Palladium-catalyzed decarboxylative rearrangements of allyl 2,2,2-trifluoroethyl malonates: direct access to homoallylic esters

Article abstract of DOI:10.1021/ol901518g

Homoallylic esters are obtained In a single transformation from allyl 2,2,2-trifluoroethyl malonates by using a Pd(O) catalyst. Facile decarboxylation of allyl 2,2,2-trifluoroethyl malonates is attributed to a decrease in pK _a compared to allyl

Full text of DOI:10.1021/ol901518g

ORGANIC
LETTERS
2009
Vol. 11, No. 18
4076-4079
Palladium-Catalyzed Decarboxylative
Rearrangements of Allyl
2,2,2-Trifluoroethyl Malonates: Direct
Access to Homoallylic Esters
Lawrence P. Tardibono, Jr., Jerod Patzner, Cara Cesario, and Marvin J. Miller*
Department of Chemistry and Biochemistry, UniVersity of Notre Dame,
Notre Dame, Indiana 46556
mmiller1@nd.edu
Received July 2, 2009
ABSTRACT
Homoallylic esters are obtained in a single transformation from allyl 2,2,2-trifluoroethyl malonates by using a Pd(0) catalyst. Facile decarboxylation
of allyl 2,2,2-trifluoroethyl malonates is attributed to a decrease in pKa compared to allyl methyl malonates. Subsequent reduction of the
homoallylic 2,2,2-trifluoroethyl ester provides a (hydroxyethyl)cyclopentenyl derivative that represents a key intermediate in the synthesis of
carbocyclic nucleosides. A select allyl 2,2,2-trifluoroethyl malonate undergoes a decarboxylative Claisen rearrangement to provide a regioisomeric
homoallylic ester.
Homoallylic esters are embedded in the core structures of
several classes of natural products including macrolide
polyketides,1 R-linolenic acid metabolites and derivatives,2
and cyclopentenone prostaglandins.3 Although homoallylic
esters may be synthesized in several steps by functional group
manipulation,2a direct access to homoallylic esters has been
achieved by Krapcho decarboxylation of malonates,4 addition
of vinyl radicals to R,ꢀ-unsaturated esters,5 and 1,4-addition
of alkenylcopper reagents.6
under mild conditions.7 Although R-cyano, R-nitro, R-keto,8
and R-sulfonyl9 allyl esters readily undergo Pd(0)-catalyzed
decarboxylative rearrangements to afford the corresponding
homoallylic derivatives, allyl methyl malonates are much less
reactive. Their diminished reactivity is attributed to the less
stable methoxyethenolate that forms upon decarboxylation.
R,R-Dialkyl allyl methyl malonates require harsh conditions
(i.e., 120 °C in DMF) to effect Pd(0)-decarboxylative
rearrangements.8 Diallyl malonates undergo decarboxylative
allylation at room temperature but must possess an aryl group
at the R-position.10 To our knowledge, Pd(0)-decarboxylative
rearrangements of R,R-unsubstituted allyl alkyl malonates
have not been reported. To achieve decarboxylation, we
envisioned replacement of the allyl methyl malonate with
an allyl 2,2,2-trifluoroethyl malonate. The strong electron-
withdrawing ability of the trifluoroethyl group would improve
We considered metal-catalyzed decarboxylative allylations
as an alternative method to directly prepare homoallylic esters
(1) Sheehan, L. S.; Lill, R. E.; Wilkinson, B.; Sheridan, R. M.; Vousden,
W. A.; Kaja, A. L.; Crouse, G. D.; Gifford, J.; Graupner, P. R.; Karr, L.;
Lewer, P.; Sparks, T. C.; Leadlay, P. F.; Waldron, C.; Martin, C. J. J. Nat.
Prod. 2006, 69, 1702.
(2) (a) Nonaka, H.; Wang, Y.-G.; Kobayashi, Y. Tetrahedron Lett. 2007,
48, 1745. (b) Pinot, D.; Guy, A.; Fournial, A.; Balas, L.; Rossi, J.-C.;
Durand, T. J. Org. Chem. 2008, 73, 3063.
(3) Negishi, M.; Katoh, H. Prostaglandins: Other Lipid Mediators 2002,
68-69, 611.
(7) For a review on decarboxylative allylations, see: (a) Tunge, J. A.;
Burger, E. C. Eur. J. Org. Chem. 2005, 1715. (b) Dai, L. X.; You, S. L.
Angew. Chem., Int. Ed. 2006, 45, 5246.
(4) Acharya, H.; Kobayashi, Y. Tetrahedron 2006, 62, 3329.
(5) (a) Miura, K.; Itoh, D.; Hondo, T.; Hosomi, A. Tetrahedron Lett.
1994, 35, 9605. (b) Foubelo, F.; Lloret, F.; Yus, M. Tetrahedron 1994, 50,
6715.
(8) Tsuji, J.; Yamada, T.; Minami, I.; Yuhara, M.; Nisar, M.; Shimizu,
I. J. Org. Chem. 1987, 52, 2988.
(9) Weaver, J.; Tunge, J. A. Org. Lett. 2008, 10, 4657.
(10) Imao, D.; Itoi, A.; Yamazaki, A.; Shirakura, M.; Ohtoshi, R.; Ogata,
K.; Ohmori, Y.; Ohta, T.; Ito, Y. J. Org. Chem. 2007, 72, 1652.
(6) Cahiez, G.; Venegas, P.; Tucker, C. E.; Majid, T. N.; Knochel, P.
J. Chem. Soc., Chem. Commun. 1992, 19, 1406.
10.1021/ol901518g CCC: $40.75
Published on Web 08/20/2009
 2009 American Chemical Society

