Thermally induced cyclization of electron-rich N-arylthiobenzamides to benzothiazoles

Article abstract of DOI:10.1055/s-0032-1316670

Heating N-(2-methoxyphenyl)benzenecarbothioamides in refluxing nitrobenzene for 24 hours gives the corresponding benzothiazoles with intramolecular ipso substitution of the ortho-methoxy substituent. The thermal cyclization of various other N-arylthiobenzamides is also explored. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0032-1316670

PAPER
▌2579
paper
Thermally Induced Cyclization of Electron-Rich N-Arylthiobenzamides to
Benzothiazoles
Cyclization of N-Arylthiobenzamides to Benzothiazoles
Oscene V. Barrett, Nadale K. Downer-Riley, Yvette A. Jackson*
Department of Chemistry, University of the West Indies, Mona, Kingston 7, Jamaica
Fax +1876(977)1835; E-mail: yvette.jackson@uwimona.edu.jm
Received: 30.04.2012; Accepted after revision: 11.06.2012
R2
Abstract: Heating N-(2-methoxyphenyl)benzenecarbothioamides
N
in refluxing nitrobenzene for 24 hours gives the corresponding ben-
R1
Ph
zothiazoles with intramolecular ipso substitution of the ortho-
methoxy substituent. The thermal cyclization of various other N-ar-
ylthiobenzamides is also explored.
S
2
Key words: cyclizations, heterocycles, thioamides
heat
Ph
N
R2
R2
S
H
N
H
N
Ph
The pharmacological significance of 2-arylbenzothia-
zoles is well documented1 and has led to increased interest
in the synthesis of this class of compounds.2 In 2004,
Downer and Jackson reported the synthesis of 2-arylben-
zothiazoles through an intramolecular cyclization of elec-
tron-rich N-arylthiobenzamides with ipso substitution of
an ortho-methoxy group.3 This reaction occurs under
Jacobson reaction conditions and in the presence of 2,2′-
azobisisobutyronitrile (AIBN) (Scheme 1). We have since
shown that these methods can be extended to the synthesis
of angular or linear benzobisthiazoles.4
Ph
heat
heat
R1
R1
R1
S
O
1
4
3
Scheme 2
N-Arylthiobenzamides 1e (Scheme 3) was prepared from
2,4-dimethoxyaniline (5) (Scheme 3). N-Arylthiobenz-
amide 1l was obtained by sulfurization of N-arylthiobenz-
amide 7 in 97% yield.
NH2
NH
Ph
PhCOCl
HNO3
AcOH
Ph
PhMe, Py
S
O
OMe
MeO
OMe
MeO
OMe
N
H
AIBN
5
N
Ph
6 (85%)
R
R
NaOH, K3Fe(CN)6
(Jacobson's reagent)
S
loss of ortho OMe
R = OMe, NH2, NHTs, NHAc
H2N
NH
Ph
O2N
NH
Ph
Pd/C, H2
MeOH
O
Scheme 1
O
MeO
OMe
MeO
OMe
8 (97%)
7 (89%)
In continuing our investigation into the cyclization of N-
arylthiobenzamides, we found that simply heating an elec-
tron-rich N-arylthiobenzamide possessing an ortho-
methoxy group in refluxing nitrobenzene gives the corre-
sponding benzothiazole in good-to-excellent yield, with
elimination of the ortho-methoxy group. We have ex-
plored this thermally induced reaction by using various
substrates, and our findings are reported here (Scheme 2
and Table 1.)
Ph
S
1. PhCOCl, Py, PhMe
2. Lawesson's reagent
NH
NH
Ph
S
MeO
OMe
1e (40%)
Scheme 3
The N-arylthiobenzamides were prepared from the corre-
sponding anilines by benzoylation and subsequent sulfu-
rization.3–7
Benzoylation of 2-nitroaniline (9; Scheme 4), followed by
reduction and subsequent dibromination, gave the N-(di-
bromoaryl)thioamide 12. Sequential benzoylation and
sulfurization of 12 gave the bisthioamide 13 (Scheme 4).
