Regiospecific organocatalytic asymmetric aldol reaction of methyl ketones and α,β-unsaturated trifluoromethyl ketones

Article abstract of DOI:10.1021/ol070217z

Figure presented The aldol reaction of methyl ketones and α,β-unsaturated trifluoromethyl ketones occurred under mild conditions with the combination of proline-derived N-sulfonylamide and trifluoroacetic acid as the catalyst to give the corresponding uns

Full text of DOI:10.1021/ol070217z

ORGANIC
LETTERS
2007
Vol. 9, No. 7
1343-1345
Regiospecific Organocatalytic
Asymmetric Aldol Reaction of Methyl
Ketones and
Trifluoromethyl Ketones
r,â-Unsaturated
Xiao-Jin Wang, Yan Zhao, and Jin-Tao Liu*
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, Shanghai, China
jtliu@mail.sioc.ac.cn
Received January 27, 2007
ABSTRACT
The aldol reaction of methyl ketones and
r,â-unsaturated trifluoromethyl ketones occurred under mild conditions with the combination of
proline-derived N-sulfonylamide and trifluoroacetic acid as the catalyst to give the corresponding unsaturated
r-trifluoromethyl tertiary alcohols
in high yields with good enatioselectivities.
The importance of fluorine-containing compounds in the
fields of agricultural, medicinal, and material chemistry is
well-known.1 Among such compounds R-trifluoromethyl terti-
ary alcohols have attracted much attention because they can
serve as liquid crystals2a and drugs such as Efavirenz (anti-
HIV)2b,c and so on. Except for the trifluoromethylation of
ketones,3 most methods for the synthesis of these compounds
utilize R-trifluoromethyl ketones as precursors and the aldol
reaction of such ketones takes an important place in those
synthetic methodologies.4 However, preformed enol or
enolate derivatives are involved in those cases, which is not
atom efficient. Recently direct organocatalytic aldol reaction
pioneered by List, Barbas, and their co-workers has achieved
great success.5 Proline-catalyzed asymmetric aldol reaction
between methyl ketones and aryl trifluoromethyl ketones was
realized by Zhang and co-workers, although only moderate
enantioselectivities were obtained.6 Herein we report the first
organocatalyzed asymmetric aldol reaction between methyl
ketones and R,â-unsaturated trifluoromethyl ketones, which
leads to a practical synthesis of unsaturated R-trifluoromethyl
tertiary alcohols with good enantioselectivities.
Since there are two reaction sites in the R,â-unsaturated
carbonyl functional group, the addition reaction can only be
of practical synthetic utility in organic synthesis if one can
control the selectivity for the two possible regioisomers.7 It
has been reported that cyclic enamines underwent Michael-
aldol reaction with R,â-unsaturated trifluoromethyl ketones
(1) (a) Banks, R. E.; Smart, B. E.; Tatlow, J. C. Organofluorine
Chemistry, Principle, and Commercial Applications; Plenum Press: New
York, 1994. (b) Hiyama, T. Organofluorine Compounds, Chemistry and
Application; Springer: Berlin, Germany, 2000. (c) Filler, R.; Kobayashi,
Y.; Yagupolskii, L. M. Organofluorine Compounds in Medicinal Chemistry
and Biomedical Applications; Elsevier: Amsterdam, The Netherlands, 1993.
(d) Ojima, I.; McCarthy, J. R.; Welch, J. T. Biomedical Frontiers of Fluorine
Chemistry; American Chemical Society: Washington, DC, 1996.
(2) (a) Mikami, K. In Asymmetric Fluoroorganic Chemistry: Synthesis,
Application and Future Directions; Ramachandran, P. V., Ed.; American
Chemical Society: Washington, DC, 1999; pp 255-269. (b) Ren, J.; Milton,
J.; Weaver, K. L.; Short, S. A.; Stuart, D. I.; Stammers, D. K. Structure
2000, 8, 1089-1094. (c) Pedersen, O. S.; Pedersen, E. B. Synthesis 2000,
479-495.
