Recyclization of tosylamino derivatives of 2-aryl-5-benzylfuran to give indoles through two alternative pathways

Article abstract of DOI:10.1007/s10593-009-0274-y

The recyclization of derivatives of 2-aryl-5-benzylfuran containing a tosylamine fragment to give indoles has been studied. If the tosylamino group is in the ortho position of the aryl substituent, the recyclization proceeds such that the furan ring may b

Full text of DOI:10.1007/s10593-009-0274-y

Chemistry of Heterocyclic Compounds, Vol. 45, No. 3, 2009
RECYCLIZATION OF TOSYLAMINO DERIVATIVES
OF 2-ARYL-5-BENZYLFURAN TO GIVE INDOLES
THROUGH TWO ALTERNATIVE PATHWAYS
A. S. Pilipenko1, A. N. Gaidarzhi1, and A. V. Butin1*
The recyclization of derivatives of 2-aryl-5-benzylfuran containing a tosylamine fragment to give
indoles has been studied. If the tosylamino group is in the ortho position of the aryl substituent, the
recyclization proceeds such that the furan ring may be seen as a formal equivalent of a 1,3-diketone. If,
on the other hand, the tosylamino group is in the ortho positions of both the aryl and benzyl
substituents, the recyclization proceeds through a pathway, in which the furan ring acts as the
equivalent of a 1,4-dicarbonyl compound.
Keywords: 1,3-diketone, 1,4-diketone, indole, furan, recyclization.
The capacity of alkylfurans under acid catalysis conditions to undergo opening to give 1,4-dicarbonyl
compounds is well known and commonly used in preparative chemistry [1-4]. Sometimes, the 1,4-diketones
enter a further reaction and cannot be isolated from the reaction mixture. In this case, the furan may be seen as
the equivalent of a 1,4-dicarbonyl compound. For many years, we have employed this property of furan
compounds in the synthesis of benzo-fused heterocycles through the recyclization of ortho-substituted benzyl
furans. In particular, we have reported that 2-(2-tosylaminobenzyl)furans under acid conditions are converted to
indole derivatives [5-7].
Ts
Ts
Ts
NH
NH
N
+
O
R1
H
O
R
R
R1
R1
O
O
R
_______
* To whom correspondence should be addressed, e-mail: alexander_butin@mail.ru.
1Research Institute of Heterocyclic Compounds Chemistry, Kuban State University of Technology, Krasnodar
350072, Russia.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 376-382, March, 2009. Original
article submitted May 28, 2008.
302
0009-3122/09/4503-0302©2009 Springer Science+Business Media, Inc.

We have recently found that 2-alkyl-5-(2-tosylaminoaryl)furans under protolytic conditions also
undergo recyclization and give indole derivatives [8]. However, in this case, furan, in contrast to
2-(2-tosylaminobenzyl)furans, may be seen as the formal equivalent of 1,3-dicarbonyl compounds. Such
reactivity of furan compounds had never been reported prior to our work.
Ts
Ts
Ts
NH
NH
+
N
H
O
O
R2
R2
O
O
R2
In the present work, we carried out a comparative analysis of the activity of furan in both types of
recyclization mentioned above through the synthesis and investigation of the reactivity of furan compound, for
which the two pathways were possible, at least in principle. 2-Aryl-5-benzylfurans are such compounds
containing nucleophilic functions in the ortho positions of both aromatic rings.
We previously established that 2-aryl-5-(2-tosylaminobenzyl)furans under acid catalysis conditions are
converted into indoles, while the furan in this case acts as a 1,4-diketone equivalent [6]. Before addressing the
major aim of this work, we decided to show that recyclization into indoles for both 2-benzyl-5-(2-tosyl-
aminoaryl)furans and 2-alkyl-5-(2-tosylaminoaryl)furans is possible through a pathway, in which the furan acts
as crypto equivalent of a 1,3-diketone.
NO2
NO2
OMe
OMe
NaBH4, AlCl3
THF
PCl5
+
AlCl3
O
O
COOH
1
2
OMe
OMe
O
NH2
NO2
Ni / Ra
N2H4
O
O
OMe
OMe
OMe
OMe
4
3
Ts
Ts
NH
N
HClO4
AcOH
TsCl
Py
O
O
OMe
OMe
OMe
OMe
6
5
303

