A copper-catalyzed synthesis of 3-aroylindoles via a sp3 C-H bond activation followed by C-C and C-O bond formation

Article abstract of DOI:10.1021/ol400692b

An efficient Cu(I)-catalyzed synthesis of 3-aroylindoles has been achieved from o-alkynylated N,N-dimethylamines via a sp³ C-H bond activation α to the nitrogen atom followed by an intramolecular nucleophilic attack with the alkyne using an aqueous solution of tert-butyl hydroperoxide (TBHP) as the oxidant. In this tandem catalytic synthesis of 3-aroylindoles both C-C and C-O bonds are installed at the expense of two sp³ C-H bond cleavages.

Full text of DOI:10.1021/ol400692b

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
A Copper-Catalyzed Synthesis of
3‑Aroylindoles via a sp3 CꢀH Bond
Activation Followed by CꢀC and
CꢀO Bond Formation
Anupal Gogoi, Srimanta Guin, Saroj Kumar Rout, and Bhisma K. Patel*
Department of Chemistry, Indian Institute of Technology, Guwahati,
Guwahati 781039, India
patel@iitg.ernet.in
Received January 25, 2013
ABSTRACT
An efficient Cu(I)-catalyzed synthesis of 3-aroylindoles has been achieved from o-alkynylated N,N-dimethylamines via a sp3 CꢀH bond activation
R to the nitrogen atom followed by an intramolecular nucleophilic attack with the alkyne using an aqueous solution of tert-butyl hydroperoxide
(TBHP) as the oxidant. In this tandem catalytic synthesis of 3-aroylindoles both CꢀC and CꢀO bonds are installed at the expense of two sp3 CꢀH
bond cleavages.
CꢀH bond functionalization processes have provided a
great impetus to modern organic synthesis. Such functio-
nalizations have led to the possibility of molecular diver-
sities through the constructions of either CꢀC or CꢀX
(X = heteroatom) bonds via the cleavage of ubiquitous
CꢀH bonds.1 The two strategies usually followed are
directing-group-assisted CꢀH bond functionalization2
and cross dehydrogenative coupling (CDC).3 However,
in recent times, the cross dehydrogenative coupling (CDC)
strategy has had an upsurge because it is step- and atom
economic. The CDC approach has mostly been applied
toward CꢀC bond-forming reactions which are important
in creating several significant building blocks. Among the
building blocks, the indolyl moiety, particularly the 3-acy-
lindole, hasimmenseimportancebecauseofits relevance in
natural products and pharmaceutical entities;4 thereby,
considerable interest has been gained for their synthesis
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10.1021/ol400692b
XXXX American Chemical Society

