Palladium-copper-cocatalyzed intramolecular oxidative coupling: An efficient and atom-economical strategy for the synthesis of 3-acylindoles

Article abstract of DOI:10.1039/c2cc37805a

A new and efficient catalytic approach to the synthesis of 3-acylindoles under Pd-Cu-cocatalyzed oxidative conditions is demonstrated. tert-Butyl hydroperoxide (TBHP) acts not only as the oxidant, but also as an oxygen source in the approach. The process allows quick and atom-economical assembly of 3-acylindoles from readily available starting materials and tolerates a broad range of functional groups.

Full text of DOI:10.1039/c2cc37805a

ChemComm
View Article Online
View Journal | View Issue
COMMUNICATION
Palladium–copper-cocatalyzed intramolecular oxidative
coupling: an efficient and atom-economical strategy
for the synthesis of 3-acylindoles†
Xiao-Feng Xia,a Lu-Lu Zhang,a Xian-Rong Song,a Yan-Ning Niu,a Xue-Yuan Liua
and Yong-Min Liang*ab
Cite this: Chem. Commun., 2013,
49, 1410
Received 27th October 2012,
Accepted 20th December 2012
DOI: 10.1039/c2cc37805a
www.rsc.org/chemcomm
A
new and efficient catalytic approach to the synthesis of cross-dehydrogenative coupling (CDC) reactions of two
3-acylindoles under Pd–Cu-cocatalyzed oxidative conditions is carbon–hydrogen (C–H) bonds have received renewed interest
demonstrated. tert-Butyl hydroperoxide (TBHP) acts not only as in recent years,7 of which the oxidative coupling of C–H bonds
the oxidant, but also as an oxygen source in the approach. The adjacent to amines with various nucleophiles has received
process allows quick and atom-economical assembly of 3-acylindoles considerable attention, and outstanding accomplishments
from readily available starting materials and tolerates a broad range of have been demonstrated in this fascinating field since the
functional groups.
pioneering work from the groups of Murahashi,7f Li,7a,g and
others.7h,8 However, to the best of our knowledge, transition-
The prevalence of the indole ring system that represents a key metal catalyzed intramolecular oxidative coupling of sp3 C–H
structural component in pharmaceutical and materials chemistry bonds with alkyne was rarely reported so far.9 On the other
is well established.1 3-Acylindoles are versatile starting materials hand, it is known that tert-butyl hydroperoxide (TBHP) was
for the synthesis of a broad range of indole derivatives since their often used as an oxidant in transition-metal catalyzed oxidative
carbonyl groups can readily undergo a variety of transforma- dehydrogenative coupling reactions.7a,i In comparison, there
tions.2 As a consequence, a practical and atom-economical were only limited reports where tert-butyl hydroperoxide was
synthesis of 3-acylindoles from simple and readily available used as a reactant.10 In our continued efforts toward the
starting materials is critical to the pharmaceutical and fine development of transition-metal-catalyzed coupling reactions
chemical industries, which needs to be pursued. Traditionally, of novel substrates,11 herein we report a Pd–Cu co-catalyzed
the most commonly used methods for the synthesis of 3-acylin- oxidative intramolecular dehydrogenative coupling for the formation
doles are Friedel–Crafts acylations,3 Vilsmeier–Haack acyla- of 3-acylindoles, in which the oxygen atom of tert-butyl hydro-
tions,4 and the reactions of indole salts with acyl chlorides.5 peroxide was incorporated into various 3-acylindoles
However, these methods have always presented some limita- (Scheme 1).
tions, such as the use of equivalent acids,3 harsh reaction
The results from the optimization studies are summarized in
conditions, and poor regioselectivities, and are not compatible Table S1 (see the ESI†). Starting from the conditions in entry 1,
with the functional groups labile under acidic conditions we first screened various palladium sources and found that
or sensitive to strong nucleophiles.5 Accordingly, the general, PdBr2 gave the best result (Table S1, entries 1–6). Then a series
efficient and operationally simple method for the synthesis of of copper salts (e.g. CuI, CuBr, CuCl, CuCl2, and CuBr2)
3-acylindoles is highly desirable.
were evaluated, wherein CuI displayed high catalytic activity
Reactions involving transition-metal catalyzed direct func- (Table S1, entries 7–10). Then, we screened a series of additives,
tionalization of relatively unreactive C–H bonds for forging new and only LiCl gave a better result (Table S1, entries 11–14). The
C–C bonds have emerged as a major topic of research in effect of solvent on the reaction efficiency was also determined
organic chemistry.6 Among them, transition-metal-catalyzed
a State Key Laboratory of Applied Organic Chemistry, Lanzhou University,
Lanzhou 730000, P. R. China
b State Key Laboratory of Solid Lubrication, Lanzhou Institute of Chemical Physics,
Chinese Academy of Science, Lanzhou 730000, P. R. China.
