Sequential Rh(l)/Pd-catalyzed 1,4-addition/Lntramolecular allylation: Stereocontrolled construction of γ-butyrolactones and cyclopropanes

Article abstract of DOI:10.1021/ol702613f

The rhodium-catalyzed conjugate addition of functionalized vinyltin reagents to alkylidene Meldrum's acids, followed by Pd-catalyzed intramolecular allylation, is a direct entry into vinyl-substituted y-lactones via Oalkylation and vinylcyclopropanes via

Full text of DOI:10.1021/ol702613f

ORGANIC
LETTERS
2008
Vol. 10, No. 3
437-440
Sequential Rh(I)/Pd-Catalyzed
1,4-Addition/Intramolecular Allylation:
Stereocontrolled Construction of
γ
-Butyrolactones and Cyclopropanes
Eric Fillion,* Se´bastien Carret, Lauren G. Mercier, and Vincent EÄ. Tre´panier
Department of Chemistry, UniVersity of Waterloo, Waterloo,
Ontario, Canada N2L 3G1
efillion@uwaterloo.ca
Received October 26, 2007
ABSTRACT
The rhodium-catalyzed conjugate addition of functionalized vinyltin reagents to alkylidene Meldrum’s acids, followed by Pd-catalyzed
intramolecular allylation, is a direct entry into vinyl-substituted
γ
-lactones via O-alkylation and vinylcyclopropanes via C-alkylation.
The synthesis of distinct types of polysubstituted cyclic
compounds from a single multifunctional reagent based on
catalyst selection would be of great synthetic interest.1 In
that regard, introduction of a synthon containing orthogonal
nucleophilic and electrophilic moieties could best serve this
purpose.2 Our group has recently reported that 3-(tributyl-
stannyl)-2-propenyl acetates are ambiphilic reagents wherein
the vinyl-tin bond acts as a base and the allyl acetate as a
Pd-activated electrophile.3 We reasoned that the latent
nucleophilicity of the C-Sn bond could be unveiled by
rhodium catalysis to increase the scope of available reactions.
In this paper, we report that (E/Z)-3-(tributylstannyl)allyl
acetate (2) and ethyl carbonate (3) add in a conjugate fashion,
under mild reaction conditions, to 5-(phenylmethylene)
Meldrum’s acids (1) in the presence of Rh(I) catalysts
(Scheme 1). Polysubstituted γ-butyrolactones 6 and cyclo-
propanes 7 are then accessed through subsequent Pd-
Scheme 1. General Strategy
catalyzed transformation of the resulting Meldrum’s acids 4
and 5.
The [Rh(cod)(MeCN)2]BF4-catalyzed 1,4-addition of alk-
enyl and arylstannanes to enones and R,â-unsaturated esters
is precedented.4-6 However, the C-C bond-forming reactions
required elevated temperatures and harsh conditions and were
limited to the introduction of trimethylstannane derivatives.
Poor yields were obtained with the analogous but much safer
(1) Panne, P.; Fox, J. M. J. Am. Chem Soc. 2007, 129, 22-23.
(2) Kimura, M.; Mukai, R.; Tamaki, T.; Horino, Y.; Tamaru, Y. J. Am.
Chem. Soc. 2007, 129, 4122-4123.
(3) Tre´panier, V. EÄ .; Fillion, E. Organometallics 2007, 26, 30-32.
10.1021/ol702613f CCC: $40.75
© 2008 American Chemical Society
Published on Web 01/10/2008

