Synthetic utilization of polynitroaromatic compounds. 4. Synthesis of nitro-free 4,6-disubstituted 3-aminobenzothiophene derivatives based on 2,4,6-trinitrobenzamide

Article abstract of DOI:10.3987/COM-05-10644

A convenient synthesis of nitro-free 4,6-disubstituted 3-aminobenzothiophenes, their S-oxides and S,S-dioxides based on the available 2,4,6-trinitrobenzamide has been developed. The synthesis entails stepwise nucleophilic substitution of all nitro groups in the starting compound by S-, N-, and O-nucleophiles followed by Thorpe-Ziegler cyclization.

Full text of DOI:10.3987/COM-05-10644

HETEROCYCLES, Vol. 68, No. 6, 2006
1109
HETEROCYCLES, Vol. 68, No. 6, 2006, pp. 1109 - 1119. © The Japan Institute of Heterocyclic Chemistry
Received, 2nd December, 2005, Accepted, 1st May, 2006, Published online, 2nd May, 2006. COM-05-10644
SYNTHETIC
UTILIZATION
OF
POLYNITROAROMATIC
COMPOUNDS. 4. SYNTHESIS OF NITRO-FREE 4,6-DISUBSTITUTED 3-
AMINOBENZOTHIOPHENE DERIVATIVES BASED ON 2,4,6-
TRINITROBENZAMIDE
Sergei G. Zlotin,a* Pavel G. Kislitsin,a Fedor A. Kucherov,a and Andrei
A. Gakhb*
a N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
Leninsky prosp. 47, Moscow, 119991, Russia; e-mail: zlotin@ioc.ac.ru
b
Oak Ridge National Laboratory, Oak Ridge, TN 37831-6242, USA; e-mail:
gakhaa@ornl.gov
Abstract
-
A
convenient synthesis of nitro-free 4,6-disubstituted
3-aminobenzothiophenes, their S-oxides and S,S-dioxides based on the available
2,4,6-trinitrobenzamide has been developed. The synthesis entails stepwise
nucleophilic substitution of all nitro groups in the starting compound by S-, N-,
and O-nucleophiles followed by Thorpe-Ziegler cyclization.
INTRODUCTION
3-Aminobenzothiophene derivatives are used for the synthesis of various biologically active compounds:
protein kinase inhibitors,1 gyrase inhibitors,2 adrenoceptor antagonists for symptomatic treatment of
bening prostatic hyperplasma,3 trombine inhibitors,4 epidermal growth factor tyrosine kinase receptor
inhibitors,5 phosphodiesterase inhibitors,6 herbicides,7 and antiallergetics.8 3-Aminobenzothiophenes are
generally synthesized by Thorpe-Ziegler cyclization of 2-alkylthiobenzonitriles, their S-oxides and S,S-
dioxides.9–11 The limited availability of functionalized 2-alkylthiobenzonitriles is the major drawback of
this approach.
A straightforward approach to the desired compounds includes exhaustive nucleophilic displacement of
nitro groups in 2,4,6-trinitrobenzonitrile (1),12, 13 but regioselectivity remains the major problem.13

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HETEROCYCLES, Vol. 68, No. 6, 2006
Alternatively, 2,4,6-trinitrobenzamide (2) is reported to react with nucleophiles, yielding 2-substituted
4,6-dinitrobenzamides (3),12, 14 but attempts to remove the remaining nitro groups have failed.12
Here we report a successful approach to the convenient synthesis of nitro-free 4,6-disubstituted 3-
aminobenzothiophene derivatives based on the available 2,4,6-trinitrobenzamide (2). The first step is
activation of the nitro groups in the 2-substituted 4,6-dinitrobenzamides (3) towards nucleophiles via
dehydration to respective nitriles. The second step is replacement of the nitro groups in the 2-substituted
4,6-dinitrobenzonitriles with O-, S-, and N-nucleophiles followed by a base-promoted Thorpe-Ziegler
cyclization of the substitution products (or their S-oxides and S,S-dioxides).
RESULTS AND DISCUSSION
2-Substituted 4,6-dinitrobenzamides (3a,b) (prepared regioselectively by the reactions of 2,4,6-
trinitrobenzamide (2) with respective RCH2SH / K2CO3 systems in DMF12, 14) were dehydrated to 2-
substituted 4,6-dinitrobenzonitriles (4a,b) by the Vilsmeier reagent (POCl3 /DMF15) (Scheme 1).
