Catalytic enantioselective conjugate addition of fluorobis(phenylsulfonyl) methane to enals: Synthesis of chiral monofluoromethyl compounds

Article abstract of DOI:10.1039/b907399j

A new highly catalytic enantioselective Michael addition of fluorobis(phenylsulfonyl)methane to α,β-unsaturated aldehydes has been developed for the preparation of chiral monofluoromethyl compounds under mild reaction conditions.

Full text of DOI:10.1039/b907399j

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COMMUNICATION
www.rsc.org/chemcomm | ChemComm
Catalytic enantioselective conjugate addition of
fluorobis(phenylsulfonyl)methane to enals: synthesis of chiral
monofluoromethyl compoundsw
Shilei Zhang, Yinan Zhang, Yafei Ji, Hao Li and Wei Wang*
Received (in College Park, MD, USA) 14th April 2009, Accepted 22nd June 2009
First published as an Advance Article on the web 13th July 2009
DOI: 10.1039/b907399j
A new highly catalytic enantioselective Michael addition of
fluorobis(phenylsulfonyl)methane to a,b-unsaturated aldehydes
has been developed for the preparation of chiral monofluoro-
methyl compounds under mild reaction conditions.
In light of the high efficiency of diarylprolinol silyl ethers10
in promoting Michael reactions between a,b-unsaturated
aldehydes and nucleophiles without 1,2-addition side
reactions, we decided to choose this class of catalysts for the
conjugate addition of bis(phenylsulfonyl)methane (2a) and
FBSM (2b) to a,b-unsaturated aldehydes (Table 1). In
exploratory studies, a Michael reaction of 4-nitrocinnam-
aldehyde (1a) with BSM (2a) and FBSM (2b) was carried
out in the presence of 20 mol% I at rt in CH2Cl2 for 24 h. No
reaction occurred with 2a, presumably due to its low reactivity
(Table 1, entry 1). However, the reaction with 2b proceeded to
give the desired product, 4a, in 53% yield, but with a low ee
Conjugate addition is one of the cornerstones of organic
synthesis and is widely used in C–C bond-forming
reactions.1–4 Significant progress has been made recently in
the utilization of reactive stabilized carbanions, such as
nitroalkanes, malonate esters, ketoesters, 1,3-diketones,
nitroesters, 1,3-dinitriles and indoles, as Michael donors in
organocatalyzed asymmetric conjugate addition reactions.2–4
In expanding the scope of this powerful process, it is impera-
tive to explore new Michael donors and receptors, thus
products with new functionalities can be introduced. It has
been realized that the development of catalytic enantio-
selective conjugate addition processes using bis(phenylsulfonyl)-
methane (BSM) and fluorobis(phenylsulfonyl) methane
(FBSM)5 as nucleophiles remains a significant challenge,
despite their broad synthetic utilities. They can be readily
converted into their respective methyl and fluorinated methyl
groups,6 which are important motifs found in a large
collection of natural products and biologically-interesting
compounds.7 To the best of our knowledge, only a single
organocatalytic study using a chiral phase transfer catalyst to
promote the enantioselective conjugate addition of FBSM to
enones has been reported by Shibata and co-workers.6c,8
However, the strategy cannot be applied to enals due to the
greater susceptibility of a,b-unsaturated aldehydes to undergo
1,2-addition under the strong basic reaction conditions.
In this Communication, we wish to describe an unprece-
dented organocatalytic enantioselective Michael addition of
FBSM to a,b-unsaturated aldehydes. The process is efficiently
catalyzed by a simple chiral diphenylprolinol TBS ether with
high levels of enantioselectivity (86 - 99% ee) under mild
reaction conditions. Furthermore, significantly, this reaction
provides a uniquely valuable approach to the enantioselective
synthesis of synthetically- and biologically-important chiral
fluoromethyl compounds that are not accessible by existing
organocatalytic asymmetric Michael reactions.9
Table 1 Optimization of the organocatalytic asymmetric Michael
addition of 1a to 2a
Yield
(%)b
ee
Entry
Cat.
Additive
Solvent
t/h
(%)c
1d
2
3
4
5
6
I
I
I
I
None
None
None
None
None
None
None
PhCO2H
CH2Cl2
CH2Cl2
Et2O
Toluene
DMSO
Toluene
Toluene
Toluene
24
24
24
24
24
24
24
50
52
75
72
96
24
24
o5
53
36
65
28
44
46
85
71
56
83
40
40
0
NDe
35
70
81
43
84
90
88
91
90
99
95
64
NDe
I
II
III
III
III
III
III
III
IV
V
7
8f
9f
LiOAcÁH2O Toluene
10f
11fg
12fg
13
14
Na2CO3
PhCO2H
Toluene
Toluene
LiOAcÁH2O Toluene
None
None
Toluene
Toluene
a
Reaction conditions unless specified: a mixture of 1a (0.10 mmol), 2b
(0.10 mmol) and catalyst (0.02 mmol) in solvent (0.8 mL) was stirred at
rt for a specified time. After purification, product 3a was reduced by
Department of Chemistry & Chemical Biology, University of New
Mexico, Albuquerque, NM 87131, USA. E-mail: wwang@unm.edu;
Fax: +1 505 277 2609; Tel: +1 505 277 0756
w Electronic supplementary information (ESI) available: Experimental
and NMR data. CCDC 717019. For ESI and crystallographic data in
CIF or other electronic format see DOI: 10.1039/b907399j
b
NaBH4 to 4a for HPLC analysis. Isolated yields based on 2 steps.
