Synthesis of 5,5-disubstituted butenolides based on a Pd-catalyzed γ-arylation strategy

Article abstract of DOI:10.1021/ol9007102

Methods for the construction of quaternary carbon centers are of great interest to synthetic chemists due to their presence in natural products. Development of the Pd-catalyzed arylation of butenolides with high selectivity for the γ-position allows for a

Full text of DOI:10.1021/ol9007102

ORGANIC
LETTERS
2009
Vol. 11, No. 12
2663-2666
Synthesis of 5,5-Disubstituted
Butenolides Based on a Pd-Catalyzed
γ-Arylation Strategy
Alan M. Hyde and Stephen L. Buchwald*
Department of Chemistry, Massachusetts Institute of Technology,
Cambridge, Massachusetts 02139
sbuchwal@mit.edu
Received April 3, 2009
ABSTRACT
Methods for the construction of quaternary carbon centers are of great interest to synthetic chemists due to their presence in natural products.
Development of the Pd-catalyzed arylation of butenolides with high selectivity for the γ-position allows for a facile construction of quaternary
centers. The preparation of a wide variety of γ-aryl butenolides containing a number of functional groups is outlined. An application of this
chemistry for a one-pot synthesis of a tricyclic tetrahydroisoquinolinone is demonstrated.
The functionalization of pre-existing heterocyclic scaffolds
through carbon-carbon bond formation represents a key
route to new structures. This allows the rapid synthesis of a
family of compounds sharing a common structural motifsan
attractive strategy for medicinal chemists and others explor-
ing structure-activity relationships. This approach has been
applied extensively through the use of cross-coupling
methods, in which the heterocyclic component can act either
as a nucleophile or an electrophile.1
have been developed for their de novo preparation from
simpler precursors.3 Of equal importance is the derivatization
of preformed butenolides, often involving C-C bond forma-
tion with an appropriate electrophile at the γ-carbon. Such
reactions include alkylations,4a-c vinylogous Mukaiyama
aldol condensations,4d-f vinylogous Mukaiyama-Michael
reactions,4g-i and vinylogous Mukaiyama-Mannich reac-
tions.4j,k It has been found that butenolide dienolates are more
nucleophilic at the γ-position, and very good selectivities
are usually observed for this position.
Butenolides, unsaturated γ-butyrolactones, are often sub-
structures of natural products and other biologically active
compounds.2 Given their prevalence in nature, many methods
We envisioned preparing γ-aryl butenolides from R,ꢀ- or
ꢀ,γ-unsaturated butyrolactones through a Pd-catalyzed cross-
coupling process (Scheme 1). The cross-coupling of ester
enolates with aryl and vinyl halides has emerged as an
(1) (a) Li, J. J.; Gribble, G. W. Palladium in Heterocyclic Chemistry: A
Guide for the Synthetic Chemist, 2nd ed.; Elsevier: Oxford, UK, 2007. For
reviews on the use of Cu-based catalysts for cross-coupling heterocyclic
compounds see: (b) Kunz, K.; Scholz, U.; Ganzer, D. Synlett 2003, 2428.
(c) Ley, S. V.; Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42, 5400. (d)
Beletskaya, I. P.; Cheprakov, A. V. Coord. Chem. ReV. 2004, 248, 2337.
(2) For representative examples: (a) Figade`re, B. Acc. Chem. Res. 1995,
28, 359. (b) Tu, L.; Zhao, Y.; Yu, Z.; Cong, Y.; Xu, G.; Peng, L.; Zhang,
P.; Cheng, X.; Zhao, Q. HelV. Chim. Acta 2008, 91, 1578. (c) de Guzman,
F. S.; Schmitz, F. J. J. Nat. Prod. 1990, 53, 926. (d) Evidente, A.; Sparapano,
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B.; de Pascual-Teresa, B.; Ramos, A.; Pozuelo, J. M.; Dom´ınguez, M. T.
Org. Biomol. Chem. 2004, 2, 1864. (f) Dogne´, J.; Supuran, C. T.; Pratico,
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(3) For general reviews, see: (a) Avetisyan, A. A.; Dangyan, M. T. Russ.