NO2
O
NO2
O
NO2
CN
NH2
NH2
RCH2SH / K2CO3
DMF, 20oC, 6 h
POCl3 / DMF
20oC, 2 h
O2N
NO2
O2N
SCH2R
O2N
SCH2R
(2)
(3a,b) R = Ph (a), CO2Me (b)
(4a,b) R = Ph (a), CO2Me (b)
3
NO2
Nu
F
NH2
6
CN
CN
1
5
4
CO2Me
2
S
O2N
Nu
SCH2R
O2N
SCH2Ph
3
(6)
(5a-f) 54-99%
R = Ph, Nu = OMe (a), OPh (b), OCH2CF3 (c), N3 (d);
R = CO2Me, Nu = SC6H4Me-p (e), SCH2CO2Me (f)
(5g)
Scheme 1
We studied reactions of the compounds (4a,b) with nucleophiles (MeONa, NaN3) and with NuH / base
systems (RSH / K2CO3, ROH / K2CO3) in DMF or in MeOH (in case of MeONa) solutions. Mixtures of
C-4/C-6 substitution products were obtained in ~1 : 3 ratio when one molar amount of the nucleophilic
reagent was used (1H NMR control). We have not been able to separate the isomers because of their
similar TLC mobility on silpearl UV-250. Products of the complete displacement of nitro groups (5a-f)
were obtained only when an excess of O-, N-, or S-nucleophile was used. Cesium fluoride in MeCN was
shown to be less reactive: despite of a 5-fold excess of the reagent, only one of the two nitro groups in the
compound (4a) was replaced by the fluoride anion to afford 2-benzylthio-6-fluoro-4-nitrobenzonitrile
1
(5g). The proposed position of the fluorine atom in 5g is in agreement with the observed H NMR data:

HETEROCYCLES, Vol. 68, No. 6, 2006
1111
19
H-
J1
with adjacent (H5, δ 8.10 ppm) and remote (H3, δ 8.17 ppm) protons are 10.0 Hz and < 2.0 Hz,
F
respectively. The observed regioselectivity is in agreement with the reported ortho-selectivity of
nucleophilic substitution reactions in 1-R-2,4-dinitro- and 1-R-2,4,6-trinitrobenzens.9, 12
The results of substitution reaction are affected by the nature of both a nucleophile and a solvent.
Reactions of the nitrile (4b) with HSC6H4Me-4 / K2CO3 and HSCH2CO2Me / K2CO3 systems in DMF
afforded nitro-free substitution products (5e, f), whereas its reaction with MeONa in MeOH gave 3-
amino-4,6-dinitrobenzothiophene (6). Similar regularities were observed in the reaction of 2,4,6-
trinitrobenzonitrile (1) with a three-fold excess of methyl α-mercaptoacetate. The reaction in a DMF
solution afforded compound (5f), yet in MeOH it yielded a Thorp-Zigler cyclization product (6)
(Scheme 2). It is possible that due to equilibrium between thiolate- and methylate-anions in MeOH, the
latter anion acted as a base initiating cyclization of the intermediate 4b to the heterocycle 6.18
SCH2CO2Me
NO2
CN
CN
3 HSCH2CO2Me / K2CO3
MeOH
3 HSCH2CO2Me / K2CO3
DMF
(6)
MeO2CCH2S
SCH2CO2Me
O2N
NO2
(5f)
(1)
Scheme 2
Substituted benzonitriles (5a-f) were found to be convenient building blocks for the synthesis of nitro-free
bezothiophene derivatives. A reaction of CH-activated compound (5e) with MeONa in MeОН yielded a
benzothiophene derivative (7) (Scheme 3). Under similar conditions, 2,4,6-tris(methoxycarbonyl-
methylthio)benzonitrile (5f) reacted with MeONa to afford methyl 4,6-bis(p-tolylthio)-3-
aminobenzo[b]thiophene-2-carboxylate (8), the first representative of a new heterocyclic system. The
reaction entails of a cascade Thorp-Zigler reaction, followed by an intramolecular cyclization of the
intermediate benzothiophene derivative with participation of adjacent amino and methoxycarbonyl groups.
Attempts to synthesize the nitro-free compounds (7) and (8) by nucleophilic displacement of the nitro
groups in 3-amino-2,4-dinitrobenzothiophene (6) failed - an indication of the synthetic value of the
proposed methodology.
O
SC6H4Me-p
S
Nu
NH2
NH
CN
MeONa / MeOH
MeONa / MeOH
CO2Me
CO2Me
for (5f)
for (5e)
S
S
p-MeC6H4S
MeO2CCH2S
Nu
SCH2CO2Me
(5e, f)
(7)
(8)
Scheme 3

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HETEROCYCLES, Vol. 68, No. 6, 2006
Unlike CH-activated nitriles (5e, f), 2-benzylthiobenzonitriles (5a-d) did not react with MeONa under
these conditions. To increase the CH-acidity, they were oxidized to S-oxides (9a-d) and S,S-dioxides
(10a-d) with m-CPBA. The S-oxides and S,S-dioxides were converted to corresponding 3-
aminobenzothiophene derivatives (11a-d), (12a, b, d) by the action of the MeONa / MeOH system
(Scheme 4).
Nu
Nu
Nu
NH2
CN
CN
m-CPBA
MeONa / MeOH
(1 or 2 equiv.)
