Furan as a 1,3-diketone equivalent: the second type furan recyclization applied to indole synthesis

Article abstract of DOI:10.1016/j.tetlet.2006.04.080

A new approach for the synthesis of indole derivatives based on protolytic recyclization of 2-alkyl-5-(2-tosylaminoaryl)-furans is described. The furan ring in this unusual transformation formally serves as a 1,3-diketone equivalent.

Full text of DOI:10.1016/j.tetlet.2006.04.080

Tetrahedron Letters 47 (2006) 4113–4116
Furan as a 1,3-diketone equivalent: the second type furan
recyclization applied to indole synthesis
Alexander V. Butin*
Research Institute of Heterocyclic Compounds Chemistry, Kuban State University of Technology, Moskovskaya st. 2,
Krasnodar 350072, Russia
Received 23 January 2006; revised 8 April 2006; accepted 19 April 2006
Abstract—A new approach for the synthesis of indole derivatives based on protolytic recyclization of 2-alkyl-5-(2-tosylaminoaryl)-
furans is described. The furan ring in this unusual transformation formally serves as a 1,3-diketone equivalent.
ꢀ 2006 Elsevier Ltd. All rights reserved.
During recent years we have been involved in the elabo-
ration of a general method for the synthesis of benzann-
elated heterocycles based on recyclization of ortho-
substituted benzylfurans under protolytic conditions.1
By varying the substituent at the ortho-position of the
benzylfuran, different types of heterocyclic systems as
benzofurans,2 indoles,3 isocoumarins,4 isoquinolones5
and isochromenes6 (Scheme 1) can be obtained. The
method is based on the ability of the furan ring, in acidic
media, to serve as a 1,4-diketone equivalent. Such reac-
tions are well known and are widely used in synthetic
organic chemistry.7
which are commonly used for the recyclization of 2-tos-
ylaminobenzylfurans into indole derivatives. In this case
indole derivatives were obtained as well. As a starting
material we employed carbonyl derivatives of 2-nitro-
arylfurans 1, readily available by arylation of furfural
and acetylfuran.8 Reduction of compounds 1 with
NaBH4 in the presence of an equimolar quantity of
AlCl3 in dry tetrahydrofuran gave 2-alkyl-5-(2-nitro-
aryl)-furans 2.9 Subsequent reduction of the nitro group
with Raney-Ni10 and tosylation of the resulting anilines
3 gave compounds 411 with good overall yields (Scheme
2).
In continuation of our ongoing interest in furan recycli-
zation reactions we studied the behavior of 2-alkyl-5-
(2-tosylaminoaryl)furans under the acidic conditions,
Refluxing compounds 4 in ethanol saturated with
hydrogen chloride afforded indole derivatives 5 in
moderate yields (Scheme 3). However, unlike the
XH
R'
XH
R'
XH
H+
H+
+
O
R"
R"
R"
X
+
O
O
R
H
R
R
H
R'
A
X
X
OH
R"
O
O
R"
R
H
R
R
R'
R'
R"
R'
X = O, NTs, NAc, COO, CONAlk, CH2O
Keywords: Furan; Recyclization; Indole.
*
Tel.: +7 861 2559556; fax: +7 861 2596592; e-mail: alexander_butin@mail.ru
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.04.080

