Enantioselective organocatalytic Michael addition of aldehydes to trifluoroethylidene malonates

Article abstract of DOI:10.1021/ol101894h

An efficient, highly enantioselective, organocatalytic Michael addition reaction of aldehydes with trifluoroethylidene malonates is described. The asymmetric reaction provided highly optically pure β-trifluoromethyl aldehydes which can be conveniently tra

Full text of DOI:10.1021/ol101894h

ORGANIC
LETTERS
2010
Vol. 12, No. 20
4655-4657
Enantioselective Organocatalytic Michael
Addition of Aldehydes to
Trifluoroethylidene Malonates
Lele Wen, Qilong Shen, and Long Lu*
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, PRC
lulong@mail.sioc.ac.cn
Received August 14, 2010
ABSTRACT
An efficient, highly enantioselective, organocatalytic Michael addition reaction of aldehydes with trifluoroethylidene malonates is described.
The asymmetric reaction provided highly optically pure ꢀ-trifluoromethyl aldehydes which can be conveniently transformed into
4,4,4-trifluoromethyl butyric acid and trifluoromethyl substituted δ-lactones without loss in enantioselectivity.
Over the past 10 years, asymmetric organocatalytic Michael
addition has emerged as a powerful and environmentally
friendly tool for the production of enantiomerically pure
organic compounds.1 Among these transformations, direct
Michael addition of carbonyl donors by chiral secondary
amines via enamine activation represents a particularly
attractive route, affording versatile functionalized adducts in
an atom-economical manner.2 A variety of Michael acceptors
such as nitroolefins,3 vinyl ketones,4,5 alkylidene malonates,6
vinyl sulfones,7,8 vinyl phosphonates,8,9 γ-keto-R, ꢀ-unsatur-
ated esters,10 and R,ꢀ-unsaturated thiol esters11 have been
shown to be efficient in these reactions. In contrast, Michael
additions of aldehydes to electron-deficient alkenes bearing
a trifluoromethyl group such as a Michael acceptor have
rarely been reported.12 Due to the unique physical
properties of organofluorine compounds, broad research
efforts have been focused on the strategic introduction of
fluorine substitution into druglike molecules in medicinal
and agricultural chemistry.13 More specifically, catalytic
enantioselective construction of trifluoromethyl-containing
stereogenicity has become a current challenge in orga-
nofluorine chemistry.14 Herein, we report a prolinol silyl
ether catalyzed highly enantioselective Michael addition
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Bernardinelli, G. AdV. Synth. Catal. 2004, 346, 1147.
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A.; Jørgensen, A. K. J. Am. Chem. Soc. 2005, 127, 18296
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10.1021/ol101894h  2010 American Chemical Society
Published on Web 09/17/2010

