Sulfoxide-mediated α-arylation of carbonyl compounds

Article abstract of DOI:10.1021/ja2031882

A novel sulfoxide-mediated α-arylation of carbonyl compounds is reported. This reaction proceeds under very mild conditions at room temperature and does not require any transition-metal promoter or catalyst.

Full text of DOI:10.1021/ja2031882

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Sulfoxide-Mediated r-Arylation of Carbonyl Compounds
Xueliang Huang and Nuno Maulide*
Max-Planck-Institut f€ur Kohlenforschung, Kaiser-Wilhelm-Platz 1, 45470 M€ulheim, Germany
S Supporting Information
b
Scheme 1. Previous Work and an Unexpected Observation
ABSTRACT: A novel sulfoxide-mediated R-arylation of
carbonyl compounds is reported. This reaction proceeds
under very mild conditions at room temperature and does
not require any transition-metal promoter or catalyst.
he selective introduction of an aryl substituent at the posi-
T
tion R to a carbonyl group is a transformation of central
importance in organic chemistry. In contrast to the broad variety
of long-known R-alkylation methods for carbonyl derivatives,1
significant progress in R-arylation technology has flourished
mostly in the past two decades and relies heavily on the advent
of powerful transition-metal catalysts.2 Useful transition-metal-
free R-arylation processes3 typically involve stoichiometric reac-
tions of enolate anions (or equivalents thereof) with electrophilic
aromatic derivatives of Bi(V),4 Pb(IV),5 I(III),6 or benzyne.7
Recently, elegant organocatalytic approaches for enantioselective
R-arylation of carbonyl compounds have also been devel-
oped.8ꢀ11 In spite of these remarkable advances, the challenge of
developing metal-free direct arylations of carbonyl compounds
remains alive within the synthetic community.3
amount of reagents did not have a marked impact (entry 5).
Solvent screening revealed dichloromethane to be the most suitable
medium for this reaction (entries 6ꢀ9), and in this solvent, the
amount of Tf2O could be further reduced to 1.5 or 1.2 equiv while
retaining high yields of product 6aa. It is interesting to note that
trifluoroacetic anhydride (TFAA) also provided very good results
(entry 10), particularly in acetonitrile as the solvent (entry 11).
Having uncovered two sets of optimal conditions for this
direct arylation, we next investigated the substrate scope further.
As matters transpired, Tf2O was not always the best activating
agent (method A), and eventually TFAA (method B) was found
to be more general in the majority of cases (Scheme 2).
In addition to six-membered cyclic β-ketoesters, five-membered
substrates bearing different ester groups afforded the correspond-
ing arylated products in very good yields under similar conditions
(Scheme 2, 6aaꢀda and 6ka). When ketoester 3e derived from
R-tetralone was employed, a lower conversion was observed, and
34% of the starting material was recovered (6ea). Conversely,
derivatives of 1-indanone proved to be better candidates for this
reaction (6faꢀja). The presence of electron-withdrawing substit-
uents on the aromatic ring (3g and 3h) had a positive effect on this
process, and the corresponding products 6ga and 6ha were
obtained in high yields. In the case of acyclic β-ketoester 3l, a
slower reaction was observed, and 6la was obtained in an acceptable
yield after stirring at room temperature for 2 days. This process also
displayed high levels of diastereoselectivity: arylated product 6ma
with a tert-butyl group at position 4 of the six-membered ring was
formed in 75% yield with a 9:1 diastereomeric ratio (dr).17
Other diaryl sulfoxides were also examined as arylating agents.
As shown in Scheme 3, the corresponding products 6ab and 6ac
were obtained in moderate yields.