c
d
Determined by chiral HPLC analysis (Chiralpak OD-H). 2a was
e
f
g
used. ND = not determined. 0.15 mmol of 1a used. At 0 1C.
ꢀc
This journal is The Royal Society of Chemistry 2009
4886 | Chem. Commun., 2009, 4886–4888

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(35%) (Table 1, entry 2). It seems that 2b is more nucleophilic
than that 2a due to the electron-withdrawing fluorine, which
renders it more prone to deprotonation under nearly neutral
conditions. It is noteworthy that the reduction of aldehyde 3a
to alcohol 4a was necessary for easy chiral HPLC analysis. An
investigation of the reaction medium revealed that the polarity
of the solvent had a pronounced effect on the yield and/or
enantioselectivity. Highly polar solvents, such as DMSO, gave
a low yield and a low ee value (Table 1, entry 5). Among the
solvents probed, the best result was achieved when toluene was
used (65% yield and 81% ee) (Table 1, entry 4), indicating that
less polar solvents render 2b more active due to lower levels of
solvation. A survey of the catalysts revealed that ether moieties
had a noticeable influence on the enantioselectivity and yield
(Table 1, entries 4, 6, 7, 13 and 14). The bulky TBDMS
catalyst, III, significantly enhanced the enantioselectivity of
the reaction (90% ee), but with a low yield (46%; Table 1,
entry 7). For other the catalysts probed, IV gave a lower ee,
and no reaction occurred with V. Accordingly, catalyst III was
selected for further optimization of the reaction. It was found
that product 3a had a high tendency to undergo a retro-
Michael reaction. Accordingly, an excess of 1a (1.5 equiv.)
was used to significantly improve reaction yields (Table 1,
entries 8–12). The effect of additives to the toluene solvent on
the enantioselectivity was also probed. Both PhCO2H and
LiOAcÁ2H2O increased yields without sacrificing enantio-
selectivity (Table 1, entries 8 and 9). It is believed that the reaction
rate is enhanced due to the facilitation of iminium formation
from the enal by the catalyst in the presence of PhCO2H. It
also reasonably assumed that the rate was increased by
LiOAcÁ2H2O owing to either the favorable formation of the
iminium ion or the speeding up of the deprotonation of
FBSM. To determine its role, a stronger base, Na2CO3, was
used (Table 1, entry 10). It was found that the reaction slowed
down significantly under the same reaction conditions. These
studies indicate that the formation of the iminium species is
critical to the process. Finally, lowering the temperature to
0 1C led to a further increase in the enantioselectivity of the
product (99% for PhCO2H: Table 1, entry 11; 95% for
LiOAcÁ2H2O: Table 1 entry 12). However, a dramatic drop
in yield with LiOAcÁ2H2O was seen (40%; Table 1, entry 12).
With the optimal reaction conditions in hand, we next
probed the generality of this asymmetric Michael addition
reaction with a wide range of a,b-unsaturated aldehydes.
