B(C6F5)3-catalyzed Markovnikov addition of indoles to aryl alkynes: An approach toward bis(indolyl)alkanes

Article abstract of DOI:10.1039/c8ob02805b

The first example of the metal-and solvent-free B(C₆F₅)₃-catalyzed Markovnikov addition of indoles to aryl alkynes was disclosed. Both N-H and N-protected indoles were tolerated, leading to a wide spectrum of versatile bis

Full text of DOI:10.1039/c8ob02805b

Organic &
Biomolecular Chemistry
View Article Online
View Journal | View Issue
PAPER
B(C6F5)3-catalyzed Markovnikov addition of
indoles to aryl alkynes: an approach toward
bis(indolyl)alkanes†
Cite this: Org. Biomol. Chem., 2018,
16, 9274
Fei Ling,
Lian Xiao, Lu Fang, Cong Feng, Zhen Xie, Yaping Lv and
Weihui Zhong
*
Received 10th November 2018,
Accepted 20th November 2018
The first example of the metal- and solvent-free B(C6F5)3-catalyzed Markovnikov addition of indoles to
aryl alkynes was disclosed. Both N–H and N-protected indoles were tolerated, leading to a wide spectrum
of versatile bis(indolyl)alkanes in moderate to good yields with high regioselectivities.
DOI: 10.1039/c8ob02805b
rsc.li/obc
important small molecules, considered as versatile building
blocks, widely used in organic chemistry, materials science
Introduction
The development of practical methodologies for the prepa- and pharmaceuticals.12 The first example of B(C6F5)3-pro-
ration of bis(indolyl)alkanes is an important issue in organic moted activation of alkynes was first achieved by Stephan’s
synthesis, owing to the prevalence of these derivatives as core group, allowing the synthesis of alkynylborane or alkynyl-
structures in a wide range of biologically interesting natural aluminium derivatives.13 Following this fundamental work,
products and pharmaceuticals (Fig. 1).1 Among a myriad of numerous efforts have been devoted to reactions where stoi-
methods to produce these structures,2 the catalytic dihydro- chiometric B(C6F5)3 activated alkynes toward cyclization to
indolation of alkynes is the most efficient way to synthesize bis form heterocyclic and aromatic compounds.14 Recently, the
(indolyl)alkanes because this method does not require pre- catalytic protocols of activation of alkynes have also been
functionalization of the reaction partners and exhibits high investigated, such as polymerization,15 hydroamination,16
atom economy. To date, various metal-based catalysts, such as cycloisomerization,17 hydrofunctionalization,18 oxoalkylation19
Pt,3 Au,4 Hg,5 Re,6 In,7 and Ru,8 have been reported for di- and other transformations.20 In general, as a strong π-Lewis
hydroindolation reactions between N-protected indoles and acid, B(C6F5)3 can activate the alkynes via π-coordination to
alkynes in solutions (Scheme 1a), while a few of them could be the C–C triple bond. Accordingly, our design is to employ
applied in this kind of reaction employing N–H indoles as sub- B(C6F5)3 as a π-Lewis acid activating terminal alkynes to facili-
strates (Scheme 1b).9 In contrast, metal-free catalytic di- tate the double Markovnikov addition of indoles. Herein, we
hydroindolation has remained an unexplored field. With describe the first example of metal-free B(C6F5)3-catalyzed
regard to the influences of trace metals on the efficiency of dihydroindolation of aryl alkynes through double Markovnikov
organic electronic devices and human consumption products addition under solvent-free conditions, providing easy access
as well as the costs associated with removing residual catalysts, to versatile bis(indolyl)alkanes (Scheme 1c).
the development of metal-free catalytic protocols for the
efficient synthesis of bis(indolyl)alkanes is of great interest
and importance.
Tris(pentafluorophenyl)-borane, as one component of
FLPs,10 has received much attention as metal-free alternatives
to transition metal catalysis for the activation of small mole-
cules and related transformations.11 Alkynes are a class of
Key Laboratory for Green Pharmaceutical Technologies and Related Equipment of
Ministry of Education, College of Pharmaceutical Sciences, Zhejiang University of
Technology, Hangzhou 310014, People’s Republic of China.
E-mail: weihuizhong@zjut.edu.cn
†Electronic supplementary information (ESI) available. CCDC 1877500. For ESI
and crystallographic data in CIF or other electronic format see DOI: 10.1039/
c8ob02805b
Fig. 1 Biological compounds containing a bis(indolyl)alkane core.
