Synthesis of 2-arylbenzothiazoles by DDQ-promoted cyclization of thioformanilides; a solution-phase strategy for library synthesis

Article abstract of DOI:10.1055/s-2007-965929

Several substituted benzothiazoles were synthesized by the intramolecular cyclization of thioformanilides using 2,6-dichloro-3,5-dicyano-1,4-benzoquinone (DDQ) in dichloromethane at ambient temperature in high yields. The resulting 2-arylbenzothiazoles we

Full text of DOI:10.1055/s-2007-965929

SHORT PAPER
819
Synthesis of 2-Arylbenzothiazoles by DDQ-Promoted Cyclization of
Thioformanilides; A Solution-Phase Strategy for Library Synthesis
2
-Arylbenzothiazo
.
les by
D
D
Q
-
S
Promote
d
Cyc
u
lization of
T
b
hioformanili
hdes as Bose,* Mohd. Idrees, Bingi Srikanth
Organic Chemistry Division III, Fine Chemicals Laboratory, Indian Institute of Chemical Technology, Hyderabad, 500 007, India
Fax +91(40)27160387; E-mail: dsb@iict.res.in; E-mail: bose_iict@yahoo.co.in
Received 10 December 2006; revised 2 January 2007
Grignard reactions of aryl isothiocyanates.11–16 More re-
cently, arylbenzothiazoles have been prepared by oxida-
tive coupling of thiophenols and aromatic nitriles17 using
ammonium cerium(IV) nitrate (CAN). However, the re-
Abstract: Several substituted benzothiazoles were synthesized by
the intramolecular cyclization of thioformanilides using 2,6-dichlo-
ro-3,5-dicyano-1,4-benzoquinone (DDQ) in dichloromethane at
ambient temperature in high yields. The resulting 2-arylbenzothi-
azoles were separated from the reduced DDQ byproduct 4,5-dichlo- ported synthesis of 2-arylbenzothiazoles mediated by am-
ro-3,6-dihydroxyphthalonitrile by treatment of the reaction mixture
monium cerium(IV) nitrate is irreproducible; the only
with a strongly basic ion-exchange resin. This protocol offers a high
products formed in this reaction are di-4-tolyl disulfide
degree of flexibility with regard to the functional groups that can be
and 4-tolyl 4-toluenethiosulfonate.18 These strategies,
placed on the benzothiazole ring or 2-aryl moiety, which in turn
however, were found to be incompatible with a nitro func-
generates scaffolds for parallel synthesis.
tionality, thus requiring multistep synthesis. Therefore, a
Key words: thioformanilide, solution phase, cyclization, 2,6-
new, alternative route needs to be found that has signifi-
dichloro-3,5-dicyano-1,4-benzoquinone, benzothiazole, sulfanyl
cant practical value for the synthesis of 2-arylbenzothi-
radical
azoles. To overcome these limitations, herein, we report
an efficient intramolecular cyclization of thioformanilides
mediated by 2,3-dichloro-5,6-dicyano-1,4-benzoquinone
In recent years, the privileged structure concept has
(DDQ)19 without the use of a metal catalyst. DDQ is a
emerged as a useful approach for the discovery of novel
well-known oxidizing agent and has proved to be a versa-
biologically active molecules. Privileged structures, with
tile reagent for various organic transformations including
their inherent affinity for diverse biological receptors, rep-
the deprotection of functional groups, cleavage of linker
resent an ideal source of core scaffolds and capping frag-
molecules from solid supports, introduction of unsatura-
ments for the design and synthesis of combinatorial
tion, and potential applications for the construction of car-
libraries targeted at various receptors.1 Arylbenzothi-
bon–carbon and carbon–heteroatom bonds.
