Unusual reactivity of β-(3-indolyl)-α,β-unsaturated ketones. 2-Acetylvinyl group removal by phenylhydrazine hydrochloride

Article abstract of DOI:10.1016/j.tetlet.2011.07.136

The unusual removal of a 2-acetylvinyl group from the C3 position of an indole core during reaction with phenylhydrazine hydrochloride affording 3-unsubstituted 2-(hetero)arylindoles is described.

Full text of DOI:10.1016/j.tetlet.2011.07.136

Tetrahedron Letters 52 (2011) 5255–5258
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Tetrahedron Letters
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Unusual reactivity of b-(3-indolyl)-
a,b-unsaturated ketones. 2-Acetylvinyl
group removal by phenylhydrazine hydrochloride
Alexander V. Butin a, , Maxim G. Uchuskin a, Arkady S. Pilipenko a, Olga V. Serdyuk b, Igor V. Trushkov c,d
⇑
a Research Institute of Heterocyclic Compounds Chemistry, Kuban State Technological University, Moskovskaya St. 2, Krasnodar 350072, Russian Federation
b Department of Chemistry, Southern Federal University, Zorge 7, Rostov-on-Don 344090, Russian Federation
c Department of Chemistry, M.V. Lomonosov Moscow State University, Leninskie Gory 1/3, Moscow 119991, Russian Federation
d Laboratory of Chemical Synthesis, Federal Research Center of Pediatric Hematology, Oncology and Immunology, Leninskii Av. 117, Moscow 117997, Russian Federation
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 23 February 2011
Revised 14 July 2011
Accepted 29 July 2011
Available online 6 August 2011
The unusual removal of a 2-acetylvinyl group from the C3 position of an indole core during reaction with
phenylhydrazine hydrochloride affording 3-unsubstituted 2-(hetero)arylindoles is described.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Indoles
3-(2-Acylvinyl)indoles
2-(Hetero)arylindoles
2-(Hetero)arylindoles have attracted increasing interest from
synthetic and medicinal chemists because of their pharmacological
properties and high reactivity which allows their efficient transfor-
mation into other derivatives with the aim of developing new
pharmaceuticals.1,2 2-(Aryl)- and 2-(heteroaryl)indoles exhibit a
wide spectrum of biological activity, such as antitumor,3 antiproto-
zoal,4 antioxidant,5 antibacterial,6 and anti-HCV.7 They are also fac-
tor Xa inhibitors,8 h5-HT2A receptor antagonists,9 calcium channel
blockers,10 neurosteroid biosynthesis promoters,11 etc.12 2,3-
Di(hetero)arylindoles are much less studied.13 However, it was
shown that they demonstrate antitumor,14 leishmanicidal,15 and
other types of biological activity.16
During our investigation of furan recyclizations into other
heterocyclic systems,17 we have proposed a new method for the
synthesis of 3-(2-acylvinyl)-2-(hetero)arylindoles 2 by the reaction
of 2-furylanilines 1 with (hetero)aromatic aldehydes under Pictet–
Spengler conditions (Scheme 1).18
stemmed from the known biological activity of indolylpyraz-
oles21a,c,22 and indolylpyrazolines.20
Initially, we investigated the model reaction between 4-[6-
chloro-2-(3,4-dimethoxyphenyl)indol-3-yl]but-3-en-2-one (2a)
and phenylhydrazine. Following published procedures for related
processes,20 we selected ethanol as the solvent for this transforma-
tion. However, compound 2a was found to have very low solubility
in this solvent. Thus, we used an ethanol/1,4-dioxane mixture
wherein substrate 2a was soluble. Reaction of 2a with PhNHNH2
afforded the target pyrazoline as a yellow-orange solid in a low
yield (ca. 25–30%).
