Palladium-catalyzed direct carboxylation of aryl bromides with carbon dioxide

Article abstract of DOI:10.1021/ja905264a

(Chemical Equation Presented) A novel protocol for the direct carbon dioxide insertion (CO₂) into aryl halides in a catalytic manner is presented herein. Unlike other carboxylation methods using CO₂, there is no need for the synthesis of the corresponding organometallic intermediates. Additionally, and in contrast to the well-established carbonylation processes, our protocol does not use highly toxic CO for the preparation of benzoic acids. Furthermore, this method is distinguished by its mild conditions, allowing the tolerance of a wide range of functional groups and substitution patterns. The crucial step of the process involves a challenging catalytic CO₂ insertion into Pd-C bonds. Copyright

Full text of DOI:10.1021/ja905264a

Published on Web 10/16/2009
Palladium-Catalyzed Direct Carboxylation of Aryl Bromides with Carbon
Dioxide
Arkaitz Correa and Rube´n Mart´ın*
Institute of Chemical Research of Catalonia (ICIQ), AV. Pa¨ısos Catalans, 16 43007, Tarragona, Spain
Received June 26, 2009; E-mail: rmartinromo@iciq.es
Because of its abundance, low cost, nontoxicity and high potential
as a renewable source, carbon dioxide (CO2) has recently gained
considerable momentum as the ideal C1 source.1 As a result, CO2
fixation has become an active area of research in both academic
and pharmaceutical laboratories.
impact on the reaction outcome. Thus, while DMA and DMF clearly
favored the carboxylation, NMP or DMSO resulted in the exclusive
formation of 3 and 4. Interestingly, the use of diethylacetamide,
structurally related to DMA, led to the preferential formation of 4,
thus indicating the subtleties of this system (entry 12). Substitution
of Et2Zn by other reducing agents had also a deleterious effect,
affording preferentially 3 and 4.9 The best results were finally
obtained by operating at a higher CO2 pressure (10 atm), thus
leading to formation of 2a in 64% isolated yield (entry 13).
Benzoic acids are important motifs found in many natural and
medicinally important compounds.2 In recent years, metal-catalyzed
carbonylation of aryl halides (Scheme 1, route a)3 and carboxylation
of carbon nucleophiles with CO2 (Scheme 1, route b)4,5 have
become powerful alternatives to the classical synthetic approaches
for these compounds. Despite the remarkable advances realized,
the high toxicity associated with CO (route a) as well as the required
synthesis of the employed organometallic reagents (route b) still
represent important issues to be overcome. Ideally, the most
straightforward route to benzoic acids from both a fundamental and
practical point of view would imply the direct CO2 insertion into
aryl halides in a catalytic manner (Scheme 1, route c). To the best
of our knowledge, no examples of this transformation have yet been
reported in the field of homogeneous catalysis.6 Herein, we present
our initial studies on the direct Pd-catalyzed carboxylation of readily
available aryl bromides with CO2.
Table 1. Screening of Reaction Conditionsa
Scheme 1
a 1a (0.5 mmol), Pd(OAc)2 (10 mol %), solvent (0.25 M), CO2
(1 atm), and Et2Zn (1.0 mmol, 1 M in hexanes), 40 °C.b GC yields
using dodecane as internal standard.c Using Pd(OAc)2 (5 mol %).d CO2
(10 atm).e Isolated yield. DEA ) Diethylacetamide.
Prompted by stoichiometric experiments reported by Osakada
and Yamamoto,7 we initially focused our efforts on the conversion
of nonactivated 1a under atmospheric pressure of CO2 using nickel
catalysts. To render the process catalytic we used Et2Zn as the
reducing agent, a similar strategy that has been described by
Iwasawa,8a Rovis,8b and Mori4a,8c,d for the efficient carboxylation
of pronucleophiles with CO2. After considerable experimentation,
the targeted benzoic acid 2a was obtained, albeit in low yields.9 In
striking contrast, Pd-based catalysts proved to be more promising
for the transformation highlighted in Scheme 1 (route c). Therefore,
the effect of variables such as palladium precatalyst, ligand, solvent,
and temperature were systematically examined (Table 1).9 In all
cases studied, significant amounts of dehalogenated and Negishi-
type products, 3 and 4, respectively, were observed.10 Among all
the ligands examined,9 we found that L411 showed the best activity
by suppressing the formation of 4 (entry 8). This remarkably
different reactivity to that observed with other simple phosphines
(entries 1, 2, and 4), carbenes (entry 3), or analogous biarylphos-
phine ligands (entries 5, 6, and 7) could be tentatively attributed,
at present, to the higher bulkiness of the resulting palladium
intermediates. Notably, the nature of the solvent had also a crucial
Encouraged by these initial results, we turned our attention to
the scope of this reaction (Table 2). A wide range of substituted
aryl bromides bearing both electron-donating and electron-
