Synthesis of benzothiazoles via ipso substitution of ortho- methoxythiobenzamides

Article abstract of DOI:10.1039/b410373d

An efficient route to the synthesis of benzothiazoles from orthoo-methoxythiobenzamides via the ipso substitution of an aromatic methoxy group is presented, and the mechanism of the Jacobson synthesis of benzothiazoles is further investigated.

Full text of DOI:10.1039/b410373d

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A R T I C L E
Synthesis of benzothiazoles via ipso substitution of ortho-
methoxythiobenzamides
Nadale K. Downer and Yvette A. Jackson*
Department of Chemistry, University of the West Indies, Mona, Kingston 7, Jamaica,
West Indies
Received 9th July 2004, Accepted 1st September 2004
First published as an Advance Article on the web 28th September 2004
An efficient route to the synthesis of benzothiazoles from ortho-methoxythiobenzamides via the ipso substitution of
an aromatic methoxy group is presented, and the mechanism of the Jacobson synthesis of benzothiazoles is further
investigated.
Introduction
Benzothiazoles are precursors to natural products, pharma-
ceutical agents and other compounds that exhibit a wide
spectrum of biological activity such as antitumour, immuno-
suppressive, immunomodulatory and antiviral properties.1
Various methods of synthesis of benzothiazoles are
known.2 Among these is the Jacobson synthesis—oxidative
cyclization of an arylthioamide on an unsubstituted ortho
position, using potassium ferricyanide in a basic medium.2b This
method has been well used for the preparation of substituted
benzothiazoles.3–5
Our previous success with the formation of benzothiazoles
2b–d by cyclization of thiobenzamides 1b–d suggested that
compound 1a was a useful precursor to 2a,3,4 which was needed
in our on-going study of the synthesis of analogues of kuanoni-
amine A, a pharmacologically active marine alkaloid.6
Scheme 1 Reagents and conditions: (i) 50% aq. HNO3, −5 °C, 30 min,
81%; (ii) H2, Pd/C, MeOH, r.t., 15 psi, 3 h, quant.; (iii) CH2Cl2, toluene,
pyridine, benzoyl chloride, reflux, 5 h, 86%; (iv) Lawesson’s reagent
(0.6 molar equiv.), toluene, 80 °C, 2 h, 72%; (v) 20% aq. K3Fe(CN)6,
1.5 M NaOH, r.t., 15 h, 15%.
The only difference between thiobenzamide 1a and
compounds 1b–d is that 1a has three electron donating groups
on the primary ring. Other similarly activated thiobenzamides
(7a–c) were thus prepared and subjected to Jacobson
conditions. Compound 7a was easily obtained from 1d4 by
reduction. Subsequent tosylation or acylation yielded 7b or 7c,
respectively (Scheme 2).
Our previous studies indicated that the presence of electron
withdrawing groups on the primary ring significantly reduced
the yield of the Jacobson synthesis (compounds 2b–d were
obtained in 80, 54 and 24% respectively after 1, 3 and 7 days at
room temperature). It was therefore anticipated that Jacobson
cyclization of the highly activated thiobenzamide 1a would
occur at a higher rate and with better yields than those
previously carried out. We noted, however, that trisubstituted
arylthioanilides are quite unpopular as substrates for the
Jacobson synthesis.
Results and discussion
Compound 1a was easily obtained from commercially
available 2,4,5-trimethoxybenzaldehyde by the pathway shown
in Scheme 1 (overall yield 50%). Addition of 2,4,5-trimethoxy-
benzaldehyde to a cold (−5 °C) solution of 50% aqueous nitric
acid resulted in ipso nitration7 to produce nitrobenzene 3.
Subsequent reduction, followed by condensation with benzoyl
chloride and thionation using Lawesson’s reagent, produced
thiobenzamide 1a.
Treatment of compound 1a with 1.5 M NaOH followed by
20% K3Fe(CN)6 at room temperature for one day, however, did
not produce the expected benzothiazole 2a, but rather, gave
benzothiazole 6,5 (entry 4, Table 1), the product of ipso substitu-
tion of a methoxy group. Not only was an unexpected product
obtained, but cyclization had occurred in low yield (15%).