9274 | Org. Biomol. Chem., 2018, 16, 9274–9278
This journal is © The Royal Society of Chemistry 2018

View Article Online
Organic & Biomolecular Chemistry
Paper
the product yield (Table 1, entries 9 and 10). Moreover,
decreasing the catalyst loading from 5 mol% to 1 mol%
resulted in a reduced yield (Table 1, entry 11). It was note-
worthy that the ratio of 1a and 2a is crucial for achieving a
high yield; the reaction yield was sharply decreased to 35%,
and the by-product 5a was obtained in 54% yield when using
1.0 mmol of 2a, while increasing the ratio from 1 : 2 to
1 : 4 had little influence on the yield (Table 1, entries 8, 12
and 13). In contrast, no product or by-product was observed in
the absence of B(C6F5)3 (Table 1, entry 14). Notably, this proto-
col could be easily conducted on a gram scale, producing 3a in
1.36 g, 81% yield (Table 1, entry 15).
Scheme 1 Catalytic systems for dihydroindolation of alkynes.
With the optimal conditions in hand, we set out to probe
its versatility in the dihydroindolation of indoles and alkynes.
The scope of this reaction was first explored with a range of
indoles 1 with ethynylbenzene (2a) and the results are shown
in Scheme 2. Both the electron-donating (–Me) and electron-
withdrawing groups (–F, –Cl, –Br, and –CO2Me) at the C4–C7
positions of the indole substrate reacted with ethynylbenzene
smoothly to give the desired products in moderate to good
yields. The substitution pattern had an influence on the reac-
tion yield; 6-position-substituted indoles afforded the corres-
ponding products (3c, 3g and 3j) in relatively higher yields
than those bearing a substituent on the 5- or 7-position
(3b, 3f, 3h and 3i). In addition, the halogen groups were well
Results and discussion
The initial assay was carried out by reacting 1H-indole (1a,
1 mmol) and ethynylbenzene (2a, 2 mmol) with 5 mol% of
B(C6F5)3 as a catalyst in toluene at 60 °C for 6 h (Table 1, entry 1).
Pleasingly, the desired bis(indolyl)alkane 3a was isolated in
78% yield. However, switching B(C6F5)3 to Brønsted acid or
less acidic boron acid failed to give the desired product
(Table 1, entries 2 and 3). Next, a set of solvents were exam-
ined; while THF and n-hexane were capable of producing 3a in
62% and 15% yields, along with the formation of the by-
product 5a in 10% and 23% yields, respectively, no product
was obtained when using DCE or DMF as the solvent (Table 1,
entries 4–7). Delightfully, 1a reacted with 2a smoothly under
solvent-free conditions, delivering 3a in 85% yield (Table 1,
entry 8). Changing the reaction temperature did not improve
Table 1 Optimization of reaction conditionsa
Entry
Cat.
Solvent
T (°C)
Yield (%) 3a/5a
1
2
3
4
5
6
7
8
B(C6F5)3
CF3CO2H
(2,6-F2C6H3)3B
B(C6F5)3
B(C6F5)3
B(C6F5)3
B(C6F5)3
B(C6F5)3
B(C6F5)3
B(C6F5)3
B(C6F5)3
B(C6F5)3
B(C6F5)3
—
Toluene
Toluene
Toluene
THF
n-Hexane
DCE
DMF
Neat
Neat
Neat
Neat
Neat
Neat
Neat
60
60
60
60
60
60
60
60
80
40
60
60
60
60
60
78/trace
—
Trace
62/10
15/23
—
—
85/trace
71/trace
62/trace
43/trace
35/54
80/trace
0/0
9
10
11b
12c
13d
14
15e
B(C6F5)3
Neat
81/trace
a Reaction conditions: 1a (1.0 mmol), 2a (2.0 mmol), and catalyst
(5 mol%) in solvent (2 mL) for 6 h under air. b With 1 mol% of
B(C6F5)3. c With 2a (1.0 mmol). d With 2a (4.0 mmol). e Gram-scale
experiment with 10 mol of 1a.
Scheme 2 Substrate scope of indoles 1.
This journal is © The Royal Society of Chemistry 2018
Org. Biomol. Chem., 2018, 16, 9274–9278 | 9275

View Article Online
Paper
Organic & Biomolecular Chemistry
tolerated to produce the corresponding products 3d–3h in
65–91% yield. Importantly, the N-methyl indole reacted with
2a smoothly to give the desired product 3k in 42% yield.
Notably, the N-protected indoles were also compatible with
this reaction, affording the expected products 3l and 3m in
55% and 61% yields, respectively.
