Decarboxylative homocoupling of (hetero)aromatic carboxylic acids

Article abstract of DOI:10.1039/c0cc01943g

A variety of hetero(aromatic) carboxylic acids are shown to undergo decarboxylative homocoupling, mediated by a Pd/Ag system. This novel methodology for the synthesis of symmetrical biaryls avoids the use of haloarenes and organometallic compounds as starting materials.

Full text of DOI:10.1039/c0cc01943g

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Decarboxylative homocoupling of (hetero)aromatic carboxylic acidsw
Josep Cornella, Hicham Lahlali and Igor Larrosa*
Received 17th June 2010, Accepted 9th September 2010
DOI: 10.1039/c0cc01943g
A variety of hetero(aromatic) carboxylic acids are shown to
undergo decarboxylative homocoupling, mediated by a Pd/Ag
system. This novel methodology for the synthesis of symmetrical
biaryls avoids the use of haloarenes and organometallic
compounds as starting materials.
activation for the homocoupling of arenes has not been
reported (eqn 4). Such methodology would provide easy access
to a variety of symmetric biaryls starting from inexpensive and
stable aromatic carboxylic acids.
During the course of our previous work on the decarboxyl-
ative C–H arylation of indoles with benzoic acids, small
amounts of the homocoupled product of the latter partner
were observed.12 Consequently, we explored the application of
this protocol for the synthesis of symmetrical biaryls. Herein,
we report the first decarboxylative homocoupling of aromatic
and heteroaromatic acids mediated by Pd and Ag salts.
Initially, we studied the homocoupling of 2-chloro-5-nitro-
benzoic acid (1a) to afford biaryl 2a in the presence of Ag2CO3,
Substituted symmetrical biaryl subunits constitute an important
motif in chiral ligands,1 monomers for conductive polymers,2
liquid crystal precursors,3 natural products,4 pharmaceuticals
and pesticides.5 These structures are traditionally synthesised
via the transition metal-mediated coupling of suitably
functionalised arene precursors, usually haloarenes or organo-
metallic compounds (Scheme 1, eqn 1 and 2).6,7 However, the
need for pre-functionalisation together with the generation of
undesired and often toxic by-products arise as main drawbacks
for both of these approaches. A strategy involving the oxidative
homocoupling of arenes via C–H bond activation has been
shown to provide a greener alternative with increased atom and
step economy (eqn 3).8 However, due to current limitations in
the control of regio- and chemo-selectivity of C–H activation
processes this approach is limited to a narrow range of arenes.
Therefore, the development of a methodology that uses
inexpensive starting materials yet allows a precise control in
regio- and chemo-selectivity for the homocoupling of a wide
variety of arenes is still highly desirable.
Table 1 Optimisation of the decarboxylative homocoupling of
2-chloro-5-nitrobenzoic acid
Pd cat.
Entry (mol%) Pd cat.
Ag2CO3/
T/1C equiv.
Yielda
(%)
Since the pioneering work of Myers and Goossen et al.,9 the
activation of C–CO2H bonds has emerged as an alternative to
C–H activation where the regioselectivity is controlled by the
position of the carboxylic acid functionality, while still
retaining the advantages of ready availability of starting
materials and innocuous by-product formation (CO2).10,11
To the best of our knowledge, the use of this mode of
Solvent
1
2
3
4
5
10
10
10
10
10
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
110
110
110
110
110
1.0
1.0
1.0
1.0
1.0
DMSO
DMF
DMA
Dioxane
DMF/DMSO 74
95 : 5
58
68
46
0
6
10
10
10
10
10
10
5
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(OAc)2
110
110
110
110
0.25
0.5
1.5
1.0
1.0
1.0
1.0
1.0
1.0
1.0
—
DMF/DMSO
95 : 5
DMF/DMSO 64
95 : 5
DMF/DMSO 72
95 : 5
DMF/DMSO 73
95 : 5
DMF/DMSO 71
95 : 5
DMF/DMSO 37
95 : 5
DMF/DMSO 64
95 : 5
DMF/DMSO 79
95 : 5
5
7
8
9
10
11
12
13
14
15
16
Pd(ACN)2Cl2 110
Pd(PPh3)2Cl2 110
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
110
110
120
120
120
7.5
Scheme 1 Strategies for the metal-mediated homocoupling of arenes.
