Sulfuric acid mediated heterocyclization of Ortho-cyanomethylnitroarenes to benzo[C]isoxazoles and fused benzo[C]isoxazoles

Article abstract of DOI:10.3987/COM-07-11148

The vicarious nucleophilic substitution of hydrogen (VNS) is used as the key step to convert substituted 5-nitrobenzimidazoles 1a-b into their ortho-cyanomethyl derivatives 2a-b. Conc. sulfuric acid mediated heterocyclization of these intermediates gave t

Full text of DOI:10.3987/COM-07-11148

HETEROCYCLES, Vol. 75, No. 1, 2008
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HETEROCYCLES, Vol. 75, No. 1, 2008, pp. 165 - 171. © The Japan Institute of Heterocyclic Chemistry
Received, 23rd June, 2007, Accepted, 14th September, 2007, Published online, 20th September, 2007. COM-07-11148
SULFURIC ACID MEDIATED HETEROCYCLIZATION OF ORTHO-
CYANOMETHYLNITROARENES TO BENZO[C]ISOXAZOLES AND
FUSED BENZO[C]ISOXAZOLES
Mehdi Bakavoli,* Mehdi Pordel, Mohammad Rahimizadeh, Pooneh
Jahandari, and Esmaeel Rezaei Seresht
Department of Chemistry, School of Sciences, Ferdowsi University, Mashhad
91375-1436, Iran
*Corresponding author. Tel.: +98 511 87 97 02 2; fax: +98 511 87 96 41 6;
e-mail: mbakavoli@yahoo.com
Abstract – The vicarious nucleophilic substitution of hydrogen (VNS) is used as
the key step to convert substituted 5-nitrobenzimidazoles 1a-b into their ortho-
cyanomethyl derivatives 2a-b. Conc. sulfuric acid mediated heterocyclization of
these intermediates gave the novel 3H-imidazo[4',5':3,4]benzo[c]isoxazole-8-
carboxamides 3a-b. To generalize this synthetic strategy for benzo[c]isoxazoles
syntheses, the VNS products of para-substituted nitrobenzene 4a-d were
successfully converted to the new benzo[c]isoxazoles derivatives 5a-d.
INTRODUCTION
Benzo[c]isoxazoles (2,1-benzisoxazoles) derivatives are prescribed as antipsychotic risperidone drugs1
and play a key role in many organic reactions,2 notably those leading to anthranilic acids. There are
several methods for the synthesis of these compounds. The formation of benzo[c]isoxazoles from ortho
nitrobenzene derivatives is generally catalyzed both by acids and by bases and can also be initiated
thermally or photochemically. A variety of ortho-nitrobenzylcarbonyl derivatives cyclize under both
acidic and basic conditions and thermally, to afford the simple benzo[c]isoxazoles derivatives.3-5 The sole
structural requirement for the success of these cyclizations appears to be depended upon the presence of a
moderately acidic benzylic C-H group. Conversion of ortho-nitrobenzylcarboxylic acids in hot
concentrated sulfuric acid to benzo[c]isoxazoles derivatives has been reported in early literature.6 To the
best of our knowledge, heterocyclization of ortho-cyanomethylnitroarenes to benzo[c]isoxazoles have not

