Conversion of thiobenzamides to benzothiazoles via intramolecular cyclization of the aryl radical cation

Article abstract of DOI:10.1016/j.tet.2008.06.023

A new and general method has been developed for the intramolecular cyclization of thiobenzamides to benzothiazoles via aryl radical cations as reactive intermediates. The method utilizes phenyliodine(III) bis(trifluoroacetate) (PIFA) in trifluoroethanol or cerium ammonium nitrate (CAN) in aqueous acetonitrile at room temperature to effect cyclization within 30 min in moderate yields.

Full text of DOI:10.1016/j.tet.2008.06.023

Tetrahedron 64 (2008) 7741–7744
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Conversion of thiobenzamides to benzothiazoles via intramolecular
cyclization of the aryl radical cation
*
Nadale K. Downer-Riley, Yvette A. Jackson
Department of Chemistry, University of the West Indies, Mona, Kingston 7, Jamaica, West Indies
a r t i c l e i n f o
a b s t r a c t
Article history:
A new and general method has been developed for the intramolecular cyclization of thiobenzamides to
benzothiazoles via aryl radical cations as reactive intermediates. The method utilizes phenyliodine(III)
bis(trifluoroacetate) (PIFA) in trifluoroethanol or cerium ammonium nitrate (CAN) in aqueous acetoni-
trile at room temperature to effect cyclization within 30 min in moderate yields.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 15 March 2008
Received in revised form 21 May 2008
Accepted 5 June 2008
Available online 10 June 2008
Keywords:
Benzothiazoles
Thiobenzamides
PIFA
CAN
1. Introduction
2. Results and discussion
2-Substituted benzothiazoles are now of great interest due to
their potent antitumor and other pharmacological activity.1,2 The
most common method for their synthesis from thiobenzamides is
the Jacobson synthesis, which involves the use of potassium
ferricyanide with sodium hydroxide.3 Recently, several new
methods have emerged, which utilize various oxidants such as
Dess–Martin periodinane,4 manganese triacetate,5 and 2,3-
dichloro-5,6-dicyano-1,4-benzoquinone (DDQ)6 to facilitate for-
mation of the thiyl radical from the thiobenzamide, which
cyclizes with loss of a hydrogen atom to produce the benzo-
thiazole (Scheme 1).
In our quest to develop new methods (not involving the thiyl
radical) for cyclization of thiobenzamides to benzothiazoles, the
use of iodine was explored.7 This reagent promotes cyclization of
thiobenzamides to benzothiazoles via the sulfenyliodide. It was
found, however, that reaction of thiobenzamides, which possess
ortho-alkoxy groups, with iodine, leads to benzoxazoles. The pres-
ent paper reports our further attempts at synthesis of benzothia-
zoles from thiobenzamides.
Hypervalent iodine reagents have facilitated synthetic trans-
formations involving carbon–carbon and carbon–heteroatom bond
formation. Phenyliodine(III) diacetate (PIDA) has successfully been
used to promote umpolong formation aiding cyclization of
N-2-phenyl formimidamides to benzimidazoles.8 Reaction of thio-
benzamides with PIDA in a similar manner was therefore consid-
ered as a route to benzothiazoles via the sulfenyliodide. Unlike the
reaction of 2-methoxythiobenzamides with iodine, the sulfenylio-
dide generated in this reaction was not sufficiently electrophilic to
allow attack of the ortho-methoxy group resulting in benzoxazole
formation. Reaction of 2-methoxythiobenzamides 1a–c with PIDA
in toluene at reflux for 3 h, however, showed only minor conversion
to benzothiazoles with the corresponding benzamides as the major
products (Scheme 2).
Another useful hypervalent iodine reagent, phenyliodine(III)
bis(trifluoroacetate) (PIFA), has been reported to facilitate nucleo-
philic attack onto aryl ethers in polar non-nucleophilic solvents by
promoting formation of the aryl radical cation.9,10 These reactions
are of particular interest to us as formation of a radical cation of
a thiobenzamide could lead to intramolecular nucleophilic attack to
produce a benzothiazole (Scheme 3).
