Direct ortho-arylation of ortho-substituted benzoic acids: Overriding Pd-catalyzed protodecarboxylation

Article abstract of DOI:10.1021/ol400065j

ortho-Arylation of ortho-substituted benzoic acids is a challenging process due to the tendency of the reaction products toward Pd-catalyzed protodecarboxylation. A simple method for preventing decarboxylation in sterically hindered benzoic acids is reported. The method described represents a reliable and broadly applicable entry to 2-aryl-6-substituted benzoic acids.

Full text of DOI:10.1021/ol400065j

ORGANIC
LETTERS
2013
Vol. 15, No. 4
910–913
Direct ortho-Arylation of
ortho-Substituted Benzoic Acids:
Overriding Pd-Catalyzed
Protodecarboxylation
Carlos Arroniz,† Alan Ironmonger,‡ Gerry Rassias,‡ and Igor Larrosa*,†
Queen Mary University of London, School of Biological and Chemical Sciences,
Joseph Priestley Building, Mile End Road, London E1 4NS, United Kingdom, and
GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage,
Hertfordshire SG1 2NY, United Kingdom
i.larrosa@qmul.ac.uk
Received January 9, 2013
ABSTRACT
ortho-Arylation of ortho-substituted benzoic acids is a challenging process due to the tendency of the reaction products toward Pd-catalyzed
protodecarboxylation. A simple method for preventing decarboxylation in sterically hindered benzoic acids is reported. The method described
represents a reliable and broadly applicable entry to 2-aryl-6-substituted benzoic acids.
Recent advances in synthetic chemistry have allowed
chemists to contemplate CꢀH bonds as an advantageous
starting point for chemical functionalization.1 Due to the
ubiquity of CꢀH bonds in organic molecules and their
inert nature, the innovation and creativity seen in CꢀH
functionalization processes over the past few decades
have been centered on achieving CꢀH bond activation in
a selective manner. In this regard, the presence of
coordinating ligands or directing groups within the sub-
strates has been successfully used to bind the metal catalyst
and selectively deliver it to a proximal CꢀH bond. In
particular, the commonly occurring carboxylic acids have
proved to be excellent directing groups for Pd-catalyzed
aromatic functionalization.2 Despite the multiple exam-
ples of Pd-catalyzed carboxylate-directed transformations,
it is surprising that the direct CꢀH arylation of ortho-
substituted benzoic acids with haloarene coupling
partners remains largely unexplored.3 Given that 2-aryl-
6-substituted benzoic acids (Scheme 1, bottom) are present
† Queen Mary University of London.
‡ GlaxoSmithKline.
(1) For a recent special issue on CꢀH functionalization, see: (a)
Doyle, M. P.; Goldberg, K. I. Acc. Chem. Res. 2012, 45, 777. For
selected reviews, see: (b) Yamaguchi, J.; Yamaguchi, A. D.; Itami, K.
Angew. Chem., Int. Ed. 2012, 51, 8960. (c) Yeung, C. S.; Dong, V. M.
Chem. Rev. 2011, 111, 1215. (d) Sun, C. -L.; Li, B.-J.; Shi, Z.-J. Chem.
Rev. 2011, 111, 1293. (e) Ackermann, L. Chem. Rev. 2011, 111, 1315.
(f) McMurray, L.; O’Hara, F. O.; Gaunt, M. Chem. Soc. Rev. 2011, 40,
1885. (g) Boorman, T. C.; Larrosa, I. Chem. Soc. Rev. 2011, 40, 1910.
(h) Hartwig, J. F. Chem. Soc. Rev. 2011, 40, 1992. (i) Wencel-Delord, J.;
(2) (a) Engle, K. M.; Mei, T.-S.; Wasa, M.; Yu, J.-Q. Acc. Chem. Res.
2012, 45, 788. (b) Satoh, T.; Miura, M. Synthesis 2010, 3395. (c) Chen,
X.; Engle, K. M.; Wang, D. H.; Yu, J.-Q. Angew. Chem., Int. Ed. 2009,
48, 5094. (d) Daugulis, O.; Do, H. Q.; Shabashov, D. Acc. Chem. Res.
