Recyclable indium(III) Chloride catalyzed site-selective double substitution in one pot for the synthesis of isatin N -ribonucleosides under microwave irradiation

Article abstract of DOI:10.1055/s-0029-1218714

A novel one-pot synthesis of isatin N-ribonucleosides from N-phenylribosylamines and diethyl oxalate in ethanol catalyzed by recyclable indium(III) chloride under microwave irradiation has been developed. The transformation consists of indium(III) chloride catalyzed nucleophilic substitution by N-phenylribosylamines on diethyl oxalate followed by rapid intramolecular electrophilic substitution, which results in annulation of a five-membered nitrogen heterocycle on to the benzene ring yielding isatin N-ribonucleosides. The reaction proceeded smoothly in quantitative yields at ambient temperatures. The starting materials, N-phenylribosylamines, were prepared by indium(III) chloride catalyzed nucleophilic substitution of the anomeric hydroxy group of -d-ribofuranose by an arylamine under microwave irradiation. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1218714

PAPER
1613
Recyclable Indium(III) Chloride Catalyzed Site-Selective Double Substitution
in One Pot for the Synthesis of Isatin N-Ribonucleosides under Microwave
Irradiation
S
ynthesi
b
s
of Isatin
N
-
a
Ribonucle
o
d
sides ur R. Siddiqui,*a Archana Singh,a Shayna Shamim,a Vishal Srivastava,a Pravin K. Singh,a Sanjay Yadav,a
Rana K. P. Singhb
a
Laboratory of Green Synthesis, Department of Chemistry, University of Allahabad, Allahabad 211002, India
E-mail: irsiddiquiau@rediffmail.com
Electroorganic and Green Synthesis Laboratory, Department of Chemistry, University of Allahabad, Allahabad 211002, India
b
E-mail: rkp.singh@rediffmail.com
Received 22 January 2010; revised 15 February 2010
moisture compatibility.5 Indium(III) chloride has been re-
Abstract: A novel one-pot synthesis of isatin N-ribonucleosides
ported as an efficient catalyst in many organic transforma-
from N-phenylribosylamines and diethyl oxalate in ethanol cata-
lyzed by recyclable indium(III) chloride under microwave irradia-
tions.6–9
tion has been developed. The transformation consists of indium(III)
chloride catalyzed nucleophilic substitution by N-phenylribosyl-
amines on diethyl oxalate followed by rapid intramolecular electro-
recyclable, less expensive metal halide catalysts in organ-
philic substitution, which results in annulation of a five-membered
nitrogen heterocycle on to the benzene ring yielding isatin N-ribo-
Recent years have witnessed a phenomenal growth in the
application of microwave irradiation10–12 and the use of
ic transformations. The application of microwave irradia-
tion in conjugation with metal halide catalysts provides an
environmentally benign process with additional advan-
tages, such as enhanced reaction rates, higher yield of
products, easier workup, and considerable reduction in re-
action times, all of which are ecofriendly attributes in the
context of green chemistry.13–15
nucleosides. The reaction proceeded smoothly in quantitative yields
at ambient temperatures. The starting materials, N-phenylribosyl-
amines, were prepared by indium(III) chloride catalyzed nucleo-
philic substitution of the anomeric hydroxy group of b-D-
ribofuranose by an arylamine under microwave irradiation.
Key words: isatin N-ribonucleoside, indium(III) chloride, one-pot
reaction, microwave, double substitution
As part of our programme to develop new, simple, selec-
tive, ecofriendly methodologies for the synthesis of bio-
dynamic heterocyclic compounds and their nucleoside
analogues,16–19 we devised an original indium(III) chlo-
ride catalyzed microwave-activated synthesis of some
novel isatin N-ribonucleosides via site-selective nucleo-
philic and electrophilic substitution reactions between N-
phenylribosylamines 3 and diethyl oxalate (4) in ethanol
in one-pot.
The development of N-methylisatin b-thiosemicarbazone
(methisazone) and N-ethylisatin b-thiosemicarbazone (N-
Et-ISTCH) for the inhibition of Moloney leukemia virus,1
as an antiviral for pox virus, and in HIV-1 therapy for clin-
ical use2 has renewed the interest in the development of
efficient, inexpensive, and green process for the synthesis
and synthetic manipulation of isatin and its nucleoside an-
alogues. Glycosylated isatin derivatives are also of con-
siderable pharmacological relevance. Notably, most
available drugs approved by the FDA to treat AIDS and
other viral diseases are nucleoside analogues. However,
negligible effort has so far been made to synthesize nu-
cleoside analogues incorporating an isatin unit as a nucleo-
base and, therefore, they appear to be an attractive
scaffold to provide a chemical diverse drug-like library.
