Enantioselective reduction of trifluoromethyl ketones with chiral organomagnesium amides (COMAs)

Article abstract of DOI:10.1021/ol026901p

(formula presented) Chiral organomagnesium amides (COMAs), readily prepared from dialkylmagnesiums and chiral secondary amines, can reduce trifluoromethyl ketones to form secondary alcohols with excellent enantioselectivities (up to 98:2 er) and chemical yields (typically ≥95% conversion, ≥85% isolated yields). These MPV-type reductions use an achiral hydride source, and the chiral amine is readily recovered.

Full text of DOI:10.1021/ol026901p

ORGANIC
LETTERS
2
002
Vol. 4, No. 23
139-4142
Enantioselective Reduction of
Trifluoromethyl Ketones with Chiral
Organomagnesium Amides (COMAs)
4
Kelvin H. Yong and J. Michael Chong*
Guelph-Waterloo Centre for Graduate Work in Chemistry and Biochemistry (GWC)2
and Department of Chemistry, UniVersity of Waterloo, Waterloo,
Ontario, Canada N2L 3G1
jmchong@uwaterloo.ca
Received September 13, 2002
ABSTRACT
Chiral organomagnesium amides (COMAs), readily prepared from dialkylmagnesiums and chiral secondary amines, can reduce trifluoromethyl
ketones to form secondary alcohols with excellent enantioselectivities (up to 98:2 er) and chemical yields (typically >95% conversion, >85%
isolated yields). These MPV-type reductions use an achiral hydride source, and the chiral amine is readily recovered.
Enantioselective reductions of ketones to chiral alcohols have
been studied extensively, and there are many excellent
methods available for reducing a wide variety of ketones
from chiral alkyl halides have been used as asymmetric
reducing agents, although selectivities are typically moder-
ate. Since reductions using COMAs likely proceed with the
6
1
with high selectivities. A particularly attractive approach
2
hydride coming from an achiral source (i.e., R Mg), the chiral
to such reductions is the use of a recoverable chiral catalyst
or reagent in conjunction with an achiral hydride source.
Thus, the use of oxazaborolidine catalysts (i.e., CBS-type
reductions) is more appealing than the use of stoichiometric
reagents such as DIP-Cl where the borane is consumed in
ligand should be recoverable and recyclable, and hence, in
principle, COMAs might be very desirable chiral reducing
agents. We report herein our initial findings in this area.
In testing a new chiral reducing agent, the standard
substrate appears to be acetophenone. However, treatment
of acetophenone with various COMA reagents, prepared from
1
2
the reaction.
We recently introduced chiral organomagnesium amides
dialkylmagnesiums (R Mg) and amine 1a, gave only trace
2
(
COMAs, RMgNR*
2
) as reagents for the enantioselective
amounts of phenethyl alcohol (Scheme 1). Deuteration
3
alkylation of aldehydes. In the course of our studies, it was
observed that transfer of hindered alkyl groups such as i-Pr
was often accompanied by competing reduction. It is
probable that such reductions arise from â-hydride transfer
via a Meerwein-Ponndorf-Verley (MPV)-type mechanism;
it is well-known that reduction is often competitive with alkyl
experiments with MeOD suggested that enolization was a
major competing pathway. Thus, it seemed that only ketones
without R-protons might be suitable substrates.
One such class of compounds are aryl trifluoromethyl
ketones. Asymmetric reduction of such ketones would furnish
chiral nonracemic trifluoromethyl carbinols. There is cur-
4
transfer when some Grignard reagents are reacted with
carbonyl compounds. In fact, Grignard reagents derived
5
(4) The reagent s-BuMgN(TMS) has been shown to reduce benzophe-
2
none, although incompletely, likely by â-hydride transfer: Henderson, K.
W.; Allan, J. F.; Kennedy, A. R. J. Chem. Soc., Chem. Commun. 1997,
1149-1150.
(
1) For recent reviews, see: (a) Itsuno, S. Org. React. 1998, 52, 395-
76. (b) Cho, B. T. Aldrichimica Acta 2002, 35, 3-16.
2) Corey, E. J.; Helal, C. J. Angew. Chem., Int. Ed. 1998, 37, 1986-
012.
5
2
3
(
(5) Wakefield, B. J. Organomagnesium Methods in Organic Synthesis;
Academic Press: London, 1995, p 249.
(
3) Yong, K. H.; Taylor, N. J.; Chong, J. M. Org. Lett. 2002, 4, 3553-
(6) Falorni, M.; Lardicci, L.; Giacomelli, G. J. Org. Chem. 1989, 54,
2383-2388.
556.
1
0.1021/ol026901p CCC: $22.00 © 2002 American Chemical Society
Published on Web 10/23/2002