2009, 42, 1074.
(3) To the best of our knowledge, only the ortho-arylation of 2-toluic
and 2-phenylbenzoic acids with haloarenes has been reported: (a) Giri,
R.; Maugel, N. L.; Li, J.-J.; Wang, D.-H.; Breazzano, S. P.; Saunders,
L. B.; Yu, J.-Q. J. Am. Chem. Soc. 2007, 129, 3510. (b) Chiong, H. A.;
Pham, Q.-N.; Daugulis, O. J. Am. Chem. Soc. 2007, 129, 9879. For three
more examples using ArꢀBF3K as the coupling partner, see: (c) Wang,
D.-H.; Mei, T.-S.; Yu, J.-Q. J. Am. Chem. Soc. 2008, 130, 17676.
€
Droge, T.; Liu, F.; Glorius, F. Chem. Soc. Rev. 2011, 40, 4740. (j) Colby,
D. A.; Bergman, R. G.; Ellman, J. A. Chem. Rev. 2010, 110, 624. (k)
Lyons, T. W.; Sanford, M. Chem. Rev. 2010, 110, 1147. (l) Ackermann,
L.; Vicente, R.; Kapdi, A. R. Angew. Chem., Int. Ed. 2009, 48, 9792.
(m) Lewis, J. C.; Bergman, R. G.; Ellman, J. A. Acc. Chem. Res. 2008, 41,
1013.
r
10.1021/ol400065j
Published on Web 02/01/2013
2013 American Chemical Society

in natural products with cytotoxic activity4a and show
promise as hGPR91 antagonists,4b glutamate carboxypep-
tidase II (GCPII) inhibitors,4c Bradykinin B1 receptor
(B1R) antagonists,4d,e and 3-HAO inhibitors,4f a general
method allowing their direct synthesis via ortho-arylation
of ortho-substituted benzoic acids would be highly useful.
development of such a method, resulting in an efficient and
practical protocol for the synthesis of these highly hindered
benzoic acids.
Table 1. Selected Optimization Resultsa
Scheme 1. Synthetic Approach to 2-Aryl-6-Substituted Benzoic
Acids 3
Pd
Ag2CO3
equiv
temp
yield (%)b
entry
mol %
additive
(°C)
3a þ 4a
1c
2
2
2
2
4
1
2
2
2
2
2
2
2
2
1
ꢀ
130
120
120
120
120
120
120
120
120
120
120
130
120
22 þ 75
70 þ 11
7 þ 80
1
ꢀ
3d
4
1
ꢀ
1
ꢀ
10 þ 70
42 þ 6
5
1
ꢀ
6
0.5
0.5
0.5
0.5
0.5
0.55
0.55
0.55
ꢀ
22 þ 70
56 þ 5
7
Li2CO3
Na2CO3
K2CO3
Cs2CO3
K2CO3
K2CO3
K2CO3
8
47 þ 10.5
70 þ 4.5
73 þ 5
9
10
11
12
13d
81 (76)e þ 5
78 þ 5
81 þ 5.5
a Unless otherwise noted, all reactions were carried out using Pd-
(OAc)2 as the catalyst, Ag2CO3, 1 equiv of 1a, and 3 equiv of 2a in AcOH
as a solventfor 24 h. b Yields were determined by 1H NMR analysis using
1,3,5-trimethoxybenzene as an internal standard. c Reaction run for 16 h.
d Reaction run for 67 h. e Yield of the isolated pure product 3a is shown in
parentheses.
