Reactions of some N-(2,5-dimethoxyaryl)thiobenzamides: En route to an analogue of kuanoniamine A

Article abstract of DOI:10.1039/a907633f

The reactions of some N-(2,5-dimethoxyaryl) thiobenzamides were studied. It was found that nitration of 2-aryl-4,7-dimethoxybenzothiazoles produced a mixture of 5- and 6-nitrobenzothiazoles which were distinguished by synthesis of the 2-aryl-4,7-dimethoxy-6-nitrobenzothiaoles by oxidative cyclization of the corresponding nitrothiobenzanilides. The results showed that the cyclization of arylthioanilides was influenced by the nature of the ring substituents.

Full text of DOI:10.1039/a907633f

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Reactions of some N-(2,5-dimethoxyaryl)thiobenzamides:
en route to an analogue of kuanoniamine A
Yvette A. Jackson,*a Michael A. Lyon,a Norman Townsend,a Kettyna Bellabeb and
Fernando Soltanikb
1
a Department of Chemistry, University of the West Indies, Mona, Kingston 7, Jamaica,
West Indies
b School of Natural and Health Sciences, Barry University, 11300 N.E. 2nd Avenue,
Miami Shores, FL 33161-6695, USA
Received (in Cambridge, UK) 21st September 1999, Accepted 9th November 1999
Nitration of 2-aryl-4,7-dimethoxybenzothiazoles 7a–7c produces a mixture of 5- and 6-nitrobenzothiazoles which
were distinguished by synthesis of the 2-aryl-4,7-dimethoxy-6-nitrobenzothiaoles 12a–12c by oxidative cyclization
of the corresponding nitrothiobenzanilides. Reaction of N-[2,5-dimethoxy-4-(p-tolylsulfonylamino)phenyl]thiobenz-
amide 17d with base to give 5-methoxy-2-phenyl-6-(p-tolylsulfonylamino)benzothiazole 18 with apparent
intramolecular replacement of a methoxy group is also described.
Introduction
In our efforts to synthesize analogues 1 of kuanoniamine A 2,1
a group of marine alkaloids which show good pharmaco-
biological activity, we required benzothiazoles of type 3 as
starting material.
Methods for the preparation of 2-substituted benzothiazoles
Scheme 1
include reaction of the acid, alkaline or zinc salts of o-amino-
thiophenols with carboxylic acids and their derivatives,2,3
cyclization of N-aryl-thiocarbamates,4 -thioamides,4,5 and -thio-
ureas,6 and base-catalysed intramolecular displacement of the
halogen of 2-halogenothioanilides.5
The mechanistic pathway proposed for the Jacobson reaction
is shown in Scheme 2.8 The ease of cyclization of arylthio-
anilides is influenced by the nature of the ring substituents, and
reaction with p-nitrothioacetanilide 8 yields 95% desulfuriz-
ation to p-nitroacetanilide 9 by attack of hydroxide on the thio-
carbonyl carbon, with subsequent loss of H2S (Scheme 3).3c The
p-nitro group clearly inhibits the thiol-enolization step (first
step) of the Jacobson reaction, and thus ring-closure is affected.
Retrosynthetic analysis shows that our desired compound 1
is available from the corresponding 6-nitrobenzothiazole
(Scheme 4). Formation of 6-nitrobenzothiazoles by the Jacob-
son reaction, however, could prove to be challenging, and we
explored nitration of the benzothiazole 7a using 1.1 molar
equivalents of conc. HNO3 in cold glacial acetic acid (Scheme
5). This produced a 6:5 mixture of two mononitrobenzo-
thiazoles in very good yield, and which were indistinguishable
by spectroscopic data.
The Jacobson method4 of synthesis of benzothiazoles
involves oxidative cyclization of an arylthioanilide on an
unsubstituted ortho-position, in the presence of potassium
ferricyanide in basic medium. We chose this method for syn-
thesis of our dimethoxybenzothiazoles as we could prepare the
required arylthioanilides in reasonable yields.
Results and discussion
Treatment of 2,5-dimethoxyaniline 4 with the appropriate aroyl
chloride produced the corresponding benzanilides 5a,1 5b and
5c, which were then converted to the thiobenzanilides 6a,1 6b
and 6c, using Lawesson’s reagent.7 The thiobenzanilide was
then dissolved in 1.5 M aq. NaOH and treated with potas-
sium ferricyanide [K3Fe(CN)6] to produce the corresponding
dimethoxybenzothiazoles in good yield (Scheme 1).
The literature shows that [(arylamino)methylene]-2,2-
dimethyl-1,3-dioxane-4,6-diones (e.g., 14) were regioselectively
J. Chem. Soc., Perkin Trans. 1, 2000, 205–210
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205

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Scheme 2
Scheme 5
Scheme 3
Scheme 6
Scheme 4
brominated and nitrated to yield the 4-substituted product,
e.g. 15a and 15b, respectively (Scheme 6).9 In a previous set of
experiments we also noted the bromination of compound 5a to
give N-(4-bromo-2,5-dimethoxyphenyl)benzamide as the sole
product.1 We therefore proceeded with nitration of 5a, and
obtained one product, N-(2,5-dimethoxy-4-nitrophenyl)benz-
amide, 16a, evidenced by the two singlets in the PMR spectrum
at δ 7.60 and 8.60 corresponding to H-3 and H-6, respectively.