withdrawing groups smoothly underwent the target carboxylation
delivering the corresponding benzoic acids in moderate to good
yields (Table 2).12 The chemoselectivity of this novel transformation
was clearly demonstrated by the tolerance of functional groups such
as amines (entry 4), ethers (entry 5), thioethers (entry 6), alkenes
(entry 10), esters (entry 11), and also heterocycles (entries 18 and
19). Additionally, ketones (entries 12 and 13) and even oxiranes
(entry 14) remained inert under these reaction conditions, thus
representing an additional bonus when comparing with the classical
protocols involving the use of Grignard reagents or organolithiums.
Moreover, the carboxylation reaction can be achieved in the
presence of an aryl chloride, thus leaving options for subsequent
manipulation (entry 8). Interestingly, the process was not hampered
by ortho substituents (entries 16 and 17).
Given that organozinc derivatives are often prepared by reaction
of Et2Zn with aryl iodides,13 we wondered whether organozinc
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15974 J. AM. CHEM. SOC. 2009, 131, 15974–15975
10.1021/ja905264a CCC: $40.75  2009 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2. Proposed Catalytic Cycle
species were the actual reaction intermediates in our carboxylation
protocol. To probe this hypothesis, PhZnBr was submitted to the
catalytic reaction conditions, in both the presence and absence of
Et2Zn. Interestingly, no benzoic acid was formed and benzene was
detected as the sole product in 91 and 96% GC yield, respectively.
Furthermore, no deuterium incorporation in 3 was found when
quenching the model reaction (entry 13, Table 1) with D2O.
Consequently, we believe these experiments rule out the interme-
diacy of organozinc species. Additional control experiments with
1a also indicated that, in the absence of metal, ligand, or Et2Zn, no
reaction took place.9 Although a detailed mechanistic picture
requires further studies, our proposed catalytic cycle implies a
challenging CO2 insertion into the Pd-aryl bond14 of an initially
formed A15 (Scheme 2) to yield B. Subsequently, transmetalation
with Et2Zn would deliver the zinc carboxylate C, with concomitant
release of D, which ultimately would lead to the regeneration of
the catalytic LnPd(0) species. At present, we cannot exclude the
intermediacy of Pd(IV) species E, which would subsequently
undergo reductive elimination to afford B. In full accordance with
the mechanistic proposal, we can rationalize the formation of 3
and 4 by competitive transmetalation of Et2Zn with intermediate
A followed by either ꢀ-hydride elimination or reductive elimination,
respectively.16
source of carbon. In further studies we aim to unravel the
mechanism and fully explore the preparative scope of this reaction.
Acknowledgment. Financial support from ICIQ foundation and
Consolider Ingenio 2010 (CSD2006-0003) is gratefully acknowl-
edged. We sincerely thank Dr. Gisela Colet for valuable support
with the performance of high pressure experiments.
Supporting Information Available: Experimental procedures and
spectral data for all compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
References
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Table 2. Pd-Catalyzed Carboxylations of Aryl Bromides with CO2
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(9) For full experimental details see Supporting Information.
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(12) In contrast to ArBr, vinyl bromides did not give rise to the corresponding
carboxylic acids; furthermore, ArI, ArCl, and ArOTf were found to be less
efficient. See ref 9 for more details.
a Reaction conditions: as in Table 1, entry 13. b Isolated yields, average
of at least two runs. c 1.5 mmol scale. d Using 4-bromobenzaldehyde
dimethyl acetal as starting material.
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M. I.; Hupe, E. Metal-Catalyzed Cross-Coupling Reactions; Wiley:
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In summary, we have developed a novel palladium catalyst
system for the carboxylation of aryl bromides with CO2. In contrast
to other catalyst systems designed for similar purposes,4,5 there is
no need to prepare the corresponding organometallic intermediates,
thus constituting an additional advantage in practical and economical
terms. We believe this transformation constitutes a straightforward
alternative for the synthesis of benzoic acids using CO2 as the sole
(14) For related insertions of CO2 into a Pd-aryl bond, see: Sugimoto, H.;
Kawata, I.; Taniguchi, H.; Fujiwara, Y. J. Organomet. Chem. 1984, 266
(3), C44; also see ref 4f.
(15) As the reaction is best performed in DMF or DMA, we can not rule out
the intermediacy of palladium cationic complexes A′ as well.
(16) Compound 3 does not come from decarboxylation of 2a. See ref 9.
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