Rhodium(iii)-catalyzed regioselective C2-amidation of indoles with N-(2,4,6-trichlorobenzoyloxy)amides and its synthetic application to the development of a novel potential PPARγ modulator

Article abstract of DOI:10.1039/c4ob00637b

A new and efficient method for the direct regioselective C2-amidation of various functionalized indoles with several N-(2,4,6-trichlorobenzoyloxy)amides via Rh(iii)-catalyzed C-H activation/N-O cleavage/C-N formation using the pyrimidyl group as a readily installable and removable directing group has been developed. With this method, a variety of valuable 2-amido indoles can be easily prepared under mild conditions with broad functional group tolerance and excellent region-/site-specificities. Application of this strategy to the synthesis of target compound 6 as a novel PPARγ modulator was also demonstrated. The results from biological evaluation showed that compound 6 had a partial PPARγ agonistic activity and a strong PPARγ binding affinity with an IC₅₀ value of 120.0 nM, along with a less pronounced adipocyte differentiation ability compared to the currently marketed anti-diabetic drug rosiglitazone, suggesting that further development of such a compound might be of great interest. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4ob00637b

Volume 12 Number 35 21 September 2014 Pages 6747–6954
Organic &
Biomolecular
Chemistry
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ISSN 1477-0520
PAPER
H. Eric Xu, Wei Yi et al.
Rhodium(III)-catalyzed regioselective C2-amidation of indoles with
N-(2,4,6-trichlorobenzoyloxy)amides and its synthetic application to the
development of a novel potential PPARγ modulator

Organic &
Biomolecular Chemistry
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PAPER
Rhodium(III)-catalyzed regioselective
C2-amidation of indoles with N-(2,4,6-
trichlorobenzoyloxy)amides and its synthetic
application to the development of a novel
potential PPARγ modulator†
Cite this: Org. Biomol. Chem., 2014,
12, 6831
Jingjing Shi,a Guanguan Zhao,a Xiaowei Wang,a H. Eric Xu*a,b and Wei Yi*a
A new and efficient method for the direct regioselective C2-amidation of various functionalized indoles
with several N-(2,4,6-trichlorobenzoyloxy)amides via Rh(III)-catalyzed C–H activation/N–O cleavage/C–N
formation using the pyrimidyl group as a readily installable and removable directing group has been
developed. With this method, a variety of valuable 2-amido indoles can be easily prepared under mild
conditions with broad functional group tolerance and excellent region-/site-specificities. Application of
this strategy to the synthesis of target compound 6 as a novel PPARγ modulator was also demonstrated.
The results from biological evaluation showed that compound 6 had a partial PPARγ agonistic activity and
a strong PPARγ binding affinity with an IC50 value of 120.0 nM, along with a less pronounced adipocyte
differentiation ability compared to the currently marketed anti-diabetic drug rosiglitazone, suggesting that
further development of such a compound might be of great interest.
Received 26th March 2014,
Accepted 9th May 2014
DOI: 10.1039/c4ob00637b
www.rsc.org/obc
Introduction
Owing to the great importance of the C2-substituted indole
unit as a key building block in numerous natural products and
pharmacophores,1 the development of efficient methods for
the synthesis of C2-functionalized indoles constitutes
a
continuing focus in synthetic organic chemistry, which has
attracted considerable attention from synthetic chemists.2
Among the current methods, transition-metal-catalyzed direct
C–H functionalization3 represents
a burgeoning field in
organic chemistry because it allows for step- and atom-econ-
omical construction of organic building blocks.
Fig. 1 Selected examples of the 2-amido indole unit.