4114
A. V. Butin / Tetrahedron Letters 47 (2006) 4113–4116
R1
NO2
NO2
NaBH4, AlCl3
Ni/Ra
EtOH
R1
O
O
O
THF
R
R
1
2
Ts
NH2
NH
TsCl
Py
R1
O
R1
O
R
R
3
4
1-4
R
H
R1
H
Yield 4 (%)
a
b
c
43
40
48
50
46
Me
Cl
H
H
d
e
OCH3
H
H
Me
Scheme 2.
Ts
Ts
NH
NH
+
O
+
R1
R1
O
H
H
B
R
R
H+
- H+
O
Ts
H
Ts
Ts
N
NH
R1
NH
+
H+
R1
H+
O
R1
O
H
H
- H+
R
R
R
C
4
Ts
Ts
N
N
R
R
R1
O
R1
HO
5
4, 5
a
R
H
R1
H
Yield 5 (%)
83
75
85
64
80
b
Me
Cl
H
c
H
d
OCH3
H
H
e
Me
Scheme 3.
2-tosylaminobenzylfurans which recyclize within 10–
40 min under these conditions,3 2-tosylaminoarylfurans
4 required much longer reaction times (4–12 h) with
incomplete conversion of the starting compounds 4. Evi-
dently, both transformations proceed via furan ring pro-
tonation with intermediate formation of furyl cations
(Schemes 1 and 3). Consideration of the structures of
these cations in both cases allowed us to assume a rea-
son for such a striking difference in the duration of the
reaction. Thus the substituents in positions 2 and 5 of
the furan ring in the case of the corresponding benzyl-
furans have approximately the same electronic proper-
ties and protonation at either alpha position of the
furan ring is equally probable. This leads to a sufficiently

A. V. Butin / Tetrahedron Letters 47 (2006) 4113–4116
FURAN RECYCLIZATION IN INDOLE SYNTHESES
4115
FIRST TYPE
Ts
Ts
Ts
NH
NH
N
O
O
O
R
R
R
O
SECOND TYPE
Ts
Ts
Ts
NH
NH
N
O
O
O
O
Scheme 4.
high concentration of the furyl cation A, amenable to
the formation of the final product (Scheme 1). In the
case of 2-tosylaminoarylfurans 4, protonation can result
in two furyl cations sufficiently different in their stability.
Evidently furyl cation B must be more thermodynami-
cally stable than cation C due to additional delocaliza-
tion of the positive charge on the aryl substituent.
Consequently, a low equilibrium concentration of the
cation C, which is an intermediate in indole 5 formation
leads to a considerable increase in reaction time. Bearing
this in mind we attempted a reaction under much more
severe conditions hoping that an increase in the acidity
would raise the concentration of the requisite cation C
under kinetic control conditions. In fact, carrying out
the reaction in boiling acetic acid in the presence of suf-
ficient amounts of 72% HClO4 allowed us to shorten the
reaction time to 10–15 min and improve the yields of the
indoles 5 (Scheme 3).12
group to the ortho-position of the aryl ring as was the
case for recyclization of benzylfurans.
Acknowledgements
Financial support was provided by Bayer HealthCare
AG and the Russian Foundation of Basic Research
(grant 03-03-32759).
References and notes
1. See the following review: Butin, A. V.; Abaev, V. T. Izvest.
AN. Seriya Khim. 2001, 1436–1443.
2. (a) Butin, A. V.; Krapivin, G. D.; Zavodnik, V. E.;
