Synthesis of 3-cyano-4,6-dinitrobenzo[d]isoxazole and its reactions with anionic nucleophiles

Article abstract of DOI:10.1007/s11172-006-0289-9

The action of various anionic O-, N-, and S-nucleophiles on 3-cyano-4,6-dinitro-benzo[d]isoxazole mostly resulted in regiospecific nucleophilic substitution for the nitro group in position 4. With an excess of an nucleophilic reagent, the nitro group in p

Full text of DOI:10.1007/s11172-006-0289-9

Russian Chemical Bulletin, International Edition, Vol. 55, No. 3, pp. 543—548, March, 2006
543
Synthesis of 3ꢀcyanoꢀ4,6ꢀdinitrobenzo[d]isoxazole
and its reactions with anionic nucleophiles

A. M. Starosotnikov, A. V. Lobach, Yu. A. Khomutova, and S. A. Shevelev
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (495) 135 5328. Eꢀmail: ams@fromru.com
The action of various anionic Oꢀ, Nꢀ, and Sꢀnucleophiles on 3ꢀcyanoꢀ4,6ꢀdinitroꢀ
benzo[d]isoxazole mostly resulted in regiospecific nucleophilic substitution for the nitro group
in position 4. With an excess of an nucleophilic reagent, the nitro group in position 6 was also
replaced.
Key words: nitro compounds, benzo[d]isoxazoles, nucleophilic substitution, the nitro group.
Earlier, we have reported regiospecific nucleophilic
substitution for 4ꢀNO2 in various 4,6ꢀdinitrobenzoꢀ
annulated heterocycles, including 3ꢀRꢀ4,6ꢀdinitrobenꢀ
zo[d]isoxazoles (R = CH=NOMe, CH=NNHAr, and
1,3ꢀdioxolanꢀ2ꢀyl)1 and 3ꢀRꢀ1ꢀarylꢀ4,6ꢀdinitroꢀ1Hꢀindꢀ
azoles (R = H, CHO, and CN).2,3 The nitro group in
position 6 remains intact both with an excess of a nucleoꢀ
phile and under more drastic reaction conditions. The
only exception is 6ꢀnitrobenzo[d]isoxazole 1 (see Ref. 4):
its treatment with excess PhSH in the presence of
K2CO3 under comparatively drastic conditions (100 °C,
Nꢀmethylpyrrolidone (NMP)) gave bissulfide 2 as the reꢀ
sult of replacement of both the nitro groups (Scheme 1).
which would facilitate the replacement of the 6ꢀNO2 group
and affect the regioselectivities of the reactions of 4,6ꢀdiꢀ
nitrobenzo[d]isoxazoles with nucleophiles.
Introduction of the formyl or carboxy group into the
isoxazole ring seems to be inexpedient because 3ꢀformylꢀ
and 3ꢀcarboxybenzo[d]isoxazoles in basic media (in parꢀ
ticular, under conditions for nucleophilic substitution
of the nitro group) usually undergo deformylation and
decarboxylation, respectively, with opening of the
isoxazole ring;5—9 the presence of the nitro groups in the
benzo[d]isoxazole system facilitates this process still furꢀ
ther. Benzo[d]isoxazoleꢀ3ꢀcarboxylates are easily hydroꢀ
lyzed by bases10—12 to give unstable salts of the correꢀ
sponding acids. Indeed, we have failed to obtain 4,6ꢀdiꢀ
nitrobenzo[d]isoxazoles with such substituents in posiꢀ
tion 3 because these compounds are very unstable.1,13
That is why the cyano group seems to be most suitable for
our purposes.
Scheme 1
Recently,14 we have developed a convenient and effiꢀ
cient singleꢀstep route to arylacetonitriles based on
βꢀ(N,Nꢀdimethylamino)styrenes by treatment of starting
enamines with NH2OH•HCl in formic acid. Other aldeꢀ
hyde derivatives such as imines and acetals can also be
transformed into nitriles under the conditions found.14
Based on the data obtained, we chose a way of introducꢀ
ing the cyano group into 4,6ꢀdinitrobenzo[d]isoxazole.