The development and applications of catalytic reactions is
a fundamental issue for the organic synthesis.3 Recent
years have witnessed a phenomenal growth in the applica-
tion of catalysts in organic transformations especially
those of Lewis acid character associated with normal/tran-
sition metal halides. Indium(III) chloride has attracted at-
tention because it has a non-toxic nature and it is
recyclability, readily availability, high selectivity,4 and
InCl3
OH
EtOH
HN
O
HO
H2N
+
O
MW
– H2O
HO
R2
R1
OH OH
R2
R1
OH OH
1
2a–j
3a–j
Scheme 1 Indium(III) chloride catalyzed microwave-activated syn-
thesis of N-phenylribosylamines
The strategy of the synthesis is outlined in Table 1. Mix-
ture of N-phenylribosylamine 3, diethyl oxalate (4), and
indium(III) chloride in ethanol at 50 °C was subjected to
intermittent microwave irradiation for two minutes in a
microwave oven at 600 W, followed by thorough mixing
for two minutes outside the oven. This intermittent irradi-
ation/mixing cycle was repeated for a total irradiation
time specified in Table 2 to afford isatin N-ribonucleo-
sides 5a–j in 75–85% yield. The starting compounds, N-
phenylribosylamines 3a–j, were prepared by irradiating a
mixture of b-D-ribofuranose, aniline, and an alcoholic so-
SYNTHESIS 2010, No. 10, pp 1613–1616
x
x.
x
x
.
2
0
1
0
Advanced online publication: 26.03.2010
DOI: 10.1055/s-0029-1218714; Art ID: Z01310SS
© Georg Thieme Verlag Stuttgart · New York

1614
I. R. Siddiqui et al.
PAPER
lution of indium(III) chloride in the manner as described
in Scheme 1.
Table 2 Indium(III) Chloride Catalyzed Microwave-Irradiated
Synthesis of Isatin N-Ribonucleosides
Product
Time
Yield (%)
Mp (°C)
Table 1 Indium(III) Chloride Catalyzed Microwave-Activated
Synthesis of Isatin N-Ribonucleosides
MW/InCl3 Thermal MW/InCl3 Thermal
(min)
(h)
8
O
O
5a
5b
5c
5d
5e
5f
7
9
80
78
77
82
83
77
78
75
76
85
37
36
35
38
39
34
33
30
32
40
130–131
137–138
137–138
134–135
134–135
131–132
131–132
140–141
140–141
133–134
InCl3
O
O
OEt
OEt
EtOH
N
HN
+
9
O
HO
MW
6–10 min
O
R2
R1
HO
R2
3a–j
R1
8
9
OH OH
4
5a–j
OH OH
5
7
Compounds 3, 5
R1
H
R2
H
6
8
a
b
c
d
e
f
8
9
H
Cl
H
5g
5h
5i
9
9
Cl
H
10
10
5
10
10
7
OMe
H
OMe
H
5j
F
g
h
i
F
H
HN
H
NO2
H
O
HO
–
R2
3a–j
R1
NO2
OMe
EtO
EtO
O
EtO
EtO
O
OH OH
+
InCl3
+
j
OMe
O
OInCl3
I
EtO
O
EtO
O
OEt
The reactions to give isatin N-ribonucleosides 5 did not
take place if they were performed using microwave irradi-
ation without indium(III) chloride, either neat or in organ-
ic solvents. However under the conditions described
above, the desired products 5a–j were isolated in high
yield. After subsequent workup, the catalyst indium(III)
chloride was recycled and reused for three or four runs
without loss in activity. The results are shown in Table 2.
–
OEt
+
Cl3InO
N
– InCl3
H
O
O
N
O
HO
H
R2
R1
HO
R2
R1
OH OH
OH OH
II
–
–
EtO
OInCl3
H
EtO
OInCl3
+
O
InCl3
– EtOH
HO
O
O
N
N
+
O
HO
All products 5a–j were characterized by spectral analysis.
All data were fully consistent with the assigned molecular
structure.
