Br?nsted Acid-Catalyzed Synthesis of N-Arylindoles from 2-Vinylanilines and Quinones

Article abstract of DOI:10.1002/asia.201600420

In the presence of a quinone, Br?nsted acid-catalyzed intramolecular C?N bond formation of o-vinylanilines by electrophilic cyclization was developed, giving the corresponding N-arylindoles in good to high yields. The reaction worked well for o-vinylanilines with terminal and internal C=C double bonds.

Full text of DOI:10.1002/asia.201600420

DOI: 10.1002/asia.201600420
Communication
Arylindoles
Brønsted Acid-Catalyzed Synthesis of N-Arylindoles from 2-
Vinylanilines and Quinones
Han-Ming Zhang, Zhong-Hua Gao, Liang Yi, and Song Ye*[a]
The preparation of indoles has been intensively pursued by
Abstract: In the presence of a quinone, Brønsted acid-cat-
many chemists,[8] and various methods have been developed
alyzed intramolecular CÀN bond formation of o-vinylani-
for the synthesis of N-arylindoles (Scheme 2). The predominant
lines by electrophilic cyclization was developed, giving the
strategy relies on the transition-metal-catalyzed coupling of an
corresponding N-arylindoles in good to high yields. The
reaction worked well for o-vinylanilines with terminal and
internal C=C double bonds.
Since its discovery,[1] indole has been well recognized as a privi-
leged structure in organic and medical chemistry.[2] Many phar-
macological and bioactive compounds contain an N-arylindole
structural motif. Such as, N-(4-fluorophenyl)indole 1 (sertindole)
is an efficient antipsychotic agent (Scheme 1),[3] N-(4-phenoxy-
phenyl)-1H-indole 2 is a designed cytosolic phospholipase in-
hibitor,[4] compound 3 is a heat shock protein 90 (HSP90) inhib-
itor,[5] N-phenylindole 4 is a potential melatonin receptor MT1
agonists,[6] and N-arylindole 5 is a good cyclooxygenase-2 in-
hibitor .[7]
Scheme 2. Typical routes and our strategy for the synthesis of N-arylindoles.
indole and haloarenes (Scheme 2, route a).[9] In addition, the
metal-catalyzed intramolecular CÀN bond forming of N-(2-halo-
styryl)aniline has also been well established (Scheme 2,
route b).[10] In 2012, Zheng et al. reported a pioneering visible-
light-mediated ruthenium-catalyzed synthesis of N-arylindoles
from styryl aniline by an oxidative coupling of CÀH and NÀH
bonds (Scheme 2, route c).[11] In this paper, we communicate
a metal-free synthesis of N-arylindoles by a Brønsted acid-cata-
lyzed CÀN bond formation from C(sp2)ÀH of o-vinylanilines
and in situ generated quinone imines.[12]
The model reaction of 2-vinylaniline 6a with 1,4-benzoqui-
none was carried out in the presence of various Brønsted acids
(Table 1). We were happy to find that the reaction catalyzed by
20 mol% of p-toluenesulfonic acid gave the desired N-arylin-
dole 7a in 66% yield (entry 1). The reaction using benzoic acid
Scheme 1. Pharmacological and bioactive N-arylindoles.
as the catalyst afforded the product in 64% yield (entry 2).
However, further exploring of carboxylic acids, such as 4-nitro-
benzoic acid, 2-phenylacetic acid, and formic acid, led to no
[a] H.-M. Zhang, Z.-H. Gao, L. Yi, Prof. S. Ye
improvement (entries 3–5). Phenol could also catalyze the reac-
tion but with low yield (entry 6). Better yield was achieved
when the reaction was carried out in 1,4-dioxane than in THF
(entries 7 and 8).
Beijing National Laboratory for Molecular Sciences
Key Laboratory of Molecular Recognition and Function
Institute of Chemistry, Chinese Academy of Sciences
Beijing 100190 (China)
E-mail: songye@iccas.ac.cn
With the optimized reaction condition in hand, the Brønsted
acid-catalyzed synthesis of N-arylindoles was then explored
Supporting information for this article can be found under http://
dx.doi.org/10.1002/asia.201600420.
Chem. Asian J. 2016, 00, 0 – 0
1
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ

Communication
To further explore the scope of the reaction, anilines with in-
ternal alkenes were investigated for the synthesis of 2,3-disub-
stituted N-arylindoles (Scheme 4). We were satisfied to find
that all the anilines with internal alkenes (R2 =Me, Et, n-C3H7, n-
Table 1. Optimization of reaction conditions.
Entry
Brønsted acid
Solvent
Yield [%][a]
1
2
3
4
5
6
7
8
TsOH·H2O
C6H5CO2H
4-NO2C6H4CO2H
C6H5CH2CO2H
HCO2H
phenol
C6H5CO2H
TsOH·H2O
THF
THF
THF
THF
THF
THF
1,4-dioxane
1,4-dioxane
66
64
47
42
38
36
70
78
[a] Isolated yields.
with various anilines with ortho-terminal alkene substituents
(Scheme 3). It was found that the reaction went well for all
ortho-vinylanilines with different alkyl and aryl substituents
(R1 =Me, Et, Ph), and the one with aryl group resulted better
yields than that with the alkyl groups (7a and 7b versus 7c).
The reaction with naphthalene-1,4-dione proceeded as well
(7d and 7e). Anilines with the para-substituents (4-F, 4-Cl, 4-Br)
were well tolerated (7 f–7k).
Scheme 4. Reaction of anilines with internal alkenes.
C4H9) worked well to give the n-arylindoles 7l–7o in good
yields. In addition, branched alkyl (R2 =cyclopropyl) and ester
groups (R2 =CO2Et) were well tolerated in spite of some de-
crease in the yields (7p and 7q). Once again, the anilines with
a-aryl worked better than with a-alkyl (7r–7w versus 7l–7q).
The example of 2,3,5-trisubstituted N-arylindole 7x could be
obtained in 80% yield.
The structure of N-arylindole 7w was established by the X-
ray analysis of its single crystal (Figure 1).[13]
Figure 1. X-ray structure of N-arylindole 7w, hydrogen is omitted for clarity.
The hydroxyl group in N-arylindole 7a could be methylated
under basic conditions [Eq. (1)], and phenylated in the pres-
ence of CuI as the catalyst [Eq. (2)].[14]
Scheme 3. Reaction of anilines with terminal alkenes.
&
&
Chem. Asian J. 2016, 00, 0 – 0
www.chemasianj.org
2
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