Ph
S
On
Nu
SCH2R
Nu
SCH2Ph
Nu
On
(5a-d)
(9a-d) n = 1, (10a-d) n = 2
(11a-d) n = 1, (12a,b,d) n = 2
For compounds (9)-(12): Nu = OMe (a), OPh (b), OCH2CF3 (c), N3 (d)
Scheme 4
CONCLUSIONS
In summary, we have developed a convenient synthesis of 4,6-disubstituted 3-aminobenzothiophenes,
their S-oxides and S,S-dioxides, based on a stepwise nucleophilic displacement of nitro groups in
available polynitroaromatic compounds with O-, S- and N- nucleophiles followed by base-promoted
cyclization of the reaction products. Although syntheses of fused nitroheterocycles from
polynitroaromatic compounds have been reported earlier,16–20 synthesis of nitro-free heterocycles remains
a major challenge.21 Taking into account that the 2,4,6-trinitrobenzamide (2) can be easily prepared from
2,4,6-trinitrotoluene, the proposed method may be considered as an approach to the chemical utilization
of polynitroaromatic compounds for the synthesis of valuable chemical products.12, 14
EXPERIMENTAL
13
1H, and C NMR spectra were recorded on a Bruker AM-300 spectrometer (300.13 MHz {1H}) and a
Bruker DRX-500 spectrometer (500.13 MHz {1H}, 125.76 MHz {13C}) in DMSO-d6. Chemical shifts of
1H were measured relative to Me4Si as the internal standard, 13C – relative to DMSO-d6. MS spectra were
recorded on a MS-30 (Kratos) instrument (EI). TLC was performed on Silpearl UV-250 silica gel. The
compounds (1)22 (2), (3a,b)12, 14 were synthesized according to the literature procedures. Solvents were
purified by standard methods.
2-Benzylthio-4,6-dinitrobenzonitrile (4a).
POCl3 (3.10 mL, 5.19 g, 33.8 mmol) was added to stirred solution of 2-benzylthio-4,6-dinitrobenzamide
(3a) (8.59 g, 25.8 mmol) in DMF (20 mL) at 0oC. The reaction mixture was allowed to warm up to 20oC,
stirred for additional 2 h and then poured into water (100 mL). The precipitate was filtered off, washed

HETEROCYCLES, Vol. 68, No. 6, 2006
1113
with water, dried in the air, and crystallized from an acetone – i-PrOH mixture to give 4a. Yield 6.42 g
(79%), mp 185-187oC. 1H NMR: δ 4.66 (s, 2H); 7.35 (m, 3H); 7.50 (d, J = 8.0 Hz, 2H); 8.61 (s, 1H); 8.63
(s, 1H). Anal. Calcd for C14H9N3O4S: C, 53.33; H, 2.88; N, 13.33; S, 10.17. Found: C, 53.58; H, 2.72; N,
13.16; S, 9.94.
Methyl 2-(2-cyano-3,5-dinitrophenylthio)acetate (4b)
This compound was prepared from 3b (8.13 g, 25.8 mmol) and POCl3 (3.10 mL, 33.8 mmol) following
the same procedure and experimental conditions noted above for 4a. Yield of 4b = 6.97 g (91%), mp 93-
1
94oC. H NMR: δ 3.75 (s, 3H); 4.39 (s, 2H); 8.65 (s, 1H); 8.68 (s, 1H). Anal. Calcd for C10H7N3O6S: C,
40.41; H, 2.37; N, 14.14; S, 10.79. Found: C, 40.69; H, 2.43; N, 13.97; S, 10.57.
2-Benzylthio-4,6-dimethoxybenzonitrile (5a)
1-Cyano-2-benzylthio-4,6-dinitrobenzene (4a) (0.97 g, 3.08 mmol) was added to a solution of Na (0.30 g,
13.0 mmol) in MeOH (15 mL). The mixture was refluxed for 4 h, cooled to 20oC, poured into water
(50 mL), and then adjusted to pH 7 with 10% HCl. The precipitate was filtered off, washed with water,
1
air-dried, and crystallized from i-PrOH to give 5a. Yield 0.81 g (92%), mp 105-107oC. H NMR: δ 3.82
(s, 3H); 3.87 (s, 3H); 4.31 (s, 2H); 6.44 (s, 1H); 6.55 (s, 1H); 7.30 (m, 4H); 7.40 (t, J = 8.0 Hz, 1H).
13C NMR: δ 35.71, 55.98, 56.52, 95.86, 101.81, 105.18, 114.75, 127.36, 128.50, 128.86, 136.18, 144.07,
163.34, 163.89. MS (m/z, I): 285 (M+, 68%), 270 (3%), 256 (7%), 194 (7%), 150 (10%), 91 (100%). Anal.
Calcd for C16H15NO2S: C, 67.34; H, 5.30; N, 4.91; S, 11.24. Found: C, 67.10; H, 5.23; N, 5.04; S, 11.13.