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HETEROCYCLES, Vol. 75, No. 1, 2008
been investigated in conc. sulfuric acid. Owing to our growing interest in the synthesis of bioactive
heterocycles and exploration of their synthetic pathways,7 we became interested in the transformation of
ortho cyanomethyl nitroarenes to the new benzo[c]isoxazoles and fused benzo[c]isoxazoles. The
vicarious nucleophilic substitution of hydrogen8 (VNS) is a highly efficient synthetic tool for the
introduction of various functionalized substituents into the ortho-position relative to nitro group.
Nitroarenes containing functionalized substituents in the ortho-position are valuable synthones in a
variety of cyclocondensation reactions yielding potentially biologically active heterocycles such as
indoles, benzimidazoles, quinolines, fused pyrimidines, fused pyrazines, etc (see a recent review and
references cited therein).9
In this work, we have introduced the CH2CN moiety into the ortho-position of nitro group in
nitrobenzene derivatives (4a-d) and N-alkyl substituted 5-nitrobenzimidazoles (1a-b) with the aim to
synthesize the new derivatives of benzo[c]isoxazoles (5a-d) and fused benzo[c]isoxazoles (3a-b) via conc.
sulfuric acid catalysis at room temperature.
RESULTS AND DISCUSSION
The
key
intermediates
2-(1-benzyl-5-nitro-1H-benzo[d]imidazol-4-yl)acetonitrile
(2a)
and
2-(1-methyl-5-nitro-1H-benzo[d]imidazol-4-yl)acetonitrile (2b) were obtained via the VNS reaction of
N-benzyl- and N-methyl-5-nitrobenzimidazoles 1a-b with 4-chlorophenoxyacetonitrile in basic DMSO
solution. The compounds 2a-b were cyclized to fused benzo[c]isoxazoles 3a-b in conc. sulfuric acid at
room temperature (Scheme 1).
NC
O2N
CONH2
N
O
N
O2N
4-ClPhOCH2CN, KOH
DMSO
N
N
1. c. H2SO4
2. H2O
N
R
N
R
N
R
1a
1b
2a
2b
3a: R=Bn
3b: R=Me
Scheme 1
The structural assignments of compounds 3a-b were based on the analytical and spectral data. For
example, in the 13C NMR spectrum of 3-benzyl-3H-imidazo[4',5':3,4]benzo[c]isoxazole-8-carboxamide
(3a), the signal at 17.39 ppm attributed to CH2CN carbon atom of compound 2a is absent but instead
there is a signal at 131.57 ppm for an aromatic carbon atom which is a clear indication of the cyclization
1
step which led to the formation of the third aromatic ring. In the H NMR spectrum of 3a the signal at
4.64 ppm assignable to cyanomethyl protons of compound 2a is not present but instead two signals
attributed to two exchangeable protons (amide NH2 group) appeared at 8.45 and 9.55 ppm which is a

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168
further indication of the heterocyclization step. Moreover, the FT-IR spectrum of 3a in KBr showed two
different absorption bands at 3170 cm-1 and 3380 cm-1 assignable to amide NH2 group, 1698 cm-1 and
1670 cm-1 assignable to C=O group. All this evidence plus the molecular ion peak at m/z 292 and
microanalytical data strongly support the cyclic structure of compound 3a.
Heterocyclization of ortho-cyanomethylnitrobenzenes 4a-d in conc. sulfuric acid afforded the new
derivatives of benzo[c]isoxazoles 5a-d (Scheme 2).
O
NO2
N
CH2CN
1. c. H2SO4
2. H2O
CONH2
5a: R=Cl
5b: R=Br
5c: R=OMe
5d: R=OBn
R
4a-d
R
5a-d
Scheme 2
Dehydration of 3a-b compounds in boiling POCl3 gave the new derivatives of 3-benzyl-3H-imidazo-
[4',5':3,4]benzo[c]isoxazol-8-yl cyanide (6a) and 3-methyl-3H-imidazo[4',5':3,4]benzo[c]isoxazol-8-yl
cyanide (6b).
CN
CONH2
N
O
O
N
N
N
POCl3
4h, reflux
N
R
N
R
3a
3b
6a: R=Bn
6b: R=Me
Scheme 3
Alkylation of 3a with different alkyl halides in DMF and KOH gave the dialkyl derivatives 7a-c (Scheme
4).
CONH2
N
CONR2
N
O
O
N
N
7a: R=Et
7b: R=Pr
7c: R=Bu
KOH, DMF
R-X
N
Bn
N
Bn
3a
7a-c
Scheme 4
In summary, this research has demonstrated that the sequential VNS reaction of nitroarenes and
heterocylization of the ortho substituted products in the presence of conc. sulfuric acid is a reliable
strategy for the synthesis of new benzo[c]isoxazoles and fused benzo[c]isoxazoles. This work can be
extended to the synthesis of other novel heterocyclic compounds.

