Migratory decarboxylative coupling of coumarins: Synthetic and mechanistic aspects

Article abstract of DOI:10.1002/anie.201100765

On the move: Decarboxylative coupling of allyl 4-methyl-3-carboxycoumarins provides the products of γ-allylation of the methyl group rather than the typical regiospecific α-allylation. Mechanistic studies show that intramolecular proton transfer from the 4-methyl group to the 3-carboxylate allows allylation of the remote methyl group. The resulting 4-butenyl-3-carboxyl coumarin undergoes Pd⁰-catalyzed decarboxylation to provide the observed products (see scheme). Copyright

Full text of DOI:10.1002/anie.201100765

DOI: 10.1002/anie.201100765
Allylation
Migratory Decarboxylative Coupling of Coumarins: Synthetic and
Mechanistic Aspects**
Ranjan Jana, James J. Partridge, and Jon A. Tunge*
of the expected allylation of the 3-position of the coumarin.[6]
In every other case of decarboxylative coupling that we have
investigated, allylation occurs regiospecifically at the site that
bears the carboxylate.[10] Thus, the observation of remote
decarboxylative allylation warranted further investigation.
Herein, we report that many other substituted coumarins
exhibit similar regiochemistry in their allylation and we
present a mechanism that explains this unusual regiochemical
outcome.
À
Construction of new C C bonds by decarboxylative coupling
is a powerful synthetic method since it avoids highly basic
reaction conditions and preformed organometallic reagents
that produce stoichiometric metal waste.[1] In addition, the
byproduct (CO2) is nontoxic and requires no special separa-
tion procedures. Thus several research groups have demon-
strated that decarboxylative couplings are practical alterna-
tives to standard cross-coupling reactions.[1–6] For example,
Gooßen and co-workers have reported a PdII-catalyzed
coupling of benzoic acids with haloaromatics to generate
biaryl products.[3] Furthermore, Myers et al. have shown a
PdII-catalyzed decarboxylative variant of the Heck reaction.[4]
Our research has focused on the development of decarbox-
ylative allylation and benzylation reactions.[5] In this arena we
have reported the decarboxylative allylation (DcA) of
heteroaromatic coumarin substrates under mild conditions
[Eq. (1)].[6]
Encouraged by the unexpected regiochemistry of allyla-
tion, we optimized the reaction conditions with the goal of
suppressing the undesired protonation product (3a). After
rigorous catalyst and solvent screening (Table 1) it was found
Table 1: Optimization of reaction conditions.[a]
Coumarins are not only “privileged” scaffolds of biolog-
ical and pharmaceutical interest,[7,8] but they are also widely
used in dyes because of their photophysical properties.[9] In
our continuing investigations of the DcA of coumarins, we
turned our attention to the investigation of decarboxylative
couplings of 4-substituted coumarins. Thus, 4-methyl-3-allyl-
coumarate 1a was synthesized and subjected to our previous
conditions for Pd0-catalyzed decarboxylative coupling at
508C.[6] Disappointingly, the starting material remained
intact even after prolonged heating. However, upon heating
the substrate at 1108C in toluene for 6 h, we observed
Entry
Catalyst[b]
Solvent[b]
Yield
[%][c]
2a:3a[c]
1
2
3
4
5
5 mol% [Pd(PPh3)4]
5 mol% [Pd(PPh3)4]
5 mol% [Pd(PPh3)4]
5 mol% [Pd(PPh3)4]
3 mol% [Pd2(dba)3],
6 mol% dppe
[D8]tol
99
65
95
87
75
77:23
63:37
80:20
83:17
70:30
CD3CN
[D7]DMF
[D8]THF
[D8]tol
À
decarboxylation and C C bond formation (2a) as well as
6
3 mol% [Pd2(dba)3],
6 mol% dppb
[D8]tol
[D8]tol
[D8]tol
[D7]DMF
[D8]tol
67
77
99
80
75
77:23
70:30
94:6
protiodecarboxylation [Eq. (2)]. Closer analysis of the prod-
ucts by 1H NMR spectroscopy revealed that allylation occurs
at the methyl terminus providing 4-homoallylcoumarin in lieu
7
3 mol% [Pd2(dba)3],
6 mol% rac-BINAP
3 mol% [Pd2(dba)3],
6 mol% Xantphos
3 mol% [Pd2(dba)3],
6 mol% Xantphos
3 mol% [Pd2(dba)3],
6 mol% dppf
8
9
80:20
72:28
[*] R. Jana, J. J. Partridge, Prof. J. A. Tunge
Department of Chemistry, University of Kansas
1251 Wescoe Hall Drive, Lawrence, KS 66045-7582 (USA)
Fax: (+1)785-864-5396
10
E-mail: tunge@ku.edu
Homepage: http://www.tunge.ku.edu
[a] All reactions were carried out at 708C for 12 h, 0.1 mmol scale, 0.2m.