azoles bearing a substituent at C2 are of great interest as
Over the past decade, the synthesis of combinatorial li-
braries using both solution- and solid-phase methods have
gained importance in pharmaceutical and academic insti-
tutions.20 The preparation of compound libraries requires
robust procedures for both synthesis and purification in
order to obtain the final products in a pure form for bio-
logical screening. In continuation of our efforts towards
the development of new methodologies in organic synthe-
sis,21 herein we describe a new and practical route for the
synthesis of 2-arylbenzothiazoles using DDQ and its ap-
plication to the synthesis of a 176-member compound li-
brary (Scheme 1). To the best of our knowledge, the
generality and applicability of DDQ in the preparation of
benzothiazoles from thioformanilides is not known. In ad-
dition, this reaction is very clean and efficient and in-
volves a simple workup procedure. Unlike previous
methods, the reported protocol does not require high tem-
peratures to produce benzothiazole derivatives. Solvents
such as acetonitrile, tetrahydrofuran, methanol, and the
ionic liquid 1-butyl-3-methylimidazolium hexafluoro-
phosphate ([bmim]PF6) proved to be effective. Further-
more, we expected that 4,5-dichloro-3,6-dihydroxy-
phthalonitrile (DDP), the reduced product of DDQ, could
be easily removed from the reaction mixture by basic ion-
exchange resins thereby enabling the solution-phase syn-
thesis of the desired library. It should be noted that other
this structural framework has proved to be an important
class of bicyclic privileged substructures owing to their
potent utility as imaging agents for b-amyloid, chemilu-
minescent agents, calcium channel antagonists, antituber-
culotics, antitumor agents, antiparasitics, and also as
photosensitizers.2–7
Arylbenzothiazoles are most commonly synthesized by
one of two major routes. The most commonly used meth-
od involves the condensation of 2-aminothiophenols with
substituted nitriles, aldehydes, carboxylic acids, acyl
chlorides, or esters.8 This method, however, suffers from
limitations such as difficulties encountered in the synthe-
sis of readily oxidizable 2-aminothiophenols bearing sub-
stituents. Another route is based on Jacobson’s cyclization
of thiobenzanilides.9,10 Other general methods include mi-
crowave-mediated reaction of 2-aminothiophenol with b-
chlorocinnamaldehydes, reaction of dibenzyl disulfides
with 2-aminothiophenol, reduction of bis(2-nitrophenyl)
disulfide, reaction of S-aryl thiobenzoate with arylhalo-
amines, ring transformation of 1,2,3-benzodithiazole 2-
oxides, radical cyclization of benzyne intermediates, and
SYNTHESIS 2007, No. 6, pp 0819–0823
x
x
.
x
x
.2
0
0
7
Advanced online publication: 08.02.2007
DOI: 10.1055/s-2007-965929; Art ID: Z25806SS
© Georg Thieme Verlag Stuttgart · New York

820
D. S. Bose et al.
SHORT PAPER
O
Et3N, THF
R2
+
R1
Cl
N
R1
NH2
R2
H
O
S
S
DDQ, CH2Cl2
r.t., 20 min
Lawesson's reagent
toluene, reflux
R1
N
R2
N
H
R1
R2
1
2
Scheme 1
reagents such as iodotrimethylsilane and molecular iodine providing a means for understanding structure–activity
were ineffective even after longer reaction times, demon- relationships of the target compounds. The method is
strating the unique ability of DDQ in this cyclization. The compatible with many substituents such as alkoxy, nitro,
most versatile route to 2-arylbenzothiazoles 2, which have and tert-butyl.
substituents on both the phenyl and benzothiazolyl rings,
A plausible mechanism for the DDQ-promoted cycliza-
began with benzanilides that were prepared by the reac-
tion reaction is presented in Scheme 2. Arylthioformanil-
tion of benzoyl chlorides and arylamines in triethylamine.
ide 3 can exist as thioiminol A, which reacts with DDQ to
produce sulfanyl radical B. Subsequently, 1,5-homolytic
radical cyclization of C followed by aromatization of rad-
ical intermediate 1c gives 2-arylbenzothiazole 4.
The benzanilides were converted into thioformanilides 1
with Lawesson’s reagent22 in refluxing anhydrous tolu-
ene.