Next, the scope of this reaction was examined with a range
of aryl alkynes 2 with 1H-indole (Scheme 3). The substitution
pattern of aryl moieties had a slight effect in this reaction; for
the electron-donating group, meta-substituted alkyne gave a
lower yield than those with ortho- and para-substituents (3o vs.
3n and 3p), while an opposite result was observed when using
fluoro-substituted alkynes (3r, 77% yield vs. 3s, 68% yield).
Moreover, the best result was obtained when using 1-ethynyl-4-
methoxybenzene as a substrate, producing 3q in 89% yield. In
addition, this process was compatible with Br and Cl, leading
to the desired products 3u and 3t in moderate to good yields.
Notably, the structure of 3t was unambiguously determined
by single-crystal X-ray analysis. Remarkably, the thienyl
group still reacted with 1a efficiently to yield the targeted
product 3v in 87% yield. Unfortunately, a strong electron-
withdrawing aryl alkyne was unable to deliver the expected
product 3w.
Scheme 4 Control experiments.
In order to get an insight into the reaction mechanism,
several control experiments were conducted (Scheme 4).
Initially, we synthesized 3-(1-phenylvinyl)-1H-indole (4a),21
which is a key intermediate according to the previous litera-
ture. Reacting 4a with 1H-indole (1a) and B(C6F5)3 in toluene
at 60 °C for 20 min resulted in the full conversion of 4a to give
3a in 96% yield (Scheme 4, eqn (1)). However, without B(C6F5)3
as a catalyst, the reaction became inefficient and only
55% yield of 3a was obtained after 16 h (Scheme 4, eqn (2)).
These results indicated that 3-(1-phenylvinyl)-1H-indole (4a)
Scheme 5 Proposed mechanism.
might be involved in this process and B(C6F5)3 could promote
the second hydroindolation of 4a and 1a. Interestingly,
3-(1-phenylvinyl)-1H-indole reacted with 1-methyl-1H-indole
(1k) smoothly to give unsymmetrical bis(indolyl)alkane 3x in
87% yield (Scheme 4, eqn (3)).
Based on the control experiments and the previous work on
B(C6F5)3-catalyzed activation of alkynes,14–20
a proposed
mechanism for this dihydroindolation is described in
Scheme 5 using 1H-indole (1a) and ethynylbenzene (2a) as
template substrates. Coordination of B(C6F5)3 with alkyne 2a
affords intermediate A. Subsequent nucleophilic attack of 1a
on the internal carbon of the C–C triple bond results in the
zwitterionic boron derivative B, which undergoes protodebory-
lation15,16 and aromatization to yield the intermediate
3-(1-phenylvinyl)-1H-indole (4a) with concomitant regeneration
of the borane catalyst. Next, B(C6F5)3 further coordinates with
4a to afford intermediate C, which is attacked by another 1a to
produce the final Markovnikov product 3a along with the
release of B(C6F5)3.
Conclusions
In conclusion, the first metal-/solvent-free procedure for the
intermolecular Markovnikov addition of indoles to aryl alkynes
was successfully developed via B(C6F5)3 catalysis. This protocol
was compatible with both N–H indoles and N-protected
indoles, thus providing a wide spectrum of versatile bis
(indolyl)alkanes with excellent selectivity.
Scheme 3 Substrate scope of alkynes 2.
9276 | Org. Biomol. Chem., 2018, 16, 9274–9278
This journal is © The Royal Society of Chemistry 2018

View Article Online
Organic & Biomolecular Chemistry
Paper
1584; (e) V. K. Pandey and P. Anbarasan, J. Org. Chem.,
2017, 82, 12328.
Experimental section
General information
3 (a) G. Buscemi, A. Biffis, C. Tubaro, M. Basato, C. Graiff
and A. Tiripicchio, Appl. Organomet. Chem., 2010, 24, 285;
(b) D. Vicenzi, P. Sgarbossa, A. Biffis, C. Tubaro, M. Basato,
R. A. Michelin, A. Lanza, F. Nestola, S. Bogialli, P. Pastore
and A. Venzo, Organometallics, 2013, 32, 7153.
4 (a) C. Ferrer, C. H. M. Amijs and A. M. Echavarren, Chem. –
Eur. J., 2007, 13, 1358; (b) C. Luo, H. Yang, R. Mao and
C. Lu, New J. Chem., 2015, 39, 3417.
All commercial materials were used as received unless other-
wise noted. Commercially available chemicals were obtained
from Energy Chemical, TCI, Alfa Aesar, and J&K. 1H NMR
spectra were recorded at 400 MHz and 600 MHz using TMS as
an internal standard, and 13C NMR spectra were recorded at
100 MHz, 125 MHz and 150 MHz using TMS as an internal
standard. The multiplicities are reported as follows: singlet (s),
doublet (d), doublet of doublets (dd), multiplet (m), triplet (t)
and broad resonances (br). The mass spectroscopy data of the
products were collected on an HRMS-TOF instrument.