literature, the urge still remains as to “what next” could be
improvised to achieve a practical route to 3-acyl/aroylindoles.
Tertiary amines possessing alkyl groups are useful pre-
cursors for the sp3 CꢀH bond functionalizations R to the
nitrogen atom.3b,d,e,h,12 These functionalizations in most
cases have been stimulated by various copper salts in
combination with organic peroxides through a single elec-
tron transfer process.12 However, a review of the literature
reveals that these functionalizations occurred via an inter-
molecular attack of various C, N, or O nucleophiles at the
iminium ion generated in situ. Following these reports, we
reasoned that if the nucleophile attacks intramolecularly,
they could be useful toward the synthesis of nitrogeneous
heterocycles. As a prelude to this motivation, N,N-di-
methyl-2-(2-phenylethynyl)benzenamine (1a) was chosen
as the precursor, where the ethynyl group is expected to
function as the internal nucleophile toward an intramole-
cular attack onto the iminium carbon. In a pursuit to the
“what next”, an elegant protocol is reported for the direct
synthesis of 3-aroylindoles that proceeds via the sp3 CꢀH
bond activation R to the nitrogen atom of an o-alknylated
amine with concomitant formation of CꢀC and CꢀO
bonds.
Scheme 1. Existing Routes and Our Strategy to 3-Aroylindoles
via CꢀH activation processes.5 Apart from their bioactive
nature they also serve as useful precursors to various other
indole-based compounds through easy functional group
transformations of its carbonyl group.4,6 Along with the
classical FriedelꢀCrafts7 and VilsmeierꢀHaack acylation
reactions,8 the 3-acylindoles have been synthesized via
the C3ꢀH activation of indoles involving various acyl group
surrogates using Fe, Ru (Scheme 1, path a),9 or Pd catalysts
(Scheme 1, paths b and c).10 Differing from these paths
(Scheme 1, paths aꢀc) which use preformed indoles, the
3-acylindoles have also been achieved through a Cu-cata-
lyzed direct CꢀC bond formation of N-aryl enaminones
via a double CꢀH bond activation (Scheme 1, path d).11
Despite the presence of several intriguing protocols in the
Scheme 2. Substrate Scope for 3-Aroylindolesa
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Choshi, T.; Matsumoto, K.; Yamabuki, A.; Ikegata, K.; Nobuhiro, J.;
Hibino, S. Tetrahedron Lett. 2005, 46, 5263. (f) Macor, J. E.; Blank,
D. H.; Fox, C. B.; Lebel, L. A.; Newman, M. E.; Post, R. J.; Ryan, K.;
Schmidt, A. W.; Schulz, D. W.; Koe, B. K. J. Med. Chem. 1994, 37, 2509.
(g) Wu, W.-L.; Su, W.-P. J. Am. Chem. Soc. 2011, 133, 11924. (h)
Robinson, B. Chem. Rev. 1969, 69, 785.
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(b) Okauchi, T.; Itonaga, M.; Minami, T.; Owa, T.; Kitoh, K.; Yoshino,
H. Org. Lett. 2000, 2, 1485. (c) Ottoni, O.; Neder, A.; De, V. F.; Dias,
A. K. B.; Cruz, R. P. A.; Aquino, L. B. Org. Lett. 2001, 3, 1005. (d)
Katritzky, A. R.; Suzuki, K.; Singh, H. K.; He, H.-Y. J. Org. Chem.
2003, 68, 5270. (e) Wynne, J. H.; Lloyd, C. T.; Jensen, S. D.; Boson, S.;
Stalick, W. M. Synthesis 2004, 2277. (f) Taylor, J. E.; Jones, M. D.;
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S. K.; Kashyap, M.; Kamble, H. J. Org. Chem. 2011, 76, 4753.
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R. J. The Chemistry of Indoles; Academic Press: New York, 1970.
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H. Tetrahedron 1994, 50, 11803. (b) Kondo, Y.; Sakamoto, T.;
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Mancuso, R.; Salerno, G.; Costa, M. Eur. J. Org. Chem. 2012, 2549. (d)
Ma, Y.; You, J.; Song, F. Chem.;Eur. J. 2013, 19, 1189.
a Reaction conditions: 1(aꢀd), 2ꢀ4(aꢀc) (0.5 mmol), CuBr (0.05
mmol), 70% aqueous TBHP (1.5 mmol) in DMSO (2 mL) at 80 °C.
Reactions were monitored by TLC. Confirmed by spectroscopic
analysis
We initiated our investigation by treating(1a) with CuBr
(10 mol %) as the catalyst and TBHP (5ꢀ6 M in decane)
(1 equiv) as the oxidant in toluene solvent at 80 °C, which
(12) (a) Li, Z.; Bohle, D. S.; Li, C.-J. Proc. Natl. Aacd. Sci. U.S.A.
2006, 103, 8928. (b) Zhang, G.; Ma, Y.-X.; Wang, S.-L.; Zhang, Y.-H.;
Wang, R. J. Am. Chem. Soc. 2012, 134, 12334. (c) Zhang, G.; Zhang, Y.;
Wang, R. Angew. Chem., Int. Ed. 2011, 50, 10429.
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Int. Ed. 2009, 48, 8078.
B
Org. Lett., Vol. XX, No. XX, XXXX

