KOtBu-Mediated Aerobic Transition-Metal-Free Regioselective β-Arylation of Indoles: Synthesis of β-(2-/4-Nitroaryl)-indoles

Article abstract of DOI:10.1021/ol503274z

A KO^tBu-mediated intermolecular oxidative C-C coupling of nitroarenes with indoles is presented in DMSO at room temperature in an open flask. By using this mild and economical methodology, syntheses of β-(2/4-nitroaryl)-indoles with sensitive f

Full text of DOI:10.1021/ol503274z

Letter
pubs.acs.org/OrgLett
t
KO Bu-Mediated Aerobic Transition-Metal-Free Regioselective
β‑Arylation of Indoles: Synthesis of β‑(2-/4-Nitroaryl)-indoles
Shailesh Kumar, Vandana Rathore, Ajay Verma, Ch. Durga Prasad, Amit Kumar, Abhimanyu Yadav,
Sadhan Jana, Moh. Sattar, Meenakshi, and Sangit Kumar*
Department of Chemistry, IISER Bhopal, Indore By-pass Road, Bhauri, Bhopal, Madhya Pradesh, India-462 066
*
S Supporting Information
t
ABSTRACT: A KO Bu-mediated intermolecular oxidative
C−C coupling of nitroarenes with indoles is presented in
DMSO at room temperature in an open flask. By using this
mild and economical methodology, syntheses of β-(2/4-
nitroaryl)-indoles with sensitive functionalities such as bromo,
iodo, cyano, and nitro were achieved chemo- and regiose-
lectively. Synthesized β-(2/4-nitroaryl) indoles were trans-
formed into densely functionalized biindoles, indoloindoles,
and (4-aminoaryl)-indoles which demonstrate post-trans-
formation utility of the developed methodology.
he direct transition-metal-free cross-coupling of two C−H
sulfinates, acids, silanes, phenylhydrazine hydrate, and [Ph-I-
T
bonds to C−C bond is an effective strategy for the synthesis
of organic molecules. This approach exhibits several interesting
features: a highly atom economic process, avoidance of expensive
transition-metal-catalysts, particularly, palladium, mild reaction
conditions, and generation of environmentally friendly side
products.
Ph]BF have been used for the synthesis of α-/β-aryl-indoles
4
3,4
under palladium- or copper-catalyzed methodologies (eq 1).
Transition-metal-catalyzed approaches to the direct C-(β)-
arylation of protected indoles using arenes have also been
5
reported under harsh reaction conditions (eq 2). Nonetheless,
these reactions provide a mixture of α-, β-, and α,β-diaryl-indoles
and are only suitable for the nonsubstituted and symmetrically
substituted arenes, as regioselective coupling of arenes has not
Aryl-indoles and their analogues constitute a large number of
biologically important pharmaceuticals, fragrances, agrochem-
1
,2
5
icals, conducting polymers, and ligands. As a result, several
methodologies have been developed to construct aryl-indoles
been achieved. Deng and Liao et al. have meticulously achieved
regioselective synthesis of β-aryl-indoles from cyclohexanone
3
−5
(
Scheme 1).
Transition-metal-catalyzed coupling of aryl
coupling partners utilizing a Pd(TFA) and DPEphos catalytic
2
5
e
halides with indoles under heating conditions is one of the
system at 140 °C for 30 h. Most of the developed
methodologies require costly transition-metal-catalysts, even
more costly additives/ligands, and harsh reaction conditions to
obtain aryl-indoles.
3a,b
conventional routes to access aryl-indoles.
Apart from aryl
halides, benign coupling partners such as boronic acids, sodium
Transition-metal-free approaches for C−C coupling reactions
Scheme 1. Synthetic Routes to Aryl-Indoles
6
−10
have attracted considerable interest recently.
Itami and co-
t
workers reported a transition-metal-free KO Bu-mediated C−C
6
coupling of heteroarenes with aryl iodides. Later Kwong, Lei et
t
al., Shi et al., and others have presented KO Bu-mediated C−C
7
,8a−d,f,h,k,l,9
coupling of unreactive arenes with aryl halides.
t
−
Pioneering work on BuO -mediated aerobic oxidative C−C
coupling has been reported by Ess and Kurti et al. for the
synthesis of α-arylated ketones. Our group has also studied
KO Bu-mediated C−C coupling in phenols and benzamides
̈
10i
t
9
using aryl halide coupling partners.