We recently reported an efficient ylide transfer reaction be-
tween Martin’s sulfurane 2 and activated carbonyl derivatives 1
(Scheme 1a).12,13 As part of our mechanistic studies of this
reaction, we investigated the reactivity of 2 toward more sub-
stituted homologues of 1 (R2 ¼ H), for which ylide formation
should not be possible. Disappointingly, when ketoester 3a was
employed in this process (Scheme 1b), swift decomposition of 2
took place, and none of the anticipated sulfonium salt 4 could be
detected in the reaction mixture by NMR or ESI-MS analysis
(Scheme 1b). In search of a surrogate for 2 that might be more
effective, we turned our attention to the known combination of
diphenyl sulfoxide (5a) and a suitable activating agent.14 To our
surprise, when triflic anhydride (Tf2O) was employed as the
electrophilic activator, arylated ketoester 6aa15 was obtained as
the main reaction product without any discernible formation of a
sulfonium salt (Scheme 1c). This intriguing result suggested that
fundamentally different reaction modes might be operative in
these transformations. We report herein our preliminary results
on the transition-metal-free arylation of carbonyl compounds
using in situ-activated sulfoxides as aryl donor reagents.16
Encouraged by this initial outcome, we then sought to compare
different anhydrides as activating reagents. As shown in Table 1, acetic
anhydride was ineffective (Table 1, entries 1 and 2), leading to only
traces of the desired product 6aa. In contrast, employing a stronger
activating reagent such as Tf2O proved beneficial (entry 3), and
increasing the amount of sulfoxide 5a to 1.2 equiv also enhanced
the reaction rate (entry 4), although further increases in the
Received: April 7, 2011
Published: May 16, 2011
r
2011 American Chemical Society
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Table 1. Optimization of the Direct Arylation of β-Ketoester
Scheme 3. Reaction of 3a with Sulfoxides 5b and 5c
6a with Sulfoxide 5aa
still obtained as the major product of the reaction, and only traces
of the “normal” Pummerer product 7ad could be detected in the
reaction mixture (Scheme 4a).18,19 This result was all the more
noteworthy in view of the fact that exposure of 5d to the action of
TFAA almost instantaneously generated trifluoroacetate 8 in
very high yield (Scheme 4b). The fact that 6ad was obtained
preferentially over its isomer 7ad despite the rapid conversion of
the latter into 8 by a “background” process strongly suggests that
the mechanism of these arylations is fundamentally different
from the classical Pummerer reaction.
Enticed by this result, we probed other aryl alkyl sulfoxides
(Scheme 5). On one hand, changing the nature of the alkyl
residue (R2) did not change the efficiency of the process, and the
corresponding arylated product 6ae was still obtained in mod-
erate yield. The aryl moiety could also be modified (6agꢀai). It is
remarkable that such arylated products were obtained by em-
ploying a sulfoxide from which a classical Pummerer reaction
would have been anticipated.20
a Performed at 25 °C, unless mentioned otherwise. b Yields of pure,
isolated material after column chromatography. c Not determined.
Scheme 2. Direct Arylation of Carbonyl Compounds with
Sulfoxide 5aa
From a mechanistic point of view, two distinct reaction path-
ways can be envisaged for this novel transformation (Scheme 6). It
is well-established that the treatment of sulfoxide 5 with TFAA
should lead to the formation of activated intermediate 10. After
enolization of the β-ketoester nucleophile 1, nucleophilic attack at
the aromatic position ortho to the cationic sulfur would lead to the
dearomatized intermediate 12 (pathway A), with concomitant
expulsion of trifluoroacetate.21,22 Rearomatization by proton loss
would account for the formation of product 6. More interestingly,
if the nucleophilic attack takes place at sulfur, the intermediate 11
would be formed instead (pathway B). A charge-accelerated [3,3]
sigmatropic rearrangement should then convert 11 to the same
dearomatized intermediate 12 as described previously.23ꢀ26
Pathway A (Scheme 6) would be akin to an extended Pum-
merer reaction of an aromatic ring.21 The extended Pummerer
chemistry of heteroarenes has been reported by both Kita and
Feldman,22 but to the best of our knowledge, all of these processes
require strongly electron-rich aromatic systems (e.g., furan, thio-
phene, or indole). In particular, Kita reported22d the arylation of
2,4-pentanedione (13a) with heteroaromatic furan- and thio-
phene-derived sulfoxides 14 (Scheme 7a). It is interesting to note
that when the analogous 1,3-dicarbonyls 13a and 13b were
employed in our system, no arylated products 16 (or their enol
tautomers) were detected (Scheme 7b). Strikingly, use of the
stronger activator Tf2O gave sulfonium ylides 17a and 17b as the
only detected products (Scheme 7c).12
a Method A: 1.5 equiv of Tf2O, 1.2 equiv of sulfoxide 5a, CH2Cl2, 0.5 M,
25 °C. Method B: 1.5 equiv of TFAA, 1.2 equiv of sulfoxide 5a, MeCN,
0.5 M, 25 °C. Method B was applied, unless mentioned otherwise.
b Method A was employed. c Based on recovered starting material (34%
of 3e was recovered). d The reaction was run at 0 °C. e Combined yield
with a dr of 9:1 (as determined by GC).
