Palladium-Catalyzed Hydroxycarbonylation of Aryl and Vinyl Halides or Triflates by Acetic Anhydride and Formate Anions ?

Article abstract of DOI:10.1021/ol0354371

(Equation presented) The palladium-catalyzed reaction of aryl and vinyl halides or triflates in the presence of acetic anhydride and lithium formate as a condensed source of carbon monoxide provides an efficient simple route to the synthesis of the corresponding carboxylic acids. The reaction proceeds very smoothly under mild conditions and tolerates a wide range of functional groups, including ether, ketone, ester, and nitro groups. The presence of ortho substituents does not hamper the reaction. Labeled carbonyl products can be easily prepared by using H¹³COONa.

Full text of DOI:10.1021/ol0354371

ORGANIC
LETTERS
2003
Vol. 5, No. 23
4269-4272
Palladium-Catalyzed
Hydroxycarbonylation of Aryl and Vinyl
Halides or Triflates by Acetic Anhydride
and Formate Anions†
Sandro Cacchi,* Giancarlo Fabrizi, and Antonella Goggiamani
Dipartimento di Studi di Chimica e Tecnologia delle Sostanze Biologicamente AttiVe,
UniVersita` degli Studi “La Sapienza”, P.le A. Moro 5, 00185 Rome, Italy
sandro.cacchi@uniroma1.it
Received July 30, 2003
ABSTRACT
The palladium-catalyzed reaction of aryl and vinyl halides or triflates in the presence of acetic anhydride and lithium formate as a condensed
source of carbon monoxide provides an efficient simple route to the synthesis of the corresponding carboxylic acids. The reaction proceeds
very smoothly under mild conditions and tolerates a wide range of functional groups, including ether, ketone, ester, and nitro groups. The
13
presence of ortho substituents does not hamper the reaction. Labeled carbonyl products can be easily prepared by using H COONa.
The palladium-catalyzed conversion of aryl and vinyl halides
or triflates into the corresponding carboxylic acids in the
presence of carbon monoxide is a key step in many synthetic
protocols, particularly in the synthesis of biologically active
compounds.1 The procedure is quite general (in terms of the
level of substituents tolerated in the aryl or vinyl fragment),
efficient, and simple. Carbon monoxide is readily available,
reactive, and cheap. However, it possesses some disadvan-
tages. It is a highly toxic gas that, for safety reasons, is not
always convenient to use. It must be stored and transported
in stainless steel cylinders, and when it is used, losses must
be avoided through carefully assembled gas delivery systems.
In addition, the widespread acceptance in pharmaceutical
industry of combinatorial chemistry, together with high-
throughput screening,2 for the discovery and production of
new substances has led to a demand for automated handling
of liquids and solids rather than of new advanced gas delivery
systems. For these reasons, the development of techniques
where carbon monoxide is gradually generated in situ is a
target of great current interest.3
(1) For recent examples, see: (a) Frenette, R.; Hutchinson, J. H.; Leger,
S.; Therien, M.; Brideau, C.; Chan, C. C.; Charleson, S.; Ethier, D.; Guay,
J.; Jones, T. R.; McAuliffe, M.; Piechuta, H.; Riendeau, D.; Tagari, P.;
Girard, Y. Bioorg. Med. Chem. Lett. 1999, 9, 2391. (b) Klein, L. L.; Li, L.
Curr. Pharm. Design 1999, 5, 57. (c) Yu, M. S.; Baine, N. H. Tetrahedron
Lett. 1999, 40, 3123. (d) Henley, P. D.; Kilburn, J. D. Chem. Commun.
1999, 1335. (e) Miller, W. H.; Bondinell, W. E.; Cousins, R. D.; Erhard,
K. F.; Jakas, D. R.; Keenan, R. M.; Ku, T. W.; Newlander, K. A.; Ross, S.
T.; Haltiwanger, R. C.; Bradbeer, J.; Drake, F. H.; Gowen, M.; Hoffman,
S. J.; Hwang, S.-M.; James, I. E.; Lark, M. W.; Lechowska, B.; Rieman,
D. J.; Stroup, G. B.; Vasko-Moser, J. A.; Zembryki, D. L.; Azzarano, L.
M.; Adams, P. C.; Salyers, K. L.; Smith, B. R.; Ward, K. W.; Johanson, K.
O.; Huffman, W. F. Bioorg. Med. Chem. Lett. 1999, 9, 1807. (f) Young, J.
R.; Huang, S. X.; Chen, I.; Walsh, T. F.; DeVita, R. J.; Wyvratt, M. J., Jr.;
Goulet, M. T.; Ren, N.; Lo, J.; Yang, Y. T.; Yudkovitz, J. B.; Cheng, K.;
Smith, R. G. Bioorg. Med. Chem. Lett. 2000, 10, 1723. (g) Maltais, R.;
Tremblay, M. R.; Poirier, D. J. Comb. Chem. 2000, 2, 604. (h) Herzner,
H.; Palmacci, E. R.; Seeberger, P. H. Org. Lett. 2002, 4, 2965. (i) Baston,
E.; Salem, O. I. A.; Hartmann, R. W. J. Enzymol. Inhib. Med. Chem. 2002,
17, 303. (j) Baston, E.; Salem, O. I. A.; Hartmann, R. W. Arch. Pharm.
2003, 336, 31.
† Dedicated to Professor Domenico Misiti on the occasion of his 70th
birthday.
(2) Curr. Opin. Chem. Biol. 2000, 4, 243 (whole issue).
10.1021/ol0354371 CCC: $25.00 © 2003 American Chemical Society
Published on Web 10/11/2003

