Hypervalent iodine mediated intramolecular cyclization of thioformanilides: Expeditious approach to 2-substituted benzothiazoles

Article abstract of DOI:10.1021/jo0609374

A new, mild, and efficient method has been developed for the synthesis of 2-substituted benzothiazoles via the intramolecular cyclization of thioformanilides by using hypervalent iodine reagents in CH₂Cl ₂ at ambient temperature. The

Full text of DOI:10.1021/jo0609374

Hypervalent Iodine Mediated Intramolecular
Cyclization of Thioformanilides: Expeditious
Approach to 2-Substituted Benzothiazoles
Arylbenzthiazoles are most commonly synthesized via one
of the two major routes. The most commonly used method
involves the condensation of o-aminothiophenols with sub-
stituted nitriles, aldehydes, carboxylic acids, acyl chlorides, or
8
esters. This method, however, suffers from limitations such as
the difficulties encountered in the synthesis of readily oxidiz-
able o-aminothiophenols bearing substituent groups. Another
route is based on the Jacobson’s cyclization of thiobenza-
D. Subhas Bose* and Mohd. Idrees
Organic Chemistry DiVision III, Fine Chemicals Laboratory,
Indian Institute of Chemical Technology, Hyderabad, 500 007,
India
9
,10
nilides.
Other general methods include the microwave-
mediated reaction of o-aminothiophenol with â-chlorocinna-
maldehydes, the reaction of dibenzyl disulfides with o-aminothio-
phenol, the reduction of o,o′-dinitrodiphenyl disulfide, the
reaction of S-aryl thiobenzoate with arylhaloamines, from 1,2,3-
benzodithiazole-2-oxides, radical cyclization of benzyne inter-
dsb@iict.res.in; bose_iict@yahoo.co.in
ReceiVed May 5, 2006
11-16
mediates, and Grignard reactions of arylisothiocyanates.
More recently, arylbenzothiazoles have been prepared from the
oxidative coupling of thiophenols and aromatic nitriles17 using
cerric ammonium nitrate (CAN). However, the reported syn-
thesis of 2-arylbenzothiazoles mediated by CAN is irreproduc-
ible; the only products formed in this reaction are bis-(p-tolyl)
1
8
disulfide and p-tolyl p-toluenethiosulfonate. These strategies,
however, were found to be incompatible with nitro functionality,
requiring multistep synthesis, and therefore a new alternative
route for the synthesis of 2-arylbenzothiazoles needs to be
explored.
A new, mild, and efficient method has been developed for
the synthesis of 2-substituted benzothiazoles via the intramo-
lecular cyclization of thioformanilides by using hypervalent
Over recent years, organic derivatives of hypervalent iodine
reagents occupy an important place in the realm of natural and
synthetic organic chemistry because of their potential applica-
tions for the construction of carbon-heteroatom and carbon-
2 2
iodine reagents in CH Cl at ambient temperature. The
reaction proceeds via a thiyl radical in high yields to give
the novel compound oxybis benzothiazole and is also
amenable to generating combinatorial libraries of heterocyclic
compounds by solid-phase synthesis.
1
9
carbon bonds. One of the field’s most significant advances,
20
the discovery of the Dess-Martin periodinane (DMP) 1,1,1-
triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one, opens the
The exploration of privileged structures in drug discovery is
a rapidly emerging theme in medicinal chemistry. These
structures represent a class of molecules capable of binding to
multiple receptors with high affinity. The exploitation of these
molecules enables the medicinal chemist to rapidly discover
biologically active compounds across a wide range of thera-
peutic areas on a reasonable time scale. 2-Arylbenzothi-
azoles are an important class of bicyclic privileged substructures
owing to their potent utility as imaging agents for â-amyloid,
antitumor agents, calcium channel antagonists, antituberculotics,
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*
To whom correspondence should be addressed. Fax: +91-40-27160387.
1) Mathis, C. A.; Wang, Y.; Holt, D. P.; Huang, G.-F.; Debnath, M. L.;
Klunk, W. E. J. Med. Chem. 2003, 46, 2740-2754.
2) Hutchinson, I.; Jenninga, S. A.; Vishnuvajjala, B. R.; Westwell, A.
D.; Stevens, M. F. G. J. Med. Chem. 2002, 45, 744-747.
3) Stevens, M. F. G.; Wells, G.; Westwell, A. D.; Poole, T. D. PCT
Int. Appl., WO 0304479, 2003.
4) Caujolle, R.; Loiseau, P.; Payard, M.; Gayral, P.; Kerhir, M. N. Ann.
Pharm. Fr. 1989, 47, 68-73.
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Oya, M.; Iso, T.; Iwao J. Med. Chem. 1988, 31, 919-930.
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Polym. Degrad. Stab. 1991, 33, 53-66.
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A. HyperValent Iodine in Organic Synthesis; Academic Press: San Diego,
1996; p 256. (c) Wirth, T.; Hirt, U. H. Synthesis 1999, 1271-1287. (d)
Nicolaou, K. C.; Baran, P. S.; Zhong, Y.-L.; Sugita, K. J. Am. Chem. Soc.
2002, 124, 2221-2232 and references therein. (e) Bose, D. S.; Reddy, A.
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Sharma, V.; Saini, R.; Verma, R. S. J. Indian Chem. 2003, 80, 1031-
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(
(
(
(
(
1
0.1021/jo0609374 CCC: $33.50 © 2006 American Chemical Society
Published on Web 09/15/2006
J. Org. Chem. 2006, 71, 8261-8263
8261