To explore the generality and scope of this process, di-
verse thioformanilides 1 were studied in the synthesis of
2-arylbenzothiazoles 2 and the results are illustrated in
Encouraged by these results, we were interested in explor-
ing the possibility of generating a library of benzothiazole
compounds. For this to be possible, the prerequisite is to
Table 1. As shown in Table 1, the synthesis of 2-arylben-
remove the DDP in a high-throughput format. Among
zothiazoles bearing substituents on both rings was accom-
various purification methods available for solution-phase
plished in high yields. It can be further seen that 2-
combinatorial synthesis, the treatment of reaction solu-
arylbenzothiazoles bearing a nitro functionality on the
tions with ion-exchange resins have proven effective in
aryl ring (entries 2, 3, 5, and 6) were obtained in high
the removal of some acidic or basic byproducts, and there
yields by this method. This contrasts, with the tributyltin
is a recent report demonstrating applicability to a 96-well
hydride/2,2¢-azobis(isobutyronitrile) promoted23 cycliza-
tion of aryl radicals onto thioamides for the synthesis of
arylbenzothiazoles, where, under these conditions thio-
amides containing a nitro functionality on the aryl ring
underwent decomposition rather than benzothiazole for-
mation. Furthermore, we have synthesized for the first
time, a bis(benzothiazole) possessing an oxygen bridge
between the rings. Since a wide variety of arylamines and
acids are commercially available, this protocol offers a
high degree of flexibility with regard to functional groups
on the benzothiazole nucleus or 2-aryl moiety, thereby
format.24 We assumed that basic ion-exchange resins
could be a good option to neutralize and absorb acidic
DDP. Amberlite IRA-900, which is a macroreticular resin
with benzyltrialkylammonium functionality, proved to be
the most efficient in this regard. The results are summa-
rized in Table 1 as isolation B.25 Thus, four grams of the
aforementioned resin was freshly washed by methanol
and used for the purification of each reaction on a 0.2-
mmol scale, and this simple treatment gave the desired
product in excellent purities. Since we used an exactly
equal amount of DDQ in the reaction, which gave compa-
R1
R1
R1
.
S
S
SH
DDQ
N
H
N
N
R2
A
R2
R2
B
3
R1
R1
S
N
S
N
R2
R2
.
4
C
Scheme 2
Synthesis 2007, No. 6, 819–823 © Thieme Stuttgart · New York

SHORT PAPER
2-Arylbenzothiazoles by DDQ-Promoted Cyclization of Thioformanilides
821
Table 1 DDQ-Catalyzed Synthesis of 2-Arylbenzothiazoles
Entry
Product
Isolationa A
Yieldb (%)
Isolationa B
Yieldc (%)
Purityd (%)
O
MeO
MeO
S
N
S
N
1
2
2a
2b
95
89
72
68
98
91
O
N
Me
Me
OMe
MeO
MeO
S
N
3
2c
95
82
89
Me
NO2
O
S
N
4
5
6
7
2d
2e
2f
88
85
82
90
85
56
61
75
92
88
86
87
O
F
S
N
NO2
Me
F
HO
S
NO2
N
Me
O
2g
N
S
OMe
N
S
N
8
9
2h
2i
95
85
90
55
97
85
O
O
S
S
N
Me
Me
N
S
N
10
2j
89
72
93
Me
a Isolation A, material produced by conventional synthesis on a 5-mmol scale as given in experimental section; Isolation B, material produced
using the solution-phase library method.
b Yield refers to the pure isolated product.
c Crude yields after ion-exchange resin treatment.
d HPLC purities of Isolation B were determined by integration peak areas at 255 nm without calibration.