Herein we report a new protocol for the palladium-
catalyzed hydroxycarbonylation of aryl and vinyl halides or
triflates utilizing the acetic anhydride/lithium formate com-
bination as a condensed source of carbon monoxide (Scheme
1).
HCOOLi is clearly superior to the other two salts. Et3N can
also be used but proved to be less efficient than EtN(Pri)2
(Table 1, compare entry 5 with entry 6, and entry 7 with
entry 8). Replacement of HCOOLi by formic acid was found
to be detrimental (the aromatic acid was isolated in 10%
yield along with the biaryl byproduct, isolated in 55% yield).6
The best conditions so far developed for ethyl p-iodo-
benzoate (1 equiv of aryl iodide, 2 equiv of acetic anhydride,
3 equiv of HCOOLi, 3 equiv of LiCl, and 2 equiv of
EtN(Pri)2 in the presence of 0.025 equiv of Pd2(dba)3 in DMF
at 80 °C) were usually employed when we extended this
novel route to carboxylic acids to a variety of aryl and vinyl
halides and triflates as shown in Table 2. Under these
conditions, the reaction proceeds very smoothly and appears
to tolerate a wide range of functionalized aryl iodides,
including those containing ethers, ketones, esters, and nitro
groups. Carboxylic acids were isolated in high yields with a
variety of electron-poor, neutral, slightly electron-rich, and
strongly electron-rich aryl iodides. The presence of ortho
substituents does not hamper the reaction (Table 2, entries
5, 11, 12, 17, 22). Only with p-iodoanisole, a model electron-
rich aryl halide, was the corresponding acid isolated in only
43% yield. We then briefly went back and examined
additional variables. It was observed that with this substrate,
the best result (74% yield after 24 h) could be obtained by
using 2 equiv of acetic anhydride and 3 equiv of HCOOK
in the presence of 0.025 mol % Pd2(dba)3 in DMF at 80 °C;
however, this procedure did not provide as high yields on a
number of other starting materials as our standard procedure
(compare, for example, entry 6 with entry 7 of Table 2) and
has thus not been widely employed. Vinyl bromides and
triflates also afforded 2 in good to high yields under our
standard conditions (Table 2, entries 24-26). Aryl bromides
and triflates appear to require the presence of phosphine
ligands, and satisfactory results were obtained by using
PdCl2(dppp) (Table 2, entries 3, 14, 15, 20). Indeed, when
p-bromobiphenyl was subjected to our standard conditions,
no carboxylic acid was observed after 24 h. Minor amounts
of byproducts derived from reduction and coupling reactions
of organopalladium intermediates were occasionally observed
as well as trace amounts, if any, of acetophenone and
benzaldehyde byproducts.
Scheme 1
During our ongoing studies on palladium-catalyzed hydro-
arylation reactions of alkynes with aryl halides using formate
anions as reducing agents,4 we observed that in the presence
of acetic anhydride, benzoic acids could be obtained in
addition to the expected hydroarylation products. We sur-
mised that benzoic acids could arise through a palladium-
catalyzed hydroxycarbonylation reaction where the acetic
anhydride/formate anion mixture could serve as a source of
carbon monoxide. As this technique of in situ delivery of
carbon monoxide would be very suitable for the preparation
of carboxylic acids in high-throughput and combinatorial
synthesis, we decided to investigate the scope and limitations
of this chemistry.
The reaction of ethyl p-iodobenzoate with acetic anhydride
(2 equiv) and HCOOLi (3 equiv) in the presence of Pd2(dba)3
(0.025 equiv) in DMF was initially examined as the model
system. We were pleased to find that, after 4 h at 80 °C, the
corresponding benzoic acid could be isolated in 61% yield
(Table 1, entry 1). The addition of LiCl5 (Table 1, entry 2)
Table 1. Bases, LiCl, and Formate Salts in the Conversion of
Ethyl p-Iodobenzoate into the Corresponding Benzoic Acid
Derivativea
entry
formate salt
base
LiCl
time (h) yield %b
1
2
3
4
5
6
7
8
HCOOLi
HCOOLi
HCOOLi
HCOOLi
HCOONa
HCOONa
HCOOK
HCOOK
-
+
-
+
+
+
+
+
4
61
73
80
91
75
67
81
59
5.5
4
EtN(Pri)2
EtN(Pri)2
EtN(Pri)2
Et3N
EtN(Pri)2
Et3N
Interestingly, Pd(OAc)2 (Table 2, entry 8) and Pd/C also
turned out to be effective for the reaction (Table 2, entry 9).
3
1.4
6
22
28
(3) (a) Carpentier, J.-F.; Castanet, Y.; Brocard, J.; Mortreux, A.; Petit,
F. Tetrahedron Lett. 1991, 32, 4705. (b) Kaise, N.-F. K.; Hallberg, A.;
Larhed, M. J. Comb. Chem. 2002, 4, 109. (c) Wan, Y.; Alterman, M.;
Larhed, M.; Hallberg, A. J. Org. Chem. 2002, 67, 6232. (d) Shibata, T.;
Toshida, N.; Takagi, K. Org. Lett. 2002, 4, 1619 and references therein.
(e) Morimoto, T.; Fuji, K.; Tsutsumi, K.; Kakiuchi, K. J. Am. Chem. Soc.
2002, 124, 3806. (f) Ko, S.; Lee, C.; Choi, M.-G.; Na, Y.; Chang, S. J.
Org. Chem. 2003, 68, 1607. (g) Morimoto, T.; Fujoka, M.; Fuji, K.;
Tsutsumi, K.; Kakiuchi, K. Chem. Lett. 2003, 32, 154.
a Reactions were conducted on a 0.855 mmol scale in starting organic
halides in anhydrous DMF (3 mL) at 80 °C using 1 equiv of organic halide,
2 equiv of acetic anhydride, 3 equiv of formate salt, 3 equiv of LiCl, and
2 equiv of the amine base in the presence of 0.025 equiv of Pd2(dba)3.
b Yields are given for isolated products.
(4) Cacchi, S.; Fabrizi, G. Carbopalladation of Alkynes Followed by
Trapping with Nucleophilic Reagents. In Handbook of Organopalladium
Chemistry for Organic Synthesis; Negishi, E., Ed.; John Wiley & Sons:
New York, 2002; Vol. 1, pp 1335-1359.
or EtN(Pri)2 (Table 1, entry 3) led to a significant increase
in the yield, but the best result in terms of yield and reaction
rate was obtained when both LiCl and EtN(Pri)2 were
employed (Table 1, entry 4). The use of other formate salts,
HCOOK and HCOONa, was explored and showed that
(5) Cacchi, S.; Fabrizi, G.; Gavazza, F.; Goggiamani, A. Org. Lett. 2003,
5, 289.
(6) Reaction was conducted under the same conditions shown in Table
1, entry 4, substituting HCOOH for HCOOLi, in the presence of 5 equiv
of EtN(Pri)2.
4270
Org. Lett., Vol. 5, No. 23, 2003