N-Arylthiobenzamides 1a–o (Table 1) were heated in re-
fluxing nitrobenzene or 1,2-dichlorobenzene for 18 to 24
hours, and the products were purified by column chroma-
SYNTHESIS 2012, 44, 2579–2586
Advanced online publication: 23.07.2012
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0032-1316670; Art ID: SS-2012-M0406-OP
© Georg Thieme Verlag Stuttgart · New York

2580
O. V. Barrett et al.
PAPER
Interestingly, on heating in nitrobenzene, N-arylthiobenz-
amide 1j (entry 10) gave benzothiazole 3j in 82% yield;
1j is resistant to AIBN-induced cyclization conditions,
and under Jacobson conditions gives only 2j, the product
of replacement of the ortho H-atom.3 N-Arylthiobenz-
amide 1m, which has no o-methoxy group and which con-
tains electron-donating groups on the aromatic ring,
cyclized with loss of an ortho-hydrogen atom to give ben-
zothiazole 2m (entry 13); a proportion of the N-arylthio-
benzamide 4m was also recovered.
O2N
NH2
Pd/C, H2
MeOH
O2N
NH
Ph
PhCOCl
PhMe, Py
O
9
10 (86%)
H2N
Br
NH
Br
Ph
PhCOCl
H2N
NH
Ph
NBS
PhMe
O
O
Py
11 (93%)
12
We obtained some interesting results in instances where
bisthiazoles might have resulted from cyclization, i.e. in
reactions involving compounds 1a–e. For 1a and 1b, cy-
clization with loss of the ortho-methoxy group proceeded
with formation of the angular bisthiazoles 3a and 3b, re-
spectively, in good yields. In the case of 1c, no loss of a
methoxy group was observed, but loss of hydrogen oc-
curred to give the angular bisthiazole 2c (≡ 3b) (61%). In
reactions with compounds 1d and 1e, loss of the ortho-
methoxy group is clearly the first reaction, as indicated by
the formation of the benzamides 4c (47%) and 15 (7%),
respectively; this is followed by loss of a hydrogen atom.
As in the case of 1c, the intermediate N-arylthiobenz-
amides could have undergone loss of the ortho-methoxy
group to give the linear product or loss of a hydrogen atom
to give the angular bisthiazole. In all cases, the latter was
the dominant reaction, as only 12% of the linear bisthia-
zole was recovered from the reaction of 1e. The factors
that are involved in determining the formation of linear
over angular bisthiazoles of this type will be the subject of
further investigations.
Ph
O
Ph
S
Lawesson's
reagent
NH
NH
Br
Ph
NH
NH
Ph
O
S
Br
Br
Br
1n (90%)
13 (77%, 2 steps)
Scheme 4
tography (Table 1). With the exception of compound 1c
(entry 3), thermal cyclization of the N-arylthiobenzamide
1a–j (entries 1–10) resulted in ipso substitution of the
ortho-methoxy group as the major or exclusive course of
the reaction. In the case of 1c, thermolysis gave the
benzothiazole 3b through loss of an ortho-hydrogen atom.
The lack of reactivity of compounds 1k (entry 11) and 1l
(entry 12) was not surprising as the primary aromatic ring
of each of these compounds has a low electron density.
Table 1 Thermally Induced Cyclization of N-Arylthiobenzamides 1a–o
R2
R2
R2
H
H
N
Ph
N
Ph
N
S
N
S
Δ
R1
Ph
R1
Ph
R1
R1
or
or
O
S
1
2
3
4
R
2 = H or OMe
loss of o-hydrogen
loss of o-methoxy
corresponding N-arylbenzamide
Entry
Substrate
Products and yields
Ph
S
S
Ph
OMe
N
NH
N
S
N
+
4a (11%)
Ph
Ph
S
1
OMe
OMe
OMe
3a (84%)
1a
OMe
OMe
OMe
N
N
S
S
N
N
S
Ph
Ph
Ph
Ph
+
S
2
NH
N
S
OMe
S
Ph
Ph
3b (85%), (52%)a,b
2b (15%)
1b
Synthesis 2012, 44, 2579–2586
© Georg Thieme Verlag Stuttgart · New York

PAPER
Cyclization of N-Arylthiobenzamides to Benzothiazoles
2581
Table 1 Thermally Induced Cyclization of N-Arylthiobenzamides 1a–o (continued)
R2
R2
R2
H
N
H
Ph
N
Ph
N
S
N
S
Δ
R1
Ph
R1
Ph
R1
R1
or
or
O
S
1
2
3
4
R
2 = H or OMe
loss of o-hydrogen
loss of o-methoxy
corresponding N-arylbenzamide
Entry
Substrate
Products and yields
Ph
S
N
3
2c (≡ 3b) (61%) + 4c (28%)
NH
OMe
S
Ph
1c
OMe
OMe
N
S
S
N
NH
Ph
Ph
Ph
S
4
NH
14 (8%)
+ 3b (30%)
S
Ph
S
+
4c (47%)
1d
Ph
N
Ph
O
S
NH
Ph
NH
S
Ph
N
S
N
S
+
Ph
Ph
NH
MeO
MeO
5
15 (7%)
16 (79%)
MeO
OMe
N
S
N
S
Ph
Ph
+
1e
17 (12%)
Ph
N
OMe
S
NH
Ph
6
7
S
MeO
MeO
1f
3f (87%)
Ph
OMe
S
OMe
OMe
NH
Ph
N
N
S
Ph
S
+
+ 4g (25%)
OMe
OMe
OMe
3g (40%)*
1g
2g (12%)
C6H4-4-Cl
S
NH
C6H4-4-Cl
N
S
+
4h (8%)
8
OMe
OMe
3h (86%)b
1h
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2579–2586