Ketone 2 was obtained as the result of the acylation of veratrole by the acid chloride of
5-(2-nitrophenyl)pyromucic acid 1. Reduction of acid 1 by NaBH4 in the presence of an equimolar amount of
anhydrous AlCl3 in dry tetrahydrofuran led to benzylfuran 3. Reduction of the nitro group by hydrazine hydrate
in the presence of Raney nickel and tosylation of amine 4 gave 2-benzyl-5-(2-tosylaminoaryl)furan 5. Indeed,
heating furan 5 in acetic acid in the presence of a significant amount of perchloric acid gave indole 6.
The following sequence of transformations was carried out for the synthesis of a model compound
containing toslyamine functions in the ortho positions of both aromatic rings. Nitration of ketone 2 by fuming
nitric acid in acetic acid gave dinitro derivative 7, whose reduction by NaBH4 in the presence of an equimolar
amount of anhydrous AlCl3 gave furan derivative 8. Further reduction of furan 8 by iron in acetic acid led to
diamine 9, whose tosylation gave the required 2-(2-tosylaminophenyl)-5-(2-tosylaminobenzyl)furan 10.
NH2
NO2
NO2
Fe
NaBH4, AlCl3
HNO3
AcOH
TsCl
Py
2
AcOH
THF
O2N
H2N
O2N
O
O
O
OMe
OMe
OMe
OMe
OMe
OMe
O
9
7
8
OMe
OMe
Ts
NH
Ts
N
NH
Ts
Ts
O
+
H
N
11
Ts
Ts
NH
HN
O
+
H
O
OMe
OMe
MeO
OMe
10
12
Maintaining furan 10 in ethanolic hydrogen chloride at 50°C for 90 min gave indole 11 as the sole
product. The furan ring in this case acts as the equivalent of a 1,4-diketone. The use of more vigorous reaction
conditions, in particular, heating furan 10 in acetic acid at reflux in the presence of perchloric acid did not lead
to reaction by an alternative pathway but rather gave considerable tar formation.
Thus, when the molecule has two suitable nucleophilic sites, the recyclization of the furan ring, in which
the furan acts as the equivalent of a 1,4-dicarbonyl compound, is preferred over the recyclization, in which the
furan acts as the formal equivalent of a 1,3-dicarbonyl compound.
EXPERIMENTAL
1
The H and 13C NMR spectra were taken on a Bruker DPX 300 spectrometer at 300 and 75 MHz,
respectively, in DMSO-d6 for 2, 7, 10, 11 and CDCl3 for 5 and 6 with TMS as the internal standard. The electron
impact mass spectra were taken on Finnigan MAT INCOS 50 mass spectrometer at 70 eV. The IR spectra were
taken on an InfraLUM FT-02 spectrometer in KBr pellets. The monitoring of the reaction course
304