rable results to the aforementioned use of 1.1 equivalents In summary, we have observed a novel DDQ-catalyzed
of DDQ, there was no need to use a polymer-bound scav- cyclization of thioformanilides to give the corresponding
enger resin for removing DDQ from the reaction solu- 2-substituted benzothiazoles in high yields with complete
tions.26
selectivity. Moreover, the combination of this procedure
with the use of basic ion-exchange resin allows for com-
Synthesis 2007, No. 6, 819–823 © Thieme Stuttgart · New York

822
D. S. Bose et al.
SHORT PAPER
dissolved in CH2Cl2 (0.2 mL) in each well, which was subsequently
treated with 0.1 M DDQ in 10% THF–CH2Cl2 (0.2 mL). The exact
equivalent amount of DDQ was used in order to facilitate subse-
quent purification. The addition of THF was used to increase the
solubility of DDQ. The reaction plates were agitated at r.t. for 2 h
before the solns were transferred to the corresponding filter bottom
plates loaded with freshly washed (MeOH) and dried Amberlite
IRA-900 (0.4 g) in each well. Additional CH2Cl2 (0.4 mL) was add-
ed to each well. The plates were clamped and rotated slowly for 1 h
before filtering the soln into collection plates. The higher freezing
temperature of CH2Cl2 allowed the solns to be frozen so that possi-
ble leakage during the transfer was avoided. Finally, removal of sol-
vents using a plate rotatory evaporator gave the desired compounds
in the collection plates. The library was characterized by LC-MS.
The purity of the individual compound determined by LC integra-
tion without calibration. As a result, 70% of the library showed pu-
rity >70%, while 10% of the compounds had purities <45%.
binatorial library synthesis. The method described here
represents the first example for benzothiazole library syn-
thesis by a solution-phase strategy. Further investigations
for broadening the synthetic application of this cyclization
to develop a combinatorial version for structure–activity
relationship studies of 2-arylbenzothiazoles for various
pharmaceutical applications are currently in progress.
Compounds 2a,c–f,h,j were characterized and found to have data
comparable to those given in the literature.20a
Substituted 2-Arylbenzothiazoles 2a–j; General Procedure
DDQ (5.5 mmol) was added to a stirred soln of thioformanilide (5.0
mmol) in CH2Cl2 at r.t. The progress of the reaction was monitored
by TLC. When the reaction was complete, it was quenched with
H2O (2 × 5 mL) and the mixture was extracted with CH2Cl2 (2 × 10
mL). The combined organic phases were dried (anhyd Na2SO4) and
the solvent was removed in vacuo, to afford the crude product which
was purified by column chromatography (silica gel, petroleum
ether–EtOAc, 8:1) to give 2a–j; yield: 82–95%.
Acknowledgment
The authors thank CSIR (M.I.) and UGC (B.S.) New Delhi, for fi-
nancial support.
2-(Dimethylamino)-6-methoxybenzothiazole (2b)
Light brown solid; yield: 91%; mp 178–180 °C.
References
1H NMR (CDCl3): d = 3.06 (s, 6 H), 3.88 (s, 3 H), 6.71 (d, J = 9.06
Hz, 2 H), 6.98 (dd, J = 9.06, 3.02 Hz, 1 H), 7.24–7.27 (m, 1 H),
7.80–7.88 (m, 3 H).
13C NMR (75.5 MHz, CDCl3): d = 40.1, 55.8, 104.4, 111.7, 114.8,
121.6, 122.7, 128.5, 135.8, 148.9, 151.9, 157.0, 166.4.
MS (EI): m/z (%) = 284 (M+, 100), 269 (80), 253 (55), 241 (75), 149
(75), 95 (50), 85 (50), 43 (75).
(1) (a) DeSimone, R. W.; Currie, K. S.; Mitchell, S. A.; Darrow,
J. W.; Pippin, D. A. Comb. Chem. High Throughput
Screening 2004, 7, 473. (b) Horton, D. A.; Bourne, G. T.;
Smythe, M. L. Chem. Rev. 2003, 103, 893.
(2) (a) Mathis, C. A.; Wang, Y.; Holt, D. P.; Huang, G.-F.;
Debnath, M. L.; Klunk, W. E. J. Med. Chem. 2003, 46,
2740. (b) Hutchinson, I.; Jennings, S. A.; Vishnuvajjala, B.
