Enantioselective α-trifluoromethylation of aldehydes via photoredox organocatalysis

Article abstract of DOI:10.1021/ja9053338

(Chemical Equation Presented) The first enantioselective, organocatalytic α-trifluoromethylation and α-perfluoroalkylation of aldehydes have been accomplished using a readily available iridium photocatalyst and a chiral imidazolidinone catalyst. A range o

Full text of DOI:10.1021/ja9053338

Published on Web 07/20/2009
Enantioselective r-Trifluoromethylation of Aldehydes via Photoredox
Organocatalysis
David A. Nagib, Mark E. Scott, and David W. C. MacMillan*
Merck Center for Catalysis at Princeton UniVersity, Princeton, New Jersey 08544
Received June 29, 2009; E-mail: dmacmill@princeton.edu
Scheme 1. Proposed Merger of Catalytic Cycles for CF3-Alkylation
Organofluorine compounds possess unique physical properties
that are exploited in a wide range of applications such as dyes,
polymers, agrochemicals, and pharmaceuticals.1 In medicinal
chemistry, for example, valuable physiological properties are often
conferred on “drug-like” molecules via the incorporation of CF3
groups that enhance binding selectivity, elevate lipophilicity, and/
or improve metabolic stability.2 It is not surprising, therefore, that
broad research efforts have been focused on the enantioselective
construction of trifluoromethyl-containing stereogenicity.3,4 While
significant progress has been made in the arena of nucleophilic 1,2-
trifluoromethylation of ketones,5 to date, the enantioselective
R-alkylfluorination of carbonyl derived enolates (or enolate equiva-
lents) remains an elusive goal.6,7 Herein we describe a conceptually
new approach to the asymmetric R-trifluoromethylation of aldehydes
via the successful merger of enamine8 and organometallic
photoredox9,10 catalysis.
Design Plan. Recently, our laboratory introduced a new mode
of organocatalytic activation, termed photoredox organocatalysis,9
whose mechanistic foundation relies on the propensity of electro-
philic radicals (derived from the reduction of an alkyl halide by a
photoredox catalyst (e.g., 1)) to combine with facially biased
enamine intermediates (derived from aldehydes and chiral amine
catalyst 2). Inspired by this strategy, we hypothesized that the
enantioselective R-trifluoromethylation of aldehydes should also be
possible by the marriage of two similar activation pathways. As
detailed in Scheme 1, we anticipated that Ir(ppy)2(dtb-bpy)+ 1,11
previously employed as a photosynthesis mimic, should readily
accept a photon from a variety of light sources within the visible
spectrum (such as a household fluorescent bulb) to populate the
*Ir(ppy)2(dtb-bpy)+ 7 excited state. Given its known tendency
toward reductive quenching, we presumed that *Ir(ppy)2(dtb-bpy)+
7 would readily accept a single electron from a sacrificial quantity
of enamine (0.5 mol %) to form a strong reductant Ir(ppy)2(dtb-
bpy) 8 (-1.51 V vs SCE in CH3CN).12,13 At this stage we
anticipated that this electron-rich iridium system 8 would participate
in single electron transfer (SET) with trifluoromethyl iodide (-1.22
V vs SCE in DMF)14 to render the electrophilic radical 3, while
regenerating the photoredox catalyst 1. In concert with this radical
formation pathway, we expected that an organocatalytic cycle would
initiate by condensation of the imidazolidinone catalyst 2 with an
aldehyde substrate to form the enamine 4. The merger of the two
activation pathways would then occur in the key alkylation step
via rapid addition of the trifluoromethyl radical 3 to the π-rich olefin
4 to form the R-amino radical 5. Given that radical 5 should have
a low barrier to oxidation,15 a second electron transfer event with
the *Ir(ppy)2(dtb-bpy)+ 7 excited state would close the photoredox
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C O M M U N I C A T I O N S
Table 1. Enantioselective R-Trifluoromethylation: Initial Studies
Table 2. Enantioselective R-Trifluoromethylation: Aldehyde Scope
a Enantiomeric excess by chiral GC analysis of the corresponding
alcohol.
cycle and deliver the iminium ion 6. Rapid hydrolysis of iminium
6 would then reconstitute the organocatalyst 2 while rendering the
optically enriched R-CF3 aldehyde.