2-Benzylthio-4,6-diphenoxybenzonitrile (5b)
Phenol (1.00 g, 10.6 mmol) and K2CO3 (1.50 g, 10.9 mmol) were added successively to stirred solution of
4a (0.97 g, 3.08 mmol) in DMF (15 mL). The reaction mixture was stirred at 80oC for 6 h, cooled to 20oC,
poured into water (100 mL), and then adjusted to pH 7 with 10% HCl. The aqueous layer was decanted
from black oil. Acetone - CCl4 (1 : 1 v/v) mixture (20 mL) was added to the residue and evaporated to
dryness under reduced pressure. The procedure was repeated twice. Crystallization of the residue from i-
PrOH gave 5b. Yield 1.16 g (92%), mp 75-81oC. 1H NMR: δ 4.28 (s, 2H); 6.13 (s, 1H); 6.69 (s, 1H); 6.99
13
(d, J = 8.0 Hz, 2H); 7.10 (d, J = 8.0 Hz, 2H); 7.22-7.32 (m, 7H); 7.38-7.45 (m, 4H). C NMR: δ 35.65,
95.32, 102.44, 109.79, 113.79, 119.65, 120.05, 125.30, 125.36, 127.34, 128.50, 128.64, 128.71, 130.32,
135.78, 145.51, 153.65, 154.04, 161.52, 161.77. MS (m/z, I): 409 (M+, 30%), 318 (15%), 91 (100%). Anal.
Calcd for C26H19NO2S: C, 76.26; H, 4.68; N, 3.42; S, 7.83. Found: C, 75.99; H, 4.60; N, 3.55; S, 7.68.
2,4-Bis(2,2,2-trifluoroethoxy)-6-(benzylthio)benzonitrile (5c)
2,2,2-Trifluoroethanol (2.00 mL, 2.79 g, 27.9 mmol) and K2CO3 (2.70 g, 19.6 mmol) were added
successively to stirred solution of 4a (1.51 g, 4.80 mmol) in DMF (10 mL). The reaction mixture was
stirred at 90oC for 6 h, cooled to 20oC and poured into water (100 mL). The precipitate was filtered off,
washed with water, air-dried, and crystallized from i-PrOH to give 5c. Yield 1.25 g (62%), mp 73-76oC.

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1H NMR: δ 4.34 (s, 2H); 4.72 (q, JH-F = 8.0 Hz, 2H); 4.76 (q, JH-F = 8.0 Hz, 2H); 6.77 (s, 1H); 6.85 (s,
1H); 7.25 (t, J = 7.5 Hz, 1H); 7.32 (t, J = 7.5 Hz, 2H); 7.40 (d, J = 7.5 Hz, 2H). MS (m/z, I): 421 (M+,
15%), 330 (3%), 309 (4%), 266 (4%), 91 (100%). Anal. Calcd for C18H13NO2F6S: C, 51.31; H, 3.11; N,
3.32; F, 27.05; S, 7.61. Found: C, 51.56; H, 3.28; N, 3.49; F, 26.83; S, 7.44.
2,4-Diazido-6-(benzylthio)benzonitrile (5d)
NaN3 (1.50 g, 23.1 mmol) was added to a solution of 4a (1.26 g, 4.00 mmol) in DMF (10 mL). The
reaction mixture was stirred at 50oC for 6 h, cooled to 20oC and poured into water (100 mL). The
precipitate was filtered off, washed with water, air-dried, and crystallized from acetone - i-PrOH mixture
to give 5d. Yield 1.17 g (95%), mp 119-120oC. 1H NMR: δ 4.39 (s, 2H); 6.90 (s, 2H); 7.28 (t, J = 8.0 Hz,
1H); 7.32 (t, J = 8.0 Hz, 2H); 7.40 (d, J = 8.0 Hz, 2H). Anal. Calcd for C14H9N7S: C, 54.71; H, 2.95; N,
31.90; S, 10.43. Found: C, 54.95; H, 3.03; N, 31.67; S, 10.29.
Methyl 2-(3,5-bis(p-tolylthio)-2-cyanophenylthio)acetate (5e)
4-Methylthiophenol (0.18 g, 1.45 mmol) and K2CO3 (0.20 g, 1.45 mmol) were added successively to a
solution of 4b (0.20 g, 0.67 mmol) in DMF (8 mL). The reaction mixture was stirred at 25oC for 5 h,
cooled to 20oC, and poured into water (50 mL). The precipitate was filtered off, washed with water, air-
dried, and crystallized from benzene to give 5e. Yield 0.17 g (60%), mp 135-137oC. 1H NMR: δ 2.38 (s,
6H); 3.66 (s, 3H); 4.12 (s, 2H); 6.00 (s, 1H); 7.04 (s, 1H); 7.14-7.37 (m, 8H). Anal. Calcd for
C24H21NO2S3: C, 63.83; H, 4.69; N, 3.10; S, 21.30. Found: C, 64.04; H, 4.80; N, 2.98; S, 21.11.
2,4,6-tris(methoxycarbonylmethylthio)benzonitrile (5f)
Method A. Methyl α-mercaptoacetate (0.13 mL, 0.15 g, 1.43 mmol) and K2CO3 (0.20 g, 1.45 mmol)
were added successively to a solution of 4b (0.20 g, 0.67 mmol) in DMF (8 mL). The reaction mixture
was stirred at 25oC for 5 h and poured into water (50 mL). The precipitate was filtered off, washed with
water, air-dried, and crystallized from benzene to give 5f. Yield 0.22 g (77%), mp 85-86oC (lit.,12 mp 84-
86oC). 1H NMR: δ 3.72 (s, 9H); 4.02 (s, 6H); 7.21 (s, 2H).