2582
O. V. Barrett et al.
PAPER
Table 1 Thermally Induced Cyclization of N-Arylthiobenzamides 1a–o (continued)
R2
R2
R2
H
N
H
Ph
N
Ph
N
S
N
S
Δ
R1
Ph
R1
Ph
R1
R1
or
or
O
S
1
2
3
4
R
2 = H or OMe
loss of o-hydrogen
loss of o-methoxy
corresponding N-arylbenzamide
Entry
Substrate
Products and yields
Ph
OMe
NH
S
N
Ph
S
9
TsHN
OMe
TsHN
OMe
1i
3i (97%)
Ph
OMe
NH
S
N
Ph
S
10
Br
Br
OMe
OMe
1j
3j (82%)
OMe
NH
Ph
11
12
no reaction
S
1k
OMe
NO2
NH
Ph
S
no reaction
MeO
1l
MeO
N
MeO
NH
Ph
+ 4m (9%) (18%)a
Ph
S
S
13
MeO
MeO
2m (63%) (18%)a,b
1m
Ph
S
S
Ph
N
S
N
S
NH
NH
Br
Ph
Ph
14
15
Br
17 (44%)b
1n
1o
NH
Ph
N
S
Ph
S
Cl
18 (67%)
a In 1,2-dichlorobenzene.
b 4–47% of the starting material was recovered.
Synthesis 2012, 44, 2579–2586
© Georg Thieme Verlag Stuttgart · New York

PAPER
Cyclization of N-Arylthiobenzamides to Benzothiazoles
2583
The thiol radical 20 (Scheme 5) may be a key intermediate In conclusion, we have reported, for the first time, a ther-
in the cyclization of N-(2-methoxyphenyl)thiobenz- mally induced cyclization of N-arylthiobenzamides sim-
amides to benzothiazoles with loss of the ortho-methoxy ply by heating in refluxing nitrobenzene for 24 hours. This
group,3 and this thermal reaction is considered to proceed route offers advantages in that no expensive reagents are
via a similar intermediate. It has been reported8 that heat- needed. Cyclizations with losses of an ortho-methoxy
ing nitrobenzene at very high temperatures for long group or an ortho-hydrogen atom are observed, with the
periods (in excess of four hours) can produce the corre- former being the dominant reaction.
sponding radical anion, a phenyl radical, or a phenol rad-
ical, any of which might initiate the generation of thiol
IR spectra were recorded on a Bruker TENSOR 37 spectrometer
radical 20. We confirmed that species formed by the de-
composition of nitrobenzene do not interfere with the re-
action by heating compounds 1b and 1m in refluxing 1,2-
dichlorobenzene for 24 hours. These reactions gave the
benzobisthiazoles 3b and 2m in 52% and 18%, respec-
tively, also confirming the superiority of nitrobenzene as
a solvent for the reaction.
equipped with a Pike Technology MIRacle system for single-reflec-
tion attenuated total reflection (ATR). NMR spectra were recorded
on Bruker 200 and 500 MHz spectrometers in CDCl3 soln, and the
resonances are referenced to TMS as an internal standard. The
NMR spectroscopic data for all known compounds were identical to
those reported in the literature. Column chromatography was car-
ried out by using silica gel as the adsorbent. All elemental analyses
were performed at the University of the West Indies, Mona, Kings-
ton, Jamaica.