Communication
internal alkenes, giving the corresponding multisubstituted N-
arylindoles in good yields. The indoline carbon cation, generat-
ed by the electrophilic cyclization of alkenes with the protonat-
ed quinone imine, is proposed as the key intermediate for the
reaction. Related reactions involving the Brønsted acid-cata-
lyzed generation of carbon cations are underway in our labora-
tory.
Experimental Section
Acid-catalyzed synthesis of N-arylindoles
To a 25 mL reaction tube equipped with a stir bar was charged
with 2-vinylanilines 6 (0.3 mmol), quinone (0.3 mmol), TsOH·H2O
(11.4 mg, 0.06 mmol). To this mixture was added distilled 1,4-diox-
ane (2 mL). The reaction mixture was stirred at 808C until the reac-
tion was completed, typically for 10–18 h. The solvent was re-
moved under reduced pressure and the residue was purified by
chromatography on silica gel (ethyl acetate/petroleum ether, typi-
cally 1/12) to give the desired product.
A plausible catalytic cycle is depicted in Figure 2. The proto-
nation of the quinone with the catalytic acid facilitates the for-
mation of the imine with aniline 6. An intramolecular electro-
philic cyclization of alkenes with the protonated quinone
imine II generates indoline cation III. The removal of the
proton by the quinone affords the N-arylindole and furnishes
the catalytic cycle.
Acknowledgements
Financial support from the National Natural Science Founda-
tion of China (no. 21425207 and 21521002) and the Chinese
Academy of Sciences is greatly acknowledged.
Keywords: aniline · Brønsted acid · carbocation · CÀN bond
formation · synthetic methods
[1] a) A. Baeyer, Justus Liebigs Ann. Chem. 1866, 140, 295–313; b) A. Baeyer,
A. Emmerling, Ber. Dtsch. Chem. Ges. 1869, 2, 679–682.
[2] a) A. J. Kochanowska-Karamyan, M. T. Hamann, Chem. Rev. 2010, 110,
4489–4497; b) M. Somei, F. Yamada, Nat. Prod. Rep. 2005, 22, 73–103;
c) T. Kawasaki, K. Higuchi, Nat. Prod. Rep. 2005, 22, 761–793; d) M.
Somei, F. Yamada, Nat. Prod. Rep. 2004, 21, 278–311; e) S. Hibino, T.
Choshi, Nat. Prod. Rep. 2002, 19, 148–180; f) B. P. Smart, R. C. Oslund,
L. A. Walsh, M. H. Gelb, J. Med. Chem. 2006, 49, 2858–2860; g) M. Lou-
nasmaa, A. Tolvanen, Nat. Prod. Rep. 2000, 17, 175–191.
[3] a) K. Andersen, T. Liljefors, J. Hyttel, J. Perregaard, J. Med. Chem. 1996,
39, 3723–3738; b) J. Perregaard, E. K. Moltzen, E. Meier, C. Sꢁnchez, J.
Med. Chem. 1995, 38, 1998–2008.
[4] T. Tomoo, T. Nakatsuka, T. Katayama, Y. Hayashi, Y. Fujieda, M. Terakawa,
K. Nagahira, J. Med. Chem. 2014, 57, 7244–7262.
[5] J. Ren, J. Li, Y. Wang, W. Chen, A. Shen, H. Liu, D. Chen, D. Cao, Y. Li, N.
Zhang, Y. Xu, M. Geng, J. He, B. Xiong, J. Shen, Bioorg. Med. Chem. Lett.
2014, 24, 2525–2529.
[6] G. Spadoni, C. Balsamini, A. Bedini, G. Diamantini, B. D. Giacomo, A. Ton-
tini, G. Tarzia, J. Med. Chem. 1998, 41, 3624–3634.
Figure 2. Proposed catalytic cycle.
[7] H. Sano, T. Noguchi, A. Tanatani, Y. Hashimoto, H. Miyachi, Bioorg. Med.
Chem. 2005, 13, 3079–3091.
To identify a possible reaction intermediate, the mass spec-
trum of the reaction mixture was tested before full consump-
tion of the starting materials, and a species with 224.1070 m/z
was observed, which is accorded with the molecular weight of
intermediate II or III (C15H14ON).[15] The observed better per-
formance of 2-vinylanilines with a-aryl (R1 =aryl) than with a-
alkyl (R1 =alkyl; Scheme 3 and 4) can also be rationalized by
better stability of the carbon cation III when a-aryl is present.
In summary, the Brønsted acid-catalyzed synthesis of N-ary-
lindoles from 2-vinyl anilines and quinones was developed.
The reaction worked well for both anilines with terminal and
[8] a) M. Inman, C. J. Moody, Chem. Sci. 2013, 4, 29–41; b) N. T. Patil, Y. Ya-
mamoto, Chem. Rev. 2008, 108, 3395–3442; c) L. Ackermann, Synlett
2007, 0507–0526; d) S. Cacchi, G. Fabrizi, Chem. Rev. 2005, 105, 2873–
2920; e) M. Shiri, Chem. Rev. 2012, 112, 3508–3549; f) M. Platon, R.
Amardeil, L. Djakovitch, J.-C. Hierso, Chem. Soc. Rev. 2012, 41, 3929–
3968; g) M. Bandini, A. Eichholzer, Angew. Chem. Int. Ed. 2009, 48,
9608–9644; Angew. Chem. 2009, 121, 9786–9824; h) G. R. Humphrey,
J. T. Kuethe, Chem. Rev. 2006, 106, 2875–2911; i) G. Zeni, R. C. Larock,
Chem. Rev. 2004, 104, 2285–2309.
[9] a) H. Wang, Y. Li, F. Sun, Y. Feng, K. Jin, X. Wang, J. Org. Chem. 2008, 73,
8639–8642; b) M. Taillefer, N. Xia, A. Ouali, Angew. Chem. Int. Ed. 2007,
46, 934–936; Angew. Chem. 2007, 119, 952–954; c) N. S. Nandurkar,
M. J. Bhanushali, M. D. Bhor, B. M. Bhanage, Tetrahedron Lett. 2007, 48,
Chem. Asian J. 2016, 00, 0 – 0
www.chemasianj.org
3
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ

Communication
6573–6576; d) H. Zhang, Q. Cai, D. Ma, J. Org. Chem. 2005, 70, 5164–
5173; e) C. J. Smith, M. W. S. Tsang, A. B. Holmes, R. L. Danheiser, J. W.
Tester, Org. Biomol. Chem. 2005, 3, 3767–3781; f) L. Shi, M. Wang, C. A.
Fan, F. M. Zhang, Y. Q. Tu, Org. Lett. 2003, 5, 3515–3517; g) G. A. Grasa,
M. S. Viciu, J. Huang, S. P. Nolan, J. Org. Chem. 2001, 66, 7729–7737;
h) G. Mann, J. F. Hartwig, M. S. Driver, C. F. Rivas, J. Am. Chem. Soc. 1998,
120, 827–828.
[12] For related examples of Brønsted -catalyzed reactions, see: a) B.
Schweitzer-Chaput, J. Demaerel, H. Engler, M. Klussmann, Angew. Chem.
Int. Ed. 2014, 53, 8737–8740; Angew. Chem. 2014, 126, 8882–8885;
b) H. Xu, S. J. Zuend, M. G. Woll, Y. Tao, E. N. Jacobsen, Science 2010,
327, 986–990.
[13] CCDC 1470773 (7w) contain the supplementary crystallographic data
for this paper. These data are provided free of charge by The Cam-
bridge Crystallographic Data Centre.
[10] a) J. A. Brown, Tetrahedron Lett. 2000, 41, 1623–1626; b) R. C. Hodgkin-
son, J. Schulzb, M. C. Willis, Org. Biomol. Chem. 2009, 7, 432–434;
c) M. C. Willis, G. N. Brace, T. J. K. Findlay, I. P. Holmes, Adv. Synth. Catal.
2006, 348, 851–856; d) L. Ackermann, Org. Lett. 2005, 7, 439–442; e) M.
Beller, C. Breindl, T. H. Riermeier, A. Tillack, J. Org. Chem. 2001, 66,
1403–1412.
[14] The cleavage of CÀO bond of the aryl ethers was reported: P. ꢂlvarez-
Bercedo, R. Martin, J. Am. Chem. Soc. 2010, 132, 17352.
[15] See the Supporting Information for details.
Manuscript received: March 28, 2016
Accepted Article published: May 4, 2016
Final Article published: && &&, 0000
[11] S. Maity, N. Zheng, Angew. Chem. Int. Ed. 2012, 51, 9562–9566; Angew.
Chem. 2012, 124, 9700–9704.
&
&
Chem. Asian J. 2016, 00, 0 – 0
www.chemasianj.org
4
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

Communication
COMMUNICATION
Arylindoles
Han-Ming Zhang, Zhong-Hua Gao,
Liang Yi, Song Ye*
&& – &&
Brønsted Acid-Catalyzed Synthesis of
N-Arylindoles from 2-Vinylanilines and
Quinones
Simple and efficient! In the presence
of a quinone, Brønsted acid-catalyzed
intramolecular CÀN bond formation of
o-vinylanilines by electrophilic cycliza-
tion was developed, giving the corre-
sponding N-arylindoles in good to high
yields (see scheme).
Chem. Asian J. 2016, 00, 0 – 0
www.chemasianj.org
5
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