and purity of the products obtained was carried out by thin-layer chromatography on Silufol plates using
1:1:2 acetone–dichloromethane–hexane as the eluent. The plates were developed either by iodine or bromine
vapor. Sorbpolimer KSK silica gel (5-40 µm) was used for column chromatography to isolate pure products.
3,4-Dimethoxyphenyl[5-(2-nitrophenyl)-2-furyl]methanone (2). A sample of PCl5 (10.8 g, 52 mmol)
was added to a suspension of compound 1 (10 g, 43 mmol) in benzene (80 ml) with water bath cooling and
heated for 2 h at 50-55°C. The reaction mixture was then cooled to -2°C and anhydrous AlCl3 (8 g, 60 mmol)
was added in portions at temperatures not exceeding +5°C. Then, veratrole (5.5 ml, 43 mmol) was added
dropwise and heated for 5 h at 55°C with monitoring by thin-layer chromatography. The reaction mixture was
poured into 500 ml ice chips and acidified by adding concentrated hydrochloric acid (2-3 ml). The organic layer
was separated. The solvent and unreacted veratrole were removed by steam distillation. The residue obtained
was separated by column chromatography using 1:2 CH2Cl2–hexane as the eluent to give 9.3 g (61%)
methanone 2 as light-yellow crystals, mp 118-119°C (CH2Cl2–hexane), Rf 0.65. IR spectrum, ν, cm-1: 1627,
1
1595, 1535, 1510, 1459, 1420, 1373, 1306, 1275, 1236, 1138, 1024, 812, 760, 754, H NMR spectrum, δ, ppm
(J, Hz): 3.84 (3H, s, OCH3); 3.87 (3H, s, OCH3); 7.08 (1H, d, J = 8.4, H Ar); 7.18 (1H, d, J = 3.9, H Fur); 7.46
(1H, d, J = 2.1, H Ar); 7.52 (1H, d, J = 3.9, H Fur); 7.63 (1H, dd, J = 2.1, J = 8.4, H Ar); 7.66-7.72 (1H, m,
H Ar); 7.78-7.83 (1H, m, H Ar); 7.93-8.01 (2H, m, H Ar). Found, %: C 64.71; H 4.07; N 4.15. C19H15NO6.
Calculated, %: C 64.59; H 4.28; N 3.96.
2-(3,4-Dimethoxybenzyl)-5-(2-nitrophenyl)furan (3). Anhydrous AlCl3 (6.85 g, 50 mmol) and
NaBH4 (1.9 g, 50 mmol) were added to a solution of compound 2 (10 g, 28 mmol) in dry THF (200 ml) with
cooling to -10°C and heated at reflux for 2 h. The reaction mixture was poured into water (800 ml) and extracted
with three ether portions (100 ml). The extract was dried over Na2SO4, filtered with activated charcoal, and
evaporated to dryness to give 9 g (93%) compound 3 as a yellow oil, Rf 0.80. This product was used in the next
step without further purification.
2-[5-(3,4-Dimethoxybenzyl)-2-furyl]aniline (4).Activated Raney nickel (2 g) was added to a solution
of compound 3 (5 g, 14.7 mmol) in ethanol (40 ml). Then, hydrazine hydrate (7 ml) was added with ice bath
cooling. The reaction mixture was heated at reflux for 30 min with monitoring by thin-layer chromatography.
The reaction mixture was filtered to remove the nickel. The solvent was evaporated in vacuum produced by a
water pump to give 4 g (87%) aniline 4 as a red oil, Rf 0.75. This product was used in the next step without
additional purification.
2-[5-(3,4-Dimethoxybenzyl)-2-furyl]-1-(4-methylphenylsulfonylamino)benzene (5). Tosyl chloride
(5 g, 26 mmol) was added to a solution of aniline 4 (4 g, 13 mmol) in pyridine (15 ml) with ice bath cooling
and stirred for 12 h with monitoring by thin-layer chromatography. The reaction mixture was poured into 200 ml
6 M hydrochloric acid. The precipitate formed was filtered off. The product obtained was separated by column
chromatography with 1:3 benzene–hexane as the eluent to give 3 g (61%) compound 5 as light-yellow crystals,
mp 114-115°C (benzene–hexane), Rf 0.85. IR spectrum, ν, cm-1: 3284, 1520, 1416, 1332, 1264, 1160, 1144,
1092, 1024, 904, 820, 756, 672. 1H NMR spectrum, δ, ppm (J, Hz): 2.26 (3H, s, CH3); 3.84 (3H, s, OCH3); 3.89
(3H, s, OCH3); 3.95 (2H, m, CH2); 6.05 (1H, d, J = 3.3, H Fur); 6.24 (1H, d, J = 3.3, H Fur); 6.81 (1H, br. s,
H Ar); 6.85-6.89 (2H, m, H Ar); 6.98 (2H, d, J = 7.8, H Ts); 7.03-7.08 (1H, m, H Ar); 7.15-7.21 (1H, m, H Ar);
7.26-7.32 (3H, m, H Ar+Ts); 7.57-7.60 (1H, m, H Ar); 7.93 (1H, br. s, NH). 13C NMR spectrum, δ, ppm: 21.3,
34.2, 55.8, 55.9, 107.8, 108.6, 111.6, 111.8, 120.7, 122.3, 123.2, 125.1, 126.8 (2C), 127.0, 128.3, 129.2 (2C),
129.8, 132.6, 135.7, 143.3, 147.9, 149.0, 150.7, 155.0. Mass spectrum, m/z (Irel, %): 463 [M]+ (7), 308 (52), 191
(69), 151 (100), 91 (29). Found, %: C 67.45; H 5.51; N 2.97. C26H25NO5S. Calculated, %: C 67.37; H 5.44;
N 3.02.
1-(3,4-Dimethoxyphenyl)-3-[1-(4-methylphenylsulfonyl)-1H-indol-2-yl]acetone (6). 70% Perchloric
acid (3 ml) was added to a solution of compound 5 (3 g, 6.5 mmol) in acetic acid (30 ml) and heated at reflux
for 7 min with monitoring by thin-layer chromatography. The reaction mixture was poured into 300 ml water.
The precipitate formed was filtered off and separated by column chromatography using1:3 benzene–hexane
305

