Stereospecific decarboxylative allylation of sulfones

Article abstract of DOI:10.1021/ja104196x

Allyl sulfonylacetic esters undergo highly stereospecific, palladium-catalyzed decarboxylative allylation. The reaction allows the stereospecific formation of tertiary homoallylic sulfones in high yield. In contrast to related reactions that proceed at -100 °C and require highly basic preformed organometallics, the decarboxylative coupling described herein occurs under mild nonbasic conditions and requires no stoichiometric additives. Allylation of the intermediate α-sulfonyl anion is more rapid than racemization, leading to a highly enantiospecific process. Density functional theory calculations indicate that the barrier for racemization is 9.9 kcal/mol, so the barrier for allylation must be <9.9 kcal/mol.

Full text of DOI:10.1021/ja104196x

Published on Web 08/17/2010
Stereospecific Decarboxylative Allylation of Sulfones
Jimmie D. Weaver, Being J. Ka, David K. Morris, Ward Thompson, and Jon A. Tunge*
Department of Chemistry, The UniVersity of Kansas, 2010 Malott Hall, 1251 Wescoe Hall DriVe,
Lawrence, Kansas 66045
Received May 15, 2010; E-mail: tunge@ku.edu
Abstract: Allyl sulfonylacetic esters undergo highly stereospecific,
palladium-catalyzed decarboxylative allylation. The reaction allows
the stereospecific formation of tertiary homoallylic sulfones in high
yield. In contrast to related reactions that proceed at -100 °C
and require highly basic preformed organometallics, the decar-
boxylative coupling described herein occurs under mild nonbasic
conditions and requires no stoichiometric additives. Allylation of
the intermediate R-sulfonyl anion is more rapid than racemization,
leading to a highly enantiospecific process. Density functional
theory calculations indicate that the barrier for racemization is
9.9 kcal/mol, so the barrier for allylation must be <9.9 kcal/mol.
Next, a variety of different enantioenriched sulfones were
similarly subjected to the conditions for palladium-catalyzed
Table 1. Stereospecificities of Decarboxylative Allylation
Catalytic decarboxylative coupling is a powerful method for C-C
bond formation that avoids the use of strong bases and/or preformed
organometallics that are typically required for cross-coupling reactions.
In 2004, we reported the first asymmetric decarboxylative allylation
of enolates.1 This was followed by several reports of decarboxylative
enolate allylations that allow enantioselective formation of quaternary
carbon centers R to ketones.2 Since these reactions proceed through
achiral enolate intermediates, the reactions are stereoconvergent,
allowing racemic starting materials to form highly enantioenriched
products (eq 1). Stereoconvergence is a common reaction profile in
carbanion chemistry, where resonance-stabilized carbanions often exist
as planar achiral intermediates and unstabilized carbanions rapidly
racemize by inversion.3 Herein we report that optically active sulfo-
nylacetic esters undergo enantiospecific decarboxylative coupling in
which the original stereochemistry is maintained in the product (eq
2). Furthermore, density functional theory (DFT) calculations are used
to examine the origin of the enantiospecificity.
From the elegant work of Corey and Cram in the early 1960s, it
has been known that the decarboxylative protonation of sulfonylacetic
esters is stereospecific.4 While there are several examples of stereospe-
cific decarboxylative protonations,4,5 none has been extended to C-C
bond-forming reactions. With this in mind, we set out to develop a
stereospecific decarboxylative C-C bond-forming reaction.
To begin, sulfone 1a was synthesized and treated with 2 mol %
Pd(PPh3)4 in toluene at room temperature (eq 3).6 It was gratifying
to find that the decarboxylative allylation was highly stereospecific,
with a conservation of enantiomeric excess (cee) of 96% [cee )
100 × (product ee)/(reactant ee)].
a Conditions A: 2 mol % Pd(PPh3)4, 0.2 M toluene, 23 °C, 0.25-2 h.
Conditions B: 5 mol % Pd2dba3, 10 mol % (()-binap, 0.2 M toluene, 95
°C, 11-15 h. b Isolated yields. c Determined via chiral stationary phase
HPLC analysis. d Linear/branched ) 8:1.
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10.1021/ja104196x  2010 American Chemical Society
J. AM. CHEM. SOC. 2010, 132, 12179–12181 12179

