Copper- and palladium-catalyzed intramolecular C-S bond formation: A convenient synthesis of 2-aminobenzothiazoles

Article abstract of DOI:10.1039/b311591g

Copper- and palladium-catalyzed intramolecular C-S bond formation by cross-coupling between an aryl halide and thiourea functionality is demonstrated for the synthesis of 2-aminobenzothiazoles, wherein the Cu-catalyzed protocol is generally superior and more cost effective than the Pd-catalyzed protocol; the Cu-catalyzed reaction also further expands recent studies exploring the utility of Cu salts as replacements for Pd in carbon-heteroatom bond-forming reactions. A one-pot variant combining the synthesis of the thiourea and the cyclization was also demonstrated.

Full text of DOI:10.1039/b311591g

Copper- and palladium-catalyzed intramolecular C–S bond formation: a
convenient synthesis of 2-aminobenzothiazoles†
Laurie L. Joyce, Ghotas Evindar and Robert A. Batey*
Davenport Research Laboratories, Department of Chemistry, University of Toronto, 80 St. George Street,
Toronto, ON, Canada M5S 3H6. E-mail: rbatey@chem.utoronto.ca
Received (in Corvallis, OR, USA) 22nd September 2003, Accepted 22nd December 2003
First published as an Advance Article on the web 28th January 2004
Copper- and palladium-catalyzed intramolecular C–S bond
formation by cross-coupling between an aryl halide and
thiourea functionality is demonstrated for the synthesis of
2-aminobenzothiazoles, wherein the Cu-catalyzed protocol is
generally superior and more cost effective than the Pd-catalyzed
protocol; the Cu-catalyzed reaction also further expands recent
studies exploring the utility of Cu salts as replacements for Pd
in carbon–heteroatom bond-forming reactions. A one-pot vari-
ant combining the synthesis of the thiourea and the cyclization
was also demonstrated.
group functionalities.9 We were also particularly interested to make
a direct comparison between the use of Pd versus Cu catalysts for
the cyclization of 1.10
The precursors 1 were readily synthesized using isothiocyanate
methodology, using commercially available ortho-haloanilines 3 or
ortho-haloaryl isothiocyanates 4 (Scheme 2). Reaction of 3 with
isothiocyanate in dimethylformamide (DMF) gave thiourea 1 in
12–48 h, whereas reaction of 4 with either primary or secondary
amines in acetonitrile gave 1 in less than 10 min, in quantitative
yield, without any requirement for work-up. The intramolecular
cyclization of 1 was investigated using either Pd(PPh3)4 (5 mol%)
or CuI (5 mol%) and 1,10-phenanthroline (10 mol%), in the
presence of a mild base (Cs2CO3, 2 equiv.), in dimethoxyethane
(DME) at 80 °C. These conditions were modified from those
previously optimized for intramolecular aryl guanidinylation.2,11
Initial studies focussed upon the reaction of N,NA-disubstituted
thioureas 1 containing an ortho-bromoaryl group (Table 1, entries
1–5). In general, good to excellent yields of 2 were obtained with
both Pd and Cu catalysis, although poorer conversions were
apparent in the case of the Pd-catalyzed reactions. In these cases,
only products 2 resulting from cyclization through S were
observed, with no evidence for the formation of N-substituted
1,3-dihydrobenzoimidazole-2-thione products that would form
from cyclization through the N atom.12 In the case of N,N,NA-
trisubstituted thioureas 1, excellent conversion ( > 98%) and yields
were obtained for both Pd and Cu catalysis (Table 1, entries 6–11).
These results reflect the presumably more nucleophilic nature of the
trisubstituted thioureas as compared with their disubstituted
analogs, which results in greater conversions in the case of the Pd-
catalyzed reactions, as well as the much greater solubility of the
products 2 when R1 and R2 ≠ H. The reaction is compatible with
both electron-withdrawing and electron-donating substituents on
the aromatic ring (Table 1, entries 12–15). The reaction also works
with ortho-iodoaryl precursors 1, giving comparable or somewhat
higher yields than the corresponding reactions from the ortho-
bromoaryl precursors (Table 1, bracketed entries 1, 4, 6, 7 and
11).
Aryl–heteroatom bond formation via transition metal-catalyzed
cross-coupling has been a subject of particular interest in recent
years. While a considerable body of work has been amassed in the
new C–N and C–O bond-forming technologies, there are few
protocols for the corresponding reactions involving C–S bond
formation, despite the importance of sulfur-containing aromatic
and heteroaromatic biologically-active compounds. One such class
of compounds are 2-aminobenzothiazoles which have both phar-
maceutical and agrochemical relevance.1 As an extension of our
recent interest in 2-aminobenzimidazole synthesis through copper-
and palladium-catalyzed intramolecular aryl guanidinylation, we
now report the synthesis of 2-aminobenzothiazoles through analo-
gous C–S bond-forming methodologies.2
Palladium catalysis has been demonstrated for cross-coupling
reactions of thiols with aryl halides to achieve aryl C–S bond
formation.3 Disadvantages of Pd-catalyzed methods include the
high cost of the catalysts and the well-known problems associated
with the removal of palladium-residues from polar reaction
products during the late stages of pharmaceutical compound
synthesis. Copper salts have also been used to mediate C–S bond
formation, although the traditional methods suffer from the use of
high reaction temperatures, functional group sensitivity, the
requirement for substrates with ortho-carbonyl groups that are both
electron-withdrawing and capable of chelating copper, and the use
of stoichiometric amounts of copper.4–5 Recently, new catalytic
copper-based processes for the intermolecular cross-coupling of
aryl iodides with thiols have been reported by Palomo et al.,6
Venkataraman and co-workers,7 and Buchwald and Kwong.8
Based on the success of these intermolecular aryl thiolation
processes, we considered that either Cu- or Pd-catalyzed cycliza-
tion of ortho-halobenzothioureas 1 would represent a viable
method for the formation of substituted 2-aminobenzothiazoles 2
(Scheme 1). This route would provide significant benefits over
traditional methods for the formation of 2, which employ multi-step
routes using harsher reaction conditions not compatible with certain
Finally, a convenient one-pot Pd- and Cu-catalyzed variant of the
reaction was developed for the formation of 2a from 4a (Scheme 3).
Treatment of ortho-bromophenylisothiocyanate with benzylamine
in acetonitrile could be accomplished at room temperature within 1
h. Addition of the appropriate catalyst/ligand [i.e. CuI and
1,10-phenanthroline, or Pd(PPh3)4] and Cs2CO3, then achieved the
essentially quantitative formation of 2a after refluxing in acetoni-
trile for 24 h.
In summary, we have demonstrated an efficient intramolecular
aryl thiolation using catalytic amounts of Pd(PPh3)4 and CuI. In
general, the copper-catalayzed protocol leads to greater yields and
conversions than the palladium-catalyzed protocol. Cu and Pd one-
pot protocols were also demonstrated, combining the thiourea
Scheme 1
† Electronic supplementary information (ESI) available: general experi-
mental details, general procedure for the preparation of 2-aminobenzothia-
zoles, and analytical data for 2-aminobenzothiazole products. See http://
www.rsc.org/suppdata/cc/b3/b311591g/
Scheme 2 Reagents and conditions: (a) R1NCS, DMF, 12–48 h; (b)
R1R2NH, MeCN, 10 min.
446
C h e m . C o m m u n . , 2 0 0 4 , 4 4 6 – 4 4 7
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4