When phenyl methyl sulfoxide 5d (1.2 equiv) was employed
as an aryl donor to ketoester 3a, a rapid reaction ensued that was
complete within 2 h (Scheme 4). Surprisingly, arylated 6ad was
All of experimental evidence thus far points toward pathway B
(Scheme 6) being operative. Indeed, the reaction is exquisitely
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Scheme 4. Reaction of 3a with Sulfoxide 5d
Scheme 7. Reaction of Acyclic Dicarbonyl Compounds 13
with Various Sulfoxides [Equation (a) Depicts Prior Work
by Kita22d
]
Scheme 5. Reaction of 3a with Sulfoxides 5dꢀha,b
Scheme 8. Functionalization of r-Arylated Product 6aa
a Conditions: 1.5 equiv of TFAA, 1.2 equiv of sulfoxide 5, MeCN, 0.5 M,
25 °C. b Ratios of 6 to 7 as determined by GC: 6ad/7ad = 96/4; 6ae/
7ae = 99/1; 6ag/7ag = 99/1; 6ah/7ah = 93/7; 6ai/7ai = 96/4.
Scheme 6. Mechanistic Proposal for Sulfoxide-Mediated
r-Arylation of Carbonyl Compounds
from the conventional Pummerer reaction but can also disrupt it
significantly.
Finally, preliminary manipulation of the adducts 6 was sought
(Scheme 8).27 The arylsulfur appendage could be easily excised
by hydrogenation with Raney Ni in acetone, leading quantita-
tively to desulfurized product 19, which is formally the product
of phenylation. When the reaction was conducted in methanol
instead of acetone, further diastereoselective reduction of the
ketone carbonyl took place, affording cyclohexanol 20 as a single
stereoisomer in high yield.
In summary, we have developed a mild, metal-free stereo-
selective arylation of carbonyl compounds using aryl sulfoxides
as arylating reagents. The ability to use simple and easily available
reagents in a room-temperature transformation is a distinctive
feature of this process, for which an intriguing sigmatropic
rearrangement mechanism has been proposed. This approach
also provides an entry into densely functionalized, aryl-substi-
tuted, all-carbon quaternary stereocenters.28 Further studies
directed toward broadening the scope and elucidating the
mechanism of this novel transformation are underway and will
be reported in due course.
ortho-selective, and we did not detect any traces of isomers
resulting from nucleophilic attack at the para position of the
aromatic ring. Such para-substituted products would be strongly
anticipated and should have been observed if pathway A were
dominant, particularly on steric grounds. Additionally, the suc-
cess observed with electron-neutral and even slightly electron-
poor diaryl sulfoxides (such as 5c) is difficult to reconcile with the
prior stringent requirement for activated, electron-rich aryl
substituents in the extended Pummerer work of Kita.22 Without
doubt, the intermediacy of an extended dearomatized species
such as 18 appears to be crucial in Kita’s work (Scheme 7a).
The most compelling piece of evidence comes from con-
sideration of aryl alkyl sulfoxides 5dꢀh (Scheme 5). It is
remarkable that arylated products could still be obtained in
reasonable yields in spite of the fast “background” Pummerer
transformation that sulfoxides 5dꢀh undergo in the absence of a
nucleophile (Scheme 5). These unambiguous results suggest that
the process described herein not only is fundamentally different
’ ASSOCIATED CONTENT
S
Supporting Information. Experimental procedures and
b
characterization data. This material is available free of charge via
the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
maulide@mpi-muelheim.mpg.de
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’ ACKNOWLEDGMENT
(14) (a) Cook, A. F.; Moffatt, J. G. J. Am. Chem. Soc. 1968, 90, 740.
(b) Daves, D., Jr.; Anderson, W. R., Jr.; Pickering, M. V. J. Chem. Soc.,
Chem. Commun. 1974, 301. (c) Hartke, K.; Strangemann, D. Heterocycles
1986, 24, 2399. (d) F€urstner, A.; Alcarazo, M.; Radkowski, K.; Lehmann,
C. W. Angew. Chem., Int. Ed. 2008, 47, 8302.
We are grateful to the Max-Planck Society, the Max-Planck-Institut
f€ur Kohlenforschung, and the Deutsche Forschungsgemeinschaft
(DFG Grant MA 4861/4-1) for generous funding of our research
programs. Invaluable assistance from our HPLC, NMR (Dr. C.
Farꢀes), and X-ray (Dr. R. Goddard) Departments is acknowledged.
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crystallographic analysis. See the Supporting Information (SI) for details.
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