Palladium-Catalyzed Double-Decarboxylative Addition to Pyrones: Synthesis of Conjugated Dienoic Esters

Article abstract of DOI:10.1021/acs.orglett.5b02308

An interceptive decarboxylative allylation protocol has been developed utilizing pyrone as a C4 synthon. This palladium-catalyzed transformation difunctionalizes the pyrone moiety by in situ generation and activation of both the electrophile and nucleophi

Full text of DOI:10.1021/acs.orglett.5b02308

Letter
pubs.acs.org/OrgLett
Palladium-Catalyzed Double-Decarboxylative Addition to Pyrones:
Synthesis of Conjugated Dienoic Esters
Tapan Maji and Jon A. Tunge*
Department of Chemistry, The University of Kansas, 2010 Malott Hall, 1251 Wescoe Hall Drive, Lawrence, Kansas 66045, United
States
S
* Supporting Information
ABSTRACT: An interceptive decarboxylative allylation protocol has
been developed utilizing pyrone as a C4 synthon. This palladium-
catalyzed transformation difunctionalizes the pyrone moiety by in situ
generation and activation of both the electrophile and nucleophile via
a double decarboxylation pathway. Ultimately, allyl carbonates react
smoothly with 2-carboxypyrone under mild reaction conditions to
generate synthetically useful acyclic dienoic esters, forming carbon dioxide as the sole byproduct.
yrones are well-known as C4 synthons, particularly in
high electrophilicity.4 Second, the nucleophile that is generated
PDiels−Alder reactions, where cycloaddition is followed by by decarboxylation of the allyl ester should not react (or react
decarboxylation.1 However, the use of pyrones as a C4
very slowly) with the π-allylpalladium electrophile to allow
“interception” by the pyrone (Scheme 2). Since palladium-π-
equivalent outside the realm of cycloadditions is much more
rare.2 Nonetheless, 3,6-addition of any nucleophile/electrophile
pair to pyrones could, in principle, give rise to useful acyclic
dienes after decarboxylation (Scheme 1). Herein, we report that
pyrones engage in a unique palladium-catalyzed double-
decarboxylative addition of allyl carbonates to form conjugated
acyclic dienes.
Scheme 2. Interceptive Decarboxylative Allylation of Pyrone
Scheme 1. Decarboxylative Diene Synthesis Concept
allyl complexes are soft electrophiles, we anticipated that hard
anions which react slowly with palladium allyl complexes would
be the best nucleophiles to investigate.5 Thus, allylic
carbonates, which generate alkoxides via decarboxylation,
were seen as ideal reagents for initial investigation.3c
The reaction of methyl 2-pyrone-3-carboxylate 1 with allyl
methyl carbonate (2a) was explored to screen the reaction
conditions using Pd(0) as a catalyst (Table 1). When pyrone 1
was treated with allyl carbonate 2a in the presence of
Pd(PPh3)4 (5 mol %) in dichloromethane at 80 °C, allylated
dienoic ester 3a was generated as a 6.6:1 mixture of geometric
isomers. Separation and isolation of both isomers followed by
spectroscopic analysis6 revealed that E-3a was generated as the
major product in 51% yield (Table 1, entry 1). Altering the
reaction time did not lead to further improvement in the
isolated yield of the diene product (Table 1, entry 2); however,
lowering the temperature to 50 °C provided an improved yield
of product E-3a (60%, entry 3). Unfortunately, further lowering
of the reaction temperature diminished the yield (Table 1,
entry 4) and did not improve the ratio of geometric isomers.