Treatment of 16a with 0.6 molar equivalents of Lawesson’s
reagent then produced 17a in 79% yield (Scheme 7).
Since there are two electron-donating methoxy groups on the
thiobenzanilide 17a, we envisaged that the Jacobson reaction
had a better chance at success than with 4Ј-nitrothiobenz-
anilide. We therefore proceeded with the cyclization reaction,
and obtained the desired 4,7-dimethoxy-6-nitrobenzothiazole
12a in 24% yield after 7 days. Unchanged starting material
(25%), and the corresponding benzanilide (31%) were also
recovered from the reaction mixture. Jacobson reaction of
compounds 17b and 17c also produced the corresponding
benzothiazoles 12b and 12c after 7–8 days reaction time and
Scheme 7
in 35% and 13% yield respectively. We have thus achieved
Jacobson cyclization of nitrothiobenzanilides.
Comparison of 12a with the products of nitration of the
benzothiazole 7a revealed that, contrary to expectation, the
major product of this nitration reaction is the 5-nitroanalogue
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13a. The 6-substituted compound is reported to be the major
product of electrophilic aromatic substitution of benzothi-
azoles,3b and, on investigation of mononitration of simple benzo-
thiazoles, the pattern which emerged was 6-NO2 > 4-/7- > 5-
NO2.10
Bromination of 7a with 1.1 molar equivalents of Br2 in
CHCl3–CCl4 (1:1) yielded a 9:2 mixture of 6- and 5-bromo-
4,7-dimethoxy-2-phenylbenzothiazole 12d and 13d, respect-
ively. (Once again the compounds were distinguished by
synthesis of the 6-bromo-4,7-dimethoxybenzothiazole via the
4-bromobenzanilide.1)
prisingly, had only one methoxy group, and had no C᎐S peak
᎐
in the 13C NMR spectrum. This product (5%) is 5-methoxy-2-
phenyl-6-(tosylamino)benzothiazole 18. Hydroxide attack at
the thiocarbonyl carbon of 17d generated a nucleophile which
attacked the phenyl ring with replacement of a methoxy group.
Nucleophilic substitutions on aromatic rings demand the pres-
ence of strong deactivating groups. If the tosyl group were act-
ing in that capacity here, then substitution of methoxy by SϪ
would be expected to occur at position 5. The product of this
reaction, however, would be a highly strained 6-membered ring,
which is most unlikely to be formed. Substitution then occurred
at position 2, resulting in compound 18. 2-Halogenothio-
anilides are known to react with base to produce the corre-
sponding benzothiazoles with replacement of halogen.5 We
have, however, encountered no examples of similar intra-
molecular replacement of methoxy groups.
For the 4,7-dimethoxybenzothiazole 7a then, bromination
proceeds as expected, giving the 6-bromo compound 12d as the
major product, but nitration gives a reversal in yields, with
the 5-nitro compound 13a being the major product. Nitration
of compounds 7b and 7c produced similar results – a 4:3
and 1.1:1 ratio, respectively, with the 5-nitro analogues 13b
and 13c being the major product in each case. A look at the
3-dimensional models of the benzothiazole 7a, the 5- and
6-bromobenzothiazoles 13d and 12d, and the 5- and 6-nitro-
benzothiazoles 13a and 12a indicate that this may be due to
steric considerations. The angle made by 7-OMe–C-(7)–C-(7a)
in the starting material 7a is bigger than that made by 4-OMe–
C(4)–C(3a). The sulfur atom is larger than the nitrogen atom,
causing the 7-methoxy group to be projected toward the 6-
position, thus hindering the approach of the incoming larger
Experimental
General
All mp are uncorrected. Organic solutions were dried over
MgSO4 unless stated otherwise. IR spectra were obtained on a
Perkin-Elmer 735B model or a Perkin-Elmer 1600 FT-IR spec-
trometer and are for KBr discs. NMR spectra (Bruker 200 MHz
spectrometer) were determined in CDCl3 solution and the
resonances are reported in δ-units downfield from TMS;
J-Values are given in Hz. Elemental analyses were carried out
by MEDAC Ltd., Egham, Surrey, UK.
ϩ
NO2 (cf. Brϩ), and resulting in more 5-nitro compound than
expected. Comparison of the distance between the substituent
and the adjacent methoxy group in these 5- and 6-substituted
benzothiazoles (12a, 13a, 12d, 13d) showed this distance to be
smallest in the 6-nitro compound 12a.
4Ј-Chloro-N-(2,5-dimethoxyphenyl)benzamide 5b
To a solution of 2,5-dimethoxyaniline 4 (2.0 g, 13.2 mmol) in a
mixture of dry toluene (16 mL) and pyridine (12 mL) was
added 4-chlorobenzoyl chloride (1.6 mL, 12.26 mmol). The
solution was heated on an oil-bath at 80–90 ЊC for 1 h. The
mixture was cooled to room temperature and poured into water
(200 mL). The two layers were separated and the aqueous layer
extracted with toluene (3 × 20 mL). The combined toluene
solutions were washed with 1 M HCl (3 × 10 mL) followed by
brine (3 × 10 mL), dried (MgSO4), and the solvent removed
in vacuo. Recrystallization from MeOH gave 5b as an off-white
solid (3.45 g, 91%), mp 90–93 ЊC (Found: C, 61.94; H, 4.97; N,
With the 6-nitrobenzothiazole 12a in hand, we were able to
progress to the desired compound 1 by the pathway referred to
in Scheme 4, albeit in low yield. Reduction of 12a by hydrogen
and catalyst produced the amino compound 12e in 62% yield.
