Mild decarboxylative allylation of coumarins

Article abstract of DOI:10.1021/ol901288r

Allyl esters of 3-carboxylcoumarins undergo facile decarboxylative coupling at just 25-50 °C. This represents the first extension of decarboxylative C-C bond-forming reactions to the coupling of aromatics with sp ³-hybridized electrophiles. Finally, the same concept can be applied to the sp²-sp³ couplings of pyrones and flavones. Thus, a variety of biologically important heteroaromatics can be readily functionalized without the need for strong bases or stoichiometric organometallics that are typically required for more standard cross-coupling reactions.

Full text of DOI:10.1021/ol901288r

ORGANIC
LETTERS
2009
Vol. 11, No. 15
3434-3436
Mild Decarboxylative Allylation of
Coumarins
Ranjan Jana,† Rushi Trivedi,‡ and Jon A. Tunge*,†
Department of Chemistry, The UniVersity of Kansas, Lawrence, Kansas 66045 and
Department of Medicinal Chemistry, The UniVersity of Kansas,
Lawrence, Kansas 66045
tunge@ku.edu
Received June 9, 2009
ABSTRACT
Allyl esters of 3-carboxylcoumarins undergo facile decarboxylative coupling at just 25-50 °C. This represents the first extension of decarboxylative
C-C bond-forming reactions to the coupling of aromatics with sp3-hybridized electrophiles. Finally, the same concept can be applied to the
sp2-sp3 couplings of pyrones and flavones. Thus, a variety of biologically important heteroaromatics can be readily functionalized without
the need for strong bases or stoichiometric organometallics that are typically required for more standard cross-coupling reactions.
In recent years, significant effort has been devoted to the
development of decarboxylative couplings that allow C-C bond
forming cross-couplings without the need for preformed orga-
nometallics.1-3 In avoiding preformed organometallic re-
agents, decarboxylative couplings often avoid the use of
highly basic reaction conditions and the production of
stoichiometric metal waste.1c One remarkable example is the
decarboxylative biaryl synthesis developed by Gooꢀen.2 For
all its potential utility, such sp2-sp2 couplings require
decarboxylative metalation of sp2-hybridized carbons which
is a relatively high-energy process that utilizes copper
cocatalysts at 120-170 °C.2a,b A similar, cocatalyst free,
decarboxylative coupling of heteroaromatics was also re-
ported to occur at 150 °C.2c Thus, these promising reactions
could still benefit from the development of more mild
conditions for the cross-coupling. In addition, the decar-
boxylative coupling of aromatics and heteroaromatics has
not been extended to sp2-sp3 couplings,1b,4 which would
dramatically expand the structures that can be synthesized
by decarboxylative arylation. Herein we report a palladium-
catalyzed decarboxylative allylation of coumarins that pro-
ceeds under exceptionally mild conditions.
In looking for scaffolds on which to develop decarboxylative
allylation of aromatic nucleophiles, we were immediately drawn
to coumarins. Coumarins are privileged structures in biological
chemistry, and numerous pharmaceuticals are based on devel-
opment of this basic scaffold (Figure 1).5 Of these, warfarin
(1) is the most well-known of a class of 3-alkyl coumarins used
as anticoagulants. In principle, a decarboxylative allylation of
† Department of Chemistry.
‡ Department of Medicinal Chemistry.
(1) (a) Shimizu, I.; Yamada, T.; Tsuji, J. Tetrahedron Lett. 1980, 3199.
(b) Tsuda, T.; Chujo, Y.; Nishi, S.-i.; Tawara, K.; Saegusa, T. J. Am. Chem.
Soc. 1980, 102, 6381. (c) Rayabarapu, D. K.; Tunge, J. A. J. Am. Chem.
Soc. 2005, 127, 13510. (d) Waetzig, S. R.; Rayabarapu, D. K.; Weaver,
J. D.; Tunge, J. A. Angew. Chem., Int. Ed. 2006, 45, 4977. (e) Waetzig,
S. R.; Tunge, J. A. J. Am. Chem. Soc. 2007, 129, 4138. (f) Weaver, J. D.;
Tunge, J. A. Org. Lett. 2008, 10, 4657. (g) Mohr, J. T.; Behenna, D. C.;
Harned, A. W.; Stoltz, B. M. Angew. Chem., Int. Ed. 2005, 44, 6924. (h)
Trost, B. M.; Bream, R. N.; Xu, J. Angew. Chem., Int. Ed. 2006, 45, 3109
.
(2) (a) Goossen, L. J.; Deng, G.; Levy, L. M. Science 2006, 313, 662.
(b) Goossen, L. J.; Zimmermann, B.; Knauber, T Angew. Chem., Int. Ed.
2008, 47, 7103. (c) Forgoine, P.; Brochu, M. C.; St-Onge, M.; Thesen,
K. H.; Bailey, M. D.; Bilodeau, F. J. Am. Chem. Soc. 2006, 128, 11350
.
(3) (a) Myers, A. G.; Tanaka, D.; Mannion, M. R. J. Am. Chem. Soc.
2002, 124, 11250–11251. (b) Tanaka, D.; Romeril, S. P.; Myers, A. G.
Figure 1. Biologically active 3-alkyl coumarins.
J. Am. Chem. Soc. 2005, 127, 10323
.
10.1021/ol901288r CCC: $40.75
Published on Web 07/09/2009
 2009 American Chemical Society

