Palladium-catalyzed direct C2-arylation of free (N–H) indoles via norbornene-mediated regioselective C–H activation

Article abstract of DOI:10.1016/j.tetlet.2017.04.066

A palladium-catalyzed direct C2-arylation reaction of free (N–H) indoles has been developed. This reaction relies on a norbornene-mediated C–H activation process on the indole ring, which features high regioselectivity and excellent functional group tolerance.

Full text of DOI:10.1016/j.tetlet.2017.04.066

Accepted Manuscript
Palladium-catalyzed direct C2-arylation of free (N-H) indoles via norbornene-
mediated regioselective C-H activation
Yadong Gao, Wangying Zhu, Long Yin, Bo Dong, Jingjing Fu, Zhiwen Ye,
Fengtian Xue, Chao Jiang
PII:
S0040-4039(17)30520-8
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.04.066
TETL 48858
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
18 March 2017
17 April 2017
21 April 2017
Please cite this article as: Gao, Y., Zhu, W., Yin, L., Dong, B., Fu, J., Ye, Z., Xue, F., Jiang, C., Palladium-catalyzed
direct C2-arylation of free (N-H) indoles via norbornene-mediated regioselective C-H activation, Tetrahedron
Letters (2017), doi: http://dx.doi.org/10.1016/j.tetlet.2017.04.066
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Graphical Abstract
To create your abstract, type over the instructions in the template box below.
Fonts or abstract dimensions should not be changed or altered.
Palladium-catalyzed direct C2-arylation of
free (N-H) indoles via norbornene-mediated
regioselective C-H activation
Leave this area blank for abstract info.
Yadong Gao, Wangying Zhu, Long Yin, Bo Dong, Jingjing Fu, Zhiwen Ye, Fengtian Xue,* Chao Jiang*

Tetrahedron Letters
1
Tetrahedron Letters
Palladium-catalyzed direct C2-arylation of free (N-H) indoles via norbornene-
mediated regioselective C-H activation
Yadong Gao,a Wangying Zhu,a Long Yin,a Bo Dong,a Jingjing Fu,a Zhiwen Ye,a Fengtian Xue,b* Chao Jianga*
aDepartment of Pharmaceutical Engineering, School of Chemical Engineering, Nanjing University of Science and Technology, Nanjing, Jiangsu, 210094, China.
bDepartment of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 Penn Street, Baltimore, Maryland 21201, United States.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A palladium-catalyzed direct C2-arylation reaction of free (N-H) indoles has been developed.
This reaction relies on a norbornene-mediated C-H activation process on the indole ring, which
features high regioselectivity and excellent functional group tolerance.
Available online
2017 Elsevier Ltd. All rights reserved.
Keywords:
palladium
norbornene
free (N-H) indoles
arylation
2-Arylindoles are an important class of building blocks for the
synthesis of various natural products and biologically or
medicinally active molecules (Figure 1).1 Many traditional
approaches to these compounds have involved cross-coupling
between a C2-prefunctionalized indole and a functionalized arene
derivatives, which often require multistep syntheses.2 Transition-
metal-catalysed direct C-H functionalization has emerged over
the past years as an attractive strategy to enhance molecular
complexity in modern organic synthesis, and recent work has
focused on the development of transition metal-catalysed
methods for the direct arylation of indoles due to the atom
efficiency.3 However, the reported methods always suffered from
low regioselectivity (C2 over C3) when no directing groups were
o
pre-installed and/or high reaction temperatures (100~150 C),
which significantly limited the substrate scope and functional
group tolerance.4 Directing groups such as amides,
carboxamides, carbamates, N-pyrimidyl and N-pyridyl have been
used to drive the arylation with C2 selectivity for indoles.5
However, an inherent limitation of the directed C-H activation
approach is that additional steps are required to preinstall and
remove the directing groups since they are often not an essential
moiety in the target compounds. The direct arylation of free (N
Figure 1． Biologically active molecules and drug candidates containing
2-arylindoles
———

Corresponding author. E-mail: chaojiang@njust.edu.cn,
fxue@rx.umaryland.edu
Scheme 1． Pd-catalysed norbornene-mediated C-H functionalization

