Intermodular decarboxylative direct C-3 arylation of indoles with benzoic acids

Article abstract of DOI:10.1021/ol902304n

"Chemical Equation Presented" A palladium catalyzed C-H activation of indoles and a silver catalyzed decarboxylative C-C activation of ortho substituted benzoic acids are synergistically combined to synthesize indoles arylated exclusively In the C-3 posit

Full text of DOI:10.1021/ol902304n

ORGANIC
LETTERS
2009
Vol. 11, No. 23
5506-5509
Intermolecular Decarboxylative Direct
C-3 Arylation of Indoles with Benzoic
Acids
Josep Cornella, Pengfei Lu, 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
i.larrosa@qmul.ac.uk
Received October 5, 2009
ABSTRACT
A palladium catalyzed C-H activation of indoles and a silver catalyzed decarboxylative C-C activation of ortho substituted benzoic acids are
synergistically combined to synthesize indoles arylated exclusively in the C-3 position. This novel decarboxylative C-H arylation methodology
is compatible with electron-donating and -withdrawing substituents in both coupling partners.
Palladium catalyzed cross-coupling reactions between orga-
nometallic and haloarene moieties are among the most
employed methodologies for the synthesis of biaryls (Scheme
1, eq 1).1 However, these methodologies present intrinsic
disadvantages, namely the need for prefunctionalization of
both coupling partners and the generation of stoichiometric
amounts of often toxic metal salts. In the past few years direct
C-H arylation has emerged as an alternative in which one
of the coupling partners is not prefunctionalized, thus saving
synthetic steps and avoiding waste formation from this
substrate (eq 2).2 Recently, a ground-breaking report from
Goossen et al. showed that benzoic acids can be employed
as aryl donors in cross-coupling reactions (eq 3), where CO2
is generated as the leaving group.3,4 These couplings are
proposed to proceed via a Pd/Cu bimetallic catalytic cycle.
A related Pd/Ag system had also been reported previously
by Myers et al. for Heck-type couplings.5 Both methodolo-
gies, C-H arylation and decarboxylative aryl-aryl cross-
couplings, still require the prefunctionalization of one of the
coupling partners as an aryl halide.
Scheme 1
.
Strategies for Biaryl Construction (X ) Cl, Br, I,
OTf, etc.)
(1) (a) Corbet, J.-P.; Mignani, G. Chem. ReV. 2006, 106, 2651. (b)
Hassan, J.; Sevignon, M.; Gozzi, C.; Shulz, E.; Lemaire, M. Chem. ReV.
2002, 102, 1359. (c) Anastasia, L.; Negishi, E. In Handbook of Organo-
palladium Chemistry for Organic Synthesis; Negishi, E., Ed.; Wiley: New
York, 2002.
(2) (a) Alberico, D.; Scott, M. E.; Lautens, M. Chem. ReV. 2007, 107,
174. (b) Campeau, L.-C.; Stuart, D. R.; Fagnou, K. Aldrichim. Acta 2007,
20, 35. (c) Satoh, T.; Miura, M. Chem. Lett. 2007, 36, 200. (d) Seregin,
I. V.; Gevorgyan, V. Chem. Soc. ReV 2007, 36, 1173. (e) Godula, K.; Sames,
D. Science 2006, 312, 67. (f) Kakiuchi, F.; Chatani, N. AdV. Synth. Catal.
2003, 345, 1077.
We recently developed a palladium-catalyzed room tem-
perature C-2 selective direct arylation of indoles with
iodoarenes, which requires the use of a silver carboxylate
(3) Goossen, L. J.; Deng, G.; Levy, L. M. Science 2006, 313, 662
.