For instance, a reaction of earlier1 obtained cyclic acetal
3 with NH2OH•HCl in boiling 95—98% HCO2H gave
previously unknown 3ꢀcyanoꢀ4,6ꢀdinitrobenzo[d]isoxꢀ
azole 4 in good yield (Scheme 2).
The structure of compound 4 was confirmed by physiꢀ
cochemical methods (NMR and IR spectroscopy, mass
spectrometry, and elemental analysis).
We studied reactions of benzo[d]isoxazole 4 with variꢀ
ous anionic Oꢀ, Nꢀ, and Sꢀnucleophiles. It turned out
that NaN3 and thiols in the presence of K2CO3 react with
Apparently, the heteroaromatic systems of most of the
4ꢀRꢀ6ꢀnitro derivatives of the benzo[d]isoxazole and
indazole series we have previously prepared are insuffiꢀ
ciently electrophilic for replacement of the 6ꢀNO2 group.
Introduction of an electronꢀwithdrawing group (CHO,
COOR, CN, etc.) in position 3 of the isoxazole ring could
be expected to make the system much more electrophilic,
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 3, pp. 523—528, March, 2006.
1066ꢀ5285/06/5503ꢀ0543 © 2006 Springer Science+Business Media, Inc.

544
Russ.Chem.Bull., Int.Ed., Vol. 55, No. 3, March, 2006
Starosotnikov et al.
Scheme 2
benzo[d]isoxazoles but also for all the 4,6ꢀdinitrobenzoꢀ
annulated fiveꢀmembered aromatic heterocycles ever studꢀ
ied: indazoles,2,3 various benzo[b]thiophenes,15 and
benzo[d]isothiazole.16 One can assume that the lowered
selectivity of the nucleophilic substitution is indirect eviꢀ
dence for the high electrophilicity of nitrile 4, because a
decreased selectivity is usually associated with an increased
reactivity, all other factors being equal.
The replacement of just the 4ꢀNO2 group in comꢀ
pound 4 was evident from the 13C NMR spectra of the
starting dinitro compounds and reaction products. For
the starting dinitro derivative 4, we performed complete
assignment of signals for the C atoms by analogy with
earlier1 obtained 4,6ꢀdinitrobenzo[d]isoxazole derivaꢀ
tives with various substituents in position 3. For all the
NO2ꢀreplacement products obtained, the signal for the
C(4) atom is considerably shifted upfield (from δ 140.5
in 4 to δ 133—136 in the mononitro derivative), while
the signals for the C(6) atoms are virtually identical
compound 4 even at room temperature to give mononitro
derivatives 5 and 6, respectively (Scheme 3). The reacꢀ
tions were carried out in aprotic dipolar solvents (NMP
and DMF); the starting dinitro compound 4 was fully
converted in 1—2 h.
Scheme 3
1
(δ 149—151). In addition, the H NMR spectrum (NOE
experiment) of compound 6b revealed dipolar couplings
between the H(5) atom and the methylene H atoms in the
substituent SCH2CO2Me, which is absent between the
CH2 fragment and the H(7) atom; this also confirms the
replacement of the nitro group in position 4.
Interestingly, with an increase in the reaction duraꢀ
tion or when an excess of K2CO3 was used in a reaction of
dinitro derivative 4 with methyl thioglycolate, intermediꢀ
ate product 6b (resulting from replacement of the 4ꢀNO2
group) underwent cyclization due to addition of the acꢀ
tive methylene fragment to the cyano group (Scheme 4).
The resulting thiochromeno[4,5ꢀcd]isoxazole (7) belongs
Reagents, conditions, and yields of the products: i. NaN3, DMF,
20 °C; ii. RSH, K2CO3, NMP, 20 °C; the yields were 91 (5),
84 (6a), 80 (6b), and 64% (6c + 6c´).
Scheme 4
R = Ph (6a), CH2CO2Me (6b), CH2Ph (6c,c´)
It should be noted that when dinitrobenzoisoxazole
and a nucleophilic reagent were used in equimolar
amounts, the nitro group in position 4 was regiospecifically
replaced, while the 6ꢀNO2 group remained intact. The
exception was PhCH2SH: its reaction with compound 4
under the same conditions gave a mixture of products 6c
and 6c´, in which the nitro groups are replaced in posiꢀ
tions 4 and 6, respectively. The substitution product at
position 4 (6c) was dominant (the ratio of the products
was 4 : 1). Apparently, such an outcome can be associated
with the highest reactivity of PhCH2SH in baseꢀcatalyzed
nucleophilic substitution for the nitro group among other
Sꢀnucleophiles.
