A general method for palladium-catalyzed direct carbonylation of indole with alcohol and phenol

Article abstract of DOI:10.1021/ol3017726

A novel strategy involving a first oxidative iodination and subsequent Pd⁰-catalyzed carbonylation to yield indole-3-carboxylate has been developed. It showed perfect generality to indole, alcohol, and phenol. The current methodology could also be conveniently applied to the synthesis of biologically active tropisetron from simple indole and tropine.

Full text of DOI:10.1021/ol3017726

ORGANIC
LETTERS
2012
Vol. 14, No. 16
4130–4133
A General Method for Palladium-Catalyzed
Direct Carbonylation of Indole with
Alcohol and Phenol
Rui Lang,†,§ Lijun Shi,† Dengfeng Li,† Chungu Xia,*,† and Fuwei Li*,†,‡
State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of
Chemical Physics, Chinese Academy of Sciences, Lanzhou 730000, P. R. China,
Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences,
Suzhou 215123, P. R. China, and Graduate University of Chinese Academy of Sciences,
Beijing 100049, P. R. China
fuweili@licp.cas.cn; cgxia@lzb.ac.cn
Received June 28, 2012
ABSTRACT
A novel strategy involving a first oxidative iodination and subsequent Pd0-catalyzed carbonylation to yield indole-3-carboxylate has been
developed. It showed perfect generality to indole, alcohol, and phenol. The current methodology could also be conveniently applied to the
synthesis of biologically active tropisetron from simple indole and tropine.
General and regioselective methods for the direct func-
tionalization of (hetero)arenes continue to be an area
of intense activity, especially in the context of natural
product and medicinal chemistry related substructures.1
Recently, transition metal catalyzed, especially Pd-cata-
lyzed, carbonylation of CÀH bonds has become one of
the most dominant themes for the functionalization of
(hetero)arenes by the introduction of a carbonyl moiety
into molecules, as it avoids the requirement of ArÀX
(X = Br, I, OTs, etc.).2,3 On the other hand, achieving
good generality and regioselectivity in direct carbonylation
is still problematic unless directing-group-containing
arenes are employed.4À6 Additionally, the key step in
the Pd-catalyzed oxidative carbonylation of CÀH bonds
is the PdII-metalation, which controls the reactivity and is
also inevitably challenged by the reduction of PdII to in-
active Pd0 species under a CO atmosphere. One alternative
(3) Selected examples for CÀX carbonylation: (a) Schoenberg, A.;
Bartoletti, I.; Heck, R. F. J. Org. Chem. 1974, 39, 3318. (b) Li, Y.; Yu, Z.;
Alper, H. Org. Lett. 2007, 9, 1647. (c) Munday, R. H.; Martinelli, J. R.;
Buchwald, S. L. J. Am. Chem. Soc. 2008, 130, 2754. (d) Vieira, T. O.;
Meaney, L. A.; Shi, Y.-L.; Alper, H. Org. Lett. 2008, 10, 4899.
(e) Siamaki, A. R.; Black, D. A.; Arndtsen, B. A. J. Org. Chem. 2008,
73, 1135. (f) Liu, Q.; Li, G.; He, J.; Liu, J.; Li, P.; Lei, A. Angew. Chem.,
Int. Ed. 2010, 49, 3371. (g) Wu, X.-F.; Neumann, H.; Beller, M. Angew.
Chem., Int. Ed. 2010, 49, 5284. (h) Wu, X.-F.; Neumann, H.; Beller, M.
Angew. Chem., Int. Ed. 2011, 50, 11142. (i) Reeves, D. C.; Rodriguez, S.;
Lee, H.; Haddad, N.; Krishnamurthy, D.; Senanayake, C. H. Org. Lett.
2011, 13, 2495. (j) Worrall, K.; Xu, B.; Bontemps, S.; Arndtsen, B. A. J.