Treating the thiobenzamides 1a–n (prepared from readily
available anilines) with PIFA (1.1 equiv) in trifluoroethanol and
stirring for 30 min at room temperature led to the corresponding
benzothiazoles. As shown in Table 1, reaction of PIFA with ortho-
methoxythiobenzamides 1a–e (entries 1–5) showed conversion to
benzothiazole in only 0–52% yield. Thiobenzamide 1d, which
* Corresponding author. Tel.: þ876 927 1910; fax: þ876 977 1835.
E-mail address: yvette.jackson@uwimona.edu.jm (Y.A. Jackson).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.06.023

7742
N.K. Downer-Riley, Y.A. Jackson / Tetrahedron 64 (2008) 7741–7744
H
N
R
N
R
N
R
N
S
[O]
R
S
S
S
H
Scheme 1.
OMe
OMe
H
N
Ph
N
O
I2
R
R
Ph
R
S
S
I
(39-95%)7
OMe
OMe
H
N
N
Ph
Ph
N
S
PIDA
Ph
R
R
I
OAc
S
Ph
1a R = H
2a R = H (26%)
1b R = 5-OMe
2b R = 7-OMe (31%)
2c R = 6,7-diOMe (5%),
(and 12% 2h)
1c R = 4,5-diOMe
Scheme 2. Iodine and PIDA-mediated cyclization of 2-methoxythiobenzamides.
OCOCF3
Ph
OCOCF3
I
H
N
H
N
Ph
Ph
PhI(OCOCF3)2
CF3CH2OH
R
R
R
NH
S
S
S
Ph
S
N
Ph
SH
N
Ph
N
S
-H
-H
Ph
R
R
R
H
Scheme 3. PIFA-mediated cyclization of thiobenzamides.
possesses a highly activated primary ring, was quickly oxidized by
PIFA to amidoquinone 3. Reaction of PIFA with other thio-
benzamides bearing electron-donating substituents on the primary
ring (entries 6–11) yielded benzothiazoles 2f–k in 71–98% yield.
Thiobenzamide 1n bearing the electron-withdrawing nitro group
(entry 14) could not be cyclized using this reaction and the corre-
sponding benzamide was obtained in quantitative yield. The low
conversion of the ortho-methoxythiobenzamides 1a–e to benzo-
thiazoles suggests that the presence of the ortho-methoxy group
may be hindering cyclization to the benzothiazole resulting in the
corresponding benzamide as byproduct.
A rational mechanism is proposed for the oxidation of ortho-
methoxythiobenzamides to benzamides under these reaction
conditions (Scheme 4). Reaction of the thiobenzamide with PIFA
yields thiol radical cation 5, along with aryl radical cation 4a, which
is required for cyclization to the benzothiazole. Reactivity of radical
cation 4a is reduced by the presence of the methoxy group, which is
able to quench the positive charge to produce 4b. The competing
reaction of thiol radical cation 5 with water in the mixture is
therefore preferred yielding benzamide as a byproduct.
carbon–heteroatom bonds.11 In aqueous acetonitrile, aryl methyl
ethers react with CAN to produce quinones.12 It was therefore
expected that upon formation of the radical cation of thio-
benzamides 1a–f, cyclization to the benzothiazole could compete
with reaction with water to generate the p-quinones. Thus, re-
action of the thiobenzamides with one molar equivalent CAN in
aqueous acetonitrile was attempted. After stirring at room tem-
perature for 30 min, the thiobenzamides were completely con-
verted to a mixture of benzothiazoles and benzamides (Table 1).
Once again, the ortho-methoxythiobenzamides (entries 1–5) were
converted to benzothiazoles in significantly lower yields (9–37%)
than the other substrates used, which had activated primary rings
(entries 6–11, 30–94%). The effect of the ortho-methoxy group on
the mechanism of this reaction is thought to be as shown in
Scheme 4. Reaction of thiobenzamides with CAN is, however,
carried out in aqueous medium and as such attack of the in-
termediate thiol radical cation by water to produce the benzamide
is very likely. This would account for the higher conversion of
thiobenzamides to benzothiazoles by PIFA when compared to
CAN.