However, in contrast to the much more developed C2-
alkenylation4 or arylation5 (C–C formation), transition-metal-
catalyzed direct C2-amination/amidation6 of indoles (C–N for-
mation) has received limited success. A particular challenge is
intermolecular direct C2-amidation for the synthesis of the
valuable 2-amido indole unit even though such a scaffold is a
ubiquitous core structural motif found in many natural pro-
ducts, bioactive molecules and synthetic intermediates
(Fig. 1),7,8a,b for which very few metal-catalyzed protocols have
been reported so far.8 For example, Li and co-workers
described a Cu(I)-catalyzed C2-amidation of indoles, where a
nonremovable methyl group was used to occupy the free-NH
position (Scheme 1a).8c Afterwards, Nagarajan and co-work-
ers8a,b also intensively reported an efficient Pd-catalyzed
C2-amidation for building 2-amido indoles. However, their
catalysis required pre-functionalized indoles as substrates
(Scheme 1b). Therefore, the development of new and efficient
aVARI/SIMM Center, Center for Structure and Function of Drug Targets, CAS-Key
Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese
Academy of Sciences, Shanghai 201203, P.R. China. E-mail: yiwei.simm@simm.ac.cn,
eric.xu@simm.ac.cn; Fax: +86-21-20231000-1709; Tel: +86-21-20231000-1715
bLaboratory of Structural Sciences, Program on Structural Biology and Drug
Discovery, Van Andel Research Institute, Grand Rapids, Michigan 49503, USA
†Electronic supplementary information (ESI) available. See DOI:
10.1039/c4ob00637b
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Table 1 Reaction optimizationa
Entry
R
Indoles
Solvent
T (°C)
Yieldg
1b
2
2-Pyrimidyl
2-Pyrimidyl
2-Pyrimidyl
H
Me
Boc
(CH3)NCO
2-Pyrimidyl
2-Pyrimidyl
2-Pyrimidyl
2-Pyrimidyl
2-Pyrimidyl
2-Pyrimidyl
2-Pyrimidyl
2-Pyrimidyl
1a
1a
1a
1b
1c
1d
1e
1a
1a
1a
1a
1a
1a
1a
1a
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
Toluene
THF
80
80
80
80
80
80
80
60
100
80
80
80
80
80
80
56%
81%
43%
0
0
0
3c
4
5
6
7
8
0
56%
70%
57%
48%
0
37%
42%
80%
9
10
11
12
13d
14e
15f
Scheme 1 Transition-metal-catalyzed direct C2-amination of indoles.
MeOH
DCE
DCE
DCE
methods for the direct construction of 2-amido indoles is still
highly desirable.
On the other hand, recently Rh(III) complexes have emerged
as very useful and highly efficient catalysts for the direct C–H
activation of various aromatic substrates and subsequent
C–C,9 C–S10 and especially C–N11 forming reactions with the
assistance of an appropriate directing group (DG). Indeed,
Rh(III) catalysts could complement other metal catalysts in the
hot area of C–H functionalization in terms of activity, selecti-
vity, substrate scope and functional group tolerance, and so
far, a large number of important and useful structural motifs
have been synthesized by using the Rh(III)-catalyzed C–H acti-
vation strategy. However, to the best of our knowledge, until
now there is no report on the synthesis of 2-amido indoles by
Rh-catalyzed transformations.
Taking advantage of the above information and in order to
improve the current limited scope with regard to both the cata-
lyst and substrate, here we report for the first time a mild
Rh(III)-catalyzed direct regioselective C2-amidation12 of indoles
for step- and atom-economical construction of versatile
2-amido indoles (Scheme 1c). Moreover, application of this
developed methodology to the synthesis of target compound 6
as a novel PPARγ modulator was demonstrated. The nice data
from the biological evaluation suggested that further develop-
ment of such a compound for antidiabetic drug discovery
might be of great interest.
a Reaction conditions: substrate 1a–e (0.20 mmol), 2a (0.24 mmol),
[Cp*Rh(MeCN)3](SbF6)2 (5 mol%), solvent (1 mL),
5
h.
b Benzoyloxyacetamide was used as substrate. c (4-Methoxybenzoyloxy)-
acetamide was used as substrate. d [Cp*RhCl2]2 (5 mol%) and AgSbF6
(20 mol%) were used as the catalysts. e Rh(III) catalyst (2.5 mol%).
f Performed on a 5.0 mmol scale. g Isolated yields.
reagent (Table 1, entry 2), and that the desired product could
be isolated in 81% yield. No conversion was observed with
indoles bearing the H–, Me–, Boc or (CH3)2NCO– as DG
(Table 1, entries 4–7). Raising or lowering the temperature
resulted in lower reaction efficiencies (Table 1, entries 8–9).
