Furan ring opening - Indole ring closure: A new modification of the Reissert reaction for indole synthesis

Article abstract of DOI:10.1016/S0040-4039(01)00066-1

A new modification of the Reissert reaction is reported. On treatment of 2-tosylaminobenzylfurans with ethanolic HCl, some indole derivatives have been obtained. The furan ring served as the origin of a carbonyl group in this reaction.

Full text of DOI:10.1016/S0040-4039(01)00066-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 2031–2033
Furan ring opening—indole ring closure: a new modification of
the Reissert reaction for indole synthesis†
Alexander V. Butin,* Tat‘yana A. Stroganova, Irina V. Lodina and Gennady D. Krapivin
Kuban State Technological University, Moskovskaya st. 2, Krasnodar 350072, Russia
Received 28 November 2000; revised 18 December 2000; accepted 10 January 2001
Abstract—A new modification of the Reissert reaction is reported. On treatment of 2-tosylaminobenzylfurans with ethanolic HCl,
some indole derivatives have been obtained. The furan ring served as the origin of a carbonyl group in this reaction. © 2001
Elsevier Science Ltd. All rights reserved.
The indole ring system is a major part of a large
number of pharmacologically active compounds; thus,
the development of new conditions for synthesis of
highly functionalized indole derivatives is always of
interest. Among a large variety of methods for indole
synthesis,2 the Reissert method has not lost its topical-
ity. In support of this view are recent investigations
using this method for the synthesis of alkaloids and
other natural compound syntheses.3
partial reduction of cyano group in o-aminophenyl-
acetonitriles.7
Various alkylfurans can serve as the source of the
carbonyl group, as it is well known that under the
conditions of the Marckwald reaction furans undergo
ring cleavage to form 1,4-dicarbonyl compounds.8 This
implies that benzylfurans, which have a nitrogen func-
tion in the o-position of the aromatic ring, can be
useful synthons for indole synthesis.
The key intermediate for indole synthesis under Reis-
sert conditions is o-aminobenzylcarbonyl compound A.
Because of the rapid spontaneous reaction of an amino
group with a carbonyl group, with subsequent aroma-
tization, compound A is not usually isolated from the
reaction mixture but generated in situ.
Earlier, the synthesis of indole derivatives from o-nitro-
phenyldifurylalkanes 1 was described.9,10 Jones and
McKinley reported that as a result of deoxygenation of
compounds 1a–c with triethylphosphite the dibenzopyr-
roles 2a–c9 were obtained. The authors suspected that
indoles 3a–c were intermediate compounds of the
transformation.
Two general ways for obtaining compound A are
described: the first is to reduce a nitro group of o-
nitrobenzylcarbonyl compounds or their derivatives;4
the other is to generate a carbonyl group either by
oxidation of appropriate alcohols5 or alkenes,6 or by
Later we isolated compound 3a after reduction of
compound 1a with SnCl2 in the presence of
(CH3)3SiCl.10 We proved that the transformation pro-
ceeded by an oxidative fission of the furan ring and
involved a 2,5-cycloaddition of the nitroso-group to
one of furan rings. However, such a method of indole
synthesis has an essential limitation. The introduction
of donor substituents (for example, a methoxy group)
in the p-position to the nitro group prevents the reac-
tion due to the decrease of the nitroso-group reactivity
as a dienophile.
Keywords: furans; Reissert reactions; indoles.
* Corresponding author. E-mail: nemol@kubstu.ru
†
Part 22 of the ‘Furyl(aryl)methanes and their derivatives’ series. For
Part 21, see Ref. 1.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00066-1

2032
A. V. Butin et al. / Tetrahedron Letters 42 (2001) 2031–2033
In this line of study, we attempted to study the
reaction of furan ring opening–indole ring clo-
sure under conditions of hydrolytic cleavage of the
furan ring for the purpose of developing more gen-
eral methods for indole synthesis. We showed a simi-
lar type of transformation in the case of the synthe-
sis of benzofuran derivatives from 2-hydroxybenzyl-
furans.11
Scheme 1.
Scheme 2.

