Microwave-assisted Cu-catalyzed protodecarboxylation of aromatic carboxylic acids

Article abstract of DOI:10.1021/jo802628z

An effective protocol has been developed that allows the smooth protodecarboxylation of diversely functionalized aromatic carboxylic acids within 5-15 min. In the presence of at most 5 mol % of an inexpensive catalyst generated in situ from copper(I) oxide and 1,10-phenanthroline, even nonactivated benzoates were converted in high yields and with great preparative ease.

Full text of DOI:10.1021/jo802628z

SCHEME 1. Proposed Mechanism for the Cu-Catalyzed
Protodecarboxylation of Aromatic Carboxylates
Microwave-Assisted Cu-Catalyzed
Protodecarboxylation of Aromatic Carboxylic
Acids
Lukas J. Goossen,* Filipe Manjolinho, Bilal A. Khan, and
Nuria Rodr´ıguez
Fachbereich Chemie, Technische UniVersita¨t Kaiserslautern,
Erwin-Schroedinger-Strasse, D-67663 Kaiserslautern, Germany
goossen@chemie.uni-kl.de
ReceiVed December 18, 2008
aromatic amines as solvents is highly beneficial. Still, stoichio-
metric quantities of copper were required in virtually all
published protocols, and the substrate scope was for a long time
limited to aromatic carboxylates bearing electron-withdrawing
groups such as nitro or halo in the ortho position as well as to
certain heterocyclic carboxylates.
We became interested in this transformation in the context
of our research on decarboxylative cross-coupling reactions8
when we optimized the copper cocatalyst that mediates the
decarboxylation step by using protodecarboxylations as a model
reaction.9 This work led to the discovery that such protodecar-
boxylations can be made catalytic in copper and extended to
the full range of benzoic acids, including even deactivated
derivatives such as 4-methoxybenzoic acid, when 4,7-diphenyl-
1,10-phenanthroline is employed as the ligand and a mixture
of NMP and quinoline as the solvent. Based on mechanistic
studies and DFT calculations, we proposed a reaction mecha-
nism that involves a direct insertion of the copper catalyst into
the aryl carboxylate bond without the previous formation of a
π-coordinated intermediate (Scheme 1).7a,9,10
Whereas this protocol avoids stoichiometric amounts of heavy
metals and thus represents major progress from an environmental
standpoint, it has some practical disadvantages. The substrates
are submitted to considerable thermal stress over the course of
the reaction (170 °C for up to 24 h), volatile products are
partially carried off by the CO2 gas released, and the high cost
of the ligand can become prohibitive for preparative applications.
We herein present an alternative protodecarboxylation pro-
tocol which involves performing the reactions in a laboratory
microwave that combines efficient heating with the possibility
to use small, contained vessels certified for pressure reactions.11,12
This protocol allows for a dramatic reduction of the reaction
times and leads to higher yields, even at lower loadings of a
An effective protocol has been developed that allows the
smooth protodecarboxylation of diversely functionalized
aromatic carboxylic acids within 5-15 min. In the presence
of at most 5 mol % of an inexpensive catalyst generated in
situ from copper(I) oxide and 1,10-phenanthroline, even
nonactivated benzoates were converted in high yields and
with great preparative ease.
Decarboxylation reactions are useful for the removal of
surplus carboxylate groups, which may arise from the use of
highly functionalized natural product starting materials or may
be left behind as a result of ring-closure reactions of oxocar-
boxylate intermediates.1,2 While highly activated carboxylic
acids, e.g., ꢀ-oxo acids, diphenylacetic acids, or polyfluorinated
benzoic acids, decarboxylate reasonably easily even in the
absence of a catalyst,3 the release of CO2 from simple aromatic
carboxylic acids is much harder to accomplish. The use of
copper as a stoichiometric mediator was disclosed already in
1930 by Shepard et al. for the decarboxylation of halogenated
furancarboxylic acids at high temperatures.4 Nilsson,5 Shepard,6
and Cohen7 found that the copper source employed has little
influence on the efficiency of protodecarboxylations but that
the presence of bipyridine ligands at the copper and the use of
(1) Smith, M. B.; March, J. AdVanced Organic Chemistry: Reactions,
Mechanisms, and Structure, 5th ed.; Wiley: New York, 2001; pp 1329-
1330.