Org. Chem. 2011, 76, 170. (k) Xin, Z.; Gøgsig, T. M.; Lindhardt, A. T.;
Skrydstrup, T. Org. Lett. 2012, 14, 284. (l) Li, Y.; Xue, D.; Wang, C.;
Liu, Z.-T.; Xiao, J. Chem. Commun. 2012, 48, 1320. (m) Wu, X.-F.;
Neumann, H.; Beller, M. Chem.;Eur. J. 2012, 18, 3831.
† Lanzhou Institute of Chemical Physics.
‡ Suzhou Institute of Nano-Tech and Nano-Bionics.
§ Graduate University of Chinese Academy of Sciences.
(1) Reviews for CÀH activation: (a) Daugulis, O.; Do, H.-Q.;
Shabashov, D. Acc. Chem. Res. 2009, 42, 1074. (b) Lyons, T. W.;
Sanford, M. S. Chem. Rev. 2010, 110, 1147. (c) Yeung, C. S.; Dong,
V. M. Chem. Rev. 2011, 111, 1215. (d) Engle, K. M.; Mei, T.-S.; Wasa,
M.; Yu, J.-Q. Acc. Chem. Res. 2012, 45, 788. (e) Colby, D. A.; Tsai, A. S.;
Bergman, R. G.; Ellman, J. A. Acc. Chem. Res. 2012, 45, 814. (f) Sun, C.-L.;
Li, B.-J.; Shi, Z.-J. Chem. Rev. 2011, 111, 1293.
(4) (a) Fujiwara, Y.; Kawauchi, T.; Taniguchi, H. J. Chem. Soc.,
Chem. Commun. 1980, 220. (b) Itahara, T. Chem. Lett. 1982, 1151.
(c) Wu, X.-F.; Anbarasan, P.; Neumann, H.; Beller, M. Angew. Chem.,
Int. Ed. 2010, 49, 7316.
(5) (a) Giri, R.; Yu, J.-Q. J. Am. Chem. Soc. 2008, 130, 14082. (b) Lu,
Y.; Leow, D.; Wang, X.; Engle, K. M.; Yu, J.-Q. Chem. Sci. 2011, 2, 967.
(2) Reviews for Pd-catalyzed CÀX carbonylation: (a) Barnard,
€
C. F. J. Organometallics 2008, 27, 5402. (b) Brennfuhrer, A.; Neumann,
H.; Beller, M. Angew. Chem., Int. Ed. 2009, 48, 4114. (c) Liu, Q.; Zhang,
H.; Lei, A. Angew. Chem., Int. Ed. 2011, 50, 10788. (d) Wu, X.-F.;
Neumann, H.; Beller, M. Chem. Soc. Rev. 2011, 40, 4986.
r
10.1021/ol3017726
Published on Web 07/27/2012
2012 American Chemical Society

strategy to overcome these limitations could possibly be to
develop a consecutive protocol under which the aryl CÀH
bond instead of the catalyst would be initially oxidized,
regioselectively affording the functionalized intermediate
that could participate in further Pd0-catalyzed carbonylation
to yield the desired carbonyl compound.
and low yield of N-unprotected indole-3-carboxylates
(27%À52%).11
Thereupon, we envision that an efficient and general Pd-
catalyzed direct carbonylation of indoles to synthesize
indole-3-carboxylates would be more fascinating than
the existing protocols and the key issue should be regio-
control, which has not been successfully resolved by a Pd
catalyst system todate. Recently, Daugulis et al. reported a
CuI/I2 catalyzed cross-coupling of (hetero)aromatic CÀH
bonds with excellent regioselectivity in which the electron-
rich arene was originally oxidized by iodine and followed
by Cu-catalyzed arylation with another aromatic CÀH
bond.12 Enlightened by that, we assume Pd0/I2 could be an
ideal catalyst system to control the positional selectivity
and yield of indole-3-carboxylate through two consecutive
in situ steps: oxidation of indole to afford 3-iodoindole and
its further carbonylation (Scheme 1, Path 4). Herein, we
reveal this novel Pd-catalyzed oxidative carbonylation of
indole with alcohol and phenol in the presence of iodine
and K2CO3 under 1 atm of CO to form corresponding
indole-3-carboxylates after the screening of reaction con-
ditions (Supporting Information Table S1).