(3) (a) Prakash, G. K. S.; Hu, J. In Fluorine-Containing Synthons;
Soloshonok, V. A., Ed.; American Chemical Society: Washington, DC,
2005; pp 16-56. (b) Langlois, B. R.; Billard, T. In Fluorine-Containing
Synthons; Soloshonok, V. A., Ed.; American Chemical Society: Washing-
ton, DC, 2005; pp 57-86. For reviews on enantiomerical synthesis of
trifluoromethyl tertiary alcohols by trifluoromethylation reaction, see: (c)
Ma, J.-A.; Cahard, D. Chem. ReV. 2004, 104, 6119-6146. (d) Billard, T.;
Langlois, B. R. Eur. J. Org. Chem. 2007, 891-897.
10.1021/ol070217z CCC: $37.00
© 2007 American Chemical Society
Published on Web 03/10/2007

to give bicyclic ketones.8 We also found that unsaturated
ketone 1a could undergo similar domino Michael-aldol
reaction with acetone when pyrrolidine was used as a catalyst
(Scheme 1, eq 1).9 However, the regioselectivity of the
Table 1. Evaluation of Catalysts for the Aldol Reaction of 1a
and Acetonea
Scheme 1. Regioselective Reaction of 1a and Acetone
catalyst
(mol %)
time,
h
conversion,b
%
ee,c
%
entry
3a/2ab
1
2
3
4
5
6
7
8
9
4 (30)
5 (5)
6 (30)
7 (5)
8 (20)
9 (20)
10 (20)
11 (20)
10 (10)
10 (10)
10 (10)
10 (10)
2
2
52
52
3
3
1
28
4
3
100
100
22
>95:5d
>95:5
>95:5
81:19
83:17
86:14
96:4
67
49
68
57
59
63
72
14
75e
87f
92f,g
94f,h
reaction could be changed by using different organocatalyst.
In the presence of L-proline the reaction of 1a and acetone
gave the corresponding 1,2-addition product with quantitative
yield and moderate enantioselectivity (Scheme 1, eq 2).
Notably, it was the first organocatalytic reaction in which
unsaturated ketone underwent aldol reaction as acceptor
instead of the usual Michael reaction as previously reported.10
We began our investigation with the reaction of acetone
and unsaturated ketone 1a. A variety of L-proline derivatives
were tested as catalysts to improve the enantioselectivity of
the reaction. As shown in Table 1, although tetrazole 511a,b,d
could also catalyze the aldol reaction efficiently, the decrease
in enantioselectivity was observed (Table 1, entry 2). Using
hydroxy proline 611c as catalyst gave the desired product in
14
100
100
100
50
100
100
100
48
98:2
>95:5
>95:5
>95:5
>95:5
10
11
12
6
8
a Experimental conditions: 1a (0.2 mmol) was added to a solution of
catalyst in acetone (1 mL) at room temperature. b Determined by 19F NMR
analysis of crude reaction mixture. c Determined by HPLC. d Only aldol
product 3a was observed. e 10 mol % acetic acid was added. f 10 mol %
TFA was added. g Reaction performed at 0 °C. h Reaction performed at
-20 °C.
(4) (a) Sosnovskikh, V. Y.; Ovsyannikov, I. S.; Aleksandrova, I. A. J.
Org. Chem. USSR (Engl. Transl.) 1992, 28, 420-426. (b) Soloshonok, V.
A.; Avilov, D. V.; Kukhar, V. P. Tetrahedron 1996, 52, 12433-12442. (c)
Soloshonok, V. A.; Kacharov, A. D.; Avilov, D. V.; Ishikawa, K.;
Nagashima, N.; Hayashi, T. J. Org. Chem. 1997, 62, 3470-3479. (d)
Funabiki, K.; Isomura, A.; Yamaguchi, Y.; Hashimoto, W.; Matsunaga,
K.; Shibata, K.; Matsui, M. J. Chem. Soc., Perkin Trans. 1 2001, 2578-
2582. (e) Barten, J. A.; Funabiki, K.; Roschenthaler, G. V. J. Fluorine Chem.