SCHEME 1
TABLE 1. Results of DMP-Promoted Synthesis of
2-Arylbenzothiazoles
door to a mild oxidation procedure allowing a myriad of alcohols
to be converted to the corresponding carbonyl compounds. As
part of our ongoing program on the synthesis and development
of new methodologies in organic synthesis,21 we herein describe
a new, efficient, and practical route for the one-step conversion
of thioformanilides into the corresponding benzothiazoles by
using Dess-Martin periodinane in CH2Cl2 at room temperature
in excellent yields for a short period of time as required to
complete the reaction (TLC) (Scheme 1). To the best of our
knowledge, the generality and applicability of DMP in the
preparation of benzothiazoles from thioformanilides is not
known. The most versatile route to 2-arylbenzothiazoles bearing
substituents in both phenyl and benzothiazolyl rings started with
benzanilide prepared by the interaction of benzoyl chlorides and
arylamines in triethylamine. The benzanilides were converted
to thiobenzanilides with Lawesson’s reagent22 in refluxing dry
toluene.
To explore the generality and scope of this process, diverse
thioformanilides were studied to illustrate this novel and general
method for the synthesis of arylbenzothiazoles, and the results
are summarized in Table 1. As shown in the table, the synthesis
of 2-arylbenzothiazoles bearing substituents in both the rings
is accomplished in high yields. It is further seen that 2-aryl-
benzothiazoles bearing nitro functionality on the aryl ring
(entries 2 and 4) are obtained in quantitative yield by this
method. This contrasts, however, with the Bu3SnH/AIBN-
2
3
a
promoted cyclization of aryl radical onto thioamides for the
synthesis of arylbenzothiazoles, where under these conditions
thioamides containing a nitro functionality on the aryl ring
underwent decomposition rather than benzothiazole formation.
Furthermore, we have synthesized for the first time a new type
of bis(benzothiazoles) having an oxygen bridge between the
rings. Since a wide variety of arylamines and acids are
commercially available, this protocol would offer a higher
degree of flexibility with regard to functional groups that can
be placed on the 2-aryl moiety, thereby providing a better
understanding of this structure activity relationship (SAR) of
the target compounds. The usefulness of this methodology lies
in the fact that the reactions are carried out rapidly under
extremely mild conditions to give the product 2-arylbenzothia-
zoles (entries 2a-h) in high yields. Moreover, the method is
compatible with many substituents such as alkoxy, nitro, tert-
butyl, etc. in the substrate.
Yield refers to the pure isolated product.
promoted cyclization reaction is presented in Scheme 2.
Arylthioformanilide 1 can exist as thioiminol 1a; the latter reacts
with DMP to produce thiyl radical 1b while iodine(V) is reduced
to iodine(IV) at the same time. Subsequently, 1,5-homolytic
radical cyclization of 1b followed by aromatization of radical
1
c gives 2-arylbenzothiazole 2.
In conclusion, the short reaction period, the simple workup,
the good yield, and the fairly mild conditions of this method
offer advantages over other procedures, and this approach should
be of further interest in synthetic chemistry. Future work will
be undertaken to develop a combinatorial version of this
synthesis for the SAR of 2-arylbenzothiazoles for various
pharmaceutical applications.
Among the hypervalent iodine reagents such as IBX, DAIB
was studied for this transformation, DMP was found to be the
most effective in terms of conversion and reaction rates. A
plausible mechanism proposed for Dess-Martin periodinane
Experimental Section
General Procedure for the Preparation of Substituted 2-Aryl
Benzothiazole (2a-h). Dess-Martin periodinane (5.5 mmol) was
2
added to a stirred solution of thioformanilide (5.0 mmol) in CH -
Cl
by TLC. After completion, it was quenched with H
and the reaction mixture was extracted with CH Cl
The combined organic phase was dried with anhydrous Na
and the solvent was removed in vacuo, to afford the crude product
which was purified by column chromatography on silica gel using
petroleum ether/EtOAc 8:1 as eluent to give 2-arylbenzothiazole
2a-h (85-95%).
2
at room temperature. The progress of the reaction was monitored
O (2 × 5 mL),
(2 × 10 mL).
SO
(
20) (a) Dess, D. B.; Martin. J. C. J. Org. Chem. 1983, 48, 4155-4156.
(
(
b) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277-7287.
c) Meyer, S. D.; Schreiber, S. L. J. Org. Chem. 1994, 59, 7549-7552.
2
2
2
(
21) (a) Bose, D. S.; Jayalakshmi, B. J. Org. Chem. 1999, 64, 1713-
4
,
2
1
(
4
1
2
714. (b) Bose, D. S.; Kumar, R. K. Tetrahedron Lett. 2006, 47, 813-816.
c) Bose, D. S.; Rudra Das, A. P.; Mereyala, H. B. Tetrahedron Lett. 2002,
3, 9195-9197. (d) Bose, D. S.; Fatima, L.; Rajender, S. Synthesis 2006,
863-1867. (e) Bose, D. S.; Chary, M. V.; Mereyala, H. B. Heterocycles
006, 68, 1217-1224.
8
262 J. Org. Chem., Vol. 71, No. 21, 2006