R2
R1
R2
R1
OH OH
OH OH
III
– InCl3
For comparison purpose the reactions were also carried
using a thermostated oil-bath at the same temperature (50
°C) as for the microwave-activated and indium(III) chlo-
ride catalyzed method for a longer (optimized) period of
time (Table 2), to ascertain whether the indium(III) chlo-
ride catalyzed and microwave activated method improved
the yield or simply increased the conversion rate. It was
found that significantly lower yields (30–40%) were ob-
tained and much higher reaction times were needed than
for the indium(III) chloride catalyzed and microwave-
activated method (Table 2). This observation can be ratio-
nalized due to the increased electrophilicity of the carbo-
nyl group of diethyl oxalate (4) because of complexation
with indium(III) chloride and formation of dipolar activat-
ed complexes I, II, and III from uncharged reagents. In
the reaction (Scheme 2) resulting in a greater stabilization
O
EtO
O
H
O
O
N
N
– EtOH
O
O
HO
HO
R2
R1
R2
R1
OH OH
OH OH
5a–j
Scheme 2 Proposed mechanism for indium(III) chloride catalyzed
and microwave activated synthesis of isatin N-ribonucleoside
of the more dipolar activated complex by dipole–dipole
interactions with the electromagnetic field of the micro-
wave, which may reduce the activation energy (DG#), re-
sulting in rate enhancement. Both of these factors may,
therefore, cause the considerable reduction in reaction
time.
Synthesis 2010, No. 10, 1613–1616 © Thieme Stuttgart · New York

PAPER
Synthesis of Isatin N-Ribonucleosides
1615
7-Methoxy-1-(b-D-ribofuranosyl)-1H-indole-2,3-dione (5d)
In conclusion, a novel and efficient, environmentally be-
nign, straightforward, and important cyclization proce-
Orange-red; yield: 82% (MW), 38% (thermal); mp 134–135 °C.
dure for the synthesis of isatin N-ribonucleosides from 1H NMR (400 MHz, CDCl3): d = 2.0–2.5 (br s, 3 H, 3 OH, exch.
D2O), 3.65–3.66 (m, 3 H, H3¢, 5¢-CH2), 3.73 (s, 3 H, OCH3), 3.91
(m, 1 H, H4¢), 4.28 (m, 1 H, H2¢), 5.93 (d, J1¢,2¢ = 4.2 Hz, 1 H, H1¢),
7.19–7.79 (m, 3 Harom).
13C NMR (100 MHz, CDCl3): d = 56.0, 61.9, 70.0, 75.4, 75.7, 82.8,
120.1, 122.2, 125.0, 125.6, 154.4, 155.7, 187.0.
simple, readily available starting materials, using the re-
cyclable indium(III) chloride catalyst, under microwave
irradiation conditions has been achieved. This procedure
provides an important route for the synthesis of N-ribonu-
cleosides without protecting functionalities of b-D-ribo-
furanose and may find application in the library synthesis
of such and other related aglycone modified N-ribonu-
cleosides.
MS (EI): m/z = 309.
6-Methoxy-1-(b-D-ribofuranosyl)-1H-indole-2,3-dione (5e)
Orange-red; yield: 83% (MW), 39% (thermal); mp 134–135 °C.
1H NMR (400 MHz, CDCl3): d = 2.0–2.5 (br s, 3 H, 3 OH, exch.
D2O), 3.65–3.66 (m, 3 H, H3¢, 5¢-CH2), 3.73 (s, 3 H, OCH3), 3.91
(m, 1 H, H4¢), 4.28 (m, 1 H, H2¢), 5.93 (d, J1¢,2¢ = 4.2 Hz, 1 H, H1¢),
6.70–7.68 (m, 3 Harom).
13C NMR (100 MHz, CDCl3): d = 56.0, 61.9, 70.0, 75.4, 75.7, 82.5,
106.5, 110.2, 120.9, 140.4, 155.7, 168.0, 187.0.
All chemicals used were reagent grade and were used as received
without further purification. NMR spectra were recorded on a
Bruker Avance DPX-400 FT spectrometer (400 MHz for 1H NMR,
100 MHz for 13C NMR) using CDCl3 as solvent and TMS as an in-
ternal reference. Mass spectra were recorded on a JEOL SX-102
(FAB) mass spectrometer at 70 eV.
MS (EI): m/z = 309.
