Intra- and Intermodular C-S bond formation using a single catalytic system: First direct access to arylthiobenzothiazoles

Article abstract of DOI:10.1021/ol9017535

We have for the first time developed two llgand-assisted Cu(I)-catalyzed sequential Intra- and intermolecular 5-arylations leading to the direct synthesis of arylthiobenzothlazoles In one pot without an Inert atmosphere. Low catalyst loading, inexpensive

Full text of DOI:10.1021/ol9017535

ORGANIC
LETTERS
2009
Vol. 11, No. 19
4254-4257
Intra- and Intermolecular C-S Bond
Formation Using a Single Catalytic
System: First Direct Access to
Arylthiobenzothiazoles
Siva Murru, Harisadhan Ghosh, Santosh K. Sahoo, and Bhisma K. Patel*
Department of Chemistry, Indian Institution of Technology Guwahati,
Guwahati 781 039, India
patel@iitg.ernet.in
Received May 21, 2009
ABSTRACT
We have for the first time developed two ligand-assisted Cu(I)-catalyzed sequential intra- and intermolecular S-arylations leading to the direct
synthesis of arylthiobenzothiazoles in one pot without an inert atmosphere. Low catalyst loading, inexpensive metal catalyst and ligand, lower
reaction temperature, and shorter reaction times make this method superior to all reported methods for the synthesis of arylthiobenzothiazole.
In recent years, there has been an ever-increasing interest in
the field of metal-catalyzed multistep processes such as
tandem, domino, cascade, sequential, and/or concurrent
catalysis in which one or more catalysts are employed for
two or more transformations in one pot.1 Great efforts and
progress have been made in the development of Pd- and Cu-
catalyzed inter- and intramolecular domino reactions involv-
ing carbon-heteroatom bond formations for the synthesis
of a wide variety of heterocycles.2 However, the Cu-catalyzed
heteroarylation has proved to be much more advantageous
over Pd and other metal catalysts in terms of efficiency,
selectivity, low costs, and high functional group tolerance.3
Although the chemistry of Cu-catalyzed C-C, C-N, and
C-O bond formations is well explored,4 methods available
for the C-S bond formation5 are rather fewer because of
(3) Cu-catalyzed: (a) Beletskaya, I. P.; Cheprakov, A. V. Coord. Chem.
ReV. 2004, 248, 2337. (b) Nelson, T. D.; Crouch, R. D. Org. React. 2004,
63, 265. (c) Ley, S. V.; Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42,
5400. (d) Kunz, K.; Scholz, U.; Ganzer, D. Synlett 2003, 2428. (e) Hassan,
J.; Se´vignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M. Chem. ReV 2002, 102,
1359. Pd-limitations: (f) Shen, Q.; Shekhar, S.; Stambuli, J. P.; Hartwig,
J. F. Angew. Chem., Int. Ed. 2005, 44, 1371. (g) Huang, X.; Anderson,
K. W.; Zim, D.; Jiang, L.; Klapars, A.; Buchwald, S. L. J. Am. Chem. Soc.
2003, 125, 6653. (h) Cacchi, S.; Fabrizi, G.; Goggiamani, A.; Zappia, G.
Org. Lett. 2001, 3, 2539.
(4) (a) Jiang, L.; Buchwald, S. L. Metal-Catalyzed Cross-Coupling
Reactions, 2nd ed.; de Meijere, A., Diederich, F., Eds.; WILEY-VCH:
Weinheim, Germany, 2004; p 699. (b) Nakamura, I.; Yamamoto, Y. Chem.
ReV. 2004, 104, 2127. (c) Evano, G.; Blanchard, N.; Toumi, M. Chem.
ReV. 2008, 108, 3054. (d) Mannier, F.; Taillefer, M. Angew. Chem., Int.
Ed. 2008, 47, 3096.
(1) (a) Ajamian, A.; Gleason, J. L. Angew. Chem., Int. Ed. 2004, 43,
3754. (b) Verma, A. K.; Kesharwani, T.; Singh, J.; Tandon, V.; Larock,
R. C. Angew. Chem., Int. Ed. 2009, 48, 1138. (c) Tietze, L. F. Chem. ReV.
1996, 96, 115. (d) Mart´ın, R.; Rivero, M. R.; Buchwald, S. L. Angew. Chem.,
Int. Ed. 2006, 45, 7079. (e) Lee, J. M.; Na, Y.; Han, H.; Chang, S. Chem.
