Enantioselective organocatalytic α-fluorination of aldehydes

Article abstract of DOI:10.1021/ja051805f

The first direct enantioselective catalytic α-fluorination of aldehydes has been accomplished. The use of enamine catalysis has provided a new organocatalytic strategy for the enantioselective fluorination of aldehydes to generate α-fluoro aldehydes, an i

Full text of DOI:10.1021/ja051805f

Published on Web 05/19/2005
Enantioselective Organocatalytic r-Fluorination of Aldehydes
Teresa D. Beeson and David W. C. MacMillan*
Contribution from the DiVision of Chemistry and Chemical Engineering, California Institute of
Technology, Pasadena, California 91125
Received March 21, 2005; E-mail: Dmacmill@caltech.edu
Abstract: The first direct enantioselective catalytic R-fluorination of aldehydes has been accomplished.
The use of enamine catalysis has provided a new organocatalytic strategy for the enantioselective fluorination
of aldehydes to generate R-fluoro aldehydes, an important chiral synthon for medicinal agent synthesis.
The use of imidazolidinone 1 as the asymmetric catalyst has been found to mediate the fluorination of a
large variety of aldehyde substrates with N-fluorobenzenesulfonimide serving as the electrophilic source
of fluorine. A diverse spectrum of aldehyde substrates can also be accommodated in this new organocatalytic
transformation. While catalyst quantities of 20 mol % were generally employed in this study, successful
halogenation can be accomplished using catalyst loadings as low as 2.5 mol %.
Scheme 1
Within the realm of drug design, the stereospecific incorpora-
tion of fluorine substituents is a powerful and widely employed
tactic to circumvent metabolism issues arising from in vivo C-H
bond oxidation.1 On this basis, the catalytic production of
carbon-fluorine stereogenicity has become a methodological
goal of central importance to practitioners of chemical and
pharmaceutical synthesis.2 Surprisingly, however, catalytic
methods for the asymmetric construction of C-F bonds are
rare,3 the majority involving R-substituted â-keto ester substrates
that are structurally precluded from product epimerization.4 As
part of a program focused upon the development of organic
catalysts for broadly useful organic reactions, we recently
reported the enamine-catalyzed R-oxidation5 and R-chlorination
of aldehydes.6 In this paper we further advance this organoca-
talysis concept to document an operationally trivial procedure
for the enantioselective R-fluorination of aldehydes (Scheme
1). This new organofluorine reaction is founded upon the use
of imidazolidinone 1,7 a commercial catalyst that enables rapid
and enantiocontrolled C-F bond formation while being inert
to product epimerization or functionalization pathways.
The stereodefining step of enamine catalysis is widely
believed to involve a generic platform of induction wherein a
proton linchpin enforces electrophile activation in the asym-
metric vicinity of a nucleophilic enamine. Provoked by the
potential of developing an enantioselective aldehyde R-fluorina-
tion, we felt that an important extension of this induction
paradigm might be realized using electrophilic fluorine reagents
that are geometrically capable of catalyst proton-association and
fluorine delivery.8 On this basis, we identified N-fluorobenze-
nesulfonimide (NFSI) as a reagent that might participate in the
requisite closed transition state 2 via sulfone-proton bonding
and concomitant fluorine/enamine activation (Scheme 1). The
use of NFSI as an electrophilic fluorine source was particularly
(1) For recent reviews see: (a) Bo¨hm, H.; Banner, D.; Bendels, S.; Kansy,
M.; Kuhn, B.; Mu¨ller, K.; Obst-Sander, U.; Stahl, M. ChemBioChem 2004,
5, 637. (b) Maienfisch, P.; Hall R. G. Chimia 2004, 58, 93. (c) Hiyama,
T.; Shimizu, M. Angew. Chem., Int. Ed. 2005, 44, 214.
(2) For reviews of fluorination see: (a) France, S.; Weatherfax, A.; Lectka, T.
Eur. J. Org. Chem. 2005, 475. (b) Ma, J.-A.; Cahard, D. Chem. ReV. 2004,
104, 6119. (c) Ibrahim, H.; Togni, A. Chem. Commun. 2004, 1147. (d)
Togni, A.; Mezzetti, A.; Barthazy, P.; Becker, C.; Devillers, I.; Frantz, R.;
Hintermann, L.; Perseghini, M.; Sanna, M. Chimia 2001, 55, 801. (e) Davis,
F. A.; Kasu, P. V. N. Org. Prep. Proc. Int. 1999, 31, 125.
(3) First catalytic asymmetric R-fluorination: Hintermann, L.; Togni, A. Angew.
Chem., Int. Ed. 2000, 36, 4359.
(4) Some recent examples of asymmetric fluorination of â-keto esters or â-keto
phosphonates (a) Hamashima, Y.; Suzuki, T.; Shimura, Y.; Shimizu, T.;
Umebayashi, N.; Tamura, T.; Sasamoto, N.; Sodeoka, M. Tetrahedron Lett.
2005, 46, 1447. (b) Shibata, N.; Ishimaru, T.; Nagai, T.; Kohno, J.; Toru,
T. Snylett 2004, 1703. (c) Ma, J.-A.; Cahard, D. Tetrahedron: Asymmetry
2004, 1007. (d) Kim D. Y. Org. Lett. 2002, 4, 545. (e) Ma, J.-A.; Cahard,
D. J. Fluorine Chem. 2004, 125, 1357.
(5) Brown, S. P.; Brochu, M. P.; Sinz, C. J.; MacMillan, D. W. C. J. Am.
Chem. Soc. 2003, 125, 10808.
(6) Brochu, M. P.; Brown, S. P.; MacMillan, D. W. C. J. Am. Chem. Soc.
2004, 126, 4108.
(8) For reviews of N-F electrophilic fluorinating agents see: (a) Mikami, K.;
Itoh, Y.; Yamanaka, M. Chem. ReV. 2004, 104, 1. (b) Lal, G. S.; Pez, G.
P.; Syvret, R. G. Chem. ReV. 1996, 96, 1737. (d) Wilkinson J. A. Chem.
ReV. 1992, 92, 505.
(7) Ahrendt, K. A.; Borths, C. J.; MacMillan, D. W. C. J. Am. Chem. Soc.
2000, 122, 4243.
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J. AM. CHEM. SOC. 2005, 127, 8826-8828
10.1021/ja051805f CCC: $30.25 © 2005 American Chemical Society