(2) (a) Maehara, A.; Tsurugi, H.; Satoh, T.; Miura, M. Org. Lett. 2008, 10,
1159–1162. (b) Hoye, T. R.; Dvornikovs, V.; Sizova, E. Org. Lett. 2006, 8,
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(3) Snow, R. A.; Degenhardt, C. D.; Paquette, L. A. Tetrahedron Lett. 1976,
4447–4450.
(4) Shepard, A. F.; Winslow, N. R.; Johnson, J. R. J. Am. Chem. Soc. 1930,
52, 2083–2090.
(5) (a) Nilsson, M. Acta Chem. Scand. 1966, 20, 423–426. (b) Nilsson, M.;
Ullenius, C. Acta Chem. Scand. 1968, 22, 1998–2002.
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837–848.
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J. Am. Chem. Soc. 2007, 129, 4824–4833.
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Synth. Catal. 2007, 349, 2241–2246.
(10) (a) Ruelle, P. J. Comput. Chem. 1987, 8, 158–169. (b) Nagy, P. I.; Smith,
D. A.; Alagona, G.; Ghio, C. J. Phys. Chem. 1994, 98, 486–493. (c) Nagy, P. I.;
Dunn, W. J., III; Alagona, G.; Ghio, C. J. Phys. Chem. 1993, 97, 4628–4642.
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2620 J. Org. Chem. 2009, 74, 2620–2623
10.1021/jo802628z CCC: $40.75 2009 American Chemical Society
Published on Web 02/24/2009

TABLE 1. Optimization of the Catalyst Systema
no.
substrate Cu source ligand
solvent
T (°C) 2 (%)
1b
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
CuOAc
CuBr
CuBr
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3b
3c
3d
4a
4b
5a
5b
6a
6b
3a
3a
NMP/quin
NMP/quin
NMP/quin
NMP/quin
NMP/quin
NMP
170
180
190
200
190
190
190
190
190
190
190
190
190
190
190
190
190
190
190
190
190
190
160
160
9
6
2b
3b
43
17
88
32
18
9
26
0
27
0
15
97
24
10
20
21
7
13
7
5
4b
5b, c
6
7
quinoline
mesit/quin
DMF/quin
DMSO/quin
NMP/quin
NMP/quin
NMP/quin
NMP/quin
NMP/quin
NMP/quin
NMP/quin
NMP/quin
NMP/quin
NMP/quin
NMP/quin
NMP/quin
NMP/quin
NMP/quin
8b
FIGURE 1. Cu ligands evaluated in the protodecarboxylation reaction.
9b
10b
11b
12b
13b, d
14b
15b
16b
17b
18b
19b
20b
21b
22b
23b
24b, e
to the solvent employed. Best results were obtained with a 3:1
mixture of NMP and quinoline, which was superior to either
solvent alone or any other solvent combination tested (entries
3 and 6-10). The chosen solvent mixture strongly absorbs
microwave radiation, causing a rapid increase in temperature
and pressure during the first few seconds. Copper(I) oxide
proved to be the copper source of choice, other copper(I) or
copper(II) salts were less effective (entries 11-13).
When extending the reaction time to 15 min at optimum
reaction conditions, the yields could finally be improved up to
an excellent 88% when using simple 1,10-phenanthroline (entry
5). Again, we found 4,7-diphenyl-1,10-phenanthroline to be even
more effective, leading to almost quantitative formation of
anisole (2a) after only 5 min (entry 14). Besides phenanthrolines,
other ligands (Figure 1) can also be employed, but none of them
was of similar effectiveness to the phenanthrolines (entries
14-22).