Here for the first time, a transition-metal-free synthesis of β-
aryl-indoles via intermolecular oxidative coupling of indole with
10
inexpensive nitroarenes is presented at rt (eq 3). Further, new
Received: November 11, 2014
©
XXXX American Chemical Society
A
dx.doi.org/10.1021/ol503274z | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
synthetic routes have been established to construct indoloindoles
and biindoles which are difficult or inaccessible by existing
methodologies.
Scheme 2. Synthesis of β-(4-Nitrophenyl)-1H-indoles
For the optimization of reaction, we began with 2-
methylindole and nitrobenzene coupling partners for screening
of various solvents, bases, and additives to obtain β-aryl-indole 1
t
(
Table 1). Bases such as K CO , Cs CO and even LiO Bu did
2
3
2
3
a
Table 1. Optimization of Reaction Conditions
entry
base
solvent
time (h)
yield (%)
1
2
3
4
5
6
7
8
9
K CO3
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
12
12
12
3
NR
NR
NR
74
48
2
Cs CO
2
3
t
LiO Bu
t
KO Bu
t
KO Bu (3 equiv)
3
t
NaO Bu
3
68
t
KO Bu + CuI
3
68
KOH
NaOH
KH
12
12
3
18
14
10
11
12
13
14
15
16
72
NaH
3
65
a
t
b
Aryl-indole 5 (25%) was also formed by the coupling of C−Cl and
KO Bu
3
40
b
C−H bonds via S Ar pathway. Reaction was carried at 100 °C;
t
N
KO Bu
DME
12
12
12
12
trace
<10
NR
20
formation of respective C−N coupled product was observed at rt (see
t
KO Bu
CH CN
3
SI, pp S-7, S-9).
t
KO Bu
EtOH
t
c
KO Bu/L
benzene
a
Reactions were carried out using 2-methylindole (1 mmol) and
nitrobenzene (2 mmol) and base (2 mmol) in an open flask for
b
c
indicated time. Side products were also observed. L, 1,10-
phenanthroline.
not provide any β-aryl-indole 1 and reactants 2-methylindole and
nitrobenzene recovered quantitatively from the reaction (entries
Figure 1. Crystal structures of β-(4/2-nitrophenyl)-indoles 2 and 22.
1
−3, Table 1). Interestingly, potassium and sodium tert-
butoxides provided 74 and 68% yields, respectively, of oxidative
coupled product 1 (entries 4 and 6, Table 1). Potassium and
sodium hydride were also effective for the promotion of C−C
coupling reaction (entries 10−11). Other strong bases KOH,
and NaOH noticed to be less effective for the oxidative C−C
coupling as poor yields of 1 was noticed. Next solvents such as
coupling of indole with 1,3-dinitrobenzene in 78% yield. Further,
2-nitrobenzonitrile, 1-methyl-3-nitrobenzene, and 1-nitronaph-
thalene reacted smoothly with indole under optimized
conditions, leading to cyano-substituted-4-nitrophenyl-, meth-
yl-substituted-, and 4-nitro-naphthyl indoles (6−8) in 48−66%
yields. After variation of substitution in nitrobenzene, the
substrate scope with respect to indole was studied. Unsubstituted
indoles underwent oxidative coupling at the β-position leading
various aryl-indoles 9−10 and 12−21 chemo- and regioselec-
tively in 45−77% yields, and formation of α-aryl-indoles was not
observed under the reaction conditions. However, oxidative C−
N coupled products, 1-(4-nitrophenyl)-indoles, were also
noticed along with the formation of β-aryl-indoles 9 and 14
(for detail information, see SI pp S7−S9). The desired β-aryl-
indoles 9 and 14 were obtained as major products by carrying out
DMF, DME, CH CN, EtOH, and benzene were screened in the
3
reaction (entries 12−16), unfortunately, none of the solvents
gave better yield of product 1.
After screening of bases and solvents, we studied the substrate
t
scope of coupling partners utilizing two equiv of KO Bu in
DMSO and results are presented in Scheme 2. 2-Chloro-
nitrobenzene and 1,4-dichloro-2-nitrobenzene coupled with
indole successfully to give respective β-aryl-indoles 2 and 3.