as the eluent to give 2.3 g (61%) compound 6 as colorless crystals, mp 108-109°C (benzene–hexane), Rf 0.60. IR
spectrum, ν, cm-1: 1727, 1594, 1515, 1450, 1354, 1259, 1172, 1092, 1050, 1023, 752, 685. 1H NMR spectrum, δ,
ppm (J, Hz): 2.30 (3H, s, CH3); 3.82 (3H, s, OCH3); 3.83 (2H, s, CH2); 3.86 (3H, s, OCH3); 4.12 (2H, s, CH2);
6.45 (1H, s, H Ind); 6.78-6.85 (3H, m, H Ar); 7.15-7.23 (4H, m, H Ar+Ts); 7.41-7.43 (1H, m, H Ar); 7.63 (2H,
d, J = 8.4, H Ts); 7.91-7.94 (1H, m, H Ar). 13C NMR spectrum, δ, ppm: 21.4, 42.1, 49.1, 55.7, 55.8, 111.2,
112.4, 112.6, 114.2, 120.5, 121.7, 123.4, 124.3, 126.4, 126.5 (2C), 129.1, 129.7 (2C), 133.9, 135.7, 136.5,
144.8, 148.0, 148.9, 204.1. Mass spectrum, m/z (Irel, %): 463 [M]+ (37), 309 (10), 178 (12), 151 (100), 130 (25),
91 (24). Found, %: C 67.29; H 5.56; N 3.08. C26H25NO5S. Calculated, %: C 67.37; H 5.44; N 3.02.
(4,5-Dimethoxy-2-nitrophenyl)-[5-(2-nitrophenyl)-2-furyl]methanone (7). Fuming nitric acid
(4.2 ml, 98 mmol) was cautiously added dropwise to a solution of compound 2 (5 g, 14 mmol) in 10 ml acetic
acid cooled on an ice bath. The reaction mixture was maintained for 20 min at 0°C and for 20 min at room
temperature with monitoring by thin-layer chromatography. The mixture was poured into ice chips (200 ml).
The precipitate was filtered off, washed with aqueous sodium bicarbonate, and recrystallized from acetone–
ethanol to give 4.2 g (77%) compound 7 as yellow crystals, mp 188-189°C, Rf 0.50. IR spectrum, ν, cm-1: 1668,
1576, 1524, 1508, 1460, 1356, 1336, 1280, 1264, 1068, 812, 788. 1H NMR spectrum, δ, ppm (J, Hz): 3.94 (3H,
s, OCH3); 3.96 (3H, s, OCH3); 7.20 (1H, d, J = 3.9, H Fur); 7.25 (1H, s, H Ar); 7.44 (1H, d, J = 3.9, H Fur);
7.65-7.71 (1H, m, H Ar); 7.76-7.82 (1H, m, H Ar); 7.78 (1H, s, H Ar); 7.90-7.94 (2H, m, H Ar). Found, %:
C 57.43; H 3.62; N 7.06. C19H14N2O8. Calculated; %: C 57.29; H 3.54; N 7.03.
2-(4,5-Dimethoxy-2-nitrobenzyl)-5-(2-nitrophenyl)furan (8) was obtained analogously to the
synthesis of furan 3 in 85% yield (8 g) as a yellow oil, Rf 0.75. This product was used in the next step without
further purification.
2-[5-(2-Aminophenyl)-2-furylmethyl]-4,5-dimethoxyaniline (9).
A
mixture of furan 8 (5 g,
12.5 mmol), 30 g iron powder, 40 ml acetic acid, 100 ml water, and 30 ml ethyl acetate was heated at reflux for
90 min with monitoring by thin-layer chromatography. The reaction mixture was carefully neutralized by adding
sodium bicarbonate. The organic layer was separated and the aqueous layer was extracted with three 70 ml
portions of ethyl acetate. The combined organic layers were dried over sodium sulfate and filtered with activated
charcoal. The solvent was removed in vacuum produced by a water pump to give 3 g (70%) aniline 9 as a red
oil, Rf 0.65. This product was used in the next step without further purification.
4,5-Dimethoxy-1-(4-methylphenylsulfonylamino)-2-{5-[2-(4-methylphenylsulfonylamino)phenyl]-
2-furylmethyl}benzene (10). Tosyl chloride (5.4 g, 28 mmol) was added to a solution of compound 9 (3 g,
9.2 mmol) in pyridine (10 ml) with ice bath cooling and stirred for 12 h with monitoring by thin-layer
chromatography. The reaction mixture was poured into 100 ml 6 M hydrochloric acid and the precipitate formed
was filtered off. The product was separated by column chromatography using 1:4 benzene–hexane as the eluent
to give 2.5 g (43%) compound 10 as light-yellow crystals, mp 113-114°C (CH2Cl2–hexane), Rf 0.70. IR
1
spectrum, ν, cm-1: 3263, 1599, 1519, 1415, 1334, 1227, 1163, 1096, 674. H NMR spectrum, δ, ppm (J, Hz):
2.33 (3H, s, CH3); 2.34 (3H, s, CH3); 3.41 (3H, s, OCH3); 3.66 (3H, s, OCH3); 3.93 (2H, s, CH3); 6.03 (1H, d,
J = 3.3, H Fur); 6.19 (1H, s, H Ar); 6.77 (1H, s, H Ar); 6.82-6.85 (1H, m, H Ar); 6.88 (1H, d, J = 3.3, H Fur);
7.10-7.16 (1H, m, H Ar); 7.24-7.37 (5H, m, H Ar+Ts); 7.53-7.62 (5H, m, H Ar+Ts); 9.41 (1H, s, NH); 9.53 (1H,
s, NH). 13C NMR spectrum, δ, ppm: 21.0 (2C), 29.0, 55.1, 55.5, 108.7, 111.0, 111.3, 112.8, 126.5, 126.6,
126.7 (2C), 127.1 (2C), 127.3, 127.4 (2C), 127.9, 128.1, 129.6 (4C), 131.5, 137.0, 137.9, 143.0, 143.1, 146.9,
147.6, 148.7, 153.8. Mass spectrum, m/z (Irel, %): 477 [M+H–Ts]+ (14), 323 (23), 190 (32), 120 (41), 91 (100).
Found, %: C 62.48; H 5.17; N 4.45. C33H32N2O7S2. Calculated, %: C 62.64; H 5.10; N 4.43.
2-{3-[5,6-Dimethoxy-1-(4-methylphenylsulfonyl)-1H-indol-2-yl]propanoyl}-1-(4-methylphenyl-
sulfonylamino)benzene (11). Ethanolic HCl (20 ml) prepared by dissolving gaseous HCl (100 g) in ethanol
(200 g) was added to a solution of compound 10 (3 g, 4.7 mmol) in ethanol (20 ml) and the reaction mixture
was maintained for 90 min at 50°C with monitoring by thin-layer chromatography. The reaction
306

