Organocatalyzed regio- and enantioselective allylic trifluoromethylation of Morita-Baylis-Hillman adducts using ruppert-prakash reagent

Article abstract of DOI:10.1021/ol201490e

The organocatalyzed regioselective allylic trifluoromethylation of Morita-Baylis-Hillman adducts using Ruppert-Prakash reagent was achieved in high to excellent yields via a successive S_N2′/S _N2′ mode for the first time. The reaction

Full text of DOI:10.1021/ol201490e

ORGANIC
LETTERS
2011
Vol. 13, No. 15
3972–3975
Organocatalyzed Regio- and
Enantioselective Allylic
Trifluoromethylation of
MoritaꢀBaylisꢀHillman Adducts Using
RuppertꢀPrakash Reagent
Tatsuya Furukawa,# Takayuki Nishimine,# Etsuko Tokunaga,# Kimiko Hasegawa,§
Motoo Shiro,§ and Norio Shibata*,#
Department of Frontier Materials, Nagoya Institute of Technology, Gokiso, Showa-ku,
Nagoya, 466-8555, Japan
nozshiba@nitech.ac.jp
Received June 2, 2011
ABSTRACT
The organocatalyzed regioselective allylic trifluoromethylation of MoritaꢀBaylisꢀHillman adducts using RuppertꢀPrakash reagent was
achieved in high to excellent yields via a successive SN20/SN20 mode for the first time. The reaction was extended to the asymmetric allylic
trifluoromethylation by the use of a bis-cinchona alkaloid catalyst with high enantioselectivities up to 94% ee.
Ruppert’s reagent,1 (trifluoromethyl)trimethylsilane
(Me3SiCF3), later renamed as the RuppertꢀPrakash re-
agent, isnow firmlyestablishedasa powerful toolfor direct
construction of CꢀCF3 bond formation. The Ruppertꢀ
Prakash reagent has been extensively studied for the
synthesis of trifluoromethyl-containing compounds,2 par-
ticularly in the fields of medicinal chemistry and material
science ever since the first report on the trifluoromethyla-
tion of aldehydes by using tetrabutylammonium fluoride
by Prakash and Olah.3 A large number of nucleophilic tri-
fluoromethylation of carbonyls and imines using Me3SiCF3
have been investigated;2 however, the addition of Me3SiCF3
to electron-deficient alkenes as represented by the Michael
addition reaction remains a challenge, even in a racemic,
nonstereoselective fashion (Scheme 1).
# Department of Frontier Materials, Graduate School of Engineering,
Nagoya Institute of Technology, Gokiso, Showa-ku, Nagoya 466-8555, Japan.
§ Rigaku Corporation, 3-9-12 Matsubara-cho, Akishima, Tokyo 196-
8666, Japan.
(1) (a) Ruppert, I.; Shlich, K; Volbach, W. Tetrahedron Lett. 1984,
24, 2195. (b) Pawelke, G. J. J. Fluorine Chem. 1989, 42, 429.
Scheme 1. Nucleophilic Trifluoromethylation of Electron-
Deficient Alkenes
(2) (a) Prakash, G. K. S.; Yudin, A. K. Chem. Rev. 1997, 97, 757. (b)
Billard, T.; Langlois, B. R. Eur. J. Org. Chem. 2007, 891. (c) Shibata, N.;
Mizuta, S.; Kawai, H. Tetrahedron: Asymmetry 2008, 19, 2633. (d)
Gritsenko, R. T.; Levin, V. V.; Dilman, A. D.; Belyakov, P. A.;
Struchkova, M. I.; Tartakovsky, V. A. Tetrahedron Lett. 2009, 50,
2994. (e) Levin, V. V.; Kozlov, M. A.; Song, Y. H.; Dilman, A. D.;
Belyakov, P. A.; Struchkova, M. I.; Tartakovsky, V. A. Tetrahedron
Lett. 2008, 49, 3108. (f) Eisenberger, P.; Gischig, S.; Togni, A. Chem.;
Eur. J. 2006, 12, 2597. (g) Allen, A. E.; MacMillan, D. W. C. J. Am.
Chem. Soc. 2010, 132, 4986. (h) Shimizu, R.; Egami, H.; Nagi, T.; Chae,
J.; Hamashima, Y.; Sodeoka, M. Tetrahedron Lett. 2010, 51, 5947. (i)
Prakash, G. K. S.; Mandal, M. J. Am. Chem. Soc. 2002, 124, 6538.