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EXPERIMENTAL
Melting points were recorded on an Electrothermal type 9100 melting point apparatus. The IR spectra
were obtained on a 4300 Shimadzu spectrometer and only noteworthy absorptions are listed. The 13C
NMR (125MHz) spectra were recorded on a Bruker Avance DRX-500 Fouriertransformer spectrometer.
1
The H NMR (100MHz) spectra were recorded on a Bruker AC 100 spectrometer. Chemical shifts are
reported in ppm downfield from TMS as internal standard; coupling constance J are given in Hertz. The
mass spectra were scanned on a Varian. Mat CH-7 at 70 ev. Elemental analysis was performed on a
Thermo Finnigan Flash EA microanalyzer.
4-Chlorophenoxyacetonitrile,10 compounds 1a-b11 and 4a-d12 were obtained according to the published
methods. Other reagents were commercially available.
1. General procedure for the synthesis of ortho disubstituted benzo[d]imidazol-4-yl)acetonitrile 2a-b.
To
a
solution of the N-substituted 5-nitrobenzimidazoles 1a-b (19.7 mmol) and
4-cholrophenoxyacetonitrile (20 mmol) in DMSO (90 mL), powdered KOH (5.6 g, 100 mmol) was added.
The reaction mixture was stirred for 3 h at rt, and then poured onto crushed ice containing (10 mL)
hydrochloric acid. The precipitate was collected by filtration and recrystallized from EtOH to give the
pure products 2a-b.
1.1. 2-(1-Benzyl-5-nitro-1H-benzo[d]imidazol-4-yl)acetonitrile (2a). Compound 2a was obtained as
bright yellow crystals, yield (72%), mp 161-163 °C; 1H NMR (100 MHz, CDCl3) δ 4.64 (s, 2H), 5.43 (s,
13
2H), 7.2-7.4 (m, 6H), 8.15 (s, 1H), 8.23 (d, J=10.9 Hz, 1H); C NMR (125MHz, DMSO-d6): δ 149.15,
143.50, 143.00, 137.61, 136.97, 129.72, 128.92, 128.36, 120.93, 119.92, 118.23, 112.24, 49.07, 17.34; IR
(KBr): 1350, 1525 (NO2), 2250 cm-1 (CN). MS, m/z (%): 292 (M+, 33), 273 (42), 251(12), 207 (38), 127
(34), 91 (100), 65 (53). Anal. Calcd for C16H12N4O2 (292.3): C, 64.74; H, 3.62; N, 20.13. Found: C,
64.92; H, 3.59; N, 20.09.
1.2. 2-(1-Methyl-5-nitro-1H-benzo[d]imidazol-4-yl)acetonitrile (2b). Compound 2b was obtained as
bright yellow crystals, yield (70%), mp 188-190 °C; 1H NMR (100 MHz, DMSO-d6) δ 3.92 (s, 3H), 4.58
(s, 2H), 7.9 (d, J =14 Hz, 1H), 8.2 (d, J =14 Hz, 1H), 8.55 (s, 1H); IR (KBr): 1350, 1525 (NO2), 2250
cm-1 (CN). MS (m/z) 216 (M+). Anal. Calcd for C10H8N4O2 (216.2): C, 53.47; H, 2.99; N, 27.71. Found:
C, 53.38; H, 2.85; N, 27.54.
2. General procedure for the synthesis of fused benzo[c]isoxazoes (3a-b) and benzo[c]isoxazoes
(5a-d).
To concentrated sulfuric acid (6 mL), which was kept in an ice-bath, compounds 2a-b and 4a-d (6.8
mmol) was gradually added, with stirring. The inside temperature was kept between 15-20 °C. The