Scheme 2 Reagents and conditions: (i) Sn, conc. HCl, ethanol, reflux,
3 h, 50%; (ii) TsCl, py, r.t., 12 h, quant.; (iii) Ac2O, py, r.t., 12 h, quant.;
(iv) 20% aq. K3Fe(CN)6, 1.5 M NaOH, r.t., 24 h, 5–10%.
Under Jacobson reaction conditions, as outlined above,
compounds 7a–c underwent cyclization with substitution of
the ortho methoxy group, to produce benzothiazoles 8a, 8b and
T h i s j o u r n a l i s
©
T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 3 0 3 9 – 3 0 4 3
3 0 3 9

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Table 1 Products of the Jacobson and AIBN-induced cyclization of o-methoxythiobenzamides
Entry
Substrate
Product of Jacobson synthesis (% yield)
Product of AIBN cyclization (% yield)
1
2
3
4
5
6
7
8
9
1b R1 = OMe, R = H
1c R1 = OMe, R = Br
1d R1 = OMe, R = NO2
1a R1 = OMe, R = OMe
7a R1 = OMe, R = NH2
7b R1 = OMe, R = NHTs
7c R1 = OMe, R = NHAc
17 R1 = H, R = NHTs
19 R1 = R = H
2b (80)
2c (45)
12 (84)
a
—
a
a
—
—
b
—
—
—
—
6 (93)
b
8a (98)c
8b (81)
8c (78)
18 (82)
b
b
—
20 (74)
a
—
a Starting material recovered. b Ipso substitution of ortho-OMe occurred in 5–15% yield. Major product = benzamide. c The product was tosylated for
characterization.
8c in yields of 5–10%; the major product being the correspond-
ing benzamide. A similar reaction had been observed when,
in an attempt at detosylation, 7b was treated with saturated
bicarbonate in refluxing methanol. In this instance, the corres-
ponding benzamide and benzothiazole 8b were obtained in 60%
and 5% yield, respectively.4 To our knowledge, this is the only
other case of cyclization of thiobenzamides with ipso substitu-
tion of an aromatic methoxy group that has been reported.
The literature provides two likely mechanisms for the
Jacobson synthesis. That proposed by Metzger and Planck
is illustrated in Scheme 3, Path A, and involves formation of
a thioimidic cation (9) which then attacks the benzene ring
with loss of a proton.8 The second mechanism proposed by
Stevens et al. (Scheme 3, Path B),5 involves reaction of the
thiobenzamide with base to form a thiolate ion (10), which then
undergoes one-electron oxidation to form the thiol radical 11.
Thiol radical 11 then attacks the unoccupied ortho position,
eliminating a hydrogen radical to form the benzothiazole.
It seemed more probable that the radical mechanism (Path B)
was the one operating in the NaOH/potassium ferricyanide
cyclization with ipso substitution of the methoxy group. The
ionic reaction (Path A) would require the unlikely loss of a
methoxy cation.
Intramolecular radical ipso substitution of an alkoxy group
is rare.9–12 Previously reported ipso substitutions of the methoxy
group were found to occur on an activated benzene or pyridine
ring and involved radical attack at the carbon bearing the
methoxy substituent, followed by re-aromatization with loss
of the methoxy radical. In these instances, AIBN was used
as the radical initiator. The use of AIBN in the synthesis of
benzothiazoles from o-halogenothiobenzamides is known to
occur with the radical abstraction of halide groups.13 AIBN-
induced cyclization with elimination of the methoxy group was
thus attempted on the substrates in hand.
Thiobenzamides 1a and 7a–c were treated with 1.1–1.5
molar equivalents of AIBN in refluxing benzene, toluene or
nitrobenzene for 15 minutes to 12 hours. Analysis of the products
revealed that cyclization with elimination of the methoxy
group did occur to produce the corresponding benzothiazoles
(6, 8a, 8b, 8c respectively) in yields of 81–98%. Interestingly,
AIBN-induced cyclization of 2,5-dimethoxythiobenzamide 1b
produced, not 2b, as in the case of the Jacobson reaction, but
benzothiazole 12 (84%) from ipso substitution of the methoxy
group (Table 1, entry 1). This was a clear indication that the
Jacobson and AIBN-induced cyclizations were occurring via
different reaction intermediates.