Interestingly, S Ar C−C coupled product or dechlorination was
N
not observed under the reaction conditions. Structure of β-(3-
chloro-4-nitrophenyl)-2-methylindole 2 is also established by X-
11
12
ray single crystal structure study, Figure 1 (vide infra).
the reaction at 100 °C. Also electron-donating groups such as
Next, 1-chloro-2,4-dinitrobenzene was coupled with indole
which furnished β-aryl-indole 4 in 51% yield and formation of
SNAr product 5 by dehydrochlorination was also observed.
Alternatively, β-aryl-indole 5 was prepared by the oxidative
methyl, methoxy or withdrawing groups such as nitro, bromo,
chloro at various positions in the benzene ring of indole could be
tolerated under the reaction conditions and gave phenyl
substituted β-aryl-indoles 11−21 in moderate to good yields.
B
dx.doi.org/10.1021/ol503274z | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
On the other hand, electron-donating 2-ethyl, 3-amino, 3-
methyl, and 4-methoxy-nitrobenzenes were observed to be
unreactive, as only 3-methyl-nitrobenzene coupled with indole to
form β-arylindole 7 in 48% yield.
β-(2-Nitroaryl)-indoles could be useful intermediates for the
preparation of indoloindoles (vide infra). We envisaged the
synthesis of β-(2-nitroaryl)-indoles by ortho-C−H coupling in
nitrobenzenes with indoles. For this purpose, para-substituted 4-
trifluoromethylnitrobenzene was reacted with indole under the
optimized reaction conditions (Scheme 3). To our delight, 4-
been achieved earlier by Pal et al. from C-α amination of indoles
using 2-iodo-N-arylsulfonylamines followed by ring closing, Pd-
catalyzed coupling of the β-C−H bond with the C−I bond of
2b
amines. Moreover, synthesis of indolo[3,2b]indoles with both
14
free N−H has not been documented. Here synthesis of
indoloindoles 28−29 has been accomplished by heating β-(2-
nitrophenyl)-indoles 22 and 24 in P(OEt)3 at 150 °C.
Unsymmetrically N-substituted indoloindoles 32 and 33 were
obtained from N-methyl-β-(2-nitrophenyl)-indoles 30 and 31,
respectively, by following the similar method. Next, we turn our
attention to the synthesis of 3,5′-biindoles from β-(4-nitroaryl)-
indoles. Addition of vinylmagnesium bromide to N-methyl-
indoles 34 and 35 gave respective 3,5′-biindoles 36 and 37 in
Scheme 3. Synthesis of β-(2-Nitrophenyl)-1H-indoles
7
0% and 85% yields. In the end, the nitro group in 1, 18, and 16
was converted into an amine using Fe-powder in EtOH/water
and the resulted electron-rich aryl-indoles (38−40) were
obtained in 70−75% yields.
A plausible mechanism is presented in Scheme 5 based on the
reactivity as well as regio- and chemoselective outcome in the
Scheme 5. Mechanism for Coupling of Indole with Nitroarene
trifluoromethyl substituted nitrobenzene underwent ortho-C−H
oxidative coupling with indole leading to β-(2-nitrophenyl)-
indole 22 in moderate yield (57%).Oxidative ortho-C−H
coupling in 4-trifluoromethylnitrobenzene was also confirmed
11
by the single crystal study of β-aryl-indole 22 (Figure 1).
Next, various substituted β-(2-nitrophenyl)-indoles 23−27
were readily synthesized by the ortho-C−H coupling of
13
substituted indoles with 4-trifluoromethyl-nitrobenzene.
Further transformation of β-(2/4-nitro-aryl)-indoles was
explored for the synthesis of indoloindoles, biindoles, and β-
oxidative coupling of indoles with nitroarenes. It seems that the
presence of the N−H group in indole is crucial for oxidative
coupling with the nitrobenzene. The N−H group reacts with
(
2/4-amino-aryl)-indoles (Scheme 4). Construction of unsym-
metrically N-substituted (N-R′ and N-R″) indoloindoles has
t
KO Bu leading to indol-1-ide I, which converts into indol-3-ide II
Scheme 4. Further functionalization of β-nitroaryl indoles
via resonance. Nucleophilic attack of II to the para position of
nitrobenzene (if para-substituted, then ortho position) would
lead to intermediate III, which might undergo resonance to form
IV. Interaction of atmospheric oxygen with the hydrogen (shown
10i
in V, Scheme 5) could transfer hydrogen to oxygen leading to a
hydroperoxide radical and carbon centered radical of inter-
mediate V, which upon combination may yield intermediate
10i
VI. This intermediate may give 3-(4-nitrophenyl)-3H-indole
VII which converts into the desired β-aryl-indole 9 by
tautomerization. Since the reaction provided a moderate yield
(
40%) of product under an argon atmosphere, DMSO could also
serve as an oxidant.