Figure 1. Representative indole-3-carboxylate derivatives with
bioactivity.
The substituted indole nucleus is a structural component
of a number of biologically active compounds such as
tropisetron (Figure 1, compound 1), which has been
proven to act as a selective 5-hydroxytryptamine receptor
(5-HT3) antagonist and used to prevent chemotherapy-
induced digestiveside effects.7,8 Traditionally, the prepara-
tion of indole-3-carboxylate derivatives required multistep
reactions via its carboxylic acid or acid chloride intermedi-
ates (Scheme 1, Path 1).9 Recently, Lei et al. developed a
Pd-catalyzed direct carbonylation of N-substituted indole
to form indole-3-carboxylate, but this carbonylation took
place at the N-position to afford indole carbamates when
the substrate was extended to free (NH)-indole (Path 2).10
Meanwhile, our group also disclosed a similar oxidative
carbonylation procedure to generate desired indole-3-
carboxylates using the [Rh(COD)Cl]2/K2S2O8 catalyst
system, and the substrate scope was applicable to various
N-substituted indoles and even part of free (NH)-indole
(Path 3). However, there have been far more hurdles to
overcome in view of the high price of the rhodium catalyst
Scheme 1. Transformation of Free (NH)-Indole to Indole-3-
carboxylate or Indole Carbamate
With the optimized conditions in hand, we next explored
the substrate scope of the carbonylation of indole with
alcohol (Scheme 2); the present Pd(OAc)2/I2 catalyst sys-
tem showed good tolerance to the variation of indole
substituents (3aÀ3k), giving indole-3-carboxylates with
moderate to excellent yield. In general, indoles bearing
anelectron-donating group (methylormethoxylgroup) on
the benzene ring (3bÀ3e) regardless of the position showed
better reactivity compared with those bearing ester, cyano,
or other electron-withdrawing groups (3fÀ3k), suggesting
that the electron-donating substituent might facilitate the
iodination step occurring on the C3-position of indole and
then accelerate the following carbonylation. It is noteworthy
that indoles with a halide (3hÀ3k) could smoothly undergo
the reaction with the halide remaining, thus providing
potential for further functionalizations. Additionally, alkyl
(6) (a) Guan, Z.-H.; Ren, Z.-H.; Spinella, S. M.; Yu, S.; Liang, Y.-M.;
Zhang, X. J. Am. Chem. Soc. 2009, 131, 729. (b) Li, H.; Cai, G.-X.; Shi,
Z.-J. Dalton Trans. 2010, 39, 10442. (c) Haffemayer, B.; Gulias, M.;
ꢀ
Gaunt, M. J. Chem. Sci. 2011, 2, 312. (d) Lopez, B.; Rodriguez, A.;
Santos, D.; Albert, J.; Ariza, X.; Garcia, J.; Granell, J. Chem. Commun.
2011, 47, 1054. (e) Dai, H.-X.; Stepan, A. F.; Plummer, M. S.; Zhang,
Y.-H.; Yu, J.-Q. J. Am. Chem. Soc. 2011, 133, 7222. (f) Hasegawa, N.;
Charra, V.; Inoue, S.; Fukumoto, Y.; Chatani, N. J. Am. Chem. Soc.
2011, 133, 8070. (g) Du, Y.; Hyster, T. K.; Rovis, T. Chem. Commun.
2011, 47, 12074. (h) Wrigglesworth, J. W.; Cox, B.; Lloyd-Jones, G. C.;
Booker-Milburn, K. I. Org. Lett. 2011, 13, 5326.
(7) (a) Bandini, M.; Eichholzer, A. Angew. Chem., Int. Ed. 2009, 48,
9608. (b) Bartoli, G.; Bencivenni, G.; Dalpozzo, R. Chem. Soc. Rev.
2010, 39, 4449. (c) Cacchi, S.; Fabrizi, G. Chem. Rev. 2011, 111, PR215.