Inferior results were also obtained in other selected solvents
such as toluene, THF or MeOH (Table 1, entries 10–12).
Change of the catalyst [Cp*Rh(MeCN)3](SbF6)2 to another well
known catalyst [Cp*RhCl2]2 obviously inhibited the process
(Table 1, entry 13). Furthermore, an attempt to reduce the cata-
lyst loading showed that lowering the amount of [Cp*Rh-
(MeCN)3](SbF6)2 to 2.5 mol% decreased the yield sharply
(Table 1, entry 14). In summary, the optimal conditions in
DCE include [Cp*Rh(MeCN)3](SbF6)2 (5.0 mol%) at 80 °C for
5 h under air. Finally, we were pleased to find that the reaction
could conveniently be scaled up to a gram level without a
decrease in isolated yield (Table 1, entry 15). It is noteworthy
to mention that by using the N-2-pyrimidyl unit as the DG,
the C–H at the C3-position or C7-position was untouched,
although it was found to be active in previous reported
transformations.14
Results and discussion
With the above established optimal conditions in hand, we
further explored the substrate scope of various N-2-pyrimidyl
indoles in the reaction with N-(2,4,6-trichlorobenzoyloxy)-acet-
amide 2a. As shown in Scheme 2, we were pleased to find that
the catalyst proved to be broadly applicable, and hence, furn-
ished the desired 2-amido indoles as the sole products in high
yields (67–85%). Both electron-donating and electron-with-
drawing substituents, including methoxy at C4- (3f) or C5-
(3o), cyano at C4- (3g) or C5- (3l), bromo at C5- (3h) or C6- (3q),
At the outset of this study, we chose N-2-pyrimidyl indole 1a as
a model substrate, which had shown relatively high reactivity
in previous studies.13 The first reaction was performed in DCE
with [Cp*Rh(MeCN)3](SbF6)2 as the catalyst and benzoyloxyacet-
amide as the amidation reagent. To our delight, the expected
product 3a was obtained in 56% yield under the initial con-
ditions (Table 1, entry 1). A survey of electronically different
aryloxyacetamides indicated that the electron-deficient (2,4,6-
trichlorobenzoyloxy)acetamide 2a was an optimal amidation
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Scheme 3 Substrate scope of N-(2,4,6-trichlorobenzoyloxy)amidesa.
a Reaction conditions: 1a (0.20 mmol), 2a–f (0.24 mmol), [Cp*Rh-
(MeCN)3](SbF6)2 (5 mol%), DCE (1 mL), 80 °C, 5 h. Isolated yields were
given. b This reaction was run for 12 h.
Scheme 2 Substrate scope of indolesa. a Reaction conditions: 1f–v
(0.20 mmol), 2a (0.24 mmol), [Cp*Rh(MeCN)3](SbF6)2 (5 mol%), DCE
(1 mL), 80 °C, 5 h. Isolated yields are given. b This reaction was run for
12 h.
Scheme 4 Competition
experiment.
Reaction
conditions:
1l
(0.20 mmol), 1o (0.20 mmol), 2a (0.20 mmol), [Cp*Rh(MeCN)3](SbF6)2
(5 mol%), DCE (1 mL), 80 °C, 5 h. Isolated yields.
chloro at C5- (3i) or C6- (3r), fluoro at C5- (3j) or C6- (3s), nitro
at C5- (3k) or C6- (3t), ester at C5- (3m), methyl at C5- (3n), C6-
(3u) or C7- (3v), and amido at C5- (3p) were all well tolerated.
Tolerance to the bromo, chloro, cyano and ester functions is
especially noteworthy since they are effective precursors for
further transformation through standard cross-coupling
strategies.
Meanwhile, with 1a as the model substrate, several N-(2,4,6-
trichlorobenzoyloxy)amides were also investigated under the
optimized conditions. As summarized in Scheme 3, amidation
reagents 2a–e reacted smoothly with 1a giving the corres-
ponding products 3a and 4b–e in 54–83% yields. Notably, com-
pound 2f bearing the pivalamide moiety was not active in the
developed procedure, probably because of steric hindrance.