(3) Prakash, G. K. S.; Krishnamurti, R.; Olah, G. A. J. Am. Chem.
Soc. 1989, 111, 393.
r
10.1021/ol201490e
Published on Web 06/24/2011
2011 American Chemical Society

Only a few examples of Michael and Michael-type reac-
tions have been reported, but their substrate generalities are
quite narrow.4 Dilman and co-workers reported a Michael-
type addition of Me3SiCF3 to highly electrophilic alkenes
bearing either two germinal nitrile groups or Meldrum’
acids.5a,b The reactions were then extended to the addition
of C6F5-substituted silanes to acylated MoritaꢀBaylisꢀ
Hillman adducts 1 using catalytic amounts of tetrabutylam-
monium acetate affording C6F5-substituted products 2 via
the SN20 substitution mode at the terminal double bond in
good yields; moreover, the reaction of acylated Moritaꢀ
BaylisꢀHillman adduct 1 using Me3SiCF3 instead is poor5c,6
(Scheme 2, from1 to 2). Our laboratory has been engaged for
several years in a program that utilizes Me3SiCF3 for the
efficient synthesis of trifluoromethylated compounds.7 We
disclose herein the first example of regio-selective nucleophilic
allylic trifluoromethylation of acylated MoritaꢀBaylisꢀ
Hillman adducts 1with Me3SiCF3 catalyzed by tertially amine
via a successive SN20/SN20 mode, additionꢀelimination/
additionꢀelimination, to provide medicinally attractive syn-
thons, R-methylene β-trifluoromethyl esters 3 in high to
excellent yields (Scheme 2, from 1 to 3). We also achieved
an organocatalyzed enantioselective allylic trifluoromethyla-
tion of MoritaꢀBaylisꢀHillman adducts with Me3SiCF3 by
commercially available cinchona alkaloid, (DHQD)2PHAL,
to furnish chiral 3 in high enantioselectivities up to 94% ee,
for the first time. The β-trifluoromethyl esters 3 obtained here
can be efficiently converted into interesting carbocyclic and
heterocyclic compounds without any loss of the enantiomeric
purities of the starting substrates (Scheme 2).
Our initial investigation started with finding out a
suitable catalyst on the successive SN20/SN20 allylic trifluoro-
methylation of Morita-Baylis-Hillman acetate 1a with
Me3SiCF3 (Table 1). 1,8-Diazabicyclo[5.4.0]undec-7-ene
(DBU), Et3N, PPh3, and 4-dimethylaminopyridine
(DMAP) were found to be ineffective in the trifluoro-
methylation reaction in THF (entries 1ꢀ4). Incontrast, the
use of a catalytic amount of quinuclidine proceeded readily
at room temperature to give trifluoromethylated product
3a in 75% yield (entry 5). The trifluoromethyl substituent
was regioselectively introduced at the benzylic position via
successive SN20/SN20 substitution and an addition to the
terminal alkene via the SN20 mode was not observed. The
yield of 3a improved to 77% when 1,4-diazabicyclo-
[2.2.2]octane (DABCO) was used (entry 6). Solvent opti-
mization was performed next. We attempted to use
CH2Cl2, toluene or DMF as the solvent, but the results
did not improve (Table 1, entries 7ꢀ9). The use of 2
equivalents of Me3SiCF3 improved the yield of 3a to
96% (Table 1, entry 10).
With the optimized conditions established, the scope of
substrates in regioselective, successive SN20/SN20 allylic
trifluoromethylation was investigated (Table 2). A series
of MoritaꢀBaylisꢀHillman acetates 1bꢀj with a variety of
substituents on the aromatic ring, such as chloro, bromo,
methyl, methoxy, and nitro group were nicely converted
into the corresponding successive SN20/SN20 mode trifluoro-
methylated products 3bꢀj in up to 99% yields (entries
1ꢀ9). The reaction of sterically demanding naphthyl moi-
ety and heteroaryl moieties alsoproceededwell in 85ꢀ92%
yields (entries 10ꢀ13). Multiply substituted aryl substrates
such as 1o and 1p gave allylic trifluoromethylated products
3o and 3p regioselectively in 93% yields (entries 14 and 15).