98
95
a Reaction conditions: 1.0 mmol of carboxylic acid, 10 mol % of Cu
source (5 mol % for Cu2O), 10 mol % of ligand, 2 mL of degassed
solvent, 5 min, 190 °C/150 W. Conversions were determined by GC
analysis using n-tetradecane as the internal standard; quin ) quinoline,
mesit ) mesitylene. b 3:1 mixture of solvents. c 15 min. d 15 mol % of
K2CO3. e 1 mol % of Cu2O, 2 mol % of 1,10-phenanthroline.
A second test reaction with 2-nitrobenzoic acid (1b) revealed
that for such highly reactive substrates the decarboxylation
proceeds in high yields even when the reaction temperature is
reduced to 160 °C and the catalyst loading to 2 mol % (entries
23 and 24).
Encouraged by the results obtained with these two rather
extreme model substrates, we set out to systematically explore
the generality of the catalytic protocol using various aromatic
and heteroaromatic carboxylic acids. Due to its easy availability
and low price, we used Cu2O/1,10-phenanthroline as the catalyst.
We were pleased to find that even with this simple system, all
substrates tested smoothly decarboxylated within 5-15 min.
Usually, the yields were significantly in excess of those obtained
after 16-24 h of conventional heating using the expensive 4,7-
diphenyl-1,10-phenanthroline ligand. Selected results are sum-
marized in Table 2.
The reactions are very easy to perform by irradiating a
suspension of the carboxylic acid (1a-t), Cu2O, and 1,10-
phenanthroline in NMP/quinoline (3:1) at 190 °C for 5-15 min
under inert conditions in a sealed crimp-top glass tube. After
air-jet cooling, the pressure is carefully released, and the product
is isolated by simple aqueous workup and removal of the
solvents by fractional distillation. The conditions are sufficiently
mild to be tolerated by a number of functionalities including
ether, ester, formyl, nitro, cyano, and hydroxyl groups. The
selectivity is high throughout, with at most traces of side
products arising from homocoupling or substitution reactions.
Lower yields were due only to incomplete conversion. All
less expensive catalyst. The loss of volatile products is avoided,
as the release of CO2 gas can be delayed until the end of the
reaction, after the reaction mixture has reached room temperature.
We based the search for a microwave-assisted decarboxylation
protocol on 4-methoxybenzoic acid (1a) as a test substrate
because this electron-rich benzoic acid is of particularly low
reactivity. In thermal decarboxylations, it gave only 82% yield
after 24 h at 170 °C in the presence of 10 mol % of a customized
copper(I)/4,7-diphenyl-1,10-phenanthroline complex and an
unsatisfactory 35% yield with simple 1,10-phenanthroline.9
In contrast, when 1a was heated in the presence of only 5
mol % of a copper(I) oxide/1,10-phenanthroline catalyst in a
mixture of NMP and quinoline at 170 °C using a maximum of
150 W microwave irradiation, traces of product were detected
after only 5 min (Table 1, entry 1). Increases in the reaction
temperature resulted in a steady improvement of the yields until
a turnaround point was reached at 190 °C, above which the
yield dropped again (entries 3 and 4). Further test reactions
performed at this temperature but at incomplete conversion (5
min) revealed that the protodecarboxylation is very sensitive
(11) For recent reviews, see: (a) Appukkuttan, P.; Van der Eycken, E. Eur.
J. Org. Chem. 2008, 113, 3–1155. (b) Kappe, C. O. Angew. Chem. 2004, 116,
6408–6443; Angew. Chem., Int. Ed. 2004, 43, 6250-6284. (c) Larhed, M.;
Moberg, C.; Hallberg, A. Acc. Chem. Res. 2002, 35, 717–727.
(12) For related microwave-accelerated reactions, see: (a) Forgione, P.;
Brochu, M. C.; St-Onge, M.; Thesen, K. H.; Bailey, M. D.; Bilodeau, F. J. Am.