Kul’nevich, V. G. Khim. Geterotsikl. Soedin. 1993, 616–
626; (b) Abaev, V. T.; Gutnov, A. V.; Butin, A. V. Khim.
Geterotsikl. Soedin. 1998, 603–607; (c) Gutnov, A. V.;
Butin, A. V.; Abaev, V. T.; Krapivin, G. D.; Zavodnik, V.
E. Molecules 1999, 4, 204–218; See the following review:
(d) Butin, A. V.; Gutnov, A. V.; Abaev, V. T.; Krapivin,
G. D. Molecules 1999, 4, 52–61.
3. Butin, A. V.; Stroganova, T. A.; Lodina, I. V.; Krapivin,
G. D. Tetrahedron Lett. 2001, 42, 2031–2033.
4. Gutnov, A. V.; Abaev, V. T.; Butin, A. V.; Dmitriev, A. S.
J. Org. Chem. 2001, 66, 8685–8686.
In conclusion, we have reported a new approach to
substituted indoles based on the recyclization of 2-tos-
ylaminoarylfurans. The method developed is of prepara-
tive value in indole chemistry since all the steps are high
yielding and reproducible. Indole derivatives available
by this reaction possess an active carbonyl group in
the side chain and a free position at C-3, which makes
them attractive for further transformations. In addition,
this transformation is of interest for improved under-
standing of furan chemistry as the furan ring here for-
mally acts as a 1,3-dicarbonyl compound equivalent.
As was noted previously,2–6 the furan ring in the benz-
ylfuran acid-catalyzed rearrangement plays the role of
a latent 1,4-dicarbonyl compound and we named this
process recyclization of the first type. Thus we have
named the rearrangement discussed in this work as the
recyclization of the second type (Scheme 4). To the best
of our knowledge recyclizations of this type in acidic
media are unknown.
5. Abaev, V. T.; Osipova, A. A.; Butin, A. V. Khim.
Geterotsikl. Soedin. 2001, 849–850.
6. Butin, A. V.; Abaev, V. T.; Mel’chin, V. V.; Dmitriev, A.
S. Tetrahedron Lett. 2005, 46, 8439–8441.
7. (a) Takano, S.; Otaki, S.; Ogasawara, K. J. Chem. Soc.,
Chem. Commun. 1983, 1172–1174; (b) Haley, J. F., Jr.;
Keehn, P. M. Tetrahedron Lett. 1973, 4017–4020; (c)
Bezoari, M. D.; Paudler, W. W. J. Org. Chem. 1980, 45,
4584–4586; (d) Faragher, R.; Gilchrist, T. L. J. Chem.
Soc., Perkin Trans. 1 1979, 258–262; (e) Short, F. W.;
Rockwood, G. M. J. Heterocycl. Chem. 1969, 6, 713–722;
(f) Vijayasarathy, P. R.; Khrishna Rao, G. S. Indian J.
Chem. 1973, 11, 301–302; (g) Popp, F. D.; Schleigh, W. R.;
Katz, L. E. J. Chem. Soc. (C) 1968, 2253–2257; (h)
Kharchenko, V. G.; Markushina, I. A.; Gubina, T. I. Zh.
Org. Khimii 1982, 18, 394–399; (i) Kurihara, T.; Harusava,
S.; Hirai, J.; Yoneda, R. J. Chem. Soc., Perkin Trans. 1
1987, 1771–1776; See also the following reviews: (j) Dean,
F. M. Adv. Heterocycl. Chem. 1982, 30, 167–238; (k)
The study of the scope of this reaction is in progress as it
can be successfully applied to the synthesis of other het-
erocycles by introduction of a suitable nucleophilic