To increase the yield of the pyrazoline, we investigated other
common reaction conditions for this transformation. We found that
the treatment of 2a with PhNHNH2ÁHCl under reflux led to the
formation of a bright-red precipitate which differed from the
pyrazoline obtained above. Attempts at dissolving this residue in
organic solvents such as acetone, acetonitrile, ethyl acetate,
a
,b-Unsaturated ketones have been utilized extensively for the
synthesis of various heterocycles.19 Thus, we decided to develop
our approach to the synthesis of 6-(un)substituted 2-aryl-3-het-
eroaryl- and 2,3-bis(heteroaryl)indoles. We started this project
by the investigation of the reaction of indoles 2 with hydrazines
as a route to prepare a series of 5-{2-[(hetero)aryl]indol-3-yl}pyr-
azolines20 and -pyrazoles.21 Our interest in these compounds
O
R2
R1
NH2
R3CHO
O
R3
R2
R1
AcOH, HCl
N
H
1
2
⇑
Corresponding author. Tel.: +7 861 255 9556; fax: +7 861 259 6592.
E-mail addresses: alexander_butin@mail.ru, av_butin@yahoo.com (A.V. Butin).
Scheme 1. Synthesis of 3-(2-acylvinyl)-2-(hetero)arylindoles 2 from 2-furylani-
lines 1 and (hetero)aromatic aldehydes.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.07.136

5256
A. V. Butin et al. / Tetrahedron Letters 52 (2011) 5255–5258
Table 1
O
Optimization of the reaction conditions for the transformation of 2a into 3a
O
.
R2
PhNHNH2 HCl
R2
N
H
DMF, reflux, 2 min
R1
N
H
R1
.
PhNHNH2 HCl
OMe
OMe
OMe
solvent, reflux
3
2
N
H
N
H
Cl
Cl
OMe
-H+
2a
3a
-
N
N
Ph
Entry
Solvent
Time (min)
Yield (%)
N
N
1
2
3
4
5
6
DMF
DMA
PhNO2
DMSO
1,4-Dioxane
HCOOH
2
2
5
20
150
7
80
76
68
30
60
54
Ph
N
Ph
N
H
H
H
H
H+
R2
R2
R1
N
R1
N
H
H
4
Scheme 2. A possible mechanism for the transformation of 2 into 3-unsubstituted
2-(hetero)arylindoles 3.
Table 2
De[2-(acetyl)vinylation] of indoles 2a–l with formation of 3a–l
O
CF3COOH at room temperature. However, this process was accom-
panied by bleaching. From the solutions obtained we isolated 6-
chloro-2-(3,4-dimethoxyphenyl)indole (3a) instead of the expected
pyrazoline.23
R2
.
R2
PhNHNH2 HCl
R1
N
N
H
2a-l
R1
DMF, reflux
R1
Intrigued by these results, we next studied the reaction condi-
tions for the direct transformation of 2a into 3a. We found that in-
dole 3a was formed in good yield by refluxing a solution of 2a and
PhNHNH2ÁHCl in DMF or DMA over a short period. The solvent
plays a crucial role in this transformation. Thus, full conversion
of the starting compounds was accomplished by reflux in DMSO
for 10 min, but product 3a was isolated in 30% yield only, possibly
due to the occurrence of alternative reactions. Attempts to improve
the yield by increasing the duration failed due to tar formation.
Similarly, tarring was evident when 2a was refluxed with
PhNHNH2ÁHCl in formic acid. Indole 3a was isolated in this case
in 54% yield over a 7 min reaction time. The same product was also
formed in reasonable yields when the reaction was performed in
nitrobenzene or 1,4-dioxane, but these processes were less attrac-
tive due to the increased reaction time when 1,4-dioxane was used
and the necessity for steam distillation for product isolation when
the reaction was performed in nitrobenzene. The results of this
optimization study are given in Table 1.
With optimized reaction conditions in hand, we next explored
the scope of this reaction by studying a wide variety of substrates
2 (Table 2). 3-(2-Acetylvinyl)indoles bearing phenyl groups with
both electron-donating or electron-withdrawing substituents, thi-
enyl or furyl groups at C2 were tolerated in this reaction and gave
efficiently the corresponding 3-unsubstituted indoles.24
We suggest that the reaction proceeds via formation of 5-(indol-
3-yl)pyrazolines 4 which are then protonated at C3 of the indole ring
followed by elimination of the indole (Scheme 2). Indeed, addition of
acid at any step during the reaction between phenylhydrazine and 2
led to the formation of 3-unsubstituted 3-(hetero)arylindoles in-
stead of 5-(indolyl)pyrazolines which were formed in low-to-mod-
erate yields under neutral or basic conditions. When we treated
these pyrazolines with HCl, products 3 were isolated. It is necessary
to point out that 5-(indol-3-yl)pyrazolines were previously found to
be incompatible with acids21c and this is consistent with our results.