2002, 113, 105-109. For enantiomerical synthesis of trifluoromethyl tertiary
alcohols from trifluoromethyl ketones, see: (f) Pierce, M. E.; Parsons, R.
L., Jr.; Radesca, L. A.; Lo, Y. S.; Silverman, S.; Moore, J. R.; Islam, Q.;
Choudhury, A.; Fortunak, J. M. D.; Nguyen, D.; Morgan, C.; Luo, S. J.;
Davis, W. P.; Confalone, P. N.; Chen, C.-Y.; Tillyer, R. D.; Frey, L.; Tan,
L.; Xu, F.; Zhao, D.; Thompson, A. S.; Corley, E. G.; Grabowski, E. J. J.;
Reamer, R.; Reider, P. J. J. Org. Chem. 1998, 63, 8536-8543. (g) To¨ro¨k,
B.; Abid, M.; London, G.; Esquibel, J.; To¨ro¨k, M.; Mhadgut, S. C.; Yan,
P.; Prakash, G. K. S. Angew. Chem., Int. Ed. 2005, 44, 3086-3089.
(5) (a) List, B.; Lerner, R. A.; Barbas, C. F., III J. Am. Chem. Soc. 2000,
122, 2395-2396. (b) Notz, W.; List, B. J. Am. Chem. Soc. 2000, 122, 7386-
7387. (c) List, B.; Pojarliev, P.; Castello, C. Org. Lett. 2001, 3, 573-575.
(d) Sakthivel, K.; Notz, W.; Bui, T.; Barbas, C. F., III J. Am. Chem. Soc.
2001, 123, 5260-5267. (e) Pidathala, C.; Hoang, L.; Vignola, N.; List, B.
Angew. Chem. 2003, 115, 2891-2894; Angew. Chem., Int. Ed. 2003, 42,
2785-2788. For reviews, see: (f) List, B. Synlett 2001, 1675-1686. (g)
List, B. Tetrahedron 2002, 58, 5573-5590. (h) List, B. Acc. Chem. Res.
2004, 37, 548-557. (i) Notz, W.; Tanaka, F.; Barbas, C. F., III Acc. Chem.
Res. 2004, 37, 580-591.
low conversion and similar ee as using L-proline (Table 1,
entry 3). A dramatic decrease in both yield and selectivity
was obtained when amide 7 was tested (Table 1, entry 4).
Further evaluation of several proline-derived N-sulfonyl-
amides11d,e showed compound 10 to be optimal, giving the
highest enantioselectivity and good regioselectivity (Table
1, entries 5-7). Addition of acids along with catalyst 10
(9) For organocatalytic domino Micheal-aldol reaction, see: (a) Eder,
U.; Sauer, G.; Wiechert, R. Angew. Chem. 1971, 83, 492-493; Angew.
Chem., Int. Ed. Engl. 1971, 10, 496-497. (b) Hajos, Z. G.; Parrish, D. R.
J. Org. Chem. 1974, 39, 1615-1621. (c) Halland, N.; Aburel, P. S.;
Jørgensen, K. A. Angew. Chem. 2004, 116, 1292-1297; Angew. Chem.,
Int. Ed. 2004, 43, 1272-1277. (d) Pukkinen, J.; Aburel, P. S.; Halland, N.;
Jørgensen, K. A. AdV. Synth. Catal. 2004, 346, 1077-1080.
(10) (a) Melchiorre, P.; Jørgensen, K. A. J. Org. Chem. 2003, 68, 4151-
4157. (b) Hechavarria Fonseca, M. T.; List, B. Angew. Chem. 2004, 116,
4048-4050; Angew. Chem., Int. Ed. 2004, 43, 3958-3960. (c) Peelen, T.
J.; Chi, Y.-G.; Gellman, S. H. J. Am. Chem. Soc. 2005, 127, 11598-11599.