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addition was accomplished over a period of 1 h, the solution was stirred at rt for further 4 h, then water (8
mL) was added to the solution in an ice-bath and it was stirred for further 2 h before it was poured onto
crushed ice, and finally it was neutralized with dilute aqueous NaOH. The reaction mixture which was
allowed to reach 50-70 °C during the neutralization, was cooled to rt, filtered and washed with water and
then CH2Cl2, to give the pure products 3a-b.
2.1. 3-Benzyl-3H-imidazo[4',5':3,4]benzo[c]isoxazole-8-carboxamide (3a). Compound 3a was obtained
as colorless crystals (1,4-dioxane), yield (90%), mp 260-263 °C; 1H NMR (100MHz, DMSO-d6) δ 5.65 (s,
2H), 7.34 (s, 5H), 7.61 (d, J = 12.0 Hz, 1H), 7.81 (d, J =12.0 Hz,1H), 8.45 (br s, 1H), 8.61 (s, 1H), 9.55
(br s, 1H); 13C NMR (125MHz, DMSO-d6): δ 157.93, 157.79, 155.39, 142.85, 137.36, 131.57, 130.31,
129.74, 128.92, 128.26, 120.74, 111.97, 111.13, 49.24; IR (KBr): 3170, 3380 cm-1 (NH2), 1698, 1670
cm-1 (C=O). MS, m/z (%): 292 (M+, 31), 290 (99), 264 (26), 248 (40), 173 (45), 91 (100), 65 (62). Anal.
Calcd for C16H12N4O2 (292.3): C, 65.75; H, 4.14; N, 19.17. Found: C, 65.54; H, 4.11; N, 18.94.
2.2. 3-Methyl-3H-imidazo[4',5':3,4]benzo[c]isoxazole-8-carboxamide (3b). Compound 3b was
obtained as colorless crystals (1,4-dioxane), yield (86%), mp 270-272 °C; 1H NMR (100MHz, DMSO-d6)
δ 3.97 (s, 3H), 7.6 (d, J=10.0 Hz, 1H), 7.9 (d, J=10.0 Hz, 1H), 8.35 (br s, 1H), 8.45 (s, 1H), 9.55 (br s,
1H); IR (KBr): 3170, 3380 cm-1 (NH2), 1698, 1670 cm-1 (C=O). MS (m/z) 216 (M+). Anal. Calcd for
C10H8N4O2 (216.2): C, 55.56; H, 3.73; N, 25.91. Found: C, 55.95; H, 3.57; N, 25.77.
2.3. 5-Chlorobenzo[c]isoxazole-3-carboxamide (5a). Compound 5a was obtained as colorless crystals
(acetone), yield (75%), mp 226-227 °C; 1H NMR (100MHz, DMSO-d6) δ 7.47 (d, J=9.0 Hz, 1H), 7.86 (d,
J=9.0 Hz, 1H), 7.95 (s, 1H), 8.25 (br s, 1H), 8.69 (br s, 1H); IR (KBr): 3185, 3390 cm-1 (NH2), 1690,
1665 cm-1 (C=O). MS (m/z) 197 (M+). Anal. Calcd for C8H5ClN2O2 (196.6): C, 48.88; H, 2.56; N, 14.25.
Found: C, 48.49; H, 2.51; N, 14.03.
2.4. 5-Bromobenzo[c]isoxazole-3-carboxamide (5b). Compound 5b was obtained as colorless crystals
(acetone), yield (55%), mp 235-237 °C; 1H NMR (100MHz, DMSO-d6) δ 7.60 (d, J=10.0 HZ, 1H), 7.80
(d, J=10.0 Hz, 1H), 8.16 (s, 1H), 8.24 (br s, 1H), 8.67 (br s, 1H); IR (KBr): 3185, 3390 cm-1 (NH2), 1690,
1665 cm-1 (C=O). MS (m/z) 241 (M+). Anal. Calcd for C8H5BrN2O2 (241.0): C, 39.86; H, 2.09; N, 11.62.
Found: C, 39.64; H, 1.99; N, 11.45.
2.5. 5-Methoxybenzo[c]isoxazole-3-carboxamide (5c). Compound 5c was obtained as colorless crystals
(acetone), yield (59%), mp 232-234 °C; 1H NMR (100MHz, DMSO-d6) δ 3.96 (s, 3H), 7.29 (d, J=10.0
HZ, 1H), 7.35 (s, 1H),7.50 (d, J=10.0 Hz, 1H), 8.15 (br s, 1H), 8.78 (br s, 1H); IR (KBr): 3185, 3390 cm-1
(NH2), 1690, 1665 cm-1 (C=O). MS (m/z) 192 (M+). Anal. Calcd for C9H8N2O3 (192.2): C, 56.25; H, 4.20;
N, 14.58. Found: C, 55.95; H, 4.16; N, 14.42.
2.6. 5-(Benzyloxy)benzo[c]isoxazole-3-carboxamide (5d). Compound 5d was obtained as colorless
crystals (acetone), yield (69%), mp 228-230 °C; 1H NMR (100MHz, DMSO-d6) δ 5.45 (s, 2H), 7.21 (s,