the stability of the transient alkoxyethenolate and promote
decarboxylation. Herein, we disclose that R,R-unsubstituted
allyl 2,2,2-trifluoroethyl malonates are suitable substrates for
Pd(0)-catalyzed decarboxylative allylations and provide
desired homoallylic 2,2,2-trifluoroethyl esters in high yields.
Our group has previously reported Pd(0)-catalyzed allylic
alkylations with cycloadduct 311 and related substrates as
key steps en route to targeted carbocyclic nucleosides.12 To
access carbonucleoside targets 5′-homocarbovir 1b13 and 5′-
homoaristeromycin 2b,14 we required a reliable method to
install the requisite 4′-hydroxyethyl side chain. We envi-
sioned a Pd(0) decarboxylative rearrangement to afford an
R-allyl ester and subsequent reduction to the (hydroxyethyl)-
cyclopentyl core structure. Further elaboration would furnish
1b and 2b (Figure 1).
resulting enolate affords ketone products. When allyl ꢀ-keto
ester 5 was treated with Pd(0), ketone 6 was isolated in 65%
yield as the exculsive product with complete diastereo- and
regiocontrol. This initial result demonstrated that appropri-
ately functionalized cyclopentenes derived from 4 are suitable
substrates for decarboxylative allylations.
Replacement of the allyl ꢀ-keto ester group with an allyl
methyl malonate system would provide access to a versatile
homoallylic ester side chain. The ester could be converted to
an alcohol or aldehyde and give access to key intermediates in
the synthesis of carbonucleosides. Cyclopentenol 4 was coupled
to methyl malonate to give allyl methyl malonate 7 in 91%
yield. Exposure of 7 to various palladium sources (Pd(OAc)2,
Pd(dba)2, Pd2(dba)3·CHCl3) and temperatures resulted in no
reaction and recovery of starting material (Scheme 2).18
Scheme 2
Figure 1. Carbonucleoside target molecules.
As a model system to explore palladium-catalyzed decar-
boxylative allylation of 1,4-syn disubstituted cyclopentenes, allyl
ꢀ-keto ester 5 was synthesized in two steps from cycloadduct
3 (Scheme 1).15,16 Allyl ꢀ-keto esters are reliable substrates
In an attempt to increase stabilization of the anionic
intermediate that is formed upon decarboxylation, acids 10a
and 10b were coupled with cyclopentenol 4 to form allyl
2,2,2-trichloroethyl malonate 11a and allyl 2,2,2-trifluoro-
ethyl malonate 11b in high yields, respectively (Scheme 3).
Scheme 1
Scheme 3
that undergo Pd(0)-catalyzed decarboxylative rearrangements
under mild conditions.8,17 The mechanism proceeds through
oxidative addition to give a metal ꢀ-keto carboxylate/π-allyl
system. Upon decarboxylation, nucleophlic attack by the
(11) Mulvihill, M. J.; Surman, M. D.; Miller, M. J. J. Org. Chem. 1998,
63, 4874.
Although trichloroethyl derivative 11a did not undergo
decarboxylative rearrangement in the presence of Pd(dba)2
and PPh3, trifluoroethyl substrate 11b provided homoallylic
(12) (a) Jiang, M. X.-W.; Jin, B.; Gage, J. L.; Priour, A.; Savela, G.;
Miller, M. J. J. Org. Chem. 2006, 71, 4164. (b) Li, F.; Brogan, J. B.; Gage,
J. L.; Zhang, D.; Miller, M. J. J. Org. Chem. 2004, 69, 4538.
(13) For total synthesis of (()-5′-homocarbovir, see: Rhee, H.; Yoon,
D.; Jung, M. E. Nucleosides, Nucleotides Nucleic Acids 2000, 19, 619.
(14) For total synthesis of (-)-5′-homoaristeromycin, see: (a) Roberts,
S. M.; Jones, M. F. J. Chem. Soc., Perkin Trans. I 1988, 2927. (b) Yang,
M.; Schneller, S. W. Bioorg. Med. Chem. Lett. 2005, 15, 149.
(15) For N-O bond reductions of cycloadducts, see: Cesario, C.;
(16) Diketene reaction conditions adapted from a procedure found in:
Collado, I.; Mazo´n, A.; Espinosa, J. F.; Blanco-Urgoiti, J.; Schoepp, D. D.;
Wright, R. A.; Johnson, B. G.; Kingston, A. E. J. Med. Chem. 2002, 45,
3619.
Tardibono, L.; Miller, M. J. J. Org. Chem. 2009, 74, 448
.
(17) Burger, E. C.; Tunge, J. A. Org. Lett. 2004, 6, 4113.
Org. Lett., Vol. 11, No. 18, 2009
4077