5 G. Maiti, U. Kayal, R. Karmakar and R. N. Bhattacharya,
Indian J. Chem., Sect. B: Org. Chem. Incl. Med. Chem., 2013,
52, 122.
General procedure for the synthesis of 3. A mixture of 1H-
indole (1a, 117.0 mg, 1.0 mmol), ethynylbenzene (2a,
204.2 mg, 2.0 mmol) and B(C6F5)3 (25.6 mg, 0.05 mmol) was
heated at 60 °C for 6 hours. After the reaction was completed,
the residue was purified by chromatography on silica gel
(n-hexane/EtOAc = 20 : 1) to obtain the product 3a (142.9 mg,
85%) as a white solid. 3b–w were synthesized in a similar way.
6 D. Xia, Y. Wang, Z. Du, Q.-Y. Zheng and C. Wang, Org. Lett.,
2012, 14, 588.
7 T. Tsuchimoto and M. Kanbara, Org. Lett., 2011, 13, 912.
8 R. Gao and C. S. Yi, J. Org. Chem., 2010, 75, 3144.
9 (a) J. Schiessl, M. Rudolph and A. S. K. Hashmi, Adv. Synth.
Catal., 2017, 359, 639; (b) J. S. Yadav, B. V. S. Reddy,
B. Padmavani and M. K. Gupta, Tetrahedron Lett., 2004, 45,
7577.
10 For a selected example, see: (a) D. W. Stephan, Science,
2016, 354, 1248. For recent reviews on FLP chemistry, see:
(b) D. W. Stephan, J. Am. Chem. Soc., 2015, 137, 10018;
(c) D. W. Stephan and G. Erker, Angew. Chem., Int. Ed.,
2015, 54, 6400; (d) D. W. Stephan, Acc. Chem. Res., 2015, 48,
306; (e) M. Oestreich, J. Hermeke and J. Mohr, Chem. Soc.
Rev., 2015, 44, 2202; (f) M. Meng, X. Feng and H. Du, Acc.
Chem. Res., 2018, 51, 191.
11 For selected examples, see: (a) K. Ishihara, N. Hananki and
H. Yamamoto, Synlett, 1993, 577; (b) J. M. Blackwell,
E. R. Sonmor, T. Scoccitti and W. E. Piers, Org. Lett., 2000,
2, 3921; (c) D. J. Parks, J. M. Blackwell and W. E. Piers,
J. Org. Chem., 2000, 65, 3090; (d) Z. M. Heiden and
D. W. Stephan, Chem. Commun., 2011, 47, 5729;
(e) I. Chatterjee and M. Oestreich, Angew. Chem., Int. Ed.,
2015, 54, 1965; (f) A. F. Maier, S. Tussing, T. Schneider,
U. Florke, Z. W. Qu, S. Grimme and J. Paradies, Angew.
Chem., Int. Ed., 2016, 55, 12219; (g) Q. Zhou, L. Zhang,
W. Meng, X. Feng, J. Yang and H. Du, Org. Lett., 2016, 18,
5189; (h) Y. Ma, L. Zhang, Y. Luo, M. Nishiura and Z. Hou,
J. Am. Chem. Soc., 2017, 139, 12434; (i) F. Ding, Y. Zhang,
R. Zhao, Y. Jiang, R. L. Y. Bao, K. Lina and L. Shi, Chem.
Commun., 2017, 53, 9262.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
We thank the National Natural Science Foundation of China
(no. 21676253 and 21706234) for financial support.
Notes and references
1 (a) M. Marrelli, X. Cachet, F. Conforti, R. Sirianni,
A. Chimento, V. Pezzi, S. Michel, G. A. Statti and
F. Menichini, Nat. Prod. Res., 2013, 27, 2039;
(b) T. R. Garbe, M. Kobayashi, N. Shimizu, N. Takesue,
M. Ozawa and H. Yukawa, J. Nat. Prod., 2000, 63, 596;
(c) S. Mahboobi, S. Teller, H. Pongratz, H. Hufsky,
A. Sellmer, A. Botzki, A. Uecker, B. Thomas, S. Baasner,
C. Schächtele, F. Überall, M. U. Kassack, S. Dove and
F.-D. Böhmer, J. Med. Chem., 2002, 45, 1002;
(d) M. Damodiran, D. Muralidharan and P. T. Perumal,
Bioorg. Med. Chem. Lett., 2009, 19, 3611; (e) C. Praveen, 12 For selected reviews on the applications of alkynes, see:
P. DheenKumar, D. Muralidharan and P. T. Perumal,
Bioorg. Med. Chem. Lett., 2010, 20, 7292; (f) P. J. Praveen,
P. S. Parameswaran and M. S. Majik, Synthesis, 2015, 47,
1827.
