Copper-Catalyzed γ-Sulfonylation of α,β-Unsaturated Carbonyl Compounds by Means of Silyl Dienol Ethers

Article abstract of DOI:10.1021/acs.orglett.5b01675

A regioselective method for the introduction of sulfonyl groups at the γ-carbon of enone systems is reported. Using a copper catalyst and readily available sulfonyl chlorides, a range of silyl dienol ethers are sulfonylated in good yield under mild reacti

Full text of DOI:10.1021/acs.orglett.5b01675

Letter
pubs.acs.org/OrgLett
Copper-Catalyzed γ‑Sulfonylation of α,β-Unsaturated Carbonyl
Compounds by Means of Silyl Dienol Ethers
Xiaoguang Liu, Xiaohong Chen, and Justin T. Mohr*
Department of Chemistry, University of Illinois at Chicago, 845 West Taylor Street, Chicago, Illinois 60607, United States
S
* Supporting Information
ABSTRACT: A regioselective method for the introduction of
sulfonyl groups at the γ-carbon of enone systems is reported.
Using a copper catalyst and readily available sulfonyl chlorides, a
range of silyl dienol ethers are sulfonylated in good yield under
mild reaction conditions. The sulfone derivatives formed are
poised for further synthetic manipulations as demonstrated by
regioselective alkylations.
creating γ-functionalized enone products that are largely
inaccessible through dienolates or the Kim system.
nsaturated carbonyl compounds are valuable synthetic
Uintermediates owing to the aggregation of multiple
locations poised for further functionalization. Perhaps most
notably, the α- and β-carbons may be substituted readily by
engaging the polarized alkene in a conjugate addition reaction
followed by an enolate alkylation. Substitution of the more
remote γ-carbon of an enone has proven substantially more
challenging. Considerable effort, including in our own
laboratory,1 has been directed toward achieving this goal, often
relying on dienolate intermediates.2 These approaches have met
with some success, but are generally limited to a narrow range of
suitable electrophilic partners and often require strongly basic
reaction conditions. Consequently, a general solution to the
problem of ketone γ-functionalization has remained elusive.
In 2004, Kim and co-workers3 introduced an elegant, radical-
based strategy for γ-functionalization relying on specifically
engineered hydroxamic acid or ester derivatives that contain an
internal reactive moiety that enables decomposition of a putative
radical intermediate, obtaining excellent results for the synthesis
of amides and esters (Scheme 1a). The substrate design
constraints limit the scope of the transformation and notably
exclude ketones and most cyclic systems as viable radical
acceptors.4 To further our efforts in the area of γ-functionaliza-
tion, we aimed to address this issue with the express goal of
Sulfones are generally useful synthetic intermediates5 and are
central moieties in a variety of useful biologically active
compounds (Figure 1). Given the value of sulfones and the
Figure 1. Biologically active sulfones.
general deficiency of existing methods to form γ-C−S bonds,3,4,6
we selected γ-sulfonyl enones to test our strategy for ketone γ-
functionalization (Scheme 1b). We reasoned that the γ-sulfonyl
enone would provide the opportunity to carry out a
regiocontrolled γ-alkylation, a concept explored by Lansbury,
Trost, and Paquette,7 which is particularly attractive since it
would facilitate access to various γ-alkylated enones. Moreover,
sulfones have garnered significant recent attention as versatile
substrates for enantioselective catalysis,8 and as a result
additional methods for installing these functional groups are of
ever-increasing value. Herein, we report the results of our first
efforts toward achieving the goal of ketone γ-C−S bond
formation using a combination of readily available silyl dienol
ethers, sulfonyl chlorides, and a Cu catalyst to access versatile
sulfone products.
