Reduction of 3-nitrophthalic anhydride by SnCl2 in different alcohols: A simple synthesis of alkyl 1,3-dihydro-3-oxo-2,1-benzisoxazole-4- carboxylates

Article abstract of DOI:10.1016/j.tetlet.2013.01.037

A new, mild and efficient process is developed for the synthesis of alkyl 1,3-dihydro-3-oxo-2,1-benzisoxazole-4-carboxylates through the reduction of 3-nitrophthalic anhydride by SnCl₂ in different alcohols. The synthesis of benzisoxazoles bearing a sulfonamide functionality is also reported. The structure of sulfonamide 8d is confirmed by X-ray diffraction analysis.

Full text of DOI:10.1016/j.tetlet.2013.01.037

Tetrahedron Letters 54 (2013) 1569–1571
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Tetrahedron Letters
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Reduction of 3-nitrophthalic anhydride by SnCl2 in different alcohols: a
simple synthesis of alkyl 1,3-dihydro-3-oxo-2,1-benzisoxazole-4-carboxylates
Hakima Chicha a, Najat Abbassi a, El Mostapha Rakib a, , Mostafa Khouili a, Lahcen El Ammari b,
⇑
Domenico Spinelli c
a Laboratoire de Chimie Organique et Analytiques, Faculté des Sciences et Techniques, Université Sultan Moulay Slimane, B.P. 523, Béni-Mellal, Morocco
b Laboratoire de Chimie du Solide Appliquée, Faculté des Sciences, Université Mohammed V-Agdal, Avenue Ibn Battouta, B.P. 1014, Rabat, Morocco
c Dipartimento di Chimica ‘G. Ciamician’, Università degli Studi di Bologna, Via Selmi 2, I-40126 Bologna, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
A new, mild and efficient process is developed for the synthesis of alkyl 1,3-dihydro-3-oxo-2,1-benzisox-
azole-4-carboxylates through the reduction of 3-nitrophthalic anhydride by SnCl2 in different alcohols.
The synthesis of benzisoxazoles bearing a sulfonamide functionality is also reported. The structure of sul-
fonamide 8d is confirmed by X-ray diffraction analysis.
Received 5 November 2012
Revised 20 December 2012
Accepted 10 January 2013
Available online 21 January 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
3-Nitrophthalic anhydride
SnCl2
Alkyl 3-oxo-2,1-benzisoxazole
-4-carboxylates
Arylsulfonamides
Reduction of aromatic nitro compounds to the corresponding
amines is an important transformation in synthetic organic chem-
istry. Numerous methods for the direct reduction of aromatic nitro
compounds to amines have been well documented.1–3
The reduction of 3-nitrophthalic anhydride (4) afforded, in all
cases, a mixture of two compounds: the expected amine 57 and,
interestingly, as a function of the present alcohols, the unexpected
compounds 6a–d. On the basis of 1H, 13C NMR and MS data, we
propose compounds 6a–d as alkyl 1,3-dihydro-3-oxo-2,1-benzis-
oxazole-4-carboxylates (Scheme 2). No trace of the alkoxy
aminophthalic anhydride 7 was found.
In the literature, the only successful cyclisation giving 2,1-ben-
zisoxazolinone was the reduction of 3-nitrophthalic acid reported
by Woolley in a 1958 patent.8
We reported previously the reduction of some nitroindazoles
with anhydrous SnCl2 in various alcohols, in the presence of aryl-
sulfonyl chlorides and pyridine.4 Thus, we observed a new kind
of transformation: 4-, 6- and 7-nitroindazoles, by the action of
SnCl2/EtOH, gave 4- or 7-ethoxy aminoindazoles, probably via an
oxidative nucleophilic substitution of hydrogen (ONSH),5 together
with the expected 4-, 6- and 7-aminoindazoles (Scheme 1).
As significant degradation of the obtained aromatic primary
amines was observed, we decided to protect them by treatment
with an arylsulfonyl chloride in the presence of pyridine. Arylsulfo-
nyl chlorides were chosen in our previous studies, and we found
that N-[7(6)-indazolyl]arylsulfonamides6 showed important anti-
proliferative activity against some human and murine cell lines.
As an extension of these results, in the present work, we inves-
tigated the reduction of other aromatic nitro compounds under
similar experimental conditions. Thus, we report our detailed stud-
ies on the reduction of 3-nitrophthalic anhydride by SnCl2 in differ-
ent alcohols.