In continuing our investigation into the use of aryl radical
cations as intermediates for benzothiazole synthesis, reaction of
thiobenzamides with ceric(IV) ammonium nitrate (CAN) was ex-
plored. CAN is a well-known one-electron oxidant and like PIFA, it
has proven to be useful in the construction of carbon–carbon and
In conclusion, a novel strategy has been developed for the
conversion of thiobenzamides to benzothiazoles in moderate yield
via the aryl radical cation as reactive intermediate. The aryl radical
cation may be generated by reaction with PIFA in trifluoroethanol
or CAN in aqueous acetonitrile.

N.K. Downer-Riley, Y.A. Jackson / Tetrahedron 64 (2008) 7741–7744
7743
Table 1
washed with 1 M HCl (50 mL) followed by aqueous sodium bi-
carbonate solution (50 mL) then water (50 mL), dried (Na2SO4), and
concentrated in vacuo to obtain pure benzamide. A mixture of the
benzamide (1.0 g) and Lawesson’s reagent (0.6 mol equiv) in dry
toluene (40 mL) was heated at reflux under an atmosphere of ni-
trogen for 2 h, after which it was concentrated, purified by column
chromatography (EtOAc/hexanes 1:4) and recrystallized from
methanol.
Reaction of thiobenzamides with PIFA and CAN
R1
R1
O
O
H
H
N
N
Ph
Ph
N
S
R2
Ph
R2
S
O
MeO
3
2
1
Entry
Substrate
R1
Benzothiazole
product
% Yield
PIFA
3.2.1. N-(2-Methoxyphenyl)thiobenzamide (1a)
Yellow needles. Yield: 0.13 g, 67% from o-anisidine; mp 78–79 ꢁC
(lit.2 121–122 ꢁC).
R2
CAN
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
OMe
OMe
OMe
OMe
OMe
H
H
2a
2b
2c
2h
2e
2f
2g
2h
2i
2j
2k
2l
2m
d
50e
52d
41c
da
26f
71
73
98
77
71
9g
37d
14e
32a
db
49
5-OMe
4-OMe
4,5-diOMe
4-Br, 5-OMe
3-OMe
4-OMe
3,4-diOMe
H
3-Me
4-Me
H
H
4-NO2
3.2.2. N-(2,5-Dimethoxyphenyl)thiobenzamide (1b)
Yellow needles. Yield: 0.14 g, 81% from 2,5-dimethoxyaniline;
mp 61–62 ꢁC (lit.13 58–61 ꢁC).
1g
1h
1i
H
H
Me
H
66
94
3.2.3. N-(2,4-Dimethoxyphenyl)thiobenzamide (1c)
9
30f
90
Yellow oil. Yield: 0.13 g, 73% from 2,4-dimethoxyaniline. (Found:
C, 65.88; H, 5.69; N, 4.93. Anal. Calcd for C15H15NO2S: C, 65.91; H,
5.53; N, 5.12%); nmax/cmꢂ1 3312, 1719, 1514; dH 3.84 (3H, s, OCH3),
3.88 (3H, s, OCH3), 6.56 (2H, m, 3,5-H), 7.48 (3H, m, 30,40,50-H), 7.85
(2H, m, 20,60-H), 8.91 (1H, m, 6-H), 9.42 (1H, s, N–H); dC 55.6,
56.0, 98.7, 103.2, 122.2, 123.0, 126.7, 128.6, 130.9, 143.9, 151.5, 158.4,
195.2.
10
11
12
13
14
1j
1k
1l
H
H
84
36d
23f
36f
dh
46d
42e
dh
1m
1n
Br
H
a
Amidoquinone 3 was recovered from the reaction mixture (60%).
Intractable mixture was obtained.
b
c
Benzamide was isolated from the reaction mixture in 11–20% yield.
Benzamide was isolated from the reaction mixture in 21–30% yield.
Benzamide was isolated from the reaction mixture in 41–50% yield.
Benzamide was isolated from the reaction mixture in 61–70% yield.
Benzamide was isolated from the reaction mixture in 81–90% yield.
Quantitative amide formation.
d
e
f
3.2.4. N-(2,4,5-Trimethoxyphenyl)thiobenzamide (1d)
Yellow needles. Yield: 0.10 g, 62% from 2,4,5-trimethoxyaniline;
mp 104–105 ꢁC (lit.14 104–105 ꢁC).
g
h
OMe
OMe
OMe
OMe
H
N
H
N
H
N
H
N
Ph
Ph
Ph
Ph
PIFA
H2O
+
S
S
S
O
1
4a
5
6
OMe H
N
OMe
Ph
N
Ph
S
S
4b
2
Scheme 4. A plausible mechanism for the PIFA-mediated oxidation of thiobenzamides to benzamides.