C O M M U N I C A T I O N S
Scheme 1
Scheme 2
decarboxylative coupling. As can be seen from the data in Table
1, a variety of R-aryl and R,R-dialkyl sulfones all undergo
decarboxylative allylation with a high degree of stereospecificity.
It is noteworthy that high cee’s were obtained even at elevated
temperatures (95 °C). Moreover, our reaction proceeds under
formally neutral conditions, in contrast to more classical alkylations
of sulfones, which typically require stoichiometric, highly basic
organolithium reagents.7 Lastly, the X-ray crystal structure of a
derivative of 2k confirmed that the allylation proceeds with overall
retention of configuration.8
The overall retention of stereochemistry in the decarboxylative
allylation can be explained if the decarboxylation directly produces
either a configurationally stable alkylpalladium complex that
undergoes reductive elimination (path 1 in Scheme 1) or if
decarboxylation produces a configurationally stable R-sulfonyl anion
that attacks the palladium π-allyl complex (path 2 in Scheme 1).9
To begin to address whether path 1 or 2 (Scheme 1) is operative,
we investigated the effect of palladium on the rates of decarboxyl-
ation of several R-sulfonylacetates. Control studies showed that the
rate of decarboxylation is relatively unaffected by the addition of
a variety of palladium sources (Table 2).8 For example, the cesium
or triethylammonium salts of R-sulfonylacetic acids readily decar-
boxylate under our reaction conditions. Addition of Pd(OAc)2 or
(Ph3P)2Pd(allyl)Cl to these reaction mixtures does not substantially
affect the rate of decarboxylation.10 When palladium is directly
involved in the decarboxylation, such experiments usually show a
dramatic acceleration of the decarboxylation.11 Ultimately, Corey
and Cram have detailed thermal decarboxylations of R-sulfonylac-
etates under conditions similar to those used by us,4 and we failed
to observe catalysis of decarboxylation by palladium. Thus, the
simplest conclusion is that decarboxylation of the R-sulfonylcar-
boxylates is a thermal process that proceeds via path 2.
nism.12 Toward this end, substrate 1n was prepared and allowed
to react under our standard reaction conditions (Scheme 2).13 The
reaction produced the 1,3-cis diastereomer as the only C-C bond-
forming product in 49% yield,14 suggesting that the decarboxylative
coupling proceeds via attack of an R-sulfonyl anion on the back
side of the palladium π-allyl complex (path 2 in Scheme 2). While
we could not generate the R-chloro-R-sulfonyl ester in enantioen-
riched form in order to test the enantiospecificity of the coupling,
the product was formed as a 1:1 mixture of diastereomers at the
sulfonyl stereocenter. Thus, the stereochemistry at the R-position
did not change during the reaction, which is consistent with a
stereospecific process.
Our control studies and stereochemical studies both suggest that
R-sulfonyl anions are formed, and react, outside the coordination
sphere of palladium. In order to form highly enantioenriched
products, these intermediate R-sulfonyl anions must be configura-
tionally stable. While it is known that R-sulfonyl anions are more
configurationally stable than typical carbanions, Gais has reported
the rapid racemization of anion 3a at -80 °C.15 Thus, we became
curious about why our reaction was highly stereospecific even at
elevated temperatures.
To address the reasons for the apparently lower rate of racem-
ization than coupling of the R-sulfonyl anion and the Pd π-allyl
complex, DFT calculations were performed to determine the
inversion barrier for the free R-sulfonyl carbanion. The calculations
revealed that the most stable conformation is 3a, which has the
major lobe of the lone pair oriented antiperiplanar to the S-Ph
bond (eq 4). A definitive number for the inversion barrier could
not be determined because all attempts to minimize the energy of
conformation 3b led to convergence to the minimum-energy
structure 3a. While we could not obtain a specific energy for
structure 3b, this result does support the conclusion that the barrier
to inversion is small (<2 kcal/mol). The small inversion barrier is
supported by other studies, as is the slightly pyramidal structure of
the carbanion.15-17
Table 2
R
R′
conditions
Pd source
time
% conv.
H
H
H
H
95 °C, Et3N
95 °C, Et3N
none
5 min
17
23
25
27
59
59
100 mol % Pd(allyl)Cl(PPh3)2 5 min
none
10 mol % Pd(OAc)2
Me Bn 95 °C, Et3N
45 min
45 min
36 h
Me Bn 95 °C, Et3N
Me
Me
H
H
23 °C, Cs2CO3 none
23 °C, Cs2CO3 10 mol % Pd(OAc)2