As shown in Table 1, the reduction of compound 4 with SnCl2 in
different alcohols led to different yields of products 5 and 6 after
separation by flash chromatography. We observed that, the reduc-
H3C
X
X
X
O
1) SnCl2/EtOH
N
+
N
N
N
HN
SO2
N
N
2) ArSO2Cl, pyridine
HN
O2N
R'
R'
R'
SO2
Ar
Ar
1
2
3
X = Cl, Br
R' = H, CH3, -CH2-CH=CH2
Ar = 4-CH3C6H4-, 4-CH3OC6H4-
⇑
Corresponding author. Tel.: +212 523485182; fax: +212 523485201.
E-mail address: elmostapha1@ymail.com (E.M. Rakib).
Scheme 1. Reduction of nitroindazoles with SnCl2 in ethanol.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.01.037

1570
H. Chicha et al. / Tetrahedron Letters 54 (2013) 1569–1571
O
NH2
tive heterocyclisation reaction of 4 in the presence of methanol as
HN
O
the solvent gave the benzisoxazole with the best yield (44%). Pre-
sumably, this could be related to the ability of methanol to dissolve
SnCl2. Stoichiometrically, this reaction requires just 2 equiv of
SnCl2 for the reduction of the nitro group, but in practice, a large
excess gave better yields and reduced the reaction times.
The formation of alkyl 1,3-dihydro-3-oxo-2,1-benzisoxazole-
4-carboxylates 6a–d can be explained by the mechanism shown
in Scheme 3. The reduction of 3-nitrophthalic anhydride with
tin(II) chloride in a protic solvent such as an alcohol presumably
proceeds by way of the hydroxylamine-like intermediate A, which
in turn undergoes an intramolecular cyclisation (an SNAc process),
followed by esterification of the intermediate acid B to give the
products 6a–d.
O
O
+
O
R
NO2
O
O
O
SnCl2
5
NH2
6 a R = CH3
b R = CH3CH2-
c R = CH3CH2CH2-
d R = CH3CH2CH2CH2-
O
ROH, r.t.
O
O
4
X
O
RO
O
7
Scheme 2. Reduction of 3-nitrophthalic anhydride with SnCl2 in different alcohols.
1,2-Benzisoxazoles and their derivatives show interesting phar-
macological and biological activities.9 One such example bearing a
sulfonamide functionality is Zonisamide (benzo[d]isoxazol-3-
ylmethanesulfonamide) which is used as an antiepileptic drug.10
Along these lines, and searching for the synthesis of new 1-aryl-
sulfonyl-1,3-dihydro-3-oxo-2,1-benzisoxazoles, which are useful
for biological screening, we examined the reduction of 3-nitroph-
thalic anhydride (4) with SnCl2 in different alcohols, followed by
coupling of the obtained amines with various arylsulfonyl chlo-
rides in pyridine.11,12 However, in all cases, we isolated a mixture
of the two sulfonamides 8 and 9 in good to excellent combined
yields (57–84%; Scheme 4 and Table 2). We are now investigating
the experimental conditions in order to address the course of the
reaction, essentially towards the formation of the most interesting
compounds 8a–h.
Table 1
Reduction of 4 with SnCl2 in different alcohols
R
Yield of 5a (%)
Mp (°C)
Yield of 6a (%)
Mp (°C)
CH3
42
28
31
26
250–252
44 (6a)
35 (6b)
36 (6c)
37 (6d)
103–105
88–90
42–44
44–46
CH3CH2
CH3(CH2)2
CH3(CH2)3
—
—
—
a
Isolated yield after separation by flash chromatography.
OH
NO2
HN
O
O
HN
B
O
ROH
O
SnCl2
6a-d
O
O
The structures of products 8 and 9 were determined from their
1H NMR and 13C NMR spectra and by MS. The structure of 8d was
further confirmed by X-ray diffraction analysis13 (Fig. 1).
In summary, we have described an efficient synthesis of some
new alkyl 1-arylsulfonyl-1,3-dihydro-3-oxo-2,1-benzisoxazole-4-
carboxylates and 4-arylsulfonamido-1,3-isobenzofurandiones by
OH
O
O
O
4
A
Scheme 3. A plausible mechanism for the reduction of 3-nitrophthalic anhydride
with SnCl2 in different alcohols.