The possibility of catalysis by the presence of traces of
metals in the reaction flasks has also been reported.9–11 In
our case, this was eliminated by use of new clean glass-
ware for the thermally induced cyclization of N-arylthio-
benzamide 1a, which gave benzothiazole 3a in 84% yield.
This led us to believe that thiol radical 20 is formed by
thermally induced homolytic cleavage of the S–H bond of
the thioiminol 19 (Scheme 5). Radical 20 then cyclizes to
benzothiazole 22 via the intermediate arene radical 21
with loss of an ortho-methoxy or ortho-hydrogen radical.
Benzoylation of Anilines; General Procedure
BzCl (1.2 equiv) was added to a soln of the appropriate aniline (6.0
g) in anhyd toluene (35 mL) and pyridine (25 mL). The soln was re-
fluxed for 2–6 h, cooled to r.t., and poured into H2O (200 mL). The
two layers were separated and the aqueous layer was extracted with
EtOAc (3 × 25 mL). The organic fractions were combined, washed
sequentially with 1 M HCl (3 × 25 mL) and sat. aq NaHCO3 (3 × 25
mL), and dried (MgSO4). The soln was filtered and the solvent was
removed in vacuo to yield the corresponding benzamide, which was
crystallized from MeOH or CH2Cl2–hexanes.
N-(2-Chlorophenyl)benzamide
R2
White needles; yield: 7.63 g (70%) from 2-chloroaniline (6 h at re-
R2
flux); mp 94–97 °C (MeOH) (Lit.13 97–98 °C).
H
N
N
Ph
Ph
– H
heat
R1
R1
N-(2,4-Dimethoxyphenyl)benzamide (6)
SH
S
Brown solid; yield: 8.59 g (85%) from 2,4-dimethoxyaniline (5) (2
19
1
h at reflux); mp 164–165 °C (MeOH) (Lit.14 173 °C).
R2 = H or OMe
1H NMR (200 MHz, CDCl3): δ = 3.82 (s, 3 H, OCH3), 3.89 (s, 3 H,
OCH3), 6.63 (m, 2 H, H-3, 5), 7.51 (m, 3 H, H-3′,4′,5′), 7.89 (d,
J = 7 Hz, 2 H, H-2′,6′), 8.35 (s, 1 H, N-H), 8.43 (d, J = 7 Hz, 1 H,
H-6).
13C NMR (50 MHz, CDCl3): δ = 55.6, 55.8, 98.7, 103.9, 120.7,
121.4, 127.0, 128.7, 131.5, 135.5, 149.5, 156.5, 165.0.
R2
N
Ph
N
– R
R1
R1
Ph
S
S
R2
20
21
N-(3-Nitrophenyl)benzamide (10)
Yellow needles; yield: 9.05 g (86%) from 2-nitroaniline (9) (4 h at
N
R1
reflux); mp 153–155 °C (MeOH) (Lit.15 156–157 °C).
Ph
S
22
N,N′-(4,6-Dibromo-1,3-phenylene)dibenzamide (13)
NBS (2.3 molar equiv) was added to a soln of the aminobenzamide
11 (0.5 g) in toluene (20 mL), and the mixture was stirred and re-
fluxed overnight (12 h). The mixture was then cooled and filtered.
The filtrate was washed sequentially with 5% aq Na2S2O3 (2 × 15
mL) and H2O (2 × 15 mL), dried (Na2SO4), and concentrated in vac-
uo to give the crude aminobenzamide 12, which was benzoylated as
described above to give white needles; yield: 0.86 g (77%, two
steps); mp 205–207 °C (MeOH).
Scheme 5
The mechanism proposed in Scheme 5 suggests that heat-
ing N-(2-haloaryl)thiobenzamides in refluxing nitroben-
zene should also generate the thiol radical 20 (R2 = X),
which could easily cyclize with loss of a halogen radical.
The free-radical-induced cyclization of N-(2-haloar-
yl)thiobenzamides in the presence of tributylstannane and
AIBN is well known.12 As expected, both the N-(2-halo-
aryl)thiobenzamides 1n and 1o, on heating in refluxing ni-
trobenzene for 24 hours, cyclized with loss of the halogen
substituent, to give benzobisthiazole 17 and benzothiazole
18, respectively (entries 14–15), thereby providing exper-
imental support for the proposed mechanism.