Considering the remarkably broad substrate scope dis-
played by the Rh(III) catalytic system, we performed mechanis-
tic studies to delineate its mode of action (Scheme 4). To this
end, the competition experiment between differently substi-
tuted indoles (1l and 1o) indicated that the electron-rich
indoles are preferentially converted, suggesting they were
better substrates than electron-poor indoles.
Scheme 5 Postulated mechanism.
deprotonated nitrogen to give B, followed by a concerted
migratory insertion to generate intermediate C. Finally, proto-
demetallation of C provides the product 3a and releases the
Rh(III)-catalyst.
On the basis of the above results and literature precedents,
a preliminary mechanistic pathway is postulated (Scheme 5).
First, coordination of the nitrogen of 1a to the Rh(III) catalyst
and subsequent C–H activation forms the five-membered
rhodacycle A.15 Then, 2a coordinates to the rhodacycle via the
Synthetic application
It is well known that, the peroxisome proliferator-activated
receptor gamma (PPARγ) belongs to the nuclear receptors
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Scheme 6 Deprotection and synthetic application.
superfamily and it is a dominant regulator of adipose cell
differentiation and development. It is also the target protein
for the currently marketed thiazolidinedione (TZD) class of
antidiabetic drugs such as rosiglitazone (rosi).16 Studies
showed that these TZD antidiabetic drugs as PPARγ full
agonists enhance insulin sensitivity in target tissues and lower
glucose and fatty acid levels in type 2 diabetic patients.17
However, despite their proven benefits in treating diabetes,
TZD drugs possess undesirable side effects, such as increased
adiposity, edema, fluid accumulation and significant cardiac
hypertrophy.18 Thus, there is an urgent need to discover new
PPARγ agonists with improved therapeutic profiles containing
partial agonistic activity, potent binding affinity and lower
stimulated adipocyte differentiation ability (called PPARγ
modulators).
Therefore, in our continuing interest to develop new PPARγ
modulators for antidiabetic drug discovery,19 here we
attempted to synthesize structure-based target compound 6.20
The synthetic route is illustrated in Scheme 6. As shown in
Scheme 6, the deprotection21 of the pyrimidyl group of com-
pound 3p was easily achieved by treatment with EtONa in dry
DMSO at 100 °C to provide free-NH indole derivative 5 as the
desired product in good yield, in which the C2- and C5-amido
moieties of the indole are untouched. Furthermore, C2-amid-
ation and subsequent deprotection reactions could be per-
formed on a 5.0 mmol scale without significant decrease in
the corresponding product yield.
Subsequently, new compound 6 was synthesized smoothly
by using the above obtained 2-amido (free-NH) indole 5 as the
starting material and its biological activity on PPARγ was also
evaluated, with marketed antidiabetic drug rosi as standard
reference (Fig. 2). The results showed that compound 6 had
partial PPARγ agonistic activity (Fig. 2a) and a strong PPARγ
binding affinity with an IC50 of 120.0 nM (Fig. 2b), along with
a less pronounced adipocyte differentiation ability compared
to rosi (Fig. 2c). All the data revealed that compound 6 is
a selective PPARγ modulator with a better pharmacological
profile than rosi, suggesting that further development of such
a compound for antidiabetic drug discovery might be of great
interest.
Fig. 2 Bioactivity results. (a) Transcriptional activity of a PPAR-derived
reporter gene in COS-7 cells following treatment with rosiglitazone
(rosi) or compound 6. (b) The competitive binding affinity of 6 and rosi
to PPARγ. (c) The adipocyte differentiation ability of 6 and rosi.
indoles bearing an N-2-pyrimidyl moiety as a readily installable
and removable DG with several N-(2,4,6-trichlorobenzoyloxy)-
amides giving access to a wide range of functionalized
2-amido indoles in a more step- and atom-economical way.
The remarkable features of this methodology include good
product yields, broad functional group tolerance, and excellent
region-/site-specificities, and thus render this methodology as
a benign alternative to the existing methods. Moreover,
specific application of this methodology to the synthesis of
target compound 6 as a novel potential PPARγ modulator was
demonstrated. All the data from the biological evaluation
suggested that compound 6 might serve as a very promising
candidate for the treatment of the increasingly prevalent dia-
betes and as a lead for further design of new potential PPARγ
modulators. The results reported here deepen the understand-
ing of Rh(III)-mediated catalytic behavior and will find future
application in the synthesis of more biologically important
indole derivatives.