A series of sterically less demanding methyl esters 1qꢀs
were also converted to the desired compounds 3qꢀs in
excellent yields, without any adducts from a nucleo-
philic CF3 attack on the carbonyl carbon observed in
the previous report.5c,6 A substrate with alkyl sub-
stitution instead of the aryl substitution, that is, tert-butyl
3-acetoxy-2-methylenebutanoate, was also examined for
Scheme 2. Two Modes of Allylic Trifluoromethylation of
MoritaꢀBaylisꢀHillman Adducts, SN20 Mode (from 1 to 2
known5c,6) and Successive SN20/SN20 Mode (from 1 to 3, un-
known, this work), and Its Application to the Enantioselective
Synthesis of Carbo- and Heterocyles 6, 7
(5) (a) Dilman, A. D.; Levin, V. V.; Belyakov, P. A.; Struchkova,
M. I.; Tartakovsky, V. A. Tetrahedron Lett. 2008, 49, 4352. (b) Zemtsov,
A. A.; Levin, V. V.; Dilman, A. D.; Struchkova, M. I.; Belyakov, P. A.
Tetrahedron Lett. 2009, 50, 2998. (c) Zemtsov, A. A.; Levin, V. V.;
Dilman, A. D.; Struchkova, M. I.; Belyakov, P. A.; Tartakovsky, V. A.;
Hu., J. Eur. J. Org. Chem. 2010, 6779.
(6) Reaction of 1q with Me3SiCF3 inefficiently provides an 1/1
mixture of SN20-substitution adduct and 1,2-adduct in 30% combined
yield.
(7) (a) Mizuta, S.; Shibata, N.; Hibino, M.; Nagano, S.; Nakamura,
S.; Toru, T. Tetrahedron 2007, 63, 8521. (b) Mizuta, S.; Shibata, N.;
Akiti, S.; Fujimoto, H.; Nakamura, S.; Toru, T. Org. Lett. 2007, 9,
3707. (c) Kawai, H.; Kusuda, A.; Nakamura, S.; Shiro, M.; Shibata,
N. Angew. Chem., Int. Ed. 2009, 48, 6324. (d) Kawai, H.; Kusuda, A.;
Mizuta, S.; Nakamura, S.; Funahashi, Y.; Masuda, H.; Shibata,
N. J. Fluorine Chem. 2009, 130, 762. (e) Kawai, H.; Tachi, K.;
Tokunaga, E.; Shiro, M.; Shibata, N. Org. Lett. 2010, 12, 5104. (f)
Kusuda, A.; Kawai, H.; Nakamura, S.; Shibata, N. Green Chem.
2009, 11, 1733.
(4) (a) Sevenard, D. V.; Sosnovskikh, V. Y.; Kolomeitsev, A. A.;
Knigsmann, M. H.; Roschenthaler, G. V. Tetrahedron Lett. 2003, 44,
7623. (b) Sosnovskikh, V. Y.; Usachev, B. I.; Sevenard, D. V.; Roschenthaler,
G. V. J. Org. Chem. 2003, 68, 7747. (c) Sosnovskikh, V. Y.; Sevenard, D. V.;
Usachev, B. I.; Roshenthler, G. V. Tetrahedron Lett. 2003,44, 2097. (d) Large,
S.; Roques, N.; Langlois, B. R. J. Org. Chem. 2000, 65, 8848.
Org. Lett., Vol. 13, No. 15, 2011
3973

Table 1. Optimization of the Reaction Conditionsa
Table 2. Trifluoromethylation of MoritaꢀBaylisꢀHillman
Acetatesa
entry
catalyst
DBU
solvent
yield (%)
entry
1
R
Ar
3-ClC6H4
3
yieldb (%)
1
THF
0
0
2
Et3N
THF
1
1b
1c
1d
1e
1f
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
Me
Me
Me
3b
3c
3d
3e
3f
98
95
67
99
98
99
91
92
87
85
92
87
85
93
93
96
90
96
3
PPh3
THF
0
2
4-ClC6H4
4
DMAP
THF
Trace
75
77
32
27
0
3
2-BrC6H4
3-BrC6H4
4-BrC6H4
3-MeC6H4
4-MeC6H4
3-MeOC6H4
4-NO2C6H4
1-Naphthyl
2-Naphthyl
2-Furyl
5
Quinuclidine
DABCO
DABCO
DABCO
DABCO
DABCO
THF
4
6
THF
5
7
CH2Cl2
Toluene
DMF
THF
6
1g
1h
1i
3g
3h
3i
8
7
9
10b
8
96
9
1j
3j
a Reactions were carried out using 1a (1.0 equiv), Me3SiCF3 (1.2
equiv), catalyst (10 mol %) in solvent at room temperature for 12 h
unless otherwise noted. b Me3SiCF3 (2.0 equiv) was used.