As far as we know, the less selective replacement of
the 4ꢀNO2 group in nitrile 4 in a reaction with equimolar
amounts of PhCH2SH and K2CO3 as a nucleophile is
observed for the first time not only for 3ꢀRꢀ4,6ꢀdinitroꢀ
Reagents and conditions: i. HSCH2CO2Me, K2CO3,
NMP, 20 °C.

4ꢀRꢀ3ꢀCyanoꢀ6ꢀnitrobenzo[d]isoxazoles
Russ.Chem.Bull., Int.Ed., Vol. 55, No. 3, March, 2006
545
Scheme 6
to a novel aromatic periꢀannulated heterocyclic system,
which provides another piece of evidence for the replaceꢀ
ment of the 4ꢀNO2 group.
Data on 14ꢀπꢀelectron periꢀannulated heteroaromatic
systems consisting of two sixꢀmembered and one fiveꢀ
membered rings are very scarce (e.g., see Refs 17 and 18).
As for the tricyclic system obtained in the present work,
no synthesis of such compounds has been documented.
Earlier,19 using an analogous approach (regiospecific
replacement of the nitro group followed by cyclizaꢀ
tion), we have synthesized for the first time some other
periꢀannulated tricyclic systems containing the indazole
fragment.
We studied reactions of dinitrobenzoisoxazole 4 with
such Oꢀnucleophiles as phenol and acetophenone oxime
(Scheme 5). The reactions were carried out in aprotic
dipolar solvents in the presence of K2CO3. As with most
other nucleophiles, the nitro group in position 4 was reꢀ
placed regiospecifically to give mononitro derivative 8.
Reagents, conditions, and yields of the products: i. PhSH, K2CO3,
NMP, 20 °C; ii. PhSH (2 equiv.), K2CO3, NMP, 20 °C; the
yields of compound 9 were 83 (from 6a) and 97% (from 4).
mononitro compound was completely converted in 4 h.
According to 1H NMR data, one of the reaction products
is diazide 10 (the signals for the H(5) and H(7) atoms are
shifted upfield compared to the signals for the starting
compound (δ 7.28 and 7.59)). The second product seems
to be tetrazole derivative 11 (Scheme 7).
Scheme 5
Scheme 7
R = Ph (8a), N=C(Me)Ph (8b)
Reagents, conditions, and yields of the products: ROH, K2CO3,
NMP, 20 °C; the yields were 44 (8a) and 70% (8b).
Interestingly, the reaction occurs at room temperaꢀ
ture, while all the 3ꢀRꢀ4,6ꢀdinitrobenzo[d]isoxazoles we
studied earlier1 react with phenol only on heating (80 °C).
The position of the nitro group replaced was proven by
13C NMR data as described above.
Further investigations showed that the 6ꢀNO2 group
in mononitro compounds 5 and 6 can also be replaced
by the nucleophiles used. For instance, the action of
benzenethiol on mononitro derivative 6a in NMP in the
presence of K2CO3 at 20 °C resulted in replacement of
the nitro group in position 6 (Scheme 6), yielding
bissulfide 9. However, this required more reaction time
(24 h) than for replacement of the 4ꢀNO2 group in comꢀ
pound 4.
In the reaction of dinitrobenzo[d]isoxazole 4 with two
equivalents of PhSH under the same conditions, both the
nitro groups were replaced to give compound 9 (see
Scheme 6).