2 For selected literature studies related to the synthesis of bis
(indolyl)alkanes, see: (a) D. Chen, L. Yu and P. G. Wang,
Tetrahedron Lett., 1996, 37, 4467; (b) M. Chakrabarty,
N. Ghosh, R. Basak and Y. Harigaya, Tetrahedron Lett.,
2002, 43, 4075; (c) H. Koshima and W. Matsusaka,
(a) Modern Acetylene Chemistry, ed. P. J. Stang and F. Diederich,
Wiley-VCH, New York, 2008; (b) Modern Alkyne Chemistry:
Catalytic and Atom-Economic Transformations, ed. B. M. Trost
and C.-J. Li, Wiley-VCH, New York, 2014; (c) R. Chinchilla and
C. Najera, Chem. Rev., 2014, 114, 1783; (d) G. Fanga and X. Bi,
Chem. Soc. Rev., 2015, 44, 8124; (e) V. P. Boyarskiy,
D. S. Ryabukhin, N. A. Bokach and A. V. Vasilyev, Chem. Rev.,
2016, 116, 5894; (f) M. Patel, R. K. Saunthwal and A. K. Verma,
Acc. Chem. Res., 2017, 50, 240.
J. Heterocycl. Chem., 2002, 39, 1089; (d) S.-J. Ji, M.-F. Zhou, 13 M. A. Dureen and D. W. Stephan, J. Am. Chem. Soc., 2009,
D.-G. Gu, Z.-Q. Jiang and T.-P. Loh, Eur. J. Org. Chem., 2004,
131, 8396.
This journal is © The Royal Society of Chemistry 2018
Org. Biomol. Chem., 2018, 16, 9274–9278 | 9277

View Article Online
Paper
Organic & Biomolecular Chemistry
14 For recent reviews on the applications of B(C6F5)3 in the
synthesis of heterocyclic and aromatic compounds, see:
D. W. Stephan, Chem. – Eur. J., 2015, 21, 11134; (c) T. Mahdi
and D. W. Stephan, Angew. Chem., Int. Ed., 2013, 52, 12418.
(a) R. L. Melen, Chem. Commun., 2014, 50, 1161; 17 S. Tamke, Z.-W. Qu, N. A. Sitte, U. Flörke, S. Grimme and
(b) J. R. Lawson and R. L. Melen, Inorg. Chem., 2017, 56, J. Paradies, Angew. Chem., Int. Ed., 2016, 55, 4336.
8627. For selected references, see: (c) C. Chen, 18 M. Shibuya, M. Okamoto, S. Fujita, M. Abe and
M. Harhausen, R. Liedtke, K. Bussmann, A. Fukazawa, Y. Yamamoto, ACS Catal., 2018, 8, 4189.
S. Yamaguchi, J. L. Petersen, C. G. Daniliuc, R. Fröhlich, 19 B. J. Frogley and L. J. Wright, Angew. Chem., Int. Ed., 2017,
G. Kehr and G. Erker, Angew. Chem., Int. Ed., 2013, 52, 56, 1.
5992; (d) R. Liedtke, M. Harhausen, R. Fröhlich, G. Kehr 20 (a) V. Fasano, J. E. Radcliffe and M. J. Ingleson,
and G. Erker, Org. Lett., 2012, 14, 1448.
15 W. Fu, L. Dong, J. Shi, B. Tong, Z. Cai, J. Zhi and Y. Dong,
Macromolecules, 2018, 51, 3254.
Organometallics, 2017, 36, 1623; (b) Y. Liu, X. Fan, Z. H. Li
and H. Wang, Chem. Commun., 2017, 53, 10890; (c) K. Yuan
and S. Wang, Org. Lett., 2017, 19, 1462.
16 (a) S. Tussing, M. Ohland, G. Wicker, U. Flörkeb and 21 Z. Wang, F. Ai, Z. Wang, W. Zhao, G. Zhu, Z. Lin and J. Sun,
J. Paradies, Dalton Trans., 2017, 46, 1539; (b) T. Mahdi and J. Am. Chem. Soc., 2015, 137, 383.
9278 | Org. Biomol. Chem., 2018, 16, 9274–9278
This journal is © The Royal Society of Chemistry 2018