Acknowledgements
We are grateful to the Jay and Betty Van Andel Foundation,
Amway (China) and the Chinese Postdoctoral Science
Foundation (2012M511158 and 2013T60477) for financial
support on this study.
Notes and references
1 (a) R. J. Sundberg, Indoles, Academic Press, New York,
1996; (b) G. R. Humphrey and J. T. Kuethe, Chem. Rev.,
2006, 106, 2875; (c) A. J. Kochanowska-Karamyan and
M. T. Hamann, Chem. Rev., 2010, 110, 4489; (d) M. Nuth,
H.-C. Guan, N. Zhukovskaya, Y. L. Saw and R. P. Ricciardi,
Conclusions
In summary, here we have developed the first example of
Rh(III)-catalyzed direct regioselective C2-amidation of various
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J. Med. Chem., 2013, 56, 3235; (e) J. A. Sindac, S. J. Barraza,
C. J. Dobry, J.-M. Xiang, P. K. Blakely, D. N. Irani,
R. F. Keep, D. J. Miller and S. D. Larsen, J. Med. Chem.,
2013, 56, 9222.
(g) A. V. Lygin and L. Ackermann, Org. Lett., 2011, 13, 3332;
(h) S. Preciado, L. Mendive-Tapia, F. Albericio and
R. Lavilla, J. Org. Chem., 2013, 78, 8129.
6 For representative examples on C2-amination/amidation of
indoles, see: (a) X.-Y. Liu, P. Gao, Y.-W. Shen and
Y.-M. Liang, Org. Lett., 2011, 13, 4196; (b) A. John and
K. M. Nicholas, Organometallics, 2012, 31, 7914; (c) J. Ryu,
K. Shin, S. H. Park, J. Y. Kim and S. Chang, Angew. Chem.,
Int. Ed., 2012, 51, 9904; (d) J.-J. Shi, B. Zhou, Y.-X. Yang and
Y.-C. Li, Org. Biomol. Chem., 2012, 10, 8953.
7 (a) B. B. Snider and X.-X. Wu, Org. Lett., 2007, 9, 4913;
(b) A. Coste, M. Toumi, K. Wright, V. Razafimahaléo,
F. Couty, J. Marrot and G. Evano, Org. Lett., 2008, 10, 3841;
(c) V. O. Iaroshenko, Y. Wang, B. Zhang, D. Volochnyuk and
V. Y. Sosnovskikhe, Synthesis, 2009, 2393; (d) A. D.
Borthwick, Chem. Rev., 2012, 112, 3641; (e) S. D. Vaidya and
N. P. Argade, Org. Lett., 2013, 15, 4006; (f) B. Tréguier and
S. P. Roche, Org. Lett., 2014, 16, 278.
8 For reported examples on Cu or Pd-catalyzed intermole-
cular direct C2-amidation of indoles for the synthesis of
2-amido indoles, see: (a) A. S. Kumar and R. Nagarajan,
Org. Lett., 2011, 13, 1398; (b) A. S. Kumar, P. V. Rao and
R. Nagarajan, Org. Biomol. Chem., 2012, 10, 5084;
(c) Q. Shuai, G.-J. Deng, Z.-J. Chua, D. S. Bohle and C.-J. Li,
Adv. Synth. Catal., 2010, 352, 632.
9 For recent selected examples of Rh(III)-catalyzed C–C bond
formation, see: (a) G.-F. Li, Z.-W. Ding and B. Xu, Org. Lett.,
2012, 14, 5338; (b) W.-W. Chan, S.-F. Lo, Z.-Y. Zhou and
W.-Y. Yu, J. Am. Chem. Soc., 2012, 134, 13565; (c) Y.-J. Lian,
R. G. Bergman and J. A. Ellman, Chem. Sci., 2012, 3, 3088;
(d) C. Zhu, R. Wang and J. R. Falck, Chem. – Asian J., 2012,
7, 1502; (e) W.-C. Zhen, F. Wang, M. Zhao, Z.-Y. Du and
X.-W. Li, Angew. Chem., Int. Ed., 2012, 51, 11819;
(f) H. Wang, N. Schroder and F. Glorius, Angew. Chem., Int.