Chem. Soc. 2006, 128, 11350–11351. (b) Voutchkova, A.; Coplin, A.; Leadbeater,
N. E.; Crabtree, R. H. Chem. Commun. 2008, 6312–6314.
J. Org. Chem. Vol. 74, No. 6, 2009 2621

TABLE 2. Scope of the Transformationa
l-t) (1.0 mmol), Cu2O (1.5 mg, 0.01 mmol), and 1,10-phenan-
throline (3.6 mg, 0.02 mmol).
Anisole (2a). Synthesized from 4-methoxybenzoic acid (1a) (152
mg, 1.00 mmol) following method A and obtained as a colorless
liquid (84 mg, 77%). The spectroscopic data (NMR, GC-MS)
matched those reported in the literature [CAS no. 100-66-3].
Nitrobenzene (2b). Synthesized from 2-nitrobenzoic acid (1b)
(167 mg, 1.00 mmol) following method B (105 mg, 85%), from
3-nitrobenzoic acid (1l) (167 mg, 1.00 mmol) following method B
(107 mg, 87%), and from 4-nitrobenzoic acid (1c) (167 mg, 1.00
mmol) following method A (105 mg, 86%), obtained each time as
a yellow liquid. The spectroscopic data (NMR, GC-MS) all
matched those reported in the literature [CAS no. 98-95-3]. A larger
scale reaction starting from 4-nitrobenzoic acid (1c) (501 mg, 3
mmol) in 6 mL of NMP gave 2b in 80% yield (293 mg).
Benzonitrile (2c). Synthesized from 4-cyanobenzoic acid (1d)
(147 mg, 1.00 mmol) following method A and obtained as a
colorless liquid (84 mg, 81%). The spectroscopic data (NMR,
GC-MS) matched those reported in the literature [CAS no. 100-
47-0].
Benzaldehyde (2d). Synthesized from 4-formylbenzoic acid (1e)
(150 mg, 1.00 mmol) following method A and obtained as a yellow
liquid (68 mg, 64%). The spectroscopic data (NMR, GC-MS)
matched those reported in the literature [CAS no. 100-52-7].
Acetophenone (2e). Synthesized from 4-acetylbenzoic acid (1f)
(164 mg, 1.00 mmol) following method A (95 mg, 79%) and from
2-acetylbenzoic acid (1n) (164 mg, 1.00 mmol) following method
B (101 mg, 84%), both times obtained as a yellow liquid. The
spectroscopic data (NMR, GC-MS) all matched those reported in
the literature [CAS no. 98-86-2].
Ethylbenzene (2f). Synthesized from 4-ethylbenzoic acid (1g)
(150 mg, 1.00 mmol) following method B. The identity of the
product 2f was confirmed by GC-MS and the yield determined
by quantitative GC to be 80% based on a response factor obtained
with commercial ethylbenzene [CAS no. 100-41-4] using n-
tetradecane (50 µL) as an internal gas chromatographic standard.
Trifluoromethylbenzene (2g). Synthesized from 4-(trifluoro-
methyl)benzoic acid (1h) (190 mg, 1.00 mmol) following method
B. The identity of the product 2g was confirmed by GC-MS and
the yield determined by quantitative GC to be 22%, based on a
response factor obtained with commercial trifluoromethylbenzene
[CAS no. 98-08-8] using n-tetradecane (50 µL) as an internal gas
chromatographic standard.
Chlorobenzene (2h). Synthesized from 4-chlorobenzoic acid (1i)
(156 mg, 1.00 mmol) following method A. The identity of the
product 2h was confirmed by GC-MS and the yield determined
by quantitative GC to be 90% based on a response factor obtained
with commercial chlorobenzene [CAS no. 108-90-7] using n-
tetradecane (50 µL) as an internal gas chromatographic standard.