Soc. ReV. 2004, 33, 302. (f) Wasilke, J.-C.; Obrey, S. J.; Baker, R. T.; Bazan,
G. C. Chem. ReV. 2005, 105, 1001. (g) de Meijere, A.; Zezschwitz, P. V.;
Brase, S. Acc. Chem. Res. 2005, 38, 413.
(5) For a review dealing with the metal-catalyzed formation of
carbon-sulfur bonds, see: (a) Kondo, T.; Mitsudo, T. Chem. ReV. 2000,
100, 3205. Cu-based C-S intermolecular: (b) Hua-Jian, X.; Xiao-Yang,
Z.; Jin Deng, Y. F.; Feng, Y.-S. Tetrahedron Lett. 2009, 50, 434, and
references cited there in. (c) Bhadra, S.; Saha, A.; Ranu, B. C. Green Chem.
2008, 10, 1224. Intramolecular: (d) Bowman, W. R.; Heaney, H.; Smith,
P. H. G. Tetrahedron Lett. 1982, 23, 5093. (e) Evindar, G.; Batey, R. A. J.
Org. Chem. 2006, 71, 1802. (f) Joyce, L. L.; Evindar, G.; Batey, R. A.
Chem. Commun. 2004, 446. (g) Ma, H. C.; Jiang, X. Z. Synlett 2008, 1335.
(h) Wang, J.; Peng, F.; Jiang, J.-l.; Lu, Z.-j.; Wang, L.-y.; Bai, J.; Pan, Y.
Tetrahedron Lett. 2008, 49, 467.
(2) (Cu and Pd): (a) Loones, K. T. J.; Maes, B. U. W.; Meyers, C.;
Deruytter, J. J. Org. Chem. 2006, 71, 260(Cu): (b) Zou, B.; Yuan, Q.; Ma,
D. W. Angew. Chem., Int. Ed. 2007, 46, 2598. (c) Cacchi, S.; Fabrizi, G.;
Parisi, L. M. Org. Lett. 2003, 5, 3843. (d) Cacchi, S.; Fabrizi, G.; Parisi,
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10.1021/ol9017535 CCC: $40.75
Published on Web 09/08/2009
 2009 American Chemical Society

the propensity of thiols toward oxidative dimerization and
their affinity for metals, causing reduced catalytic efficiency.
Despite the plethora of C-heteroatom bond formation re-
ported, involving Pd, Cu-catalyzed multicatalytic processes,
there is no report on the tandem, domino, cascade, sequential,
and/or concurrent catalytic methods involving intramolecular
and intermolecular S-arylations. As a part of our ongoing
research in developing methods for the synthesis of hetero-
cycles,6 we were further interested in developing newer
protocols for the synthesis of heterocycles via two sequential
intra- and intermolecular C-S bond formations using a single
catalyst (Cu) in one pot.
2-Arylthiobenzothiazoles or 2-arylsulfanylbenzothiazole or
substituted 2-mercaptobenzothiazoles (MBTs) are an impor-
tant class of heterocycles that are found in a broad spectrum
of biologically active compounds. Some therapeutic agents
containing this core structure include potent heat shock
protein-90 inhibitors (A)7a and an inhibitor of Cathepsin-D
(B)7b(Figure 1). They also act as antimicrobial agents
basic condition.8 Alternatively, several cross-coupling reac-
tions were developed with similar coupling partners to
include a wide range of substrates.9 Pd-catalyzed synthesis
of thioethers from aryl iodides and arylthiols9a,b as well as
the Cu-catalyzed reaction of boronic acids with aryl, hetero
aryl, and alkyl N-thioimides to yield thioethers has been
reported.9c Recently, Bolm et al. reported the Fe-catalyzed
S-arylation protocol of aromatic and heteroaromatic thiols9d
but uncertanities exist about the exact catalytic role of Fe.9f
A Pd-catalyzed, Cu-mediated coupling of heteroaromatic
thioethers with aryl, hetero aryl, and alkenyl stannanes has
been described.9e Alternatively, Wang et al. developed a
method for the synthesis of 2-arylthiobenzothiazoles by the
S-arylation of benzothiazol-2-thiol with diaryliodonium salts
in an ioinic liquid [bmim]BF4.10 In addition, methods exist
for the syntheses of arylthiobenzothiazoles.11 However, the
preparation of arylthiobenzothiazoles with these methods
depends largely on the availability of the requisites, suitably
substituted 2-halo benzothiazole or mercapto benzothiazoles.