10.1021/ol902304n CCC: $40.75
Published on Web 10/30/2009
 2009 American Chemical Society

as the base.6 Interestingly, when we attempted these reactions
at higher temperatures, we observed the formation of side
products derived from the decarboxylation of the silver
carboxylate followed by coupling with either the iodoarene
(eq 3) or the indole (eq 4). These results led us to hypothesize
that it should be possible to develop an oxidative cross-
coupling methodology combining both C-H and decarboxy-
lative activations (eq 4), which, potentially, would only
generate water and CO2 as byproduct if oxygen was used as
the terminal oxidant. Such a methodology could allow for
excellent control of regio- and chemo-selectivity. As a
comparison, these are significant problems in double C-H
activation oxidative couplings that are generally overcome
by using large excesses of one of the substrates (up to 60
equiv).7
During the preparation of this manuscript, Crabtree et al.
reported four examples of the decarboxylative coupling of
2,6-dimethoxybenzoic acid with arene donors in low to
moderate yields using a Pd/Ag catalyst system at 200 °C.8
Subsequently, Glorius and co-workers reported the intramo-
lecular decarboxylative C-H arylation of 2-phenoxybenzoic
acids.9 Both of these methodologies are restricted to the use
of ortho alkoxy benzoic acids. No examples have been
reported of the use of benzoic acids bearing electron-
withdrawing groups. Here we report the first intermolecular
direct arylation of indoles with several benzoic acids bearing
ortho electron-withdrawing substituents via a C-H func-
tionalization-decarboxylation process. This process occurs
with high chemo- and regio-selectivity in both coupling
partners. Furthermore, contrary to the usual C-2 regioselec-
tivity in indole direct arylation with palladium, this meth-
odology affords exclusively the C-3 arylated indole
adducts.7c,10-12
Initially, we studied the coupling of N-pivaloylindole (1a)
and 2-chloro-5-nitrobenzoic acid (2a, Table 1) using catalytic
Table 1. Optimization of the Decarboxylative Direct C-H
Arylation of N-Pivaloylindole (1a) and 2-Chloro-5-nitrobenzoic
Acid (2a)a
(4) For extensions of this methodology, see: (a) Bi, H.-P.; Zhao, L.;
Liang, Y.-M.; Li, C.-J. Angew. Chem., Int. Ed. 2009, 48, 792. (b) Goossen,
L. J.; Zimmermann, B.; Knauber, T. Angew. Chem., Int. Ed. 2008, 47, 7103.
(c) Goossen, L. J.; Rodriguez, N.; Linder, C. J. Am. Chem. Soc. 2008, 130,
15248. (d) Becht, J.-M.; Le Drian, C. Org. Lett. 2008, 10, 3161. (e) Becht,
J.-M.; Catala, C.; Le Drian, C.; Wagner, A. Org. Lett. 2007, 9, 1781. (f)
Goossen, L. J.; Rodriguez, N.; Melzer, B.; Linder, C.; Deng, G.; Levy,
L. M. J. Am. Chem. Soc. 2007, 129, 4824. (g) Forgione, P.; Brochu, M.-
C.; St-Onge, M.; Thesen, K. H.; Bailey, M. D.; Bilodeau, F. J. Am. Chem.
Soc. 2006, 128, 11350. For reviews, see: (h) Bonesi, S. M.; Fagnoni, M.;
Albini, A. Angew. Chem., Int. Ed. 2008, 47, 10022. (i) Goossen, L. J.;
Rodriguez, N.; Goossen, K. Angew. Chem., Int. Ed. 2008, 47, 3100.
(5) (a) Tanaka, D.; Romeril, A. S. P.; Myers, A. G. J. Am. Chem. Soc.
2005, 127, 10323. (b) Tanaka, D.; Myers, A. G. Org. Lett. 2004, 6, 433.
(c) Myers, A. G.; Tanaka, D.; Mannion, M. R. J. Am. Chem. Soc. 2002,
124, 11250.
entry
Pd cat.
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(dppf)Cl2
Pd-PEPPSI-IPr
Pd(MeCN)2Cl2
AgX
3a (%)b
1
2
3
4
5
6
7
8
Ag2O
33
53
72
25
62
77
0
AgOAc
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
-
c
Pd(MeCN)2Cl2
-
Ag2CO3
0
(6) Lebrasseur, N.; Larrosa, I. J. Am. Chem. Soc. 2008, 130, 2926.
(7) For selected references on oxidative couplings, see: (a) Brasche, G.;
Garcia-Fortanet, J.; Buchwald, S. L. Org. Lett. 2008, 10, 2207. (b) Hull,
K. L.; Sanford, M. S. J. Am. Chem. Soc. 2007, 129, 11904. (c) Stuart, D. R.;
Villemure, E.; Fagnou, K. J. Am. Chem. Soc. 2007, 129, 12072. (d) Stuart,
D. R.; Fagnou, K. Science 2007, 316, 1172. (e) Dwight, T. A.; Rue, N. R.;
Charyk, D.; Josselyn, R.; DeBoef, B. Org. Lett. 2007, 9, 3137.