[b] dba=dibenzylideneacetone; dppe=1,2-bis(diphenylphosphino)-
[**] This work was supported by the National Institute of General
Medical Sciences (NIGMS 1R01M079644).
ethane; dppb=1,4-bis(diphenylphosphino)butane; BINAP=2,2’-bis(di-
phenylphosphino)-1,1’-binaphthyl; dppf=1,1’-bis(diphenylphosphino)-
ferrocene; tol=toluene. [c] Yields and product distributions were
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201100765.
1
determined by H NMR spectroscopy.
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that 3 mol% [Pd2(dba)3] in combination with 6 mol%
Xantphos provided excellent yields of 4-butenylcoumarin
(2a) when allowed to react with substrate 1a in toluene at
708C.
Under the optimized reaction conditions, we explored the
substrate scope for this decarboxylative allylation reaction
(Table 2). A wide variety of 4-methyl-3-allylcoumarates with
substitution on arene were synthesized and examined.
Gratifyingly, it was found that a variety of aryl substitutions
Table 2: Migratory decarboxylative allylation.
well. Toward this end, the 4-ethyl-substituted substrate 1l was
prepared and allowed to react under our standard reaction
conditions. Interestingly, the substrate underwent typical site-
specific allylation as previously reported.[6] Thus, it appears
that sterics disfavor the mechanism by which the 4-alkyl group
is allylated. Similarly, substrate 1m did not undergo remote
allylation of the methyl group, rather it underwent a-
allylation to give (2m) along with the diallylation to give 2m’.
At the outset, several mechanisms seemed reasonable for
the formation of the remotely allylated coumarins such as 2a.
First, decarboxylative metalation could produce an aryl
palladium species that is capable of undergoing a 1,3-
migration (path a; Scheme 2).[11] Alternatively, the intermedi-
ate carboxylate may deprotonate the methyl group to
generate a stabilized malonic acid dienolate. Such a proposal
is reasonable given that the pKa values of carboxylates (ca. 12
in DMSO) and malonates (ca. 14 in DMSO) are compara-
ble.[12] Allylation and decarboxylation would then produce
2a. Lastly, the observation of the diallylated product (2m’,
Scheme 1) suggested that the allylation of the methyl group
might be proceeding through an a-allylation/Cope rearrange-
ment mechanism (path c, Scheme 2).[13]
Product
Yield
[%][a]
Product
Yield
[%][a]
90
88
90
87
93
90
92
93
92
92
90
[a] Yields of isolated products for reactions performed at 0.2m on a
0.5 mmol scale.
allow formation of coupling products in excellent yields,
irrespective of the electronics. Even halogen substituents,
such as Br, are compatible with our coupling conditions (2d,
2g, 2k, Table 2). Thus, one-pot decarboxylative allylation/
cross-coupling reactions are feasible [Eq. (3)]. In addition to
the couplings of unsubstituted allyl esters, a variety of
substituted and functionalized allyl esters undergo coupling
to provide products in excellent yields. However, one
limitation of the reaction is that allyl esters that possess b-
hydrogens preferentially form elimination products [Eq. (4)].
Since the successful substrates for the remote allylation
were 4-methyl substituted, we became curious whether larger
4-alkyl groups would participate in migratory allylation as
Scheme 1. Sterics inhibit migration.
