Mechanistic origin of the stereodivergence in decarboxylative allylation

Article abstract of DOI:10.1021/ol101042x

A stereochemical test has been used to probe the mechanism of decarboxylative allylation. This probe suggests that the mechanism of DcA reactions can change based on the substitution pattern at the α-carbon of the nucleophile; however, reaction via stabilized malonate nucleophiles is the lower energy pathway. Lastly, this mechanistic proposal has predictive power and can be used to explain chemoselectivities in decarboxylative reactions that were previously confounding.

Full text of DOI:10.1021/ol101042x

ORGANIC
LETTERS
2010
Vol. 12, No. 13
3042-3045
Mechanistic Origin of the
Stereodivergence in Decarboxylative
Allylation
Kalicharan Chattopadhyay, Ranjan Jana, Victor W. Day, Justin T. Douglas, and
Jon A. Tunge*
Department of Chemistry, The UniVersity of Kansas, Lawrence, Kansas 66045
tunge@ku.edu
Received May 6, 2010
ABSTRACT
A stereochemical test has been used to probe the mechanism of decarboxylative allylation. This probe suggests that the mechanism of DcA
reactions can change based on the substitution pattern at the r-carbon of the nucleophile; however, reaction via stabilized malonate nucleophiles
is the lower energy pathway. Lastly, this mechanistic proposal has predictive power and can be used to explain chemoselectivities in
decarboxylative reactions that were previously confounding.
Decarboxylative allylation reactions (DcA) have received
considerable attention as methods for the asymmetric ally-
lation of ketone enolates.1,2 While much attention has been
paid to the development of enantioselective decarboxylative
allylations,2 little attention has been paid to the investigation
of the diastereoselectivity of DcA reactions.3,4 Herein we
report that the stereoselectivity of DcA reactions changes
depending on the substitution of the substrate. We attribute
the observed stereochemical reversal to a change in reaction
mechanism.
As part of our efforts to develop chemical libraries derived
from dihydrocoumarins, we became interested in the decar-
boxylative coupling of 3-carboxydihydrocoumarin derivatives.5
Initial investigations showed that such substrates (1a and 1b)
readily undergo DcA at ambient temperature (Scheme 1). This
is noteworthy since simple aliphatic diesters require high
(1) (a) Shimizu, I.; Yamada, T.; Tsuji, J. Tetrahedron Lett. 1980, 21,
3199. (b) Tsuda, T.; Chujo, Y.; Nishi, S.-i.; Tawara, K.; Saegusa, T. J. Am.
Chem. Soc. 1980, 102, 6384. (c) Tsuda, T.; Okada, M.; Nishi, S.-i.; Saegusa,
T. J. Org. Chem. 1986, 51, 421. (d) Tsuji, J.; Yamada, T.; Minami, I.;
Yuhara, M.; Nisar, M.; Shimizu, I. J. Org. Chem. 1987, 52, 2988. (e) Imao,
D.; Itoi, A.; Yamazaki, A.; Shirakura, M.; Ohtoshi, R.; Ogata, K.; Ohmori,
Y.; Ohta, T.; Ito, Y. J. Org. Chem. 2007, 72, 1652. (f) Trdibono, L. P.;
Scheme 1
Patzner, J.; Cesario, C.; Miller, M. J. Org. Lett. 2009, 11, 4076
.
(2) (a) Sherden, N. H.; Behenna, D. C.; Virgil, S. C.; Stoltz, B. M.
Angew. Chem., Int. Ed. 2009, 48, 6840. (b) Trost, B. M.; Xu, J.; Schmidt,
T. J. Am. Chem. Soc. 2009, 131, 18343. (c) White, D. E.; Stewart, I. C.;
Grubbs, R. H.; Stoltz, B. M. J. Am. Chem. Soc. 2008, 130, 810. (d) Mohr,
J. T.; Behenna, D. C.; Harned, A. M.; Stoltz, B. M. Angew. Chem., Int. Ed.
2005, 44, 6924. (e) You, S.-L.; Dai, L.-X. Angew. Chem., Int. Ed. 2006,
45, 5246. (f) Trost, B. M.; Bream, R. N.; Xu, J. Angew. Chem., Int. Ed.
2006, 45, 3109. (g) Nakamura, M.; Hajra, A.; Endo, K.; Nakamura, E.
Angew. Chem., Int. Ed. 2005, 44, 7248. (h) Kuwano, R.; Ishida, N.;
Murakami, M. Chem. Commun. 2005, 3951. (i) Burger, E. C.; Barron, B. R.;
Tunge, J. A. Synlett 2006, 2824. (j) Trost, B. M.; Xu, J. J. Am. Chem. Soc.
2005, 127, 17180. (k) Behenna, D. C.; Stoltz, B. M. J. Am. Chem. Soc.
2004, 126, 15044. (l) Burger, E. C.; Tunge, J. A. Org. Lett. 2004, 6, 4113
.
10.1021/ol101042x  2010 American Chemical Society
Published on Web 06/10/2010