As a critical design element, we anticipated high levels of
enantiocontrol resulting from positioning of the 4π-electron system
of activated enamine DFT-4 away from the bulky tert-butyl group,
while also adopting an (E)-configuration to minimize nonbonding
interactions.16 In this arrangement, the methyl group on the
imidazolidinone scaffold effectively shields the Re face, leaving
the Si face exposed toward electrophilic radical addition.
Our photoredox fluoroalkylation was first evaluated using octanal
and trifluoromethyl iodide along with imidazolidinone catalysts 2
or 10, photoredox catalysts 1 or 9, and a 26 W fluorescent household
lamp (Table 1). Initial experiments revealed that the proposed
alkylation reaction was indeed possible using a combination of
Ru(bpy)32+ (9) and the amine catalyst 10 (entry 1, 51% yield), albeit
to render a racemic product. Importantly, exclusion of light from
this protocol resulted in almost complete loss of catalyst efficiency
(<5% yield), in accord with the photoredox mechanism outlined in
Scheme 1. While the use of Ir(ppy)2(dtb-bpy)+ 1 allowed a
significant increase in reaction yield (entry 3, 85%), it was not until
subambient temperatures were employed that enantioinduction was
observed (entry 4, -20 °C, 52% ee). Moreover, implementation
of the trans-tert-butyl-methyl imidazolidinone catalyst 2 (along with
photocatalyst 1) provided almost perfect enantiocontrol in the
trifluoromethylation step without detectable post-reaction racem-
ization (entry 6, 79% yield, 99% ee).17 The superior levels of
induction and efficiency exhibited by the combination of organo-
catalyst 2 with photoredox catalyst 1 in DMF at -20 °C prompted
us to select these conditions for further exploration.18,19
a Stereochemistry assigned by chemical correlation or by analogy.
b Isolated yields of the corresponding alcohol. c Enantiomeric excess
determined by chiral SFC or HPLC analysis. d Using catalyst 11; ref 20.
Notably, this protocol enables the formation of a benzylic-CF3
R-formyl stereocenter without significant erosion in enantiopurity
(entry 8, 61% yield, 93% ee).21 As highlighted in entries 10 and
11, exposure of enantiopure (R)-3-phenyl-butyraldehyde to catalyst
(2S,5R)-2 results in the diastereoselective production of the anti
R,ꢀ-disubstituted isomer, while the use of (S)-3-phenyl-butyralde-
hyde with the same amine catalyst affords the corresponding syn
Table 3. Enantioselective R-Perfluoroalkylation: Alkyl Iodide Scope
We next performed a series of experiments to determine the scope
of the aldehydic component in this asymmetric trifluoromethylation
protocol. As revealed in Table 2, these mild redox conditions are
compatible with a wide range of functional groups including ethers,
esters, amines, carbamates, and aromatic rings (entries 2-4, 6, 8,
9, 61-86% yield, 93-98% ee). Moreover, significant variation in
the steric demand of the aldehyde substituent can be accommodated
without loss in enantiocontrol (entries 5-7, 10, and 11, g90% ee).
a Stereochemistry assigned by chemical correlation or by analogy.
b Isolated yields of the corresponding alcohol. c Enantiomeric excess
determined by chiral HPLC analysis of corresponding 2-naphthoyl ester.
d The perfluoroalkyl bromide was employed as starting material.
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C O M M U N I C A T I O N S
Scheme 2. Access to Enantioenriched Organofluorine Synthons
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(3) For a review of strategies for trifluoromethylation, see: Ma, J.-A.; Cahard,
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(4) For reviews of asymmetric trifluoromethylations, see: (a) Ma, J.-A.; Cahard,
D. Chem. ReV. 2008, 108, PR1-PR43. (b) Shibata, N.; Mizuta, S.; Kawai,
H. Tetrahedron: Asymmetry 2008, 19, 2633–2644. (c) Billard, T.; Langlois,
B. R. Eur. J. Org. Chem. 2007, 891–897.
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Dolbier, W. R., Jr. Org. Lett. 2001, 3, 4271–4273.
