. B.; Gravel, M.; Rawal, V. H. Org. Lett. 2005, 7, 5657–5660; (c)
McGilvra, J. D.; Unni, A. K.; Modi, K.; Rawal, V. H. Angew. Chem., Int. Ed. 2006, 45,
6130–6133.
11. Strong Brønsted acids, such as TfOH and HNTf2, have been used in Mukaiyama
aldol reaction. However, the actual catalyst is believed to be silylated Brønsted
acids in situ generated between the Brønsted acid and silyl enol ether, see:
Boxer, M. B.; Yamamoto, H. J. Am. Chem. Soc. 2006, 128, 48–49.
12. Armand, M.; Choquette, Y.; Gauthier, M.; Michot, C. Vol. EP0850920 (A2), 1998.
13. Compound 2 is air- and moisture-stable for more than 3 months. Even in
solution 2 still keeps its catalytic reactivity after 2 months.
Table 4
H
cat (1 mol %)
TMS
O
O
O
O
additive (1 mol %)
H
CH3CN (1 mL)
rt, time (h)
4a
3a
Entry
Cat
Additive (mol %)
Time (h)
% Conversiona
1
2
3
4
5
6
2
—
—
—
<30 min
100
85
70
60
55
40
2-TMS
2-TMS2
2
2-TMS
2-TMS2
2
2
2
2
2
DTBPb (2 mol %)
DTBPb (2 mol %)
DTBPb (2 mol %)
a
Conversion was determined by 1H NMR.
DTBP is 2,6-di(t-butyl)pyridine.
b
O
O
O
O
O
O
3a (1 eq)
3a (1 eq)
14. Representative procedure: To
a solution of 2 (0.75 mg; 0.0020 mmol;
TfN
NTf
CD3CN, rt, 5 min
CD3CN, rt, 5 min
TfHN
NTf
0.010 equiv) in acetonitrile (1 mL) was added 4a (21 mg; 0.20 mmol;
1.0 equiv) and the mixture was stirred for 10 min. After that, 3a (42 mg;
0.22 mmol; 1.1 equiv) was added dropwise to the reaction mixture. The
reaction mixture was allowed to stir at room temperature while the reaction
was monitored by TLC. When the 4a was completely consumed, 1 N HCl (1 mL)
TfHN
NHTf
TMS TMS
TMS
(TMS)2-2
2
TMS-2
Scheme 2.