This reactivity of 3-(2-acylvinyl)indoles is quite different from
H
3a-l
Product
R2
Yield (%)
80
OMe
OMe
3a
Cl
H
3b
3c
76
73
Br
Me
F
3d
3e
H
71
83
NO2
Cl
3f
Cl
62
NO2
Me
Et
3g
3h
Cl
71
70
O
O
OMe
O
N
3i
3j
Cl
65
71
O
O
O
OMe
CF3
NO2
3k
3l
H
59
71
O
S
Cl
the usual behavior of
a,b-unsaturated ketones including those
containing an indole ring as a substituent. Two main factors are
responsible for this result. The first is easy protonation of the
indole carbon atom connected to the pyrazoline ring in 4. The second
is pyrazoline aromatization which is the driving force for this elimi-
nation. A related aromatization process due to indole elimination
methylene chloride, 1,2-dichloroethane, toluene, etc., were unsuc-
cessful, even under heating. The residue was partially dissolved in
refluxing acetic acid. We found that the residue could be dissolved
in DMF, DMA, DMSO, PhNO2 and HCOOH under heating as well as in

A. V. Butin et al. / Tetrahedron Letters 52 (2011) 5255–5258
5257
was described recently.25 To the best of our knowledge, we have de-
scribed here the first example of the transformation of a pyrazoline
into a pyrazole via aromatic compound elimination.26 The process of
Madeira, M.; Karanam, B.; Green, M.; Forrest, M. J.; Abbadie, C.; McGowan, E.;
Mistry, S.; Jochnowitz, N.; Duffy, J. L. Bioorg. Med. Chem. Lett. 2011, 21, 869–873.
11. Da Settimo, F.; Simorini, F.; Taliani, S.; La Motta, C.; Marini, A. M.; Salerno, S.;
Bellandi, M.; Novellino, E.; Greco, C.; Cosimelli, B.; Da Pozzo, E.; Costa, B.;
Simola, N.; Morelli, M.; Martini, C. J. Med. Chem. 2008, 51, 5798–5806.
12. (a) Seggio, A.; Priem, G.; Chevallier, F.; Mongin, F. Synthesis 2009, 3617–3632;
(b) Taliani, S.; Da Pozzo, E.; Bellandi, M.; Bendinelli, S.; Pugliesi, I.; Simorini, F.;
La Motta, C.; Salerno, S.; Marini, A. M.; Da Settimo, F.; Cosimelli, B.; Greco, G.;
Novellino, E.; Martini, C. J. Med. Chem. 2010, 53, 4085–4093; (c) Velankar, A. D.;
Quintini, G.; Prabhu, A.; Weber, A.; Hunaeus, G.; Voland, B.; Wuest, M.; Orjeda,
C.; Harel, D.; Varghese, S.; Gore, V.; Patil, M.; Gayke, D.; Herdemann, M.; Heit, I.;
Zaliani, A. Bioorg. Med. Chem. 2010, 18, 4547–4559; (d) Watanabe, H.; Ono, M.;
Haratake, M.; Kobashi, N.; Saji, H.; Nakayama, M. Bioorg. Med. Chem. 2010, 18,
4740–4746; (e) Herdemann, M.; Heit, I.; Bosch, F.-U.; Quintini, G.; Scheipers,
C.; Weber, A. Bioorg. Med. Chem. Lett. 2010, 20, 6998–7003; (f) Pike, V. W.;
Taliani, S.; Lohith, T. G.; Owen, D. R. J.; Pugliesi, I.; Da Pozzo, E.; Hong, J.; Zoghbi,
S. S.; Gunn, R. N.; Parker, C. A.; Rabiner, E. A.; Fujita, M.; Innis, R. B.; Martini, C.;
Da Settimo, F. J. Med. Chem. 2011, 54, 366–373.