Isatin N-Ribonucleosides 5a–j; General Procedure
Diethyl oxalate (4, 2.5 mmol), N-phenylribosylamine 3a–j (2.5
mmol) and InCl3 (3 mol%) in EtOH (20 mL) was taken in a flame-
dried 50-mL round-bottom flask. The mixture was stirred and the
solvent was evaporated. The content was subjected to microwave ir-
radiation for 2 min at 600 W. The reaction mixture was thoroughly
mixed outside the microwave oven for 1–2 min and again irradiated
for another 2 min. This irradiation mixture cycle was repeated for
the total irradiation time (Table 2). After completion of the reaction
as indicated by TLC (n-hexane–EtOAc, 7:3) the product was ex-
tracted with Et2O and purified by flash column chromatography to
give analytically pure 5a–j. The catalyst InCl3 was eluted with
EtOH and reused.
7-Fluoro-1-(b-D-ribofuranosyl)-1H-indole-2,3-dione (5f)
Orange-red; yield: 77% (MW), 34% (thermal); mp 131–132 °C.
1H NMR (400 MHz, CDCl3): d = 2.0–2.5 (br s, 3 H, 3 OH, exch.
D2O), 3.65–3.66 (m, 3 H, H3¢, 5¢-CH2), 3.91 (m, 1 H, H4¢), 4.28 (m,
1 H, H2¢), 5.93 (d, J1¢,2¢ = 4.2 Hz, 1 H, H1¢), 7.17–7.56 (m, 3 Harom).
13C NMR (100 MHz, CDCl3): d = 61.9, 70.0, 75.4, 75.7, 82.5,
121.5, 125.5, 126.2, 126.4, 130.2, 154.5, 155.7, 187.0.
MS (EI): m/z = 297.
6-Fluoro-1-(b-D-ribofuranosyl)-1H-indole-2,3-dione (5g)
Orange-red; yield: 78% (MW), 33% (thermal); mp 131–132 °C.
1H NMR (400 MHz, CDCl3): d = 2.0–2.5 (br s, 3 H, 3 OH, exch.
D2O), 3.65–3.66 (m, 3 H, H3¢, 5¢-CH2), 3.91 (m, 1 H, H4¢), 4.28 (m,
1 H, H2¢), 5.93 (d, J1¢,2¢ = 4.2 Hz, 1 H, H1¢), 6.90–7.77 (m, 3 Harom).
13C NMR (100 MHz, CDCl3): d = 61.9, 70.0, 75.4, 75.7, 82.5,
107.9, 111.6, 124.2, 131.5, 141.0, 155.7, 168.1, 187.0.
1-(b-D-Ribofuranosyl)-1H-indole-2,3-dione (5a)
Orange-red solid; yield: 80% (MW), 37% (thermal); mp 130–131
°C.
1H NMR (400 MHz, CDCl3): d = 2.0–2.5 (br s, 3 H, 3 OH, exch.
D2O), 3.65–3.66 (m, 3 H, H3¢, 5¢-CH2), 3.91 (m, 1 H, H4¢), 4.28 (m,
1 H, H2¢), 5.93 (d, J1¢,2¢ = 4.2 Hz, 1 H, H1¢), 7.19–7.79 (m, 4 Harom).
MS (EI): m/z = 297.
13C NMR (100 MHz, CDCl3): d = 61.9, 70.0, 75.4, 75.7, 82.5,
7-Nitro-1-(b-D-ribofuranosyl)-1H-indole-2,3-dione (5h)
120.9, 124.6, 128.6, 129.9, 134.5, 139.4, 155.7, 187.0.
Orange-red; yield: 75% (MW), 30% (thermal); mp 140–141 °C.
MS (EI): m/z = 279.
1H NMR (400 MHz, CDCl3): d = 2.0–2.5 (br s, 3 H, 3 OH, exch.
D2O), 3.65–3.66 (m, 3 H, H3¢, 5¢-CH2), 3.91 (m, 1 H, H4¢), 4.28 (m,
1 H, H2¢), 5.93 (d, J1¢,2¢ = 4.2 Hz, 1 H, H1¢), 7.45–8.18 (m, 3 Harom).
13C NMR (100 MHz, CDCl3): d = 61.9, 70.0, 75.4, 75.7, 81.5,
125.5, 129.5, 129.6, 134.5, 136.0, 140.8, 155.7, 187.0.
7-Chloro-1-(b-D-ribofuranosyl)-1H-indole-2,3-dione (5b)
Orange-red; yield: 78% (MW), 36% (thermal); mp 137–138 °C.
1H NMR (400 MHz, CDCl3): d = 2.0–2.5 (br s, 3 H, 3 OH, exch.