probe reductions with COMA reagents further, we assessed
a number of ligand/i-Pr Mg combinations for their ability
2
Scheme 1
to reduce trifluoroacetophenone and 1-naphthyl trifluoro-
methyl ketone (Table 2).
Table 2. Effect of Ligand Structure on Stereoselectivity
Ar ) Ph
Ar ) 1-Nap
ligand
erb
erb
entry
R
no. yielda
R:S
yielda
R:S
rently considerable interest in asymmetric syntheses of
fluorinated organics, particularly as potential pharmaceuti-
cals. In addition, asymmetric reductions of trifluoromethyl
ketones have received relatively little attention (compared
to other carbonyl compounds). We were thus very pleased
to find that treatment of 2,2,2-trifluoroacetophenone with
COMA reagents 2 rapidly (-78 °C, 1 h) and efficiently
1
2
3
4
5
6
7
8
Me
Et
i-Pr
t-Bu
Ph
1a
1b
1c
1d
1e
1f
93
87
86
94
84c
89
71:29
76:24
54:46
21:79
13:87
66:34
97
86
92
94
87
92
93
92
16:84
31:69
11:88
21:79
46:54
7:93
7
PhCH2
(R)-PhCH(Me) 1g
(S)-PhCH(Me) 1h
9:91
24:76
(>95% GC yields, >85% isolated yields) afforded the
desired alcohol 3a (Scheme 1). A survey of different alkyl
groups showed that the enantioselectivity depended on the
alkyl group used as a hydride source (Table 1). The best
a
Percent isolated yields of chromatographed alcohol. b Determined by
HPLC analysis with a Chiralcel OD column. c Ether was used as the only
solvent. Selectivities were lower under standard conditions.
In all cases, good to excellent yields of the desired alcohol
were isolated. For 1-naphthyl trifluoromethyl ketone, reduc-
tions using COMAs with (S)-ligands consistently provided
the (S)-carbinol as the major product. There is no obvious
relationship between the size of the N-alkyl/aryl (R) group
and the observed selectivity. However, it is noteworthy that
N-benzyl ligand 1f gave high selectivities (entry 6). Since
both diastereomers of the R-methylbenzyl analogues (1g and
Table 1. Reactions of COMA 2 with Trifluoroacetophenone
erb
1
h) were readily available, they were also tested. As
entry
R
yielda
R:S
expected, they behaved differently. One isomer gave results
essentially identical to those of the nor-methyl case, while
the other isomer gave noticeably lower selectivity.
Results may be rationalized in terms of six-membered
chairlike transition states (Scheme 2). One would expect that
1
2
3
4
n-Bu
i-Bu
i-Pr
86
93
92
88
34:66
33:67
29:71
49:51
t-Bu
a
Percent isolated yields of chromatographed alcohol. b Determined by
HPLC analysis on a Chiralcel OD column.
Scheme 2. Proposed transition states for reduction of
3 2
ArC(O)CF with i-Pr Mg/1f
2
selectivities were observed with R ) i-Pr, so i-Pr Mg was
used for all further studies.
Enantioselective reductions of trifluoroacetophenone often
proceed with relatively low selectivities (compared to aceto-
phenone). This is likely due to the similar size of trifluo-
romethyl and phenyl groups.8 Nonetheless, some good
9
selectivities have been reported, and in some cases, reduc-
tions of trifluoromethyl ketones proceed with much higher
selectivities than their methyl analogues.10 Therefore, to
(
7) For leading references, see: Myers, A. G.; Barbay, J. K.; Zhong, B.
J. Am. Chem. Soc. 2001, 123, 7207-7219.
8) Note, however, that a CF3 group is similar to a tert-butyl group in
(
reductions using DIP-Cl: Ramachandran, P. V.; Teodorovic, A. V.; Gong,
B.; Brown, H. C. Tetrahedron: Asymmetry 1994, 5, 1075-1086.
4140
Org. Lett., Vol. 4, No. 23, 2002