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adduct with high fidelity. These transformations clearly demonstrate
the synthetic advantages of catalyst-enforced induction versus
substrate-directed stereocontrol.
We have found that a broad range of perfluoroalkyl iodides and
bromides also participate in this enantioselective alkylation reaction
(Table 3). For example, n-perfluoroalkyl substrates of varying chain
length undergo reductive radical formation and enamine addition
without loss in enantiocontrol or reaction efficiency (entries 1-3
and 5-8, 67-89% yield, 96-99% ee). We have also found that
the aldehyde R-functionalization step can be performed with
sterically demanding coupling partners such as perfluoro-isopropyl
iodides (entry 4, 72% yield, 98% ee). Moreover, benzylic, R-ester,
and R-ether difluoromethylene carbons are readily incorporated as
part of this new enantioselective catalytic R-carbonyl alkylation.
We fully expect that the R-trifluoromethyl aldehyde products
generated in this study will be of value for the production of a variety
of organofluorine synthons. As shown in Scheme 2, reduction or
oxidation of the formyl group is possible to generate ꢀ-hydroxy and
R-trifluoromethyl acids (the latter we expect will be a key building
block for the formation of heterocycles that incorporate CF3 at the
benzylic position). Moreover, these aldehyde products can be employed
in a reductive amination sequence without significant loss in enanti-
oselectivity to produce ꢀ-trifluoromethyl amines. Last, and perhaps
most important, aldehyde oxidation followed by a Curtius rearrange-
ment allows enantioselective formation of R-trifluoromethyl amine
containing stereocenters, a commonly employed amide isostere in
medicinal chemistry.2 In this case, careful selection of base and reaction
temperature is essential to maintain the enantiopurity obtained in the
initial alkylation step.
(7) For examples of moderately stereoselective methods, see: (a) Kitazume,
T.; Ishikawa, N. J. Am. Chem. Soc. 1985, 107, 5186–5191. (b) Umemoto,
T.; Adachi, K. J. Org. Chem. 1994, 59, 5692–5699. (c) Itoh, Y.; Mikami,
K. Tetrahedron 2006, 62, 7199–7203.
(8) (a) Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B. Chem. ReV. 2007,
107, 5471–5569. (b) MacMillan, D. W. C. Nature 2008, 455, 304–308.
(9) Nicewicz, D. A.; MacMillan, D. W. C. Science 2008, 322, 77–80.
(10) For recent examples of photoredox catalysis applications in organic
synthesis, see: (a) Ischay, M. A.; Anzovino, M. E.; Du, J.; Yoon, T. P.
J. Am. Chem. Soc. 2008, 130, 12886–12887. (b) Koike, T.; Akita, M. Chem.
Lett. 2009, 38, 166–167. (c) Narayanam, J. M. R.; Tucker, J. W.;
Stephenson, C. R. J. J. Am. Chem. Soc. 2009, 131, 8756–8757. (d) Mu¨ller,
C.; Bauer, A.; Bach, T. Angew. Chem., Int. Ed. 2009, 48, DOI: 10.1002/
anie.200901603. (e) Du, J.; Yoon, T. P. J. Am. Chem. Soc. 2009, 131,
DOI: 10.1021/ja903732v.
(11) Although Ir(ppy)2(dtb-bpy)PF6 1 was optimal for this transformation,
commercially available Ru(bpy)3Cl2 could also be used to afford the desired
products in slightly diminished yields and enantioselectivities (Table 1,
entry 5). 1 is available in a single step from commercially available
[Ir(ppy)2Cl]2 (Sigma-Aldrich, CAS-No 92220-65-0). See ref 12.