coumarins may provide access to compounds like warfarin and
also allow the synthesis of a wide variety of 3-alkylcoumarins
for biological screening.
Table 1. Decarboxylative Coupling of Coumarins
To begin, 4a was synthesized and treated with Pd(PPh3)4 in
dry CH2Cl2 (Scheme 1). It was gratifying to find the reaction
Scheme 1
went to 100% conversion, allowing 3-allylcoumarin 5a to be
isolated in 73% yield. In addition to product (5a), the reaction
forms ca. 10% 6-nitrocoumarin, which results from protonation
of a putative coumarin anion equivalent.6 It is particularly
noteworthy that the decarboxylative metalation took place at
just 50 °C. While decarboxylation of 3-carboxycoumarins can
be effected by heating with strong acid or base, decarboxylative
metalation under neutral conditions is difficult. For example,
copper-catalyzed decarboxylation of a related 2-carboxycou-
marin takes place at 248 °C in refluxing quinoline.6,7 Moreover,
the allylation took place without the need for preformed
organometallics that are typically required for the allylation
of sp2 carbons,8,9 and it is more efficient than typical
syntheses of 3-allylcoumarins.10
Next, a range of coumarins were subjected to our standard
conditions for the coupling. As can be seen in Table 1, the yields
of the coupling are generally good. The reaction is compatible
with electron-donating and electron-withdrawing functional
(4) The decarboxylative allylation of silylenol ethers has been reported.
(a) Tsuji, J.; Ohashi, Y.; Minami, O. Tetrahedron Lett. 1987, 28, 2397. (b)
Snider, B. B.; Buckman, B. O. J. Org. Chem. 1992, 57, 4883. (c) Coates,
R. M.; Sandefur, L. O.; Smillie, R. D. J. Am. Chem. Soc. 1975, 97, 1619.
(5) (a) Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. ReV. 2003,
103, 893. (b) Estevez-Craun, A.; Gonzalez, A. G. Nat. Prod. Rep. 1997,
465. (c) Ngameni, B.; Touaibia, M.; Patnam, R.; Belkaid, A.; Sonna, P.;
Ngadjui, B. T.; Annabi, B.; Roy, R. Phytochemistry 2006, 67, 2573. (d)
Chun, K.; Park, S.-K.; Kim, H. M.; Choi, Y.; Kim, M.-H.; Park, C.-H.;
Joe, B.-Y.; Chun, T. G.; Choi, H.-M.; Lee, H.-Y.; Hong, S. H.; Kim, M. S.;
Nam, K.-Y.; Han, G. Biorg. Med. Chem. 2008, 16, 530.
a Isolated yield using 10 mol % of Pd(PPh3)4, 50 °C, 12-15 h. b At
room temperature.
groups. This fact argues against simple electrophilic allylation
of the coumarin.11 While coumarins with oxygen donors are
excellent substrates, an amine-containing substrate (entry 9)
provides a relatively low yield of product. Importantly, aryl
bromides are tolerated, allowing tandem reactions involving
decarboxylative coupling and standard cross-coupling chemistry.
Lastly, a thiocoumarin substrate reacts similarly to the coumarin
substrate, providing a 63% yield of 3-allyl thiocoumarin
(Scheme 2).
(6) Worden, L. R.; Kaufman, K. D.; Weis, J. A.; Schaaf, T. K. J. Org.
Chem. 1969, 34, 2311.
(7) (a) Adams, R.; Bockstahler, T. E. J. Am. Chem. Soc. 1952, 74, 5346.
(b) Posakony, J.; Hirao, M.; Stevens, S.; Simon, J. A.; Bedalov, A. J. Med.
Chem. 2004, 47, 2635
.
(8) Cross-couplings of coumarins: (a) Zhang, L.; Meng, T.; Fan, R.;
Wu, J. J. Org. Chem. 2007, 72, 7279. (b) Schiedel, M.-S.; Briehn, C. A.;
Bauerle, P. J. Organomet. Chem. 2002, 653, 200. (c) Wu, J.; Yun, L.; Yang,
Z. J. Org. Chem. 2001, 66, 3642
.
(9) Allylation of sp2-carbon nucleophiles: (a) Kayaki, Y.; Koda, T.;
Takao, I. Eur. J. Org. Chem. 2004, 4989. (b) Del Valle, L.; Stille, J. K.;
Hegedus, L. S. J. Org. Chem. 1990, 55, 3019. (c) Kobayashi, Y.; Watatani,
K.; Tokoro, Y. Tetrahedron Lett. 1998, 29, 7533. (d) Tseng, C. C.; Paisley,
Scheme 2
S. D.; Goering, H. L. J. Org. Chem. 1986, 51, 2884
.
(10) (a) Ahluwalia, V. K.; Prakash, C.; Gupta, R. Synthesis 1980, 48.
(b) Mali, R. S.; Tilve, S. G.; Yeola, S. N.; Manekar, A. R. Heterocycles
1987, 26, 121.
(11) Electrophilic allylation of coumarins is generally only successful
with electron-rich coumarins, and the regioselectivity favors allylation of
the benzenoid ring. (a) Ramachandra, M. S.; Subbaraju, G. V. Synth.
Commun. 2006, 36, 3723. (b) Cairns, N.; Harwood, L. M.; Astles, D. P.
J. Chem. Soc., Perkin Trans. 1 1994, 3101.
Next, we turned our attention to the investigation of the
coupling of substituted allyl electrophiles with coumarins (Table
Org. Lett., Vol. 11, No. 15, 2009
3435