Previous studies in our group have shown that the core
to the difficulty in synthesizing 2-aryl-6-substituted ben-
zoic acids is their intrinsic instability toward Pd-catalyzed
protodecarboxylation under the reaction conditions
(Scheme 1, path A).5 In line with our experimental observa-
tion, recent DFT studies on decarboxylation reactions
have concluded that ortho substituents can significantly
enhance metal-catalyzed protodecarboxylation.6 To access
the elusive 2-aryl-6-substituted benzoic acids it would be
necessary to develop a catalytic system where the Pd-
mediated decarboxylation event could be switched off after
the coupling has occurred (path B). Herein, we disclose the
On the basis of our previous work5 and Daugulis’
pioneering studies,3b the reaction optimization was carried
out with ortho-substituted benzoic acid 1a and iodoarene
2a as the coupling partner in a Pd/Ag system (Table 1).
Implementation of our previously reported conditions, as
expected, led to decarboxylated biaryl 4a as the major
product (entry 1). Lowering the reaction temperature to
120 °C minimized the protodecarboxylation step and
allowed the formation of the desired product, 3a (entry 2).7
However, under these conditions benzoic acid3a proved to
be very sensitive toward protodecarboxylation with longer
reaction times favoring this undesired process (entry 3).
Seeking a more robust catalytic system, we confirmed that
Pd species (and not Ag) were responsible for the decarbox-
ylation of the product 3a: raising the catalyst loading to
4 mol % appeared to promote extrusion of CO2, allowing
good conversion to side product 4a (entry 4). On the
contrary, low catalyst loadings led to a slower decarbox-
ylation although these conditions proved to be counter-
productive as they compromise the ortho-arylation
step (entry 5). On the other hand, decreasing the amount
of Ag2CO3 to 0.5 equiv led to a significant increase in
€
(4) (a) Aly, A. H.; Edrada-Ebel, R.; Indriani, I. D.; Wray, V.; Muller,
W. E. G.; Totzke, F.; Zirrgiebel, U.; Schachtele, C.; Kubbutat, M. H. G.;
€
Lin, W. H.; Proksch, P.; Ebel, R. J. Nat. Prod. 2008, 71, 972. (b)
Bhuniya, D.; Umrani, D.; Dave, B.; Salunke, D.; Kukreja, G.; Gundu,
J.; Naykodi, M.; Shaikh, N. S.; Shitole, P.; Kurhade, S.; De, S.;
Majumdar, S.; Reddy, S. B.; Tambe, S.; Shejul, Y.; Chugh, A.; Palle,
V. P.; Mookhtiar, K. a; Cully, D.; Vacca, J.; Chakravarty, P. K.;
Nargund, R. P.; Wright, S. D.; Graziano, M. P.; Singh, S. B.; Roy, S.;
Cai, T.-Q. Bioorg. Med. Chem. Lett. 2011, 21, 3596. (c) Stoermer, D.;
Vitharana, D.; Hin, N.; Delahanty, G.; Duvall, B.; Ferraris, D. V;
Grella, B. S.; Hoover, R.; Rojas, C.; Shanholtz, M. K.; Smith, K. P.;
Stathis, M.; Wu, Y.; Wozniak, K. M.; Slusher, B. S.; Tsukamoto, T. J.
Med. Chem. 2012, 55, 5922. (d) Huang, H.; Placer, M. P. J. Med. Chem.
2010, 53, 5383. (e) Kuduk, S. D.; Di Marco, C. N.; Chang, R. K.; Wood,
M. R.; Schirripa, K. M.; Kim, J. J.; Wai, J. M. C.; DiPardo, R. M.;
Murphy, K. L.; Ransom, R. W.; Harrell, C. M.; Reiss, D. R.; Holahan,
M. A.; Cook, J.; Hess, J. F.; Sain, N.; Urban, M. O.; Tang, C. J. Med.
€
Chem. 2007, 50, 272. (f) Linderberg, M.; Hellberg, S.; Bjork, S.;
€
Gotthammar, B.; Hogberg, T. Eur. J. Med. Chem. 1999, 34, 729.
(5) Cornella, J.; Righi, M.; Larrosa, I. Angew. Chem., Int. Ed. 2011,
50, 9429.
(6) (a) Xue, L.; Su, W.; Lin, Z. Dalton Trans. 2011, 40, 11926. (b) Xue,
L.; Su, W.; Lin, Z. Dalton Trans. 2010, 39, 9815.