ester 12b under similar reaction conditions with complete
diastereo- and regiocontrol. The electron-withdrawing effect
of the trifluoroethyl group plays a significant role in
accelerating the decarboxylative rearrangement.
1,2-syn cyclopentene derivative 13 by employing a decar-
boxylative Claisen rearrangement. The base-catalyzed [3,3]-
sigmatropic rearrangement-decarboxylation of tosylmalonic
mono(allylic) esters has recently been reported.22 While
substrate 11b does not have the additional electron-
withdrawing Ts group at the R-position, it was envisioned
that the increased electron-withdrawing effects of the trif-
luoroester would allow for the rearrangement to occur.
Malonate 11b was subjected to N,O-bis(trimethylsilyl)ac-
etamide (BSA) and KOAc in anhydrous toluene at 100 °C
(Scheme 4).23 Unfortunately, partial decomposition occurred,
Next, we turned our attention to optimizing the reaction
conditions for formation of R-allyl ester 12b (Table 1).
Table 1. Selected Reaction Conditions for Optimization Studies
Scheme 4
isolated
entry
Pd/ligand
solv.
temp time
yield
1
2
3
4
5
6
7
8
Pd(OAc)2/PPh3
DMF 100 °C
DMF 100 °C
DMF 100 °C
DMF 100 °C
DMF 100 °C
DMF 100 °C
5 h
5 h
8 h
4 h
4 h
4 h
6 hc
40%
40%
0%a
51%
56%
60%
82%
0%a
Pd2(dba)3·CHCl3/PPh3
Pd(dba)2/P(OPh)3
Pd(dba)2/rac-BINAP
Pd(dba)2/PS-PPh3
Pd(dba)2/dppe
Pd(dba)2/dppeb
no palladium/no ligand DMF 145 °C 16 h
THF
75 °C
a Starting material was recovered. b Reaction conducted with 5 mol %
Pd(dba)2, and 15 mol % dppe resulted in 50% conversion to product (by
1H NMR integration) after 6 h. c Longer reactions time (16 h) resulted in
lower yield (53%).
and product 13 was not detected. This result was not
unexpected considering the steric bulk imparted by the Boc-
protected amine in the pseudoboat transition state TS-1.
To avoid a sterically hindered transition state, we synthe-
sized 1,4-trans diastereomer 14 as a substrate for the
decarboxylative Claisen rearragement. Alcohol 4 was sub-
jected to Mitsunobu conditions in the presence of acid 10b
to afford 1,4-trans malonate 14 (Scheme 5). Malonate 14
Accordingly, a series of palladium sources and ligands were
investigated with DMF as solvent. The combination of
Pd(dba)2 and 1,2-bis(diphenylphosphino)ethane (dppe) emerged
as the optimal source of Pd(0). However, heating the reaction
mixture at 100 °C in DMF was undesirable, and removal of
DMF complicated the purification and isolation process.
Several solvents were explored at lower temperatures.
Ultimately, THF proved to be optimal (Table 1, entry 7),
and a yield of 82% was obtained.19,20 A control reaction
(Table 1, entry 8) in the absence of Pd(0) and ligand was
also performed to confirm that the process was not thermally
driven. Decomposition of malonate 11b was not observed
after stirring at 145 °C in DMF for 16 h. The retention of
the 1,4-syn stereochemistry of 12b was expected due to the
double inversion via the palladium π-allyl system. The 1,4-
syn stereochemistry of ester 12b was confirmed by 1H NMR.
A characteristic coupling pattern (J ) 6.5, 6.5, 13.5 Hz and
J ) 7.8, 7.8, 13.5 Hz) was observed for the diastereotopic
methylene protons in the cyclopentene core.21
Scheme 5
With a reliable method to 1,4-syn cyclopentene derivative
12b established, we turned our attention to the synthesis of
was exposed to the decarboxylative Claisen rearrangement
conditions, and ester 15 was obtained in 52% yield. The
unfavorable boat-like six-membered transtion state TS-2
could have contributed to the relatively low yield. Malonate
(18) For a detailed table of reaction conditions, see Supporting
Information.
(19) The reaction is performed under anhydrous conditions in a sealed
tube. High yields (76%) were observed on a 1.5 mmol scale. Decreased
yields (61%) were observed on a 6 mmol scale.
(20) Crude reaction mixture was analyzed by 1H NMR and showed
complete consumption of the allyl 2,2,2-trifluoroethyl malonate and the
formation of a single product with complete diastereo- and regiocontrol.
(21) For a brief discussion of coupling constants of 1,4-disubstituted
cyclopentenes, see: Mulvihill, M. J.; Surman, M. D.; Miller, M. J. J. Org.
Chem. 1998, 63, 4874.
(22) Craig, D.; Grellepois, F. Org. Lett. 2005, 7, 463.
(23) For mechanistic discussions of the decarboxylative Claisen rear-
rangement, see: (a) Bourgeois, D.; Craig, D.; King, N. P.; Mountford, D. M.
Angew. Chem., Int. Ed. 2005, 44, 618. (b) Craig, D.; Grellepois, F.; White,
A. J. P. J. Org. Chem. 2005, 70, 6827.
4078
Org. Lett., Vol. 11, No. 18, 2009