IR (ATR): 3431, 3292, 1696, 1575 cm–1.
1H NMR (200 MHz, CDCl3): δ = 7.55 (m, 6 H, H-3′,4′,5′ and H-
3′′,4′′,5′′), 7.78 (s, 1 H, H-3), 7.96 (m, 4 H, H-2′,6′ and H-2′′,6′′),
8.39 (s, 2 H, 2 × N-H), 9.73 (s, 1 H, H-6).
13C NMR (50 MHz, CDCl3): δ = 108.4, 115.1, 127.2, 128.9, 132.3,
134.2, 134.3, 135.9, 165.0.
Anal. Calcd for C20H14Br2N2O4: C, 50.66; H, 2.98; N, 5.91. Found:
C, 50.35; H, 2.68; N, 5.82.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2579–2586

2584
O. V. Barrett et al.
PAPER
Sulfurization of Benzamides; General Procedure
Lawesson’s reagent (0.6 equiv) was added to a soln of the appropri-
ate benzamide (1.0 g) in anhyd toluene (40 mL). The mixture was
refluxed under N2 for 4–6 h, then concentrated and purified by col-
umn chromatography or by crystallization (MeOH or EtOAc–hex-
anes).
Anal. Calcd for C15H14N2O5: C, 59.60; H, 4.67; N, 9.27. Found: C,
59.92; H, 4.43; N, 9.31.
Palladium-Catalyzed Reduction of Nitrobenzothiazoles and Ni-
trobenzamides; General Procedure
A suspension of the nitro compound (6.0 g) in MeOH (100 mL) was
treated with a catalytic amount of 10% Pd/C (0.1 equiv) and the
mixture was shaken on a Parr apparatus under H2 at 20 psi for 6 h.
The mixture was then filtered through kieselguhr and the solvent
was removed in vacuo.
N-(2-Chlorophenyl)benzenecarbothioamide (1o)
Yellow crystals; yield: 1.04 g (97%) from 2-chlorobenzamide (4 h
at reflux); mp 71–72 °C (MeOH) (Lit.7 73–74 °C).
N,N′-(4,6-Dimethoxy-1,3-phenylene)dibenzenecarbothioamide
(1e)
Yellow crystals; yield: 1.49 g (40%) from aminobenzamide 8 (6 h
at reflux); mp 217–219 °C (MeOH).
N-(5-Amino-2,4-dimethoxyphenyl)benzamide (8)
Brown crystals; yield: 5.24 g (97%) from nitrobenzamide 7; mp
320–323 °C (MeOH).
IR (ATR): 3451, 3365, 1696, 1060 cm–1.
1H NMR (200 MHz, CDCl3): δ = 2.91 (s, 2 H, NH2), 3.85 (s, 6 H, 2
× OCH3), 6.51 (s, 1 H, H-3), 7.50 (m, 3 H, H-3′,4′,5′), 7.86 (m, 2 H,
H-2′,6′), 8.02 (s, 1 H, H-6), 8.35 (s, 1 H, N-H).
IR (ATR): 3362, 1613, 1538, 1078 cm–1.
1H NMR (200 MHz, CDCl3): δ = 3.94 (s, 6 H, 2 × OCH3), 6.61 (s,
1 H, H-3), 7.49 (m, 6 H, H-3′,4′,5′ and H-3′′,4′′,5′′), 7.88 (d, J = 8
Hz, 4 H, H-2′,6′ and H-2′′,6′′), 9.29 (s, 2 H, 2 × N-H), 10.05 (s, 1 H,
H-6).
13C NMR (50 MHz, CDCl3): δ = 56.3, 95.2, 118.8, 120.6, 126.8,
128.5, 131.0, 143.4, 150.1, 196.5.
13C NMR (50 MHz, CDCl3):_δ = 56.1, 56.8, 96.9, 108.2, 121.4,
126.9, 128.6, 129.6, 131.4, 135.5, 141.5, 143.5, 164.8.
This compound was benzoylated (6 h at reflux) and sulfurized (6 h
at reflux) to give compound 1e.
Anal. Calcd for C22H20N2O2S2: C, 64.68; H, 4.93; N, 6.86. Found:
C, 64.76; H, 4.88; N, 6.92.
