Enantioselective α-arylation of aldehydes via the productive merger of iodonium salts and organocatalysis

Article abstract of DOI:10.1021/ja2008906

The enantioselective α-arylation of aldehydes has been accomplished using diaryliodonium salts and a combination of copper and organic catalysts. These mild catalytic conditions provide a new strategy for the enantioselective construction and retention of enolizable α-formyl benzylic stereocenters, a valuable synthon for the production of medicinal agents. As one example, this new asymmetric protocol has been applied to the rapid synthesis of (S)-ketoprofen, a commercially successful oral and topical analgesic.

Full text of DOI:10.1021/ja2008906

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pubs.acs.org/JACS
Enantioselective r-Arylation of Aldehydes via the Productive Merger
of Iodonium Salts and Organocatalysis
Anna E. Allen and David W. C. MacMillan*
Merck Center for Catalysis at Princeton University, Princeton, New Jersey 08544, United States
S Supporting Information
b
A notable exception is the seminal work of Fu and co-workers
who have realized the enantioselective Negishi and Kumada
ABSTRACT: The enantioselective R-arylation of alde-
hydes has been accomplished using diaryliodonium salts
coupling of R-methine bromo ketones and amides with organo-
metallic arenes at low temperature.4 Recently, we questioned
and a combination of copper and organic catalysts. These
mild catalytic conditions provide a new strategy for the
enantioselective construction and retention of enolizable R-
formyl benzylic stereocenters, a valuable synthon for the
whether enolizable R-aryl aldehydes might also be enantioselec-
tively created and retained via a novel, tandem catalysis mechan-
ism that employs diaryliodonium salts as an arylation partner in
the presence of both amine and metal catalysts.5 Herein, we
production of medicinal agents. As one example, this new
asymmetric protocol has been applied to the rapid synthesis
describe the successful execution of these ideals and present an
of (S)-ketoprofen, a commercially successful oral and topi-
operationally trivial, room temperature protocol that is suffi-
cal analgesic.
ciently mild to generate R-carbonyl benzylic stereogenicity
without postreaction racemization (eq 2).
Design Plan. Recently, we described the enantioselective R-
trifluoromethylation of aldehydes using the hypervalent Togni
reagent,6 in combination with an imidazolidinone catalyst and
ver the past decade, the catalytic union of nascent enolates
Lewis acid additives (eq 1).7 Inspired by these studies, we
O
with aryl coupling partners has become a mainstay trans-
hypothesized that iodonium salts that incorporate aromatic
groups, such as diphenyliodonium triflate, might analogously
function as arylating agents with transiently generated enamines,
thereby providing a new pathway for asymmetric aldehyde
arylation with amine catalysts (Scheme 1). Often viewed as an
electrophilic species that undergoes CꢀAr bond formation via an
iodonium addition/reductive elimination mechanism, diarylio-
donium salts have previously been utilized for the racemic R-
arylation of silyl enol ethers and silyl ketene acetals.8 As a further
consideration, we recognized that these electrophilic salts are
nontoxic, readily accessible, and air and moisture stable, valuable
characteristics with respect to the development of an efficient
organocatalytic reaction.5c
formation in organic synthesis, primarily driven by advances in
transition metal catalysis.1,2 In particular, the pioneering work of
Buchwald and Hartwig has provided a number of enantioselec-
tive enolate R-arylations that enable quaternary carbon forma-
tion directly adjacent to both ketone and lactone moieties.2
Slower to develop, however, have been protocols that allow the
enantioselective production of enolizable R-carbonyl benzylic
stereocenters (methine stereocenters), presumably due to the
propensity for postreaction racemization when elevated tem-
peratures or basic conditions are employed.2,3
We began our investigation using diphenyliodonium triflate,
octanal, and amine catalyst 1 (Table 1). While noncatalytic
reactions with enolates9 or silyl enol ethers10 often proceed
without activation of the diaryliodonium salt, enamine-activated
octanal failed to couple with diphenyliodonium triflate (entry 1).11
In accord with our previous trifluoromethylation studies, we next