Chem. ReV. 1977, 46, 643. (b) Rao, Y. S. Chem. ReV. 1976, 76, 625. For
an approach based on ring-closing metathesis: (c) Bassetti, M.; D’Annibale,
A.; Fanfoni, A.; Minissi, F. Org. Lett. 2005, 7, 1805. For approaches based
on Lewis- or Brønsted-acid-initiated cyclization: (d) Browne, D. M.;
Niyomura, O.; Wirth, T. Org. Lett. 2007, 9, 3169. (e) Goldsmith, D.; Liotta,
D.; Lee, C.; Zima, G. Tetrahedron Lett. 1979, 20, 4801. For methods which
rely on the oxidation of furans: (f) Pelter, A.; Rowlands, M. Tetrahedron
Lett. 1987, 28, 1203. (g) Kuwajima, I.; Urabe, H. Tetrahedron Lett. 1981,
22, 5191. (h) Machado-Araujo, F. W.; Gore, J. Tetrahedron Lett. 1981, 22,
1969. For a metal-mediated carbonylative ring closure: (i) Yoneda, E.;
Kaneko, T.; Zhang, S.; Onitsuka, K.; Takahashi, S. Org. Lett. 2000, 2, 441.
10.1021/ol9007102 CCC: $40.75
Published on Web 05/18/2009
 2009 American Chemical Society

1 with bromobenzene in the presence of Pd2dba3, MePhos
(2, Figure 1), and a fluoride source (Table 1). We found that
Scheme 1
.
General Reaction for the Preparation of
5,5-Disubstituted Butenolides
Figure 1. Ligands used in these studies.
important and convenient route for the production of either
R-aryl- or R-vinyl-substituted esters.5 We and others have
developed procedures for the γ-arylation of R,ꢀ- or ꢀ,γ-
unsaturated ketones,6 but to date, no analogous method to
our knowledge has been reported for the direct arylation of
an unsaturated ester.7
Table 1. Arylation of Silyl Dienol Ether 1
One potential issue is that butenolides are prone to
dimerize in the presence of base through Michael reactions.4g
Therefore, we began our studies by reacting silyl dienol ether
additive
% yielda
(4) (a) Jefford, C. W.; Sledeski, A. W.; Boukouvalas, J. Chem. Commun.
1988, 364. (b) Ma, S.; Lu, L.; Lu, P. J. Org. Chem. 2005, 70, 1063. (c)
Jiang, Y.; Shi, Y.; Shi, M. J. Am. Chem. Soc. 2008, 130, 7202. (d) Nagao,
H.; Yamane, Y.; Mukaiyama, T. Chem. Lett. 2007, 36, 8. (e) Asaoka, M.;
Yanagida, N.; Ishibashi, K.; Takei, H. Tetrahedron Lett. 1981, 22, 4269.
(f) Kong, K.; Romo, D. Org. Lett. 2006, 8, 2909. (g) Kraus, G. A.; Roth,
B. Tetrahedron Lett. 1977, 18, 3129. (h) Suga, H.; Kitamura, T.; Kakehi,
A.; Baba, T. Chem. Commun. 2004, 1414. (i) Brown, S. P.; Goodwin, N. C.;
MacMillan, D. W. C. J. Am. Chem. Soc. 2003, 125, 1192. (j) de Oliveira,
M. C. F.; Santos, L. S.; Pilli, R. A. Tetrahedron Lett. 2001, 42, 6995. (k)
Yamaguchi, A.; Matsunaga, S.; Shibasaki, M. Org. Lett. 2008, 10, 2319.
(5) For a review on the Pd-catalyzed R-arylation of esters, see: (a) Lloyd-
Jones, G. C. Angew. Chem., Int. Ed. 2002, 41, 953–956. (b) Moradi, W. A.;
Buchwald, S. L. J. Am. Chem. Soc. 2001, 123, 7996. (c) Lee, S.; Beare,
N. A.; Hartwig, J. F. J. Am. Chem. Soc. 2001, 123, 8410. (d) Jørgenson,
M.; Lee, S.; Liu, X.; Wolkowski, J. P.; Hartwig, J. F. J. Am. Chem. Soc.