7.5
0
DMF/DMSO 84
95 : 5
DMF/DMSO 0b
95 : 5
Queen Mary University of London, School of Biological and Chemical
Sciences, Joseph Priestley Building, Mile End Road, E1 4NS, London,
UK. E-mail: i.larrosa@qmul.ac.uk; Fax: +44 (0)20 7882 7427;
Tel: +44 (0)20 7882 8404
w Electronic supplementary information (ESI) available: Experimental
procedures and analytical data are provided. See DOI: 10.1039/c0cc01943g
100
DMF/DMSO
95 : 5
0
a
Yields were determined by 1H NMR using an internal standard.
1
100% protodecarboxylation of 1a to 3a was observed by H NMR.
b
c
8276 Chem. Commun., 2010, 46, 8276–8278
This journal is The Royal Society of Chemistry 2010

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different solvent systems and catalytic amounts of a Pd salt
(Table 1). The use of highly polar solvents was found essential
for the reaction to proceed, a mixture of DMF : DMSO 95 : 5
being optimal (entries 1–5). The only observed by-product
corresponded to the proto-decarboxylation of 1a, leading to
p-chloronitrobenzene (3a). Optimisation of the amount of
Ag2CO3 showed that an excess of this oxidant (1.0 equiv.) is
necessary to achieve high yields (entries 6–8). Further
optimization of the nature of the Pd catalyst (entries 9–11)
and its stoichiometry (entries 12 and 13), highlighted the use of
7.5 mol% of Pd(TFA)2, with a 79% yield of the homocoupling
product 2a. Finally, raising the temperature to 120 1C led to
biaryl 2a in 84% yield (entry 14). It is noteworthy that in the
absence of the Pd catalyst (entry 15) protodecarboxylation was
observed exclusively. Similarly, in the absence of Ag2CO3 but
with 1.0 equiv. of Pd(TFA)2 (entry 16) no dimerisation was
detected. This indicates that both metals are essential for the
reaction and that the role of the Ag salt is not just as the
terminal oxidant.
yields (entries 1–3), even in the presence of an electron-
donating para MeO substituent (entry 3).
Pleasingly, oxygen and sulfur based heteroarenes, such as
furans (1d), benzofurans (1e), benzothiophenes (1f) and
thiophenes (1g), containing a carboxylic acid in C-2 reacted
smoothly under the reaction conditions to afford biaryls 2d–g
in good yields (entries 4–8). The dimerisation of thiophene 1h
Table 2 Substrate scope for the decarboxylative homocoupling of
aromatic acidsa
Entry Acid
Product
Yieldb (%)
1
79
A plausible mechanism for this transformation is outlined in
Scheme 2. Since Ag(I) salts have been shown to mediate the
decarboxylation of ortho substituted benzoic and hetero-
aromatic acids,13 the formation of Ag(I)–arene I from benzoic
acid 1 was envisaged as the initial step in the reaction. I would
then undergo transmetalation to Pd(II) affording intermediate
II. A second transmetalation with another Ag(I)–arene, I,
would generate bisaryl–Pd species III. Subsequent reductive
elimination would then afford the biaryl 2. Finally, two
equiv. of Ag(I) would reoxidise Pd(0) to Pd(II), regenerating
the catalyst. The observation of small amounts of proto-
decarboxylated product 3 is consistent with the formation of
Ag(I)–arene I, which has been reported to be highly reactive
towards proto-demetalation.14
2c
94
76
3c
We next explored the scope of this novel decarboxylative
homocoupling reaction (Table 2). Benzoic acids bearing the
electron-withdrawing groups Cl or NO2 in ortho, underwent
homocoupling to produce the desired biaryls 2a–c in excellent
4
5
56
78
6c
57
7
66
64
8
a
Conditions: 7.5 mol% Pd(TFA)2 and 1.0 equiv. of Ag2CO3 in 95 : 5
b
c
DMF/DMSO at 120 1C. Yields of isolated pure material. Reaction
carried out at 130 1C.