Previously, Batey and others have developed methods for
the synthesis of 2-substituted benzothiazoles from the cor-
responding 2-halothioanilides and 2-halothioureas via Pd-
and Cu-catalyzed intramolecular S-arylation.5e,12 In continu-
ation of our efforts in the synthesis of substituted 2-mer-
captobenzimidazole via Cu-catalyzed intramolecular C-N
bond formation6a we envisioned that it would be possible to
combine both the intra- and the intermolecular S-arylations
using a single catalytic system (Cu) in one pot for the
synthesis of 2-arylthiobenzothiazoles. Herein, we report our
efforts toward this target, resulting in the first direct access
to 2-arylthiobenzothiazoles (Scheme 1). In this single
Figure 1. Structures of some biologically important molecules
containing the 2-arylthiobenzothiazole moiety.
especially against Piricularia oryzae and Xanthomonas
oryzae.7c
Scheme 1. The Design of Direct Synthesis of
Classical methods for the synthesis of substituted MBTs
involve mainly two types of nucleophilic substitution reac-
tions. One by the nucleophilic attack of arylthiols with a
preformed 2-halobenzothiazoles and the second by the
nucleophilic attack of mercaptobenzothiazole with haloarenes
containing strongly deactivating substituents under a strongly
Arylthiobenzothiazoles via Two Sequential C-S Bond
Formations
(6) (a) Murru, S.; Patel, B. K.; Le Bras, J.; Muzart, J. J. Org. Chem.
2009, 74, 2217. (b) Murru, S.; Singh, C. B.; Kavala, V.; Patel, B. K.
Tetrahedron 2008, 64, 1931. (c) Yella, R.; Ghosh, H.; Patel, B. K. Green
Chem. 2008, 10, 1307. (d) Singh, C. B.; Murru, S.; Kavala, V.; Patel, B. K.
Org. Lett. 2006, 8, 5397.
catalytic one-pot double arylation strategy, intramolecular
S-arylation of dithiocarbamate salt would yield benzothiazol-
2-thiol or MBT, which is then followed by an intermolecular
C-S coupling giving directly 2-arylthiobenzothiazoles as
shown in Scheme 1.
(7) (a) Zhang, L.; Fan, J.; Vu, K.; Hong, K.; Le Brazidec, J.-Y.; Shi, J.;
Biamonte, M.; Busch, D. J.; Lough, R. E.; Grecko, R.; Ran, Y.; Sensintaffar,
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Bossio, R.; Marcaccini, S.; Pepino, R.; Torroba, T. Heterocycles 1996, 43,
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L. A.; Kirsch, G. Synlett 2007, 2121. (d) Ma, H. C.; Jiang, X. Z. Synlett
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Org. Lett., Vol. 11, No. 19, 2009
4255

The dithiocarbamate salt of 2-iodoaniline 1 was prepared
by treating it with CS2 and triethylamine following the
literature procedure,13 which was then used as a model
substrate for reaction optimization. Initially, the coupling of
dithiocarbamate 1 and iodobenzene (a) was selected to
optimize the reaction conditions taking CuI as the precatalyst
and K2CO3 as the base. In the absence of suitable ligand,
the first step (intramolecular) of the reaction was slow and
the second step (intermolecular) was not at all effective, while
phenanthroline ligand (L1) (Figure 2) was found to be most
zothiazole (MBT), the intermediacy of which has been
confirmed by its isolation. Since MBTs have found a wide
range of applications in different fields and their synthesis
involves arduous reaction conditions, in the absence of
iodoarenes the reaction can be stopped to isolate MBT in
quantitative yields.14 In the absence of any ligand or with
less efficient ligands (Figure 2), 2-mercaptobenzothiazole
(MBT) was obtained as the major product confirming the
faster intramolecular over the intermolecular S-arylation
(Scheme 2). For aryldithiocarbamates having o-halo (I or
Scheme 2. Synthesis of 2-Arylthiobenzothiazoles via Sequential
Cu-Catalyzed Intra- and Intermolecular S-Arylations
Figure 2. Effects of ligands on the Cu(I)-catalyzed reaction.