13. For recent publications on the synthesis of 2,3-di(hetero)arylindoles, see: (a)
Kim, T.; Kim, K. Tetrahedron Lett. 2010, 51, 868–871; (b) Kraus, G. A.; Guo, H.;
Kumar, G.; Pollock, G.; Carruthers, H.; Chaudhary, D.; Beasley, J. Synthesis 2010,
1386–1393; (c) Niu, T.; Zhang, Y. Tetrahedron Lett. 2010, 51, 6847–6851; (d) Su,
Y.; Zhao, M.; Han, K.; Song, G.; Li, X. Org. Lett. 2010, 12, 5462–5465.
14. Medarde, M.; Ramos, A. C.; Caballero, E.; Peláez-Lamamié de Clairac, R.; López,
J. L.; Grávalos, D. G.; San Feliciano, A. Bioorg. Med. Chem. Lett. 1999, 9, 2303–
2308.
2-acylvinylgroupremovalfrom
ported previously.
a,b-unsaturatedketoneswasnotre-
In summary, we have reported on the unusual removal of a 2-
acetylvinyl group from C3 of an indole by heating with phenylhydr-
azine hydrochloride in DMF or DMA to afford 3-unsubstituted
2-(hetero)arylindoles. This transformation, which proceeds via the
formation of 5-indolylpyrazolines followed by indole elimination,
is a new facet of a,b-unsaturated ketone reactivity. The described
procedure, together with the previously described reaction of 2-
furylanilines with (hetero)aromatic aldehydes, allow for the prepa-
ration of both 3-substituted- and 3-unsubstituted 2-arylindoles
including 6-substituted examples and 2-furylindoles which are
not easily prepared by reported procedures. Further study of this
new pattern of reactivity of a,b-unsaturated ketones is ongoing.
Acknowledgments
15. del Rey, B.; Ramos, A. C.; Caballero, E.; Inchaustti, A.; Yaluff, G.; Medarde, M.;
Rojas de Arias, A.; San Feliciano, A. Bioorg. Med. Chem. Lett. 1999, 9, 2711–2714.
16. Zhang, X.; He, Y.; Liu, S.; Yu, Z.; Jiang, Z.-X.; Yang, Z.; Dong, Y.; Nabinger, S. C.;
Wu, L.; Gunawan, A. M.; Wang, L.; Chan, R. J.; Zhang, Z.-Y. J. Med. Chem. 2010,
53, 2482–2493.
17. (a) Butin, A. V.; Smirnov, S. K.; Stroganova, T. A.; Bender, W.; Krapivin, G. D.
Tetrahedron 2007, 63, 474–491; (b) Dmitriev, A. S.; Abaev, V. T.; Bender, W.;
Butin, A. V. Tetrahedron 2007, 63, 9437–9447; (c) Butin, A. V.; Tsiunchik, F. A.;
Abaev, V. T.; Zavodnik, V. E. Synlett 2008, 1145–1148; (d) Butin, A. V.; Nevolina,
T. A.; Shcherbinin, V. A.; Uchuskin, M. G.; Serdyuk, O. V.; Trushkov, I. V.
Synthesis 2010, 2969–2978; (e) Butin, A. V.; Nevolina, T. A.; Shcherbinin, V. A.;
Trushkov, I. V.; Cheshkov, D. A.; Krapivin, G. D. Org. Biomol. Chem. 2010, 8,
3316–3327.
We thank the Russian Foundation of Basic Research (Grant 10-
03-00254a) and the Ministry of Education and Science of the Rus-
sian Federation (Grant 2.1.1/12031) for financial support of this
work.
References and notes
1. (a) Cacchi, S.; Fabrizi, G. Chem. Rev. 2005, 105, 2873–2920; (b) Bellina, F.; Rossi,
R. Tetrahedron 2009, 65, 10269–10310; (c) Boorman, T. C.; Larrosa, I. Prog.
Heterocycl. Chem. 2010, 22, 1–20.
2. For some recent publications on the synthesis of 2-(hetero)arylindoles, see: (a)
Verniest, G.; England, D.; De Kimpe, N.; Padwa, A.; Mao, H.; Wan, J.-P.; Pan, Y.;
Sun, C. Tetrahedron Lett. 2010, 51, 1844–1846; (b) Arcadi, A.; Cianci, R.; Ferrara,
G.; Marinelli, F. Tetrahedron 2010, 66, 2378–2383; (c) Rohini, R.; Muralidhar, P.