Scheme 2 Proposed mechanism for the decarboxylative homocoupling
of benzoic acids.
c
This journal is The Royal Society of Chemistry 2010
Chem. Commun., 2010, 46, 8276–8278 8277

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bearing the carboxylic acid functionality in C-3 and an
ortho Cl also afforded good yields of the corresponding biaryl,
2h. On the other hand, m- and p-nitrobenzoic acids failed to
react. This underscores our previous observations on the
requirements for Ag(I)-mediated decarboxylation: namely,
the presence of an ortho electron-withdrawing substituent or
an a heteroatom.12,13 The main side reaction observed was in
all cases protodecarboxylation to arene 3, accounting for the
remainder of the mass balance. Unfortunately, when benzoic
acids ortho substituted with Br, OMe, or F were tested under
these conditions decarboxylation to 3 was the main product
observed, with only small amounts (10–20%) of dimer
P. LeFloch and C. Gosmini, Chem.–Eur. J., 2009, 15, 4770;
(f) V. Calo, A. Nacci, A. Monopoli and P. Cotugno, Chem.–Eur. J.,
2009, 15, 1272; (g) X. Chen and L. Wang, Chin. J. Chem., 2009, 27,
2037; (h) C. Qi, X. Sun, C. Lu, J. Yang, Y. Du, H. Wu and
X.-M. Zhang, J. Organomet. Chem., 2009, 694, 2912; (i) M.
Zeng, Y. Du, L. Shao, C. Qi and X.-M. Zhang, J. Org. Chem.,
2010, 75, 2556.
7 (a) E. Shirakawa, Y. Nakao, Y. Murota and T. Hiyama,
J. Organomet. Chem., 2003, 670, 132; (b) T. Nagano and
T. Hayashi, Org. Lett., 2004, 7, 491; (c) A. Krasovskiy,
A. Tishkov, V. del Amo, H. Mayr and P. Knochel, Angew. Chem.,
Int. Ed., 2006, 45, 5010; (d) G. Cahiez, A. Moyeux, J. Buendia and
C. Duplais, J. Am. Chem. Soc., 2007, 129, 13788; (e) H. Sakurai,
H. Tsunoyama and T. Tsukuda, J. Organomet. Chem., 2007, 692,
368; (f) M. S. Maji, T. Pfeifer and A. Studer, Angew. Chem.,
Int. Ed., 2008, 47, 9547.
1
detected by H NMR analysis. These results suggest that the
8 (a) K. Masui, H. Ikegami and A. Mori, J. Am. Chem. Soc., 2004,
126, 5074; (b) M. Takahashi, K. Masui, H. Sekiguchi,
N. Kobayashi, A. Mori, M. Funahashi and N. Tamaoki, J. Am.
Chem. Soc., 2006, 128, 10930; (c) Q.-X. Guo, Z.-J. Wu, Z.-B. Luo,
Q.-Z. Liu, J.-L. Ye, S.-W. Luo, L.-F. Cun and L.-Z. Gong, J. Am.
Chem. Soc., 2007, 129, 13927; (d) Y. Rong, R. Li and W. Lu,
Organometallics, 2007, 26, 4376; (e) A. Kar, N. Mangu,
H. M. Kaiser, M. Beller and M. K. Tse, Chem. Commun., 2008,
386; (f) H.-Q. Do and O. Daugulis, J. Am. Chem. Soc., 2009, 131,
17052; (g) S. Oi, H. Sato, S. Sugawara and Y. Inoue, Org. Lett.,
2008, 10, 1823; (h) Y. Li, W.-H. Wang, S.-D. Yang, B.-J. Li,
C. Fengab and Z.-J. Shi, Chem. Commun., 2010, 4553.
9 (a) A. G. Myers, D. Tanaka and M. R. Mannion, J. Am. Chem.