2
Tetrahedron Letters
-H) indoles holds significant synthetic potential as it eliminates
Indole (1a) was employed as the initial model substrate. After
examining a range of Pd, ligand, additive, and solvent
combinations based on Bach’s work, we found that the desired
arylation can be achieved using iodobenzene as the arylation
reagent, PdCl2(MeCN)2 and norbornene as the catalyst, K2CO3 as
the base, a solution of water in DMA (0.5 M) as the solvent. 2-
Phenyl-1H-indole (2a) was obtained in 83% yield after column
chromatography. Then a series of control experiments were
subsequently conducted to understand the role of each reactant
(Table 1). When bromobenzene was used as the arylation reagent,
the reaction gave 2a in 62% yield (entry 2), which indicates aryl
bromide is compatible for this reaction. However chlorobenzene
showed almost no reactivity in the reaction while Pd(TFA)2 and
PdCl2 showed much lower reactivity (entries 4-6). Change
K2CO3 to other commonly used inorganic bases (entries 7-10)
dropped the yield significantly, which indicates its important role
in promoting the reaction. The use of pure DMA or DMF as
solvents gave comparable yields of 2a (entries 11, 12), but
acetonitrile proved to be less efficient as solvent for this reaction
(entry 13). Increasing or decreasing the reaction temperature both
led to dropped yields (entries 14-16). Eventually, aryl iodide (2
equiv.) as the arylation reagent, PdCl2(MeCN)2 (10 mol %) as the
catalyst, norbornene (2 equiv.) as the mediator, K2CO3 (2 equiv)
as the base, DMA with H2O (0.5 M) as the solvent, a reaction
temperature of 70 oC, were selected as the optimal conditions.
the need for introducing protecting groups and reactive
functionalities prior to C-C formation, thereby enabling direct
access to valuable heteroaromatic compounds.6 Such methods
require selective targeting of C-H bonds in the presence of a
reactive N-H functionality.7
The Catellani reaction is a powerful tool for the construction of
polyfunctionalized arenes (Scheme 1, a).8 The capacity to
functionalize both the ortho and ipso positions of aryl halides in a
single transformation held great appeal. Since its discovery,
Catellani, Lautens, and others enriched this chemistry
significantly, making this methodology a reliable part of the
toolbox for the synthesis of polysubstituted arenes as well as
carbo- and heterocycles.9 In the traditional Catellani reaction
where aryl halides are used as the starting materials, a Pd(0)
catalyst is required to generate an arylpalladium(II) species and
thus initiate the reaction. In 2011, Bach demonstrated this type of
reaction could also be catalysed by Pd(II) complexes. Starting
from free (N-H) indoles, selective C2-alkylation was achieved
under Pd(II) catalysis using norbornene as a transient mediator
(Scheme 1, b),10 and tryptophan derivatives, electron-deficient
pyrroles could also be alkylated using the same strategy.11 It is
worth mentioning that aryl iodides was also observed to affect
C2-arylation of indoles. Considering the significant synthetic
potential for the direct arylation of free (N-H) indoles, we
decided to study the Pd(II)-catalyzed direct C2-arylation of free
(N-H) indoles.
With the optimal reaction conditions in hand, the scope of the
indole component was first explored with iodobenzene (Table 2).
Indoles bearing different substitutions at C3, C4, C5, C6 or C7
positions participated in the C2-arylation reaction smoothly with
high regioselectivity. Indoles containing electron-donating
groups such as methyl (2b, 2c, 2i and 2j) and methoxy (2d)
groups afforded the C2-arylation products in excellent to good
yields. Indoles containing different halogen groups (fluoro, 2e,
2g; bromo, 2f) gave the desired product in moderate yields. For
6-chloroindole substrate, 2h was obtained in only 26% yield.
With strong electron-withdrawing group substituted indole
substrates, such as 5-nitroindole and 5-cyanoindole, the reaction
couldn’t give the desired products probably due to the
disadvantage of electrophilic metalation (C-H activation) towards
electron-poor indole system.
Table 1
Optimization Studies for the C2-Arylation of Indole
Table 2
C2-Arylation of Substituted Indole Derivativesa,b
a Reaction conditions: 1a (0.2 mmol, 1eq), iodobenzene (0.4 mmol, 2 eq.),
PdCl2(MeCN)2 (0.02 mmol, 10 mol %), norbornene (0.4 mmol, 2 equiv.),
K2CO3 (0.4 mmol, 2 equiv), DMA (1mL) with H2O (0.5 M), 70 oC, 17 h.
b Determined by HPLC, 1,2,3,4-Tetrahydronaphthalene as internal standard.
a Reaction scale: 0.2 mmol.
b Isolated yield.
c Isolated yield.