Scheme 1. Strategy for Carbonyl γ-Functionalization
We chose cyclohexenone as a model substrate owing to
literature reports of selective formation of the thermodynami-
cally preferred extended dienolate isomer and trapping of this
intermediate as an isolable dienol ether.9 The first critical design
element we sought to address was the nature of the oxygen
substituent which could serve a number of roles depending on
the precise reaction pathway. We reasoned that a group capable
Received: June 8, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01675
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Letter
a
of sustaining a radical chain process would be ideal, and given the
prevalence of enol silanes we first examined these derivatives. We
found that the TBS-derived ether (1a, Table 1) was easily
Table 2. Scope of Sulfonyl Chlorides
a
Table 1. Optimization of Reaction Conditions
a
Yields determined by 1H NMR (using CH2Br2 as an internal
standard) for reaction of dienol ether (0.25 mmol), PhSO2Cl (1.1
b
equiv), in solvent (1 mL) for 4 h. In parentheses is the isolated yield
for reaction on 0.50 mmol scale.
prepared and offered good stability that allowed purification and
storage. With this material in hand, we turned our attention to
identifying a suitable coupling partner. Truce and co-workers
reported that sulfonyl chlorides add to diene systems in the
presence of Cu catalysts,10 and although this technique is rarely
used,11 recent interest in the chemistry of sulfonyl radicals
prompted us to explore this system in detail.12
a
Isolated yield (average of two runs) for reaction of dienol ether (0.50
mmol), sulfonyl chloride (1.1 equiv), in CH3CN (2 mL) at 80 °C for 4
h. Yield in parentheses for 10 mmol scale reaction. Reaction at 22 °C
for 10 h. Contains 21% isomeric vinyl sulfone. Contains 14%
isomeric vinyl sulfone.
b
c
d
e
To adapt the Cu-catalyzed sulfonylation conditions to our
more complex substrates, we first investigated a stoichiometric
reaction with a 1:1:1 ratio of siloxydiene, PhSO2Cl, and Cu salts.
We were pleased to find that the desired γ-sulfonylation product
(3a, Table 1) was formed, validating our regiocontrol hypothesis,
although the yield was less than 10% and therefore the capacity
for catalysis was in question. Fortunately, simply reducing the
loading of Cu to 5 mol % increased the efficiency of the reaction
dramatically and the sulfone formed in 45% NMR yield with CuI
(entry 2). Screening additional Cu catalysts revealed CuCl to be
most effective (entries 3−6). Increasing the CuCl loading to 10
mol % gave a very efficient reaction from which sulfone 3a was
isolated in 83% yield (entry 8). Several solvents were viable, but
substantially higher yield was observed with acetonitrile (entries
8−10). This difference may be explained by the fact that the
reaction is homogeneous only in acetonitrile. Finally, varying the
temperature from 80 °C caused a substantial drop in yield over
the 4 h reaction time (entries 11−12); at lower temperature
unreacted starting material remained, and at higher temperature
nonspecific decomposition occurred. We also investigated
different silyl groups, but observed little difference from the
initial TBS-derived compound.
present without major complications (entries 7, 10, and 11).
Camphorsulfonyl chloride (2l) engaged in the reaction as well,
although no stereoinduction was apparent.
We turned next to the dienol ether reaction partner (1, Table
3). These materials were readily prepared from the correspond-
ing enones by trapping the thermodynamically preferred γ-
dienolate1,9 or utilizing soft enolization techniques.14 We were
pleased to find that many dienol ethers participated in the
reaction (entries 1−9), only moderately perturbed in cases where
a
Table 3. Scope of Cyclic Dienol Ethers
Given the variety of commercially available sulfonyl chlorides,
the scope of the transformation was readily elucidated (Table 2).
Several arenesulfonyl chlorides varying in structure and
electronics participated in the reaction with good results (2a−
2g, entries 1−7). The reaction is readily scaled to produce
multigram quantities of product with no decrease in efficiency
(entry 1). We found that with certain sulfonyl halides (e.g., 2c−
2e) the product formed in low yield under our typical reaction
conditions at 80 °C.13 However, these problems were mitigated
by performing the reaction at room temperature over longer
reaction times (entries 3−5). Alkanesulfonyl halides 2h−2k
provided uniformly good results and the steric demands of the
sulfonyl chloride appear to have little influence on the efficiency
of the reaction (entries 8−12). Sensitive functional groups such
as heterocycles, primary alkyl chlorides, or cyclopropanes may be
a
Isolated yield (average of two runs) for reaction of dienol ether (0.50
mmol), PhSO2Cl (1.1 equiv), in CH3CN (2 mL) at 80 °C for 4 h.
b
c
Contains 14% isomeric vinyl sulfone. Contains 13% isomeric vinyl
sulfone.