O
O
S
O
N
O
S
NO2
O
NH
O
R'
O
1) SnCl2, ROH, r.t.
O
O
R'
O
+
O
R
2) R'C6H4SO2Cl, pyridine
O
4
O
O
8
a R = CH3 , R' = CH3
b R = CH3 , R' = CH3O
9
a R' = CH3
b R' = CH3O
c R = CH3CH2 , R' = CH3
d R = CH3CH2 , R' = CH3O
e R = CH3(CH2)2, R' = CH3
f
R = CH3(CH2)2, R' = CH3O
g R = CH3(CH2)3, R' = CH3
h R = CH3(CH2)3, R' = CH3O
Scheme 4. Reduction of 4 in different alcohols and protection with arylsulfonyl chlorides in pyridine.
Table 2
Reduction of 4 in different alcohols and protection with arylsulfonyl chlorides in pyridine
Entry
R
R0
Yield of 8a (%)
Mp (°C)
Yield of 9a (%)
Mp (°C)
1
2
3
4
5
6
7
8
CH3
CH3
CH3
CH3O
CH3
CH3O
CH3
CH3O
CH3
42 (8a)
46 (8b)
40 (8c)
48 (8d)
36 (8e)
50 (8f)
38 (8g)
46 (8h)
75–77
129–131
93–95
122–124
44–46
58–60
38 (9a)
35 (9b)
32 (9a)
36 (9b)
26 (9a)
31 (9b)
19 (9a)
30 (9b)
96–98
114–116
96–98
114–116
96–98
114–116
96–98
CH3CH2
CH3CH2
CH3(CH2)2
CH3(CH2)2
CH3(CH2)3
CH3(CH2)3
59–61
80–82
CH3O
114–116
a
Isolated yields over the two steps after separation by flash chromatography.

H. Chicha et al. / Tetrahedron Letters 54 (2013) 1569–1571
1571
Figure 1. X-ray crystal structure of compound 8d.
6. (a) Bouissane, L.; El Kazzouli, S.; Léonce, S.; Pfeiffer, B.; Rakib, E. M.; Khouili, M.;
Guillaumet, G. Bioorg. Med. Chem. 2006, 14, 1078–1088; (b) Abbassi, N.; Chicha,
H.; Rakib, E. M.; Hannioui, A.; Alaoui, M.; Hajjaji, A.; Geffken, D.; Aiello, C.;
Gangemi, R.; Rosano, C.; Viale, M. Eur. J. Med. Chem. 2012, 57, 240–249.
7. Eliel, E. E.; Burgstahler, A. W.; Rivard, D. E.; Haefele, L. J. Am. Chem. Soc. 1955, 77,
5092–5095.
8. Wooley, J. M. U.S. Patent 2846307, 1958; Chem. Abstr. 1959, 53, 33465.
9. (a) Sharma, A.; Gupta, S. P.; Upmanyu, N.; Jain, S.; Garg, G. Pharm. Chem. 2011,
3, 253–264; (b) Sakuma, S.; Endo, T.; Kanda, T.; Nakamura, H.; Yamasaki, S.;
Yamakawa, T. Bioorg. Med. Chem. 2011, 19, 3255–3264; (c) Jain, M.; Kwon, C. H.
J. Med. Chem. 2003, 46, 5428–5436; (d) Nuhrich, A.; Varache-Lembege, M.;
Vercauteren, J.; Dokhan, R.; Renard, P.; Devaux, G. Eur. J. Med. Chem. 1996, 31,
957–964; (e) Kumbhare, R. M.; Ingle, V. N. Asian J. Chem. 2000, 12, 1317–1319.
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Aasved-Hoyt, K. Epilepsia 1985, 26, 206–211.
11. General procedure for the synthesis of compounds 5 and 6a–d, 8a–h and 9a,b. A
mixture of 3-nitrophthalic anhydride (0.5 g, 2.6 mmol) and SnCl2 (2.9 g,
15.5 mmol) in 20 mL of alcohol was stirred at room temperature. After the
reduction, the pH was made slightly basic (pH 7.2–8.0) by the addition of 5%
aqueous KHCO3 before extraction with EtOAc (3 ꢀ 50 mL). The organic phase
was dried over MgSO4. At this point the synthesis of 5 and 6a–d was achieved
and they could be obtained from the crude by flash chromatography by elution
with a mixture of EtOAc/hexane (1:9). The solvent was removed to afford the
amine, which was immediately dissolved in pyridine (10 mL) and then treated
with the arylsulfonyl chloride (1.1 equiv). The reaction mixture was stirred at
room temperature overnight, and then concentrated in vacuo. The resulting
residue was purified by flash chromatography by elution with a mixture of
EtOAc/hexane (1:9).
simple reduction of 3-nitrophthalic anhydride in different alcohols,
and protection with an arylsulfonyl chloride. This appears to be a
general method to prepare new building blocks of possible interest
in medicinal chemistry.