Organocatalytic
R
-Fluorination of Aldehydes
A R T I C L E S
Table 2. Enantioselective R-Fluorination: Substrate Scope
Table 1. Effect of Catalyst, Solvent, and Temperature on
R-Fluorination
temp
C)
time
(h)
%
%
eeb
entry
catalyst
solvent
(
°
convrsna
1
2
3
4
5
6
7
8
9
L-proline
THF
THF
THF
CH3CN
EtOAc
acetone
CHCl3
THF
23
23
23
23
23
23
23
4
4
0.3
0.5
3
0.5
1
1
6
12
79
96
73
75
84
89
73
97
98
26
63
98
96
96
97
96
98
98
3
1
1
1
1
1
1
1
THF
-10
a Conversion determined by GLC analysis of product relative to an
internal standard (benzyl methyl ether). b Enantiomeric excess determined
by chiral GLC analysis (Bodman Γ-TA).
attractive, as it is an inexpensive, bench-stable solid that is
readily handled by experimentalists or automated systems.9
As revealed in Table 1, the proposed organocatalytic R-flu-
orination is indeed possible with a variety of amine catalysts;
however, poor stereoselectivities are observed with L-proline
or imidazolidinone 3 (Table 1, entries 1 and 2, e63% ee). In
contrast, exposure of cyclohexylacetaldehyde to NFSI in the
presence of imidazolidinone 1 leads to the desired R-fluoro
aldehyde adduct with excellent levels of enantiocontrol (entry
3, 98% ee). A survey of reaction media with catalyst 1 reveals
that a number of solvents (in combination with 10% i-PrOH10)
may be utilized without significant loss in asymmetric induction
or reaction efficiency (entries 3-7). It is interesting to note that
carbonyl-containing solvents (e.g. acetone) do not sequester the
catalyst or electrophile to an extent that is detectable (entry 6,
89% conversion, 97% ee). The impact of temperature on
enantioselectivity was minimal (cf. entries 3 and 9); however,
improved conversion was observed at -10 °C (entry 9). The
superior levels of induction and efficiency exhibited by amine
salt 1 in THF-i-PrOH at -10 °C to afford (R)-2-fluorocyclo-
hexylacetaldehyde in 98% ee and 98% conversion prompted
us to select these catalytic conditions for further exploration.
We next examined the scope of the aldehyde component in
this enantioselective R-fluorination protocol. As highlighted in
Table 2, a wide range of functional groups, including olefins,
esters, amines, carbamates, and aryl rings, can be readily
tolerated on the aldehydic substrate (entries 2-4, 6-8; 91-
99% ee). Moreover, extensive variation in the steric demands
of the aldehyde substituent can be realized (entries 1, 5, 7-9;
a Enantiomeric excess determined by chiral HPLC analysis of the
2-naphthoyl derivative (Chiralcel OJ). b Enantiomeric excess determined
by chiral GLC analysis (Macherey-Nagel Hydrodex-B-TBDAc).
Table 3. Effect of Catalyst Loading on Aldehyde R-Fluorination
mol %
catalyst
temp
C)
%
%
eeb
entry
1
(
°
time
convrsna
1
2
3
4
5
6
7
20
20
10
10
5
23
30 min
12 h
3 h
8 h
3 h
73
98
78
97
66
95
79
98
98
98
98
98
98
98
-10
23
4
23
4
5
2.5
25 h
12 h
23
a Conversion determined by GLC analysis of product relative to an
internal standard (benzyl methyl ether). b Enantiomeric excess determined
by chiral GLC analysis (Bodman Γ-TA).
R ) nonyl, cyclohexyl, Bn, Ph, adamantyl) without loss in
efficiency or enantiocontrol (54-96% yield, 94-99% ee). A
catalyst exposure study has revealed that product epimerization
is not observed over the indicated reaction time for any case
shown in Table 2. These results serve to illustrate the remarkable
capacity of imidazolidinone 1 to successfully differentiate
between the aldehyde R-methylene substrates and the R-fluoro
(9) (a) Development of NFSI: Differding, E.; Ofner, H. Synlett 1991, 187. (b)
For an investigation of the reactivity of NFSI, see: Antelo, J. M.; Crugeiras,
J.; Leis, J. R.; R´ıos A. J. Chem. Soc., Perkin Trans. 2 2000, 2071.
(10) While the use of i-PrOH as the reaction medium was less than fruitful, the
addition of 10% i-PrOH as a cosolvent generally resulted in improved
enantiocontrol and efficiency. Studies to understand this phenomenon are
now underway.
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J. AM. CHEM. SOC. VOL. 127, NO. 24, 2005 8827