Ed., 2013, 52, 5386; (g) J. M. Neely and T. Rovis, J. Am.
Chem. Soc., 2013, 135, 66; (h) B.-Q. Liu, Y. Fan, Y. Gao,
C. Sun, C. Xu and J. Zhu, J. Am. Chem. Soc., 2013, 135, 468;
(i) D.-G. Yu, M. Suri and F. Glorius, J. Am. Chem. Soc., 2013,
135, 8802; ( j) S. Cui, Y. Zhang and Q. Wu, Chem. Sci., 2013,
4, 3421; (k) Y. Zhang, Q. Wu and S. Cui, Chem. Sci., 2014, 5,
297.
2 (a) J. Jiang and G. W. Gribble, Tetrahedron Lett., 2002, 43,
4115; (b) S.-G. Pan, N. Ryu and T. Shibata, J. Am. Chem.
Soc., 2012, 134, 17474; (c) M. Schinkel, I. Marek and
L. Ackermann, Angew. Chem., Int. Ed., 2013, 52, 3977;
(d) C.-D. Pan, H.-M. Jin, X. Liu, Y.-X. Cheng and C.-J. Zhu,
Chem. Commun., 2013, 49, 2933; (e) L.-Q. Zhang, S.-P. Yang,
X.-L. Huang, J.-S. You and F.-J. Song, Chem. Commun.,
2013, 49, 8830; (f) C.-D. Pan, H.-M. Jin, P. Xu, X. Liu,
Y.-X. Cheng and C.-J. Zhu, J. Org. Chem., 2013, 78, 9494.
3 For a recent review on transition-metal-catalyzed direct
C–H functionalization, see: (a) C. S. Yeung and V. M. Dong,
Chem. Rev., 2011, 111, 1215; (b) J. Wencel-Delord,
T. Droege, F. Liu and F. Glorius, Chem. Soc. Rev., 2011, 40,
4740; (c) S. H. Cho, J. Y. Kim, J. Kwak and S. Chang, Chem.
Soc. Rev., 2011, 40, 5068; (d) L. Ackermann, Chem. Rev.,
2011, 111, 1315; (e) F. W. Patureau, J. Wencel-Delord and
F. Glorius, Aldrichimica Acta, 2012, 45, 31; (f) K. M. Engle,
T.-S. Mei, M. Wasa and J.-Q. Yu, Acc. Chem. Res., 2012, 45,
788; (g) G.-Y. Song, F. Wang and X.-W. Li, Chem. Soc. Rev.,
2012, 41, 3651; (h) D. A. Colby, A. S. Tsai, R. G. Bergman
and J. A. Ellman, Acc. Chem. Res., 2012, 45, 814; (i) C. Zhu,
R. Wang and J. R. Falck, Chem. – Asian J., 2012, 7, 1502;
( j) N. Kuhl, M. N. Hopkinson, J. Wencel-Delord and
F. Glorius, Angew. Chem., Int. Ed., 2012, 51, 10236;
(k) S. R. Neufeldt and M. S. Sanford, Acc. Chem. Res., 2012,
45, 936; (l) S. I. Kozhushkov and L. Ackermann, Chem. Sci.,
2013, 4, 886; (m) J. Wencel-Delord and F. Glorius, Nat.
Chem., 2013, 5, 369; (n) J. L. Jeffreya and R. Sarpong,
Chem. Sci., 2013, 4, 4092; (o) V. S. Thirunavukkarasu,
S. I. Kozhushkov and L. Ackermann, Chem. Commun., 2014,
50, 29; (p) L. Ackermann, Acc. Chem. Res., 2014, 47,
281.