R.; Shanker, K.; Ravinder, V.; Hu, A. Eur. J. Med. Chem. 2010, 45, 1200–1205; (d)
Beaumard, F.; Dauban, P.; Dodd, R. H. Synthesis 2010, 4033–4042; (e) Boyer, A.;
Isono, N.; Lackner, S.; Lautens, M. Tetrahedron 2010, 66, 6468–6482; (f)
Borthakur, M.; Gogoi, S.; Gogoi, J.; Boruah, R. C. Tetrahedron Lett. 2010, 51,
5160–5163; (g) Carpita, A.; Ribecai, A.; Stabile, P. Tetrahedron 2010, 66, 7169–
7178; (h) Potavathri, S.; Pereira, K. C.; Gorelsky, S. I.; Pike, A.; LeBris, A. P.;
DeBoef, B. J. Am. Chem. Soc. 2010, 132, 14676–14681; (i) Ackermann, L.; Song,
W.; Sandmann, R. J. Organomet. Chem. 2011, 696, 195–201.
3. (a) Kaufmann, D.; Pojarova, M.; Vogel, S.; Liebl, R.; Gastpar, R.; Gross, D.;
Nishino, T.; Pfaller, T.; von Angerer, E. Bioorg. Med. Chem. 2007, 15, 5122–5136;
(b) Jacquemard, U.; Dias, N.; Lansiaux, A.; Bailly, C.; Loge, C.; Robert, J.-M.;
Lozach, O.; Maijer, L.; Merour, J.-Y.; Routier, S. Bioorg. Med. Chem. 2008, 16,
4932–4953; (c) Bursavich, M. G.; Brooijmans, N.; Feldberg, L.; Hollander, I.;
Kim, S.; Lombardi, S.; Park, K.; Mallon, R.; Gilbert, A. M. Bioorg. Med. Chem. Lett.
2010, 20, 2586–2590; (d) Ziedan, N. I.; Stefanelli, F.; Fogli, S.; Westwell, A. D.
Eur. J. Med. Chem. 2010, 45, 4523–4530.
4. (a) Colletti, S. L.; Li, C.; Fisher, M. H.; Wyvratt, M. J.; Meinke, P. T. Tetrahedron
Lett. 2000, 41, 7825–7829; (b) Reichwald, C.; Shimony, O.; Dunkel, U.;
Sacerdoti-Sierra, N.; Jaffe, C. L.; Kunick, C. J. Med. Chem. 2008, 51, 659–665;
(c) Farahat, A. A.; Kumar, A.; Say, M.; Barghash, A. E. M.; Goda, F. E.; Eisa, H. M.;
Wenzler, T.; Brun, R.; Liu, Y.; Mickelson, L.; Wilson, W. D.; Boykin, D. W. Bioorg.
Med. Chem. 2010, 18, 557–566.
5. (a) Biradar, J. S.; Sasidhar, B. S.; Parveen, R. Eur. J. Med. Chem. 2010, 45, 4074–
4078; (b) Praveen, C.; DheenKumar, P.; Muralidharan, D.; Perumal, P. T. Bioorg.
Med. Chem. Lett. 2010, 20, 7292–7296.
6. (a) Ambrus, J. I.; Kelso, M. J.; Bremner, J. B.; Ball, A. R.; Casadei, G.; Lewis, K.
Bioorg. Med. Chem. Lett. 2008, 18, 4294–4297; (b) Opperman, T. J.; Williams, J.
D.; Houseweart, C.; Panchal, R. G.; Bavari, S.; Peet, N. P.; Moir, D. T.; Bowlin, T. L.
Bioorg. Med. Chem. 2010, 18, 2123–2130.
7. (a) Beaulieu, P. L.; Jolicoeur, E.; Gillard, J.; Brochu, C.; Coulombe, R.; Dansereau,
N.; Duan, J.; Garneau, M.; Jakalian, A.; Kühn, P.; Lagase, L.; LaPlante, S.;
McKercher, G.; Perrault, S.; Poirier, M.; Poupart, M.-A.; Stammers, T.; Thauvette,
L.; Thavonekham, B.; Kukolj, G. Bioorg. Med. Chem. Lett. 2010, 20, 857–861; (b)
LaPlante, S. R.; Gillard, J. R.; Jakalian, A.; Aubry, N.; Coulombe, R.; Brochu, C.;
Tsantrizos, Y. S.; Poirier, M.; Kukolj, G.; Beaulieu, P. L. J. Am. Chem. Soc. 2010,
132, 15204–15212.