(8) Voutchkova, A.; Coplin, A.; Leadbeater, N. E.; Crabtree, R. H. Chem.
Commun. 2008, 6312.
a Unless otherwise noted, all reactions were carried out using 20 mol
% Pd cat., 3.0 equiv of AgX, 2.0 equiv of 2a, 2.4 equiv of DMSO and 1.0
equiv of 1a in a 0.1 M DMF solution, for 16 h at 110 °C. b Yield of 3a was
measured by 1H NMR analysis of the crude product using an internal
standard. c Pd(MeCN)2Cl2 (100 mol %) was used.
(9) Wang, C.; Piel, I.; Glorius, F. J. Am. Chem. Soc. 2009, 131, 4194.
(10) For an excellent review on indole arylation see: Joucla, L.;
Djakovitch, L. AdV. Synth. Catal. 2009, 351, 673.
Pd(TFA)2 and a range of silver salts as oxidants (entries
1-3).13 Gratifyingly, the use of Ag2CO3 afforded the C-3
adduct 3a in good yield (72%, entry 3). A survey of different
palladium catalysts identified Pd(MeCN)2Cl2 as the best
catalyst for this transformation increasing the yield to 77%
(entry 6). In addition to adduct 3a, protodecarboxylation
product 6, decarboxylative homocoupling adduct 7 and traces
of indole dimer 5a were observed. The use of molecular
sieves to prevent the formation of 6 proved unsuccessful.
Remarkably, the reaction is completely regioselective for the
(11) For selected examples of C-2 arylation see: (a) Yang, S.-D.; Sun,
C.-L.; Fang, Z.; Li, B.-J.; Li, Y.-Z.; Shi, Z.-J. Angew. Chem., Int. Ed. 2008,
47, 1473. (b) Wang, X.; Gribkov, D. V.; Sames, D. J. Org. Chem. 2007,
72, 1476. (c) Zhang, Z.; Hu, Z.; Yu, Z.; Lei, P.; Chi, H.; Wang, Y.; He, R.
Tetrahedron Lett. 2007, 48, 2415. (d) Bellina, F.; Calandri, C.; Cauteruccio,
S.; Rossi, R. Tetrahedron 2007, 63, 1970. (e) Deprez, N. R.; Kalyani, D.;
Krause, A.; Sanford, M. S. J. Am. Chem. Soc. 2006, 128, 4972. (f) Toure´,
B. B.; Lane, B. S.; Sames, D. Org. Lett. 2006, 8, 1979. (g) Bellina, F.;
Cauteruccio, S.; Rossi, R. Eur. J. Org. Chem. 2006, 1379. (h) Wang, X.;
Lane, B. S.; Sames, D. J. Am. Chem. Soc. 2005, 127, 4996. (i) Lane, B. S.;
Brown, M. A.; Sames, D. J. Am. Chem. Soc. 2005, 127, 8050. (j) Bressy,
C.; Alberico, D.; Lautens, M. J. Am. Chem. Soc. 2005, 127, 4990. (k) Lane,
B. S.; Sames, D. Org. Lett. 2004, 6, 2897. For selected examples of C-3
arylation, see: (l) Ackermann, L.; Barfuesser, S. Synlett 2009, 808. (m)
Cusati, G.; Djakovitch, L. Tetrahedron Lett. 2008, 49, 2499. (n) Bellina,
F.; Benelli, F.; Rossi, R. J. Org. Chem. 2008, 73, 5529. (o) Djakovitch, L.;
Dufaud, V.; Zaidi, R. AdV. Synth. Catal. 2006, 348, 715. (p) Djakovitch,
L.; Rouge, P.; Zaidi, R. Catal. Commun. 2007, 8, 1561. (q) Zhang, Z.; Hu,
Z.; Yu, Z.; Lei, P.; Chi, H.; Wang, Y.; He, R. Tetrahedron Lett. 2007, 48,
2415. (r) Akita, Y.; Itagaki, Y.; Takizawa, S.; Ohta, A. Chem. Pharm. Bull.