2002, 124, 12557. (e) Gaertzen, O.; Buchwald, S. L. J. Org. Chem. 2002,
67, 465. (f) Bercot, E. A.; Caille, S.; Bostick, T. M.; Ranganathan, K.;
Jensen, R.; Faul, M. M. Org. Lett. 2008, 10, 5251. (g) Wang, Y.; Nair, R.
Tetrahedron Lett. 2007, 48, 1191. (h) Hama, L.; Liu, X.; Culkin, D. A.;
Hartwig, J. F. J. Am. Chem. Soc. 2003, 125, 11176. (i) Hama, T.; Hartwig,
J. F. Org. Lett. 2008, 10, 1545–1548. (j) Hama, T.; Hartwig, J. F. Org.
Lett. 2008, 10, 1549–1552. (k) For a Ni-catalyzed asymmetric R-arylation
of butyrolactones, see: Spielvogel, D. J.; Buchwald, S. L. J. Am. Chem.
Soc. 2002, 124, 3500. (l) For an approach that involves the reaction of
R-bromo esters with boronic acids, see: Gooꢀen, L. J. Chem. Commun.
2001, 669.
CsF
KF
0
0
0
0
0
ZnF2
CuF2
TBAF
TBAT
Bu3SnF
7
83
a GC yield (calibrated).
this approach worked quite well, but unfortunately Bu3SnF
was the only fluoride source that efficiently promoted the
reaction. The difficulty in separating the stoichiometric tin
byproducts from the product coupled with the extra step to
prepare the substrate prompted us to find conditions to arylate
butenolides directly.
We next attempted the arylation of commercially available
R-angelicalactone (5) with bromobenzene under a variety
of conditions in the presence of a Pd catalyst and a base as
shown in Table 2. It should be pointed out that the ꢀ,γ-
unsaturated isomer is the more stable form of this lactone.
This is fortunate because we previously showed that ꢀ,γ-
unsaturated ketones are arylated more efficiently than their
R,ꢀ-unsaturated counterparts.6a We immediately found that
the nature of the solvent was critical to the success of this
reactionsin most cases, only decomposition products were
observed. Although the use of either toluene or tert-amyl
alcohol alone gave poor yields (3% and 11%, respectively),
remarkably, use of a 2:1 mixture of toluene/tert-amyl alcohol
gave the product in 75% yield. One explanation for the role
of the tert-amyl alcohol cosolvent is that it stabilizes the
dienolate, preventing decomposing. DMA also works well
as a solvent (77% yield), but we chose to adopt the toluene/
tert-amyl alcohol system because its use proved more general
(6) (a) Hyde, A. M.; Buchwald, S. L. Angew. Chem., Int. Ed. 2008, 47,
177. (b) Yamamoto, Y.; Hatsuya, S.; Yamada, J. Chem. Commun. 1988,
86. (c) Terao, Y.; Satoh, T.; Miura, M.; Nomura, M. Tetrahedron Lett.
1998, 39, 6203. (d) Terao, Y.; Satoh, T.; Miura, M.; Nomura, M. Bull.
Chem. Soc. Jpn. 1999, 72, 2345. (e) Terao, Y.; Kametani, Y.; Wakui, H.;
Satoh, T.; Miura, M.; Nomura, M. Tetrahedron 2001, 57, 5967. (f) Wang,
T.; Cook, J. Org. Lett. 2000, 2, 2057. (g) Varseev, G. N.; Maier, M. E.
Org. Lett. 2005, 7, 3881.