yielded the aroylindole (10a) in 45% isolated yield (entry 1,
Table S1, see Supporting Information [SI]). Interestingly,
the use of an aqueous TBHP (70 wt % in water) instead of
TBHP in decane, gave a superior yield of 55% (entry 2,
Table S1 [SI]). Further, increasing the amount of TBHP to
2 equiv and 3 equiv improved the yield to 62% and 70%,
respectively (entries 3ꢀ4, Table S1 [SI]). Copper(I) bro-
midewas found tobesuperiortothe othercopper (I and II)
salts employed such as CuCl, CuI, Cu(OAc)2, CuCl2, and
CuBr2 (entries 5ꢀ9, Table S1 [SI]). Decreasing the catalyst
loading to 5 mol %, significantly lowered the product yield
(52%) (entry 10, Table S1 [SI]). Further, when the reaction
was carried out in DMSO solvent instead of toluene, an
improved yield of 77% was obtained (entry 11, Table S1
[SI]). The reaction in other solvents such as o-xylene, 1,4-
dioxane, DMF, and THF did not give any satisfactory
yields compared to that with DMSO (entries 12ꢀ15, Table
S1 [SI]). Both increase (100 °C) and decrease (60 °C) in the
reaction temperature had an adverse effect on the product
yields (entries 16ꢀ17, Table S1 [SI]). The control experi-
ments carried out with either the copper salt or TBHP
alone did not give any trace of product (entries 18ꢀ19,
Table S1 [SI]). The use of other catalysts such as Pd(OAc)2,
CoCl2, and FeCl3 in combination with aq TBHP gave
inferior yields compared to CuBr (entries 20ꢀ22, Table S1
[SI]). During the optimization process, it was observedthat
copper(I) bromide as the catalyst and TBHP as the oxidant
were sufficient to carry out the transformation without the
requirement of any other additives. Thus, the nonrequire-
ment of expensive Pd catalyst or the additives make the
present protocol more economical and viable in compar-
ison to the recently reported synthesis of 3-acylindoles by
Liang et al.13
transformed to their corresponding 3-aroylindoles. Initially,
the effects of various substituents on the aryl ring (R2) were
examined. Irrespective of the nature of the substituents
such as p-Me (1b), p-tBu (1c), and p-NO2 (1d), all gave their
corresponding 3-aroylindoles (10b), (10c), and (10d) with
yields ranging from 73 to 80%. The structure of the
3-aroylindole (10b) has been unequivocally confirmed by
X-ray crystallography (Figure 1). When the N,N-dimethyl
substituted aryl ring (R1) of 2-alkynyl-N,N-dimethyl aniline
is substituted with an electron-donating group such as p-Me
and the other aryl moiety (R2) without a substituent (2a)
and with substituents such as p-Me (2b) and p-tBu (2c), all
yielded their 3-aroylated products (20a), (20b), and (20c),
respectively, in excellent yields. Similarly, when the N,N-
dimethyl substituted aryl ring (R1) of 2-alkynyl-N,N-di-
methyl aniline is substituted with 3,4-dimethyl group and
the other aryl moiety (R2) without a substituent (3a) and
with substituents such as p-Me (3b) and p-tBu (3c), all gave
their expected aroylated products (30a), (30b), and (30c),
respectively, but in a slightly lesser yields. However, a
significant drop in the yields were observed for substrates
possessing a moderately electron-withdrawing group such
as p-Br as has been demonstrated with substrates (4a), (4b),
and (4c) all giving their expected products (40a), (40b), and
(40c) in the yields ranging from 60 to 70% as shown in
Scheme 2.
Scheme 3. Proposed Mechanism for the Formation of 3-Aroy-
lindole
As a probe to the mechanism, when the standard reac-
tion was carried out in the presence of radical scavenger
TEMPO (3 equiv), the reaction gave many other side
products and only a trace of the desired product
(<10%), indicating the possibility of a radical mechanism.
As a further support to the radical path of the mechanism,
the reactions were carried out independently with Pd(OAc)2
and CuBr without the use of aq TBHP. Both of these
reactions failed to give any traces of the desired product,
and the starting material was recovered completely. These
control experiments suggest that neither Pd(II) nor Cu(I)
alone is sufficient to form the iminium cation and the
radical initiator TBHP is essential for this transformation.
On the basis of literature reports12and observations of the
control reactions and yield of the products obtained from
substituted substrates, a mechanism analogous to the one
recently proposed13 can be envisaged for these reactions.
Figure 1. ORTEP View of 10b.
The scope of this novel methodology was next explored
toward the synthesis of various 3-aroylated indoles from
their respective o-alkynylated N,N-dimethylamines under
the optimized reaction conditions. As shown in Scheme 2,
a variety of 2-alkynyl-N,N-dimethyl anilines could be
(13) While our manuscript was under preparation, a similar method
was reported by Liang et al. for the synthesis of 3-acylindole. Xia, X.-F.;
Zhang, L.-L.; Song, X.-R.; Niu, Y.-N.; Liu, X.-Y.; Liang, Y.-M. Chem.
Commun. 2013, 49, 1410.
Org. Lett., Vol. XX, No. XX, XXXX
C