temperatures to effect decarboxylative coupling.1f In addition
to the mildness of the reaction conditions, the high diastereo-
selectivities of the DcA reactions are remarkable. Since little
attention has been paid to the diastereoselectivities of DcA
reactions, we wanted to determine the relative stereochemistries
of the coupling products. Fortunately, two analogues could be
crystallized and analyzed by X-ray crystallography (Figure 1).6
not occur under the catalytic reaction conditions, the cis
selectivity must be kinetic in origin.
Next, a small variety of dihydrocoumarins were subjected
to DcA reactions to test whether the stereochemical reversal
would hold for multiple substrates (Table 1). Indeed the
Table 1. Diastereoselective Allylation
Figure 1. Crystal structures of 2a and 2b.
Intriguingly, the R-protio derivative 1b selectively produced cis-
2b as the major diastereomer, while the R-methyl derivative
1a produced trans-2a exclusively. Thus, on going from R,R-
disubstituted malonic ester 1a to an R-monosubstituted malonic
ester 1b there was a complete reVersal in stereochemical
outcome of the allylation.
One potential explanation for the reversal in stereoselec-
tivity is that the R-protio compound 2b simply undergoes
base-catalyzed epimerization under the reaction conditions
to form a more stable cis compound. However, simple MM2
calculations suggest that the cis and trans stereoisomers of
2b are nearly equienergetic.7 More convincingly, addition
of independently synthesized trans-2b to a catalytic reaction
mixture does not lead to any appreciable epimerization
(Scheme 2); the small decrease in dr from 6.7:1 to 5.6:1 is
a 10:1 linear/branched, branched dr ) 1:1.
allylations of R-protio malonate derivatives selectively
formed the cis stereoisomer, while the R-alkylated derivatives
produced the trans products exclusively. While R-methyl
dihydrocoumarins were formed with excellent diastereose-
lectivity, an R-benzyl derivative was formed with lower dr.
Notably, a variety of functional groups (OMe, CF3, Br, Cl,
NO2) were tolerated by the mild reaction conditions. It is
also important to note that the dr of the product was
independent of the stereochemistry of the reactant.8 Such
stereoconvergence is expected for reactions that proceed via
planar enolate intermediates.
Scheme 2
To explain the observed substitution-dependent stereo-
chemical divergence, we propose that the two classes of
substrates (R-protio vs R-alkyl) react via different mecha-
(4) Single examples suggest that 1,3 and 1,4-diastereocontrol in double-
decarboxylative allylations is not high. See ref 2d and: Enquist, J. A., Jr.;
Stoltz, B. M. Nature 2008, 453, 1228.
attributed to the conversion of 1b to cis-2b under the reaction
conditions. Since epimerization of the R-stereocenter does
(5) (a) Li, K.; Tunge, J. A. J. Comb. Chem. 2008, 10, 170. (b) Duan,
S.; Jana, R.; Tunge, J. A. J. Org. Chem. 2009, 74, 4612.
(6) Attempts to crystallize the direct analogue of 2a failed, so 2b was
used for confirmation of stereochemistry by crystallography.
(7) Using the MM2 force field of ChemBio 3D indicates that cis-2b is
more stable than trans-2b by 0.1 kcal/mol.
(3) (a) Waetzig, S. R.; Tunge, J. A. J. Am. Chem. Soc. 2007, 129, 4138.
(b) Grenning, A. J.; Tunge, J. A. Org. Lett. 2010, 12, 740. (c) Carcache,
D. A.; Cho, Y. S.; Hua, Z.; Tian, Y.; Li, Y.-M.; Danishefsky, S. J. J. Am.
Chem. Soc. 2006, 128, 1016–1022.
(8) See the Supporting Information for details.
Org. Lett., Vol. 12, No. 13, 2010
3043