10
11
12
13
14
15
16
17
18
1k
1l
3k
3l
1m
1n
1o
1p
1q
1r
1s
3m
3n
3o
3p
3q
3r
3s
2-Pyridyl
3,4-Cl2C6H3
3,5-Br2-4-MeOC6H2
Ph
allylic trifluoromethylation under the same reaction con-
ditions, but complex mixture was resulted. To our knowl-
edge, this is the first example of allylic trifluoromethylation
of MoritaꢀBaylisꢀHillman adducts via the successive
SN20/SN20mode.
4-MeOC6H4
4-BrC6H4
a Reactions were carried out using 1a (1.0 equiv), Me3SiCF3 (2.0
equiv), DABCO (10 mol %) in THF at room temperature for 12 h unless
otherwise noted. b Isolated yield.
Next, a preliminary investigation of asymmetric cataly-
sis was conducted (Table 3). Asymmetric allylic alkylation
(AAA)8 is one of the most powerful tools for making
enantiomeric compounds and for developing creative syn-
thetic methodologies in the synthesis of optically active
natural products. Such a reaction is in general most
actively investigated by transition-metal catalysts repre-
sented by the TsujiꢀTrost reaction.8 On the other hand,
recent advances in asymmetric organocatalysis have in-
duced another strategy for the asymmetric allylic alkyla-
tion or substitution of MoritaꢀBaylisꢀHillman adducts
using various carbon-or heterocentered nucleophiles.9 For
the organocatalyzed asymmetric allylic alkylation based
on carbonꢀcarbon bond-formation, allylic alkylations
with soft nucleophiles, including 1,3-dicarbonyl com-
pounds and dicyanoalkenes, have been reported; however,
organocatalyzed allylic alkylations with a hard nucleo-
phile, the CF3 anion, have not been reported. In this
context, we first attempted our allylic trifluoromethylation
reaction of 1a with Me3SiCF3 in the presence of a catalytic
amount of bis-cinchona alkaloid, (DHQD)2PHAL.10 Un-
fortunately, even after heating, no reaction was observed
(Table 3, entry 1). After a brief survey of the reaction
conditions, MoritaꢀBaylisꢀHillman carbonates 4aꢀd
were found to be effective substrates for the asymmetric
allylic trifluoromethylation reaction to furnish the desired
chiral R-methylene β-trifluoromethyl esters in high enan-
tioselectivities up to 94% ee, although the conversion was
lower than that of racemic condition (entries 2;5). The
short list of the enantioselective version of this transforma-
tion, however, was carefully chosen to demonstrate suffi-
cient diversity of the present chemistry, which included
nonsubstituted aromatic, o- or p-substituted aromatics
with halogenyl moiety, sterically demanding or a sterically
less demanding ester group. These results indicated that
the substitution of the aromatic ring and ester moiety did
not significantly affectthe reactivityand enantioselectivity.
(8) (a) Trost, B. M. Chem. Rev. 1996, 96, 395. (b) Trost, B. M.;
Crawley, M. L. Chem. Rev. 2003, 103, 2921.
(9) (a) Zhang, S. J.; Cui, H. L.; Jiang, K.; Li, R.; Ding, Z. Y.; Chen,
Y. C. Eur. J. Org. Chem. 2009, 5804. (b) Huang, J. R.; Cui, H. L.; Lei, J.;
Sun, X. H.; Chen, Y. C. Chem. Commun. 2011, 47, 4784. (c) Hong, L.;
Sun, W.; Liu, C.; Zhao, D.; Wang, R. Chem. Commun. 2010, 46, 2856. (d)
Cui, H. L.; Huang, J. R.; Lei, J.; Wang, Z. F.; Chen, S.; Wu, L.; Chen,
Y. C. Org. Lett. 2010, 12, 720. (e) Peng, J.; Huang, X.; Cui, H. L.; Chen,
Y. C. Org, Lett. 2010, 12, 4260. (f) Cui, H. L.; Peng, J.; Feng, X.; Du, W.;
Jiang, K.; Chen, Y. C. Chem.;Eur. J. 2009, 15, 1574. (g) Jiang, K.; Peng,
J.; Cui, H. L.; Chen, Y. C. Chem. Commun. 2009, 45, 3955. (h) Du, Y.;
Han, X.; Lu, X. Tetrahedron Lett. 2004, 45, 4967. (i) Steenis, D. J. V. C.;
Marcelli, T.; Lutz, M.; Spek, A. L.; Maarseveen, J. H.; Hiemstra, H.