In summary, we have shown that β-arylation in unprotected
indoles could be achieved chemo- and regioselectively by
t
employing KO Bu at room temperature in air without using
the TM catalyst and aryl halide coupling partner. Because of the
mild conditions, this methodology tolerates sensitive function-
alities such as iodo, bromo, chloro, and nitro on indole and
chloro and nitro on nitroarene coupling partners. β-(2-
Nitroaryl)-indoles were also accessed by using 4-substituted
nitrobenzenes. Postmodification of the nitro group in β-(2/4-
nitroaryl)-indoles has also been demonstrated for the synthesis
of indoloindoles, and biindoles. Currently, oxidative coupling of
another class of aromatic amines is in progress in our laboratory.
C
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Organic Letters
Letter
arylindole by Pd-catalyzed cross-coupling of pentafluorobenzene: He,
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ASSOCIATED CONTENT
Supporting Information
■
*
S
Experimental details, NMR spectra, and X-ray crystallographic
data. This material is available free of charge via the Internet at
http://pubs.acs.org.
(6) (a) Yanagisawa, S.; Ueda, K.; Taniguchi, T.; Itami, K. Org. Lett.
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(
AUTHOR INFORMATION
Corresponding Author
■
*
Pierini, A. B.; Penenory, A. B. Chem. Rev. 2003, 103, 71. (b) Sun, C.-L.;
Li, H.; Yu, D.-G.; Yu, M.; Zhou, X.; Lu, X.-Y.; Huang, K.; Zheng, S.-F.; Li,
B.-J.; Shi, Z.-J. Nat. Chem. 2010, 2, 1044. (c) Sun, C.-L.; Gu, Y.-F.; Wang,
B.; Shi, Z.-J. Chem.Eur. J. 2011, 17, 10844. (d) Sun, C.-L.; Gu, Y.-F.;
Huang, W.-P.; Shi, Z.-J. Chem. Commun. 2011, 47, 9813. (e) Yanagisawa,
S.; Itami, K. ChemCatChem. 2011, 3, 827. (f) Chan, T. L.; Wu, Y.; Choy,
P. Y.; Kwong, F. Y. Chem.Eur. J. 2013, 19, 15802. (g) Sun, C.-L.; Shi,
Z.-J. Chem. Rev. 2014, 114, 9219.
E-mail: sangitkumar@iiserb.ac.in.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(8) (a) Recent reports on TM-free C−H functionalization: Liu, W.;
S.K. thanks the DST New Delhi, DRDO New Delhi, DAE-BRNS
Mumbai, and IISER Bhopal for generous funding. S.K. and S.J.
thank IISER Bhopal, and V.R., A.V., A.K., A.Y., D.P., and M.S.
thank UGC, CSIR New Delhi for a fellowship, respectively.
Cao, H.; Zhang, H.; Zhang, H.; Chung, K. H.; He, C.; Wang, H.; Kwong,
F. Y.; Lei, A. J. Am. Chem. Soc. 2010, 132, 16737. (b) Laha, J. K.; Barolo,
S. M.; Rossi, R. A.; Cuny, G. D. J. Org. Chem. 2011, 76, 6421. (c) Vaillard,
V. A.; Guastavino, J. F.; Buden, M. E.; Bardagi, J. I.; Barolo, S. M.; Rossi,
R. A. J. Org. Chem. 2012, 77, 1507. (d) Zhang, H.; Shi, R.; Ding, A.; Lu,
L.; Chen, B.; Lei, A. Angew. Chem., Int. Ed. 2012, 51, 12542. (e) Xiao, F.;
Liao, Y.; Wu, M.; Deng, G.-J. Green Chem. 2012, 14, 3277. (f) Wu, Y.;
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014, 12, 2864.
D
dx.doi.org/10.1021/ol503274z | Org. Lett. XXXX, XXX, XXX−XXX