4116
A. V. Butin / Tetrahedron Letters 47 (2006) 4113–4116
Dean, F. M. Adv. Heterocycl. Chem. 1982, 31, 237–344;
(l) Piancatelli, G.; D’Auria, M.; D’Onofrio, F. Synthesis
1994, 867–889.
in the next step. Warning: Care should be taken when
handling benzene as a solvent due to its carcinogenic
properties.
8. Compounds 1 were prepared using the Meerwein method.
For a typical procedure see: Janda, L.; Voticky, Z. Chem.
Zvesti 1984, 38, 507–513. A general method for the
arylation reaction is as follows: A mixture of 2-nitroaniline
derivative (0.3 mol), 400 ml of water and 200 ml of 36%
hydrochloric acid was stirred for 30 min at 80 ꢁC. To the
resulting suspension of aniline hydrochloride, under stir-
ring and cooling (À10 to 0 ꢁC), a solution of NaNO2 (25 g,
0.36 mol) in 120 ml of water was added gradually. The
resulting solution of the diazonium salt was stirred for
another 40 min at À5 to 0 ꢁC, then filtered, and a solution
of furfural (0.3 mol) in 150 ml of acetone was added
followed by a solution of CuCl2 (8 g, 0.06 mol) in 100 ml
of water. The reaction mixture was stirred for 12 h at
room temperature. After completion of the reaction, the
resulting precipitated product was filtered off and recrys-
tallized from ethanol/acetone mixture. Yields of 5-aryl-
furfurals 1a–d were 45–53%. The yield of 2-acetyl-5-
phenylfuran 1e was 41%.
11. A typical procedure is as follows: To a solution of amine
3a (6.09 g, 0.035 mol) in 15 ml of pyridine under stirring
and cooling in a water bath, para-toluenesulphonyl
chloride (10.07 g, 0.053 mol) was added gradually. The
mixture was stirred for 0.5 h and after completion of the
reaction (TLC monitoring), the mixture was poured into
1 l of 6 M hydrochloric acid. The oil which separated was
washed with water until it crystallized. The crystals were
filtered off, dried, dissolved in benzene/hexane mixture
(1:1) and passed through a pad of silica gel. The refined
solution was evaporated under reduced pressure and the
residue crystallized from ethanol. The yield of the com-
pound 4a, based on starting material 1a, was 43% as
colorless crystals. Mp 88 ꢁC. Anal. Found: C, 66.22; H,
5.07%. C18H17NO3S requires: C, 66.03; H, 5.23%; dH
(250 MHz, CDCl3): 2.32 (3H, s, CH3), 2.38 (3H, s, CH3),
5.99 (1H, d, J = 3.0 Hz, 4-HFur), 6.22 (1H, d, J = 3.0 Hz,
3-HFur), 7.08–7.14 (1H, m, HAr), 7.09 (2H, d, J = 8.3 Hz,
H
Ts), 7.21–7.24 (1H, m, HAr), 7.31–7.34 (1H, m, HAr), 7.32
9. Compounds 2 were synthesized according to the proce-
dure reported earlier: Ono, A.; Suzuki, N.; Kamimura, J.
Synthesis 1987, 736–738. A typical procedure is as follows:
To a stirred and cooled solution (0–5 ꢁC) of aldehyde 1a in
tetrahydrofuran (8.68 g, 0.04 mol), anhydrous aluminum
chloride (9.58 g, 0.072 mol) and sodium borohydride
(2.74 g, 0.072 mol) were added portionwise and the
resulting suspension was stirred at 0–5 ꢁC for 20 min and
then brought to reflux. After 1–2 h (TLC monitoring) the
reaction mixture was cooled and poured into 700 ml of
water. The product was extracted with ether (3 · 50 ml)
and the combined ethereal extract was dried over sodium
sulfate, treated with active charcoal and evaporated under
reduced pressure. The obtained residue 2a was used in the
next step as such.
10. A typical procedure is as follows: To an ethanolic solution
of compound 2a (8.12 g, 0.04 mol) active Raney nickel
was added (4 g) along with 10 ml of hydrazine hydrate and
the reaction mixture refluxed for 1–2 h. After completion
of the reaction (TLC monitoring) the nickel was filtered off
and the filtrate was evaporated under reduced pressure.
The residue was dissolved in benzene/hexane mixture (1:1)
and filtered through a pad of silica gel and evaporated
under reduced pressure. The obtained residue 3a was used
(2H, d, J = 8.3 Hz, HTs), 7.61–7.64 (1H, m, HAr), 7.86
(1H, s, NH). Warning: Care should be taken when
handling benzene as a solvent due to its carcinogenic
properties.
12. A typical procedure is as follows: To a solution of
compound 4a (3 g, 0.009 mol) in 30 ml of glacial acetic
acid, 3 ml of 70% perchloric acid was added and the
mixture refluxed for 10 min. After completion of the
reaction (TLC monitoring) the mixture was poured into
500 ml of water and brought to pH = 7 with sodium
carbonate. The resulting precipitate was filtered off, dried,
dissolved in benzene/hexane mixture (1:1) and passed
through a pad of silica gel. The refined solution was
evaporated under reduced pressure and the residue
recrystallized from ethanol. The yield of compound 5a
was 83% as colorless crystals. Mp 95 ꢁC. Anal. Found: C,
65.89; H, 5.12%. C18H17NO3S requires: C, 66.03; H,
5.23%; mmax (KBr): 1700 cmÀ1; dH (250 MHz, CDCl3):
2.31 (3H, s, CH3), 2.34 (3H, s, CH3), 4.13 (2H, s, CH2),
6.52 (1H, s, 3-H), 7.20–7.23 (3H, m, HAr), 7.25 (2H, d,
J = 8.5 Hz, HTs), 7.44–7.45 (1H, m, HAr), 7.68 (2H, d,
J = 8.5 Hz, HTs), 7.93–7.96 (1H, m, HAr). Warning: Care
should be taken when handling benzene as a solvent due to
its carcinogenic properties.