N-(3-Aminophenyl)benzamide (11)
Brown solid; yield: 4.89 g (93%) from nitrobenzamide 10; mp 107–
N-(2,4-Dimethoxy-5-nitrophenyl)benzenecarbothioamide (1l)
Yellow crystals; yield: 1.02 g (97%) from benzamide 7 (6 h at re-
flux); mp 297–300 °C (MeOH).
IR (ATR): 3415, 1666, 1528, 1018 cm–1.
1H NMR (200 MHz, CDCl3): δ = 3.94 (s, 3 H, OCH3), 4.03 (s, 3 H,
OCH3), 6.53 (s, 1 H, H-3), 7.52 (m, 3 H, H-3′,4′,5′), 7.86 (d, J = 7
Hz, 2 H, H-2′,6′), 9.32 (s, 1 H, H-6), 9.75 (s, 1 H, N-H).
110 °C (MeOH) (Lit.16 108–109 °C).
Thermal Cyclization of N-Arylthiobenzamides in Nitrobenzene
or 1,2-Dichlorobenzene
A stirred soln of the thiobenzamide (0.1 g) in PhNO2 or 1,2-dichlo-
robenzene (5 mL) was refluxed under an inert atmosphere for 18–
24 h. The mixture was then purified by column chromatography
[silica gel, hexanes then CH2Cl2–hexanes (gradient 1:3 to 3:1)]. The
product was finally crystallized from MeOH, EtOH, or CH2Cl2–
hexanes.
13C NMR (50 MHz, CDCl3): δ = 56.8, 56.9, 96.0, 120.2, 121.2,
126.7, 128.7, 130.8, 131.3, 143.1, 153.1, 155.3, 196.6.
5-Methoxy-2,7-diphenyl[1,3]thiazolo[5,4-e][1,3]benzothiazole
(3a)
Anal. Calcd for C15H14N2O4S: C, 56.59; H, 4.43; N, 8.80. Found: C,
56.61; H, 4.19; N, 8.67.
Off-white crystals; yield: 77 mg (84%) from 1a (PhNO2); mp 235–
236 °C (MeOH) (Lit.4 235–236 °C).
N,N′-(4,6-Dibromo-1,3-phenylene)dibenzenecarbothioamide
(1n)
4-Methoxy-2,7-diphenyl[1,3]thiazolo[4,5-g][1,3]benzothiazole
(3b)
Yellow green needles; yield: 78 mg (85%) from 1b (PhNO2); 56.2
mg (61%) from 1c (PhNO2); 27.6 mg (30%) from 1d (PhNO2); 47.9
mg (52%) from 1b (1,2-dichlorobenzene); mp 225–227 °C (EtOH)
(Lit.4 225–227 °C).
Yellow crystals: yield: 0.96 g (90%) from 15 (15 h at reflux); mp
198–200 °C (MeOH).
IR (ATR): 3158, 2918, 1650, 1350 cm–1.
1H NMR (200 MHz, CDCl3): δ = 7.50 (m, 6 H, H-3′,4′,5′ and H-
3′′,4′′,5′′), 7.90 (m, 5 H, H-2′,6′,H-2′′,6′′ and H-3), 9.21 (s, 2 H,
2 × N-H), 9.77 (s, 1 H, H-6).
4,8-Dimethoxy-2,6-diphenyl[1,3]thiazolo[5,4-f][1,3]benzothia-
zole (2b)
13C NMR (50 MHz, CDCl3): δ = 115.4, 121.8, 126.9, 128.8, 131.7,
135.6, 136.7, 146.1, 199.4.
Yellow crystals; yield: 15 mg (15%) from 1b (PhNO2); mp 274–
276 °C (MeOH) (Lit.4 274–276 °C).
Nitration of Benzamides; General Procedure
A mixture of concd HNO3 (1.6 equiv) and glacial AcOH (5 mL) was
added to a cold soln of the appropriate benzamide (6.0 g) in glacial
AcOH (35 mL). The mixture was stirred at r.t. for 4 h then poured
into H2O (600 mL). The yellow solid that formed was filtered by
suction, dried in an oven at 100 °C (30 min), and crystallized from
CH2Cl2–hexanes.
N-(5-Methoxy-2-phenyl-1,3-benzothiazol-6-yl)benzamide (4c)
Finely divided yellow crystals; yield: 25 mg (28% recovery) from
1c; 42 mg (47%) from 1d; mp 182–184 °C (MeOH) (Lit.4 182–
184 °C).