(7) For the Pd-catalyzed γ-arylation of an O-silyl furan with aryl
antimonates, see: (a) Kang, S.; Ryu, H.; Hong, Y. Perkin Trans. 1 2000,
3350. (b) For the Pd-catalyzed γ-arylation of an O-silyl furan with
hypervalent iodonium salts, see: Kang, S.; Yamaguchi, T.; Ho, P.; Kim,
W.; Yoon, S. Tetrahedron Lett. 1997, 38, 1947. (c) For one example of a
γ-arylated butenolide generated as a side product from the R-arylation of
a butyrolactone, see: Malcolm, S. C.; Ribe, S.; Wang, F.; Hewitt, M. C.;
Bhongle, N.; Bakale, R. P.; Shao, L. Tetrahedron Lett. 2005, 46, 6871. (d)
For the Pd-catalyzed arylation of γ-stannyl R,ꢀ-unsaturated esters, see:
Yamamoto, Y.; Hatsuya, S.; Yamada, J. Chem. Commun. 1988, 86.
(8) Buchwald, S. L.; Mauger, C.; Mignani, G.; Scholz, U. AdV. Synth.
Catal. 2006, 348, 23.
2664
Org. Lett., Vol. 11, No. 12, 2009

Table 2. Optimization of Conditions for the Arylation of
R-Angelicalactone (5)
Table 3. γ-Arylation of R-Angelicalactone
entry
ligand
base
solvent
dioxane
% yielda
1
2
3
4
5
6
7
8
2
2
2
2
2
2
2
2
2
2
2
2
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
Na2CO3
K3PO4
3
0
DME
ethyl propionate
t-amyl alcohol
toluene
tol/t-amylOH (2:1)
DMA
tol/t-amylOH (2:1)
tol/t-amylOH (2:1)
tol/t-amylOH (2:1)
39
11
3
75
77
50
0
28
14
84b
7
67
0
0
61
0
10
26
0
9
10
11
12
13
14
15
16
17
18
19
20
21
NaOt-Bu tol/t-amylOH (2:1)
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
tol/t-amylOH (2:1)
tol/t-amylOH (2:1)
tol/t-amylOH (2:1)
tol/t-amylOH (2:1)
tol/t-amylOH (2:1)
tol/t-amylOH (2:1)
tol/t-amylOH (2:1)
tol/t-amylOH (2:1)
tol/t-amylOH (2:1)
tol/t-amylOH (2:1)
XPhos
SPhos
IMesc
JohnPhos
DavePhos K2CO3
PPh3
P(t-Bu)3
K2CO3
K2CO3
K2CO3
K2CO3
d
Xantphos
dppf
a GC yield (calibrated). b 2 mol % of Pd(OAc)2 used in place of
Pd2(dba)3. c [(IMes)Pd(NQ)]2 complex used; IMes ) 1,3-bis(mesityl)imi-
dazole-2-ylidene, NQ ) naphthoquinone. d HBF4 salt used.
and did not require an aqueous workup. Further, we found
K2CO3 to be the optimal base, while stronger bases (e.g.,
NaOt-Bu) promoted rapid decomposition of 5. Changing the
Pd source to Pd(OAc)2 also increased the yield slightly (entry
12).
With the base and solvent chosen, we conducted a broad
screen examining the use of a diverse range of ligand
architectures which revealed that moderately hindered biaryl
monophosphines were uniquely effective for this transforma-
tion, with MePhos (1) giving the highest yields.8 The use of
more hindered monophosphines (XPhos, entry 13), N-
heterocyclic carbenes (IMes, entry 15), smaller phosphines
(PPh3, entry 18; P(t-Bu)3, entry 19), and bidentate ligands
(Xantphos, entry 20; dppf, entry 21) resulted in the formation
of the product in very low yields. In contrast to our method
published for the γ-arylation of ketones,6a the identity of
the ligand did not have any effect on the regioselectivity of
the process. In all cases, excellent selectivity favoring
arylation at the γ-position was observed (>98:2).
a Isolated yields (average of two runs). b Reaction run with 4 mol % of
Pd and 8 mol % of ligand. c Reaction run at 110 °C. d DMA used as the
solvent. e Reaction run for 18 h.
in good yield if DMA is used as solvent. The electron-rich
aryl bromide 4-morpholinobromobenzene was not a good
substrate using MePhos but could be coupled in reasonably
good yield (68% yield) with RuPhos (entry 6). Electron-
deficient and hindered aryl bromides also did not react
efficiently, prompting us to re-evaluate the general conditions
which led us to discover that ligand 4 was much more
effective in these cases than MePhos or RuPhos. The use of
this ligand allowed the efficient coupling of electron-deficient
(entries 7 and 9-11), heterocyclic (entry 8), and even very
hindered aryl bromides (entry 12). Although 4 closely
resembles Hayashi’s MOP ligand,9 its use gives slightly
improved yields over MOP and is straightforward to prepare
(see Supporting Information).