The pyridine ring was then formed by Doebner–Miller syn-
thesis11 using methyl vinyl ketone (11%), and the resultant
quinoline 11 was treated with ammonium cerium() nitrate
(CAN) to produce quinolinequinone 10 (62%). This compound
was identical in all respects to the product of Diels–Alder reac-
tion of 6-bromo-4,7-dioxo-2-phenyl-4,7-dihydrobenzothiazole
with crotonaldehyde dimethylhydrazone, and from which we
have previously synthesized the desired 1.1
Continuing our studies on reaction of the thioanilides we
treated 2,5-dimethoxy-4-nitrothiobenzanilide 17a, with satur-
ated bicarbonate in refluxing methanol for 24 h and obtained
only quantitative conversion to the corresponding amine
(Scheme 8).12 In a similar reaction with the 4-tosylamino-
4.68. Calc. for C15H14ClNO3: C, 61.84; H, 4.85; N, 4.81%); νmax
/
cmϪ1 3340, 1663; δH 3.81 and 3.88 (each 3H, s, OCH3), 6.62 (1H,
dd, J 3.4 and 9, 4-H), 6.82 (1H, d, J 9, 3-H), 7.46 (2H, d, J 9, 2Ј-,
6Ј-H), 7.83 (2H, d, J 9, 3Ј-, 5Ј-H), 8.23 (1H, d, J 3.4, 6-H), 8.50
(1H, br s, NH); δC 55.71, 56.18, 105.86, 108.86, 110.55, 128.36,
128.41, 128.95, 142.22, 153.76, 164.02.
N-(2,5-Dimethoxyphenyl)-4Ј-methylbenzamide 5c
To a solution of p-toluic acid (3.0 g, 22.06 mmol) in methylene
dichloride (30 mL) were added pyridine (5.2 mL, 64.3 mmol)
and thionyl dichloride (1.8 mL, 24 mmol) and the mixture
stirred at room temperature for 90 min.13 After this time, pyr-
idine (13 mL) and toluene (10 mL) were added to the mixture,
followed by 2,5-dimethoxyaniline 4 (3.0 g, 22.06 mmol), and the
whole heated at reflux overnight. The reaction mixture was then
concentrated in vacuo and the residue was triturated with hex-
ane to give 5c as a tan-coloured solid (4.0 g, 67%), mp 62–65 ЊC
(from MeOH) (Found: C, 70.64; H, 6.27; N, 5.11. Calc. for
C16H17NO3: C, 70.82; H, 6.32; N, 5.16%); νmax/cmϪ1 3400, 1653;
δH 2.45 (3H, s, CH3), 3.80 and 3.88 (each 3H, s, OCH3), 6.60
(1H, dd, J 3.5 and 9, 4-H), 6.83 (1H, d, J 9, 3-H), 7.28 (2H, d,
J 9, 3Ј-, 5Ј-H), 7.79 (2H, d, J 9, 2Ј-, 6Ј-H), 8.28 (1H, d, J 3.5,
6-H), 8.58 (1H, br s, NH); δC 21.4, 55.69, 56.2, 105.67, 108.59,
110.57, 126.91, 128.41, 129.34, 132.19, 142.21, 142.27, 153.8,
165.10.
Scheme 8
thiobenzanilide 17d, desulfurization to the corresponding benz-
anilide 16e was the dominant reaction (60%). We recovered
some starting material (25%) and another product which, sur-
Nitration of benzamides 5
To a cold solution of a benzamide (1.0 g) in glacial acetic acid
J. Chem. Soc., Perkin Trans. 1, 2000, 205–210
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(10 mL) was added a solution of conc. nitric acid (69%) (1.1
molar equiv.) in glacial acetic acid (5 mL) and the resulting
mixture stirred at ambient temperature for 1.5 h. The mixture
was then poured into water (50 mL) and the precipitate which
formed was collected by filtration and washed throughly with
cold water.
9.92 (1H, br s, NH); δC 56.72, 57.16, 105.08, 107.36, 126.58,
128.82, 131.61, 134.44, 141.82, 143.73, 149.0, 197.4.
4Ј-Chloro-N-(2,5-dimethoxy-4-nitrophenyl)thiobenzamide
17b. Reaction time: 12 h (993 mg, 98%), mp 189–191 ЊC
(Found: C, 50.94; H, 3.83; N, 7.64. Calc. for C15H13ClN2O4S:
C, 51.07; H, 3.71; N, 7.94%); νmax/cmϪ1 3315, 1592, 1543,
1313; δH 3.98 and 3.99 (each 3H, s, OCH3), 7.43 (2H, d, J 8,
3Ј-, 5Ј-H), 7.62 (1H, s, 3-H), 7.78 (2H, d, J 8, 2Ј-, 6Ј-H), 9.59
(1H, s, 6-H) and 9.86 (1H, br s, NH); δC 56.78, 57.18, 105.16,
107.43, 127.94, 129.08, 134.25, 138.01, 141.81, 141.97, 148.98,
195.69.