Previously, we and others have demonstrated that good
Michael acceptors can be utilized in interceptive decarbox-
ylative allylation (iDcA, Scheme 1) reactions.3 These reactions
are typically limited to the use of extremely electrophilic olefins,
and benzylidene malonic esters rarely undergo addition. Thus,
the combination of decarboxylative addition to pyrones with
iDcA reactions required careful consideration. To begin, we
chose to focus on reactions of 2-carboxypyrones due to their
Received: August 8, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b02308
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Letter
Table 1. Optimization of Reaction Conditions
Table 2. Palladium(0)-Catalyzed Allylation
yield
a
temp
(°C)
(%)
entry
1
Pd source
ligand
none
solvent
CH2Cl2
E-3a
Pd(PPh3)4
5 mol %
80
51
b
2
Pd(PPh3)4
5 mol %
none
none
none
none
none
none
CH2Cl2
CH2Cl2
CH2Cl2
1,4-dioxane
toluene
toluene
toluene
toluene
80
50
40
50
50
50
50
50
50
52
60
49
63
69
3
Pd(PPh3)4
5 mol %
4
Pd(PPh3)4
5 mol %
5
Pd(PPh3)4
5 mol %
6
Pd(PPh3)4
5 mol %
c
7
8
Pd(PPh3)4
2.5 mol %
68 (4)
Pd2(dba)3
3 mol %
xantphos
6 mol %
14
6
9
Pd2(dba)3
3 mol %
rac. BINAP
6 mol %
c
10
CpPdallyl
3 mol %
dppf 6 mol % toluene
19 (22)
a
Isolated yield of E-3a after purification by column chromatography
b
c
on SiO2. Isolated yield of E-3a after 4 h. Numbers in parentheses are
the isolated yield of Z-3a.
For continued reaction optimization, different solvents were
also evaluated. Doing so revealed that toluene was the best
solvent for this transformation (cf. entries 5 and 6) and allowed
lowering the catalyst loading to 2.5 mol % without sacrificing
yield (entry 7). Lastly, other catalyst and ligand combinations
were briefly examined (entries 8−10); however, none were as
efficient as Pd(PPh3)4. Nonetheless, it is notable that the
combination of CpPd(allyl) and diphenylphosphinoferrocene
(dppf) generated the Z-3a as the major diastereomer (entry
10), indicating some catalyst control of the olefin stereo-
chemistry.
Having found an effective protocol for the double
decarboxylative allylation of pyrone 1, the scope of the reaction
was explored using different allyl carbonates under the
optimized conditions (1 equiv of 1, 1.2 equiv of 2, 2.5 mol %
of Pd(PPh3)4, toluene at 50 °C for 1.5 h). Under these
conditions, regardless of the substitution pattern, allyl methyl
carbonates 2 couple with pyrone 1 to provide the conjugated
1,3 dienoic ester derivatives E-3a−l in moderate to good
isolated yields (Table 2). Analysis of the crude reaction
mixtures showed uniform E-selectivity, but the E/Z ratio varied
from moderate (3.8:1, entry 5) to good (9.1:1, entry 4).
Fortunately, the geometric isomers were separable via column
chromatography. For example, the commercially available
carbonate 2a provided 68% isolated yield of E-3a (Table 2,
entry 1) along with a 4% isolated yield of isomeric Z-3a. Both
aliphatic (2a−h) and aromatic (2i−l) allyl carbonates undergo
the coupling, with cinnamyl carbonates (2j−l), giving higher
yields of E-dienoate products. The intermediacy of palldium-π-
allyl intermediates is supported by the fact that isomeric
primary and secondary allyl carbonates react to provide the
a
E/Z ratio detremined by 1H NMR spectroscopy of the crude reaction
b
c
mixture. Isolated yield of E-3 after purification. Isolated yield of Z-3a
was 4%. Inseparable 1:1 mixture.
d
same linear allylation product (E-3c) in comparable yield
(entries 3 and 4, Table 2). Similarly, a pentadienyl carbonate
gives the linear diene 3f as an inseparable mixture of cis/trans
isomers about the terminal diene (entry 7). Notably, 3-
cyclopropyl allyl carbonate was also a suitable coupling partner
for this method (entry 5), while a cyclic secondary allyl
carbonate provided the allylated product E-3g in poor yield.