AIBN-induced cyclization of 17 occurred in good yield, with
replacement of the ortho methoxy group, whereas attempts at a
similar reaction using 19 failed, and only starting material was
recovered (thiobenzamides 17 and 19 were prepared as shown in
Scheme 4 from the known benzamide 13, which is itself readily
available by the Schotten–Baumann reaction of o-anisidine).
Scheme 4 Reagents and conditions: (i) conc. HNO3, AcOH, r.t., 1 day,
60%; (ii) H2, 10% Pd/C, r.t., 15 psi, 1 h, 96%; (iii) TsCl, py, r.t., 12 h,
quant.; (iv) Lawesson’s reagent, toluene, reflux, 2 h; (v) 1.1 equiv. AIBN,
nitrobenzene, reflux, 15 min.
Scheme 3 Proposed mechanisms for the Jacobson synthesis.
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 3 0 3 9 – 3 0 4 3
3 0 4 0

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The AIBN-induced cyclization of ortho-methoxythio-
benzamides clearly requires a benzene ring with high electron
density. When there are two or more electron donating
groups on the primary ring, AIBN-induced cyclization
is accomplished with ipso substitution of the methoxy
group (Table 1, entries 1 and 4–8). When there is only one
electron donating group on the primary ring, or two electron
donating groups and one electron withdrawing group, there is
no reaction (Table 1, entries 2, 3 and 9).
Jacobson cyclization of ortho-methoxythiobenzamides
bearing one or two electron donating groups on the primary ring
occurs with replacement of the ortho hydrogen.3–5 When there
are three electron donating groups on the primary ring, however,
cyclization occurs in very low yield, and with ipso substitution of
the ortho methoxy group (Table 1, entries 3–7).
We suggest that the AIBN-induced cyclization and the
Jacobson reaction of these compounds may be linked, as
shown in Scheme 5. Under Jacobson reaction conditions the
mechanism of cyclization of these arylthiobenzamides seems
to depend on the electron density of the primary aromatic ring,
and on the stability of ions X and Y (Scheme 5). For R1 = R = H
or R1 = OMe, R = H (Table 1, entries 9 and 1, respectively), the
reaction proceeds via cation Y with replacement of ortho H+, and
yields are good. As R becomes more electron withdrawing, i.e. H
to Br to NO2 (Table 1, entries 1–3), the reaction goes more and
more slowly (80, 45 and 0% yield respectively after one day, with
compound 1d undergoing cyclization with loss of H+ in 24%
yield after 7 days). Anion X is stabilized by the delocalization of
negative charge onto the R groups, leading to formation of only
small amounts of X or Y, and these need greater electron density
on the primary ring for effective cyclization.
2,4,5-Trimethoxynitrobenzene (3)
To a cold aqueous solution of 50% nitric acid (100 mL) was
added over a 5 min period, with stirring, 2,4,5-trimethoxy-
benzaldehyde (5.1 g, 26.2 mmol). The resulting mixture was
stirred for a further 30 min with cooling in an ice bath, after
which water was added to form a slurry. The precipitate was
filtered and rinsed with water to yield 3 as a yellow powder (5.0 g,
90%), mp 123–124 °C (acetone) (lit.,14 87–89 °C); mmax/cm−1 3009,
1588, 1277; dH 4.04 (3H, s, OCH3), 4.12 (3H, s, OCH3), 4.13 (3H,
s, OCH3), 6.70 (1H, s, 3-H), 7.73 (1H, s, 6-H); dC 56.8, 56. 9, 57.6,
98.0, 109.4, 131.2, 142.8, 150.8, 155.2.
2,4,5-Trimethoxyaniline (4)
To a solution of 2,4,5-trimethoxynitrobenzene 3 (1.1 g,
5.2 mmol) in methanol (200 mL) was added 5% Pd/C (0.1 g).