1989, 37, 1477.
(12) For a C-2/C-3 regioselective indole arylation under copper catalysis
see: Phipps, R. J.; Grimster, N. P.; Gaunt, M. J. J. Am. Chem. Soc. 2008,
130, 8172
(13) (a) Other protecting groups for the indole were also examined. See
Supporting Information for more details. (b) Other oxidants tested in the
presence of catalytic amounts of silver and copper salts included: O2, Oxone,
Cu(OTf)2, AgOTf and TEMPO. Adduct 3a was not observed in any of
these experiments.
.
Org. Lett., Vol. 11, No. 23, 2009
5507

C-3 position of the indole (the C-2 adduct 4a was not
detected by GCMS or NMR). In contrast, palladium cata-
lyzed oxidative C-H arylations of N-pivaloyl protected
indoles have previously been reported to afford the C-2
arylated adducts instead.7c In the absence of palladium
catalyst (entry 8), indole 1a and p-chloronitrobenzene (6)
were the only observed products. In the absence of silver
salts no coupling product 3a was observed even when using
100 mol % Pd(MeCN)2Cl2 (entry 7), indicating that both
metals are required in the reaction. To further explore the
role of each metal, acid 2a was stirred for 16 h in DMF/
DMSO at 110 °C in the presence of 1.5 equiv of Ag2CO3,
leading to quantitative formation of arene 6.14 On the other
hand, when 20 mol % Pd(TFA)2 was used instead of the
silver salt, benzoic acid 2a was recovered unreacted, indicat-
ing that the Pd catalyst is not responsible for the decarboxy-
lation step.
suggesting that a radical mechanism is not in place for
this transformation. The rates of both catalytic cycles
require a fine balance to maximize transmetalation and
minimize the formation of byproduct. Obviously, such
rates could be highly dependent on the substrates, and
therefore we were concerned that a change in the
substrates may require a reoptimization of the reaction
conditions.
We next examined the scope of the reaction with a variety
of indoles 1 bearing electron-withdrawing and donating
substituents (Table 2, 3b-h). Pleasingly, no adjustments on
Table 2. Scope of Decarboxylative Direct C-3 Arylation of
N-Pivaloyl Indoles (1) and 2-Chloro-5-nitrobenzoic Acid (2a)a
A working hypothesis for this transformation, consistent
with these observations, is outlined in Scheme 2. In two
Scheme 2. Working Hypothesis for the Intermolecular
t
Decarboxylative C-H Arylation Strategy (R ) BuCO-, Ar )
2-Cl-5-NO2-C6H3-)
a All reactions were carried out using 20 mol % Pd(MeCN)2Cl2, 3.0
equiv of Ag2CO3, 2.0 equiv of 2a, 2.4 equiv of DMSO and 1.0 equiv of
indole 1 in a 0.1 M DMF solution, for 16 h at 110 °C. b Isolated yields
after column chromatography.
intertwined catalytic cycles, a palladium catalyst performs
an electrophilic palladation (I to II) and the biaryl
formation through reductive elimination (III to 3a),
whereas a silver species mediates the decarboxylative
activation step (IV to V) followed by transmetalation to
arylpalladium III. Finally, oxidation of Pd0 to PdII (I),
also performed by the silver salt, completes the arylation
cycle. By-products 5a and 6-7 are formed from palladium
and silver arenes II and V, respectively. Silver arenes have
been reported to readily undergo protodemetalation and
radical formation at high temperatures.15 A radical
pathway for this transformation was also considered.16
When a reaction was carried out under the standard
conditions in the presence of 1.0 equiv of TEMPO, a
radical trap,17 the same yield of adduct 3a was obtained,
the reaction conditions were necessary to afford good yields
of the coupled products 3, showing that the reaction tolerates
changes in the indole core. Substituents such as an ester (3f),
a Cl (3c) and a Br (3d and 3g) were compatible with the
reaction conditions, allowing for further cross-coupling
reactions to be performed on the products. It is noteworthy
that even highly hindered indoles substituted in C4 and C7
(which are rarely reported to undergo C-H arylation),10
afforded moderate to good yields of the C3 coupling adducts
3g and 3h without further optimization of the reaction
conditions. Furthermore, to the best of our knowledge, no
examples have been reported of a C3 selective direct
arylation on a C4 substituted indole. In all cases the C-3
adducts were obtained with excellent regioselectivities (>99:1
by GCMS) even when having substituents in C4 and C7.