E-mail: liangym@lzu.edu.cn
† Electronic supplementary information (ESI) available: Experimental procedures
and analysis data for new compounds. CCDC 892560 (2b). For ESI and crystallo-
Scheme 1 Designed route to substituted 3-acylindoles.
graphic data in CIF or other electronic format see DOI: 10.1039/c2cc37805a
c
1410 Chem. Commun., 2013, 49, 1410--1412
This journal is The Royal Society of Chemistry 2013

View Article Online
Communication
ChemComm
subjected to the reaction, a mixture was observed. To confirm
further the structural assignment of products in the present
oxidative cyclization, the structure of the product 2b was unam-
biguously assigned by X-ray crystallography (see the ESI†).12
It is noteworthy that under the current reaction conditions,
2-arylindoles were also obtained in good to moderate yields
(Scheme 3). This means the benzyl group was more easily
oxidized than the methyl group in the reaction. Substrates with
an electron-withdrawing group in the aryl group of the alkyne
gave better yields (2v and 2w). When N-ethyl-N-methyl-2-(phenyl-
ethynyl)aniline was subjected to the reaction, a 1 : 1.3 mixture
product was observed (Scheme 4), which meant the methyl and
ethyl substituents have similar activities to transform into the
iminium intermediate. Notably, when N-benzyl-N-(2-(phenyl-
ethynyl)phenyl)benzamide was introduced into the reaction, no
reaction was observed, which may be ascribed to the fact that the
acid amide was not easily oxidized to form the iminium ion. To
our disappointment, N-cinnamyl-N-ethyl-2-((4-methoxyphenyl)-
ethynyl)aniline was decomposed in the reaction system.
Some control experiments were carried out to elucidate the
mechanism (see the ESI†). The reaction of substrate 1a with
H218O under the optimal reaction conditions afforded the
3-acylindole product without any 18O incorporation, as deter-
mined by MS and HRMS. This result indicated that the oxygen
atom in the ketone did not originate from water. When the
reaction was carried out under an Ar atmosphere, only a slightly
decreased yield was detected, which means the oxygen atom in
Scheme 2 The synthesis of 3-acylindoles by oxidative coupling.
(Table S1, entries 15–19). Among the tested solvents, toluene the ketone did not come from molecular oxygen. The desired
gave the best result. To our delight, the reduction of CuI product 2a was also not detected when the indole 3 was
loading to 10 mol% gave rise to an increase in yield. In order introduced into the reaction system, which meant 3 was not
to further increase the yield, we screened various oxidants and the intermediate of this reaction.
found that other oxidants are either ineffective or less effective
Based on the above results and ESI/MS analysis (see the
than TBHP (Table S1, entries 21–24). A worse result was ESI†), a plausible mechanism for the Pd–Cu cocatalyzed oxidative
obtained when TBHP in decane was changed to TBHP in water cyclization is illustrated in Scheme 5. First, the substrate 1a reacts
(70%). When the loading of the oxidant was increased, the yield with two molecules of TBHP under copper catalysis via a radical
was decreased due to the decomposition of the starting material mechanism to form peroxide A and tert-butyl alcohol, which could
(Table S1, entry 25). Control experiments showed that only a be detected by ESI/MS analysis (m/z = 332.1623, see the ESI†).13 An
trace amount of product was detected in the reaction without iminium intermediate B is formed in small amounts in rapid
either PdBr2 or CuI (Table S1, entries 26 and 27).
equilibrium from A, aided by Lewis acid catalysis by CuI, which could
Using these optimized conditions (Table S1, entry 20), the also be detected by ESI/MS analysis (m/z = 220.1124, see the ESI†).13
oxidative coupling scope of the transformation was investi-
gated. As shown in Scheme 2, a great variety of aminoalkynes
were converted to the corresponding 3-acylindoles. Several
useful functional groups were tolerated, including chloro,
fluoro, nitro, acetyl, ether and alkyl substituents, at the different
positions of aminoalkynes. An electron-withdrawing substituent
favored product formation, whereas an electron-donating group
slightly hindered the reaction. When there were substituents
para to the nitrogen atom regardless of whether they were
electron-donating or -withdrawing, the oxidative coupling
products were achieved (2p and 2q). In addition, a heterocycle-
derived thiophene substrate also appeared to be tolerated in the
reaction, and the product 2r was isolated in 46% yield. Notably,
the oxidative coupling could also be extended to annular tertiary
amines. The substrates with a five-membered ring and a
six-membered ring gave a similar result (2s and 2t). To our
disappointment, when 2-(hept-1-ynyl)-N,N-dimethylaniline was Scheme 3 The synthesis of 2-arylindoles by oxidative coupling.