3. Experimental
3.1. General
3.2.5. N-(4-Bromo-2,5-dimethoxyphenyl)thiobenzamide (1e)
Fine yellow crystals. Yield: 0.09 g, 85% from N-(4-bromo-2,5-
dimethoxyphenyl)thiobenzamide; mp 157–158 ꢁC (lit.13 154–
156 ꢁC).
IR spectra were obtained on a Perkin–Elmer 735B FT-IR spec-
trometer as KBr discs. NMR spectra (Bruker 200 and 500 MHz) were
obtained in CDCl3 solution and the resonances are reported in
3.2.6. N-(3-Methoxyphenyl)thiobenzamide (1f)
Yellow needles. Yield: 0.14 g, 71% from m-anisidine; mp 81–
82 ꢁC (lit.2 81–82 ꢁC).
d
units downfield from TMS as an internal standard; J values are
given in hertz. Elemental analyses were carried out by MEDAC Ltd,
Egham, Surrey, UK. Column chromatography was carried out using
silica gel as adsorbent. For all known compounds, 1H NMR spec-
troscopic data were identical to that reported in the literature.
3.2.7. N-(4-Methoxyphenyl)thiobenzamide (1g)
Yellow needles. Yield: 0.13 g, 68% from p-anisidine; mp 129–
130 ꢁC (lit.2 131–133 ꢁC).
3.2. Preparation of thiobenzamides
3.2.8. N-(3,4-Dimethoxyphenyl)thiobenzamide (1h)
Fine yellow crystals. Yield: 0.11 g, 63% from 3,4-dimethoxyani-
line; mp 152–153 ꢁC (lit.2 154–155 ꢁC).
A
mixture of the aniline (1.0 g) and benzoyl chloride
(1.1 mol equiv) in dry toluene (6 mL) and pyridine (5 mL) was
heated at reflux for 2 h then poured into water (100 mL) and
extracted with ethyl acetate (2ꢀ15 mL). The organic layer was
3.2.9. N-(2-Methylphenyl)thiobenzamide (1i)
Viscous yellow oil. Yield 0.14 g, 67% from o-toluidine.15

7744
N.K. Downer-Riley, Y.A. Jackson / Tetrahedron 64 (2008) 7741–7744
3.2.10. N-(3-Methylphenyl)thiobenzamide (1j)
3.3.9. 5-Methyl-2-phenylbenzothiazole (2j)
White needles. Yield: 0.07 g, 71% from 1j; mp 147–148 ꢁC (lit.20
150–151 ꢁC).
Yellow feathers. Yield: 0.14 g, 65% from m-toluidine; mp 80–
81 ꢁC. (Found: C, 73.90; H, 5.83; N, 6.13%. Anal. Calcd for
C
14H13NS: C, 73.97; H, 5.76; N, 6.16%); nmax/cmꢂ1 3175, 1607,
1357; dH 2.37 (3H, s, CH3), 7.08 (1H, d, J 7.5, 4-H), 7.24–7.52 (6H,
m, 2,5,6-H and 30,40,50-H), 7.80 (2H, m, 20,60-H), 9.03 (1H, s, N–H);
dC 21.4, 120.9, 124.3, 126.7, 127.8, 128.6, 128.9, 131.2, 138.9, 139.1,
143.1, 198.4.
3.3.10. 6-Methyl-2-phenylbenzothiazole (2k)
Fine white crystals. Yield: 0.08 g, 84% from 1k; mp 118–119 ꢁC
(lit.21 121–122 ꢁC).
3.3.11. 2-Phenylbenzothiazole (2l)
White needles. Yield: 0.05 g, 46% from 1l; mp 111–112 ꢁC (lit.17
3.2.11. N-(4-Methylphenyl)thiobenzamide (1k)
Yellow feathers. Yield: 0.15 g, 73% from p-toluidine; mp 129–
130 ꢁC (lit.16 128–129.5 ꢁC).