The mixture was shaken under hydrogen (Parr apparatus) at a
pressure of 15 psi for 3 h, after which it was filtered through
Celite and concentrated to yield 4 as a purple crystalline solid
(0.95 g, quant.), mp 89.5–90.5 °C (dichloromethane–hexanes)
(lit.,15 92–93 °C); mmax/cm−1 3391, 2841; dH 3.22 (2H, s, N–H),
3.71 (3H, s, OCH3), 3.73 (3H, s, OCH3), 3.74 (3H, s, OCH3), 6.31
(1H, s, 3-H), 7.45 (1H, s, 6-H); dC 57.0, 57.7, 100.7, 102.4, 130.2,
141.3, 141.9, 144.3.
N-(2,4,5-Trimethoxyphenyl)benzamide (5)
To a solution of 2,4,5-trimethoxyaniline 4 (11.5 g, 62.6 mmol)
in dichloromethane (100 mL) was added benzoyl chloride
(8 mL, 68.9 mmol), toluene (30 mL) and pyridine (40 mL). The
mixture was heated at reflux for 5 h, after which time it was
concentrated, extracted with dichloromethane and rinsed with
1 M HCl (200 mL) followed by a saturated aqueous solution of
sodium bicarbonate (100 mL). The organic layer was then dried
(Na2SO4) and concentrated to produce 5 as a purple crystalline
solid (15.3 g, 86%), mp 134–135 °C (dichloromethane–hexanes)
(Found: C, 66.70; H, 6.01; N, 4.92%. Calc. for C16H17NO4: C,
66.89; H, 5.96; N, 4.87%); mmax/cm−1 3201, 1651, 1539, 1209; dH
3.82 (3H, s, OCH3), 3.83 (3H, s, OCH3), 3.84 (3H, s, OCH3), 6.52
(1H, s, 3-H), 7.45 (3H, m, 3,4,5-H), 7.78 (2H, m, 2,6-H), 8.22
(1H, s, 6-H), 8.34 (1H, s, N–H); dC 56.9, 58.0, 57.0, 98.0, 105.8,
121.3, 127.3, 128.8, 129.2, 129.9, 130.5, 132.1, 142.7, 143.3,
145.5, 165.4.
Thionation of benzamides
To a solution of the benzamide (1.0 g) in dry toluene (40 mL)
was added Lawesson’s reagent (0.6 molar equiv.). The mixture
was heated under an atmosphere of nitrogen at reflux for
2 h, after which it was concentrated and purified by column
chromatography or recrystallized from methanol or ethyl
acetate–hexanes to give yellow crystals.
Scheme 5 Likely mechanistic link between AIBN-induced and
Jacobson cyclizations.
When R is an electron donating group, the Jacobson reac-
tion with replacement of H+ does not occur. Here the thiomidic
cation Y which is formed is stabilized and thus made less reactive
by electron donating groups para to the thioamide substituent.
The radical X, which is formed en route from X to Y, may then
be the effective reacting species, leading to substitution of the
ortho methoxy group in low yield. Further studies in this area
are in progress.
N-(2,4,5-Trimethoxyphenyl)thiobenzamide (1a). (72%), mp
104–105 °C (methanol) (Found: C, 63.25; H, 5.78; N, 4.67%.
Calc. for C16H17NO3S: C, 63.34; H, 5.65; N, 4.62%); mmax/cm−1
3359, 1530, 1197; dH 3.91 (3H, s, OCH3), 3.92 (3H, s, OCH3),
3.93 (3H, s, OCH3), 6.64 (1H, s, 3-H), 7.50 (3H, m, 3,4,5-H),
7.88 (2H, m, 2,6-H), 9.07 (1H, s, 6-H), 9.60 (1H, s, N–H); dC
56.8, 57.0, 57.1, 97.3, 107.0, 122.1, 127.1, 129.0, 131.3, 142.3,
144.4, 144.7, 195.0.