Phenol (2i). Synthesized from 4-hydroxybenzoic acid (1j) (138
mg, 1.00 mmol) following method A. The identity of the product
2i was confirmed by GC-MS and the yield determined by
quantitative GC to be 64%, based on a response factor obtained
with commercial phenol [CAS no. 108-95-2] using n-tetradecane
(50 µL) as an internal gas chromatographic standard.
Ar-COOH
method Ar-H yield (GC) (%)
1a
1b
1c
1d
1e
1f
1g
1h
1i
4-MeO-C6H4-COOH
2-NO2-C6H4-COOH
4-NO2-C6H4-COOH
4-CN-C6H4-COOH
4-CHO-C6H4-COOH
4-MeC(O)-C6H4-COOH
4-Et-C6H4-COOH
4-CF3-C6H4-COOH
4-Cl-C6H4-COOH
4-HO-C6H4-COOH
3-Me-C6H4-COOH
3-NO2-C6H4-COOH
A
B
A
A
A
A
A
A
A
A
A
B
B
B
B
B
Bc
Bc
B
B
2a
2b
2b
2c
2d
2e
2f
2g
2h
2i
2b
2j
2k
2e
2l
77 (88)
85 (98)
86b (94)
81 (89)
64 (77)
79 (87)
(80)
(22)
(90)
(64)
(96)
1j
1k
1l
(99)
1m 2-PhNH-C6H4-COOH
63 (88)
84 (91)
70 (82)
85 (94)
(62)
(99)
38 (56)
80 (94)
1n
1o
1p
1q
1r
1s
1t
2-MeC(O)-C6H4-COOH
2-MeS(O)2-C6H4-COOH
2-iPrOC(O)-C6H4-COOH
2-thienyl-COOH
2-furyl-COOH
1-naphthyl-COOH
2m
2n
2o
2p
2q
2-NO2-5-Me-C6H3-COOH
a Reaction conditions. Method A: 1.0 mmol of carboxylic acid, 5 mol
% of Cu2O, 10 mol % of 1,10-phenanthroline, 1.5 mL of NMP, 0.5 mL
of quinoline, 190 °C, 150 W, 15 min; isolated yields. Method B: 1.0
mmol of carboxylic acid,
1 mol % of Cu2O, 2 mol % of
1,10-phenanthroline, 1.50 mL of NMP, 0.50 mL of quinoline, 190 °C,
150 W, 5 min; isolated yields. GC yields were determined using
n-tetradecane as the internal standard and calibrated for each product. b a
yield of 80% was isolated on 3 mmol scale c 160 °C.
reactions were performed on a 1 mmol scale in 10 mL vessels.
When using these standard microwave vials, the reactions can
be scaled up to a maximum of 3 mmol with comparable yields
as shown for compound 2b. Larger scales should also be
possible but require additional equipment.
In conclusion, an efficient microwave-based protocol has been
developed for Cu-catalyzed decarboxylations of arenecarboxy-
lates. It is ideally suited for the demands of parallel synthesis
as commonly used, for example, in drug discovery. Because
test reactions can now be completed within a few minutes rather
than an entire day, it will also serve to expedite the development
of more effective catalyst systems.
Experimental Section
Protodecarboxylation of Aromatic Carboxylic Acids.
Method A (Table 2). An oven-dried 10 mL microwave vial was
charged with the carboxylic acid (1a,c-k) (1.0 mmol), Cu2O (7.2
mg, 0.05 mmol), and 1,10-phenanthroline (18 mg, 0.10 mmol).
After the reaction mixture was made inert, a mixture of NMP (1.5
mL) and quinoline (0.5 mL) was added via syringe. The resulting
mixture was submitted to microwave irradiation at 190 °C for 15
min at a maximum power of 150 W and subsequently air-jet cooled
to room temperature. The maximum pressure detected during the
reaction was 5.5 bar. The mixture was then diluted with aqueous
HCl (5N, 10 mL) and extracted repeatedly with diethyl ether (2
mL portions). The combined organic layers were washed with water
and brine, dried over MgSO4, and filtered. The corresponding arene
2 was obtained in pure form after removal of the solvents by
distillation over a Vigreux column.