examined the use of catalytic Lewis acids that we hoped would
activate the hypervalent iodine reagent toward nucleophilic
attack via counterion binding.6,7 Remarkably, all metal salt
additives resulted in no observable reaction (entries 2ꢀ4) with
the exception of CuCl, which produced the desired R-arylation
adduct in a notable 58% yield and 76% ee (entry 5). It has long
been established that the arylation of carbon and oxygen based
nucleophiles with diaryliodonium salts can be facilitated by the
presence of catalytic copper salts; however, the mechanism of
activation typically involves a Cu(I) mediated oxidative addition
Received: January 28, 2011
Published: March 09, 2011
r
2011 American Chemical Society
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Table 1. Evaluation of Metal Additives and Amine Catalysts
Scheme 2. Revised Mechanism for the Aldehyde R-Arylation
As outlined in Table 2, this R-arylation strategy is tolerant to
aldehydic coupling partners that incorporate a wide range of
functional groups, including arenes and olefins (entries 2 and 3,
84ꢀ87%, 94% ee) as well as ethers, esters, and carbamates
(entries 4ꢀ7, 74ꢀ81%, 91ꢀ93% ee). Notably, sterically de-
manding substrates (R = piperidinyl or isopropyl) are also
accommodated with minimal impact on yield or enantiocontrol
(entries 7 and 8, 68ꢀ81%, 90ꢀ93% ee). In addition, enantiopure
β-chiral aldehydes can also be used for the diastereoselective
construction of both syn- and anti-R,β-disubstituted products
(entries 9 and 10, 67ꢀ81%, 20:1 to 5:1 dr). While a matched and
mismatched outcome is observed in each case, respectively, it is
interesting to note that the induced stereochemistry in both
examples is dominated by the catalyst architecture.
a GC yield. b Determined by chiral HPLC analysis of the corresponding
alcohol; absolute configuration determined by chemical correlation or
by analogy. c Performed with 2:1 toluene/Et2O.
Scheme 1. Initial Hypothesis for the R-Arylation of
Aldehydes
We have also found that a broad range of aryl and heteroaryl
rings can be enantioselectively coupled with aldehyde-derived
enamines in this tandem-catalysis reaction (Table 3). While
symmetrical diaryliodonium triflates can be successfully em-
ployed in this context, we have found that the elegant approach
of Gaunt to generate ArꢀCu(III)ꢀXY systems from nonsym-
metrical aryl-mesityl reagents is preferred for reasons of
practicality.12aꢀc,16 Notably, electron-poor (entries 1ꢀ4, 6ꢀ7)
as well as electron-rich arenes (entries 5, 8ꢀ10) transfer readily
with excellent levels of enantiocontrol (g91% ee). Moreover, a
broad range of para- and meta-substituted aryl rings with diverse
steric and electronic properties (ethers, esters, nitro groups, and
halides) can be readily exploited in this protocol (entries 2ꢀ4,
6ꢀ10, 67ꢀ91%, 91ꢀ93% ee). It is important to note, however,
that ortho-substitution has thus far been restricted to small
groups such as fluorine (entry 7, 67%, 91% ee). In addition
to phenyl rings, we were delighted to find that heteroaromatics
of an electron-rich (entry 11, 81%, 92% ee) or electron-poor
nature (entry 12, 70%, 93% ee) are suitable coupling partners, a
valuable finding with respect to potential medicinal chemistry
applications.
into the arylꢀiodonium bond to generate a highly electrophilic
ArꢀCu(III)ꢀXY system.12,13 With this alternative pathway in
mind (see Scheme 2), further improvements were realized when
CuBr was employed (entry 6), and both yield and enantioselec-
tivity were increased when amine catalyst 1 was replaced with
catalyst 3 (entry 8). Moreover, use of trichloroacetic acid as the
cocatalyst along with a mixed solvent system of toluene and
diethyl ether provided an excellent chemical yield and enantios-
electivity (entries 9 and 10). Finally, the observed levels of
efficiency and enantiocontrol were maintained with 10 mol %
of catalyst 3, thereby establishing optimal conditions for further
exploration.14,15
Mechanistic Considerations. As illustrated in Scheme 2, we
propose that this tandem-catalysis17 pathway begins with con-
current formation of both the activated chiral enamine 4 (from
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Table 2. Aldehyde Scope for the Enantioselective r-
Table 3. Scope of the Diaryliodonium Triflate
Arylationa,b,c
Componenta,b,c
a Absolute configuration assigned by chemical correlation or by analogy.