to use tributylstannanes. Furthermore, functional group
compatibility has not been demonstrated.
With these results in hands, the scope of the conjugate
addition was defined (Table 1). The nature and electronic
character of the group present on the electrophilic carbon
atom of the alkylidene did not substantially affect the
reactivity, with the exception of derivative 1g, which required
a longer reaction time.8 As alkylidenes 1f and 1k were
insoluble in THF at rt, the reactions were carried out at 40
°C. The addition was not limited to benzylidene Meldrum’s
acids; ethylidene Meldrum’s acid 1m furnished the 1,4-
adducts 4m and 5m in excellent yields at rt in only 3 h.9
These results exemplify the mildness and high chemoselec-
tivity of this transformation, as halo, cyano, nitro, and methyl
ester substituents were tolerated.
We postulated that the superior electrophilicity of alky-
lidene Meldrum’s acids7 would allow the efficient addition
of alkenyltributylstannane under mild reaction conditions,
preferably at room temperature. Gratifyingly, it was found,
after some preliminary screening of solvent and catalyst, that
[RhCl(cod)]2 (3 mol % of Rh) catalyzed the addition of (E)-2
to 1a at ambient temperature in just 6 h. As depicted in Table
1, 4a was isolated in 91% yield. The analogous carbonate
Table 1. Scope of the 1,4-Addition of Vinylstannanes 2 and 3
The conjugate addition of the corresponding (Z)-stannyl
acetate (Z)-2 to alkylidenes 1a and 1e was also investigated.
Addition products (Z)-4a and (Z)-4e were isolated in 82-
83% yield at rt with total retention of the double-bond
geometry (Scheme 2).
Scheme 2. Conjugate Addition of (Z)-Stannyl Acetate
1,4-Addition products 4 and 5 feature an enolizable
Meldrum’s acid moiety with, respectively, an appending allyl
acetate and carbonate that can be activated by introduction
of catalytic palladium. Further synthetic elaboration was
envisaged in which Meldrum’s acid, an ambident nucleo-
phile, could trap the π-allylpalladium complex to lead
directly and selectively to a vinyl γ-butyrolactone by
O-alkylation or a vinylcyclopropane by C-alkylation.10,11
Conditions previously described for intramolecular allylic
C-alkylation of malonate derivatives and cyclopropane
formation (Pd(PPh3)4 (7 mol %), Et3N (4 equiv) in THF at
reflux for 16 h), when applied to 4a, afforded exclusively
the product of O-alkylation, lactone 8, in 28% yield rather
than vinylcyclopropane 7a (Scheme 3).12 A similar low yield
a The reaction was carried out at 40 °C.
(E)-3 added to 1a with comparable efficiency.
This result is striking as it represents a large increase in
reactivity compared to previously described alkenyl- and
arylstannane Rh(I)-catalyzed conjugate additions. This in-
crease is attributed to the electron-withdrawing allylic acetate
or carbonate, which seemingly facilitates Rh-Sn transmeta-
lation. This was confirmed by reacting vinyltributyltin with
benzylidene Meldrum’s acid (1a) under [RhCl(cod)]2 (3 mol
% Rh) or [Rh(cod)(MeCN)2]BF4 (3 mol % Rh) catalysis; at
rt only 70% conversion was obtained after 18 h.
(8) The conversion was >99% in all cases.
(9) Similar results were obtained with [Rh(cod)(MeCN)2]BF4. An 86%
yield of 4m was obtained with 6 mol % of Rh at rt for 15 h.
(10) Intermolecular C-allylation of Meldrum’s acids with π-allylpalladium
complexes: (a) Trost, B. M.; Brennan, M. K. Org. Lett. 2007, 9, 3961-
3964. (b) Trost, B. M.; Lee, C. B. J. Am. Chem. Soc. 2001, 123, 3687-
3696. (c) Ross, J.; Chen, W.; Xu, L.; Xiao, J. Organometallics 2001, 20,
138-142.
(4) (a) Oi, S.; Moro, M.; Ito, H.; Honma, Y.; Miyano, S.; Inoue, Y.
Tetrahedron 2002, 58, 91-97. (b) Oi, S.; Moro, M.; Ono, S.; Inoue, Y.
Chem. Lett. 1998, 83-84.
(5) (a) Venkatraman, S.; Meng, Y.; Li, C.-J. Tetrahedron Lett. 2001,
42, 4459-4462. (b) For an intramolecular version, see: Dziedzic, M.;
Maleka, M.; Furman, B. Org. Lett. 2005, 7, 1725-1727. (c) For a review
on Rh(I)-catalyzed conjugate additions, see: Hayashi, T.; Yamasaki, K.
Chem. ReV. 2003, 103, 2829-2844.
(6) To date, a single asymmetric example has been reported, see:
Hayashi, T.; Ueyama, K.; Tokunaga, N.; Yoshida, K. J. Am. Chem. Soc.
2003, 125, 11508-11509.
(7) Asymmetric synthesis of all-carbon quaternary centers from alkylidene
Meldrum’s acids via Cu-catalyzed conjugate addition of dialkylzinc reagents,
see: Fillion, E.; Wilsily, A. J. Am. Chem. Soc. 2006, 128, 2774-2775.
(11) Meldrum’s acid C- and O-dialkylation: Snyder, C. A.; Selegue, J.
P.; Dosunmu, E.; Tice, N. C.; Parkin, S. J. Org. Chem. 2003, 68, 7455-
7459.
(12) The Pd-catalyzed synthesis of vinylcyclopropanes via intramolecular
C-allylation of malonate derivatives with π-allylpalladium complexes has
been reported; see: (a) Ba¨ckvall, J. E.; Vågberg, J. O.; Zercher, C.; Geneˆt,
J.-P.; Denis, A. J. Org. Chem. 1987, 52, 5430-5435. (b) Trost, B. M.;
Tometzki, G. B.; Hung, M.-H. J. Am. Chem. Soc. 1987, 109, 2176-2177.
(c) Hashimoto, S.; Shinoda, T.; Ikegami, S. Tetrahedron Lett. 1986, 27,
2885-2888. (d) Geneˆt, J.-P.; Balabane, M.; Charbonnier, F. Tetrahedron
Lett. 1982, 23, 5027-5030.
438
Org. Lett., Vol. 10, No. 3, 2008