(d) Shiri, M. Chem. Rev. 2012, 112, 3508.
(8) (a) Richardson, B. P.; Engel, G.; Donatsch, P.; Stadler, P. A.
Nature 1985, 316, 126. (b) Clark, R. D.; Miller, A. B.; Berger, J.; Repke,
D. B.; Weinhardt, K. K.; Kowalczyk, B. A.; Eglen, R. M.; Bonhaus,
D. W.; Lee, C.-H.; Miche1, A. D.; Smith, W. L.; Wong, E. H. F. J. Med.
Chem. 1993, 36, 2645.
(9) Peterson, P. E.; Wolf, J. P., III; Niemann, C. J. Org. Chem. 1958,
23, 303.
(10) Zhang, H.; Liu, D.; Chen, C.; Liu, C.; Lei, A. Chem.;Eur. J.
2011, 17, 9581.
(11) Lang, R.; Wu, J. L.; Shi, L. J.; Xia, C. G.; Li, F. W. Chem.
(12) (a) Do, H.-Q.; Daugulis, O. Org. Lett. 2009, 11, 421. (b) Do,
H.-Q.; Daugulis, O. Org. Lett. 2010, 12, 2517. (c) Do, H.-Q.; Daugulis, O.
J. Am. Chem. Soc. 2011, 133, 13577.
Commun. 2011, 47, 12553.
Org. Lett., Vol. 14, No. 16, 2012
4131

Scheme 2. Direct Carbonylation of Indole with Alcohola
Scheme 3. Direct Carbonylation of Indole with Phenol
a Isolated yield. b80 °C, 48 h.
indole-3-carboxylates were structurally confirmed by the
X-ray crystal diffraction analysis of a representative product
(3h, CCDC number 873074). The 7-azaindole with another
nitrogen atom meta to the NH-group gave no reaction (3l),
and the iodinated intermediate was also not observed.
Compared with the reported Pd and Rh catalyst system,
N-methylindole could furnish a higher yield of the corre-
sponding carboxylate (3m, 89%) under the current catalytic
system.10,11 Gratifyingly, low-carbon aliphatic alcohols such
as methanol and ethanol, which are not efficient nucleophilic
alcohols in many other direct carbonylations,5c,10,11 can read-
ily be used affording high yields of the target products (3n and
3o) under a lower reaction temperature.
Unlike alcohol, phenol has been rarely utilized as a
terminatingnucleophileinthecarbonylation toyieldtarget
ester;13 however, its indole-3-carboxylate is indeed a privi-
leged structure that could be found in many biologically
active compounds, such as Herdmanines D (Figure 1,
compound 2), which demonstrated antibacterial activity
in recent studies.14 To the best of our knowledge, no one-
step preparation of phenyl indole-3-carboxylate has ever
been achieved. As summarized in Scheme 3, the present
Pd(OAc)2/I2 catalyst system showed good generality toward
the carbonylation of indole with an aromatic hydroxyl-
nucleophile. Various N-substituted indoles could be readily
carbonylated with phenols generating moderate to excellent
yields of the desirable esters (5aÀ5c), and free (NH)-indole
was also well tolerated (5d). As expected, N-substituted
indoles with electron-giving groups on the benzene ring
tend to furnish higher yields (5eÀ5i), and among them a
representative structure of 5i was verified by X-ray crystal
diffraction analysis (CCDC number 873075). Furthermore,
carbonylations of indoles having electron-withdrawing
functionalities proceeded smoothly in to provide moderate
to good yields of 5jÀ5m. Taking N-methylindole as an
example, the electronic and steric effects of the aromatic
hydroxyl-nucleophile were also investigated. Naphthol af-
forded good yields of target esters (5o and 5p). The sub-
stituent on the para-position of the phenol would not
significantly affect the reactivity; both phenol and 4-chloride
phenol could go through the reaction (5q and 5r). But the
steric hindrance of the ortho-substituent drastically reduced
the reactivity (5s and 5t); phenol with a tert-butyl group on
the meta-position (5u) was less active than that with chloride
(5v), suggesting the electronic negativity of the ÀOH group
also played an important role in the carbonylative reactivity.