4 For representative examples on C2-alkenylation of indoles,
see: (a) N. P. Grimster, C. C. R. Gauntlett, A. Godfrey and
M. J. Gaunt, Angew. Chem., Int. Ed., 2005, 44, 3125;
(b) E. Capito, J. M. Brown and A. Ricci, Chem. Commun.,
2005, 1854; (c) A. Maehara, H. Tsurugi, T. Satoh and
M. Miura, Org. Lett., 2008, 10, 1159; (d) A. García-Rubia, 10 For the latest example of Rh(III)-catalyzed C–S bond
R. Gómez Arrayás and J. C. Carretero, Angew. Chem., Int.
Ed., 2009, 48, 6511; (e) A. García-Rubia, B. Urones,
R. Gómez Arrayás and J. C. Carretero, Chem. – Eur. J., 2010,
formation, see: Y.-X. Yang, W. Hou, L.-H. Qin, J.-J. Du,
H.-J. Feng, B. Zhou and Y.-C. Li, Chem. – Eur. J., 2014, 20,
416.
16, 9676; (f) B. Li, J.-F. Ma, W.-J. Xie, H.-B. Song, S.-S. Xu 11 For recent examples of Rh(III)-catalyzed C–N bond for-
and B.-Q. Wang, J. Org. Chem., 2013, 78, 9345.
mation, see: (a) K.-H. Ng, Z.-Y. Zhou and W.-Y. Yu, Org.
Lett., 2012, 14, 272; (b) C. Grohmann, H.-G. Wang and
F. Glorius, Org. Lett., 2012, 14, 656; (c) C. Grohmann,
H.-G. Wang and F. Glorius, Org. Lett., 2013, 15, 3014;
(d) S.-J. Yu, B.-S. Wan and X.-W. Li, Org. Lett., 2013, 15,
3706; (e) H. Zhao, Y. Shang and W. Su, Org. Lett., 2013, 15,
5106; (f) M. R. Yadav, R. K. Rit and A. K. Sahoo, Org. Lett.,
2013, 15, 1638; (g) K. Wu, Z.-L. Fan, Y. Xue, Q.-Z. Yao and
A. Zhang, Org. Lett., 2014, 16, 42; (h) B. Zhou, J.-J. Du,
Y.-X. Yang, H.-J. Feng and Y.-C. Li, Org. Lett., 2014, 16, 592;
5 For representative examples on C2-arylation of indoles, see:
(a) B. S. Lane, M. A. Brown and D. Sames, J. Am. Chem. Soc.,
2005, 127, 8050; (b) B. B. Touré, B. S. Lane and D. Sames,
Org. Lett., 2006, 8, 1979; (c) S.-D. Yang, C.-L. Sun, Z. Fang,
B.-J. Li, Y.-Z. Li and Z.-J. Shi, Angew. Chem., Int. Ed., 2008,
47, 1473; (d) J.-L. Zhao, Y.-H. Zhang and K. Cheng, J. Org.
Chem., 2008, 73, 7428; (e) L. Joucla, N. Batail and
L. Djakovitch, Adv. Synth. Catal., 2010, 352, 2929; (f) L. Jiao
and T. Bach, J. Am. Chem. Soc., 2011, 133, 12990;
This journal is © The Royal Society of Chemistry 2014
Org. Biomol. Chem., 2014, 12, 6831–6836 | 6835

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(i) S. H. Park, J. Kwak, K. Shin, J. Ryu, Y. Park and
S. Chang, J. Am. Chem. Soc., 2014, 136, 2492.
12 Direct evidence for the exclusive regioselectivity at the C-2
and not the C-3 position of the indole core can be obtained
from 1H NMR spectra. For example, see below (1f vs. 3f):
X.-W. Wang, Y.-N. Yan, Q. Li, Y.-Q. Meng, H. E. Xu and
W. Yi, Adv. Synth. Catal., 2014, 356, 137; (m) J.-J. Shi,
Y.-N. Yan, Q. Li, H. E. Xu and W. Yi, Chem. Commun., 2014,
50, 6483.
14 (a) S. Yanagisawa, T. Sudo, R. Noyori and K. Itami, J. Am.
Chem. Soc., 2006, 128, 11748; (b) V. Lanke and
K. R. Prabhu, Org. Lett., 2013, 15, 2818.
15 M. Nonoyama and K. Nakajima, Polyhedron, 1998, 18, 533.
16 J. M. Lehmann, L. B. Moore, T. A. Smith-Oliver,
W. O. Wilkison, T. M. Willson and S. A. Kliewer, J. Biol.
Chem., 1995, 270, 12953.
