The productive merger of iodonium salts and organocatalysis: A non-photolytic approach to the enantioselective α-trifluoromethylation of aldehydes

Article abstract of DOI:10.1021/ja100748y

An enantioselective organocatalytic α-trifluoromethylation of aldehydes has been accomplished using a commercially available, electrophilic trifluoromethyl source. The merging of Lewis acid and organocatalysis provides a new strategy for the enantioselective construction of trifluoromethyl stereogenicity, an important chiral synthon for pharmaceutical, materials, and agrochemical applications. This mild and operationally simple protocol allows rapid access to enantioenriched α-trifluoromethylated aldehydes through a nonphotolytic pathway.

Full text of DOI:10.1021/ja100748y

Published on Web 03/18/2010
The Productive Merger of Iodonium Salts and Organocatalysis: A Non-photolytic
Approach to the Enantioselective r-Trifluoromethylation of Aldehydes
Anna E. Allen and David W. C. MacMillan*
Merck Center for Catalysis, Princeton UniVersity, Princeton, New Jersey 08544
Received January 27, 2010; E-mail: dmacmill@princeton.edu
Scheme 1. Proposed Mechanism for Direct R-Trifluoromethylation
Within the realm of drug design, the stereospecific incorporation of
polyfluorinated alkyl substituents is a powerful and widely employed tactic
to enhance binding selectivity, elevate lipophilicity, and/or circumvent
metabolism issues arising from in vivo C-H bond oxidation.1 In particular,
the catalytic production of CF3-containing stereogenicity has become a
methodological goal of central importance to practitioners of chemical
and pharmaceutical synthesis.2 Recently, we reported the first highly
enantioselective R-trifluoromethylation of aldehydes using photoredox
organocatalysis, a protocol that employs fluorescent household lights to
generate ·CF3 radicals that can intercept stereofacially biased enamines
(eq 1).2a In this communication, we describe a new mechanistic (non-
photolytic) approach to the same product class via the merger of Lewis
acid and organocatalysis with an electrophilic trifluoromethyl alkylating
reagent (eq 2).3,4 Through this alternative chemical pathway, enantioen-
riched R-trifluoromethylated aldehydes (and R-CF3 carbonyl building
blocks) can be generated under mild reaction conditions using com-
mercially available,5 bench-stable6 reagents and catalysts without the
requirement of a light source.
in an enantioselective C-I bond formation with 2 via a closed-shell
pathway. In accord with similar mechanisms described by Togni3e and
Baran,8 we expected the resulting λ3-iodane species 5 to rapidly undergo
reductive elimination with stereoretentive alkyl transfer, a step that would
forge the critical C-CF3 bond. Bifurcation of iminium ion 6 via hydrolysis
would then liberate the imidazolidinone catalyst 3 along with the desired
R-formyl CF3 product. As described in previous studies,9 we presumed
that high levels of enantioinduction should be possible using catalyst 3
on the basis of enamine olefin geometry control and selective Si-facial
exposure (via benzyl shielding of the Re face of enamine 4).
The proposed R-formyl trifluoromethylation was first evaluated using
hydrocinnamaldehyde, imidazolidinone 3, and a series of Lewis acids at
-20 °C (Table 1). To our delight, this new transformation was found to
Table 1. Effect of the Lewis Acid Catalyst on R-Trifluoromethylation
Inspired by the recent studies of Togni, we hypothesized that 3,3-
dimethyl-1-trifluoromethyl-1,2-benziodoxole (Togni’s reagent, 1) might
function as a trifluoromethylation agent for enamine-activated aldehydes
in a manner analogous to that observed for the racemic R-alkylation of
nitroesters, ꢀ-ketoesters, silyl enol ethers, and silyl ketene acetals.3 Since
1 is generally considered to be an electrophilic species that enables C-CF3
bond formation via an iodonium addition/reductive elimination mechanism,
we felt that such hypervalent iodonic reagents might also function
successfully in enamine catalysis.7 As described in Scheme 1, we
envisioned that 1 should undergo Lewis acid-catalyzed bond cleavage to
generate the highly electrophilic iodonium salt 2. At the same time,
condensation of amine catalyst 3 with an aldehyde substrate should
generate a chiral enamine 4 that is sufficiently π-electron-rich to participate
entry
Lewis acid
% yielda
% eeb
1
2
3
4
5
6
7
8
9
none
FeCl3
CuCl2
14
7
92
89
87
64
66