(14) Catalytic amounts of Ag(I) salts have been recently shown to
promote the protodecarboxylation of ortho substituted benzoic acids:
Cornella, J.; Sanchez, C.; Banawa, D.; Larrosa, I. Chem. Commun. 2009,
DOI:10.1039/B916646G.
(15) Miller, W. T.; Sun, K. K. J. Am. Chem. Soc. 1970, 92, 6985.
(16) Yu, W.-Y.; Sit, W. N.; Zhou, Z.; Chan, A. S.-C. Org. Lett. 2009,
11, 3174.
(17) For an example of the use of TEMPO as a radical trap, see: (a)
Sibbald, P. A.; Michael, F. E. Org. Lett. 2009, 11, 1147. (b) Albeniz, A. C.;
Espinet, P.; Lopez-Fernandez, R.; Sen, A. J. Am. Chem. Soc. 2002, 124,
11278.
5508
Org. Lett., Vol. 11, No. 23, 2009

Having demonstrated the generality of our decarboxylative
C-H arylation procedure toward changes in the indole core,
we then examined the effect of the substitution pattern of
the benzoic acid coupling partner (Table 3). As expected,
and reaction times, good yields of the coupling adducts 3
were obtained for a variety of substituted benzoic acids
(Table 3). We observed that for the reaction to occur
smoothly, an electron-withdrawing group, such as NO2, Cl
or F, is necessary in the ortho position (3a and 3i-m),
whereas no product was observed when in meta (3n) or para
position. Furthermore, while electron-donating substituents
are tolerated in meta and para positions (3k-m), the ortho
substituted 2,6-dimethoxybenzoic acid did not afford any
coupling product (3o) showing the complementary nature
of our methodology when compared with the previously
reported decarboxylative C-H arylation procedures.8,9 Since
2,6-dimethoxybenzoic acid has been shown to undergo
decarboxylation promoted by Ag2CO3,14 its lack of reactivity
toward the cross-coupling could be due to both catalytic
cycles being out of phase as a consequence of a step change
in reactivity for intermediate V.
Table 3. Scope of Decarboxylative Direct C-3 Arylation of
N-Pivaloyl Indole (1a) and Benzoic Acids (2)a
In summary, we have developed a decarboxylative direct
C-H arylation methodology that allows the intermolecular
coupling of a variety of electron-poor benzoic acids with
indoles to give C-3 arylated adducts, based on a Pd/Ag
bimetallic system. This transformation occurs with high
regio- and chemo-selectivity, representing an excellent
alternative to double C-H activation oxidative couplings.
Ongoing studies are being directed toward performing the
coupling with electron-rich benzoic acids, understanding the
mechanism of this new transformation and its regioselec-
tivity, and developing a C-2 arylation procedure.
Acknowledgment. We gratefully acknowledge QMUL for
a studentship (J.C.), the Engineering and Physical Sciences
Research Council for generous funding, the EPSRC National
Mass Spectrometry Service (Swansea) and Dr. S. M. Goldup
(QMUL) for discussions.
a Unless otherwise noted, all reactions were carried out using 20 mol
% Pd(MeCN)2Cl2, 3.0 equiv of Ag2CO3, 2.0 equiv of 2, 2.4 equiv of DMSO
and 1.0 equiv of indole 1a in a 0.1-0.4 M DMF solution, for 3-16 h at
110-120 °C. See Supporting Information for further details. b Isolated yields
after column chromatography. c 2,6-Difluorobenzoic acid (3.0 equiv) and
4.5 equiv of Ag2CO3 were used. d Pd(TFA)2 was used as the catalyst.
Supporting Information Available: Experimental pro-
cedures and full spectroscopic data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
due to the variations in rates of decarboxylation of IV and
decomposition/transmetalation of V, a small degree of
optimization was required for each new carboxylic acid.
Gratifyingly, by slightly adjusting concentration, temperature
OL902304N
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