R.; Westwell, A. D.; Stevens, M. F. G. J. Med. Chem. 2002,
45, 744. (c) Alagille, D.; Baldwin, R. M.; Tamagnan, G. D.
Tetrahedron Lett. 2005, 46, 1349.
(3) Stevens, M. F. G.; Wells, G.; Westwell, A. D.; Poole, T. D.
WO 03,004,479, 2003; Chem. Abstr., 2003, 138, 106698.
(4) Caujolle, R.; Loiseau, P.; Payard, M.; Gayral, P.; Kerhir, M.
N. Ann. Pharm. Fr. 1989, 47, 68.
(5) Yamamoto, K.; Fujita, M.; Tabashi, K.; Kawashima, Y.;
Kato, E.; Oya, M.; Iso, T.; Iwao, J. J. Med. Chem. 1988, 31,
919.
2-(4-Methoxyphenyl)-6-morpholin-4-ylbenzothiazole (2g)
Pale yellow solid; yield: 90%; mp 182–184 °C.
1H NMR (DMSO-d6): d = 3.20 (t, J = 4.6 Hz, 4 H), 3.77 (t, J = 4.6
Hz, 4 H), 3.82 (s, 3 H), 7.07 (d, J = 8.6 Hz, 2 H), 7. 21 (dd, J = 8.9,
2.4 Hz, 1 H), 7.55 (d, J = 2.3 Hz, 1 H), 7.82 (d, J = 8.9 Hz, 1 H),
7.93 (d, J = 8.8 Hz, 2 H).
13C NMR (75.5 MHz, DMSO-d6): d = 48.8, 55.4, 66.0, 106.3, 114.8,
116.2, 122.5, 125.7, 128.2, 136.0, 147.2, 149.0, 161.2, 163.3.
(6) Yoshida, H.; Nakao, R.; Nohta, H.; Yamaguchi, M. Dyes
Pigm. 2000, 47, 239.
(7) Petkov, I.; Deligeorgiev, T.; Markov, P.; Evstatiev, M.;
Fakirov, S. Polym. Degrad. Stab. 1991, 33, 53.
(8) Ben-Alloum, A.; Bakkas, S.; Soufiaoui, M. Tetrahedron
Lett. 1997, 38, 6395.
(9) (a) Shi, D.-F.; Bradshaw, T. D.; Wrigley, S.; McCall, C. J.;
Lelieveld, I. F.; Stevens, M. F. G. J. Med. Chem. 1996, 39,
3375. (b) Klunk, W. E.; Mathis, C. A. Jr.; Wang, Y. WO
2004,083,195, 2004.
(10) Hein, D. W.; Alheim, R. J.; Leavitt, J. J. J. Am. Chem. Soc.
1957, 79, 427.
(11) (a) Paul, S.; Gupta, M.; Gupta, R. Synth. Commun. 2002, 32,
3541. (b) Kamila, S.; Koh, B.; Biehl, E. R. J. Heterocycl.
Chem. 2006, 43, 1609.
(12) Shirinian, V. Z.; Melkova, S. Yu.; Belen’kii, L. I.;
Krayushkin, M. M.; Zelinsky, N. D. Russ. Chem. Bull. 2000,
49, 1859.
(13) Zhong, W. H.; Zhang, Y. M.; Chen, X. Y. J. Indian Chem.
Soc. 2001, 78, 316.
(14) (a) Huang, S.; Connolly, P. J. Tetrahedron Lett. 2004, 45,
9373. (b) Roe, A.; Tucker, W. P. J. Heterocycl. Chem. 1965,
2, 148.
LC-MS (ESI): m/z [M]+ calcd for C18H18N2O2S2: 326.11; found:
326.22.
Bis[4-(4-Tolyl)benzothiazol-6-yl Ether (2i)
Light yellow solid; yield: 85%; mp 216–217 °C.
1H NMR (CDCl3): d = 2.48 (s, 6 H), 7.18–7.28 (m, 6 H), 7.51 (s, 2
H), 7.89–8.02 (m, 6 H).