B
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Letter
sterically large substituents neighbored the reactive center
(entries 8−9). Despite the demanding sterics, α-tertiary sulfone
4i was isolated in respectable yield (entry 9). Lactam-derived
dienol 1j was employed to access dihydropyridone 4j. In the case
of the carvone-derived siloxydiene, sulfone 4k was isolated as a
single diastereomer, although the nature of the stereocontrol in
this case is not clear at this point.
Scheme 2. Synthetic Transformations of Sulfones
Pleased with the range of cyclohexanone derivatives that were
accessible, we next sought to employ conjugated ethers that
resided partially, or completely, outside of a ring (Table 4).
a
Table 4. Sulfonylation of Exocyclic Dienol Ethers
also regioselective, forming ester 7 in 53% yield. When methyl
vinyl ketone was employed, a stereoselective cascade conjugate
addition/aldol sequence occurred leading to [3.3.1]bicycle 8 in
71% yield.15 A similar transformation described by Paquette and
co-workers required discrete conjugate addition and aldol
steps.7d,f Allylation of carvone-derived sulfone 4k with allyl
iodide as an electrophile yielded enone 9 as a single diastereomer
(Scheme 2b). Finally, engaging sulfonylated isophorone 6b in
the [3 + 3] benzannulation reaction recently disclosed by Menon
and co-workers yielded tetralones 10 and 11 as a partially
separable 1:1 mixture (Scheme 2c).16
Although our working hypothesis was based on the
intermediacy of a sulfonyl radical,10 we wished to gain empirical
evidence in support of this supposition. Use of stoichiometric
quantities of CuCl led to low yield, possibly due to excess Cu(I)
behaving as a radical inhibitor. The reaction is air sensitive,
perhaps due to decomposition of CuCl, although the reaction
may be performed on the benchtop.17 Addition of potential
radical inhibitor butylated hydroxyl toluene (BHT) reduced the
yield of the γ-sulfone, and 2,2,6,6-tetramethylpiperidine 1-oxyl
(TEMPO) or CuCl2 negated the addition reaction completely.
In the absence of Cu, other radical initiators (2,2′-azobis-
(isobutyronitrile) (AIBN),18 benzoyl peroxide, or Et3B/O2) did
lead to a significant amount of sulfone product. Tosyl fluoride,
bromide, or iodide do not provide appreciable quantities of the γ-
addition product under Cu-initiated conditions. The addition of
NaI to a prototypical reaction with TsCl completely inhibited the
addition and only cyclohexenone was observed. In the presence
of allyltributylstannane, the addition reaction does proceed and
allyl phenyl sulfone also is observed.19
The above data are all consistent with the postulated sulfonyl
radical intermediate, but we have not succeeded in obtaining
direct evidence for the putative alkoxyallyl radical intermediate
that would form after addition. We noted that substrates
containing strained rings (Table 2, entry 11 and Table 4, entries 3
and 8) showed no evidence of ring-opening under our standard
reaction conditions, suggesting that if a radical intermediate does
exist it may have a very short lifetime. To date we have found no
byproducts that might be expected from a free silyl radical. In
light of these observations it is tempting to consider an ionic
mechanism with Cu behaving as a Lewis acid. We noted,
however, that use of stoichiometric CuCl inhibited the reaction.
To further probe this idea, we attempted to replace CuCl with
TMSOTf, AlCl3, Ti(Oi-Pr)4, or ZnBr2 since these Lewis acids are
unlikely to participate in single electron chemistry, but observed
no sulfonylation products. To assess the nucleophilicity of dienol
ether 1a we treated the substrate with BzCl or p-nitro-
a
Isolated yield (average of two runs) for reaction of dienol ether (0.50
mmol), PhSO2Cl (1.1 equiv), in CH3CN (2 mL) at 80 °C for 4 h.
b
Isolated yield over two steps for reaction with 1.0 mmol of crude
c
dienol ether. Contains 10% isomeric vinyl sulfone.