c
This journal is The Royal Society of Chemistry 2013
Chem. Commun., 2013, 49, 1410--1412 1411

View Article Online
ChemComm
Communication
8, 5287; (c) S. Tohyama, T. Choshi, K. Matsumoto, A. Yamabuki,
K. Ikegata, J. Nobuhiro and S. Hibino, Tetrahedron Lett., 2005,
46, 5263; (d) J. E. Macor, D. H. Blank, C. B. Fox, L. A. Lebel,
M. E. Newman, R. J. Post, K. Ryan, A. W. Schmidt, D. W. Schulz
and B. K. Koe, J. Med. Chem., 1994, 37, 2509; (e) W.-L. Wu and
W.-P. Su, J. Am. Chem. Soc., 2011, 133, 11924; ( f ) B. Robinson, Chem.
Rev., 1969, 69, 785.
Scheme 4 The synthesis of 2-alkylindole by oxidative coupling.
3 (a) E. Wenkert, P. D. R. Moeller, S. R. Piettre and A. T. McPhail,
J. Org. Chem., 1988, 53, 3170; (b) D. M. Ketcha and G. W. Gribble,
J. Org. Chem., 1985, 50, 5451; (c) T. Okauchi, M. Itonaga, T. Minami,
T. Owa, K. Kitoh and H. Yoshino, Org. Lett., 2000, 2, 1485;
(d) O. Ottoni, A. Neder, V. F. de, A. K. B. Dias, R. P. A. Cruz and
L. B. Aquino, Org. Lett., 2001, 3, 1005; (e) A. R. Katritzky, K. Suzuki,
S. K. Singh and H.-Y. He, J. Org. Chem., 2003, 68, 5720.
4 (a) R. J. Sundberg, The Chemistry of Indoles, Academic Press,
New York, 1970; (b) J. C. Powers, J. Org. Chem., 1965, 30, 2534.
5 (a) S. K. Davidsen, J. B. Summers, D. H. Albert, J. H. Holms,
H. R. Heyman, T. J. Magoc, R. G. Conway, D. A. Rhein and
G. W. Carter, J. Med. Chem., 1994, 37, 4423; (b) J. Szmuszkovicz,
J. Am. Chem. Soc., 1960, 82, 1180; (c) J. Bergman and L. Venemalm,
Tetrahedron, 1990, 46, 6061.
6 Selected reviews: (a) F. Kakiuchi and N. Chatani, Adv. Synth. Catal.,
2003, 345, 1077; (b) V. Ritleng, C. Sirlin and M. Pfeffer, Chem. Rev.,
2002, 102, 1731; (c) K. R. Campos, Chem. Soc. Rev., 2007, 36, 1069;
(d) L.-C. Campeau and K. Fagnou, Chem. Commun., 2006, 1253;
(e) D. Alberico, M. E. Scott and M. Lautens, Chem. Rev., 2007,
107, 174; ( f ) R. Giri, B.-F. Shi, K. E. Engle, N. Maugel and J.-Q. Yu,
Chem. Soc. Rev., 2009, 38, 3242; (g) R. Jazzar, J. Hitch, A. Renaudat,
J. Sofack-Kreutzer and O. Baudoin, Chem.–Eur. J., 2010, 16, 2654;
(h) T. W. Lyons and M. S. Sanford, Chem. Rev., 2010, 110, 1147;
(i) S. R. Neufeldt and M. S. Sanford, Acc. Chem. Res., 2012, 45, 936;
( j) K. M. Engle, T.-S. Mei, M. Wasa and J.-Q. Yu, Acc. Chem. Res.,
2012, 45, 788; (k) J.-P. Corbet and G. Mignani, Chem. Rev., 2006,
106, 2651.
7 Selected reviews: (a) C.-J. Li, Acc. Chem. Res., 2009, 42, 335;
(b) A. E. Wendlandt, A. M. Suess and S. S. Stahl, Angew. Chem., Int.
Ed., 2011, 50, 11062; (c) S. R. Chemler and P. H. Fuller, Chem. Soc.
Rev., 2007, 36, 1153; (d) I. P. Beletskaya and A. V. Cheprakov, Coord.
Chem. Rev., 2004, 248, 2337; (e) E. A. Mitchell, A. Peschiulli,
N. Lefevre, L. Meerpoel and B. U. W. Maes, Chem.–Eur. J., 2012,
18, 10092; ( f ) S.-I. Murahashi and D. Zhang, Chem. Soc. Rev., 2008,
37, 1490; (g) C.-J. Li, Chem. Rev., 2005, 105, 3095; (h) C.-L. Sun,
B.-J. Li and Z.-J. Shi, Chem. Rev., 2011, 111, 1293; (i) C. Liu, H. Zhang,
W. Shi and A. Lei, Chem. Rev., 2011, 111, 1780.
8 (a) G. Zhang, Y.-X. Ma, S.-L. Wang, Y.-H. Zhang and R. Wang, J. Am.