Scheme 4. Direct Carbonylative Synthesis of Tropisetron
(13) Zeng, F.; Alper, H. Org. Lett. 2011, 13, 2868.
(14) Li, J. L.; Han, S. C.; Yoo, E. S.; Shin, S.; Hong, J.; Cui, Z.; Li, H.;
Jung, J. H. J. Nat. Prod. 2011, 74, 1792 and references therein.
4132
Org. Lett., Vol. 14, No. 16, 2012

As mentioned above, tropisetron (7) is one kind of
5-HT3 antagonist and now is in clinical use for the treat-
ment of cancer chemotherapy-induced emesis. Its tradi-
tional synthetic method involvedusing indole-3-carboxylic
acid chloride and a strong base such as n-butyl lithium
through multistep reactions;15 currently there is no direct
way to synthesize tropisetron from simple indole and
tropine (6) under mild conditions. Surprisingly, only a
trace amount of tropisetron product (7a) was detected in
the direct carbonylation of 1 with 6 under the above
conditions, indicating that tropine showed an extremely
different nucleophilic property in the present reaction
compared with the previous alcohol and phenol. Finally,
under the reoptimized conditions (Scheme 4), a 51% yield
of 7a was obtained, and other tropisetron analogues
(7bÀ7d) could also be smoothly synthesized. Among the
array of these bioactive compounds, a representative
structure of 7a was further confirmed by X-ray single
crystal diffraction analysis (CCDC number 885831). For
a comparison, the reported oxidative Pd- and Rh-catalyst
systems were also applied to this direct synthesis of 7 but
failed (Table S2 in Supporting Information). Therefore,
the present Pd-catalyzed procedure may provide a more
convenient way toward a vast expansion in the scope of
valuable tropisetron analogues.
Based on the above experimental investigations and
other related studies,2,12,16 the excellent regioselectivity of
the reaction could probably be elucidated by iodination
and a further Pd0-initiated carbonylation mechanism
(Scheme 5). Taking 1H-indole (1a) for example, it is
originally oxidized to 3-iodo-1H-indole (A), which could
be detected by GC/MS analysis, and then a reactive Pd0
species generated from CO reduction of PdII would pre-
ferentially initiate oxidative addition affording intermediate
B rather than coordinate to the HN-position of 1a, which
usually lead to a carbamate or urea product. Subse-
quently, insertion of CO and alcohol yields the PdII acyl
intermediate C that undergoes reductive elimination to
release target product 3 and simultaneously regenerates
the Pd0 species.
Scheme 5. A Plausible Catalytic Cycle
In conclusion, a novel strategy for the Pd-catalyzed
direct carbonylation of various indoles to synthesize
indole-3-carboxylates in moderate to excellent yields has
been successfully developed. This methodology showed
good generality to indole, alcohol, and/or phenol with
high regioselectivity. Furthermore, the current cataly-
tic procedure could be conveniently applied to the sys-
tematic synthesis of biologically active tropisetron from
easily available starting materials. Further explora-
tions on the mechanism and more synthetic applica-
tions of the present method are under investigation in our
laboratory.
Acknowledgment. We gratefully acknowledge the
Chinese Academy of Sciences and the National Natural
Science Foundation of China (21002106, 21133011) for
generous financial support.
Supporting Information Available. General experimen-
tal procedures, CIF information, and full spectroscopic
data for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
(15) Langlois, M.; Soulier, J. L.; Yang, D.; Bremont, B.; Florac, C.;
Rampillon, V.; Giudice, A. Eur. J. Med. Chem. 1993, 28, 869.
(16) (a) Seregin, I. V.; Gevorgyan, V. Chem. Soc. Rev. 2007, 36, 1173.
(b) Joucla, L.; Djakovitch, L. Adv. Synth. Catal. 2009, 351, 673.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 16, 2012
4133