114 ꢁC).
3.3.12. 4-Bromo-2-phenylbenzothiazole (2m)
White needles. Yield 0.04 g, 42% from 1m; mp 91–92 ꢁC. (Found:
C, 53.96; H, 2.88; N, 4.71%. Anal. Calcd for C13H8NSBr: C, 53.81; H,
2.78; N, 4.83%); nmax/cmꢂ1 1479, 972, 757, 685; dH 7.23 (1H, d, J 7.8,
5-H), 7.50 (3H, m, 30,40,50-H), 7.70 (1H, dd, J 1.1 and 7.8, 6-H), 7.81
(1H, dd, J 1.1 and 8.0, 7-H), 8.11 (2H, m, 20,60-H); dC 116.9, 120.8,
126.0, 127.8, 129.0, 129.8, 131.4, 133.2, 135.9, 152.3, 168.6.
3.2.12. N-Phenylthiobenzamide (1l)
Yellow needles. Yield: 0.18 g, 80% from aniline; mp 97–98 ꢁC
(lit.5 115–116 ꢁC).
3.2.13. N-(2-Bromophenyl)thiobenzamide (1m)
Fine yellow crystals. Yield: 0.13 g, 75% from o-bromoaniline; mp
61–62 ꢁC (lit.17 85–86 ꢁC).
3.4. Reaction of thiobenzamides with CAN
3.2.14. N-(4-Nitrophenyl)thiobenzamide (1n)
Yellow needles. Yield: 0.12 g, 63% from p-nitroaniline; mp 143–
144 ꢁC (lit.18 145–146 ꢁC).
To a solution of the thiobenzamide (0.10 g) in acetonitrile (6 mL)
was added a solution of CAN (1.1 mol equiv) in water (4 mL). The
mixture was then stirred at room temperature for 30 min, extracted
into EtOAc (2ꢀ10 mL), dried, evaporated in vacuo, and then purified
by column chromatography.
3.3. Reaction of thiobenzamides with PIFA
3.4.1. N-(4-Methoxy-3,6-dioxocyclohexa-1,4-dien-1-yl)-
benzamide (3)
To a solution of the thiobenzamide (0.10 g) in CF3CH2OH
(1 mL) under an atmosphere of nitrogen was added PIFA
(1.1 mol equiv). The mixture was then stirred at room tempera-
ture for 30 min, evaporated in vacuo and then purified by column
chromatography. The benzothiazoles were recrystallized from
ethanol.
Orange solid. Yield: 0.05 g, 60% from 1d; mp 246–247 ꢁC
(decomp.). (Found: C, 65.52; H, 4.26; N, 5.41%. Anal. Calcd for
C
14H11NO4: C, 65.37; H, 4.31; N, 5.44%); nmax/cmꢂ1 3395, 3052,
1649; dH 3.89 (3H, s, OCH3), 6.59 (1H, s, 3-H), 7.53 (3H, m, 30,40,50-H),
7.87 (2H, m, 20,60-H), 8.29 (1H, s, 6-H), 8.43 (1H, s, N–H); dC 56.5,
97.4, 105.3, 120.8, 127.0, 128.8, 131.7, 135.1, 142.4, 142.8, 145.1.
3.3.1. 4-Methoxy-2-phenylbenzothiazole (2a)
White feathers. Yield: 0.05 g, 50% from 1a; mp 99–100 ꢁC (lit.2
103–104 ꢁC).
Acknowledgements
We gratefully acknowledge support of N.D.-R. by a University of
the West Indies (UWI) Research Fellowship.
3.3.2. 4,7-Dimethoxy-2-phenylbenzothiazole (2b)
White needles. Yield: 0.05 g, 52% from 1b; mp 118–119 ꢁC (lit.13
122–124 ꢁC).
References and notes
3.3.3. 4,6-Dimethoxy-2-phenylbenzothiazole (2c)
White needles. Yield: 0.04 g, 41% from 1c; mp 125–126 ꢁC (lit.19
125–127 ꢁC).