17 (a) A. J. Wagstaff and K. L. Goa, Rosiglitazone, Drugs, 2002,
62, 1805; (b) M. Diamant and R. J. Heine, Drugs, 2003, 63,
1373.
18 (a) R. W. Nesto, D. Bell, R. O. Bonow, V. Fonseca,
S. M. Grundy, E. S. Horton, M. Le Winter, D. Porte,
C. F. Semenkovich, S. Smith, L. H. Young and R. Kahn,
Diabetes Care, 2004, 27, 256; (b) S. E. kahn, B. Zinman,
J. M. Lachin, S. M. Haffner, W. H. Herman, R. R. Holman,
B. G. Kravitz, D. Yu, M. A. Heise, R. P. Aftring and
G. Viberti, Diabetes Care, 2008, 31, 845.
19 (a) R. R. Malapaka, S. K. Khoo, J.-F. Zhang, J. H. Choi,
X. E. Zhou, Y. Xu, Y.-H. Gong, J. Li, E. L. Yong,
M. J. Chalmers, L. Chang, J. H. Resau, P. R. Griffin,
Y. E. Chen and H. E. Xu, J. Biol. Chem., 2012, 287, 183;
(b) S. Yu and H. E. Xu, Structure, 2012, 20, 2.
20 Recently the co-crystal structure data of parent
compound (1-(4-chloro-3-fluorobenzyl)-N-benzyl-1H-indole-
5-carboxamide)–PPARγ LBD complexes has been obtained
by our group, revealing that a potential region of the hydro-
phobic pocket near to C2-position of indole moiety
could be exploited for drug design, and the above results
will be reported in a more specialized journal soon.
For the similar information, see: J. H. Choi, A. S. Banks,
T. M. Kamenecka, S. A. Busby, M. J. Chalmers, N. Kumar,
D. S. Kuruvilla, Y. Shin, Y. He, J. B. Bruning,
D. P. Marciano, M. D. Cameron, D. Laznik, M. J. Jurczak,
S. C. Schurer, D. Vidovic, G. I. Shulman, B. M. Spiegelman
and P. R. Griffin, Nature, 2011, 477, 477.
When the CH3CONH moiety was introduced, the C2-H
completely disappeared, and the chemical shift value of
C3-H slightly changes (δ = 6.84 vs. δ = 6.97). Moreover,
by analyzing the 1H NMR spectra data of other products,
the same conclusion was drawn that the corresponding
amidation reagent was specifically attached at C-2
position of indole cores. For detail, see the supporting
information.
13 For examples of transition-metal-catalyzed C–H functional-
ization by using N-2-pyrimidyl indole as the substrate, see:
(a) L. Ackermann and A. V. Lygin, Org. Lett., 2011, 13, 3332;
(b) Z. Ding and N. Yoshikai, Angew. Chem., Int. Ed., 2012,
51, 4698; (c) M. Nishino, K. Hirano, T. Satoh and M. Miura,
Angew. Chem., Int. Ed., 2012, 51, 6993; (d) Z. Ding and
N. Yoshikai, Beilstein J. Org. Chem., 2012, 8, 1536;
(e) S.-G. Xu, X.-M. Huang, X.-H. Hong and B. Xu, Org. Lett.,
2012, 14, 4614; (f) Z. Wang, F. Song, Y. Zhao, Y. Huang,
L. Yang, D. Zhao, J. Lan and J. You, Chem. – Eur. J., 2012,
18, 16616; (g) J. Ryu, K. Shin, S. H. Park, J. Y. Kim and
S. Chang, Angew. Chem., Int. Ed., 2012, 51, 9904; (h) C. Pan,
H. Jin, P. Xu, X. Liu, Y. Cheng and C. Zhu, J. Org. Chem.,
2013, 78, 9494; (i) Z. Shi, M. Boultadakis-Arapinis and
F. Glorius, Chem. Commun., 2013, 49, 6489; ( j) M. Schinkel,
I. Marek and L. Ackermann, Angew. Chem., Int. Ed., 2013,
52, 3977; (k) V. P. Reddy, R. Qiu, T. Iwasaki and N. Kambe,
Org. Lett., 2013, 15, 1290; (l) B.-W. Gong, J.-J. Shi,
21 For the deprotection procedure, see ref. 6d and 13 and the
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