Scheme 1
.
Synthesis of 2,2,2-Trifluoroethylidene Malonates
Table 1. Optimization of Reaction Conditionsa
temp time convnb
eec
(%)
entry catalyst solvent
(°C)
(h)
(%)
drb
1
2
3
4
5
6
7
8
C1
C2
C3
C4
C4
C4
C4
C4
C4
C4
C4
DMSO
CH3CN
CHCl3
CH3CN
CH3OH
DMF
rt
rt
rt
rt
rt
rt
17
24
48
48
24
24
24
24
24
24
24
66
trace
27
84
48
trace
35
93
95
91
5.0:1 13
-
-
-
2.6:1
4.0:1 95
5.2:1 96
-
-
-
Dioxane rt
5.7:1
Toluene
CHCl3
CHCl3
CHCl3
rt
rt
0
-15
3.7:1 97
4.2:1 97
5.2:1 99
5.5:1 99
of aldehydes to 2,2,2-trifluoroethylidene malonates (Scheme
1).
9
10
11
2,2,2-Trifluoroethylidene malonates 1a-c were prepared
according to a modified procedure reported in the literature.15
Condensation of trifluoroacetaldehyde methyl hemiacetal and
4-methoxyaniline under acidic conditions gave N,O-disub-
stituted aminal intermediate. Reaction of the aminal inter-
mediate with dialkyl malonate and sodium hydride in dry
THF proceeded smoothly, producing 2-substituted malonic
acid dialkyl ester in high yield. Treatment of 2-substituted
malonic acid dialkyl ester under acidic conditions gave the
corresponding deamination products 1a-c in moderate to
good yields.
69
a Reaction conditions: 1a (0.1 mmol), 2a (0.2 mmol), and catalyst (10
mol %) in solvent (0.5 mL) at the indicated temperature. b The conversion
and dr (syn/anti) of adducts were determined by 19F NMR analysis of the
crude reaction mixture. c The ee value was determined by chiral-phase HPLC
analysis.
after 17 h at room temperature, affording 3a in low yield
and 13% ee (Table 1, entry 1). Reactions in the presence of
substituted pyrrolidines C2 or C3 were even slower (Table
1, entries 2 and 3). When prolinol silyl ether C4 was used
as the catalyst,4 to our delight, good diastereoselectivity and
excellent enantioselectivity were observed (Table 1, entry
4). Different solvents were then examined to improve the
yield and diastereoselectivity. It was found that reactions in
toluene or chloroform occurred to full conversion after 24 h
at room temperature to give the desired product 3a in
excellent enantioselectivity, while reactions in methanol or
dioxane occurred much more slowly (Table 1, entries 5-9).
Furthermore, the diastereoselectivity and enantioselectivity
of the reaction in chloroform was further improved from 4.2:
1 dr and 97% ee to 5.2: 1 dr and 99% ee, respectively, by
lowering the temperature to 0 °C (Table 1, entry 10).
On the basis of the results summarized in Table 1, the
reaction conditions of entry 10 in Table 1 were chosen to
study the scope of the Michael reactions using a series of
aldehydes and 2,2,2-trifluoroethylidene malonates, and the
results are summarized in Table 2. In most cases, the adducts
were obtained in excellent yields, excellent enantioselectivi-
ties (up to 99% ee), and moderate diastereoselectivities (up
to 14: 1 dr). Generally, the nature of the substituents on 2,2,2-
trifluoroethylidene malonates slightly influences the yields
and enantioselectivities. The reactions of methyl, ethyl, or
benzyl 2,2,2-trifluoroethylidene malonates proceeded smoothly
to afford Michael adducts in excellent enantioselectivities
(96-99% ee) and good diastereoselectivities (syn/anti up to
We initially examined L-proline and three substituted
pyrrolidines (10 mol % each) as potential catalysts for the
reaction of diethyl 2,2,2-trifluoroethylidene malonate 1a with
phenylpropyl aldehyde 2a (Table 1). When L-proline was
used as the catalyst, the reaction occurred to 66% conversion
(13) (a) McClinton, M. A.; McClinton, D. A. Tetrahedron 1992, 48,
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2633. (g) Blay, G.; Ferna´ndez, I.; Monleo´n, A.; Pedro, J. R.; Vila, C. Org.
Lett. 2009, 11, 441. (h) Blay, G.; Ferna´ndez, I.; Mun˜oz, M. C.; Pedro, J. R.;
Vila, C. Chem.sEur. J. 2010, 9117. (i) Huang, Y.; Tokunaga, E.; Suzuki,
S.; Shiro, M.; Shibata, N. Org. Lett. 2010, 12, 1136. (j) Ogawa, S.; Iida,
N.; Tokunaga, E.; Shiro, M.; Shibata, N. Eur. Chem. J. 2010, 16, 7090. (k)
Kawai, H.; Kusuda, A.; Nakamura, S.; Shiro, M.; Shibata, N. Angew. Chem.,
Int. Ed. 1999, 48, 6324. (l) Prakash, G. K. S.; Mandal, M.; Olah, G. A.
Angew. Chem., Int. Ed. 2001, 40, 589. (m) 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. (n) Prakash, G. K. S.; Beier, P.
Angew. Chem., Int. Ed. 2006, 45, 2172.
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4656
Org. Lett., Vol. 12, No. 20, 2010