Soc., 2002, 124, 11250; (b) L. J. Goossen, G. Deng and L. M. Levy,
Science, 2006, 313, 662.
10 O. Baudoin, Angew. Chem., Int. Ed., 2007, 46, 1374; L. J. Goossen,
N. Rodriguez and K. Goossen, Angew. Chem., Int. Ed., 2008, 47,
3100.
relative rates of protodemetallation of I versus transmetallation
to Pd are highly affected by the nature of the group in ortho.
The addition of molecular sieves did not improve the result.
Further studies to overcome this problem and extend the
substrate scope are underway.
In summary, we have developed the first decarboxylative
homocoupling of aromatic and heteroaromatic carboxylic
acids. This protocol, based on a Pd(II)/Ag(I) system allows
the preparation of a variety of biaryls in good to excellent
yields.
We gratefully acknowledge EPSRC and the Royal Society
for generous funding, QMUL for a scholarship (JC), Conseil
regional de Picardie for a travel bursary (HL), and Dr Goldup
´
(QMUL) for discussions.
11 For recent references see: (a) L. J. Goossen, B. Zimmermann and
T. Knauber, Angew. Chem., Int. Ed., 2008, 47, 7103;
(b) A. Maehara, H. Tsurugi, T. Satoh and M. Miura, Org. Lett.,
2008, 10, 1159; (c) A. Voutchkova, A. Coplin, N. E. Leadbeater
and R. H. Crabtree, Chem. Commun., 2008, 6312; (d) C. Wang,
I. Piel and F. Glorius, J. Am. Chem. Soc., 2009, 131, 4194;
(e) P. Hu, J. Kan, W. Su and M. Hong, Org. Lett., 2009, 11,
2341; (f) Z. Li, S.-L. Zhang, Y. Fu, R. Shang, Q.-X. Guo and
L. Liu, J. Am. Chem. Soc., 2009, 131, 8815; (g) R. Shang, Y. Fu,
J. B. Li, S. L. Zhang, Q. X. Guo and L. Liu, J. Am. Chem. Soc.,
2009, 131, 5738; (h) R. Shang, Y. Fu, Y. Wang, Q. Xu, H.-Z. Yu
and L. Liu, Angew. Chem., Int. Ed., 2009, 48, 9350;
(i) L. J. Goossen, F. Manjolinho, B. A. Khan and N. Rodriguez,
J. Org. Chem., 2009, 74, 2620; (j) Z.-M. Sun, J. Zhang and P. Zhao,
Org. Lett., 2010, 12, 992; (k) R. Shang, Q. Xu, Y.-Y. Jiang,
Y. Wang and L. Liu, Org. Lett., 2010, 12, 1000;
(l) F. A. Arroyave and J. R. Reynolds, Org. Lett., 2010, 12,
1328; (m) L. J. Goossen, N. Rodriguez, P. P. Lange and
C. Linder, Angew. Chem., Int. Ed., 2010, 49, 1111; (n) K. Xie,
Z. Yang, X. Zhou, X. Li, S. Wang, Z. Tan, X. An and C.-C. Guo,
Org. Lett., 2010, 12, 1564; (o) F. Zhang and M. F. Greaney,
Angew. Chem., Int. Ed., 2010, 49, 2768; (p) L. J. Goossen,
P. P. Lange, N. Rodriguez and C. Linder, Chem.–Eur. J., 2010,
16, 3906; (q) J. Zhou, P. Hu, M. Zhang, S. Huang, M. Wang and
W. Su, Chem.–Eur. J., 2010, 16, 5876; (r) M. Li and H. Ge,
Org. Lett., 2010, 12, 3464.