the concept of decarboxylative allylation extends to heteroaromatics
other than coumarins.
Table 2. Decarboxylative Coupling of Substituted Allylic Esters
While decarboxylative couplings are often used in lieu of
standard cross-coupling reactions that are more costly or
wasteful,1a,3 decarboxylative couplings are oftentimes comple-
mentary to standard palladium-catalyzed coupling reactions.
For instance, the decarboxylative sp2-sp3 coupling reported
herein can be readily utilized in a tandem decarboxylative
allylation/Heck olefination sequence to provide coumarin 11
(Scheme 3).
a Isolated as a 94:6 mixture of linear:branched regioisomers.
Scheme 3. Decarboxylative Coupling/Heck Reaction
2). The coupling of 2-methallyl alcohol derivatives proceeds
smoothly and provides products in somewhat higher yields than
those without methallyl substituents (entries 1-3). Importantly,
the chemistry is also compatible with 3-alkyl-substituted allyl
groups (entries 4-6). This is particularly noteworthy because
the coupling is the formal allylation of a very basic vinyl anion.
Typically, such strong bases simply induce elimination of the
π-allyl palladium intermediates.12
In the interest of exploring the features of the coumarin that allow
decarboxylative coupling under such mild conditions, several
experiments were performed. First, an acyclic analogue of the
coumarin (6) was subjected to the standard reaction conditions for
decarboxylative allylation of coumarins, and it did not produce any
product (eq 1). While the reaction with the acyclic derivative failed,
pyrone (7) reacts to form the product of decarboxylative coupling
(8) under identical conditions to those used in the coumarin
coupling (eq 2).13 Thus, the benzenoid ring of the coumarin is not
required for reactivity. Lastly, the isomeric chromone derivative 9
provided coupling product (10) in good yield (eq 3), showing that
In conclusion, we have developed an exceptionally mild
decarboxylative sp2-sp3 coupling that results in the allylation
of pharmacologically relevant oxygenated heteroaromatics.
Continuing studies are aimed at elucidating the mechanism of
this transformation in hopes of defining the reasons that
decarboxylative couplings of coumarins and related heteroaro-
matics are so facile.
Acknowledgment. We thank the National Institute of
General Medical Sciences (1R01GM079644) and the KU
Chemical Methodologies and Library Development Center of
Excellence (P50 GM069663).
Supporting Information Available: Experimental proce-
dures and characterization data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(12) (a) Tsuji, J.; Yamakawa, T.; Kaito, M.; Mandai, T. Tetrahedron
Lett. 1978, 2075. (b) Shimizu, I. In Handbook of Organopalladium
Chemistry for Organic Synthesis; Negishi, E.-i., Ed.; Wiley: New York,
2002; p 1981.
(13) 3-Allylpyrone was previously synthesized in comparable yield via
stoichiometric copper coupling. Posner, G. H.; Harrison, W.; Wettlaufer,
D. G. J. Org. Chem. 1985, 50, 5041.
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Org. Lett., Vol. 11, No. 15, 2009