Again, an excess of 1 (ranging from 1.5 to 5.0 equiv.) was
used in the reactions, and aldehydes 3 were reduced to alcohols
4 for convenient chiral HPLC analysis. As revealed in Table 2,
the conjugate addition processes were tolerant of Michael
acceptors 1 with significant structural variations. Remarkably,
the aromatic moieties bearing electron-withdrawing (Table 2,
entries 1–6), -neutral (Table 2, entries 7 and 8) and -donating
(Table 2, entry 9) substituents on the enals could efficiently
participate in the process with high efficiency. Furthermore, a
similar trend was observed with heteroaromatic (Table 2, entry
10), alkenyl (Table 2, entry 11) and alkyl (Table 2, entries
12–14 ) enals. It was noted that when alkyl a,b-unsaturated
aldehyde 1m was investigated in the Michael reaction under
the same reaction conditions in the presence of catalyst III, the
process proceeded very slowly and gave only a 17% yield after
Table 2 The scope of III-promoted Michael reactions of a,b-
unsaturated aldehydes with FBSMa
Entry
R
Equiv. 1 t/h Yield (%)b ee (%)c
1
2
3
4
5
6
7
8
4-NO2C6H4 (1a)
4-CNC6H4 (1b)
4-BrC6H4 (1c)
4-CF3C6H4 (1d)
3-NO2C6H4 (1e)
2-FC6H4 (1f)
1.5
1.5
3.0
3.0
2.0
2.4
5.0
2.0
5.0
5.0
72 83
67 72
72 81
70 80
59 75
70 74
72 71
73 42
76 71
58 79
45 77
48 66
96 17
79 81
99
99
499
499
97
499
499
96
92
86
C6H5 (1g)
2-Naphthyl (1h)
4-MeOC6H4 (1i)
2-Furanyl(1j)
9d
10
11
12
13
14e
trans-PhCHQCH (1k) 3.0
93
94
98
92
Me (1l)
n-Pr (1m)
n-Pr (1m)
5.0
5.0
5.0
a
Reaction conditions unless specified: a mixture of 1 (0.10 mmol), 2b
(0.10 mmol) and catalyst (0.02 mmol) in solvent (0.8 mL) was stirred at
rt for a specified time. After purification, product 3 was reduced by
b
NaBH4 to 4 for HPLC analysis. Isolated yields based on 2 steps.
c
Determined by chiral HPLC analysis (Chiralpak AS-H, AD or
d
Chiralcel OD-H). One equiv. of PhCO2H (0.10 mmol) and an
e
additional 0.2 mL of hexane were employed. Catalyst I was used
and no PhCO2H was added.
96 h, despite an excellent level of enantioselectivity (Table 2,
entry 13). However, the change of catalyst from III to I in the
absence of PhCO2H led to a significant enhancement in
reactivity of the reaction with a high yield (81%) and a high
enantioselectivity (92% ee) (Table 2, entries 13 vs. 14). The
absolute stereoconfiguration of the Michael adducts was
determined by single-crystal X-ray analysis based on enone 5
derived from aldehyde 3a, through a Wittig reaction with
Ph3PQCHCO2Et (Fig. 1).11
As demonstrated, Michael adduct-derived alcohol 4g can be
conveniently converted into its respective monofluoro-
methylated compound
6 by reductive removal of the
phenylsulfonyl group using activated Mg in MeOH in high
yield and without racemization (Scheme 1).6c
Fig. 1 The single-crystal X-ray structure of compound 5 (non-
disordered view of one of two molecules; all thermal ellipsoids at a
20% probability).
ꢀc
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3 For recent reviews on organocatalytic asymmetric conjugate
additions, see: (a) D. Almasi, D. A. Alonso and C. Najera,
Tetrahedron: Asymmetry, 2007, 18, 299; (b) S. B. Tsogoeva,
Eur. J. Org. Chem., 2007, 1701.
4 For selected examples of organocatalytic asymmetric Michael
additions of stabilized carbanions, see: Nitroalkanes: (a) H. Li,
Y. Wang, L. Tang and L. Deng, J. Am. Chem. Soc., 2004, 126,
9906; (b) T. Okino, Y. Hoashi, T. Furukawa, X. Xu and
Y. Takemoto, J. Am. Chem. Soc., 2005, 127, 119; (c) J. Ye,
D. J. Dixon and P. S. Hynes, Chem. Commun., 2005, 4481;
Ketoesters: (d) A. Berkessel, F. Cleemann and S. Mukherjee,
Angew. Chem., Int. Ed., 2006, 45, 947; Diketones: (e) J. Wang,
H. Li, W.-H. Duan, L. Zu and W. Wang, Org. Lett., 2005, 7, 4713;
(f) J. P. Malerich, K. Hagihara and V. H. Rawal, J. Am. Chem.
Soc., 2008, 130, 14416; Nitroesters: (g) I. T. Raheem,
S. N. Goodman and E. N. Jacobsen, J. Am. Chem. Soc., 2004,
126, 706; Dinitriles: (h) Y. Hoashi, T. Okino and Y. Takemoto,
Angew. Chem., Int. Ed., 2005, 44, 4032; Indoles: (i) D.-P. Li,
Y.-C. Guo, Y. Ding and W.-J. Xiao, Chem. Commun., 2006, 799;
(j) L. Li, E. G. Klauber and D. Seidel, J. Am. Chem. Soc., 2008,
130, 16464.
Scheme 1 The transformation of 4g into chiral monofluromethyl
compound 6.