(12) For synthesis and photophysical properties of Ir(ppy)2(dtb-bpy)PF6 1, see:
Slinker, J. D.; Gorodetsky, A. A.; Lowry, M. S.; Wang, J.; Parker, S.; Rohl,
R.; Bernhard, S.; Malliaras, G. G. J. Am. Chem. Soc. 2004, 126, 2763–
2767. For a review on the photoproperties of iridium complexes, see:
Flamigni, L.; Barbieri, A.; Sabatini, C.; Ventura, B.; Barigelletti, F. Top.
Curr. Chem. 2007, 281, 143–203.
(13) Fluorescence quenching experiments using preformed enamine 4 (R ) Bn)
confirmed quenching of *Ir(ppy)2(dtb-bpy)PF6, Stern-Volmer constant )
185; see Supporting Information for details.
(14) (a) Andrieux, C. P.; Gelis, L.; Me´debielle, M.; Pinson, J.; Saveant, J. M.
J. Am. Chem. Soc. 1990, 112, 3509–3520. (b) Bonesi, S. M.; Erra-Balsells,
R. J. Chem. Soc., Perkin Trans. 2 2000, 1583–1595.
(15) Wayner, D. D. M.; Dannenberg, J. J.; Griller, D. Chem. Phys. Lett. 1986,
131, 189–191.
In summary, the first enantioselective, organocatalytic R-trifluo-
romethylation and R-perfluoroalkylation of aldehydes have been
accomplished using a readily available iridium photocatalyst and a
commercial imidazolidinone catalyst. Full details of this survey will
be forthcoming.
(16) Performed using B3LYP/6-311+G(2d,p)//B3LYP/6-31G(d). See ref 9.
(17) We have recently shown the disruption of a postreaction racemization
pathway via design of catalyst 2 (versus catalyst 10); see: Amatore, M.;
Beeson, T. D.; Brown, S. P.; MacMillan, D. W. C. Angew. Chem., Int. Ed.
2009, 48, 5121–5124.
(18) The transformation does not proceed in the absence of the amine catalyst.
The addition of 2,6-lutidine is necessary to remove hydroiodic acid that is
formed during the reaction. Rapid racemization of the R-CF3 formyl adduct
was observed at room temperature but not at -20 °C.
Acknowledgment. Financial support was provided by the
NIHGMS (R01 GM078201-01-01) and kind gifts from Merck and
Amgen. M.E.S. acknowledges the Natural Sciences and Research
Council (NSERC) of Canada for postdoctoral funding. We thank
Dr. David Nicewicz for preliminary experimental contributions.
(19) Lower reaction efficiency appears to lead to lower enantiopurity as the
product is exposed to unconsumed base (i.e., Table 1, entry 5, catalyst 9).
(20) A hitherto unreported amine catalyst 11 was employed in entry 7 (Table 2);
see Supporting Information.
(21) Efficient construction of a benzylic CF3 bond on the unsubstituted parent
compound, phenylacetaldehyde, is also attainable (cf. 89% 19F NMR yield);
however facile postreaction racemization is observed.
(22) General Procedure for the Enantioselective R-Trifluoromethylation of
Aldehydes: To a dry test tube were added organocatalyst 2 (0.20 equiv),
photocatalyst 1 (0.005 equiv), and DMF (0.3 M). The resultant yellow
solution was degassed by alternating vacuum evacuation/argon backfill (×3)
at -78 °C before addition of CF3I (∼8 equiv), followed by aldehyde (0.76
mmol, 1.0 equiv) and 2,6-lutidine (1.1 equiv). The reaction vessel was
placed near a 26 W compact fluorescent light bulb in a -20 °C bath for
7.5-8 h. Upon reaction completion, the R-trifluoromethyl aldehydes were
typically reduced in situ with NaBH4 (10 equiv) in CH2Cl2 and MeOH to
afford ꢀ-trifluoromethyl alcohols in high yield and enantioselectivity.
Supporting Information Available: Experimental procedures and
spectral data. This material is available free of charge via the Internet
at http://pubs.acs.org.
References
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Chemistry: Principles and Commercial Applications; Plenum Press: New
York, 1994.
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