Palladium-catalyzed decarboxylative sp3-sp3 coupling of nitrobenzene acetic esters

Article abstract of DOI:10.1021/ja077070r

Allylic esters of nitrobenzene acetic acids undergo facile palladium-catalyzed decarboxylative coupling. Both mono- and dinitroarene substrates give high yields of the coupled products. Moreover, the rates of the reactions suggest that decarboxylation is

Full text of DOI:10.1021/ja077070r

Published on Web 11/08/2007
Palladium-Catalyzed Decarboxylative sp3-sp3 Coupling of Nitrobenzene
Acetic Esters
Shelli R. Waetzig and Jon A. Tunge*
Department of Chemistry, The UniVersity of Kansas, 2010 Malott Hall, 1251 Wescoe Hall DriVe,
Lawrence, Kansas 66045
Received September 12, 2007; E-mail: tunge@ku.edu
Table 1. Catalyst and Ligand Screening
Nitroarenes are important intermediates in the synthesis of
polymers, azo dyes, and pharmaceuticals such as Viagra, Zyvox,
and Angerase.1 Thus, it is expected that the development of new
methods for the cross-couplings of nitroarenes will facilitate
synthesis of heterocycles that are prevalent in pharmaceuticals.
Recently, interest in the area of decarboxylative coupling has
grown, in part because these reactions occur under neutral conditions
and avoid the use of reagents that are typically necessary for trans-
metalation.2 For example, Gooâen and co-workers have reported a
Pd(II)-catalyzed coupling of nitrobenzoic acids with haloaromatics
to generate biaryl products.3 Furthermore, Myers has shown a Pd-
(II)-catalyzed decarboxylative variant of the Heck reaction.4 While
these advancements represent significant accomplishments in the
field of palladium-catalyzed coupling of sp2-hybridized carbons,
catalysis of the decarboxylative coupling of sp3-hybridized carbons
remains a significant challenge. Current methods for sp3-sp3
coupling are limited by the requirement for a stoichiometric
organometallic that is necessary to effect transmetalation.5
entry
R
catalyst/Ln
temp (
°
C)
2/3a
1
2
3
4
5
6
o-NO2
o-NO2
o-NO2
p-NO2
p-NO2
p-NO2
Pd(PPh3)4
Pd(PPh3)4
Pd2dba3/rac-BINAP
Pd2dba3/rac-BINAP
Pd2dba3/dppe
25
110
110
110
110
110
NR
1.8:1
100:0
4.9:1
2:1
Pd2dba3/dppf
1.6:1
a Ratios determined by 1H NMR spectroscopy of crude reaction mixtures.
Table 2. Decarboxylative Coupling of Substituted
Nitrophenylacetic Estersa
We recently demonstrated the Pd-catalyzed decarboxylative
benzylic coupling of nitrogen-containing heteroaromatics with allyl
electrophiles (eq 1).6 This reaction proceeded by a unique allylation/
aza-Cope rearrangement that did not translate to more general
benzylic couplings. Herein, we report a new method for the
decarboxylative coupling of nitrobenzene acetic esters.
To begin, both o- and p-nitrophenylacetic esters were synthesized
to screen different catalyst/ligand combinations for activity (Table 1).
Although the reaction failed to produce any product at ambient
temperature, increasing the temperature to 110 °C readily promoted
decarboxylation in the presence of the palladium catalysts; however,
products of aromatic allylation were prevalent. Ultimately, rac-
BINAP proved to be the most selective ligand for benzylic allylation
of both o- and p-nitro benzyl derivatives (entries 3 and 4).
Once standard conditions were determined, a variety of o-nitro-
and p-nitro-substituted aryl substrates were tested (Table 2). All
terminally unsubstituted allyl esters gave clean conversion to the
desired products in high yield. It is noteworthy that functional
groups, such as esters and ketones (1b, 1c), were tolerated and no
products arising from allylation of enolates were observed.7
Furthermore, addition of electron-donating methoxy substituents
did not affect reaction time or yield (Table 2, entry 4).
The fact that R-mono- and R,R-disubstituted p-nitrophenyl acetic
esters (1f-h) underwent facile decarboxylative coupling indicates
that decarboxylation must precede CsC bond formation.8 Interest-
ingly, decarboxylative coupling of o-nitrophenyl acetic esters is
limited to substrates that are R-monosubstituted; treatment of 1i to
a Conditions: 0.3 mmol substrate, 0.0075 mmol Pd2dba3, 0.015 mol rac-
BINAP, 3 mL toluene, 110 °C, 1-3 h. b Pd(PPh3)4 used as catalyst.
9
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J. AM. CHEM. SOC. 2007, 129, 14860-14861
10.1021/ja077070r CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Table 3. Decarboxylative Coupling of Dinitrophenyl Acetic Estersa
competing elimination (entry 2). However, functional group
compatibility similar to that observed for the mononitroarene
complexes was maintained (entry 5). Moreover, the reactions were
facile at ambient temperature; all starting material was consumed
within 3 h. The fact that the rate of the reaction increases with
increased stability of the benzylic anion suggests that the rate-
limiting step of catalysis is decarboxylation.
The utility of nitroarenes in pharmaceutical synthesis lies in their
facile reduction to anilines. For example, decarboxylative coupling
can be followed by reductive cyclization to afford dihydroquino-
lones or quinolines (eq 3). Thus, the coupling of decarboxylative
allylation with nitro reduction allows the synthesis of alkylated
heterocycles that are common in biologically active molecules.
In conclusion, a new method for catalytic sp3-sp3 coupling has
been developed that is based on the facile decarboxylative coupling
of nitrobenzene acetic esters. The process occurs under neutral
conditions and does not require reagents that are typically needed
for transmetalation.
a Conditions: 0.3 mmol substrate, 0.015 mol Pd(PPh3)4, toluene, room
temp, 1-3 h. b Linear/branched ratio ) 1.5:1.
the standard conditions of catalysis produced no product nor
degradation of starting material (eq 2).9
Acknowledgment. We thank the National Institute of General
Medical Sciences (1R01GM079644) and the National Science
Foundation (CHE-0548081) for funding.
Supporting Information Available: Experimental procedures and
characterization data for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
It can be reasoned that for decarboxylation to occur, the carboxylate
must align perpendicular to the electron-accepting arene. This results
in a high energy conformation where there is significant A-strain
(A), thus precluding decarboxylation. Since this steric hindrance
is not present when the p-nitro group is employed, decarboxylation
of those substrates can be achieved.
While the previous examples have focused on terminally
unsubstituted allyl electrophiles, the coupling of alkyl-substituted
allyl groups is also desirable. Unfortunately, when ester 1e was
synthesized and subjected to the standard reaction conditions, the
reaction did not proceed (Table 1). The reaction did proceed when
Pd(PPh3)4 was employed as the catalyst; however, elimination to
form 1,3-pentadiene was prevalent.
The hypothesis that elimination was favored because the
intermediate benzylic anion was too basic led us to believe that
dinitroarene substrates would be suitable for coupling with substi-
tuted allyl electrophiles (Table 3). While the previously optimized
reaction conditions failed to produce clean reaction mixtures with
the dinitroarene substrates, Pd(PPh3)4 was found to be a very
efficient catalyst. Under these conditions, alkyl- and aryl-substituted
allyl electrophiles (1j, 1l) undergo smooth decarboxylative coupling
with the dinitroarene reactants. For example, when employing 1j,
no elimination products were observed and a 95% yield was
obtained; no decarboxylative coupling product was observed with
the related mononitrobenzyl ester (1e). Unfortunately, the coupling
of a prenyl-substituted allyl ester still led to low yields owing to
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