This assumption is supported by the presence of
1H signals for the H(5) and H(7) atoms in the range
characteristic of mononitrobenzo[d]isoxazoles (δ 8.12
and 8.67). In addition, the spectrum shows a broadened
signal with the chemical shift varying with the recording
conditions. Apparently, this signal corresponds to the
mobile H atom of the tetrazole NH fragment. According
to TLC data, the two reaction products strongly differ in
polarity, which also confirms our assumption. We failed
to separate and completely characterize these compounds
because of their instabilities. It should be noted that an
Azidonitrobenzo[d]isoxazole 5 reacted with NaN3
(1 equiv.) to form a mixture of two products in the raꢀ
tio 1 : 1. The reaction was carried out at 50 °C (since it did
not occur at room temperature) in DMF; the starting

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Starosotnikov et al.
analogous mixture of products was also obtained by a
reaction of dinitrobenzo[d]isoxazole 4 with two equivaꢀ
lents of NaN3 under the same conditions. It is known20,21
that closure of the tetrazole ring via addition of N3– to the
triple CN bond requires heating (also in DMF); i.e., this
reaction occurs under the conditions of replacement of
the nitro group.
Oxidation of phenylthiobenzo[d]isoxazole 6a with
aqueous 30% H2O2 in CF3COOH at room temperature
gave sulfone 12 (Scheme 8). We studied nucleophilic subꢀ
stitution pathways in its reaction with benzenethiol.
demonstrated with a number of examples that nucleoꢀ
philic substitution in reactions of 3ꢀsubstituted 4ꢀ(Rꢀsulꢀ
fonyl)ꢀ6ꢀnitrobenzo[d]isoxazoles (R = CH=NOMe)
and ꢀindazoles (R = CN) with thiols is regiospecific and
does not obey the known order of replacement of nitro
and sulfonyl groups metaꢀarranged to each other: only
RSO2 is replaced, while the nitro group remains intact.
Presumably, the high electrophilicity of the heteroꢀ
aromatic system of compound 12 substantially facilitates
the replacement of the 6ꢀNO2 group as well.
Thus, we obtained for the first time 3ꢀcyanoꢀ4,6ꢀ
dinitrobenzo[d]isoxazole, developed the convenient route
to novel 4ꢀRꢀ3ꢀcyanoꢀ6ꢀnitrobenzo[d]isoxazoles via
regiospecific nucleophilic substitution for the 4ꢀNO2
group, and showed that the nitro group in position 6 of
these compounds can also be replaced by various anionic
nucleophiles, which opens up a route to not easily accesꢀ
sible 4ꢀRꢀ6ꢀR´ꢀ3ꢀcyanobenzo[d]isoxazoles.
Scheme 8
The whole of the data obtained (replacement of one or
both nitro groups that are meta to each other in nitrile 4
under very mild conditions and the lowered selectivity of
their replacement compared to other 4,6ꢀdinitrobenzoꢀ
annulated fiveꢀmembered aromatic heterocycles) suggests
the high electrophilicity of nitrile 4.
Experimental
1
H and 13C NMR spectra were recorded in DMSOꢀd6 on
Reagents and conditions: i. H2O2, CF3CO2H, 20 °C; ii. PhSH
(1 equiv.), K2CO3, NMP, 20 °C.
Bruker ACꢀ200 and Bruker AMꢀ300 instruments, respectively.
Chemical shifts δ are referenced to SiMe4. IR spectra were reꢀ
corded on a Specord Mꢀ80 instrument (KBr pellets). Mass specꢀ
tra were recorded on a Kratos MSꢀ30 instrument (EI, 70 eV).
The course of the reactions was monitored and the purity of the
compounds was checked by TLC on Silufol UVꢀ254 plates. Dry
DMF was used for reactions; the other solvents were not addiꢀ
tionally dried.
3ꢀCyanoꢀ4,6ꢀdinitrobenzo[d]isoxazole (4). A solution of
compound 3 (0.56 g, 2 mmol) (see Ref. 1) and NH2OH•HCl
(0.20 g, 2.8 mmol) in 95—98% formic acid (15 mL) was refluxed
for 15 h, cooled, and poured into water (60 mL). The precipitate
that formed was filtered off and dried in air to give compound 4
(0.34 g, 72%), m.p. 147—149 °C. Found (%): C, 41.02; H, 0.82.