In summary, allyl 2,2,2-trifluoroethyl malonates undergo
efficient Pd-catalyzed decarboxylative allylation. Installation
of the trifluoroethyl group resulted in improved stabilization
of the reactive carbanion intermediate. Simple esters and
trichloroethyl ester groups were not effective. We have also
identified substrate 14 as a new system for the decarboxy-
lative Claisen rearrangement. Alcohol (-)-17 is currently
being used as a key intermediate to synthesize carbocyclic
nucleosides. Those investigations will be reported in due
course.
Scheme 6
14 also underwent efficient Pd(0)-catalyzed decarboxylative
rearrangement to 1,4-trans cyclopentene 16 (Scheme 6).20
The stereochemistry of 15 and 16 was confirmed by analyses
of the COSY and/or ROESY NMR spectra.
Finally, allyl 2,2,2-trifluoroethyl malonate (-)-11b was
synthesized from the readily available aminocyclopentenol
(-)-424 and converted to ester (-)-12b. Treatment with
diisobutylaluminum hydride provided alcohol (-)-17 in 85%
yield (Scheme 7). Alcohol (-)-17 represents a key interme-
Acknowledgment. We gratefully acknowledge Nonka
Sevova (University of Notre Dame) for mass spectroscopic
analyses, Dr. Jaroslav Zajicek (University of Notre Dame)
for NMR assistance, and Dr. Jed Fisher (University of Notre
Dame) for helpful discussions. We acknowledge the Uni-
versity of Notre Dame and NIH (GM 068012 and GM
075885) for support of this work.
Scheme 7
Supporting Information Available: General methods,
experimental details, and 1H and 13C NMR spectra for 5-7,
10a,b, 11a,b, 12b, and 14-17. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL901518G
diate toward the synthesis of (-)-5′-homocarbovir 1b and
(-)-5′-homoaristeromycin 2b.
(24) Mulvihill, M. J.; Gage, J. L.; Miller, M. J. J. Org. Chem. 1998, 63,
3357.
Org. Lett., Vol. 11, No. 18, 2009
4079