Nowadays, the incorporation of fluorine atom(s) into bio-
active molecules to improve their physiochemical and
biological properties has become general practice in drug
design.12 Motivated by the broad utilities of chiral monofluoro-
methyl compounds in organic synthesis and medicinal
chemistry, and the lack of catalytic asymmetric methods for
their preparation, we have developed a novel organocatalytic
asymmetric Michael addition approach to these structures that
offers high enantiomeric excesses. This transformation is
efficiently carried out in the presence of a simple chiral
diarylprolinol TBS ether catalyst under mild reaction
conditions. The significance of the methodology is highlighted
by the fact that the iminium catalysis strategy employed here for
enals is different from the chiral phase transfer protocol developed
by Shibata co-workers, which can only be applied to enones.6c
Furthermore, the more synthetically-versatile aldehyde adducts
have more broad synthetic applications, such as oxidation to
carboxylic acids, reductive aminations, aldol reactions, etc., than
ketones, that will constitute our future endeavours.
5 For a review of selective fluoroalkylations with fluorinated
sulfones, see: G. K. S. Prakash and J. Hu, Acc. Chem. Res.,
2007, 40, 921.
6 There are only three examples of catalytic asymmetric methods
involving the use of FBSM as a nucleophile, see: (a) T. Fukuzumi,
N. Shibata, M. Sugiura, H. Yasui, S. Nakamura and T. Toru,
Angew. Chem., Int. Ed., 2006, 45, 4973; (b) S. Mizuta, N. Shibata,
Y. Goto, T. Furukawa, S. Nakamura and T. Toru, J. Am. Chem.
Soc., 2007, 129, 6394; (c) T. Fukuzumi, N. Shibata, S. Mizuta,
S. Nakamura, T. Toru and M. Shiro, Angew. Chem., Int. Ed., 2008,
47, 8051.
7 For selected examples, see: (a) R. B. Silverman and
S. M. Nanavati, J. Med. Chem., 1990, 33, 931;
(b) G. L. Grunewald, M. R. Seim, R. C. Regier, J. L. Martin,
L. Gee, N. Drinkwater and K. R. Criscione, J. Med. Chem.,
2006, 49, 5424; (c) E. E. Parent, K. E. Carlson and
J. A. Katzenellenbogen, J. Org. Chem., 2007, 72, 5546;
(d) F. G. Simeon, A. K. S. Brown, S. Zoghbi, V. M. Patterson,
R. B. Innis and V. W. Pike, J. Med. Chem., 2007, 50, 3256.
8 For examples of the use of chiral precursors and auxiliaries for the
asymmetric addition of FBSM, see: (a) Y. Li, C. Ni, J. Liu,
L. Zhang, J. Zheng, L. Zhu and J. Hu, Org. Lett., 2006, 8, 1693;
(b) G. K. S. Prakash, S. Chacko, S. Alconcel, T. Stewart,
T. Mathew and G. A. Olah, Angew. Chem., Int. Ed., 2007, 46, 4933.
9 (a) L. Hao, S.-L. Zhang, G.-Y. Chen, X.-X. Song and W. Wang,
Chem. Commun., 2009, 2136; (b) X. Han, J. Luo, C. Liu and
X.-Y. Lu, Chem. Commun., 2009, 2044.
Financial support for this work provided by the NSF
(CHE-0704015) is gratefully acknowledged. Thanks are
expressed to Dr Elieen N. Duesler for performing the X-ray
crystallographic analysis. The Bruker X8 X-ray diffractometer
was purchased via an NSF CRIF:MU award to the University
of New Mexico, CHE-0443580.
Notes and references
1 (a) P. Perlmutter, Conjugate Addition Reactions in
Organic Synthesis, Pergamon, Oxford, 1992; (b) M. Sibi and
S. Manyem, Tetrahedron, 2001, 56, 8033; (c) O. M. Berner,
L. Tedeschi and D. Enders, Eur. J. Org. Chem., 2002, 1877;
(d) J. Christoffers and A. Baro, Angew. Chem., Int. Ed., 2003, 42,
1688; (e) R. Ballini, G. Bosica, D. Fiorini, A. Palmieri and
M. Petrini, Chem. Rev., 2007, 107, 933.
10 For a review of diaryl prolinol ether catalysis, see: C. Palomo and
A. Mielgo, Angew. Chem., Int. Ed., 2006, 45, 7876.
11 The absolute stereoconfiguration of Michael products was
determined by single-crystal X-ray structural analysis, see the
ESI for detailsw.
2 (a) A. Berkessel and H. Groger, Asymmetric Organocatalysis: From
¨
Biomimetic Concepts to Applications in Asymmetric Synthesis,
Wiley-VCH Verlag GmbH & Co. KgaA, Weinheim, Germany,
2005; (b) Special issue on asymmetric organocatalysis: Chem. Rev.,
2004, 37, 5413.
12 For recent reviews on the applications of fluorinated compounds in
medicinal chemistry and drug discovery, see: (a) C. Isanbor and
D. O’Hagan, J. Fluorine Chem., 2006, 127, 303; (b) K. Muller,
C. Faeh and F. Diederich, Science, 2007, 317, 1881.
ꢀc
This journal is The Royal Society of Chemistry 2009
4888 | Chem. Commun., 2009, 4886–4888