C8H2N4O5. Calculated (%): C, 41.04; H, 0.86. 1H NMR, δ:
9.02 (s, 1 H, H(5).); 9.50 (s, 1 H, H(7)). 13C NMR, δ: 109.2
(CN), 113.8 (C(7)), 117.2 (C(5), C(3a)), 136.4 (C(3)), 140.5
(C(4)), 149.0 (C(6)), 163.5 (C(7a)). IR, ν/cm–1: 3100, 3080,
2264, 1608, 1560, 1544, 1356, 1340, 1248, 1068, 1016, 964, 932,
800, 744, 742, 692, 640.
The reactions yielded two products with close polariꢀ
ties (TLC), which hindered their separation and identifiꢀ
1
cation. H NMR data allowed us to identify phenylthio
derivative 6a obtained in the present work (see above) and
propose a structure for the other product (13). Thus, prodꢀ
ucts 13 and 6a in the ratio ∼1 : 1 were obtained as the
result of replacement of both the nitro and sulfonyl groups.
A reaction of nitro sulfone 12 with an excess of PhSH
(2 equiv.) at room temperature gave the sole product,
bissulfide 9, in high yield (Scheme 9).
Scheme 9
4ꢀAzidoꢀ3ꢀcyanoꢀ6ꢀnitrobenzo[d]isoxazole (5). Sodium azide
(0.13 g, 2 mmol) was added to a solution of compound 4 (0.47 g,
2 mmol) in DMF (5 mL). The reaction mixture was stirred at
∼20 °C for 1 h and poured into water with ice (50 mL). The
precipitate that formed was filtered off and dried in air to give
compound 5 (0.42 g, 91%), m.p. 121—122 °C. Found (%):
C, 41.53; H, 0.87; N, 35.96. C8H2N6O3. Calculated (%)
C, 41.75; H, 0.88; N, 36.52. 1H NMR, δ: 8.24 (s, 1 H, H(5));
8.76 (s, 1 H, H(7)). 13C NMR, δ: 103.3, 109.1, 110.5, 116.2,
Reagents and conditions: PhSH (2 equiv.), K2CO3, NMP, 20 °C.
The results obtained suggest that the replacement rates
of the sulfonyl and NO2 groups in compound 12 under
the action of PhSH are virtually equal. Earlier,4 we have

4ꢀRꢀ3ꢀCyanoꢀ6ꢀnitrobenzo[d]isoxazoles
Russ.Chem.Bull., Int.Ed., Vol. 55, No. 3, March, 2006
547
136.2, 146.1, 150.8, 163.5. IR, ν/cm–1: 3112, 3060, 2220, 2152,
2132, 1620, 1608, 1540, 1488, 1372, 1348, 1316, 1216, 1200,
1064, 932, 920, 876, 788, 740. MS, m/z: 230 (M+).
Synthesis of sulfides 6 (general procedure). Potassium carꢀ
bonate (0.28 g, 2 mmol) and an appropriate thiol (2 mmol) were
added to a solution of compound 4 (0.47 g, 2 mmol) in NMP
(5 mL). The reaction mixture was stirred at ∼20 °C for 1 h,
poured into water with ice (50 mL), and acidified with
conc. HCl to pH 3. The precipitate that formed was filtered off
and dried in air.
3ꢀCyanoꢀ6ꢀnitroꢀ4ꢀphenylthiobenzo[d]isoxazole (6a). The
yield was 0.50 g (84%), m.p. 122—123 °C. Found (%): C, 41.53;
H, 0.87; N, 35.96. C14H7N3O3S. Calculated (%): C, 41.75;
H, 0.88; N, 36.52. 1H NMR, δ: 7.58 (m, 3 H, Ph); 7.64 (m, 2 H,
Ph); 7.68 (s, 1 H, H(5)); 8.84 (s, 1 H, H(7)). 13C NMR, δ:
105.0, 109.5, 119.0, 122.4, 129.0, 130.0, 130.5, 133.6, 134.6,
135.6, 150.0, 162.9. IR, ν/cm–1: 3104, 3060, 2132, 1592, 1576,
1540, 1444, 1352, 1332, 1216, 1196, 1024, 1000, 984, 940, 876,
852, 752.
C, 60.33; H, 2.91; N, 14.90. C14H7N3O4. Calculated (%):
C, 59.79; H, 2.51; N, 14.94. H NMR, δ: 7.40 (m, 3 H, OPh);
1
7.42 (s, 1 H, H(5)); 7.60 (m, 2 H, OPh); 8.72 (s, 1 H, H(7)).