N-(2,5-Dimethoxy-4-nitrophenyl)benzamide 16a. Yellow-
green crystals (1.05 g, 89%), mp 169–171 ЊC (from CH2Cl2–
hexane) (Found: C, 59.39; H, 4.62; N, 9.20. Calc. for C15H14-
N2O5: C, 59.58; H, 4.67; N, 9.27%); νmax/cmϪ1 3415, 1680; δH 4.0
and 4.05 (each 3H, s, OCH3), 7.55 (3H, m, 3Ј-, 4Ј-, 5Ј-H), 7.60
(1H, s, 3-H), 7.91 (2H, m, 2Ј-, 6Ј-H), 8.60 (1H, s, 6-H), 8.90
(1H, br s, NH); δC 56.60, 56.97, 104.58, 107.46, 127.11, 129.02,
132.58, 134.15, 140.86, 149.81, 165.62.
N-(2,5-Dimethoxy-4-nitrophenyl)-4Ј-methylthiobenzamide
17c. Reaction time: 12 h, yellow solid (895 mg, 85%), mp 167–
170 ЊC (Found: C, 57.78; H, 4.98; N, 8.20. Calc. for C16H16-
N2O4S: C, 57.82; H, 4.85; N, 8.43%); νmax/cmϪ1 3363, 1589,
1524; δH 2.41 (3H, s, CH3), 3.97 (6H, s, 2 × OCH3), 7.26 (2H, d,
J 8, 3Ј-, 5Ј-H), 7.61 (1H, s, 3-H), 7.75 (2H, d, J 8, 2Ј-, 6Ј-H), 9.65
(1H, s, 6-H) and 9.89 (1H, br s, NH); δC 21.36, 56.74, 57.17,
105.16, 107.37, 126.62, 129.45, 133.33, 134.61, 141.06, 141.83,
142.44, 149.06, 197.20.
4Ј-Chloro-N-(2,5-dimethoxy-4-nitrophenyl)benzamide
16b.
Yellow solid (854 mg, 81%), mp 188–192 ЊC (from acetone–
MeOH) (Found: C, 53.33; H, 3.89; N, 8.25. Calc. for C15H13-
ClN2O5: C, 53.50; H, 3.89; N, 8.32%); νmax/cmϪ1 3405, 1686,
1594, 1539; δH 3.98 and 4.01 (each 3H, s, OCH3), 7.51 (2H, d,
J 8, 3Ј-, 5Ј-H), 7.60 (1H, s, 3-H), 7.82 (2H, d, J 8, 2Ј-, 6Ј-H), 8.56
(1H, s, 6-H) and 8.72 (1H, br s, NH); δC 56.69, 57.03, 104.69,
107.54, 128.52, 129.35, 132.47, 139.02, 140.77, 149.62, 164.56.
Preparation of benzothiazoles 7b,c, 12a–c
The thiobenzamide (2.0 g) was dissolved in 1.5 M aq. sodium
hydroxide (150 mL) and the solution cooled in an ice–water-
bath. To this was added freshly prepared (20%) aq. potassium
ferricyanide (15 mL gϪ1 of thiobenzamide). The mixture was
stirred at room temperature for the appropriate time and the
benzothiazole was collected by filtration, washed with cold
water and recrystallized.
N-(2,5-Dimethoxy-4-nitrophenyl)-4Ј-methylbenzamide
16c.
Pale yellow solid (992 mg, 85%), mp 163–165 ЊC (from MeOH)
(Found: C, 60.72; H, 5.06; N, 8.62. Calc. for C16H16N2O5: C,
60.74; H, 5.10; N, 8.86%); νmax/cmϪ1 3400, 1602, 1529; δH 2.45
(3H, s, CH3), 3.98 and 4.02 (each 3H, s, OCH3), 7.34 (2H, d, J 8,
3Ј-, 5Ј-H), 7.61 (1H, s, 3-H), 7.80 (2H, d, J 8, 2Ј-, 6Ј-H), 8.62
(1H, s, 6-H) and 8.77 (1H, br s, NH); δC 21.56, 56.61, 57.00,
104.47, 107.49, 127.13, 129.69, 131.24, 134.31, 140.74, 143.33,
149.97, 165.60.
2-(4Ј-Chlorophenyl)-4,7-dimethoxybenzothiazole 7b. Reaction
time: 24 h. White needles (1.7 g, 85%), mp 182–184 ЊC (from
MeOH) (Found: C, 58.64; H, 3.91; N, 4.42. Calc. for C15H12-
ClNO2S: C, 58.92; H, 3.96; N, 4.58%); νmax/cmϪ1 1495, 1445,
1267; δH 3.92 and 4.05 (each 3H, s, OCH3), 6.72 (1H, d, J 8,
5- or 6-H), 6.82 (1H, d, J 8, 6- or 5-H), 7.42 (2H, d, J 10, 2Ј-,
6Ј-H), 8.06 (2H, d, J 10, 3Ј-, 5Ј-H); δC 56.05, 56.34, 105.51,
107.14, 125.5, 128.8, 129.1, 132.01, 136.62, 141.75, 145.25,
149.04, 166.23.