N-[2-Methoxy-4-(p-tolylsulfonylamino)phenyl]thiobenzamide
(17). (76%), mp 149–150 °C (ethyl acetate–hexanes) (Found: C,
61.17; H, 4.80; N, 6.79%. Calc. for C21H20N2O3S2: C, 61.14; H,
4.89; N, 6.79%); mmax/cm−1 3361, 1531; dH 2.32 (3H, s, CH3), 3.73
(3H, s, OCH3), 6.63 (1H, m, 5-H), 6.89 (1H, m, 3-H), 7.21 (2H,
d, J 8, tosyl), 7.39 (4H, m, 3,4,5-H and N–H), 7.70 (2H, d,
J 8, tosyl), 7.76 (2H, m, 2,6-H), 8.90 (1H, m, 6-H), 9.54 (1H,
s, N–H); dC 21.5, 56.1, 104.5, 112.4, 121.9, 125.7, 126.7, 128.6,
129.7, 131.0, 135.1, 135.8, 144.0, 150.5, 195.5.
Experimental
General
IR spectra were obtained on a Perkin-Elmer 735B model and
are for KBr discs. NMR spectra (Bruker 200 and 500 MHz)
were determined in CDCl3 solution and the resonances are
reported in ppm downfield from TMS; J values are given in Hz.
Elemental analyses were carried out by MEDAC Ltd., Egham,
Surrey, UK.
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 3 0 3 9 – 3 0 4 3
3 0 4 1

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N-(2-Methoxyphenyl)thiobenzamide (19). (80%), mp 78–79 °C
(ethyl acetate–hexanes) (lit.,5 121–122 °C); dH 3.91 (3H, s, OCH3),
6.99 (2H, m, 3,5-H), 7.21 (1H, m, 4-H), 7.46 (3H, m, 3,4,5-H),
7.83 (2H, m, 2,6-H), 9.13 (1H, d, J 7, 6-H), 9.64 (1H, s, N–H);
dC 56.4, 110.7, 120.8, 121.9, 126.9, 127.2, 129.0, 131.4, 144.5,
150.3, 196.5.
5-Methoxy-2-phenylbenzothiazole (12). (AIBN cyclization:
benzene, 1.5 h, 84%), mp 75–77 °C (ethyl acetate–hexanes)
(Found: C, 69.49; H, 4.78; N, 5.80%. Calc. for C14H11NOS: C,
69.68; H, 4.59; N, 5.80%); mmax/cm−1 1597, 1462, 1256; dH 3.87
(3H, s, OCH3), 7.04 (1H, dd, J 3 and 9, 6-H), 7.45 (3H, m,
3,4,5-H), 7.55 (1H, d, J 2, 4-H), 7.68 (1H, d, J 9, 7-H), 8.05
(2H, m, 2,6-H); dC 56.0, 106.1, 115.9, 122.2, 127.4, 127.8, 129.4,
131.2, 134.2, 155.9, 159.6, 169.6.
General procedure for the Jacobson synthesis
To the thiobenzamide (0.1 g) in ethanol (0.5 mL) was added
1.5 M sodium hydroxide (7 mL). The solution was cooled in
an ice–water bath and freshly prepared (20%) aq. potassium
ferricyanide (2–3 molar equiv.) added. The mixture was stirred
at room temperature for 1 day, the mixture neutralized with 1 M
HCl and extracted with ethyl acetate. The organic layer was
dried (Na2SO4), the solvent removed in vacuo and the residue
purified by column chromatography or recrystallization from
ethanol or ethyl acetate–hexanes to give white needles.
N-(4-Amino-2,5-dimethoxyphenyl)thiobenzamide (7a)
To
a
solution of N-(2,5-dimethoxy-4-nitrophenyl)thio-
benzamide (1d) (2.6 g, 8.6 mmol) in ethanol (40 mL) was added
tin pellets (3 g, 25.3 mmol) and conc. hydrochloric acid (10 mL).