Scheme 2
Table 2. Palladium-Catalyzed Synthesis of Carboxylic Acids 2
from Aryl and Vinyl Halides or Triflates 1a
introducing a labeled carbonyl into products. This reaction
also shows that the formate anion is the source of the
carbonyl group.
We believe that the reaction involves the intermediacy of
formic acetic anhydride (generated in situ by the reaction of
the formate anion with acetic anhydride) that, as a result of
thermal instability of formic anhydrides,7 decarbonylates
under reaction conditions (Scheme 3).8 An acylpalladium
Scheme 3
complex is subsequently generated that reacts with acetate.
Hydrolysis of the resultant mixed anhydride affords the
carboxylic acid9 (the carboxylic acid could also arise from
a mixed formic anhydride, not shown in Scheme 3, derived
from the reaction of the acylpalladium complex with for-
mate).10
The involvement of formic acetic anhydride as a con-
densed source of carbon monoxide is supported by control
(7) Fife, W. K.; Zhang, Z.-d. J. Org. Chem. 1986, 51, 3744.
(8) Role of carbon monoxide generated via decarbonylation is supported
by the following experiment. A mixture of HCOOLi (2.56 mmol), acetic
anhydride (1.71 mmol), and EtN(Pri)2 (1.71 mmol) in anhydrous DMF (1
mL) was stirred at room temperature for 1 h and, subsequently, at 80 °C
for 1 h. After the mixture was cooled, argon was bubbled through the
reaction mixture for 5 min. Then, ethyl p-iodobenzoate (0.85 mmol),
Pd2(dba)3 (0.021 mmol), and LiCl (2.56 mmol) in anhydrous DMF (2 mL)
were added. The reaction mixture was stirred at 80 °C for 3 h, but no
evidence of the corresponding acid was attained (compare with Table 2,
entry 21).
(9) For the palladium-catalyzed synthesis of carboxylic acids from aryl
and vinyl halides or triflates via hydrolysis of mixed anhydrides, see: (a)
Cacchi, S.; Morera, E.; Ortar, G. Tetrahedron Lett. 1985, 26, 1109. (b)
Pri-Bar, I.; Buchman, O. J. Org. Chem. 1988, 53, 624. (c) Baird, J. M.;
Kern, J. R.; Lee, G. R.; Morgans, D. J., Jr.; Sparacino, M. L. J. Org. Chem.
1991, 56, 1928. (d) Cacchi, S.; Lupi, A. Tetrahedron Lett. 1992, 33, 3939.
(e) Grushin, V. V.; Alper, H. J. Am. Chem. Soc. 1995, 117, 4305.
(10) Though our working hypothesis (Scheme 3) is consistent with the
obtained results, we did not obtain experimental evidence of the formation
of mixed anhydrides derived from acylpalladium complexes.
a Unless otherwise stated, reactions were conducted on a 0.855 mmol
scale in starting organic halides in anhydrous DMF (3 mL) at 80 °C using
1 equiv of organic halide, 2 equiv of acetic anhydride, 3 equiv of HCOOLi,
3 equiv of LiCl, and 2 equiv of EtN(Pri)2 in the presence of 0.025 equiv of
Pd2(dba)3. b Yields are given for isolated products. c Performed with 1 equiv
of organic halide, 2 equiv of acetic anhydride, and 3 equiv of HCOOK in
the presence of 0.025 equiv of Pd2(dba)3. d Performed with 0.05 equiv of
PdCl2(dppp). e Performed with 0.05 equiv of Pd(OAc)2. f Performed with
0.05 equiv of 5% palladium on charcoal. g At 100 °C. h At 60 °C.
As shown in Scheme 2, the employment of the com-
mercially available H13COONa allows for an easy way of
Org. Lett., Vol. 5, No. 23, 2003
4271