13C NMR, δ: 101.5, 105.1, 109.3, 116.1, 120.6, 126.6, 130.9,
134.7, 151.1, 151.7, 153.6, 164.0. IR, ν/cm–1: 3060, 1632, 1620,
1588, 1540, 1488, 1372, 1344, 1296, 1200, 1100, 1072, 1056,
952, 936, 872, 788, 744, 692.
6ꢀNitroꢀ4ꢀ[(1ꢀphenylethylidene)aminooxy]benzo[d]isoxꢀ
azoleꢀ3ꢀcarbonitrile (8b). The yield was 0.45 g (70%), m.p. 210 °C
(decomp.). Found (%): C, 59.14; H, 3.25; N, 16.90.
C16H10N4O4. Calculated (%): C, 59.63; H, 3.13; N, 17.38.
1H NMR, δ: 2.67 (s, 3 H, Me); 7.56 (m, 3 H, OPh); 7.91 (m,
2 H, OPh); 8.22 (s, 1 H, H(5)); 8.65 (s, 1 H, H(7)). 13C NMR,
δ: 14.1, 100.8, 103.2, 109.6, 127.1, 128.9, 131.2, 133.9, 151.5,
152.0, 163.4, 163.7. IR, ν/cm–1: 3116, 2916, 2852, 1624, 1548,
1468, 1444, 1320, 1284, 1188, 1112, 1088, 1056, 984, 956, 928,
904, 880, 836, 768, 756, 744, 696.
3ꢀCyanoꢀ4,6ꢀbis(phenylthio)benzo[d]isoxazole (9). Potassium
carbonate (0.56 g, 4 mmol) and PhSH (0.4 mL, 4 mmol) were
added to a solution of compound 4, 6a, or 12 (2 mmol) in NMP
(5 mL). (In the case of compound 6a, the following amounts
were added: K2CO3 (0.28 g, 2 mmol) and PhSH (0.2 mL,
2 mmol).) The reaction mixture was stirred at ∼20 °C for 24 h,
poured into water with ice (50 mL), and acidified with conc. HCl
to pH 3. The precipitate that formed was filtered off and dried in
air. The yield of product 9 was 0.70 g (97%) from dinitro
compound 4 and 0.60 g (83%) from mononitro sulfone 12.
M.p. 110—111 °C. Found (%): C, 66.55; H, 3.41; N, 7.92.
C20H12N2OS2. Calculated (%): C, 66.64; H, 3.36; N, 7.77.
1H NMR, δ: 6.58 (s, 1 H, H(5)); 7.42 (m, 10 H, 2 Ph); 7.57 (s, 1
H, H(7)). 13C NMR, δ: 105.7, 110.0, 116.5, 123.5, 129.4, 129.6,
129.9, 130.3, 132.7, 133.1, 134.2, 134.5, 145.3, 164.2. IR,
ν/cm–1: 3068, 1592, 1572, 1476, 1456, 1440, 1368, 1352, 1332,
1224, 1100, 1056, 1028, 972, 924, 832, 780, 748, 708, 688.
3ꢀCyanoꢀ6ꢀnitroꢀ4ꢀphenylsulfonylbenzo[d]isoxazole (12).
Hydrogen peroxide (0.37 mL) was added to a solution of comꢀ
pound 6a (0.33 g, 1.1 mmol) in CF3COOH (5 mL). The reacꢀ
tion mixture was stirred at room temperature for 1 h and poured
into water with ice (50 mL). The precipitate that formed was
filtered off and dried in air to give compound 12 (0.36 g, 95%),
m.p. 182—184 °C. Found (%): C, 51.33; H, 2.19; N, 12.31;
C14H7N3O5S. Calculated (%):C, 51.06; H, 2.14; N, 12.76.
1H NMR, δ: 7.69—7.80 (m, 3 H, m,pꢀPh); 8.17 (d, 2 H, oꢀPh,
J = 7.8 Hz); 8.86 (s, 1 H, H(5)); 9.45 (s, 1 H, H(7)).