The mechanism illustrated by path c (Scheme 2) is easily
probed, since such a mechanism predicts that a substituted
allyl ester will react to form the branched allylated product
rather than the linear product.[5e,14] To test this, the coumaryl
cinnamyl ester 1n was treated with Pd catalyst [Eq. (5)]. The
resulting product forms in high yield with a 83:17 linear/
branched (l:b) ratio. The regioselective formation of the
linear allylated product, 2n, suggests that the methyl group is
directly allylated and that a-allylation/Cope rearrangement is
not the dominant mechanism for product formation. How-
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In addition to the observation of crossover, some mech-
anistic insight was obtained from the preparation of the
requisite deuterated coumarin ([D3]-1a). Specifically, it was
observed that treatment of the allyl ester 1a with K2CO3 and
D2O did not lead to any appreciable deuterium incorporation
(Scheme 3). However, treatment of the carboxylic acid under
the same conditions led to extensive deuterium incorporation.
Thus, the carboxylate group is necessary to facilitate depro-
tonation of the 4-methyl coumarin.
Scheme 2. a-Allylation versus g-allylation.
ever, most decarboxylative cinnamylations provide product
with l:b ratios of > 95:5,[2a,g,5f,h,6,15] so the relatively low
selectivity in this case may indicate a minor contribution of
the allylation/Cope rearrangement mechanism.
Scheme 3. Carboxylate-assisted deuteration.
While the observations of extensive crossover and car-
boxylate-assisted deprotonation seemed to implicate a mech-
anism that follows path b, path a could not be ruled out based
on these experiments alone. The mechanistic ambiguity was
further clarified by a simple but crucial experiment. When a
typical reaction was arrested after 2 h, the g-allylated, a-
coumaric acid 5 f was isolated in good yield. When the
coumaric acid 5 f was resubjected to the reaction conditions,
the decarboxylated g-allylation product 2 f was obtained
(Scheme 4).
With the above information in hand, further mechanistic
studies were necessary to refine our mechanistic hypothesis.
To begin, a deuterium-labeling study was performed to
determine the origin of proton that comes at the a-carbon
after decarboxylation. Toward this end, [D3]-1a was prepared
and allowed to undergo decarboxylative coupling. The a-
carbon of the resulting product was 75% deuterated at the a-
position. Thus, deuterium is clearly transferred from the
methyl group to the a-carbon.
Next, a crossover experiment showed extensive crossover
between the deuterated reactant [D3]-1a and a protiocou-
marin [Eq. (7)].
Scheme 4. Isolation of an intermediate.
It is noteworthy that a PdII source, Pd(OAc)2, failed to
catalyze decarboxylation of 5 f under the reaction condi-
tions.[2b,d,14] However, Pd0 sources such as [Pd(PPh3)4] and
[Pd2(dba)3]/Xantphos were effective catalysts for decarbox-
ylation of 5 f. Thus, it appears that decarboxylation is
catalyzed by Pd0.
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Communications
See the Supporting Information for full experimental procedures
and 1H NMR, 13C NMR, and GC–MS data.
Combination of all of the mechanistic studies suggests the
following mechanism for this unusual decarboxylative g-
allylation. First palladium undergoes oxidative addition to
form a p-allyl palladium complex and the coumarin carbox-
ylate counterion. Then 1,5-proton transfer occurs to generate
a stabilized carbanion at the methyl terminus. Next, nucleo-
philic substitution of the p-allyl palladium complex forms the
Received: January 29, 2011
Revised: March 3, 2011
Published online: April 19, 2011
Keywords: g-allylation · coumarins · decarboxylative coupling ·
.
À
À
C C bond. The C C bond could form by nucleophilic attack
on the allyl ligand from the stabilized carbanion (Scheme 5)
regiospecificity
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Scheme 5. Mechanistic pathway of g-allylation.
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À
that can undergo decarboxylation followed by C H bond
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Experimental Section
General procedure for the palladium-catalyzed decarboxylative g-
allylation of 3-allylcoumarates: In an oven-dried Schlenk flask, 1a
(0.50 mmol) was dissolved in toluene (2.5 mL) under argon followed
by the addition of [Pd2(dba)3] (0.015 mmol, 3 mol%) and Xantphos
(0.03 mmol, 6 mol%). The resulting reaction mixture was heated at
708C for 12 h. The solution was then concentrated on a rotary
evaporator and the residue was purified directly by flash chromatog-
raphy on silica gel (EtOAc/hexane 20:80).
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