We next investigated the scope of nucleophiles that
participate in the reaction by use of various allylic carbonates
and carbamates (Scheme 3). While methoxide, ethoxide, and
tert-butoxide were all effective nucleophiles for the trans-
formation, the E/Z selectivity decreased with the bulkier tert-
butoxide nucleophile (E-3a, E-3m, and E-3n, Scheme 3). It is
noteworthy that transesterification does not occur, and the
methyl ester of the pyrone remains intact when ethoxide or tert-
butoxide nucleophiles are utilized. Expectedly, attempts to
couple a much softer phenoxide nucleophile7 failed to provide
the product of interceptive coupling. Instead, typical decarbox-
ylative coupling took place to form the O-allylated product 4a
(Scheme 3).3b,8 After demonstrating the feasibility of utilizing
allylic carbonates, the more difficult task of allylation employing
allylic carbamates was addressed.9 An allylic carbamate derived
B
DOI: 10.1021/acs.orglett.5b02308
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Letter
Scheme 3. Scope of Nucleophiles
Scheme 5. Possible Mechanism
alkoxide nucleophile.12 While it may be possible for the
alkoxide to react with the pyrone (Scheme 2), we favor a
mechanism involving prior allylation of the pyrone to generate
intermediate C on the basis of observations made by
Yamamoto (Scheme 5).3c Nucleophilic trapping of intermedi-
ate C would afford intermediate D. The observed diene then
can be readily formed by oxidative addition of intermediate D
to palladium to form E. Subsequent decarboxylative elimination
would provide the diene and regenerate the palladium
catalyst.3b,13 Alternatively, one could envision a direct retro-
cycloaddition of CO2 from intermediate D; however, related
decarboxylations require substantially higher temperatures than
those employed in our reaction.1c−f,14 Thus, we favor a metal-
catalyzed decarboxylation process.
a
b
Isolated yield of E-3 after column chromatography. Determined by
1H NMR spectroscopy of the crude reaction mixture.
from pyrrole indeed reacted with 1 under our standard reaction
conditions to deliver the corresponding allylated product E-3o,
albeit in low yield (Scheme 3). Although the yield of E-3o was
not significant, the demonstrated reactivity of the allyl
carbamate prompted us to test a related imidazole-derived
allylic carbamate. This substrate formed the desired product in
better yield; however, the yield was still low (E-3p).
We envisioned a further extension of the scope of this new
protocol by utilizing diallyl carbonates, which should generate
the O-allyl product A (Scheme 4). Interestingly, the reaction of
In conclusion, we have developed a double decarboxylative
coupling of allylic carbonates and 2-carboxypyrone. This is a
rare example of the use of a pyrone as an acyclic diene source.
The protocol constitutes a practical, user-friendly, and opera-
tionally simple strategy for the synthesis of a variety of donor−
acceptor conjugated dienes in a short reaction time. The
process is highlighted by its double decarboxylation pathway
which leads to the formation of dieneoate products with carbon
dioxide as the only byproduct. Dienoic esters obtained by this
method can serve as effective substrates for 1,6-conjugate
addition reactions.15
Scheme 4. Allylation with Diallylic Carbonate
a
ASSOCIATED CONTENT
* Supporting Information
Combined yield
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b02308.
1 and 2q did not provide the expected product A, but instead
formed a 1:3.5 mixture of C-allylated aldehydes 3q and 3q′.
The observation of these products suggests that A underwent
rearrangement. The observed products could have arisen via
Claisen (3q) and Claisen/Cope (3q′) rearrangement sequen-
ces, or alternatively, both products could arise from a
palladium-catalyzed rearrangement that proceeds through
intermediate B (Scheme 4).10 To distinguish between these
mechanisms, a substituted diallyl carbonate 2r was allowed to
react under identical conditions. In this case products 3r/3r′
were formed. The linear allyl regiochemistry of 3r′ cannot arise
from a concerted Claisen rearrangement of A; however, this
regiochemistry is consistent with a palladium-catalyzed
rearrangement mechanism where attack on the palldium-π-
allyl complex preferentially occurs at the less substituted carbon
(Scheme 4).7a
Although a detailed mechanistic picture of the double-
decarboxylative addition to 2-carboxypyrone requires further
studies, the above-mentioned experimental results and
literature reports3c,11 suggest a logical catalytic pathway for
the formation of dienoates 3 (Scheme 5). It is likely that the
allylic carbonate undergoes oxidative addition to Pd(0) to
generate a π-allyl-Pd complex and, after decarboxylation, an
Experimental procedures and characterization data for all
new compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: tunge@ku.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Support for this research was provided by the National Science
Foundation (CHE-1465172) and the Kansas Bioscience
Authority Rising Star Program.
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