Tetrahedron Letters
3
Table 3
This might be related to the difficulties encountered in the
Arylation of Indole at the C2-Position with Different Aryl
oxidative addition of electron-rich aryl iodides towards palladium.
Iodidesa,b
The indole C2-arylation may follow the same pathway
previously proposed for the alkylation of indole by Bach.12 Its
plausible mechanism is shown in Scheme 2. The catalytic cycle
involves an initial N-palladation of indoles, aminopalladation of
norbornene then forms Pd(II) species A, which undergoes ortho-
C-H activation to provide the palladacycle B. Thus, following
oxidative addition of aryl iodides to the palladacycle, reductive
elimination and norbornene extrusion, a 2-aryl-N-palladaindole
species C is generated and subsequently hydrolysed to give the
final product and regenerate the Pd(II) catalyst. In coincidence
with our observation in Table 2 and 3, electron-rich indoles and
electron-poor aryl iodides would facilitate the ortho-C-H
activation and oxidative addition steps respectively, which might
be the reason leading to a better yields of the desired product.
In conclusion, a palladium-catalyzed direct C2-arylation
reaction of free (N-H) indoles was developed based on a
norbornene-mediated regioselective C-H activation. This reaction
is compatible with a wide range of functionalized aryl iodides, as
well as various substituents on indole with different electronic
natures. The present method highlights a facile one-step
transformation from easily available free (N-H) indoles and aryl
components to structurally diverse 2-arylindole derivatives.
a Reaction scale: 0.2 mmol.
b Isolated yield.
c KHCO3 as the base, 90 oC
Aryl iodides with different substitutions were also examined
for the C-2 arylation of indoles (Table 3). It was found that the
reaction is compatible with a variety of functionalized aryl
iodides with para-, meta- or orth- substitutions. Aryl iodides
containing electron-withdrawing groups (3a and 3b) afforded the
desired product efficiently in excellent yields. For halogen (F, Cl,
Br) substituted aryl iodides (3c-3e and 3g-3i), the reaction gave
the C2-arylation products smoothly. These bromo- or chloro-
substituted 2-arylindole products could be further manipulated to
synthesize more complicated poly-aromatic systems. Aryl
iodides containing electron-donating groups (3f, 3k and 3l)
tended to give the desired product in moderate yields using
Acknowledgment
This work was supported by the National Natural Science
Foundation of China (NSFC) (Grant No. 21402092), Natural
Science Foundation of Jiangsu Province – China (Grant No.
BK20140775), Nanjing University of Science and Technology –
China (‘‘Zijin Star Program”), the Priority Academic Program
development of Jiangsu Higher Education Institutions – China
(PAPD).
Supporting Information
References and notes
o
KHCO3 as the base under higher temperature (90 C) while 3j
could be obtained under standard conditions with excellent yields.
1. (a) Shi, W.; Marcus, S. L.; Lowary, T. L. Bioorg. Med.
Chem. 2011, 19, 603-612. (b) Kaushik, N. K.; Kaushik, N.;
Attri,P.; Kumar, N.; Kim, C. H.; Verma, A. K.; Choi, E. H.
Molecules 2013, 18, 6620-6662. (c) Daly, S.; Hayden, K.;
Malik, I.; Porch, N.; Tang, H.; Rogelj, S.; Frolova, L. V.;
Lepthien, K.; Kornienko, A.; Magedov, I. V. Bioorg. Med.
Chem. Lett. 2011, 21, 4720-4723. (d) Ambrus, J. I.; Kelso,
M. J.; Bremner, J. B.; Ball, A. R.; Casadei, G.; Lewis, K.
Bioorg. Med. Chem. Lett. 2008, 18, 4294-4297. (e)
Potavathri, S.; Kantak, A.; DeBoef, B. Chem. Commun.
2011, 47, 4679-4681. (f) Rohini, R.; Muralidhar Reddy, P.;
Shanker, K.; Hu, A.; Ravinder, V. Eur. J. Med. Chem.
2010, 45, 1200-1205; (g) Leboho, T. C.; Michael, J. P.; van
Otterlo, W. A.; van Vuuren, S. F.; de Koning, C. B. Bioorg.
Med. Chem. Lett. 2009, 19, 4948-4951. (h) Suzen, S.; Das-
Evcimen, N.; Varol, P.; Sarıkaya, M. Med. Chem. Res.
2007, 16, 112-118.
2. (a) Cacchi, S.; Fabrizi, G. Chem. Rev. 2005, 105, 2873-
2920. (b) Hartung, C.G.; Fecher, A.; Chapell, B.; Snieckus,
V. Org. Lett. 2003, 5, 1899-1902. (c) Djakovitch, L.;
Rouge, P. J. Mol. Catal. A. 2007, 273, 230-239. (d)
Chouzier, S.; Gruber, M.; Djakovitch, L. J. Mol. Catal. A.
2004, 212, 43-52.
Scheme 2．Plausible catalytic cycle
3. (a) Lane, B. S.;Sames, D. Org. Lett. 2004, 6, 2897-2900.
(b) Bressy, C.; Alberico, D.; Lautens, M. J. Am. Chem. Soc.