Chem. Soc., 2012, 134, 12334; (b) G. Zhang, Y. Zhang and R. Wang,
Angew. Chem., Int. Ed., 2011, 50, 10429; (c) A. J. Catino, J. M. Nichols,
B. J. Nettles and M. P. Doyle, J. Am. Chem. Soc., 2006, 128, 5648.
9 B.-X. Tang, R.-J. Song, C.-Y. Wu, Z.-Q. Wang, Y. Liu, X.-C. Huang,
Y.-X. Xie and J.-H. Li, Chem. Sci., 2011, 2, 2131.
10 For selected recent references, see: (a) W.-P. Liu, Y.-M. Li, K.-S. Liu
and Z.-P. Li, J. Am. Chem. Soc., 2011, 133, 10756; (b) S. K. Rout,
S. Guin, K. K. Ghara, A. Banerjee and B. K. Patel, Org. Lett., 2012,
14, 3982; (c) Y. Zhao, W.-L. Yim, C. K. Tan and Y.-Y. Yeung, Org. Lett.,
2011, 13, 4308; (d) H.-F. Jiang, H.-W. Huang, H. Cao and C.-R. Qi,
Org. Lett., 2010, 12, 5561; (e) Y. Wei, H.-Q. Ding, S.-X. Lin and
F.-S. Liang, Org. Lett., 2011, 13, 1674.
Scheme 5 Proposed mechanism for the direct transformation.
Nucleophilic attack of TBHP on the alkyne of B under
palladium catalysis generates the intermediate C.14 Then, the
intermediate C underwent intramolecular cyclization to give
3-acylindoline D, which was oxidized to the intermediate E. The
intermediate E underwent deprotonation to give the product 2a.
In summary, we have disclosed a novel method for the
synthesis of polyfunctionalized acylindoles through the Pd–Cu
cocatalyzed oxidative cyclization reaction of aminoalkynes
using TBHP both as an oxidant and as a reactant. The mecha-
nism was discussed according to the labeling experiment and
ESI/MS analysis. This method provided an alternative approach
to the current CDC reaction via an intramolecular oxidative
coupling and allowed the rapid construction of diverse indole
derivatives in one step from easily-available starting materials
and in a direct, efficient, and atom-economical process. Studies
on the applications of this intriguing oxidative cyclization in
organic syntheses are currently underway in our laboratory.
We thank the National Science Foundation NSF 21072080
for financial support. We acknowledge National Basic Research
Program of China (973 Program) 2010CB833203 and ‘‘111’’
program of MOE.
11 (a) X.-F. Xia, N. Wang, L.-L. Zhang, X.-R. Song, X.-Y. Liu and
Y.-M. Liang, J. Org. Chem., 2012, 77, 9163; (b) X.-F. Xia,
L.-L. Zhang, X.-R. Song, X.-Y. Liu and Y.-M. Liang, Org. Lett., 2012,
14, 2480.
Notes and references
12 CCDC 892560 (2b)†.
13 E. Boess, C. Schmitz and M. Klussmann, J. Am. Chem. Soc., 2012,
134, 5317.
1 (a) J. E. Saxton, Nat. Prod. Rep., 1997, 14, 559; (b) M. Toyota and
N. Ihara, Nat. Prod. Rep., 1998, 15, 327, and references therein;
(c) J. A. Joule, Product Class 13: Indole and Its Derivatives, Thieme,
Stuttgart, 2001; (d) T. Kawasaki and K. Higuchi, Nat. Prod. Rep.,
2005, 22, 761; for a recent review, see; (e) M. Bandini and
A. Eichholzer, Angew. Chem., Int. Ed., 2009, 48, 9608.
14 (a) The cleavage of the O–O bond of TBHP under Pd catalysis:
M. S. Sigman and E. W. Werner, Acc. Chem. Res., 2012, 45, 874;
(b) LiCl likely serves to enhance the p-Lewis acidity of Li[PdCl3],
which can activate the alkyne and facilitate the nucleophilic attack
of TBHP: Y. Lan, L. Deng, J. Liu, C. Wang, O. Wiest, Z. Yang and
Y.-D. Wu, J. Org. Chem., 2009, 74, 5049.
2 (a) I. Coldham, B. C. Dobson, S. R. Fletcher and A. I. Franklin, Eur. J.
Org. Chem., 2007, 2676; (b) R. Lauchli and K. J. Shea, Org. Lett., 2006,
c
1412 Chem. Commun., 2013, 49, 1410--1412
This journal is The Royal Society of Chemistry 2013