The mixture was heated at reflux for 3 h, cooled to room temper-
ature, poured into water (100 mL) and the pH adjusted to 7 with
10% aq. sodium hydroxide. The resultant yellow precipitate was
collected by filtration, purified by column chromatography and
recrystallized from ethyl acetate–hexanes as fine orange crystals
(1.2 g, 50%), mp 104–106 °C (ethyl acetate–hexanes); mmax/cm−1
3361, 1535, 1266; dH 3.79 (3H, s, OCH3), 3.84 (3H, s, OCH3), 6.35
(1H, s, 3-H), 7.43 (3H, m, 3,4,5-H), 7.80 (2H, m, 2,6-H), 8.89
(1H, s, 6-H), 9.58 (1H, s, N–H); dC 56.7, 56.8, 99.0, 106.3, 119.8,
127.1, 129.0, 131.1, 135.2, 140.0, 144.5, 145.4, 193.5.
General procedure for the AIBN-induced cyclization of
thiobenzamides
To a solution of the thiobenzamide (0.1 g) in benzene, toluene
or nitrobenzene (10 mL) was added AIBN (1.1 molar equiv.)
and the mixture was stirred at reflux for the appropriate time.
The solvent was removed in vacuo, the crude product eluted
through a neutral alumina column and recrystallized from
ethyl acetate–hexanes or ethanol. When nitrobenzene was used
as solvent, this was removed by eluting the reaction mixture
through a silica column with hexanes followed by ethyl acetate.
The ethyl acetate fraction was concentrated and recrystallized
from ethyl acetate–hexanes or ethanol.
Tosylation of 7a and 15
To a solution of the amino compound (200 mg) in dry pyridine
(5 mL) was added toluene-p-sulfonyl chloride (1.2 equiv.). The
resulting mixture was stirred at room temperature for 12 h,
toluene (15 mL) added and the solvent removed in vacuo. The
product was then recrystallized from ethyl acetate–hexanes.
N-[2,5-Dimethoxy-4-(p-tolylsulfonylamino)phenyl]thio-
benzamide (7b). Orange crystals (quant.), mp 145–146 °C (lit.,4
146–149 °C).
5,6-Dimethoxy-2-phenylbenzothiazole (6). (Jacobson syn-
thesis: 15%; AIBN cyclization: nitrobenzene, 15 min, 93%), mp
145–146 °C (ethanol) (lit.,5 142–144 °C); dH 3.91 (3H, s, OCH3),
3.93 (3H, s, OCH3), 7.58 (3H, m, 3,4,5-H), 7.66 (1H, s, 7-H),
7.73 (1H, s, 4-H), 8.07 (2H, m, 2,6-H); dC 56.1, 56.3, 103.7,
105.8, 126.7, 126.9, 129.7, 131.0, 133.6, 148.2, 148.9, 165.2.
N-[2-Methoxy-4-(p-tolylsulfonylamino)phenyl]benzamide
(16). Orange-brown crystals (quant.), mp 172–173 °C (Found:
C, 63.28; H, 4.87; N, 7.07%. Calc. for C21H20N2O4S: C, 63.62;
H, 5.03; N, 7.07%); mmax/cm−1 3427, 1531, 1203; dH 2.37 (3H, s,
CH3), 3.91 (3H, s, OCH3), 6.85 (2H, m, 3,5-H), 7.22 (2H, d, J
8, tosyl), 7.50 (3H, m, 3,4,5-H), 7.69 (2H, d, J 8, tosyl), 7.88
(2H, m, 2,6-H), 8.16 (1H, s, 6-H), 8.51 (1H, s, N–H); dC 21.9,
56.5, 114.9, 118.4,127.4, 127.5,127.7, 127.8, 129.2, 130.0, 132.3,
144.0, 146.4, 166.0.
6-Amino-5-methoxy-2-phenylbenzothiazole (8a). (Jacobson
synthesis: <10%; AIBN cyclization: nitrobenzene, 15 min,
98%), mp 150–151 °C (ethyl acetate–hexanes); mmax/cm−1 3461,
1474, 1327; dH 3.87 (3H, s, OCH3), 7.03 (1H, s, 7-H), 7.39 (4H, m,
3,4,5-H and 4-H), 7.91 (2H, m, 2,6-H); dC 54.7, 102.9, 103.6,
125.8, 127.9, 129.0, 133.1, 134.9, 146.4, 146.9, 164.5.