Thionation of benzamides 5b,c, 16a–c
To a solution of the benzamide (1.0 g) in dry toluene (40 mL)
was added Lawesson’s reagent (0.6 mol. equiv.). The mixture
was heated under an atmosphere of nitrogen at 80 ЊC for 2 h,
after which time it was cooled and filtered. The solvent was
evaporated in vacuo and the thiobenzamide product (yellow
crystalline solid) was purified by recrystallization from ethanol
or by column chromatography (CH2Cl2–hexane 3:2).
4,7-Dimethoxy-2-(4Ј-methylphenyl)benzothiazole 7c. Reac-
tion time: 24 h. White needles (1.60 g, 80%), mp 151–152.5 ЊC
(from CH2Cl2–MeOH) (Found: C, 67.37; H, 5.29; N, 4.89. Calc.
for C16H15NO2S: C, 67.34; H, 5.30; N, 4.91%); νmax/cmϪ1 1503,
1495, 1267; δH 2.50 (3H, s, CH3), 4.0 and 4.10 (each 3H, s,
OCH3), 6.69 (1H, d, J 8, 5- or 6-H), 6.81 (1H, d, J 8, 6- or 5-H),
7.28 (2H, d, J 8, 3Ј-, 5Ј-H), 8.03 (2H, d, J 8, 2Ј-, 6Ј-H); δC 21.48,
56.01, 56.3, 105.14, 106.97, 127.59, 129.53, 130.85, 141.19,
147.91, 148.06, 167.75.
4Ј-Chloro-N-(2,5-dimethoxyphenyl)thiobenzamide 6b. (0.89 g,
85%), mp 120–123 ЊC (Found: C, 58.36; H, 4.61; N, 4.46. Calc.
for C15H14ClNO2S: C, 58.62; H, 4.60; N, 4.56%); νmax/cmϪ1
3350, 1605, 1235; δH 3.79 and 3.88 (each 3H, s, OCH3), 6.75
(1H, dd, J 3.8 and 9, 4-H), 6.88 (1H, d, J 9, 3-H), 7.39 (2H, d,
J 9, 2Ј-, 6Ј-H), 7.79 (2H, d, J 9, 3Ј-, 5Ј-H), 9.0 (1H, br s, 6-H),
9.68 (1H, br s, NH); δC 55.79, 56.31, 106.85, 110.84, 111.36,
127.98, 128.7, 128.97, 137.16, 143.63, 152.97, 193.99.
4,7-Dimethoxy-6-nitro-2-phenylbenzothiazole 12a. Reaction
time: 7 days. Bright yellow crystals (470 mg, 24%), mp 186–
187 ЊC (from CH2Cl2–MeOH) (Found: C, 56.80; H, 3.82; N,
N-(2,5-Dimethoxyphenyl)-4Ј-methylthiobenzamide 6c. (670
mg, 63%), mp 115–117 ЊC (Found: C, 66.97; H, 5.99; N, 4.78.
Calc. for C16H17NO2S: C, 66.88; H, 5.97; N, 4.88%); νmax/cmϪ1
3342, 1534, 1233; δH 2.38 (3H, s, CH3), 3.80 and 3.86 (each 3H,
s, OCH3), 6.72 (1H, dd, J 3 and 9, 4-H), 6.87 (1H, d, J 9, 3-H),
7.22 (2H, d, J 8, 3Ј-, 5Ј-H), 7.75 (2H, d, J 8, 2Ј-, 6Ј-H), 9.08 (1H,
br s, 6-H), 9.70 (1H, br s, NH); δC 21.39, 55.76, 56.31, 106.96,
110.85, 111.06, 126.61, 127.45, 128.55, 128.68, 141.49, 143.69,
152.96, 195.54.
8.79. Calc. for C15H12N2O4S: C, 56.95; H, 3.83; N, 8.86%); νmax
/
cmϪ1 1518, 1472, 1354; δH 4.10 and 4.15 (each 3H, s, OCH3),
7.53 (4H, m, 5-, 3Ј-, 4Ј-, 5Ј-H), 8.13 (2H, m, 2Ј-, 6Ј-H); δC 56.60,
61.64, 104.07, 127.93, 129.15, 131.98, 132.59, 143.19, 148.31,
149.16, 172.11.
2-(4Ј-Chlorophenyl)-4,7-dimethoxy-6-nitrobenzothiazole 12b.
Reaction time: 8 days. Bright yellow crystals (691 mg, 35%), mp
229–230.5 ЊC (from EtOH) (Found: C, 51.17; H, 3.14, N, 7.89.