nisms. Indeed, two limiting mechanisms for decarboxylative
coupling of allyl ꢀ-ketoesters have been proposed.1d The
mechanisms differ mainly in the timing of two chemical
events; mechanism A involves decarboxylation prior to
allylation, while mechanism B involves decarboxylation after
allylation. More specifically, mechanism A involves forma-
tion of the π-allyl palladium carboxylate ion pair followed
by decarboxylation to produce an allyl palladium enolate that
is either directly bound to palladium or forms a tight ion
pair with the cationic palladium allyl complex (Scheme 3).
Allylation of the enolate provides the observed products.
derivative which reacts via mechanism A is expected to
proceed by addition of the allyl anti to the bulky aryl
substituent (Scheme 4). Conversely, the reaction of the
R-monosubstituted malonate derivative1b proceeds through
mechanism B and thus the stereochemistry is determined
by addition of a proton anti to the aryl group, producing
the 3,4-cis product.12,13
If our mechanistic hypothesis is correct, we can further
conclude that mechanism A is a higher energy pathway than
mechanism B. This conclusion can be drawn because
R-protio substrates like 1b, which can react via either
pathway A or B, react primarily via mechanism B.
To further investigate the mechanism of decarboxylative
allylation, the reactions of 1c (R-protio) and 1d (R-methyl)
were monitored by 1H NMR spectroscopy. While no
intermediates were observed in the formation of 2d, monitor-
ing the reaction of 1c revealed the growth and disappearance
of a carboxylic acid (Figure 2).8 This observation supports
Scheme 3
Alternatively, formation of the π-allyl palladium carboxy-
late ion pair may be followed by a proton transfer from the
R-carbon of the ꢀ-oxo ester (pKa ∼14 in DMSO) to the
carboxylate (pKa ∼12 in DMSO) (path B, Scheme 3).9 This
stabilized anion can undergo allylation followed by decar-
boxylation of the ꢀ-oxoacid to form the product.8,10
Aside from the different timing of steps, the two mech-
anisms differ in another critical area: the stereochemistry
determining step. For mechanism A, the stereochemistry at
the R-carbon is determined by allylation. For mechanism B,
the stereochemistry at the R-carbon is determined by
protonation. The conformation of the intermediate enolate
most likely has a pseudoaxial aryl group (Scheme 4). We
Figure 2. Observation of intermediate carboxylic acid.
Scheme 4
our hypothesis that R-protio malonate derivatives react
through path B (Scheme 3) and further suggests that
decarboxylation is the rate-limiting step.
Ultimately, our observations suggest that R-protio malonate
derivatives undergo DcA primarily through a mechanism that
is different from that for R,R-dialkyl malonates. Such a proposal
also readily explains differences in chemoselectivity exhibited
in decarboxylative couplings of differently substituted ꢀ-keto
esters. For example, we predict that the dialkyl ꢀ-keto ester 1p
will react via mechanism A, which goes through a basic enolate
base this assumption on calculated conformational energies
of similar half-chair dihydrocoumarin intermediates11 as
well as the fact that the crystal structure of the products
2a and 2b both contain pseudoaxial aryl groups (Figure
1). Thus, DcA of the R,R-disubstituted malonate 1a
(12) Cis 2,3-selectivity is obtained in kinetic protonations of ketone
enolates: Tamura, R.; Watabe, K.-i.; Kamimura, A.; Hori, K.; Yokomori,
Y. J. Org. Chem. 1992, 57, 4903. Trans 2,3-selectivtity is observed in the
alkylation of enolates: Posner, G. H.; Sterling, J. J.; Whitten, C. E.; Lentz,
(9) Bordwell, F. G. Acc. Chem. Res. 1988, 21, 456.
C. M.; Brunelle, D. J. J. Am. Chem. Soc. 1975, 97, 107.
(10) Clark, L. W. J. Phys. Chem. 1967, 71, 2597
.
(13) Asymmetric decarboxylative protonation reactions deliver protons
to the same prochiral enolate face that is allylated in decarboxylative
allylations. Compare footnote 2d with: Mohr, J. T.; Nishimata, T.; Behenna,
(11) MM2 and DFT calculations support a half-chair conformation with
a pseudoaxial aryl group: Li, K.; Vanka, K.; Thompson, W. H.; Tunge,
J. A. Org. Lett. 2006, 8, 4711.
D. C.; Stoltz, B. M. J. Am. Chem. Soc. 2006, 128, 11348
.
3044
Org. Lett., Vol. 12, No. 13, 2010

intermediate (eq 1). Indeed, 1p reacts exclusively by elimination
when treated with Pd(PPh3)4. Alternatively, we predict that 1r
reacts via mechanism B and less basic stabilized enolate
intermediates (eq 2). In fact, the unsubstituted derivative 1r
provides high conversion to the allylated product with no observ-
able elimination.2l Such a result is not easily ascribed to sterics
alone since large, carbon-based nucleophiles are readily allylated
by π-allyl palladium complexes.14 However, the results are readily
interpreted using our proposed mechanistic dichotomy.
explained by the operation of two competing mechanisms.
Furthermore, the results reported herein indicate that DcA
reactions that proceed via stabilized malonate nucleophiles
is the lower energy pathway. Lastly, this mechanistic
proposal has predictive power and can be used to rationalize
chemoselectivities in decarboxylative reactions that were
previously unexplained.
Acknowledgment. We thank the National Institutes of
Health KU Chemical Methodologies and Library Devel-
opment Center of Excellence (P50 GM069663) and the
National Science Foundation (CHE-0548081) for fun-
ding.
Supporting Information Available: Experimental pro-
cedures and characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL101042X
In conclusion, the divergent stereoselectivity of DcA
reactions with differently substituted ꢀ-oxo esters is readily
(14) Trost, B. M.; Van Vranken, D. L. Chem. ReV. 1996, 96, 395.
Org. Lett., Vol. 12, No. 13, 2010
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