4
Tetrahedron Letters
2005, 127, 13148-13149. (c) Biajoli, A. F. P.; da Penha,
X.; Gribkow, D. V.; Sames, D. J. Org. Chem. 2007, 72,
1476-1479. (f) Huang, Y.-B.; Shen, M.; Wang, X.; Huang,
P.; Chen, R.; Lin, Z.-J.; Cao, R. J. Catal. 2016, 333, 1-7.
(g) Yang, S.-D.; Sun, C.-L.; Fang, Z.; Li, B.-J.; Li, Y.-Z.;
Shi, Z.-J. Angew. Chem., Int. Ed. 2008, 47, 1473-1476. (h)
Zhang, L.; Li, P.; Liu, C.;Yang, J.; Wang, M.; Wang, L.
Catal. Sci. Technol. 2014, 4, 1979-1988. (i) Preciado, S.;
Mendive-Tapia, L.; Albericio, F.; Lavilla,R. J. Org. Chem.
2013, 78, 8129-8135. (j) Bellina, F.; Calandri, C.;
Cauteruccio, S.; Rossi, R. Tetrahedron 2007, 63, 1970-
1980. (k) Miao, T.; Li, P.; Wang, G.-W.; Wang, L. Chem. -
Asian J. 2013, 8, 3185-3190. (l) Malmgren, J.; Nagendiran,
A.; Tai, C.-W.; Baeckvall, J.-E.; Olofsson, B. Chem. - Eur.
J. 2014, 20, 13531-13535. (m) Lu, G.-p.; Cai, C. Synlett
2012, 23, 2992-2996. (n) Duan, L.; Fu, R.; Zhang, B.; Shi,
W.; Chen, S.; Wan, Y. ACS Catal. 2016, 6, 1062-1074. (o)
Deprez, N. R.; Kalyani, D.; Krause, A.; Sanford, M. S. J.
Am. Chem. Soc. 2006, 128, 4972-4973. (p) Lane, B. S.;
Brown, M. A.; Sames, D. J. Am. Chem. Soc. 2005, 127,
8050-8057.
E. T.; Correia, C. R. D. RSC Adv. 2012, 2, 11930-11935.
(d) Huang, Y.; Ma, T.; Huang, P.; Wu, D.; Lin, Z.; Cao, R.
Chem. Cat. Chem. 2013, 5, 1877-1883. (e) Islam, S.;
Larrosa, I. Chem. - Eur. J. 2013, 19, 15093-15096. (f)
Zhou, J.; Hu, P.; Zhang, M.; Huang, S.; Wang, M.; Su, W.
Chem. - Eur. J. 2010, 16, 5876-5881. (g) Dwight, T. A.;
Rue, N. R.; Charyk, D.; Josselyn, R.; DeBoef, B. Org. Lett.
2007, 9, 3137-3139. (h) Stuart, D. R.; Villemure, E.;
Fagnou, K. J. Am. Chem. Soc. 2007, 129, 12072-13073. (i)
Phipps, R. J.;Grimster, N. P.; Gaunt, M. J. J. Am. Chem.
Soc. 2008, 130, 8172-8174. (j) Campbell, A. N.; Meyer, E.
B.; Stahl, S. S. Chem. Commun. 2011, 47, 10257-10259.
(k) Stuart, D. R.; Fagnou, K. Science 2007, 316, 1172-
1175. (l) Pena, M. A.; Sestelo, J. P.; Sarandeses, L. A. J.
Org. Chem. 2007, 72, 1271-1275. (m) Kannaboina,
P.;Anilkumar, K.; Aravinda, S.; Vishwakarma, R. A.; Das,
P. Org. Lett. 2013, 15, 5718-5721. (n) Takeda, D.;
Yamashita, M.; Hirano, K.; Satoh, T.; Miura, M. Chem.