(d) Chi, Y.-G.; Gellman, S. H. Org. Lett. 2005, 7, 4253-4256. (e) Wang,
J.; Li, H.; Zu, L.; Wang, W. AdV. Synth. Catal. 2006, 348, 425-428.
(11) (a) Torii, H.; Nakadai, M.; Ishihara, K.; Saito, S.; Yamatoto, H.
Angew. Chem., Int. Ed. 2004, 43, 1983-1986. (b) Hartikka, A.; Arvidsson,
P. I. Tetrahedron: Asymmetry 2004, 15, 1871-1934. (c) Tang, Z.; Yang,
Z. H.; Hua, X. H.; Cun, L. F.; Mi, A. Q.; Yao, Y. Z.; Gong, L. Z. J. Am.
Chem. Soc. 2005, 127, 9285-9289. (d) Cobb, A. J. A.; Shaw, D. M.;
Longbottom, D. A.; Gold, J. B.; Ley, S. V. Org. Biomol. Chem. 2005, 3,
84-96. (e) Berkessel, A.; Koch, B.; Lex, J. AdV. Synth. Catal. 2004, 346,
1141-1146.
(6) Qiu, L.; Shen, Z.; Shi, C.; Liu, Y.; Zhang, Y. Chin. J. Chem. 2005,
23, 584-588.
(7) Perlmutter, P. Conjugate Addition Reactions in Organic Synthesis;
Pergamon Press: Oxford, UK, 1992.
(8) (a) Andrew, R. J.; Mellor, J. M.; Reid, G. Tetrahedron 2000, 56,
7255-7260. (b) Nenajdenko, V. G.; Druzhinin, S. V.; Balenkova, E. S.
Russ. Chem. Bull., Int. Ed. 2004, 53, 435-442.
1344
Org. Lett., Vol. 9, No. 7, 2007

could improve the selectivity significantly, and strong acid
provided higher enantioselectivity than weak acid (Table 1,
entries 9 and 10). The best result with respect to both yield
and selectivity was achieved by carrying out the reaction
with catalyst 10 and trifluoroacetic acid additive at 0 °C
(Table 1, entry 11).
However, cyclic ketones such as cyclohexanone failed to
yield the desired product.
The stereochemistry of the reaction may be rationalized
by the transition state shown in Figure 1, which is based on
Experiments that probed the scope of R,â-unsaturated
trifluoromethyl ketone component are summarized in Table
2. With use of the optimized conditions, the corresponding
Table 2. Aldol Reaction of R,â-Unsaturated Trifluoromethyl
Ketones and Acetonea
Figure 1. Proposed transition state of the aldol reaction.
a previous model for proline supported by both experiments
and DFT calculations.12 In the transition state the bulky
trifluoromethyl group adopts a pseudoequatorial position to
avoid the nonbonding interactions with the sulfonylamide
moiety.13 The role of TFA additive is still unknown.14 It
might not only favor the formation of the enamine intermedi-
ate in Figure 1, but also serve to decrease the electron density
of the carbonyl group of unsaturated ketones through the
hydrogen bonding interaction and make it more active toward
nucleophilic attack.14i
In summary, organocatalyzed asymmetric aldol reaction
of methyl ketones and R,â-unsaturated trifluoromethyl
ketones was achieved for the first time. By using the
combination of proline-derived N-sulfonylamide 10 and
trifluoroacetic acid as catalyst, the reaction occurred under
mild conditions to give the corresponding unsaturated
R-trifluoromethyl tertiary alcohols in high yields with good
enatioselectivities.