Method B. This compound was prepared from 1 (1.00 g, 4.40 mmol), methyl α-mercaptoacetate (1.60 g,
15.3 mmol) and K2CO3 (2.12 g, 15.3 mmol) in DMF following the procedure and experimental
conditions described in the literature.12
2-Benzylthio-6-fluoro-4-nitrobenzonitrile (5g)
2-Benzylthio-4,6-dinitrobenzonitrile (4a) (0.10 g, 0.32 mmol) was added to a suspension of freshly dried
CsF (0.25 g, 1.64 mmol) in dry MeCN (5 mL). The reaction mixture was refluxed for 4 h and evaporated
under reduced pressure. Water (2 mL) was added to the residue. The precipitate was filtered off, washed
1
with water, air-dried, and crystallized from benzene to give 5g. Yield 0.05 g (54%), mp 122-125oC. H
NMR: δ 4.60 (s, 2H); 7.30 (t, J = 8.0 Hz, 1H); 7.35 (t, J = 8.0 Hz, 2H); 7.45 (d, J = 8.0 Hz, 2H); 8.10 (d,
JH-F = 10 Hz, 1H); 8.17 (s, 1H). MS (m/z, I): 288 (M+, 5%), 197 (2%), 91 (100%). Anal. Calcd for

HETEROCYCLES, Vol. 68, No. 6, 2006
1115
C14H9N2O2FS: C, 58.33; H, 3.15; N, 9.72; F, 6.59; S, 11.12. Found: C, 58.09; H, 3.00; N, 9.87; F, 6.38; S,
10.95.
Methyl 3-amino-4,6-dinitrobenzo[b]thiophene-2-carboxylate (6)
Method A. 4b (0.56 g, 1.90 mmol) was added to a solution of sodium (0.17 g, 7.39 mmol) in MeOH
(5 mL). The reaction mixture was stirred for 10 min at 20oC, diluted with water to 50 mL, and adjusted to
pH 7 with 10% HCl. The precipitate was filtered off, washed with water, air-dried, and crystallized from
acetone – i-PrOH mixture to give 6. Yield 0.53 g (95%), mp 195-197oC (lit.,13 mp 196-198oC). 1H NMR:
δ 3.91 (s, 3H); 6.59 (s, 2H); 8.66 (s, 1H); 9.30 (s, 1H).
Method B. Methyl α-mercaptoacetate (0.30 mL, 0.35 g, 3.29 mmol) and K2CO3 (0.45 g, 3.26 mmol)
were added successively to a solution of 1-cyano-2,4,6-trinitrobenzene (1) (0.37 g, 1.55 mmol) in MeOH
(5 mL). The reaction mixture was stirred at 20oC for 1 h, poured into water (20 mL), and adjusted to pH 7
with 10% HCl. The precipitate was filtered off, washed with water, air-dried and crystallized from EtOH
to give 6. Yield 0.33 g (72%), mp 196-198oC.
Methyl 4,6-bis(p-tolylthio)-3-aminobenzo[b]thiophene-2-carboxylate (7)
The nitrile (5e) (0.14 g, 0.31 mmol) was added to KOH (0.05 g, 0.89 mmol) solution in MeOH (6 mL).
The reaction mixture was stirred at 35oC for 4 h, the precipitate was filtered off, washed with water (3 × 7
mL), air-dried, and crystallized from the benzene-THF mixture to afford the 7. Yield 0.10 g (74%), mp
1
141-142oC. H NMR: δ 2.23 (s, 6H); 3.72 (s, 3H); 6.80 (s, 1H); 7.01-7.27 (m, 10H); 7.53 (s, 1H). Anal.
Calcd for C24H21NO2S3: C, 63.83; H, 4.69; N, 3.10; S, 21.30. Found: C, 63.60; H, 4.54; N, 3.23; S, 21.45.
Methyl 4,5-dihydro-8-(methoxycarbonylmethylthio)-4-oxo-3H-thieno[4,3,2-ef][1,4]benzothiazepine-
2-carboxylate (8)
2,4,6-Tris(methoxycarbonylmethylthio)benzonitrile (5f) (0.50 g, 1.20 mmol) was added to a solution of
Na (0.06 g, 2.61 mmol) in MeOH (10 mL). The reaction mixture was stirred at 20oC for 2 h, diluted with
water (40 mL) and adjusted to pH 7 with 10% HCl. The precipitate was filtered off, washed with water,
air-dried, and crystallized from acetone – i-PrOH mixture to give 8. Yield 0.27 g (58%), mp 150-152oC.
1H NMR: δ 3.68 (s, 3H); 3.87 (s, 2H); 3.91 (s, 3H); 4.05 (s, 2H); 7.40 (s, 1H); 7.83 (s, 1H); 10.04 (s, 1H).