53
87
91
94
c
39
48
52
66
80
76
86
Sc(OTf)3
Zn(NTf2)2
Sm(OTf)3
FeCl2
FeCl2 + tert-amyl alcohol
c
CuCl
a Determined by 19F NMR spectroscopy using an internal standard.
b Enantiomeric excess was determined by chiral HPLC analysis of the
corresponding alcohol. c Using 5 mol % Lewis acid.
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4986 J. AM. CHEM. SOC. 2010, 132, 4986–4987
10.1021/ja100748y  2010 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Scope of Catalytic Enantioselective R-Trifluoromethylation
Scheme 2. Access to Enantioenriched Trifluoromethyl Synthons
To highlight the utility of enantioenriched R-CF3 aldehydes, we
undertook their conversion to a variety of valuable organofluorine
synthons. As outlined in Scheme 2, in situ reduction or oxidation
of the formyl group creates enantioenriched ꢀ-CF3 alcohols or
R-CF3 carboxylic acids with excellent stereofidelity. Moreover,
reductive amination of these R-CF3 aldehydes provides ꢀ-CF3
amines with only a slight reduction in optical purity (86% ee).
In summary, we have introduced a new mechanistic approach to
the enantioselective R-trifluoromethylation of aldehydes using only
commercially available reagents. We expect that this paradigm of
merging asymmetric organocatalysis (and Lewis acids) with iodonium
salts will be broadly useful across many reaction types.
Acknowledgment. Financial support was provided by NIGMS
(R01 01 GM093213-01) and kind gifts from Merck and Amgen.
A.E.A. thanks the Natural Sciences and Engineering Research
Council (NSERC) for a predoctoral fellowship (PGS D).
Supporting Information Available: Experimental procedures,
structural proofs, and spectral data for all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
References
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a Stereochemistry assigned by chemical correlation or analogy. b Isolated
yield of the corresponding alcohol. c Enantiomeric excess determined by
chiral HPLC or SFC analysis. d Performed using FeCl2 (10 mol %) and
tert-amyl alcohol. e Yield determined by 19F NMR spectroscopy.
be both high yielding and enantioselective using catalytic Fe(II) or Cu(I)
salts. Interestingly, the use of stronger Lewis acids led to markedly lower
levels of enantiomeric excess, presumably because of a post-reaction
racemization pathway. Indeed, the addition of tert-amyl alcohol was found
to rescue the product optical purity in the case of the FeCl2 system
(presumably via in situ hemiacetal formation; entries 7 and 8).10 The
superior levels of enantiocontrol and reaction yield obtained with CuCl
and imidazolidinone 3 at -20 °C prompted us to select these conditions
for further exploration.
As highlighted in Table 2, these mild Lewis acid-organocatalytic
conditions tolerate a wide range of functional groups in this R-trifluorom-
ethylation protocol, including aryl rings, ethers, esters, carbamates, and
imides (entries 1-8; 71-87% yield, 93-96% ee). Sterically demanding
aldehydes (R ) 4-piperidinyl, cyclohexyl, adamantyl) were also accom-
modated with little impact on the yield or enantiocontrol (entries 8-10;
70-80% yield, 94-97% ee). In addition, enantiopure ꢀ-chiral substrates
can be used for the diastereoselective construction of either the syn- or
anti-R,ꢀ-disubstituted products, highlighting the remarkable catalyst control
of these alkylations (entries 11 and 12; 19-20:1 dr). It should be noted
that catalyst 3 was ineffective in our photolytic trifluoromethylation
studies,2a providing further evidence that the protocol described herein
does not involve a radical pathway.
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(5) Imidazolidinone 3 can be purchased from Sigma-Aldrich as the hydrochloric
acid salt (CAS no. 278173-23-2). The hydrochloric acid salt was converted
to the trifluoroacetic acid salt before use in this protocol.
(6) 3,3-Dimethyl-1-trifluoromethyl-1,2-benziodoxole can be handled in moist
air without any special precautions. However, it should be stored at -20
°C to prevent slow degradation over time (see ref 3a).
(7) An alternate mechanism wherein Togni’s reagent might participate in a
redox one-electron alkylation pathway was also considered initially.
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(10) Time studies showed erosion of enantiopurity over time, and the use of
tert-amyl alcohol appeared to impede this post-reaction racemization.
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