8. Rai, R.; Kolesnikov, A.; Li, Y.; Young, W. B.; Leahy, E.; Sprengeler, P. A.; Verner,
E.; Shrader, W. D.; Burgess-Henry, J.; Sangalang, J. C.; Allen, D.; Chen, X.; Katz, B.
A.; Luong, C.; Elrod, K.; Cregar, L. Bioorg. Med. Chem. Lett. 2001, 11, 1797–1800.
9. Stevenson, G. I.; Smith, A. L.; Lewis, S.; Michie, S. G.; Neduvelil, J. G.; Patel, S.;
Marwood, R.; Patel, S.; Castro, J. L. Bioorg. Med. Chem. Lett. 2000, 10, 2697–2699.
10. Tyagarajan, S.; Chakravarty, P. K.; Park, M.; Zhou, B.; Herrington, J. B.; Ratliff, K.;
Bugianesi, R. M.; Williams, B.; Haedo, R. J.; Swensen, A. M.; Warren, V. A.;
Smith, M.; Garcia, M.; Kaczorowski, G. J.; McManus, O. B.; Lyons, K. A.; Li, X.;
18. Butin, A. V.; Uchuskin, M. G.; Pilipenko, A. S.; Tsiunchik, F. A.; Cheshkov, D. A.;
Trushkov, I. V. Eur. J. Org. Chem. 2010, 920–926.
19. For a recent review, see: Druzhinin, S. V.; Balenkova, E. S.; Nenajdenko, V. G.
Tetrahedron 2007, 63, 7753–7808.
20. (a) Kumar, A.; Sharma, S.; Bajaj, K.; Bansal, D.; Sharma, S.; Saxena, A. K. K.; Lata,
S.; Gupta, B.; Srivastava, V. K. Ind. J. Chem. 2003, 42B, 1979–1984; (b) El-Shihi, T.
H.; Abdel Latif, N. A.; El-Sawy, E. R. Egypt. J. Chem. 2005, 48, 365–376; (c)
Budakoti, A.; Bhat, A. R.; Athar, F.; Azam, A. Eur. J. Med. Chem. 2008, 43, 1749–
1757; (d) Reddy, M. V. R.; Billa, V. K.; Pallela, V. R.; Mallireddigari, M. R.;
Boominathan, R.; Gabriel, J. L.; Reddy, E. P. Bioorg. Med. Chem. 2008, 16, 3907–
3916; (e) Budakoti, A.; Bhat, A. R.; Azam, A. Eur. J. Med. Chem. 2009, 44, 1317–
1325.
21. (a) Gorbunova, V. P.; Grekova, G. S.; Suvorov, N. N.; Gus’kova, T. A.; Kukushkina,
T. S.; Pershin, G. N. Pharm. Chem. J. 1977, 11, 897–900 [Khim.-Farm. Zh. 1977,
11, No 7, 21–25]; (b) Dandia, A.; Sehgal, V.; Singh, P. Indian J. Chem. 1993, 32B,
1288–1291; (c) Cocconcelli, G.; Diodato, E.; Caricasole, A.; Gaviraghi, G.;
Genesio, E.; Ghiron, C.; Magnoni, L.; Pecchioli, E.; Plazzi, P. V.; Terstappen, G. C.
Bioorg. Med. Chem. 2008, 16, 2043–2052.
22. (a) Singh, S. K.; Saibaba, V.; Rao, K. S.; Reddy, P. G.; Daga, P. R.; Rajjak, S. A.;
Misra, P.; Rao, Y. K. Eur. J. Med. Chem. 2005, 40, 977–990; (b) Zhang, N.; Ayral-
Kaloustian, S.; Anderson, J. T.; Nguyen, T.; Das, S.; Venkatesan, A. M.;
Brooijmans, N.; Lucas, J.; Yu, K.; Hollander, I.; Mallon, R. Bioorg. Med. Chem.
Lett. 2010, 20, 3526–3529.
23. Phenylhydrazine hydrochloride (2.4 mmol) was added slowly to a solution of
compound 2a (2 mmol) in refluxing EtOH/1,4-dioxane mixture (1:2, 15 mL).