Br) substituents, no initial intermolecular S-arylation was
observed. In the absence of 2-halo substituents Cu-
nanoparticle catalyzed intermolecular S-arylation has been
reported.5c The intramolecular S-arylation is then followed by
an intermolecular S-arylation giving the arylthiobenzothiazole
in excellent yield as shown in Scheme 2 and Table 1.
effective (81%), an observation consistent with our previous
report on intramolecular C-N bond formation.6a Surpris-
ingly, the less expensive cyclohexyl-1,2-diamine ligand (L5)
was found to be even better in terms of superior yield (86%)
in a short reaction time (4 h) for this sequential reaction.
Thus from a series of experiments (Figure 2) the optimum
ratios of dithiocarbamate:aryl iodide:CuI:ligand (L5):base
were found to be 1:1:0.05:0.1:3. Further experimentation
revealed the significance of the solvent dependence for both
steps. Among the various solvents (DMF, 1,4-dioxane,
DMSO, DMA, and toluene) tested, the reaction was found
to be fastest in DMSO, and K2CO3 was found to be the ideal
base. Although the reaction works faster at higher temper-
ature we maintained a uniform temperature of 90 °C for both
steps for all the reactions. Further, the reactions are much
faster (4-8 h) compared to several similar intermolecular
C-S bond forming reactions reported to be taking place
above 100 °C for several hours.5
Even though the reaction is carried out in an air atmo-
sphere, no disulfide formation of any kind was observed,
thus ruling out the possibility of an oxidative path involving
dithiocarbamate disulfide as intermediate (Scheme 2), an
observation consistent with recent Fe-catalyzed C-S bond
formation.9d
Next, the scope of the reaction with various dithiocar-
bamates of 2-halo anilines and substituted anilines such as
2-iodoaniline 1, 2-bromoaniline 1′, 2-iodo-4-methylaniline
2, 2-bromo-4-methylaniline 2′, 4-chloro-2-iodoaniline 3,
4-bromo-2-iodoaniline 4, 2,4-dibromoaniline 4′, 2-bromo-
4-methoxyaniline 5′, 2-iodo-4,5-dimethylaniline 6, 2-bromo-
4,5-dimethylaniline 6′, and 2-bromo-4-(2-methyl[1,3]dithiolan-
2-yl-aniline 7′ was evaluated with various iodoarenes (a-h)
as their intermolecular coupling partners. In general, all the
reactions were very clean, and the 2-arylthiobenzothiazole
derivatives were obtained in high yields under the optimized
reaction conditions (Table 1). In these reactions, the most
crucial aspect is the formation of dithiocarbamate salts,13
and once the dithiocarbamate salts are obtained, the intramo-
lecular S-arylation is very effective. So far as the intramo-
lecular S-arylation is concerned both dithiocarbamate salts
of substituted 2-iodoanilines 1, 2, 3, 4, and 6 and 2-bromoa-
nilines 1′, 2′, 4′,5′, 6′, and 7′ are equally effective (Table 1).
The current catalytic system for double S-arylation is
effective for aryl iodide and substituted aryl iodides contain-
ing activating and deactivating substituents (a-h) (Table 1).
Although iodoarenes works efficiently, bromo- and chloro-
arenes were found not to be effective as the intermolecular
coupling partners.
It is reasonable to assume that the initial reaction proceeds
by an intramolecular S-arylation to give 2-mercaptoben-
(13) (a) Wong, R.; Dolman, S. J. J. Org. Chem. 2007, 72, 3969. (b) Li,
G.; Tajima, H.; Ohtani, T. J. Org. Chem. 1997, 62, 4539. (c) Emami, S.;
Foroumadi, A. Chin. J. Chem. 2006, 24, 791. (d) Sattigeri, V. J.; Soni, A.;
Singhal, S.; Khan, S.; Pandya, M.; Bhteja, P.; Mathur, T.; Rattan, A.;
Khanna, J. M.; Mehta, A. ArkiVoc 2005, 11, 46.