N-(2,5-Dimethoxy-4-nitrophenyl)thiobenzamide 17a. Reac-
tion time: 12 h (830 mg, 79%), mp 162–164 ЊC (from CH2Cl2–
MeOH) (Found: C, 56.64; H, 4.43; N, 8.77. Calc. for
C15H14N2O4S: C, 56.59; H, 4.44; N, 8.81%); νmax/cmϪ1 3357,
1542, 1223; δH 4.0 (6H, s, 2 × OCH3), 7.49 (3H, m, 3Ј-, 4Ј-, 5Ј-
H), 7.60 (1H, s, 3-H), 7.84 (2H, m, 2Ј-, 6Ј-H), 9.65 (1H, s, 6-H),
Calc. for C15H11ClN2O4S: C, 51.36; H, 3.16; N, 7.98%); νmax
/
cmϪ1 1579, 1526, 1336; δH 4.10 and 4.12 (each 3H, s, OCH3),
7.46 (2H, d, J 8, 3Ј-, 5Ј-H), 7.48 (1H, s, 5-H), 8.04 (2H, d, J 8,
2Ј-, 6Ј-H); δC 56.83, 61.89, 104.18, 129.08, 129.46, 131.06,
138.23, 143.13, 148.18, 149.19, 170.60.
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4,7-Dimethoxy-2-(4Ј-methylphenyl)-6-nitrobenzothiazole 12c.
Reaction time: 7 days. Pale yellow crystals (260 mg, 13%), mp
223–226 ЊC (from MeOH) (Found: C, 57.20; H, 4.19; N, 8.28.
Calc. for C16H14N2O4Sؒ1/4H2O: C, 57.39; H, 4.36; N, 8.36%);
νmax/cmϪ1 1582, 1531, 1481, 1339; δH 2.44 (3H, s, CH3), 4.10 and
4.11 (each 3H, s, OCH3), 7.31 (2H, d, J 8, 3Ј-, 5Ј-H), 7.47 (1H, s,
5-H), 8.02 (2H, d, J 8, 2Ј-, 6Ј-H); δC 21.59, 56.78, 61.80, 104.02,
127.87, 129.84, 142.72, 143.21, 148.99.
0.86 mmol), FeCl3 (370 mg, 1.38 mmol) and ZnCl2 (50 mg, 0.36
mmol) were stirred in 95% ethanol (20 mL). To this mixture was
added ethanolic conc. HCl (25%; 20 mL). The resulting solu-
tion was warmed to 60–65 ЊC and methyl vinyl ketone (1 mL, 12
mmol) was added slowly over 2 h. After this time, the mixture
was heated at reflux for a further 5 h and then stirred at room
temperature for 10 h. The solvent was removed in vacuo, and
the residue was basified with 1.5 M aq. NaOH (16 mL). The
mixture was extracted exhaustively with ethyl acetate, dried
(MgSO4), and the solvent removed in vacuo. The residue was
purified by column chromatography (SiO2; CH2Cl2) to give 11
General method for nitration of benzothiazoles 7
A solution of the benzothiazole (2.0 g) in glacial acetic acid
(50 mL) was cooled in an ice–water-bath, with stirring. To this
cold solution was added conc. nitric acid (69%) (1.1 mol
equiv.) in glacial acetic acid (2.5 mL) and the mixture was
stirred at ambient temperature for 1 h. The mixture was then
poured into water (300 mL) and the precipitate which formed
was collected by filtration, washed with water, and oven-dried
(temp. ~80 ЊC). Column chromatography (dichloromethane–
hexane 1.5:2) yielded the 5- and 6-nitrobenzothiazoles as yellow
crystalline solids.
(i) Reaction with 7a yielded 4,7-dimethoxy-6-nitro-2-phenyl-
benzothiazole 12a (1.01 g, 43%), and 4,7-dimethoxy-5-nitro-2-
phenylbenzothiazole 13a (1.18 g, 51%), mp 162–163 ЊC (from
CH2Cl2–MeOH) (Found: C, 56.57; H, 3.87; N, 8.84. Calc. for
C15H12N2O4S: C, 56.95; H, 3.82; N, 8.86%); νmax/cmϪ1 1580,
1529, 1479; δH 4.0 and 4.39 (each 3H, s, OCH3), 7.25 (1H, s,
6-H), 7.53 (3H, m, 3Ј-, 4Ј-, 5Ј-H), 8.12 (2H, m, 2Ј-, 6Ј-H);
δC 56.54, 63.33, 102.02, 127.67, 129.15, 131.69, 132.75, 140.57,
148.45.
(ii) Reaction with 7b yielded 2-(4Ј-chlorophenyl)-4,7-
dimethoxy-6-nitrobenzothiazole 12b (740 mg, 32%), and 2-(4Ј-
chlorophenyl)-4,7-dimethoxy-5-nitrobenzothiazole 13b (1.05 g,
46%), mp 248–249 ЊC (from MeOH) (Found: C, 51.11; H, 3.13,
N, 7.89. Calc. for C15H11ClN2O4S: C, 51.36; H, 3.16; N, 7.98%);
νmax/cmϪ1 1530, 1338, 1129, 1090; δH 4.03 and 4.38 (each 3H, s,
OCH3), 7.27 (1H, s, 6-H), 7.49 (2H, d, J 8, 3Ј-, 5Ј-H), 8.05 (2H,
d, J 8, 2Ј-, 6Ј-H); δC 56.60, 63.37, 101.25, 128.86, 129.47, 130.94,
131.29, 137.89, 148.52.