2,6-Diphenyl[1,3]thiazolo[5,4-f][1,3]benzothiazole (14)
Cream crystals; yield: 7 mg (8%) from 1d (PhNO2, 24 h at reflux);
5 mg (6%) from 1d (1,2-dichlorobenzene); mp >250 °C (MeOH)
(Lit.17 303–304 °C).
IR (ATR): 1512, 1480, 1309, 1234 cm–1.
1H NMR (200 MHz, CDCl3): δ = 7.55 (br s, 6 H, H-3′,4′,5′ and H-
3′′,4′′,5′′), 8.14 (br s 4 H, H-2′,6′ and H-2′′,6′′), 8.57 (s, 2 H, H-4, 8).
N-(2,4-Dimethoxy-5-nitrophenyl)benzamide (7)
Yellow-green crystals; yield: 6.27 g (89%) from benzamide 6; mp
148–151 °C (MeOH).
IR (ATR): 3415, 1667, 1528, 1076 cm–1.
1H NMR (500 MHz, CDCl3): δ = 3.94 (s, 3 H, OCH3), 4.03 (s, 3 H,
OCH3), 6.53 (s, 1 H, H-3), 7.52 (m, 3 H, H-3′,4′,5′), 7.86 (d, J = 7
Hz, 2 H, H-2′,6′), 8.28 (s, 1 H, H-6), 9.15 (s, 1 H, N-H).
13C NMR (50 MHz, CDCl3): δ = 115.5, 127.7, 129.1, 131.3, 133.5,
134.5, 152.2, 169.1.
13C NMR (125 MHz, CDCl3): δ = 56.6, 56.9, 96.1, 117.9, 120.7,
127.0, 128.2, 128.8, 132.0, 134.4, 151.3, 153.1, 165.0.
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Cyclization of N-Arylthiobenzamides to Benzothiazoles
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6-Methoxy-2-phenyl-1,3-benzothiazole (3f)
Anal. Calcd for C21H14N2OS2: C, 67.35; H, 3.77; N, 7.48. Found: C,
67.01; H, 3.52; N, 7.30.
Cream crystals; yield: 77 mg (87%) from 1f (PhNO2, 22 h at reflux);
mp 114–116 °C (MeOH) (Lit.18 114–115 °C).
5,6-Dimethoxy-2-phenyl-1,3-benzothiazole (2m)
Cream crystals; yield: 63 mg (63%) from 1m (PhNO2, 24 h at re-
flux); 17.9 mg (18%) from 1m (1,2-dichlorobenzene); mp 144–
146 °C (MeOH) (Lit.3 145–146 °C).
5-Methoxy-2-phenyl-1,3-benzothiazole (3g)
Cream crystals; yield: 35.3 mg (40%) from 1g (PhNO2, 24 h at re-
flux); mp 76–77 °C (MeOH) (Lit.3 75–77 °C).
4,7-Dimethoxy-2-phenyl-1,3-benzothiazole (2g)
White needle-like crystals; yield: 12 mg (12%) from 1g (PhNO2);
mp 122–123 °C (MeOH) (Lit.6 122–124).
N-(3,4-Dimethoxyphenyl)benzamide (4m)
Brown solid; yield: 8 mg (9%) from 1m (PhNO2, 24 h at reflux);
17.0 mg (18%) from 1m (1,2-dichlorobenzene); mp 172–174 °C
(MeOH) (Lit.20 173–175 °C).
2-(4-Chlorophenyl)-5-methoxy-1,3-benzothiazole (3h)
Cream crystals; yield: 81 mg (90%) from 1h (PhNO2); mp 105–
107 °C (MeOH).
IR (ATR): 3004, 1593, 1465, 1026 cm–1.
1H NMR (200 MHz, CDCl3): δ = 3.95 (s, 3 H, OCH3), 7.04 (dd,
J = 6, 3 Hz, 1 H, H-6), 7.44 (d, J = 7 Hz, 2 H, H-3′,5′), 7.55 (d, J = 3
Hz, 1 H, H-4), 7.73 (d, J = 6 Hz, 1 H, H-7), 8.00 (d, J = 7 Hz, 2 H,
H-2′,6′.
2,6-Diphenyl[1,3]thiazolo[4,5-f][1,3]benzothiazole (17)
Yellow crystals; yield: 30 mg (44%) from 1n (PhNO2, 24 h at re-
flux); mp 260–262 °C (MeOH) (Lit.21 268–271 °C).