Lett. 2011, 40, 1015-1017. (o) Feng, J.; Lu, G.; Lv, M.;
Cai, C. J. Organomet. Chem. 2014, 761, 28-31. (p) Liang,
Z.; Yao, B.; Zhang, Y. Org. Lett. 2010, 12, 3185-3187. (q)
Wang, L.; Yi, W.-b.; Cai, C. Chem. Commun. 2011, 47,
806-808. (r) Liu, C.; Ding, L.; Guo, G.; Liu, W.; Yang, F.-
L. Org. Biomol. Chem., 2016, 14, 2824-2827.
7. Wang, X.; Lane, B. S.; Sames, D. J. Am. Chem. Soc. 2005,
127, 4996-4997.
8. Catellani, M.; Frignani, F.; Rangoni, A. Angew. Chem. Int.
Ed. 1997, 36, 119-122.
9. (a) Marta, C.; Elena, M.; Nicola, D. C. Acc. Chem. Res.
2008, 41, 1512-1522. (b) Martins, A.; Mariampillai, B.;
Lautens, M. Top. Curr. Chem. 2010, 292, 1-33. (c) Ye, J.;
Lautens, M. Nat. Chem. 2015, 7, 863-870. (d) Della, Ca.
N.; Fontana, M.; Motti, E.; Catellani, M. Acc. Chem. Res.
2016, 49, 1389-1400.
10. Jiao, L.; Bach, T. J. Am. Chem. Soc. 2011, 133, 12990-
12993.
11. (a) Jiao, L.; Bach, T. Angew. Chem. Int. Ed. 2013, 52,
6080-6083. (b) Potukuchi, H. K.; Bach, T. J. Org. Chem.
2013, 78, 12263-12267.
4. Xu, Z.; Xu, Y.; Lu, H.; Yang, T.; Lin, X.; Shao, L.; Ren, F.
Tetrahedron 2015, 71, 2616-2621.
5. (a) Zheng, J.; Zhang, Y.; Cui, S. Org. Lett. 2014, 16, 3560-
3563. (b) Ackermann, L.; Lygin,A. V. Org. Lett. 2011, 13,
3332-3335. (c) Song, W.; Ackermann, L. Angew. Chem.,
Int. Ed. 2012, 51, 8251-8254. (d) Lu, M.-Z.; Lu, P.; Xu, Y.-
H.; Loh, T.-P. Org. Lett. 2014, 16, 2614-2617. (e) Tiwari,
V. K.; Kamal, N.; Kapur, M. Org. Lett. 2015, 17, 1766-
1769.
6. (a) Sezen, B.; Sames, D. J. Am. Chem. Soc. 2003, 125,
5274-5275. (b) Joucla, L.; Batail, N.; Djakovitch, L. Adv.
Synth. Catal. 2010, 352, 2929-2936. (c) Yang, L.; Luo, L.;
Zhang, S.; Su,X.; Lan, J.; Chen, C.-T.; You, J. Chem.
Commun. 2010, 46, 3938-3940. (d) Zhao, J.; Zhang, Y.;
Cheng, K. J. Org. Chem. 2008, 73, 7428-7431. (e) Wang,
12. Jiao, L.; Herdtweck, E.; Bach, T. J. Am. Chem. Soc. 2012,
134, 14563-14572.
Click here to remove instruction text...

Tetrahedron Letters
5
◆
◆
A one-step transformation from free (N-H) indoles to 2-arylindole derivatives.
Using norbornene as a transient directing group mediator.
◆
◆
This reaction is compatible with a wide range of functionalized aryl iodides and various substituents on indole.