The mixture was refluxed for ca. 2 min until full dissolution of the hydrazine
and then cooled to room temperature. The resulting red precipitate was
filtered, washed with cold EtOH (5 mL) and air-dried. DMF (10 mL) was added
to the residue and the mixture was refluxed for 1 min, poured into H2O
(100 mL), extracted with CH2Cl2 (3 Â 20 mL), dried over Na2SO4 and
evaporated under reduced pressure. The residue was purified by column
chromatography on silica gel (eluent: CH2Cl2/petroleum ether, 1:6). Indole 3a
was recrystallized from CH2Cl2/petroleum ether.
Compound 3a: 6-Chloro-2-(3,4-dimethoxyphenyl)-1H-indole: colorless solid,
mp 153–154 °C. IR (KBr):
m
3432, 1540, 1500, 1472, 1452, 1428, 1296, 1248,
1216, 1148, 1032, 1012, 808 cmÀ1
.
1H NMR (300 MHz, CDCl3): d 8.32 (1H, br s),
7.49 (1H, d, J = 8.4 Hz), 7.35 (1H, d, J = 1.8 Hz), 7.17 (1H, d, J = 8.1 Hz), 7.15 (1H,
s) 7.07 (1H, dd, J = 1.8, 8.4 Hz), 6.92 (1H, d, J = 8.1 Hz), 6.68 (1H, br s), 3.96 (3H,
s), 3.92 (3H, s). 13C NMR (75 MHz, CDCl3): d 149.4, 149.2, 138.8, 137.0, 127.9,
127.6, 125.1, 121.1, 120.8, 117.7, 111.6, 110.7, 108.9, 98.9, 55.9 (2C). MS (EI,
70 eV): m/z (%) = 289/287 (33/100, M+), 274/272 (8/24), 243 (15), 229 (23), 214
(15), 209 (33), 193 (58), 165 (24), 144 (15), 59 (16), 43 (22). Anal. Calcd for
C16H14ClNO2: C, 66.79; H 4.90; N, 4.87. Found: C, 67.01; H, 5.01; N, 5.04.
24. General procedure: mixture of compound (2 mmol), phenylhydrazine
A
2
hydrochloride (2.4 mmol) and DMF (10 mL) was refluxed for 2 min (TLC
monitoring). The reaction mixture was poured into H2O (100 mL) and
extracted with CH2Cl2 (3 Â 20 mL). The combined organic fractions were

5258
A. V. Butin et al. / Tetrahedron Letters 52 (2011) 5255–5258
dried over Na2SO4 and evaporated under reduced pressure. Purification of
product 3 was as described in Ref. 23.
Compound 3b: 2-Phenyl-1H-indole: colorless solid, mp 187–188 °C (Lit. 27
br s), 7.46 (1H, d, J = 8.4 Hz), 7.33 (1H, d, J = 1.8 Hz), 7.06 (1H, dd, J = 1.8,
8.4 Hz), 6.62 (1H, br s), 6.52 (1H, d, J = 3.3 Hz), 6.08 (1H, d, J = 3.3 Hz), 2.38
(3H, s). 13C NMR (75 MHz, CDCl3): d 152.0, 145.5, 136.3, 130.3, 127.7, 127.6,
121.2, 120.9, 110.6, 107.9 106.8, 97.7, 13.6. MS (EI, 70 eV): m/z (%) = 233/231
(33/100, M+), 190/188 (18/54), 167 (10), 58 (18), 43 (34). Anal. Calcd for
hexane/Et2O 189–190 °C). IR (KBr):
m 3440, 1480, 1456, 1448, 1404, 1352,
1342, 1300, 796, 764, 744 cmÀ1 1H NMR (300 MHz, DMSO-d6): d 11.52 (1H,
.
s), 7.88–7.84 (2H, m), 7.55–7.52 (1H, m), 7.49–7.43 (2H, m), 7.42–7.39 (1H,
m), 7.34–7.28 (1H, m), 7.12–7.07 (1H, m), 7.02–6.97 (1H, m), 6.89 (1H, br s).