13C NMR: δ 33.64, 35.50, 52.34, 52.56, 109.15, 119.37, 123.95, 127.87, 134.42, 136.67, 138.48, 141.43,
163.65, 168.76, 169.23. MS (m/z, I): 383 (M+, 100%), 350 (20%), 323 (25%). Anal. Calcd for
C15H13NO5S3: C, 46.98; H, 3.42; N, 3.65; S, 25.09. Found: C, 47.23; H, 3.57; N, 3.48; S, 24.90.
4,6-Disubstituted
2-(benzylsulfinyl)benzonitriles
(9a-d)
and
4,6-disubstituted
2-
(benzylsulfonyl)benzonitriles (10a-d) (General procedure)
m-CPBA (86% purity, 0.79 g, 3.92 mmol for (9a-d) or 1.60 g, 7.94 mmol for (10a-d)] was added to a
solution of 4,6-disubstituted 1-cyano-2-alkylthiobenzene (5a-d) (3.92 mmol) in CH2Cl2 (10 mL) at 0oC.
The reaction mixture was stirred at 20oC for 2 h (TLC-monitoring) and adjusted to pH 7 with saturated

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HETEROCYCLES, Vol. 68, No. 6, 2006
NaHCO3 water solution. The aqueous layer was separated, extracted with CH2Cl2 (5 mL) and discarded.
Combined organic layers were dried over anhydrous MgSO4 and evaporated to dryness. The solid residue
was crystallized from i-PrOH to give 9a-d or 10a-d. The following compounds were obtained:
2-(Benzylsulfinyl)-4,6-dimethoxybenzonitrile (9a)
Yield 90%, mp 126-128oC. 1H NMR: δ 3.30 (s, 3H); 3.96 (s, 3H); 4.03 (d, J = 13.9 Hz, 1H); 4.38 (d, J =
13.9 Hz, 1H); 6.60 (s, 1H); 6.81 (s, 1H); 7.06 (d, J = 8.0 Hz, 2H); 7.30 (m, 3H). 13C NMR: δ 56.24, 57.02,
60.69, 88.68, 100.92, 102.55, 113.05, 128.14, 129.21, 130.33, 149.57, 163.15, 164.44. MS (m/z, I): 301
(M+, 10%), 285 (2%), 210 (5%), 91 (100%). Anal. Calcd for C16H15NO3S: C, 63.77; H, 5.02; N, 4.65; S,
10.64. Found: C, 63.54; H, 5.16; N, 4.48; S, 10.41.
2-(Benzylsulfinyl)-4,6-diphenoxybenzonitrile (9b)
Yield 78%, mp 156-159oC. 1H NMR: δ 4.17 (d, J = 12.5 Hz, 1H); 4.50 (d, J = 12.5 Hz, 1H); 6.49 (s, 1H);
6.53 (s, 1H); 6.81 (d, J = 8.0 Hz, 2H); 7.02 (d, J = 8.0 Hz, 2H); 7.23 (m, 3H); 7.30-7.45 (m, 6H); 7.50 (t, J
= 8.0 Hz, 2H). 13C NMR: δ 59.91, 92.68, 107.13, 107.72, 112.26, 119.64, 120.18, 125.62, 125.75, 128.11,
128.19, 128.46, 130.32, 130.46, 150.38, 153.17, 154.23, 161.33, 162.24. MS (m/z, I): 425 (M+, 2%), 409
(2%), 334 (2%), 317 (2%), 285 (5%), 91 (100%). Anal. Calcd for C26H19NO3S: C, 73.39; H, 4.50; N,
3.29; S, 7.54. Found: C, 73.59; H, 4.63; N, 3.23; S, 7.40.
2,4-Bis(2,2,2-trifluoroethoxy)-6-(benzylsulfinyl)benzonitrile (9c)
Yield 80%, mp 127-128oC. 1H NMR: δ 4.04 (d, J = 12.5 Hz, 1H); 4.33 (d, J = 12.5 Hz, 1H); 4.63 (m, JH-H
=10 Hz, JH-F = 8.3 Hz, 1H); 4.77 (m, JH-H =10 Hz, JH-F = 8.3 Hz, 1H); 4.89 (m, JH-F = 8.3 Hz, 2H); 6.87 (s,
1H); 7.30 (s, 1H); 7.24 - 7.40 (m, 5H). MS (m/z, I): 437 (M+, 5%), 421 (3%), 346 (15%), 331 (5%), 91
(100%). Anal. Calcd for C18H13NO3F6S: C, 49.43; H, 3.00; N, 3.20; F, 26.06; S, 7.33. Found: C, 49.62; H,
3.08; N, 3.07; F, 25.89; S, 7.20.
2,4-Diazido-6-(benzylsulfinyl)benzonitrile (9d)
Yield 84%, mp 164-167oC. 1H NMR: δ 4.13 (d, J = 13.9 Hz, 1H); 4.42 (d, J = 13.9 Hz, 1H); 6.87 (s, 1H);
7.08 (d, J = 8.0 Hz, 2H); 7.26-7.35 (m, 4H). MS (m/z, I): 323 (M+, 10%), 91 (100%). Anal. Calcd for
C14H9N7OS: C, 52.01; H, 2.81; N, 30.32; S, 9.92. Found: C, 52.25; H, 2.93; N, 30.18; S, 9.84.