b Isolated yield of the corresponding alcohol.15 c Enantiomeric excess
determined by chiral HPLC analysis of the corresponding alcohol. d 1:1
toluene/Et2O. e 20 mol % 3 TCA. f 20 mol % CuBr. g 40 mol % 3 TCA.
3
3
a Absolute configuration assigned by chemical correlation or analogy.
b Isolated yield of the corresponding alcohol. c Enantiomeric excess
determined by chiral HPLC analysis of the corresponding alcohol.
d Symmetrical diaryliodonium triflate was used. e Using 20 mol %
condensation of amine catalyst 3 with the aldehyde substrate)
and the electron-deficient aryl-Cu(III) species 5 (arising from
oxidative addition of Cu(I) into the CꢀI bond of the diarylio-
donium triflate system). We expect that the highly electrophilic
Cu(III)ꢀaryl system 5 will rapidly coordinate to the Re face of
the enamine (Si face shielded by the phenyl substituent of 3; see
618) to form the π-Cu complex 6. Rapid bond isomerization will
subsequently lead to the η1-iminium 7 organocopper, which
upon reductive elimination should release the optically enriched
R-aryl iminium 8 and reconstitute the Cu(I)Br catalyst. Hydro-
lysis of iminium 8 will subsequently regenerate the organocata-
lyst partner 3 along with the desired R-aryl aldehyde product.
To further demonstrate the value of this new R-arylation
strategy, we focused upon the development of a unique and
expeditious route to ketoprofen, an oral and topical nonsteroidal
anti-inflammatory drug.19 As shown in detail in Scheme 3,
f
3 TCA. Using 40 mol % 3 TCA. g Using 20 mol % CuBr. h Using
3
3
1:1 toluene/Et2O. i Using 5 mol % CuBr.
implementation of our standard arylation conditions at 0 °C
with propionaldehyde and iodonium 9 (prepared in two steps
from 3-aminobenzophenone; see Supporting Information), fol-
lowed by in situ aldehyde oxidation, successfully furnished (S)-
ketoprofen in 71% yield and 92% ee (a total of three chemical
operations from commercial materials).
In conclusion, we have developed a new technology that
allows the direct and enantioselective R-arylation of aldehydes
using a combination of metal and organic catalysis. The value of
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COMMUNICATION
Scheme 3. Rapid Enantioselective Synthesis of (S)-
Ketoprofen
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(14) The addition of NaHCO3 is necessary to remove the trifluor-
omethanesulfonic acid that is formed during the reaction.
(15) The isolated R-formyl adducts are generally stable at room
temperature without significant racemization. 2-Phenyloctanal was
isolated with 90% ee through direct purification by flash chromatogra-
phy (see Supporting Information). Rechecking the enantiopurity of the
2-phenyloctanal after 3 weeks confirmed the initial 90% ee (i.e., no
erosion in optical purity).
(16) Sanford and co-workers also used this approach in the Pd-
catalyzed arylation of CꢀH bonds, see: (a) Kalyani, D.; Deprez, N. R.;
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’ ASSOCIATED CONTENT
S
Supporting Information. Experimental procedures and
b
spectral data are provided. This material is available free of charge
via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
dmacmill@princeton.edu
’ ACKNOWLEDGMENT
Financial support was provided by NIHGMS (R01
GM078201-05) and kind gifts from Merck and Bristol-Myers
Squibb. A.E.A. thanks the Natural Sciences and Engineering
Research Council of Canada (NSERC) for a predoctoral
fellowship.
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