rich phosphine and Et3N were required. Cyclization of 4a
could also be achieved under Pd(II) catalysis with similar
results (Table 2, entries 4 and 5).16 Two mechanisms can be
considered for the formation of the lactones. The first one
involves η3-allyl species for Pd(0) catalysts.17 Alternatively,
for Pd(II) catalysts, the new C-O bond would be formed
by hydroxypalladation of the alkene, followed by elimination
of the acetate.18
Scheme 3. Initial Cyclization Attempts
A one-pot lactone synthesis was also developed (Scheme
5). Starting with 1a and 3, Rh(I)-catalyzed 1,4-addition was
(20%) but equal O- vs C-alkylation selectivity was observed
with allyl carbonate 5a, which led to lactone ester 6a
(Scheme 3).
Scheme 5. One-Pot γ-Butyrolactone Synthesis
Formation of 6a pointed to the intermediacy of an
acylketene formed by cycloreversion of the dioxinone
resulting from O-alkylation,13 trapping with ethoxide ac-
counts for 6a, while rapid decomposition of the acylketene
explains the low yields (Scheme 4).14
Scheme 4. Lactone Formation Mechanism
carried out using the optimal conditions leading to tin enolate
intermediate 9.19 Addition of Pd(PPh3)4 and tetrabutylam-
monium bromide (TBAB) in THF/EtOH provided lactone
6a in 73% yield, also with excellent stereoselectivity.20-22
Of note, lactone 6c was not formed from 9 when water was
used as cosolvent; rather, lactone 8 was isolated in 48% yield
(Scheme 5).23
Therefore, performing the reactions with alcohol or water
as cosolvent allowed efficient interception of the acylketene,
and lactones 6a-c were formed from 5a in 73-87% yield,
with excellent diastereoselectivity (Table 2, entries 1-3).15
3,4-Disubstituted lactone 8 could alternatively be obtained
by decarboxylation of lactone ester 6a in 89% yield (Scheme
6).24
Table 2. Lactone Formation via O-Alkylation
The selective synthesis of cyclopropanes25,26 through
intramolecular C-alkylation was then studied. As Pd(0) and
Pd(II) only afforded O-alkylation, in the absence and
(15) Selectivities of 18:1 up to >20:1 anti/syn for the â- and γ-substit-
uents were determined by analysis of the 1H NMR spectra of the crude
reaction mixtures.
(16) Attempts to generate the π-allylrhodium complex by modifying the
catalyst in situ by the addition of P(OEt)3 failed; see: (a) Evans, P. A.;
Robinson, J. E.; Moffett, K. K. Org. Lett. 2001, 3, 3269-3271. (b) Evans,
P. A.; Nelson, J. D. J. Am. Chem. Soc. 1998, 120, 5581-5582.
(17) Hayashi, T.; Yamane, M.; Ohno, A. J. Org. Chem. 1997, 62, 204-
207.
(18) Tenaglia, A.; Kammerer, F. Synlett 1996, 576-578.
(19) The formation of tin enolate 9 was confirmed by analysis of the 1H
NMR spectra of the crude mixture.
(20) C-Allylation of stannyl ketone enolates with Pd(II) π-allyl complexes
was reported; see: (a) Trost, B. M.; Schroeder, G. M. Chem. Eur. J. 2005,
11, 174-184. (b) Trost, B. M.; Schroeder, G. M. J. Am. Chem. Soc. 1999,
121, 6759-6760.
(21) Activation of stannyl ketone enolates with TBAB: Yasuda, M.;
Chiba, K.; Ohigashi, N.; Katoh, Y.; Baba, A. J. Am. Chem. Soc. 2003,
125, 7291-7300.
(22) Unfortunately, the addition of both catalysts at the beginning of
the domino reaction failed.
(23) It is postulated that decarboxylation to 8 is promoted by tributyltin
species in combination with TBAB.
(24) (a) Krapcho, A. P.; Weimaster, J. F.; Eldridge, J. M.; Jahngen, J.
E. G. E.; Lovey, A. J.; Stephens, W. P. J. Org. Chem. 1978, 43, 138-147.
(b) Krapcho, A. P.; Lovey, A. J. Tetrahedron Lett. 1973, 12, 957-960.
entry
R
R′
time (h)
T (°C)
yield (%)
1
2
3
4
5
CO2Et (5a)
CO2Et (5a)
CO2Et (5a)
Ac (4a)
Et (6a)
Me (6b)
H (6c)
Et (6a)
Me (6b)
6
6
15
8
60
60
40
50
50
80a
73a
87a
69,b 73c
60,b 56c
Ac (4a)
8
a Method A: Pd(PPh3)4 (7 mol %). b Method B: Pd2dba3‚CHCl3 (2.5
mol %), [(p-MeO)C6H4]3P (18 mol %), Et3N (1.2 equiv). c Method C:
PdCl2(MeCN)2 (5 mol %) in R′OH at 60 °C.
In the case of the acetate derivative 4a, the conditions were
modified to obtain lactones 6a and 6b, as a more electron-
(13) Sato, T.; Ban, H.; Kaneko, C. Tetrahedron Lett. 1997, 38, 6689-
6692.
(14) The formation of 8 from 4a in the absence of excess alcohol may
be attributed to the interception of the acylketene by the actetate formed in
the course of the reaction. The resulting anhydride is then hydrolyzed in
the workup with concommitent decarboxylation.
Org. Lett., Vol. 10, No. 3, 2008
439