Taking into account the small barrier to inversion, our mecha-
nistic hypothesis is as follows. Ionization and decarboxylation of
1a generates sulfonyl anion 3a, which is likely ion-paired with the
Pd π-allyl complex (Scheme 3). The C-C bond formation proceeds
via path A, where the carbanion can react through the low-energy,
staggered transition state to form the product with retention of
stereochemistry. Coupling through the inverted conformer 3b (path
B) to form the enantiomeric product not only requires the anion to
react through a higher-energy conformer but also requires a higher-
energy transition state to form the eclipsed product.4 Alternatively,
the enantiomer ent-2a could be formed by allylation of the anion
36 h
Reaction via path 1 or path 2 can also be distinguished via the
observed diastereoselectivity in nucleophilic attack of a stere-
ochemically labeled allyl ester substrate (Scheme 2).12 In such a
reaction, nucleophiles that are bound to palladium prior to reductive
elimination, as in path 1, would react with overall inversion of
configuration. Alternatively, if the free nucleophile directly attacks
the allyl ligand, as in path 2, then one would observe retention of
stereochemistry by way of the standard double-inversion mecha-
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C O M M U N I C A T I O N S
Scheme 3
Scheme 4
Supporting Information Available: Experimental procedures and
characterization data for all new compounds and a CIF file. This
material is available free of charge via the Internet at http://pubs.acs.org.
References
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hypothesize that the reaction is stereospecific because rotation about
the C-S bond of the sulfone (path C) is slower than reaction of
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path A.
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theory revealed that the lowest barrier to rotation about the R-C-S
bond is 9.9 kcal/mol, which is consistent with experimental
measurements in related systems (Scheme 4).15-17 Thus, the barrier
for allylation of the R-sulfonyl anion must be <9.9 kcal/mol or
rotation would lead to racemization. Such a low barrier is consistent
with the reaction between an ion pair of a highly nucleophilic
R-sulfonyl anion and a palladium π-allyl complex.8,18 Thus, the
stark contrast between our observations and those of Gais can be
attributed to the fact that our reaction generates the reactive
R-sulfonyl anion intermediates in the presence of highly electro-
philic π-allyl palladium electrophiles, allowing it to effect the C-C
bond formation faster than rotation.
In conclusion, we have developed a stereospecific decarboxy-
lative coupling reaction that provides access to enantioenriched
homoallylic sulfones. The enantiospecific nature of this reaction is
unique among, yet complementary to, existing decarboxylative
allylation methodologies. The stereospecificity is made possible by
the relatively high barrier for racemization of axially chiral
R-sulfonyl anions and the low barrier for their reaction with
palladium π-allyl complexes.
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(8) See the Supporting Information for more details.
(9) Complete crossover was observed when two sulfonyl esters were allowed
to undergo coupling in the same flask. The interpretation of complete
crossover is ambiguous since crossover can likely occur via either the
intermediate π-allylpalladium carboxylates or the π-allylpalladium R-sul-
fonyl anion complexes.
(10) The presence of acidic protons from the carboxylic acid resulted in the
formation of the protonation product rather than the allylation product that
may be expected from (allyl)PdCl(PPh3)2
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3-ol gave 78% elimination product. Thus, it could not be used for the
stereochemical test. Elimination is less problematic with an R-chloro
substitutent (see ref 6b).
(14) Analysis of the crude reaction mixture by 1H NMR spectroscopy indicated
that the mass balance of the decarboxylative allylation of 1n was made up
of elimination products.
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S. Angew. Chem., Int. Ed. 1989, 28, 1025.
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Acknowledgment. We thank the National Institute of General
Medical Sciences (1R01GM079644) for financial support. D.K.M.
thanks the NSF-REU Program (CHE-0649246) for funding. We
thank Dr. Victor Day for X-ray crystallographic analysis.
JA104196X
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