As shown in Table 3, electron-neutral and slightly electron-
rich aryl bromides (entries 1, 4, and 5) are efficiently coupled
using MePhos. An aryl chloride was also successfully
coupled when the more hindered ligand RuPhos (3) was used
(entry 2). Further, aryl triflates may be efficiently coupled
Org. Lett., Vol. 11, No. 12, 2009
2665

We next evaluated the reaction of butenolides with other
substitution patterns to further probe the scope of the reaction
(Table 4). A larger substituent at the γ-position was tolerated
(entry 5). We believe that in both cases unhindered dienolates
are formed which rapidly decompose.
To demonstrate the utility of this method further, we
reacted Boc-protected 2-bromobenzylamine 11 with R-an-
gelicalactone using slightly modified conditions that afforded
tricyclic compound 12 in 78% yield (Scheme 2). Similar to
Table 4. Arylation of Substituted Butenolides
Scheme 2. Synthesis of Tricyclic Tetrahydroisoquinolinone 12
what we have seen for analogous reaction of ketone
enolates,6a we believe that the reaction proceeds via CsC
bond formation, followed by conjugate addition to form the
tricyclic structure. Attempts to perform this reaction with
alternative protecting groups or with unprotected benzy-
lamines failed to give the desired product.
In summary, we have described an efficient preparation
of quaternary γ-aryl butenolides with a Pd-catalyzed cross-
coupling method. Careful optimization of the conditions was
required to suppress decomposition of the butenolide starting
material. We have shown that this reaction is quite general
with respect to the aryl halide. The butenolide component
must be substituted at the γ-position, and R-substitution is
tolerated. Further, we have applied this reaction to a one-
pot synthesis of a novel tricyclic tetrahydroisoquinolinone.
We are currently studying the mechanism of the reaction
with the purpose of explaining the observed regioselectivity.
Acknowledgment. We are grateful to the National Insti-
tutes of Health (GM46059) as well as Merck, Amgen, and
Boehringer Ingelheim for support of this research. We are
indebted to BASF for providing a generous gift of Pd(OAc)2
and Rhodia for providing ligand 2. AMH would like to thank
Sigma-Aldrich for a Graduate Student Innovation Award and
MIT for a Nicholas A. Milas Fellowship supporting this
research. The Varian NMR instruments used for these studies
were purchased with funds from the NSF (CHE 9808061
and DBI 9729592).
a Isolated yield (average of two runs). b Reaction run with 4 mol % of
Pd and 8 mol % of ligand. c Reaction run for 18 h. d Reaction run at 110
°C.
in this reaction as was demonstrated in the case of n-butyl-
substituted lactone 6, which coupled to 3,5-dimethylbro-
mobenzene in 74% yield (entry 1). γ-Aryl, R-alkyl-
disubstituted lactone 7 may be reacted with 3-isopropoxy
bromobenzene in 91% yield (entry 2). The reaction of lactone
8 gave the γ-arylated product in a modest yield of 54% (entry
3). It is likely that this lower yield can be attributed to the
use of an R,ꢀ-unsaturated lactone without an acidifying group
(e.g., lactone 7). Another problematic group of substrates
are ꢀ-substituted butenolides with an enolizable group (e.g.,
methyl) at this position such as 9 (entry 4). Furthermore,
the lack of substitution at the γ-position, as demonstrated
with 10, also failed to provide any desired arylation products
Supporting Information Available: Experimental pro-
cedures and spectral data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL9007102
(9) Uozumi, Y.; Tanahashi, A.; Lee, S. Y.; Hayashi, T. J. Org. Chem.
1993, 58, 1945.
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Org. Lett., Vol. 11, No. 12, 2009