D2O), 3.65–3.66 (m, 3 H, H3¢, 5¢-CH2), 3.91 (m, 1 H, H4¢), 4.28 (m,
1 H, H2¢), 5.93 (d, J1¢,2¢ = 4.2 Hz, 1 H, H1¢), 7.13–7.67 (m, 3 Harom).
MS (EI): m/z = 324.
13C NMR (100 MHz, CDCl3): d = 61.9, 70.0, 75.4, 75.7, 82.0,
6-Nitro-1-(b-D-ribofuranosyl)-1H-indole-2,3-dione (5i)
126.0, 126.2, 128.0, 30.0, 134.9, 139.8, 155.7, 187.0.
Orange-red; yield: 76% (MW), 32% (thermal); mp 140–141 °C.
MS (EI): m/z = 313.
1H NMR (400 MHz, CDCl3): d = 2.0–2.5 (br s, 3 H, 3 OH, exch.
D2O), 3.65–3.66 (m, 3 H, H3¢, 5¢-CH2), 3.91 (m, 1 H, H4¢), 4.28 (m,
1 H, H2¢), 5.93 (d, J1¢,2¢ = 4.2 Hz, 1 H, H1¢), 8.05–8.76 (m, 3 Harom).
13C NMR (100 MHz, CDCl3): d = 61.9, 70.0, 75.4, 75.7, 82.5,
116.0, 119.7, 130.8, 134.7, 140.3, 154.4, 155.7, 187.0.
6-Chloro-1-(b-D-ribofuranosyl)-1H-indole-2,3-dione (5c)
Orange-red; yield: 77% (MW), 35% (thermal); mp 137–138 °C.
1H NMR (400 MHz, CDCl3): d = 2.0–2.5 (br s, 3 H, 3 OH, exch.
D2O), 3.65–3.66 (m, 3 H, H3¢, 5¢-CH2), 3.91 (m, 1 H, H4¢), 4.28 (m,
1 H, H2¢), 5.93 (d, J1¢,2¢ = 4.2 Hz, 1 H, H1¢), 7.20–7.84 (m, 3 Harom).
MS (EI): m/z = 324.
13C NMR (100 MHz, CDCl3): d = 61.9, 70.0, 75.4, 75.7, 82.5,
6,7-Dimethoxy-1-(b-D-ribofuranosyl)-1H-indole-2,3-dione (5j)
121.3, 125.0, 126.7, 131.3, 139.8, 140.8, 155.7, 187.0.
Orange-red; yield: 85% (MW), 40% (thermal); mp 133–134 °C.
MS (EI): m/z = 313.
1H NMR (400 MHz, CDCl3): d = 2.0–2.5 (br s, 3 H, 3 OH, exch.
D2O), 3.65–3.66 (m, 3 H, H3¢, 5¢-CH2), 3.91 (m, 1 H, H4¢), 3.73 (s,
Synthesis 2010, No. 10, 1613–1616 © Thieme Stuttgart · New York

1616
I. R. Siddiqui et al.
PAPER
(8) Loh, T. P.; Living, S. B. K. W.; Tan, K. L.; Wei, L. L.
6 H, OCH3), 4.28 (m, 1 H, H2¢), 5.93 (d, J1¢,2¢ = 4.2 Hz, 1 H, H1¢),
6.59–7.24 (m, 2 Harom).
Tetrahedron 2000, 56, 3227.
(9) Miyai, T.; Onishi, Y.; Baba, A. Tetrahedron Lett. 1998, 39,
6291.
13C NMR (100 MHz, CDCl3): d = 56.3, 61.9, 70.0, 75.4, 75.7, 82.8,
111.2, 121.9, 123.2, 126.0, 140.0, 153.6, 155.7, 187.0.
(10) McGee, D. P. C.; Martin, J. C.; Smee, D. F.; Verheyden, J.
P. H. Nucleosides Nucleotides 1990, 9, 815.
(11) Ugi, I.; Domling, A. Endeavour 1994, 18, 115.
(12) Kraus, G. A.; Nagy, J. O. Tetrahedron 1985, 41, 3537.
(13) Zeigler, T.; Kaisers, H. J.; Schlomer, R.; Koch, C.
Tetrahedron 1999, 55, 8397.
(14) Caddick, S. Tetrahedron 1995, 51, 10403.
(15) Meshram, H. M.; Sekhar, K. C.; Ganesh, Y. S. S.; Yadav, J.
S. Synlett 2000, 1273.
MS (EI): m/z = 339.
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Synthesis 2010, No. 10, 1613–1616 © Thieme Stuttgart · New York