IR (ATR): 1509, 1480, 1305, 1239 cm–1.
1H NMR (200 MHz, CDCl3): δ = 7.53 (m, 6 H, H-3′,4′,5′ and H-
3′′,4′′,5′′), 8.13 (m, 4 H, H-2′,6′ and H-2′′,6′′), 8.55 (s, 1 H, H-4),
8.74 (s, 1 H, H-8).
13C NMR (50 MHz, CDCl3): δ = 55.6, 105.6, 115.7, 121.8, 126.9,
128.5, 129.2, 132.3, 136.9, 155.4, 159.3, 167.8.
13C NMR (50 MHz, CDCl3): δ = 112.4, 115.7, 126.5, 127.9, 130.1,
132.3, 147.0, 170.2.
Anal. Calcd for C14H10ClNOS: C, 60.98; H, 3.66; N, 5.08. Found:
C, 61.25; H, 3.40; N, 5.15.
2-Phenyl-1,3-benzothiazole (18)
Cream crystals; yield: 57 mg (67%) from 1o (PhNO2, 24 h at re-
flux); mp 109–110 °C (MeOH) (Lit.12 110–111 °C).
N-(5-Methoxy-2-phenyl-1,3-benzothiazol-6-yl)-4-methylben-
zenesulfonamide (3i)
Light-brown needles; yield: 90 mg (97%) from 1i (PhNO2, 18 h at
References
reflux); mp 171–173 °C (MeOH) (Lit.5 mp 184–186 °C).
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(2) For selected reviews on the synthesis of benzothiazole ring
systems, see: (a) Yadav, P. S.; Devprakash; Senthilkumar,
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6-Bromo-5-methoxy-2-phenyl-1,3-benzothiazole (3j)
White needles; yield: 75 mg (82%) from 1j (PhNO2, 22 h at reflux);
mp 157–159 °C (MeOH).
IR (ATR): 3069, 1592, 1454, 1037 cm–1.
1H NMR (200 MHz, CDCl3): δ = 4.00 (s, 3 H, OCH3), 7.51 (m, 3 H,
H-3′,4′,5′), 7.57 (s, 1 H, H-4), 8.01 (m, 3 H, H-7, 2′,6′).
13C NMR (50 MHz, CDCl3): δ = 56.5, 105.3, 110.5, 125.0, 127.4,
127.8, 129.1, 131.1, 133.4, 154.6, 155.2, 169.6.
Anal. Calcd for C14H10BrNOS: C, 52.51; H, 3.15; N, 4.37. Found:
C, 52.56; H, 3.02; N, 4.44.
N-(6-Methoxy-2-phenyl-1,3-benzothiazol-5-yl)benzamide (15)
Finely divided brown crystals; yield: 6 mg (7%) from 1e (PhNO2,
24 h at reflux); mp 184–186 °C (MeOH).
IR (ATR): 3429, 1660, 1572, 1057 cm–1.
1H NMR (200 MHz, CDCl3): δ = 4.01 (s, 3 H, OCH3), 7.35 (s, 1 H,
H-7), 7.51 (m, 6 H, H-3′,4′,5′ and H-3′′,4′′,5′′), 7.93 (m, 2 H, H-2′,6′)
8.06 (m, 2 H, H-2′′,6′′), 8.65 (s, 1 H, NH), 9.27 (s, 1 H, H-4).
13C NMR (50 MHz, CDCl3): δ = 56.4, 101.7, 114.0, 127.1, 127.3,
127.6, 128.8, 129.0, 130.5, 131.8, 133.8, 135.3, 138.1, 147.3, 148.8,
165.2, 166.2.
Anal. Calcd for C21H16N2O2S·0.5H2O: C, 68.27; H, 4.37; N, 7.58.
Found: C, 68.55; H, 4.46; N, 7.75.
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4-Methoxy-2,7-diphenyl[1,3]thiazolo[5,4-e][1,3]benzothiazole
(16)
Cream crystals; yield: 73 mg (79%) from 1e (PhNO2, 24 h at re-
flux); mp 239–241 °C (MeOH).
IR (ATR): 3429, 1660, 1572, 1057 cm–1 (Lit.19).
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© Georg Thieme Verlag Stuttgart · New York
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Synthesis 2012, 44, 2579–2586
© Georg Thieme Verlag Stuttgart · New York