Of particular interest appears the formation of compounds 8. As
a matter of fact, their benzene ring is substituted with an arylsulf-
onamide functionality which represents a very ‘important’ phar-
macophore,14 and by an ester functionality that can be modified
by a series of SNAc (nucleophilic acyl substitution) reactions, or
via different reduction or coupling processes. Moreover, com-
pounds 9 present interesting modes of reactivity strictly related
to the presence of a heterocyclic ring.
Acknowledgments
The synthetic work was supported by a grant of the University
of Sultan Moulay Slimane, Béni-Mellal and the National Centre for
Scientific and Technical Research (CNRST), Rabat, Morocco.
Supplementary data
12. (a) Characterisation data for compound 8d: 1H NMR (CDCl3, 300 MHz) d: 1.36 (t,
3H, J = 7.2 Hz, CH3), 3.82 (s, 3H, CH3O), 4.37 (q, 2H, J = 7.2 Hz, CH2O), 6.84 (d,
2H, J = 9 Hz, HAr), 7.60 (d, 2H, J = 9 Hz, HAr), 7.78–7.84 (m, 2H, HAr), 8.05 (dd,
1H, J = 6.8 Hz, HAr); 13C NMR (CDCl3, 75 MHz) d: 13.9 (CH3), 55.8 (CH3O), 62.3
(CH2O), 112.4 (Cq), 114.6 (2CH), 119.8 (CH), 121.7 (Cq), 128.9 (CH), 131.5 (Cq),
131.8 (2CH), 135.4 (CH), 150.7 (Cq), 162.7 (Cq), 163.9 (CO), 165.2 (CO); EI-MS
(m/z): 378 (M+H)+. Anal. Calcd for C17H15NO7S: C, 54.11; H, 4.01; N, 3.71.
Supplementary data (relevant spectra, 1H, 13C NMR and DEPT
for selected compounds) associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.01.
037.
Found: C, 54.25; H, 3.83; N, 3.65. (b) Characterisation data for compound 9b: 1
H
References and notes
NMR (DMSO-d6, 300 MHz) d: 3.78 (s, 3H, CH3O), 7.05 (d, 2H, J = 9 Hz, HAr), 7.56
(d, 2H, J = 9 Hz, HAr), 7.71–7.75 (m, 1H, HAr), 7.96–8.01 (m, 2H, HAr), 8.58 (s,
1H, NH); 13C NMR (DMSO-d6, 75 MHz) d: 56.5 (CH3O), 111.0 (Cq), 115.6 (2CH),
119.1 (CH), 120.7 (Cq), 128.7 (CH), 131.2 (Cq), 132.2 (2CH), 137.5 (CH), 150.1
(Cq), 163.1 (Cq), 165.6 (CO), 165.7 (CO); EI-MS (m/z): 334 (M+H)+. Anal. Calcd
for C15H11NO6S: C, 54.05; H, 3.33; N, 4.20. Found: C, 54.18; H, 3.42; N, 4.08.
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ꢀ
13. Crystal structure data for compound 8d: Crystals of C17H15NO7S belong to the P1
space group [a = 8.2245 (4), b = 10.4699 (5), c = 10.4795 (5) Å,
b = 69.084 (2),
= 80.925 (2)°; Z = 2; V = 822.41 (7) Å3]. The 7636 room-
temperature diffraction data were measured on a Bruker X8 diffractometer
using Mo K radiation up to a 2-h max of 52.04°. The crystal structure was
a = 78.547 (2),
c
a
refined to a final R-index of 0.0404 for 3041 unique reflections and 237 least-
squares parameters. The crystallographic information file has been deposited
with the Cambridge Crystallographic Data Centre, CCDC 903962.
´
14. Brzozowski, Z.; Sa˛czewski, F.; Sławinnski, J.; Bednarski, P. J.; Grünert, R.; Gdaniec,
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