Notes and references
1 (a) R. Noyori, Chem. Soc. Rev., 1989, 18, 187; (b) L. Pu, Chem.
Rev., 1998, 98, 2405.
2 (a) T. Yamamoto, T. Maruyama, Z. Zhou, T. Ito, T. Fukada,
Y. Yoneda, F. Begum, T. Ikeda, S. Sasaki, H. Takezoe, A. Fukada
and K. Kubota, J. Am. Chem. Soc., 1994, 116, 4832; (b) S. S. Zhu and
T. M. Swager, Adv. Mater., 1996, 8, 497; (c) L. Papillon, E. Schulz,
S. A. Gelinas, J. Lessard and M. Lemaire, Synth. Met., 1998, 96, 155;
´
(d) H. Meier, Angew. Chem., Int. Ed., 2005, 44, 2482; (e) M. B. Nielsen
and F. Driedrich, Chem. Rev., 2005, 105, 1837; (f) I. McCulloch,
M. Heeney, M. L. Chabinyc, D. DeLongchamp, R. J. Kline,
M. Colle, W. Duffy, D. Fischer, D. Gundlach, B. Hamadani,
R. Hamilton, L. Richter, A. Salleo, M. Shkunov, D. Sparrowe,
S. Tierney and W. Zhang, Adv. Mater., 2009, 21, 1091.
3 K. Yamamura, S. Ono and I. Tabushi, Tetrahedron Lett., 1988, 29,
1797.
4 (a) G. Bringmann, C. Gunther, M. Osche, O. Schupp and
S. Tasler, Progress in the Chemistry of Organic Compounds,
Springer, New York, 2001, vol. 82, pp. 1–23; (b) P. Lloyd-Williams
and E. Giralt, Chem. Soc. Rev., 2001, 30, 145; (c) M. Vrettou,
A. A. Gray, A. R. E. Brewer and A. G. M. Barrett, Tetrahedron,
2007, 63, 1487.
5 (a) K. C. Nicolaou, C. N. C. Boddy, S. Brase and N. Winssinger,
¨
Angew. Chem., Int. Ed., 1999, 38, 2096; (b) S. C. Stinson, Chem.
Eng. News, 1999, 77, 69; (c) O. Baudoin, M. Cesario, D. Guenard
and F. Gueritte, J. Org. Chem., 2002, 67, 1199.
6 For selected examples on homocoupling of haloarenes see:
(a) T. E. Krafft, J. D. Rich and P. J. McDermott, J. Org. Chem.,
1990, 55, 5430; (b) K. W. R. de Franc¸ a, J. L. Oliveira, T. Florencio,
A. P. da Silva, M. Navarro, E. Leonel and J.-Y. Nedelec, J. Org.
Chem., 2005, 70, 10778; (c) G. Cahiez, C. Chaboche, F. Mahuteau-
Betzer and M. Ahr, Org. Lett., 2005, 7, 1943; (d) Y. Yuan and
Y. Bian, Appl. Organomet. Chem., 2008, 22, 15; (e) A. Moncombe,
12 J. Cornella, P. Lu and I. Larrosa, Org. Lett., 2009, 11, 5506.
13 (a) J. Cornella, C. Sanchez, D. Banawa and I. Larrosa, Chem.
Commun., 2009, 7176; (b) P. Lu, C. Sanchez, J. Cornella and
I. Larrosa, Org. Lett., 2009, 11, 5710; (c) L. J. Goossen,
C. Linder, N. Rodriguez, P. P. Lange and A. Fromm, Chem.
Commun., 2009, 7173.
14 (a) W. T. Miller and K. K. Sun, J. Am. Chem. Soc., 1970, 92, 6985;
(b) T. Furuya, A. E. Strom and T. Ritter, J. Am. Chem. Soc., 2009,
131, 1662; (c) T. Furuya and T. Ritter, Org. Lett., 2009, 11, 2860.
c
8278 Chem. Commun., 2010, 46, 8276–8278
This journal is The Royal Society of Chemistry 2010