1. Bradshaw, T. D.; Wrigley, S.; Shi, D.; Schultz, R. J.; Paull, K. D.; Stevens, M. F. G. Br.
J. Cancer 1998, 77, 745.
2. Stevens, M. F. G.; McCall, C. J.; Lelieveld, P.; Alexander, P.; Richter, A. J. Med.
Chem. 1994, 37, 1689.
3. Jacobson, P. Chem. Ber. 1886, 19, 1067.
4. Bose, D. S.; Idrees, M. J. Org. Chem. 2006, 71, 8261.
3.3.4. 6-Bromo-4,7-dimethoxy-2-phenylbenzothiazole (2e)
White needles. Yield: 0.03 g, 26% from 1e; mp 120–121 ꢁC (lit.13
123–125 ꢁC).
5. Mu, X.; Zou, J.; Zeng, R.; Wu, J. Tetrahedron Lett. 2005, 46, 4345.
6. Bose, D. S.; Idrees, M. Tetrahedron Lett. 2007, 48, 669.
7. Downer-Riley, N. K.; Jackson, Y. A. Tetrahedron 2007, 63, 10276.
8. Ramsden, C. A.; Rose, H. L. J. Chem. Soc., Perkin Trans. 1 1995, 615.
9. Kita, Y.; Takada, T.; Tohma, H. Pure Appl. Chem. 1996, 68, 627.
10. Kita, Y.; Takada, T.; Mihara, S.; Tohma, H. Synlett 1995, 211.
11. (a) Chu, C.-M.; Gao, S.; Sastry, M. N. V.; Kuo, C.-W.; Lu, C.; Liu, J.-T.; Yao, C.-F.
Tetrahedron 2007, 63, 1863; (b) Hwu, J. R.; King, K.-Y. Curr. Sci. 2001, 8, 1043; (c)
Nair, V.; Matthew, J.; Prabhakaran, J. Chem. Soc. Rev. 1997, 127.
12. (a) Jacob, P.;Callery, P. S.;Shulgin,A. T.;Castagnoli, N.J.Org.Chem.1976, 41, 3627;(b)
Radeke, H. S.; Digits, C. A.; Bruner, S. D.; Snapper, M. L. J. Org. Chem. 1997, 62, 2823.
13. Lyon, M. A.; Lawrence, S.; Williams, D. J.; Jackson, Y. A. J. Chem. Soc., Perkin Trans.
1 1999, 437.
3.3.5. 5-Methoxy-2-phenylbenzothiazole (2f)
Fine white crystals. Yield: 0.07 g, 71% from 1f; mp 75–77 ꢁC
(lit.14 75–77 ꢁC).
3.3.6. 6-Methoxy-2-phenylbenzothiazole (2g)
White feathers. Yield: 0.07 g, 73% from 1g; mp 113–114 ꢁC (lit.2
114–115 ꢁC).
14. Downer, N. K.; Jackson, Y. A. Org. Biomol. Chem. 2004, 2, 3039.
15. Poor-Barltork, I. M.; Khodaei, M. M.; Nikoofar, K. Tetrahedron Lett. 2003, 44, 591.
16. Yonemoto, K.; Shibuya, I.; Tsuchiya, T.; Yasumoto, M.; Taguchi, Y. Bull. Chem. Soc.
Jpn. 1990, 63, 2933.
17. Bunnett, J. F.; Hrutfiord, B. F. J. Am. Chem. Soc. 1961, 83, 1691.
18. Okamoto, K.; Yamamoto, T.; Kanbara, T. Synlett 2007, 2687.
19. Charrier, J.; Landreau, C.; Deniaud, D.; Reliquet, F.; Reliquet, A.; Meslin, J. C.
Tetrahedron 2001, 57, 4195.
3.3.7. 5,6-Dimethoxy-2-phenylbenzothiazole (2h)
White needles. Yield: 0.10 g, 98% from 1h; mp 145–146 ꢁC (lit.2
142–144 ꢁC).
3.3.8. 4-Methyl-2-phenylbenzothiazole (2i)
Fine white crystals. Yield: 0.08 g, 77% from 1i; mp 123–124 ꢁC
(lit.19 124–125 ꢁC).
20. Perry, R. J.; Wilson, B. D. Organometallics 1994, 13, 3346.
21. Perregaard, J.; Lawesson, S. O. Acta Chem. Scand., Ser. B 1977, 31, 203.