the diamine ligand would chelate the Mg atom and that the
phenyl and N-alkyl groups would be preferentially oriented
anti to each other on the resulting five-membered ring.
Approach of the ketone to this reagent from the less hindered
face could then take place with the CF group oriented axial
3
or equatorial in a six-membered ring transition state. Since
relatively large aryl groups would prefer to be equatorial,
similar to that shown in Scheme 2 leads to the conclusion
that ligands of (S)-configuration should give products of (R)-
configuration. In fact, reductions of 1-naphthyl trifluoro-
methyl ketone using COMAs derived from (S)-proline (e.g.,
4, Scheme 3) consistently gave rise to (R)-3b as the major
product.
3
the transition state with an axial CF group is energetically
more favorable and gives rise to the major product. On the
basis of this model, ligands of the (S)-configuration should
afford (S)-carbinol as the major product. This is what is
observed.
Scheme 3
The enhanced selectivity observed with N-benzyl ligand
1f compared to ligands with smaller or larger N-alkyl groups
can also be explained using this model if one invokes a
stabilizing effect on one of the possible transition states by
the benzyl group. Specifically, an Ar-H‚‚‚F-C interaction
3
may help to stabilize the transition state where the CF is
axial. Such interactions, although known to be very weak,
have been observed in the solid state.11 In our case, the
presence of such interactions helps to explain the differences
in selectivities observed for ligands 1f, 1g, and 1h. Thus,
using the model shown in Scheme 2, it would be expected
that replacement of the benzylic pro-(R) hydrogen in 1f (to
give 1g) should have little influence on selectivity but that
replacement of the pro-(S) hydrogen (to give 1h) should give
decreased selectivity since steric interactions would make it
difficult for the favorable conformation shown to be attained.
The experimental evidence, namely, that 1f and 1g give
essentially identical selectivities while 1h gives significantly
lower selectivity (Table 2, entries 6-8), is consistent with
these expectations.
While the arguments presented above explain the differ-
ences in enantioselectivities observed with different ligands
and trifluoroacetophenone, they do not explain why there
are differences between aryl groups. Perhaps with acyclic
ligands, the orientation of the N-alkyl group is always anti
and the transition states shown in Scheme 2 pertain. Thus,
larger aryl groups will show a stronger preference for
adopting an equatorial orientation and be more likely to show
high (S)-selectivity. With trifluoroacetophenone, the two
With trifluoroacetophenone, the major product formed
using ligands 1a-f (all of the (S)-configuration) was
sometimes R and sometimes S. In general, ligands with
3
groups (Ph and CF ) are relatively similar in size, and thus
the selectivity may be more sensitive to changes in ligand
structure. However, the changes in enantioselectivities
observed, particularly reversals, with different N-alkyl groups
on the ligand are difficult to accommodate with this model.
Thus, neither explanation is completely satisfactory.
2
smaller N-alkyl groups (e.g., Me, Et, PhCH ) were (R)-
selective, while ligands with larger groups (e.g., t-Bu, Ph)
were (S)-selective. This may be because ligands with smaller
N-alkyl groups can adopt conformations in which the N-alkyl
group and the phenyl group of the phenylglycine-derived
ligand are cis. Approach of the ketone to the reagent would
then be on the opposite face to that depicted in Scheme 2,
and the opposite (R)-enantiomer would predominate. Thus,
with trifluoroacetophenone, larger N-substituents were needed
to obtain good selectivities, and the best numbers were
observed with ligand 1e (R ) Ph, Table 2, entry 5).
Other aryl trifluoromethyl ketones were also reduced with
the i-Pr COMA derived from 1f (Table 3). In general,
selectivities were excellent, particularly with larger aryl
groups. Product 3e, derived from aryl ) 9-anthryl, is
especially interesting since it is a useful chiral auxiliary and
it is known that enrichment to high enantiomeric purity is
12
easily achieved by recrystallization. The selectivity ob-
The idea that the relative orientation of the N-alkyl group
and the phenyl (side-chain) group is important in determining
the absolute configuration of the product is supported by
results using derivatives of proline as ligands. With such
ligands, the “side-chain” and N-alkyl group are confined in
a five-membered ring and may be considered cis-oriented
in a COMA complex. An analysis of possible transition states
served with COMA i-Pr
with results reported for other established chiral reducing
agents: BINAL-H, 92-98% ee; DIP-Cl, 82% ee; CBS-
catecholborane, 94% ee.
When an alkynyl trifluoromethyl ketone was reduced with
2
i-Pr Mg/1f, only moderate selectivity was observed and the
major isomer was the (R)-enantiomer (Table 3, entry 6),
2
Mg/1f (96% ee) compares favorably
12
13
14
reflecting the relatively small size of an alkynyl group
(9) (a) Bradshaw, C. W.; Hummel, W.; Wong, C.-H.; J. Org. Chem.
1
5
992, 57, 1532-1536. (b) Kanth, J. V. B.; Brown, H. C. Tetrahedron 2002,
8, 1069-1074.
(12) (a) Chong, J. M.; Mar, E. K. J. Org. Chem. 1991, 56, 893-896.
(13) Ramachandran, P. V.; Teodorovic, A. V.; Brown, H. C. Tetrahedron
1993, 49, 1725-1738.
(10) Kuroki, Y.; Sakamaki, Y.; Iseki, K. Org. Lett. 2001, 3, 457-459.
11) (a) Shimoni, L.; Glusker, J. P. Struct. Chem. 1994, 5, 383-397.
(
(b) Parsch, J.; Engels, J. W. J. Am. Chem. Soc. 2002, 124, 5664-5672.
(14) Corey, E. J.; Bakshi, R. K. Tetrahedron Lett. 1990, 31, 611-614.
Org. Lett., Vol. 4, No. 23, 2002
4141