Methyl [(3ꢀcyanoꢀ6ꢀnitrobenzo[d]isoxazolꢀ4ꢀyl)sulfanyl]aceꢀ
tate (6b). The yield was 0.47 g (80%), m.p. 77—78 °C.
Found (%): C, 44.69; H, 2.38; N, 14.26. C11H7N3O5S. Calcuꢀ
lated (%): C, 45.05; H, 2.41; N, 14.33. 1H NMR, δ: 3.69 (s, 3 H,
Me); 4.40 (s, 2 H, CH2); 8.26 (s, 1 H, H(5)); 8.82 (s, 1 H, H(7)).
13C NMR, δ: 34.3, 52.6, 104.7, 109.6, 118.7, 122.5, 133.7, 135.6,
150.0, 162.5, 168.8. IR, ν/cm–1: 3092, 2976, 1736, 1608, 1544,
1440, 1352, 1316, 1292, 1232, 1200, 1152, 988, 944, 884, 748.
4ꢀBenzylthioꢀ3ꢀcyanoꢀ6ꢀnitrobenzo[d]isoxazole (6c) and
6ꢀbenzylthioꢀ3ꢀcyanoꢀ4ꢀnitrobenzo[d]isoxazole (6c´). The yield
of a mixture of compounds 6c and 6c´ was 0.40 g (64%).
Found (%): C, 57.69; H, 3.38; N, 13.26. C15H9N3O3S. Calcuꢀ
1
lated (%):C, 57.87; H, 2.91; N, 13.50. 6c: H NMR, δ: 4.64 (s,
2 H, CH2); 7.2—7.5 (m, 5 H, Ph); 8.22 (s, 1 H, H(5)); 8.75 (s,
1
1 H, H(7)). 6c´: H NMR, δ: 4.58 (s, 2 H, CH2); 7.2—7.5 (m,
5 H, Ph); 8.32 (s, 1 H, H(5)); 8.44 (s, 1 H, H(7)).
Methyl 3ꢀaminoꢀ7ꢀnitrothiochromeno[4,5ꢀcd]isoxazoleꢀ4ꢀ
carboxylate (7). Potassium carbonate (0.56 g, 4 mmol) and meꢀ
thyl thioglycolate (0.18 mL, 2 mmol) were added to a solution of
compound 4 (0.47 g, 2 mmol) in NMP (5 mL). The reaction
mixture was stirred at ∼20 °C for 24 h, poured into water with ice
(50 mL), and acidified with conc. HCl to pH 3. The precipitate
that formed was filtered off, washed with acetone (30 mL), and
dried in air to give compound 7 (0.25 g, 42%), m.p. 249—251 °C.
Found (%): C, 44.60; H, 2.43; N, 13.96. C11H7N3O5S. Calcuꢀ
lated (%): C, 45.05; H, 2.41; N, 14.33. 1H NMR, δ: 3.86 (s, 3 H,
Me); 7.97 (s, 2 H, NH2); 8.23 (s, 1 H, H(5)); 8.29 (s, 1 H,
H(7)). 13C NMR, δ: 52.6, 94.9, 100.3, 112.1, 131.5, 139.4, 150.8,
157.2, 161.5, 165.5. IR, ν/cm–1: 3484, 3360, 3096, 2964, 1696,
1640, 1596, 1548, 1536, 1496, 1440, 1428, 1368, 1348, 1264,
1136, 1092, 1028, 988, 948, 904, 884, 856, 800, 764, 744. MS,
m/z: 293 (M+).
This work was financially supported by the Council on
Grants of the President of the Russian Federation (the
Program for State Support to young Russian scientists,
Grant MKꢀ1770.2005.3).
References
Synthesis of compounds 8a,b (general procedure). Potassium
carbonate (0.28 g, 2 mmol) and an appropriate nucleophilic
reagent (2 mmol) were added to a solution of compound 4
(0.47 g, 2 mmol) in NMP (5 mL). The reaction mixture was
stirred at ∼20 °C for 2 h, poured into water with ice (50 mL), and
acidified with conc. HCl to pH 3. The product was extracted
with ethyl acetate (3×30 mL), the extract was dried and concenꢀ
trated, and the residue was recrystallized from EtOH.
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Received December 29, 2005;
in revised form March 23, 2005