SCHEME 2
Preparation of 6-Methoxy-2-[3,4-methylenedioxyphenyl]ben-
zothiazole (2a). Dess-Martin periodinane (2.33 g, 5.5 mmol) was
added to a stirred solution of thioformanilide (1.43 g, 5.0 mmol)
Preparation of 6,6′-Oxybis-2-[4-methylphenyl]benzothiazole
(2g). Dess-Martin periodinane (4.66 g, 11 mmol) was added to a
stirred solution of thioformanilide (2.34 g, 5.0 mmol) in CH Cl at
2 2
in CH
2
Cl
2
at room temperature. The progress of the reaction was
O (2
Cl (2
10 mL). The combined organic phase was dried with anhydrous
SO , and the solvent was removed in vacuo, to afford the crude
room temperature. The progress of the reaction was monitored by
TLC. After completion, it was washed and diluted with H
O (2 ×
5 mL), and the reaction mixture was extracted with CH Cl
(2 ×
10 mL). The combined organic phase was dried with anhydrous
Na SO , and the solvent was removed in vacuo, to afford the crude
monitored by TLC. After completion, it was washed with H
2
2
×
×
5 mL); and the reaction mixture was extracted with CH
2
2
2
2
Na
2
4
2
4
product which was purified by column chromatography on silica
gel using petroleum ether/EtOAc 8:1 as eluent to give subtituted
product which was purified by column chromatography on silica
gel using petroleum ether/EtOAc 8:1 as eluent to give oxybis
benzothiazole 2a (1.35 g, 95%) as a pale yellow solid: mp 164-
benzothiazole 2g (1.98 g, 85%) as a pale yellow solid: mp 216-
1
1
1
66 °C. H NMR (CDCl
3
): δ 3.88 (s, 3H), 6.02 (s, 2H), 6.83 (d,
217 °C. H NMR (CDCl
3
): δ 2.48 (s, 3H), 7.18-7.28 (m, 3H),
1
H, J ) 8.3 Hz), 7.02 (dd, 1H, J ) 2.26 Hz), 7.25 (1H, d, J ) 3.0
7.51 (s, 1H), 7.89-8.02 (m, 3H). 13C NMR (75 MHz): δ 21.5,
13
Hz), 7.48-7.58 (m, 2H), 7.85 (d, 1H, J ) 9.0 Hz). C NMR (75
MHz): δ 55.8, 101.6, 104.4, 107.3, 108.6, 115.4, 122.0, 123.5,
1
111.0, 118.7, 124.0, 127.3, 129.7, 130.9, 141.4, 150.3, 155.3. MS
+
(ESI): m/z (%) ) 465 (M , 55), 145 (100), 102 (78). Anal. Calcd
28.3, 136.3, 148.4, 148.7, 149.8, 157.7. MS (EI): m/z (%) ) 285
20 2 2
for C28H N OS : C, 72.38; H, 4.34; N, 6.02; S, 13.80. Found: C,
+
(
M , 100), 270 (80), 242 (15), 143 (13), 95 (20). Anal. Calcd for
S: C, 63.14; H, 3.88; N, 4.90; S, 11.24. Found: C,
3.05; H, 3.82; N, 4.96; S, 11.15.
72.32; H, 4.30; N, 5.94; S, 13.72.
15 3
C H11NO
6
Acknowledgment. M. Idrees thanks CSIR, New Delhi, for
financial support.
(
22) Thomsen, I.; Clausen, K.; Scheibye, S.; Lawesson, S.-O. Org. Synth.
984, 62, 158-164.
23) Bowman, W. R.; Heaney, H.; Jordan, B. M. Tetrahedron 1991, 47,
0119-10128.
24) Shi, D.-F.; Bradshaw, T. D.; Wrigley, S.; McCall, C. J.; Lelieveld,
P.; Fichtner, I.; Stevens, M. F. G. J. Med. Chem. 1996, 39, 3375-3384.
Supporting Information Available: Experimental procedure,
copies of H NMR, and C NMR spectra of 2a, 2c-h. This material
is available free of charge via the Internet at http://pubs.acs.org.
1
1
13
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1
(
JO0609374
J. Org. Chem, Vol. 71, No. 21, 2006 8263