13C NMR (75 MHz, DMSO-d6): d 137.6, 137.1, 132.2, 128.9 (2C), 128.6, 127.4,
125.0 (2C), 121.5, 120.0, 119.4, 111.3, 98.7. MS (EI, 70 eV): m/z (%) = 193
(100, M+), 165 (25), 139 (12), 90 (41), 83 (26), 76 (13), 63 (28), 51 (25), 43
(15).
C
13H10ClNO: C, 67.40; H 4.35; N, 6.05. Found: C, 67.57; H, 4.34; N, 6.20.
Compound 3h: 2-(5-Ethylfuran-2-yl)-6-methoxy-1H-indole: pale-yellow
solid, mp 143–144 °C. IR (KBr): 3416, 1616, 1584, 1452, 1436, 1348,
1264, 1164, 1112, 1016, 812, 780 cmÀ1 1H NMR (300 MHz, DMSO-d6): d
m
.
11.24 (1H, br s), 7.37 (1H, d, J = 8.4 Hz), 6.84 (1H, d, J = 2.1 Hz), 6.65 (1H, dd,
J = 2.1, 8.4 Hz), 6.64 (1H, d, J = 3.3 Hz), 6.52 (1H, br s), 6.20 (1H, d, J = 3.3 Hz),
3.77 (3H, s), 2.69 (2H, q, J = 7.5 Hz), 1.23 (3H, t, J = 7.5 Hz). 13C NMR
(75 MHz, DMSO-d6): d 156.4, 155.8, 146.3, 137.4, 128.6, 122.5, 120.5, 109.4,
106.3, 105.5, 96.9, 94.3, 55.1, 20.9, 12.1. MS (EI, 70 eV): m/z (%) = 241 (100,
M+), 226 (56), 211 (22), 113 (17), 98 (12), 43 (21). Anal. Calcd for
Compound 3f: 6-Chloro-2-(3-nitrophenyl)-1H-indole: orange solid, mp 214-
215 °C. IR (KBr):
m
3372, 1536, 1512, 1476, 1352, 1308, 1244, 1060, 924,
820, 808, 736 cmÀ1
.
1H NMR (300 MHz, DMSO-d6): d 12.02 (1H, br s), 8.70–
8.69 (1H, m), 8.33–8.30 (1H, m), 8.18–8.14 (1H, m), 7.78–7.73 (1H, m), 7.59
(1H, d, J = 8.4 Hz), 7.44 (1H, s), 7.18 (1H, d, J = 1.8 Hz), 7.05 (1H, dd, J = 1.8,
8.4 Hz). 13C NMR (75 MHz, DMSO-d6): d 148.5, 137.8, 136.3, 133.4, 131.4,
130.5, 127.1, 127.0, 122.0, 121.9, 120.2, 119.0, 111.0, 100.9. MS (EI, 70 eV):
m/z (%) = 274/272 (33/100, M+), 242 (16), 226 (20), 199 (10), 191 (47), 164
(14), 113 (10), 101 (20), 89 (10), 59 (32), 43 (36). Anal. Calcd for
C
15H15NO2: C, 74.67; H 6.27; N, 5.80. Found: C, 74.86; H, 6.38; N, 5.79.
25. (a) Stachel, S. J.; Nilges, M.; Van Dranken, D. L. J. Org. Chem. 1997, 62, 4756–
4762; (b) Venkatesh, G.; Ila, H.; Junjappa, H.; Mathur, S.; Hush, V. J. Org. Chem.
2002, 67, 9477–9480.
26. For related pyrazoline aromatization via C–C bond breaking, see: Djapa, F.;
Msaddek, M.; Ciamala, K.; Vebrel, J.; Riche, C. Eur. J. Org. Chem. 2000, 1271–
1278.
C
14H9ClN2O2: C, 61.66; H 3.33; N, 10.27. Found: C, 61.77; H, 3.35; N, 10.38.
Compound 3g: 6-Chloro-2-(5-methylfuran-2-yl)-1H-indole: pale-green solid,
mp 163–164 °C. IR (KBr): 3408, 1580, 1564, 1344, 1304, 1240, 1224, 1208,
1064, 1020, 952, 864, 808, 780 cmÀ1 1H NMR (300 MHz, CDCl3): d 8.37 (1H,
m
27. Kobayashi, K.; Iitsuka, D.; Fukamachi, S.; Konishi, H. Tetrahedron 2009, 65,
7523–7526.
.