Copper salt in combination with peroxide serves as a
single-electron oxidant.13 This active oxidant accepts an
electron from the nitrogen atom to form an aminyl radical
cation species (A) (Scheme 3). Abstraction of a proton
radical R to the nitrogen atom gave an iminium intermedi-
ate (B). The intramolecular attack of the alkynyl group
onto the iminium carbon in the intermediate (B) resulted in
CꢀC bond formation with concurrent formation of a
CꢀO bond by the attack of either water or TBHP onto
the alkynyl moiety to give intermediate (C). Ketonization
of the intermediate (C) provided 3-aroylindoline (D) which
underwent further oxidation to give its 3-aroylindole (10a).
Although Liang et al. have proposed the nucleophilic
attack of TBHP to the alkyne intermediate (B), in our case
the attack of water as the nucleophile cannot be completely
ruled out since the reaction proceeds better with aqueous
TBHP. The proposed mechanism (Scheme 3) is supported
by the fact that substrates containing an electron-with-
drawing group such as bromo (4a, 4b, and 4c) in the N,N-
dimethyl substituted aryl ring (R1) gave poor yields be-
cause of the instability of the aminyl radical cation (A).
Further, when both the rings are substituted with electron-
donating groups as in the caseof2a, 2b, and 2c, the product
yields were found to be better which is partly because of the
enhanced stability of the intermediate (B).
of 3-aroylindoles through a copper-catalyzed oxidative
process involving o-alkynylated N,N-dimethylamines in
the presence of aqueous TBHP as the oxidant in DMSO
solvent. This protocol simultaneously installs CꢀC and
CꢀO bonds through an intramolecular oxidative path in
the construction of 3-aroylindoles. This method uses an
inexpensive Cu catalyst without the requirement of any
cocatalyst and additives and proceeds at a relatively lower
temperature. Besides being one-pot and atom economical,
judging the practical utility makes the present method the
best alternative synthesis for 3-aroylindoles.
Acknowledgment. B.K.P. and A.G. acknowledge the
support of this research by the Department of Science
and Technology (DST) (SR/S1/OC-79/2009), New Delhi,
and the Council of Scientific and Industrial Research
(CSIR) (02(0096)/12/EMR-II). S.G. and S.K.R. thank
CSIR for fellowships. Thanks are due to Central Instru-
ments Facility (CIF) IIT, Guwahati.
Supporting Information Available. General information,
experimental procedures, spectral data and copies of
1H NMR and 13C NMR spectra for all products. This
material is available free of charge via the Internet at http://
pubs.acs.org.
In conclusion, irrespective of the nature of the mechan-
isms, we have developed an elegant method for the synthesis
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX