Decarboxylative allylations of ester enolate equivalents

Article abstract of DOI:10.1039/c4ob01752h

A variety of ester enolate equivalents are generated in situ and undergo α-allylation in high yields via palladium-catalyzed decarboxylative allylation. The transformations are complete within very short reaction times under ambient conditions. Synthesis of α-allylated acyl derivatives provides access to other carboxylic acid and alcohol derivatives via acyl group substitution or reduction. This journal is

Full text of DOI:10.1039/c4ob01752h

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Decarboxylative allylations of ester enolate
equivalents†
Cite this: Org. Biomol. Chem., 2014,
12, 8386
Yamuna Ariyarathna and Jon A. Tunge*
Received 15th August 2014,
Accepted 12th September 2014
DOI: 10.1039/c4ob01752h
www.rsc.org/obc
A variety of ester enolate equivalents are generated in situ and
undergo α-allylation in high yields via palladium-catalyzed de-
carboxylative allylation. The transformations are complete within
very short reaction times under ambient conditions. Synthesis of
α-allylated acyl derivatives provides access to other carboxylic acid
and alcohol derivatives via acyl group substitution or reduction.
Allylation of nucleophiles via palladium-catalyzed decarboxyla-
tive allylation is a chemically mild and environmentally benign
approach to produce allylic amines, ketones, nitriles and
nitroalkanes.1 While the α-allylation of ketone enolates has
received significant attention, preparation of α-allylic esters via
decarboxylative allylation is comparatively difficult and
demands harsher conditions.1b,2 In 2007, Ohta and coworkers
reported a palladium-catalyzed decarboxylative allylation of
diallyl malonates under milder conditions.2a However, the
reported method is restricted to malonates with an α-aryl
group; no reaction with diallyl 2,2-dialkylmalonates was obser-
ved.2a More recently, Miller showed that allyl 2,2,2-trifluoroethyl
malonates allow the α-allylation of esters, however the reported
chemistry was limited to α-unsubstituted malonates.2c,3 To
allow the allylation of α-monosubstituted ester enolate equiva-
lents, Trost has also utilized 2-imidazolo-substituted enol car-
bonate reactants.2d However, the imidazole leaving group must
be activated by alkylation prior to substitution.4 Herein, we
report the decarboxylative allylation of ester enolate equivalents
utilizing synthetically flexible β-dicarbonyl reactants that
undergo substitution without prior activation (Scheme 1).
Scheme 1
Table 1 Screening of catalysts
Yielda
(%)
Entry
Catalyst, ligand
Solvent
1
2
3
4
Pd(PPh3)4
Pd(PPh3)4
C6H6
THF
C6H6
C6H6
97
90
97
90
Pd2dba3, dppf
CpPd(allyl), dppf
a Isolated yield.
Our initial studies were focused on allylation of acyl pyr-
roles. To our delight 1 underwent decarboxylative allylation
quickly and cleanly with 10 mol% of Pd(PPh3)4 within
25 minutes (Table 1, entry 1). Furthermore, it was found that
the reaction could be carried out in THF solvent or with other
palladium sources such as Pd2dba3 and CpPd(allyl) in the
presence of dppf ligand (Table 1, entries 3 and 4).
As expected, the acylpyrrole products are excellent precur-
sors for further derivatization.5 Evans,5a,b Fu5c and Arai5d have
shown that N-acyl pyrroles undergo acyl substitution with
water, alcohols and amines to produce acids, esters and
amides. Our acylpyrrole derivative behaves similarly, allowing
transformation to a tertiary alcohol, primary alcohol and car-
boxylic acid in high yields (Scheme 2).
The University of Kansas Department of Chemistry, 2010 Malott Hall,
1251 Wescoe Hall Dr, Lawrence KS 66045, USA. E-mail: tunge@ku.edu
†Electronic supplementary information (ESI) available: Full characterization of
all new compounds, spectra of all new compounds, crystal structure file (CIF) of
1c. CCDC 1019501. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/c4ob01752h
Having established a successful method for decarboxylative
α-allylation of an acyl pyrrole, we chose to investigate the
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Table 2 Diastereoselective DcA
Scheme 2
a After recrystallization. b drs based on 1H NMR spectroscopic analysis
of the crude reaction mixtures.
Scheme 3
enantioselectivity of the reaction with Pd2dba3 using various
chiral non-racemic ligands such as (S)-QUINAP, (R)-BINAP,
(S)-tBu-PHOX, and TROST ligands. Even though the conver-
sions are excellent with these ligands, the observed enantio-
meric excesses were low. The maximum enantiomeric excess
(49% ee) was observed using the (R,R)-anden-phenyl Trost
ligand at −40 °C in toluene (Scheme 3). Since it is known that
enolates with a defined geometry undergo highly enantio-
Fig. 1 Stereochemical rationale.
selective allylation,2d,6,7 our relatively low ee is most easily whether other ester/amide enolate equivalents would partici-
explained by a low E/Z selectivity in generation of the enolate.
pate in decarboxylative allylation. Indeed, other amide enolates
Having investigated catalyst control of the product stereo- such as pyrrole-2-carbonitrile, indole, and indole-5-carbonitrile
chemistry, we turned our attention to investigation of substrate undergo high-yielding allylation in just 10–15 minutes at room
control of the stereoselectivity. Several acyl oxazolidinone reac- temperature (Table 3, entries 2–4) while somewhat less reac-
tants were synthesized and subjected to conditions for decar- tive, a Weinreb amide enolate underwent allylation with
boxylative allylation. Gratifyingly, all of them underwent Pd2dba3 in the presence of dppf ligand at 80 °C in high yield
decarboxylative allylation within 30 minutes, giving good (Table 3, entry 5). A phenyl ester enolate also underwent decar-
yields of product (Table 2). While the yields are good, the use boxylative allylation in high yield (entry 6), while an aryl thio-
of chiral auxiliaries only led to modest improvement in stereo- ester enolate provided product in only moderate yield (57%,
control, with the maximum diastereoselectivity being 85 : 15. entry 7). Lastly, it was found that the methodology could be
Nonetheless, this is the highest stereoselectivity achieved for successfully applied toward the allylation of α,α-dialkyl sub-
the decarboxylative allylation of acyclic β-oxo esters. In one strates (entries 8 and 9). Interestingly, while the α,α-diallyl acyl
case, the major diastereomer of 1c could be obtained diastereo- pyrrole (entry 8) underwent decarboxylative coupling in THF
pure in 53% yield by recrystallization and X-ray crystallo- solvent under ambient conditions, significantly harsher con-
graphic analysis proved the stereochemical outcome of the ditions were required for the allylation of α-methyl, α-ethyl acyl
reaction (Fig. 1). The observed stereochemistry is most easily pyrrole amide enolate (2i). Nonetheless, each product was iso-
explained based on an inner-sphere allylation8 based on Evans lated in high yield.
chiral auxiliary model (Fig. 1).9,10
Next the substrate scope of decarboxylative allylation of
Having shown that acyl pyrroles and acyl oxazolidinones phenyl ester enolates was examined using easily substituted
undergo efficient decarboxylative allylation, we became curious dimethylphenyl esters (Table 4). Among α-monosubstituted
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Table 3 DcA of ester enolate equivalents
Time
(min)
Yielda,e
(%)
Time
(min)
Yielda,e
(%)
Entry
1
Product
Entry
6
Product
25
97
60
99
2
3
15
10
81
99
7
8
30
30
57
99c
4
5
10
90
96
9
180
98d
89b
a Pd(PPh3)4 10 mol%, C6H6, rt, 0.03 M. b Pd2dba3 10 mol%, dppf 10 mol%, C6H6, 80 °C, 0.03 M. c Pd(PPh3)4 10 mol%, THF, rt, 0.03 M. d Pd2dba3
5 mol%, dppf 10 mol%, toluene, 110 °C, 0.03 M. e Isolated yield.
Table 4 DcA of ester enolate equivalents
Time
(min)
Yielda,c
(%)
Time
(min)
Yielda,c
(%)
Entry
1
Product
Entry
5
Product
15
95b
60
93
2
3
4
120
300
180
97
92
95
6
7
8
15
60
99b
99b
82b
360
a Pd2dba3 5 mol%, dppf 10 mol%, toluene, 110 °C, 0.03 M. b Pd(PPh3)4 10 mol%, C6H6, rt, 0.03 M. c Isolated yield.
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phenolic ester substrates, an α-phenyl aryl ester (entry 1)
underwent allylation smoothly with Pd(PPh3)4 in 15 minutes
under ambient conditions, while α-methyl substituted aryl
esters (entries 2 and 3) required elevated temperatures and
longer reaction times for reaction completion. In addition,
α,α-dialkyl aryl esters gave good yields under the reported reac-
tion conditions (entries 4 and 5). Lastly, various allyl function-
alities including cinnamyl (3c), β-methallyl (3e) and hexenyl
(3g, h) are well tolerated under the reaction conditions.
3 The mechanism of allylation of α-unsubstituted malonates
is different than the mechanism for allylation of α,α-di-
substituted malonates. See ref. 2b.
4 (a) D. A. Evans, K. R. Fandrick, H.-J. Song, K. A. Scheidt
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6 For reviews on catalytic enantioselective allylation, see:
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Conclusions
In conclusion, we have developed a rapid, high yielding
method for the synthesis of α-allylated ester equivalents. A
wide range of different ester enolates and ester enolate equiva-
lents undergo catalytic allylation under conditions that are
conducive to decarboxylative enolate formation. Importantly,
the method allows the construction of quaternary carbon
centers, although there remains significant room for improve-
ment of the stereoselectivity.
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