(iii) Reaction with 7c yielded 4,7-dimethoxy-2-(4Ј-methyl-
phenyl)-6-nitrobenzothiazole 12c (864 mg, 37%), and 4,7-
dimethoxy-2-(4Ј-methylphenyl)-5-nitrobenzothiazole 13c (932
mg, 40%), mp 172–174 ЊC (from MeOH) (Found: C, 58.47; H,
4.33; N, 8.48. Calc. for C16H14N2O4S: C, 58.17; H, 4.27; N,
8.48%); νmax/cmϪ1 1581, 1522, 1513, 1356, 1330; δH 2.44 (3H,
s, CH3), 4.01 and 4.35 (each 3H, s, OCH3), 7.27 (3H, m, 6-,
3Ј-, 5Ј-H), 7.99 (2H, d, J 8, 2Ј-, 6Ј-H); δC 21.52, 56.44, 63.18,
100.61, 127.51, 129.78, 130.06, 140.50, 142.24, 142.57, 148.20,
148.37.
as a green solid (32 mg, 11%), mp 167–169 ЊC (MeOH): νmax
/
cmϪ1 1679, 1578, 1433; δH 3.01 (3H, s, CH3), 4.26 and 4.39 (each
3H, s, OCH3), 7.17 (1H, d, J 4, 7-H), 7.54 (3H, m, 3Ј-, 4Ј-, 5Ј-H),
8.20 (2H, m, 2Ј-, 6Ј-H) and 8.76 (1H, d, J 4, 6-H); δC 24.13,
61.43, 62.86, 122.11, 123.03, 127.97, 129.05, 131.49, 133.34,
145.44, 146.14, 149.28.
This compound was then oxidized using CAN to give the
known quinone 10.
8-Methyl-2-phenylthiazolo[4,5-g]quinoline-4,9-dione 10
4,9-Dimethoxy-8-methyl-2-phenylthiazolo[4,5-g]quinoline 11
(25 mg, 0.08 mmol) was stirred in acetonitrile (2.5 mL) on an
ice–water-bath. To this cold solution was added, over 5 min, a
cold solution of CAN (82 mg, 0.15 mmol) in 2.5 mL of H2O.
The mixture was then stirred at room temperature for 30 min,
diluted with water (5 mL), and the resulting solid was collected
by filtration, washed with water, and dried at the pump. The
solid was chromatographed (methylene dichloride) to yield 10
as a yellow powder (14 mg, 62%), mp 277 ЊC (decomp.).1
N-(4-Amino-2,5-dimethoxyphenyl)benzamide 16d
To a solution of N-(2,5-dimethoxy-4-nitrophenyl)benzamide
16a (10 g, 33 mmol) in ethanol (200 mL) were added finely
divided tin (16 g, 132 mmol) and conc. hydrochloric acid (50
mL). The mixture was heated at reflux for 3 h, cooled to room
temperature, poured into water (200 mL) and the pH adjusted
to 7 with 10% aq. sodium hydroxide. The resultant cream pre-
cipitate was collected by filtration, washed with cold water, and
dried in the oven. Recrystallization from CH2Cl2–hexane pro-
duced 16d as tan coloured crystals (7.79 g, 89%), mp 167–
169 ЊC (Found: C, 66.11; H, 5.96; N, 10.25. Calc. for C15H16-
N2O3: C, 66.15; H, 5.93; N, 10.29%); νmax/cmϪ1 3436, 3357,
1646; δH 3.81 (5H, s, OCH3 and 4-NH2), 3.88 (3H, s, OCH3),
6.38 (1H, s, 3-H), 7.49 (3H, m, 3Ј-, 4Ј-, 5Ј-H), 7.85 (2H, m, 2Ј-,
6Ј-H), 8.18 (1H, s, 6-H), 8.83 (1H, br s, NH); δC 56.21, 56.31,
99.17, 104.73, 118.8, 128.88, 129.68, 131.43, 132.19, 135.42,
140.76, 142.88, 164.65.
6-Amino-4,7-dimethoxy-2-phenylbenzothiazole 12e
N-[2,5-Dimethoxy-4-(p-tolylsulfonylamino)phenyl]benzamide
4,7-Dimethoxy-6-nitro-2-phenylbenzothiazole 12a (1.68 g, 5.3
mmol) was stirred in methanol (210 mL) containing pH 7 buffer
solution (55 mL). To this suspension was added 10% Pd/C (187
mg) with stirring and the mixture was stirred at room temper-
ature under hydrogen gas (15 psi) for 2.5 h. The mixture was
then filtered through Celite to remove the catalyst, and the sol-
vent was removed in vacuo. The residue was diluted with H2O
(140 mL), extracted with CHCl3 (3 × 70 mL), the extract was
dried, and the solvent removed to give 12e as a green solid
(948 mg, 62%), mp 100–102 ЊC (from MeOH) (Found: C, 63.22;
H, 4.98; N, 9.69. Calc. for C15H14N2O2S: C, 62.92; H, 4.93;
N, 9.79%); νmax/cmϪ1 3464, 3366, 1611, 1497; δH 3.85 and 3.91
(each 3H, s, OCH3), 6.33 (1H, s, 5-H), 7.39 (3H, m, 3Ј-, 4Ј-, 5Ј-
H), 8.04 (2H, m, 2Ј-, 6Ј-H); δC 55.93, 58.59, 97.88, 126.92,
128.58, 129.89, 132.91, 133.48, 137.54, 150.04, 162.23.