(7) For the initial screening of solvents and various palladium and
silver sources, see Table S1 in the Supporting Information.
Org. Lett., Vol. 15, No. 4, 2013
911

Scheme 2. Scope of Benzoic Acidsa
Scheme 3. Scope of Iodoarenesa
a Yields are of the isolated pure material. The ratio of 3:4 products
was determined by 1H NMR analysis of the reaction crude. b Reaction
performed with 2 equiv of iodoarene and 0.5 equiv of Ag2CO3. c Reaction
carried out at 130 °C.
reactions were performed in the absence of K2CO3, the
products of protodecarboxylation 4bꢀd were obtained
as the major products. Benzoic acids with other ortho
electron-withdrawing substitutents, F and CF3, also
afforded the desired products 3e and 3f, respectively, with
exceptional selectivity. Despite the fact that electron-
donating substituents generally facilitate Pd-mediated
decarboxylation,8,9 the reaction proceeded smoothly with
more electron-rich benzoic acids 1gꢀi. Remarkably, the
reaction tolerated even an ortho MeO group, allowing
access to 3j with little decarboxylation. On the other hand,
highly electron-rich 3k was shown to be very unstable
under the present reaction conditions, and its decarboxy-
lated side-product 4k was exclusively detected. Of signifi-
cant interest was the arylation of sterically hindered
5-fluoro-2-methoxybenzoic acid, affording 1,2,3,4-tetra-
substituted arene derivative 3l.
a Yields are of the isolated pure material. The ratio of 3:4 products
b
was determined by 1H NMR analysis of the reaction crude. The
reaction was performed in the absence of K2CO3. Yields were deter-
c
mined by 1H NMR analysis using 1,3,5-trimethoxybenzene as an
internal standard. d Reaction carried out at 130 °C.
protodecarboxylation, reversing the 3a:4a ratio (entries 2
and 6). These results led us to hypothesize that addition of
an external base might have a beneficial effect on suppres-
sing the protodecarboxylation side reaction. The test of Li,
Na, K, and Cs carbonate salts as additives (entries 7ꢀ10)
highlighted that K2CO3 and Cs2CO3 were indeed able to
inhibit protodecarboxylation, dramatically reducing the
formation of 4a. Ultimately, a subtle increase to 0.55 equiv
of Ag2CO3 in the presence of K2CO3 as an additional base
turned out to be the most effective combination for high
yielding ortho-arylation with near-complete suppression
of the undesired decarboxylation side reaction (entry 11).
These optimized conditions proved to be much more
robust and reliable as higher temperatures and longer
reaction times barely affect product distribution (entries
12 and 13).
The generality of this method was further demonstrated,
varying the stereoelectronic properties of the coupling
partner (Scheme 3). Taking into account that the nature
of the newly installed aryl substituent on the ortho position
(8) For reviews on transition metal mediated protodecarboxylation,
see: (a) Rodriguez, N.; Goossen, L. J. Chem. Soc. Rev. 2011, 40, 5030.
(b) Cornella, J.; Larrosa, I. Synthesis 2012, 653.
(9) For selected examples of Pd-mediated decarboxylation, see: (a)
Tanaka, D.; Romeril, S. P.; Myers, A. G. J. Am. Chem. Soc. 2005, 127,
10323. (b) Dickstein, J. S.; Mulrooney, C. A.; O’Brien, E. M.; Morgan,
B. J.; Kozlowski, M. C. Org. Lett. 2007, 9, 2441. (c) Hu, P.; Kan, J.; Su,
W.; Hong, M. Org. Lett. 2009, 11, 2341. (d) Zhang, S.-L.; Fu, Y.; Shang,
R.; Guo, Q.-X.; Liu, L. J. Am. Chem. Soc. 2010, 132, 638.