A R T I C L E S
Beeson and MacMillan
aldehyde products. A defining example of such chemoselectivity
is found in the production of (R)-2-fluorophenylacetaldehyde,
a highly enolizable aldehyde that is configurationally stable
under these mild organocatalytic conditions (entry 7, 99% ee).
Last, the effect of catalyst loading on reaction efficiency has
been evaluated (Table 3). Catalyst loadings as low as 2.5 mol
% can be utilized without loss in enantiocontrol (entry 7, 98%
ee). In terms of operational convenience, the use of 20 mol %
imidazolidinone 1 at -10 °C or of 5-10 mol % of 1 at 4 °C
ensures high levels of reaction efficiency and enantioselectivity
while expedient reaction times are maintained (entry 4, 4 °C,
10 mol % 1, 97% conversion, 98% ee, 8 h; entry 6, 4 °C, 5
mol % 1, 95% conversion, 98% ee, 25 h).
stereogenicity in a wide variety of structural contexts using a
commercial catalyst and electrophilic fluorine source.
Acknowledgment. Financial support was provided by the
NIHGMS (R01 GM66142-01) and kind gifts from Amgen and
Merck. Mike Brochu is thanked for experimental efforts.
Supporting Information Available: Experimental procedures,
structural proofs, and spectral data for all new compounds are
provided. This material is available free of charge via the
Internet at http://pubs.acs.org.
JA051805F
In summary, we have described the first enantioselective
R-fluorination of aldehydes.11 This mild, operationally simple,
organocatalytic protocol allows direct access to carbon-fluorine
(11) Note added in proof: After the submission of this paper, a study outlining
the R-fluorination of aldehydes with low enantioselectivities was reported
online: Enders, D.; Huttl, M. R. M. Synlett 2005, 6, 991.
9
8828 J. AM. CHEM. SOC. VOL. 127, NO. 24, 2005