16e
N-(4-Amino-2,5-dimethoxyphenyl)benzamide 16d (853 mg,
3.13 mmol) was stirred in dry pyridine (10 mL). To this solution
was added toluene-p-sulfonyl chloride (84 mg, 4.69 mmol) and
the resulting mixture was stirred at room temperature for 24 h.
The mixture was poured into water (50 mL), and then extracted
with ethyl acetate (3 × 50 mL). The extract was washed succes-
sively with 2 M HCl (3 × 50 mL), brine (3 × 50 mL) and water
(3 × 50 mL), dried and evaporated. Compound 16e was
obtained as a cream coloured solid (1.2 g, 90%), mp 169–171 ЊC
(from MeOH–hexane) (Found: C, 62.10; H, 5.24; N, 6.58. Calc
for C22H22N2O5S: C, 61.95; H, 5.20; N, 6.57%); νmax/cmϪ1 3443,
3259, 1668; δH 2.40 (3H, s, CH3), 3.60 and 3.93 (each 3H, s,
OCH3), 6.90 (1H, s, 3-H), 7.20 (3H, m, 3Ј-, 4Ј-, 5Ј-H), 7.53 (4H,
m, 2Ј-, 6Ј-H and 2Љ-, 6Љ-H), 7.76 (2H, m, 3Љ-, 5Љ-H), 8.18 (1H, s,
6-H) and 8.53 (1H, br s, NH); δC 21.48, 56.16, 56.52, 103.65,
105.74, 120.65, 125.35, 126.90, 127.17, 128.62, 129.32, 131.91,
134.92, 135.95, 142.11, 143.69, 144.18, 165.18.
4,9-Dimethoxy-8-methyl-2-phenylthiazolo[4,5-g]quinoline 11
6-Amino-4,7-dimethoxy-2-phenylbenzothiazole 12f (246 mg,
J. Chem. Soc., Perkin Trans. 1, 2000, 205–210
209

View Article Online
N-[2,5-Dimethoxy-4-(p-tolylsulfonylamino)phenyl]thio-
benzamide 17d
4.41; N, 6.76. Calc. for C21H18N2O3S2: C, 61.45; H, 4.42; N,
6.83%); νmax/cmϪ1 3287, 1465, 1336; δH 2.32 (3H, s, CH3), 3.70
(3H, s, OCH3), 7.15 (3H, m, 7-H and 2 × tosyl), 7.40 (1H, s,
4-H), 7.45 (3H, m, 3Ј-, 4Ј-, 5Ј-H), 7.65 (2H, m, 2Ј-, 6Ј-H), 8.02
(2H, m, tosyl); δC 21.46, 55.94, 104.18, 113.18, 124.93, 127.18,
127.35, 129.0, 129.44, 130.85, 133.43, 135.98, 143.86, 149.43,
151.56, 168.66.
The benzamide 16e (950 mg, 2.23 mmol) was stirred in dry
toluene (20 mL). To this solution was added Lawesson’s reagent
(0.95 g, 2.34 mmol) and the resulting suspension was heated at
80 ЊC under an atmosphere of nitrogen for 2 h. The suspension
was filtered and the filter cake washed with toluene. The com-
bined filtrate was concentrated to afford a green oil. Column
chromatography with hexane–chloroform (1.2:1) as eluent,
and recrystallization from hexane–methanol, produced 17d as
orange crystals (909 mg, 92%), mp 146–148 ЊC (Found: C,
59.72; H, 5.00; N, 6.30. Calc. for C22H22N2O4S2: C, 59.71; H,
5.02; N, 6.33%); νmax/cmϪ1 3389, 3259, 1524, 1327; δH 2.40 (3H,
s, p-CH3), 3.63 and 3.90 (each 3H, s, OCH3), 7.0 (1H, s, 3-H),
7.25 (2H, m, tosyl), 7.43 (3H, m, 3Ј-, 4Ј-, 5Ј-H), 7.64 (2H, m, 2Ј-,
6Ј-H), 7.78 (2H, m, tosyl), 9.19 (1H, s, 6-H), 9.70 (1H, br s,
NH); δC 21.51, 56.38, 56.63, 104.53, 122.94, 125.79, 126.59,
127.13, 128.68, 129.49, 131.06, 135.96, 142.67, 143.66, 143.99,
195.0.
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To a saturated aq. solution of potassium bicarbonate (8 mL)
was added a suspension of N-[2,5-dimethoxy-4-(p-tolylsulfonyl-
amino)phenyl]thiobenzamide 17d (110 mg, 0.25 mmol) in
methanol (20 mL) and the mixture refluxed for 24 h. The solv-
ent was removed, and water added (100 mL) to the residue,
which was then extracted with chloroform (3 × 50 mL), and the
extract dried over sodium sulfate and evaporated. Purification
by column chromatography (CH2Cl2) yielded unchanged start-
ing material 17d (38 mg, 35% recovery), the corresponding benz-
amide 16e (63 mg, 60%), and compound 18 (5 mg, 5%) as cream
crystals, mp 184–186 ЊC (CH2Cl2–MeOH) (Found: C, 61.17; H,
Paper a907633f
210
J. Chem. Soc., Perkin Trans. 1, 2000, 205–210