13C NMR (75 MHz): d = 21.5, 111.0, 118.7, 124.0, 127.3, 129.7,
130.9, 136.3, 141.4, 150.3, 155.3.
HRMS (ESI): m/z [M + H]+ calcd for C28H21N2OS2: 465.1095;
found: 465.1100.
Preparation of a 176-Member Library Using a Solution-Phase
Method
Stock 0.1 M solns of 8 substituted anilines and 22 benzoyl chlorides
in THF were prepared. They were then mixed in two 2-mL 96
(8 × 12) deep-well plates using substituted aniline (0.2 mL), ben-
zoyl chloride (0.2 mL), and Et3N (0.2 mL) in each well. The result-
ing plates were stirred at r.t. for 5 h. Et3N and THF were then
removed by a plate rotary evaporator and the resulting residue was
redissolved using toluene (0.2 mL) and Lawesson’s reagent (0.2
mL) in each well. The resulting plates were refluxed at 100 °C for 2
h. The toluene was then removed and the resulting residue was re-
(15) Stanetty, P.; Krumpark, B. J. Org. Chem. 1996, 61, 5130.
Synthesis 2007, No. 6, 819–823 © Thieme Stuttgart · New York

SHORT PAPER
2-Arylbenzothiazoles by DDQ-Promoted Cyclization of Thioformanilides
823
(16) (a) Ares, J. J. Synth. Commun. 1991, 21, 625. (b) Majo, V.
J.; Prabhakaran, J.; Mann, J. J.; Kumar, J. S. D. Tetrahedron
Lett. 2003, 44, 8535.
(21) (a) Thompson, L. A.; Ellman, J. A. Chem. Rev. 1996, 96,
555. (b) Balkenhohl, R.; Bussche-Hunnefeld, C. V. D.;
Lansky, A.; Zechel, C. Angew. Chem. Int. Ed. 1996, 35,
2288. (c) Baldino, C. M. J. Comb. Chem. 2000, 2, 89.
(22) Thomsen, I.; Clausen, K.; Scheibye, S.; Lawesson, S.-O.
Org. Synth. Coll. Vol. VII; John Wiley & Sons: London,
1990, 372.
(17) Tale, R. H. Org. Lett. 2002, 4, 1641.
(18) Nair, V.; Augustine, A. Org. Lett. 2003, 5, 543.
(19) (a) Buckle, D. R. Encyclopedia of Reagents for Organic
Synthesis, Vol. 3; Paquette, L. A., Ed.; John Wiley & Sons:
Chichester, 1995, 1699. (b) Bharate, B. Synlett 2006, 496.
(c) Zhang, Y.; Li, C.-J. J. Am. Chem. Soc. 2006, 128, 4242.
(20) (a) Bose, D. S.; Idrees, Md. J. Org. Chem. 2006, 71, 8261.
(b) Bose, D. S.; Kumar, R. K. Tetrahedron Lett. 2006, 47,
813. (c) Bose, D. S.; Fatima, L.; Rajender, S. Synthesis 2006,
1863. (d) Bose, D. S.; Idrees, Md. J. Heterocycl. Chem.
2007, 44, 211. (e) Bose, D. S.; Narsimha Reddy, A. V.
Tetrahedron Lett. 2003, 44, 3543.
(23) Bowman, W. R.; Heaney, H.; Jordan, B. M. Tetrahedron
1991, 47, 10119.
(24) Bookser, B. C.; Zhu, S. J. Comb. Chem. 2001, 3, 205.
(25) The material loss, as indicated by crude yields in Table 1,
was mainly due to the binding of the product to the resin. In
order to keep the same method as used in the final library
synthesis, we did not use excessive solvent, which was
limited by the volume of the collection plate, to wash the
resin to improve the yields
(26) Deegan, T. L.; Gooding, O. W.; Baudart, S.; Porco, J. A.
Tetrahedron Lett. 1997, 38, 4973.
Synthesis 2007, No. 6, 819–823 © Thieme Stuttgart · New York