Table 2. Enantioselective Michael Addition of Aldehydes to
Table 3. Synthesis of δ-Lactones 5a-ca
2,2,2-Trifluoroethylidene Malonatesa
entry
R
R′
product
yieldb (%)
drc
eed (%)
entry
R
R′
product
yielda (%)
drb
eec (%)
1
2
3
Me
Bn
Bn
Bn
Et
Me
5a
5b
5c
95
88
91
13.7:1
15:1
4.7:1
91
97
98
1
2
3
4
Bn
Bn
Bn
Et
3a
3b
3c
3d
3e
3f
3g
3h
3h
91
94
90
94
84
91
91
93
93g
5.2:1
5.7:1
5.1:1
6.5:1
6.1:1
5.9:1
14:1
99
98d
96
91d
97
98
96
97
97
Me
Bn
Bn
Bn
Bn
Bn
Bn
Bn
a Reaction conditions: (i) 1 (0.1 mmol), 2 (0.2 mmol), and catalyst (10
mol %) in chloroform (0.5 mL) at 0 °C for 24 h; (ii) 1.5 equiv of NaBH3CN
in HOAc/THF at rt for 24 h. b Isolated yield. c Determined by 19F NMR.
d Determined by chiral-phase HPLC analysis.
Me
Et
5e
6e
7
nPr
iPr
8
Allyl
Allyl
6.9:1
5.3:1
pure 4,4,4-trifluoromethylbutyric acid 4 under mild oxidation
conditions (eq 1).17 Alternately, Michael adducts 3a and 3b
were converted into δ-lactones 5b,c with three consecutive
asymmetric centers in excellent yields under similar condi-
tions, as in the case of 3d (Table 3, entries 1-3).
In conclusion, we have developed a new protocol for the
asymmetric Michael addition of aldehydes to trifluoroeth-
ylidene malonates in good yields and with good diastereo-
selectivities and excellent enantioselectivities. The Michael
adducts could be readily transformed into polyfunctionalized,
optically pure 4,4,4-trifluoromethyl butyric acid 4 and
δ-lactones 5a-c in high yields without loss in enantiose-
lectivities. Mechanistic studies, synthetic applications of these
transformations as well as development of other organocata-
lytic enantioselective conjugate addition reactions are ongo-
ing in our laboratory.
9f
a Isolated yield. b Determined by 19F NMR of the crude adducts. c The
ee value was determined by chiral-phase HPLC analysis. d The ee value
was determined by chiral-phase HPLC analysis after conversion to the
corresponding lactone. e The reaction was stirred for 48 h. f 5 mol % catalyst
loading. The reaction was stirred for 36 h. g The conversion was determined
by 19F NMR analysis of the crude adducts.
5.7:1) (Table 2, entries 1-3). While the length of the linear
chain aldehydes slightly influenced the yields, enantioselec-
tivities, or diastereoselectivities (Table 2, entries 4-6), the
steric bulk of the substituents on the aldehydes significantly
affected the diastereoselectivity of the Michael adducts. Upon
changing the substituent on the aldehyde from n-propyl to
isopropyl, the diastereoselectivity of the Michael additions
increased from 5.9:1 to 14:1 (Table 2, entries 6 and 7). In
addition, lowering the catalyst loading to 5 mol % led to a
slight decrease in diastereoselectivity but without loss in
enantioselectivity (Table 2, entries 8 and 9).
The relative configuration of the Michael adduct 3d was
determined by NOE and COSY experiments of its derivative
5a (see the Supporting Information). Compound 5a was
obtained in high yield by reduction of 3d with NaBH3CN,
followed by intramolecular lactonization (Table 3, entry 1).
The relative stereochemical results can be explained by
related transition-state models previously discussed for (S)-
diphenylprolinol silyl ether catalyzed Michael reactions.16
Acknowledgment. The authors gratefully acknowledge the
financial support from the National Natural Science Founda-
tion of China (Grant Nos. 29825104 and 29632003), the
project of Application of Nuclear Techniques in Agriculture
(200803034), the Key Program of National Natural Science
Foundation of China (20632070), the National Basic Re-
search Program of China (2010CB126103), and SIOC startup
funds (QS) for financial support.
Supporting Information Available: All experimental
procedures and spectroscopic data of new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL101894H
(16) (a) Hayashi, Y.; Itoh, T.; Ohkubo, M.; Ishikawa, H. Angew. Chem.,
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Angew. Chem., Int. Ed. 2005, 44, 4212.
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2006, 127, 620. (b) Rueping, M.; Albert, M.; Seebach, D. HelV. Chim. Acta
2004, 87, 2473.
To demonstrate the utility of the reaction, Michael adduct
3a was converted to multifunctionalized and highly optically
Org. Lett., Vol. 12, No. 20, 2010
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