2-(Benzylsulfonyl)-4,6-dimethoxybenzonitrile (10a)
Yield 83%, mp 169-172oC. 1H NMR: δ 3.88 (s, 3H); 4.03 (s, 3H); 4.70 (s, 2H); 6.85 (s, 1H); 7.01 (s, 1H);
13
7.23 (d, J = 8.0 Hz, 2H); 7.32 (m, 3H). C NMR: δ 56.58, 57.41, 60.16, 90.79, 102.93, 108.89, 113.10,
127.34, 128.56, 128.69, 130.98, 142.30, 163.51, 164.46. MS (m/z, I): 317 (M+, 3%), 254 (5%), 253 (40%),
238 (8%), 210 (13%), 91 (100%). Anal. Calcd for C16H15NO4S: C, 60.55; H, 4.76; N, 4.41; S, 10.10.
Found: C, 60.37; H, 4.62; N, 4.55; S, 9.94.
2-(Benzylsulfonyl)-4,6-diphenoxybenzonitrile (10b)

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Yield 82%, mp 181-184 oC. 1H NMR: δ 4.80 (s, 2H); 6.70 (s, 1H); 6.85 (s, 1H); 6.95 (d, J = 8.0 Hz, 2H);
7.20-7.28 (m, 5H); 7.30 (t, J = 8.0 Hz, 1H); 7.36-7.43 (m, 5H); 7.50 (t, J = 8.0 Hz, 2H). Anal. Calcd for
C26H19NO4S: C, 70.73; H, 4.34; N, 3.17; S, 7.26. Found: C, 70.97; H, 4.49; N, 3.06; S, 7.10. MS (m/z, I):
441 (M+, 2%), 377 (30%); 91 (100%).
2,4-Bis(2,2,2-trifluoroethoxy)-6-(benzylsulfonyl)benzonitrile (10c)
1
Yield 91%, mp 132-134oC. H NMR: δ 4.69 (s, 2H); 4.81 (q, JH-F = 8.0 Hz, 2H); 4.94 (q, JH-F = 8.0 Hz,
2H); 7.12 (s, 1H); 7.27 - 7.32 (m, 5H); 7.43 (s, 1H). MS (m/z, I): 453 (M+, 5%), 439 (2%), 390 (14%),
389 (100%), 320 (5%), 91 (100%). Anal. Calcd for C18H13NO4F6S: C, 47.69; H, 2.89; N, 3.09; F, 25.14; S,
7.07. Found: C, 47.87; H, 3.01; N, 2.96; F, 24.95; S, 7.00.
2,4-Diazido-6-(benzylsulfonyl)benzonitrile (10d)
Yield 80%, mp 203-206oC. 1H NMR: δ 4.80 (s, 2H); 7.20 (d, J = 8.0 Hz, 2H);7.34 (m, 3H); 7.48 (s, 1H);
7.61 (s, 1H). Anal. Calcd for C14H9N7O2S: C, 49.55; H, 2.67; N, 28.89; S, 9.45. Found: C, 49.77; H, 2.73;
N, 28.68; S, 9.31.
4,6-Disubstituted 2-phenylbenzo[b]thiophen-3-amine-1-oxides (11a-d) and 1,1-dioxides (12a, b, d)
(General procedure)
S-Oxide (9a-d) or S,S-dioxide (10a-d) (1.98 mmol) was added to a solution of Na (0.10 g, 4.35 mmol) in
MeOH (10 mL). The reaction mixture was stirred at 65oC for 4 h and evaporated in vacuo to dryness.
Water (20 mL) was added to the residue, and the mixture was acidified to pH 2 with 10% HCl. The
precipitate was filtered off, washed with water, air-dried, and crystallized from acetone – i-PrOH mixture
to give 11a-d or 12a, b, d. The following compounds were obtained:
4,6-Dimethoxy-2-phenylbenzo[b]thiophen-3-amine-1-oxide (11a)
Yield 84%, mp 163-166oC. 1H NMR: δ 3.91 (s, 3H); 3.99 (s, 3H); 6.36 (s, 2H); 6.80 (s, 1H); 7.10 (s, 1H);
7.22 (t, J = 8.0 Hz, 1H); 7.41 (t, J = 8.0 Hz, 2H); 7.55 (d, J = 8.0 Hz, 2H). MS (m/z, I): 301 (M+, 30%),
285 (25%), 224 (30%), 196 (100%), 105 (20%), 77 (45%). Anal. Calcd for C16H15NO3S: C, 63.77; H,
5.02; N, 4.65; S, 10.64. Found: C, 63.55; H, 4.97; N, 4.81; S, 10.49.