COMAs are very useful reducing agents in select cases. Work
to improve the range of substrates and increase selectivities
is in progress.
Table 3. Reduction of Various Ketones with COMA Reagents
A typical experimental procedure is as follows. A solution
16
of i-Pr Mg (0.50 mmol) was added to a precooled (-78 °C)
2
solution of diamine (0.51 mmol) in ether (12 mL) under
argon. The resultant solution was then stirred at ambient
temperature for 30 min. THF (1.5 mL) was added, and the
i-Pr-COMA solution was cooled to -78 °C. A solution of
trifluoromethyl ketone (ca. 0.25-0.3 mmol) in ether (1 mL)
was added, and the reaction was stirred at -78 °C and
allowed to warm to rt slowly (5-6 h). The reaction was
erb
entry
Ar
product
yielda
R:S
1c,d
2
3
4
5
6c
Ph
3a
3b
3c
3d
3e
3f
84
92
95
89
95
88
13:87
7:93
7:93
3:97
2:98
61:39
1-naphthyl
2-Me-1-Naph
mesityl
9-anthryl
Bu-t-
quenched with saturated aqueous NH
separated. Standard extractive workup followed by silica gel
column chromatography (10f20% Et O in hexanes) gave
4
Cl, and the layers were
2
a
b
Percent isolated yields of chromatographed alcohol. Determined by
HPLC analysis on a Chiralcel OD column. Lower isolated yield reflects
the slightly volatile product. Ligand 1e used under standard conditions.
the desired alcohol. The enantiomeric ratio of the product
was determined by chiral-phase HPLC.
c
d
Acknowledgment. We thank the Natural Sciences and
Engineering Research Council of Canada for financial
support and the Ontario Ministry of Training, Colleges, and
Universities for a postgraduate scholarship (to K.H.Y.)
3
compared to a CF group. Overall, results can be explained
by relative sizes aryl > CF > alkynyl, consistent with A
3
values for these groups.15
While stoichiometric amounts of COMA reagents are used
in these reductions, it is important to note that the hydride
is transferred from an achiral source and that the chiral ligand
is easily recovered by acid-base extraction. Reactions
proceed under very mild conditions, with high yields, and
with selectivities up to 98:2 er. These attributes suggest that
Supporting Information Available: Experimental details
for the preparation of ligands 1a-h and reductions and
details for determinations of enantiomeric ratios and absolute
configurations. This material is available free of charge via
the Internet at http://pubs.acs.org.
OL026901P
(
15) Eliel, E. L.; Wilen, S. H. Stereochemistry of Organic Compounds;
Wiley: New York, 1994; pp 696-697.
(16) See Supporting Information for the preparation of i-Pr2Mg.
4142
Org. Lett., Vol. 4, No. 23, 2002