mixture was poured into 200 ml water. The precipitate formed was filtered off, washed with saturated aqueous
sodium bicarbonate, and recrystallized from ethanol to give 2.1 g (70%) compound 11 as light-yellow crystals,
mp 185-186°C (CH2Cl2–hexane), Rf 0.60. IR spectrum, ν, cm-1: 1654, 1491, 1327, 1196, 1156, 1092, 663.
1H NMR spectrum, δ, ppm (J, Hz): 2.28 (3H, s, CH3); 2.30 (3H, s, CH3); 3.22-3.31 (2H, m, CH2); 3.43-3.52 (2H,
m, CH2); 3.73 (3H, s, OCH3); 3.84 (3H, s, OCH3); 6.51 (1H, s, H Ind); 7.00 (1H, s, H Ar); 7.17-7.41 (6H, m,
H Ar+Ts); 7.52-7.70 (6H, m, H Ar+Ts); 8.03-8.06 (1H, m, H Ar); 11.22 (1H, br. s, NH). 13C NMR spectrum, δ,
ppm: 20.9, 21.1 (2C), 23.2, 55.6, 55.8, 98.6, 102.5, 109.9, 119.6, 122.4, 123.8, 124.4, 126.2 (2C), 127.0 (2C),
129.9 (2C), 130.2 (2C), 130.3, 131.7, 134.6 (2C), 135.7, 138.0, 138.8, 144.1, 145.3, 146.9, 147.1, 203.5. Mass
spectrum, m/z (Irel, %): 478 [M–Ts]+ (4), 322 (16), 274 (17), 190 (22), 120 (74), 91 (100). Found, %: C 62.75;
H 5.21; N 4.37. C33H32N2O7S2. Calculated, % : C 62.64; H 5.10; N 4.43.
This work was carried out with the financial support of the Russian Basic Research Fund
(Grant 07-03-00352-a) and Bayer Health Care AG, Germany.
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