Cyclohexenones bearing a β-methyl substituent are readily
converted to the exocyclic methylene derivative (5a−c),
although these compounds are quite sensitive. To circumvent
this issue we often used crude dienol ether products directly;14
the sulfonyl addition reaction was affected minimally, although
yields (measured over two steps) are diminished somewhat due,
in part, to substrate decomposition (entries 1−3). In the case of
verbenone we observed no ring-opened products despite the
strained ring system adjoining the reactive moiety (entry 3). Acyl
cyclohexenes are accessible (entry 4) and in a decalin system the
octalone product is isolated as a single diastereomer (entry 5).
Pulegone-derived dienol ether 5f participates in the trans-
formation, indicating that a rigidly aligned diene system is not
required for reactivity, and the sulfone geometric isomers are
separable (entry 6).14 Encouraged by this result, we explored
acyclic substrates: both ethyl crotonate and a cyclopropyl vinyl
ketone were transformed to the corresponding sulfones in good
yield under our standard reaction conditions (entries 7−8).2f
Given the presence of two electron-withdrawing groups in our
products, we reasoned that deprotonation would be facile and a
subsequent alkylation event may be regioselective (Scheme 2a).
This hypothesis was bolstered by studies in related systems by
Lansbury and co-workers, although the generality of this strategy
was not widely established.7a,b Indeed, methylation of sulfone 3a
using 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as base was
highly selective for the carbon adjacent to the sulfone and enone
4i was isolated in 77% yield. The addition to methyl acrylate was
C
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benzaldehyde in the presence of CuCl, but observed no addition
products. Highly electrophilic sulfonyl chlorides 2c and 2f also
do not react with dienol ether 1a in the absence of CuCl. As a
result of these experiments we consider an ionic mechanism
unlikely, although we cannot rigorously rule out this possibility.
Further mechanistic investigations are ongoing.
In conclusion, we have demonstrated the first regioselective
addition to ketone-derived dienol ethers using a Cu(I) salt to
form putative sulfonyl radicals from widely available sulfonyl
chlorides. Through this process we obtain a wide variety of
ketone products that are poised for further transformations
controlled by versatile sulfone functionalities. Our system is
amenable to both cyclic and acyclic substrates without the need
to prepare any specialized amide or ester derivatives to facilitate
radical termination. We are currently exploring further
implementations of the radical/dienol coupling strategy to
provide a more general solution to the problem of γ-
functionalization of carbonyl systems.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, characterization data, and NMR
spectra. The Supporting Information is available free of charge
on the ACS Publications website at DOI: 10.1021/acs.or-
glett.5b01675.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: jtmohr@uic.edu
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Funding was provided by the UIC Department of Chemistry. We
thank Profs. Vladimir Gevorgyan, Duncan Wardrop, Tom
Driver, Laura Anderson, Daesung Lee, and Neal Mankad
(UIC) for helpful discussions and use of reagents and equipment.
́
D.; Herle, B.; Sach, N.; Collins, M. R.; Ishihara, Y.; Baran, P. S. Nature
2012, 492, 95−100. (c) Tang, X.; Huang, L.; Xu, Y.; Yang, J.; Wu, W.;
Jiang, H. Angew. Chem., Int. Ed. 2014, 53, 4205−4208. (d) Mao, S.; Gao,
Y.-R.; Zhu, X.-Q.; Guo, D.-D.; Wang, Y.-Q. Org. Lett. 2015, 17, 1692−
1695.
(13) Mesityl and trisyl derivatives led to the phenol as a major product.
(14) See the Supporting Information for details.
(15) A small amount of the diastereomeric alcohol also formed.
(16) Joshi, P. R.; Undeela, S.; Reddy, D. D.; Singarapu, K. K.; Menon,
R. S. Org. Lett. 2015, 17, 1449−1452.
(17) Our standard procedure calls for weighing the CuCl salt in a
glovebox. However, when CuCl was weighed on the bench followed by
purging the vessel with inert gas, the reaction proceeded in 80% NMR
yield. Exposure of a solution of CuCl in CH3CN to dry air followed by
purging with Ar provided a catalyst that formed TBS phenyl ether as the
major product after introduction of substrate and sulfonyl chloride.
(18) A small amount of the isobutyronitrile addition product formed as
a side product in this case, consistent with a competing radical pathway.
(19) No allyl-containing enone products were observed.
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