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5H), 7.29 (s, 1H), 7.37 (d, J=10.0 Hz, 1H), 7.54 (d, J=10.0 Hz, 1H), 8.26 (br s, 1H), 8.77 (br s, 1H); IR
(KBr): 3185, 3390 cm-1 (NH2), 1690, 1665 cm-1 (C=O). MS (m/z) 268 (M+). Anal. Calcd for C15H12N2O3
(268.3): C, 67.16; H, 4.51; N, 10.44. Found: C, 66.88; H, 4.49; N, 10.37.
3. General procedure for the synthesis of 6a-b from 3a-b.
The mixture of 3a-b (0.2 g, 0.68 mmol) and POCl3 (3 mL) was refluxed with stirring for 3 h. After
cooling to rt the product poured into crushed ice and neutralized with ammonia solution. The product was
extract with EtOAC (2¯50 mL). The extract was dried, and evaporated to give pure 6a-b.
3.1. 3-Benzyl-3H-imidazo[4',5':3,4]benzo[c]isoxazol-8-yl cyanide (6a). Compound 6a was obtained as
pale yellow crystals, yield (75%), mp 182-184 °C; 1H NMR (100MHz, DMSO-d6) δ 5.65 (s, 2H), 7.33 (s,
5H), 7.67 (d, J=10.0 Hz, 1H),7.95 (d, J=10.0 Hz, 1H), 8.56 (s, 1H); 13C NMR (125MHz, DMSO-d6): δ
157.71, 144.51, 137.39, 133.22, 131.92, 130.53, 129.79, 128.89, 128.20, 121.96, 119.00, 111.73, 110.58,
49.09; IR (KBr): 2220 cm-1 (CN). MS (m/z) 274 (M+). Anal. Calcd for C32H20N8O2 (274.3): C, 70.07; H,
3.67; N, 20.43. Found: C, 70.33; H, 3.72; N, 20.56.
3.2. 3-Methyl-3H-imidazo[4',5':3,4]benzo[c]isoxazol-8-yl cyanide (6b). Compound 6b was obtained as
pale yellow crystals, yield (72%), mp 128-130 °C; 1H NMR (100MHz, CDCl3) δ 3.95 (s, 3H), 7.65 (d,
J=9.5 Hz, 1H), 7.85 (d, J=9.5 Hz, 1H), 7.92 (s, 1H); IR (KBr): 2220 cm-1 (CN). MS (m/z) 198 (M+).
Anal. Calcd for C20H12N8O2 (198.18): C, 60.61; H, 3.05; N, 28.27. Found: C, 60.55; H, 3.05; N, 28.39.
4. General procedure for the synthesis of 7a-c from 3a.
To a solution of 3a (0.68 mmol) in DMF (5 mL), alkyl halide (1.4 mmol) and KOH (0.34 g, 6 mmol) was
added. The mixture was stirred for 1 day and then poured into water. The precipitate was collected by
filtration, washed with water and air-dried to give 7a-e.
4.1. N,N-Diethyl-3-benzyl-3H-imidazo[4',5':3,4]benzo[c]isoxazole-8-carboxamide (7a). Compound 7a
was obtained as yellow crystals (EtOH), yield (65%), mp 184-187 °C; 1H NMR (100MHz, CDCl3) δ 1.4
(t, J=8.0 Hz, 3H), 1.6 (t, J=8.0 Hz, 3H), 3.6 (q, J=6.7 Hz, 2H) 4 (q, J=6.7 Hz, 2H), 5.45 (s, 2H), 7.1-7.5
(m, 7H), 7.95 (s, 1H). MS (m/z) 348 (M+). Anal. Calcd for C20H20N4O2 (348.4): C, 68.95; H, 5.79; N,
16.08. Found: C, 68.73; H, 5.65; N, 15.92.
4.2. N,N-Dipropyl-3-benzyl-3H-imidazo[4',5':3,4]benzo[c]isoxazole-8-carboxamide (7b).
Compound 7b was obtained as yellow crystals (EtOH), yield (67%), mp 129-132 °C; 1H NMR (100MHz,
CDCl3) δ 0.9 (t, J=8.0 Hz, 3H), 1.15 (t, J=8.0 Hz, 3H), 1.6-2 (m, 4H), 3.4-3.8 (m, 4H), 5.45 (s, 2H),
7.15-7.6 (m, 7H), 7.95 (s, 1H). MS (m/z) 376 (M+). Anal. Calcd for C22H24N4O2 (376.5): C, 70.19; H,
6.43; N, 14.88. Found: C, 70.45; H, 6.20; N, 15.16.
4.3. N,N-Dibutyl-3-benzyl-3H-imidazo[4',5':3,4]benzo[c]isoxazole-8-carboxamidz (7c).

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1
Compound 7c was obtained as yellow crystals (EtOH), yield (60%), mp 91-94 °C; H NMR (100MHz,
CDCl3) δ 0.8-1.95 (m, 14H), 3.35-3.8 (m, 4H), 5.4 (s, 2H), 7.1-7.5 (m, 7H), 7.9 (s, 1H). MS (m/z) 404
(M+). Anal. Calcd for C24H28N4O2 (404.5): C, 71.26; H, 6.98; N, 13.85. Found: C, 71.49; H, 6.79; N,
13.64.
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