To explore the generality of this new method, we
examined the reaction of a variety of ortho-substituted
benzoic acids (Scheme 2). Gratifyingly, benzoic acids1bꢀd
underwent ortho-arylation to 3bꢀd in high yields with
minimal protodecarboxylation. Remarkably, when these
912
Org. Lett., Vol. 15, No. 4, 2013

may have a significant influence on the decarboxylation
rate of the products, we were pleased to find that a
variety of iodoarenes were tolerated with no, or very little,
modification being required. Iodoarenes with electron-
donating substituents in the meta and para position
furnished products 3mꢀo in good yields. Remarkably,
4-iodoanisole allowed the ortho-arylation process to occur
with total prevention of the subsequent decarboxylation
step. Despite competing protodecarboxylation, iodoben-
zene also provided the corresponding benzoic acid deriva-
tive 3p in good yield. Finally, we examined iodoarenes
bearing weak and strong electron-withdrawing groups. All
reactions proceeded well, and products 3qꢀt were accessed
in good to very good yields.10
Scheme 4. Proposed Pathways in Either the Presence or Absence
of K2CO3
Based on our experimental observations, we postulated
a reaction scenario that could explain the influence of
K2CO3 on product distribution (Scheme 4). After the
consumptionofstoichiometricamountsofAg(I) foriodide
removal in the form of AgI,11 the excess of base KX
(X = OAc, HCO3ꢀ) could allow ligand exchange with
the Pd-carboxylate intermediate I, thus preventing the
Pd-catalyzed decarboxylation process. However, in the
absence of KX (Table 1, entry 6) no transmetalation would
take place, and the Pd-mediated extrusion of CO2 would
occur preferentially. On the other hand, when excess
Ag2CO3 is used (Table 1, entries 1ꢀ3) the resulting Ag-
carboxylate can also undergo protodecarboxylation, lead-
ing to a less reliable procedure.12
further optimization, affording 7.67 g of pure crystalline 3g
(60%).
In conclusion, we have developed a practical and general
CꢀH functionalization protocol to access the elusive
2-aryl-6-substituted benzoic acid compounds. The pivotal
role of K2CO3 in switching off the Pd-mediated proto-
decarboxylation side reaction hasenabled a broad reaction
scope overriding the challenging electronic and steric bias
of the substrates. The process is scalable, and the sterically
hindered benzoic acids formed can be easily purified by
recrystallization.
The method is practically simple, often with only an
acidꢀbase workup and/or a recrystallization being re-
quired to obtain analytically pure material. This makes
the process easily scalable. As an example, the reaction of
8.40 g of 1g (45 mmol) was directly carried out without
Acknowledgment. We gratefully acknowledge Glaxo-
SmithKline and the Engineering and Physical Sciences
Research Council for generous support via ImpactQM
KTA and the European Research Council for a Starting
Research Grant (to I.L.). We are also thankful to the
EPSRC National Mass Spectrometry Service (Swansea).
(10) Only iodoarenes were found to undergo the desired CꢀH
arylation reaction, with Ph-Br and Ph-OTf affording only recovered
starting materials. Further, 2- and 3-iodo substituted pyridines were also
found to be unreactive under our reaction conditions.
(11) For a mechanistic discussion on the role of Ag(I) salts in the
CꢀH arylation step, see ref 3b. For a discussion on the role of
carboxylate salts on the CꢀH arylation step, see ref 2d.
Supporting Information Available. Experimental pro-
cedures and characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(12) See ref 8 and: (a) Cornella, J.; Sanchez, C.; Banawa, D.; Larrosa,
I. Chem. Commun. 2009, 7176. (b) Lu, P.; Sanchez, C.; Cornella, J.;
Larrosa, I. Org. Lett. 2009, 11, 5710. (c) Goossen, L. J.; Linder, C.;
Rodriguez, N.; Lange, P. P.; Fromm, A. Chem. Commun. 2009, 7173.
(d) Goossen, L. J.; Rodriguez, N.; Linder, C.; Lange, P. P.; Fromm, A.
ChemCatChem 2010, 2, 430.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 4, 2013
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