N-(4-Acetylamino-2,5-dimethoxyphenyl)thiobenzamide
(7c). To a solution of N-(4-amino-2,5-dimethoxyphenyl)thio-
benzamide 7a (0.20 g, 0.7 mmol) in dry pyridine (5 mL) was
added acetic anhydride (0.06 mL, 0.8 mmol). The resulting
mixture was stirred at room temperature for 12 h, toluene
(15 mL) added and the solvent removed in vacuo. The product
was then recrystallized from ethyl acetate–hexanes as yellow
crystals (quant., 0.23 g), mp 174–175 °C (Found: C, 61.58; H,
5.54; N, 8.56%. Calc. for C17H18N2O3S: C, 61.80; H, 5.49; N,
8.47%); mmax/cm−1 3419, 1587, 1542, 1210; dH 2.21 (3H, s, CH3),
3.90 (6H, s, 2 × OCH3), 7.46 (3H, m, 3,4,5-H), 7.86 (3H, m,
2,6-H and N–H), 8.25 (1H, s, 3-H), 9.21 (1H, s, 6-H), 9.75 (1H,
s, N–H); dC 25.4, 56.8, 56.9, 103.3, 104.5, 124.3, 125.7, 127.1,
129.1, 131.4, 140.7, 144.0, 144.5, 168.8, 194.9.
5-Methoxy-2-phenyl-6-(p-tolylsulfonylamino)benzothiazole
(8b). (Jacobson synthesis: <10%; AIBN cyclization: toluene,
12 h, 81%), mp 184–186 °C (lit.,4 184–186 °C).
6-Acetylamino-5-methoxy-2-phenylbenzothiazole (8c).
(Jacobson synthesis: <5%; AIBN cyclization: toluene, 12 h,
78%), mp 169–170 °C (ethyl acetate–hexanes) (Found: C, 64.02;
H, 4.68; N, 9.26%. Calc. for C16H14N2O2S: C, 64.41; H, 4.73; N,
9.39%); mmax/cm−1 3422, 3055, 1690, 1262; dH 2.26 (3H, s, CH3),
3.99 (3H, s, OCH3), 7.47 (3H, m, 3,4,5-H), 7.54 (1H, s, 4-H),
7.96 (1H, s, N–H), 8.04 (2H, m, 2,6-H), 8.97 (1H, s, 7-H); dC
25.4, 56.4, 103.9, 111.6, 127.0, 127.5, 128.0, 129.3, 131.0, 134.1,
148.2, 150.5, 168.7.
6-(p-Tolylsulfonylamino)-2-phenylbenzothiazole (18). (AIBN
cyclization: nitrobenzene, 15 min, 82%), mp 209–210 °C (ethyl
acetate–hexanes) (Found: C, 62.96; H, 4.16; N, 7.30%. Calc.
for C20H16N2O2S2: C, 63.13; H, 4.24; N, 7.36%); mmax/cm−1 3433,
1647; dH 2.40 (3H, s, CH3), 6.74 (1H, s, N–H), 7.25 (3H, m, 7-H
and tosyl), 7.52 (3H, m, 3,4,5-H), 7.70 (2H, d, J 8, tosyl), 7.72
(1H, m, 5-H), 7.80 (1H, d, J 9, 4-H), 8.07 (2H, m, 2,6-H); dC
21.9, 116.6, 120.7, 122.5, 127.7, 127.9, 129.5, 130.2, 131.6, 132.7,
133.8, 135.7, 136.5, 144.4, 155.2, 170.1.
N-(2-Methoxy-4-nitrophenyl)benzamide (14). A solution
of the benzamide 13 (3.0 g, 13.2 mmol) in glacial acetic acid
(65 mL) was cooled in an ice–water bath, with stirring. To this
cold solution was added conc. nitric acid (1.2 mL, 26.8 mmol)
in glacial acetic acid (5 mL) and the mixture stirred at ambient
temperature overnight. The mixture was poured into water
(500 mL) and the white precipitate collected by filtration,
purified by column chromatography and obtained as white
crystals (2.16 g, 60%), mp 147–148 °C (lit.,16 149–150 °C).