Adv. Synth. Catal. 2007, 349, 281. (j) Sun, W.; Kim, L. H. J. N.; Lee,
H. J.; Gong, J. H. Tetrahedron Lett. 2002, 43, 9141. (k) Zhang, T. Z.; Dai,
L. X.; Hou, X. L. Tetrahedron: Asymmetry 2007, 18, 1990. (l) Jiang,
Y. Q.; Shi, Y. L.; Shi, M. J. Am. Chem. Soc. 2008, 130, 7202. (m) Wang,
L.; Prabhudas, B.; Clive, D. L. J. J. Am. Chem. Soc. 2009, 131, 6003. (n)
Bengoa, E. G.; Landa, A.; Lizarranga, A.; Mielgo, A.; Oiarbide, M.;
Palomo, C. Chem. Sci. 2011, 2, 353. (o) Baidya, M.; Remennikov, G. Y.;
Mayer, P.; Mayr, H. Chem.;Eur. J. 2010, 16, 1365. (p) Cui, H. L.; Feng,
X.; Peng, J.; Lei, J.; Jiang, K.; Chen, Y. C. Angew. Chem., Int. Ed. 2009,
48, 5737.
(10) Catalyst and solvent screening are shown in Tables S1 and S2 in
the Supporting Information.
3974
Org. Lett., Vol. 13, No. 15, 2011

The absolute stereochemistry of (S)-3f was confirmed
by X-ray crystallographic analysis of the derivative
(1R,2S)-7 described in the later part of the text (Figure 1
and Scheme 3) and the absolute stereochemistry of other
trifluoromethylated compounds 3 was tentatively assumed
by analogy.
proceeded efficiently in the presence of nBu3SnH and AIBN
to stereoselectively afford Indane derivative 6. The relative
stereochemistry of 6 was tentatively assigned to be a thermo-
dynamically stable trans-configuration by the NMR analysis
of 6. Heterocycle 7, having a spiro center, was also synthe-
sized as a mixture of diastereoisomers by the 1,3-dipolar
cycloaddition reaction of trifluoromethylated product 3f
with chlorobenzaldoxime in the presence of triethylamine
in CH2Cl2 in 88% yield. In both cases, enantiopurities of the
starting substrates 3 were retained.
Table 3. Enantioselective Trifluoromethylation of Moritaꢀ
BaylisꢀHillman Carbonatesa
Scheme 3. Conversion of Chiral R-Methylene β-Trifluoro-
methyl Esters 3 into Carbo- and Heterocycles 5 and 6
entry 1/4
R1
Ac
R2
tBu C6H5
Ar
3
yieldb (%) ee (%)
1
2
3
4
5
1a
4a
4b
4c
4d
3a
3a
Trace
39
ND
92
88
90
94
Boc tBu C6H5
Boc tBu 2-BrC6H4 3d
Boc tBu 4-BrC6H4 3f
37
60
Boc Me
C6H5
3q
52
a Reactions were carried out using 1a (1.0 equiv), Me3SiCF3 (5.0
equiv), (DHQD)2PHAL (10 mol %) in THF at 60 °C for 120 h unless
otherwise noted. b Isolated yield.
In summary, the organocatalyzed regioselective allylic
trifluoromethylation of MoritaꢀBaylisꢀHillman adducts
using Ruppert’s reagent was achieved in high to excellent
yields via a successive SN20/SN20 mode for the first time.
The reaction was extended to the asymmetric allylic tri-
fluoromethylation by the use of bis-cinchona alkaloid
catalyst with high enantioselectivities up to 94% ee. This
should be a powerful protocol for accessing enantiomeric
R-methylene β-trifluoromethyl esters that are useful syn-
thetic building blocks for further transformation.
Acknowledgment. This study was financially supported
inpart by Grants-in-Aid for Scientific Research(21390030,
22106515, Project No. 2105: Organic Synthesis Based on
Reaction Integration). We also thank TOSOH F-TECH
INC. and the Asahi Glass Foundation.
Figure 1. X-ray Crystallographic analysis of (1R,2S)-7 (CCDC
827782).
The chiral R-methylene β-trifluoromethyl esters 3obtained
here could be smoothly transformed into biologically
attractive carbo- and heterocycles 6 and 7. Two examples
were performed (Scheme 3). First, intramolecular radical
cyclization of the allylic trifluoromethylated product 3d
Supporting Information Available. Experimental proce-
dures and characterization. This material is available free of
charge via the Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 15, 2011
3975