isolated in 71% yield as a single diastereomer. The relative
stereochemistry was confirmed by X-ray analysis. Similar
results were obtained with 4e, demonstrating the efficiency
of this methodology to access trans-vinylcyclopropanes.
In summary, we have shown that distinct types of
polysubstituted cyclic compounds can be accessed from a
single multifunctional reagent based on catalyst and reaction
conditions selection. Bisfunctionalized 3-(tributylstannyl)-
2-propenyl acetate and ethyl carbonate reagents add in a
conjugate fashion to various alkylidene Meldrum’s acids at
room temperature under mild reaction conditions. The ease
of Rh-Sn transmetalation in 3-(tributylstannyl)-2-propenyl
acetate and ethyl carbonate reagents is noteworthy and
deserving of further study. Treatment of the 1,4-addition
products with Pd catalyst, in a sequential or one-pot fashion,
led to the highly stereocontrolled synthesis of vinyl-γ-
butyrolactones and vinylcyclopropanes.
Scheme 6. Decarboxylation of Lactone 6a
presence of base, the intramolecular allylic alkylation was
attempted under Lewis acidic conditions. After screening a
wide range of Lewis acids in the presence of various sources
of Pd(II),27 it was found that PdCl2(PhCN)2 (10 mol %) and
Yb(OTf)3 (20 mol %) in THF at rt gave the best selectivity
between C- and O-allylic alkylation (Scheme 7). Under these
Acknowledgment. This work was supported by Astra-
Zeneca Canada, Inc., Boehringer Ingelheim (Canada) Ltd.,
the Merck Frosst Centre for Therapeutic Research, the
Natural Sciences and Engineering Research Council of
Canada (NSERC), the Canadian Foundation for Innovation,
the Ontario Innovation Trust, and the University of Waterloo.
V.EÄ .T. is indebted to NSERC for a PGS-D scholarship. We
thank Aaron M. Dumas, University of Waterloo, for helpful
suggestions and proofreading the manuscript and the late Dr.
N. J. Taylor, University of Waterloo, for X-ray structure
determination.
Scheme 7. Cyclopropane Synthesis
conditions, an 8:1 mixture of cyclopropane 7a to lactone 6c
was formed from Meldrum’s acid 4a.14,28 The cyclopropa-
nation proceeded with excellent stereoselectivity, and 7a was
Supporting Information Available: Experimental pro-
cedures, NMR spectra, and X-ray data for 7a (CIF). This
material is available free of charge via the Internet at
http://pubs.acs.org.
(25) (a) Melancon, B. J.; Perl, N. R.; Taylor, R. E. Org. Lett. 2007, 9,
1425-1428. (b) For a review on the stereoselective synthesis of cyclopro-
panes, see: Lebel, H.; Marcoux, J.-F.; Molinaro, C.; Charette, A. B. Chem.
ReV. 2003, 103, 977-1050.
(26) (a) Mu¨ller, P.; Allenbach, Y.; Robert, E. Tetrahedron: Asymmetry
2003, 14, 779-785. (b) Chen, Y.; Ding, W.; Cao, W.; Lu, C. Synth.
Commun. 2002, 32, 1953-1960. (c) Sato, M.; Hisamichi, H.; Kaneko, C.
Tetrahedron Lett. 1989, 30, 5281-5284. (d) Livinghouse, T.; Stevens, R.
V. J. Chem. Soc. Chem. Commun. 1978, 754-756.
OL702613F
(28) As proposed in footnote 14, the acylketene intermediate en route
to 6c is likely intercepted by the acetate leaving group to furnish an
anhydride. However, no data are available to rationalize the divergence in
reaction pathways and the absence of decarboxylation in the presence of
Yb(OTf)3 to form byproduct 6c.
(27) Yang, D.; Li, J.-H.; Gao, Q.; Yan, Y.-L. Org. Lett. 2003, 5, 2869-
2871.
440
Org. Lett., Vol. 10, No. 3, 2008