4,6-Diphenoxy-2-phenylbenzo[b]thiophen-3-amine-1-oxide (11b)
Yield 71%, mp 172-175oC. 1H NMR: δ 6.40 (s, 2H); 6.49 (s, 1H); 7.11 (d, J = 8.0 Hz, 2H); 7.21 (m, 2H);
7.26 (m, 4H); 7.42-7.48 (m, 6H); 7.57 (d, J = 8.0 Hz, 2H). MS (m/z, I): 425 (M+, 30%), 409 (30%), 348
(25%), 320 (100%), 105 (30%), 77 (100%). Anal. Calcd for C26H19NO3S: C, 73.39; H, 4.50; N, 3.29; S,
7.54. Found: C, 73.15; H, 4.44; N, 3.41; S, 7.40.
4,6-Bis(2,2,2-trifluoroethoxy)-2-phenylbenzo[b]thiophen-3-amine-1-oxide (11c)
1
Yield 64%, mp 179-182oC. H NMR: δ 4.94 (q, JH-F = 8.0 Hz, 2H); 5.13 (q, JH-F = 8.0 Hz, 2H) 6.34 (s,
2H); 7.18 (s, 1H); 7.19 (s, 1H); 7.26 (t, J = 8.0 Hz, 1H); 7.43 (t, J = 8.0 Hz, 2H); 7.56 (d, J = 8.0 Hz, 2H).
2
1
13C NMR: δ 65.3 (q, JC-F = 33.9 Hz), 104.7, 106.5, 109.9, 115.5, 123.7 (q, JC-F = 277.9 Hz), 125.8,

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127.3, 128.9, 132.4, 143.2, 148.1, 153.4, 159.1. Anal. Calcd for C18H13NO3F6S: C, 49.43; H, 3.00; N,
3.20; F, 26.06; S, 7.33. Found: C, 49.31; H, 2.96; N, 3.29; F, 25.93; S, 7.18.
4,6-Diazido-2-phenylbenzo[b]thiophen-3-amine-1-oxide (11d)
Yield 80%, mp 203-206oC. 1H NMR: δ 4.80 (s, 2H); 7.20 (d, J = 8.0 Hz, 2H);7.34 (m, 3H); 7.48 (s, 1H);
7.61 (s, 1H). MS (m/z, I): 323 (M+, 30%), 307 (10%), 266 (5%), 251 (10%), 238 (10%), 218 (5%), 105
(100%), 77 (80%). Anal. Calcd for C14H9N7OS: C, 52.01; H, 2.81; N, 30.32; S, 9.92. Found: C, 51.84; H,
2.89; N, 30.18; S, 9.77.
4,6-Dimethoxy-2-phenylbenzo[b]thiophen-3-amine-1,1-dioxide (12a)
Yield 88%, mp 206-209oC. 1H NMR: δ 3.93 (s, 3H); 4.01 (s, 3H); 6.61 (s, 2H); 6.82 (s, 1H); 6.97 (s, 1H);
7.28 (t, J = 8.0 Hz, 1H); 7.42 (t, J = 8.0 Hz, 2H); 7.58 (d, J = 8.0 Hz, 2H). Anal. Calcd for C16H15NO4S: C,
60.55; H, 4.76; N, 4.41; S, 10.10. Found: C, 60.72; H, 4.69; N, 4.45; S, 9.98.
4,6-Diphenoxy-2-phenylbenzo[b]thiophen-3-amine-1,1-dioxide (12b)
Yield 94%, mp 169-171oC. 1H NMR: δ 6.45 (s, 1H); 6.74 (s, 2H); 7.04 (s, 1H); 7.13 (d, J = 8.0 Hz, 2H);
7.22 (t, J = 8.0 Hz, 1H); 7.28 (m, 3H); 7.34 (t, J = 8.0 Hz, 1H); 7.44 (t, J = 8.0 Hz, 2H); 7.46 (t, J = 8.0
Hz, 2H); 7.48 (t, J = 8.0 Hz, 2H); 7.59 (d, J = 8.0 Hz, 2H). MS (m/z, I): 441 (M+, 60%), 409 (10%), 336
(15%), 319 (15%), 105 (40%), 77 (100%). Anal. Calcd for C26H19NO4S: C, 70.73; H, 4.34; N, 3.17; S,
7.26. Found: C, 70.94; H, 4.42; N, 3.02; S, 7.17.
4,6-Diazido-2-phenylbenzo[b]thiophen-3-amine-1,1-dioxide (12d)
Yield 70%, mp 190-192oC. 1H NMR: δ 6.72 (s, 2H); 7.25 (s, 1H); 7.30 (t, J = 8.0 Hz, 1H); 7.47 (t, J = 8.0
Hz, 2H); 7.50 (s, 1H); 7.60 (d, J = 8.0 Hz, 2H). Anal. Calcd for C14H9N7O2S: C, 49.55; H, 2.67; N, 28.89;
S, 9.45. Found: C, 49.73; H, 2.79; N, 28.66; S, 9.31.
ACKNOWLEDGEMENTS
This research was sponsored by the IPP program. Oak Ridge National Laboratory is managed and
operated by UT-Battelle, LLC, under contract DE-AC05-00OR22725 for the U.S. Department of Energy.
Contribution 15, the Discovery Chemistry Project.
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