entry
1
R
time, h
3b
yield,c % ee,d
%
1
2
3
4
5
6
7
8
9
1a
Ph
6
10
14
24
20
22
12
22
31
28
3a
3b
3c
3d
3e
3f
3g
3h
3i
93
92
98
94
99
85
87
99
76
86
92
94
1b 4-Cl-Ph
1c 4-Br-Ph
1d 4-MeO-Ph
1e
1f
95e
94
89
92
86
81
87
88
4-Me-Ph
1-naphthyl
2-furyl
1g
1h Ph-CtC
1i
1j
Ph-CHdCH
Ph(CH2)3
10
3j
a Experimental conditions: unsaturated ketone 1 (0.4 mmol) was added
to a solution of catalyst 10 (10 mol %) and TFA (10 mol %) in acetone (2
mL) at 0 °C, and the reaction mixture was stirred for the time indicated in
the table. b 3 was the only product as determined by 19F NMR analysis of
crude reaction mixture. c Yields of isolated products. d Determined by
HPLC. e Reaction performed at -20 °C.
R-trifluoromethyl tertiary alcohols were obtained in excellent
yields with high enantioselectivities in all cases. As shown
in Table 2 entries 2-5, the reaction tolerated both electron-
rich and electron-deficient phenyl-substituted unsaturated
ketones. Similar results were obtained in the cases of ketones
with heteroaromatic and naphthyl groups (Table 2, entries 6
and 7). Furthermore, unsaturated ketones carrying alkynyl,
alkenyl, or alkyl substituents at the â position were also good
substrates for the reaction (Table 2, entries 8-10). The
assignment of the absolute stereochemistry of the resulting
â-hydroxyl-â-trifluoromethyl ketones was based on X-ray
crystallographic studies of product 3c.
Acknowledgment. Financial support from the National
Natural Science Foundation of China (No. 20572124) is grate-
fully acknowledged. We also thank Dr. Ye Meng-Chun, Dr.
Jian Zhou, and Dr. Huang Lin-Ling for helpful discussion.
Supporting Information Available: Experimental pro-
cedures, structural proofs, NMR spectra, and HPLC chro-
matograms. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL070217Z
(12) (a) Bahmanyar, S.; Houk, K. N.; Martin, H. J.; List, B. J. Am. Chem.
Soc. 2003, 125, 2475-2479. (b) List, B.; Hoang, L.; Martin, H. J. Proc.
Natl. Acad. Sci. U.S.A. 2004, 101, 5839-5842.
(13) Seebach, D. Angew. Chem., Int. Ed. Engl. 1990, 29, 1320-1367;
Angew. Chem. 1990, 102, 1363-1409.
Except for acetone, other ketones were also investigated.
Butanone and 2-pentanone gave similar results (Scheme 2).
(14) For the influence of acid additive in organocatalytic aldol reaction,
see: (a) Nakadai, M.; Saito, S.; Yamamoto, H. Tetrahedron 2002, 58, 8167-
8177. (b) Mase, N.; Tanaka, F.; Barbas, C. F., III Org. Lett. 2003, 5, 4369-
4372. (c) Chen, J. R.; Lu, H. H.; Li, X. Y.; Cheng, L.; Wan, J.; Xiao, W.
J. Org. Lett. 2005, 7, 4543-4545. (d) Ji, C.; Peng, Y.; Huang, C.; Wang,
N.; Jiang, Y. Synlett 2005, 986-990. (e) Wu, Y. S.; Chen, Y.; Deng, D.
S.; Cai, J. Synlett 2005, 1627-1629. (f) Kriis, K.; Kanger, T.; Laars, M.;
Kailas, T.; Mu¨u¨risepp, A. M.; Pehk, T.; Lopp, M. Synlett 2006, 1699-
1702. (g) Majewski, M.; Niewczas, I.; Palyam, N. Synlett 2006, 2387-
2390. (h) Cheng, C.; Wei, S.; Sun, J. Synlett 2006, 2419-2422. (i) Zhou,
Y.; Shan, Z. Tetrahedron: Asymmetry 2006, 17, 1617-1677. (j) Pihko, P.
M.; Laurikainen, K. M.; Usano, A.; Nyberg, A. I.; Kaavi, J. A. Tetrahedron
2006, 62, 317-328.
Scheme 2. Aldol Reaction of 1a with Butanone and
2-pentanone
Org. Lett., Vol. 9, No. 7, 2007
1345