(14) See for applications and synthesis of MBT: As vulcanizing
accelerator: (a) Carr, E. L.; Smith, G. E. P. J.; Alliger, G. J. Org. Chem.
1949, 14, 921. As a reagent in Julia-olefinations: (b) Baudin, J. B.; Hareau,
G.; Julia, S. A.; Ruel, O. Tetrahedron Lett. 1991, 32, 1175. In catalysis:
(c) Kozikowski, A. P.; Tu¨ckmantel, W.; Bo¨ttcher, G.; Romanczyk, L. J.,
Jr. J. Org. Chem. 2003, 68, 1641. (d) Aimar, M. L.; Rossi, R. H. Tetrahedron
Lett. 1996, 37, 2137. (e) Aimar, M. L.; Rossi, R. H. Synthesis 2000, 1749.
As anticancer compounds: (f) Xanthopoulou, M. N.; Hadjikakou, S. K.;
Hadjiliadis, N.; Schu¨rmann, M.; Jurkschat, K.; Michaelidis, A.; Skoulika,
S.; Bakas, T.; Binolis, J.; Karkabounas, S.; Charalabopoulos, K. J. Inorg.
Biochem. 2003, 96, 425. Industrial preparation: (g) Isaacs, N. S.; Ismail,
Y.; Hilton, M. J.; Coulson, M. J. Phys. Org. Chem. 1998, 11, 1. Classical
synthesis: (h) Somerville, W. T.; Andersen, C. N. J. Org. Chem. 1960, 25,
656. (i) Aichaoui, H.; Lesieur, D.; Henichart, J. P. J. Heterocycl. Chem.
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4256
Org. Lett., Vol. 11, No. 19, 2009

p-NO2 (d), o-NO2 (e), o-COOMe (h) accelerate the rate of
the reaction giving products in shorter reaction times, whereas
electron donating substituents p-OMe (c), p-Me (b) retards
the reaction. This fact has been further verified with a
substrate containing strongly activating group (-NH2), where
no desired product was observed. However when NH2 group
was converted to moderatively activating group NHAc (f),
good conversion was observed giving product (1f) in 72%
yield. Thus, from the present study we found the following
Table 1. Synthesis of 2-Arylthiobenzothiazoles via Sequential
Cu-Catalyzed Intra- and Intermolecular S-Arylationsa
order of reactivity in aryl iodides p-NO2 > o-NO2
o-COOMe > m-Cl > H > p-Me > p-OMe.
>
The success of this strategies was finally applied to the
synthesis of Cathespin-D inhibitor analogues (2i) as shown
in Figure 3 demonstrating its potential utility.
Figure 3. Synthesis of cathespin-D analogues.
In summary, we have for the first time developed a single
catalytic system for two sequential intra- and intermolecular
S-arylations leading to a direct synthesis of 2-arylthioben-
zothiazoles from dithiocarbamates. Low catalyst loading,
inexpensive metal catalyst and ligand, lower reaction tem-
perature, and shorter reaction times make this method
superior to all methods reported so far, thus of potential
industrial significance.
Acknowledgment. We are grateful to the DST (SR/S1/
OC-15/2006) and CSIR [01(2270)/08/EMR-II] for funding.
S.M. and H.G. thank the CSIR for fellowships. Thanks are
also due to CIF, IIT Guwahati for mass and NMR spectra.
a Reactions were monitored by TLC. b Confirmed by IR, 1H NMR, and
13C NMR spectroscopy. c Isolated yields. d Reactions were carried out for
4 h. e Reactions were carried out for 6 h. f Reactions were carried out for
8 h.
Supporting Information Available: General information,
The reactions are equally effective irrespective of the
nature of the substituents (Y and Z) present in the dithio-
carbamate salts. However, an interesting trend in reactivity
was observed in its intermolecular coupling partners aryl
iodides. The presence of electron withdrawing substituents
1
experimental procedures, spectral data, and copies of H
NMR and 13C NMR spectra for all products. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL9017535
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