A. V. Butin et al. / Tetrahedron Letters 42 (2001) 2031–2033
2033
The o-tosylaminobenzylfurans 4 were obtained via the
well-known alkylation reaction of furans with the
appropriate alcohols 512 in high yields (Scheme 1).
7. (a) Makosza, M.; Danikiewicz, W.; Wojciechowski, K.
Liebigs Ann. Chem. 1988, 203; (b) Macor, J. E.; Wehner,
J. M. Tetrahedron Lett. 1991, 32, 7195; (c) Marino, J. P.;
Hurt, C. R. Synth. Commun. 1994, 24, 839.
Compounds 4, when heated in ethanolic HCl, were
converted into indoles 6 in good yields13 (Scheme 2).
We believe that the mechanism of the reaction is similar
to one described earlier for benzofuran derivatives.11,14
8. See the following reviews: (a) Dean, F. M. Adv. Hetero-
cyclic Chem. 1982, 30, 167; (b) Dean, F. M. Adv. Hetero-
cyclic Chem. 1982, 31, 237; (c) Piancatelli, G.; D’Auria,
M.; D’Onofrio, F. Synthesis 1994, 867.
9. (a) Jones, G.; McKinley, W. H. Tetrahedron Lett. 1977,
18, 2457; (b) Jones, G.; McKinley, W. H. J. Chem. Soc.,
Perkin Trans. 1 1979, 599.
10. (a) Butin, A. V.; Abaev, V. T.; Stroganova, T. A. Khim.
Geterotsikl. Soedin. 1995, 1578; (b) Butin, A. V.;
Stroganova, T. A.; Abaev, V. T.; Zavodnik, V. E. Khim.
Geterotsikl. Soedin. 1997, 1614; (c) Butin, A. V.; Abaev,
V. T.; Stroganova, T. A.; Gutnov, A. V. Molecules 1997,
2, 62.
11. (a) Butin, A. V.; Krapivin, G. D.; Zavodnik, V. E.;
Kul’nevich, V. G. Khim. Geterotsikl. Soedin. 1993, 616;
(b) Abaev, V. T.; Gutnov, A. V.; Butin, A. V. Khim.
Geterotsikl. Soedin. 1998, 603; (c) Gutnov, A. V.; Butin,
A. V.; Abaev, V. T.; Krapivin, G. D.; Zavodnik, V. E.
Molecules 1999, 4, 204; (d) See the following review:
Butin, A. V.; Gutnov, A. V.; Abaev, V. T.; Krapivin, G.
D. Molecules 1999, 4, 52.
12. Typical procedure is as follows: To a boiling solution of
5d (4.13 g, 10 mmol) in CH2Cl2 (120 mL), p-TsOH (40
mg) and 2-methylfuran (3.7 mL, 40 mmol) were added.
The reaction mixture was heated to reflux for 3–5 min,
then cooled and washed with NaHCO3 solution, water,
dried over Na2SO4, evaporated to one-third its initial
volume. After addition of hexane the residue obtained
was crystallized to afford 4d as colorless crystals (3.9 g,
82% yield). Mp 125–126°C (hexane/CH2Cl2); anal. found:
C, 67.63; H, 5.51; N, 3.27. C27H27NO5S requires: C,
67.90; H, 5.70; N, 2.93%; wmax (Nujol): 3300 cm−1; lH (60
In conclusion, we would like to point out that this
method of indole synthesis is general and allows varia-
tion of the substituents R, R% and R¦. Additionally the
presence of the alkanone side chain in the indoles 6
substantially extends the possibilities for their synthetic
application. Thus, for example, compounds 6 can be
utilized as convenient intermediates for the synthesis of
mytomicin and mitosene derivatives and new synthetic
analogs of the antitumor drug EO-9.15
Acknowledgements
The authors are grateful to Professor Gurnos Jones for
his interest in this work and assistance in the prepara-
tion of the manuscript. We also wish to thank our
young colleague Sergey Smirnov, student of the
Department of Chemical Technology of the Kuban
State Technological University, for his assistance in the
experimental work.
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MHz, CCl4): 2.15 (3H, s, CH3
(3H, s, OCH3), 3.62 (3H, s, OCH3
5.48 (1H, d, J=3.2 Hz, 3-HFur), 5.67 (1H, d, J=3.2 Hz,
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6
(3H, m, HAr), 6.92–7.25 (5H, m, HAr), 7.52 (2H, d, J=8.5
Hz, HAr).
13. Typical procedure is as follows: A solution of 4d (4.77 g,
10 mmol) in ethanolic HCl (150 mL) was heated to reflux
for 15 min, cooled and then poured into water. The
crystalline product was filtered off, washed with water,
air-dried and recrystallized from hexane/CH2Cl2 mixture
to give indole 6d (3.8 g, 80% yield). Mp 175–176°C; anal.
found: C, 68.15; H, 5.44; N, 2.61. C27H27NO5S requires:
C, 67.90; H, 5.70; N, 2.93%; wmax (Nujol): 1700 cm−1; lH
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(60 MHz, CDCl3): 2.07 (3H, s, COCH3
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3.73 (3H, s, OCH3), 3.93 (3H, s, OCH3), 6.68 (1H, s,
Ind), 7.07–7.67 (9H, m, HAr), 7.83 (1H, s, HInd).
6
), 2.27 (3H, s,
6
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H
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.