experiments, conducted with p-iodoanisole and preformed
formic acetic anhydride,11 whose results are presented in
Table 3. The possibility that DMF can act as a carbon
formate salts in the presence of acetic anhydride provides
an efficient, straightforward route to carboxylic acids. The
reaction tolerates important functional groups and compares
well with most common procedures based on the palladium-
catalyzed reaction in the presence of carbon monoxide,1 as
well as with procedures based on the use of carbon
monoxide-releasing agents.12 It can be particularly useful
when the utilization of common palladium-catalyzed reac-
tions of organic halides or triflates in the presence of carbon
monoxide using gas delivery systems is impractical, as in
the synthesis of compound libraries. Furthermore, it can allow
for an easy way of introducing a labeled carbonyl into
products, without the need to use expensive labeled gaseous
carbon monoxide. Research on the scope and limitations of
this chemistry are actively underway in our laboratory.
Table 3. Conversion of p-Iodoanisole into p-Anisic Acid by
Using Preformed Formic Acetic Anhydridea
anisic acid
entry
base (equiv)
time (h)
yield %b
1
2
3
16
24
24
12
70
80
Et3N (2)
KOAc (2), HCOOK (1)
a Reactions were conducted on a 0.855 mmol scale in p-iodoanisole in
anhydrous DMF (3 mL) at 80 °C using 1 equiv of p-iodoanisole, 2 equiv
of formic acetic anhydride, and the amount of base reported in Table, in
the presence of 0.025 equiv of Pd2(dba)3. b Yields are given for isolated
products.
Acknowledgment. Work was carried out in the frame-
work of the National Project “Stereoselezione in Sintesi
Organica. Metodologie ed Applicazioni” supported by
MURST, Rome. Financial support of this research by the
University “La Sapienza” is also gratefully acknowledged.
monoxide source3c could be ruled out on the basis of the
observation that no carboxylic acid derivative was observed
by subjecting p-iodoanisole to Pd2(dba)3, Et3N, AcOK, and
DMF at 80 °C for 24 h.
Supporting Information Available: Complete descrip-
tion of experimental details and product characterization. This
material is available free of charge via the Internet at
http://pubs.acs.org.
In conclusion, we have demonstrated that the palladium-
catalyzed reaction of organic halides and triflates with
OL0354371
(11) Formic acetic anhydride was prepared according to: Krimen, L. I.
Org. Synth. 1970, 50, 1.
(12) Grushin, V. V.; Alper, H. Organometallics 1993, 12, 3846.
4272
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