Toluene (2j). Synthesized from 3-methylbenzoic acid (1k) (136
mg, 1.00 mmol) following method A. The identity of the product
2j was confirmed by GC-MS and the yield determined by
quantitative GC to be 99%, based on a response factor obtained
with commercial toluene [CAS no. 108-88-3] using n-tetradecane
(50 µL) as an internal gas chromatographic standard.
Diphenylamine (2k). Synthesized from 2-(phenylamino)benzoic
acid (1m) (213 mg, 1.00 mmol) following method B and obtained
as a white solid (107 mg, 63%): mp 49-51 °C. The spectroscopic
data (NMR, GC-MS) matched those reported in the literature for
diphenylamine [CAS no. 122-39-4].
Method B (Table 2). Method B is analogous to method A but
with a lower loading of the copper/phenanthroline catalyst and
microwave irradiation at 190 °C for 5 min at a maximum power of
150 W. The following amounts were used: carboxylic acid (1b,
Methyl Phenyl Sulfone (2l). Synthesized from 2-(methylsulfo-
nyl)benzoic acid (1o) (200 mg, 1.00 mmol) following method B
and obtained as a white solid (109 mg, 70%): mp. 85-87 °C. The
2622 J. Org. Chem. Vol. 74, No. 6, 2009

spectroscopic data (NMR, GC-MS) matched those reported in the
literature for methyl phenyl sulfone [CAS no. 3112-85-4].
Isopropyl Benzoate (2m). Synthesized from 2-(isopropyloxy-
carbonyl)benzoic acid (1p) (208 mg, 1.00 mmol) following method
B and obtained as a yellow liquid (139 mg, 85%). The spectroscopic
data (NMR, GC-MS) matched those reported in the literature for
isopropyl benzoate [CAS no. 939-48-0].
Thiophene (2n). Synthesized from thiophene-2-carboxylic acid
(1q) (128 mg, 1.00 mmol) following method B but at 160 °C
reaction temperature. The identity of the product 2n was confirmed
by GC-MS and the yield determined by quantitative GC to be
62%, based on a response factor obtained with commercial
thiophene [CAS no. 110-02-1] using n-tetradecane (50 µL) as an
internal gas chromatographic standard.
Furan (2o). Synthesized from furan-2-carboxylic acid (1r) (112
mg, 1.00 mmol) following method B but at 160 °C reaction
temperature. The identity of the product 2o was confirmed by
GC-MS and the yield determined by quantitative GC to be 99%
based on a response factor obtained with commercial furan [CAS
no. 110-00-9] using n-tetradecane (50 µL) as an internal gas
chromatographic standard.
(49 mg, 38%): mp.78-80 °C. The spectroscopic data (NMR,
GC-MS) matched those reported in the literature for naphthalene
[CAS no. 91-20-3].
4-Nitrotoluene (2q). Synthesized from 5-methyl-2-nitrobenzoic
acid (1t) (197 mg, 1.00 mmol) following method B and obtained
as a colorless liquid (109 mg, 80%). The spectroscopic data (NMR,
GC-MS) matched those reported in the literature for 4-nitrotoluene
[CAS no. 99-99-0].
Acknowledgment. We thank Prof. Jens Hartung for giving
us access to his microwave equipment. We also thank the DFG,
the Saltigo GmbH, and NanoKat for funding, Umicore AG for
the generous donation of catalysts, the A. v. Humboldt Founda-
tion for a scholarship to N.R., and the HEC Pakistan for a
scholarship to B.A.K.
Supporting Information Available: NMR spectra for all
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
Naphthalene (2p). Synthesized from 1-naphthoic acid (1s) (172
mg, 1.00 mmol) following method B and obtained as a white solid
JO802628Z
J. Org. Chem. Vol. 74, No. 6, 2009 2623