3 0 4 2
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 3 0 3 9 – 3 0 4 3

View Article Online
1689; (e) A. Ben-Alloum, S. Bakkas and M. Soufiaoui, Tetrahedron
Lett., 1997, 38, 6395; (f) R. R. Gupta and R. Kumar, Heterocycles,
1984, 22, 87.
3 M. A. Lyon, S. Lawrence, D. J. Williams and Y. A. Jackson, J. Chem
Soc., Perkin Trans. 1, 1998, 437.
4 Y. A. Jackson, M. A. Lyon, N. Townsend, K. Bellabe and
F. Soltanik, J. Chem Soc., Perkin Trans. 1, 1999, 205.
5 M. F. G. Stevens, C. J. McCall, P. Lelieveld, P. Alexander and
A. Richter, J. Med. Chem., 1994, 37, 1689.
6 A. R. Carroll and P. J. Scheuer, J. Org. Chem., 1990, 50, 4426.
7 (a) R. B. Moodie and K. Schofield, Acc. Chem. Res., 1976, 9, 287;
(b) J. G. Traynham, J. Chem. Educ., 1983, 11, 927.
8 J. Metzger and H. Planck, Chim. Ind. (Paris), 1956, 75, 930.
9 W. Zhang and G. Pugh, Tetrahedron Lett., 2001, 42, 5613.
10 H. Ohno, R. Wakayama, S. Maeda, H. Iwasaki, M. Okumura,
C. Iwata, H. Mikamiyama and T. Tanaka, J. Org. Chem., 2003, 68,
5909.
N-(4-Amino-2-methoxyphenyl)benzamide(15).Toasuspension
of the nitrobenzamide 14 (3.0 g, 11.1 mmol) in methanol
(200 mL) was added 10% Pd/C (0.4 g). The mixture was shaken
under hydrogen (Parr apparatus) at a pressure of 15 psi for 1 h,
after which it was filtered through Celite, concentrated in vacuo
and recrystallized from ethyl acetate–hexanes. Compound
15 was obtained as light brown crystals (2.7 g, 99%), mp
112–113 °C; mmax/cm−1 3430, 1265; dH 3.84 (3H, s, OCH3), 6.30
(2H, m, 3,5-H), 7.50 (3H, m, 3,4,5-H), 7.88 (2H, m, 2,6-H),
8.21 (1H, d, J 8, 6-H), 8.25 (1 H, br s, N–H); dC 56.1, 98.8, 107.4,
119.8, 121.8, 127.3, 129.1, 131.8, 135.9, 143.9, 149.9, 165.2.
Acknowledgements
The authors wish to thank Professor Paul Reese (UWI) for
helpful discussions.
11 A. M. Rosa, A. M. Lobo, P. S. Branco and S. Prabhakar, Tetra-
hedron, 1997, 53, 285.
12 S. A. Glover, S. L. Golding, A. Goosen and C. W. McCleland,
J. Chem. Soc., Perkin Trans. 1, 1981, 842.
13 W. R. Bowman, H. Heany and B. M. Jordan, Tetrahedron, 1991, 47,
10119.
References
1 (a) A. R. Carroll and P. J. Schuer, J. Am. Chem. Soc., 1990, 55,
4426; (b) G. P. Gunwardana, S. Kohmoto, S. P. Gunasekera, O. J.
McConnell and F. E. Koehn, J. Am. Chem. Soc., 1988, 110, 4856.
2 (a) H. Kunzek and G. Barnikow, Chem. Ber., 1968, 102,
351; (b) P. Jacobson, Ber. Dtsch. Chem. Ges., 1886, 19, 1067;
(c) W. R. Bowman, H. Heaney and B. M. Jordan, Tetrahedron, 1991,
47, 10119; (d) P. Stanetty and B. Krumpak, J. Org. Chem., 1996, 61,
14 R. Rathore, E. Bosch and J. K. Kochi, Tetrahedron, 1994, 50,
6727.
15 L. A. Levy and L. Fishbein, Tetrahedron Lett., 1969, 43, 3773.
16 T. A. Engler, S. P. Meduna, K. O. Lynch and W. Chai, J. Org. Chem.,
1996, 61, 8598.
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 3 0 3 9 – 3 0 4 3
3 0 4 3