View Article Online
Table 1 Intramolecular 2-aminobenzothiazole 2 synthesis from ortho-
bromo- and -iodo-arylthioureas 1
for an USRA fellowship. G. E. thanks the University of Toronto for
fellowship support. R. A. B. gratefully acknowledges receipt of a
Premier’s Research Excellence Award. We thank Dr A. B. Young
for mass spectrometric analysis.
Pd catalyst
Cu catalyst
Notes and references
Conv. Yield
Conv. Yield
1 For example, see: Frentizole (immunosuppressive agent): C. J. Paget, K.
Kisner, R. L. Stone and D. C. DeLong, J. Med. Chem., 1969, 12,
1016–1018; Methanezthiazuron (herbicide): P. Lours, Def. Veg., 1970,
24, 91–99; Zolantidine (centrally acting H2 receptor histamine antago-
nist): R. C. Young, R. C. Mitchell, T. H. Brown, C. R. Ganellin, R.
Griffiths, M. Jones, K. K. Rana, D. Saunders, I. R. Smith, N. E. Sore and
T. J. Wilks, J. Med. Chem., 1988, 31, 656–671.
2 G. Evindar and R. A. Batey, Org. Lett., 2003, 5, 133–136.
3 T. Migita, T. Shimizu, Y. Asami, J.-I. Shiobara, Y. Kato and M. Kosugi,
Bull. Chem. Soc. Jpn., 1980, 53, 1385–1389; M. Kosugi, T. Ogata, M.
Terada, H. Sano and T. Migita, Bull Chem. Soc. Jpn., 1985, 58,
3657–3658; N. Zheng, J. C. McWilliams, F. J. Fleitz, J. D. Armstrong
III and R. P. Volante, J. Org. Chem., 1998, 63, 9606–9607; G. Y. Li,
Angew. Chem., Int. Ed., 2001, 40, 1513–1516; G. Y. Li, G. Zheng and
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Schlapbach, Tetrahedron, 2001, 57, 3069–3073; J. C. McWilliams, F. J.
Fleitz, N. Zheng and J. D. Armstrong III., Org. Synth., 2002, 79, 43–51;
G. Y. Li, J. Org. Chem., 2002, 67, 3643–3650.
4 For a review, see: J. Lindley, Tetrahedron, 1984, 40, 1433–1456.
5 G. P. Dhareshwar, P. N. Chhaya and B. D. Hosangadi, Indian J. Chem.,
Sect. B, 1980, 831–835; T. Yamamoto and Y. Sekine, Can. J. Chem.,
1984, 62, 1544–1547; N. N. Kulkarni, V. S. Kulkarni, S. R. Lele and B.
D. Hosangadi, Tetrahedron, 1988, 44, 5145–5149; J. Rabai, I. Kapovits,
B. Tanacs and J. Tamas, Synthesis, 1990, 847–849; A. J. G. Baxter and
S. J. Teague, Tetrahedron, 1993, 49, 9089–9094; A. Pinchart, C.
Dallaire and M. Gingras, Tetrahedron Lett., 1998, 39, 543–546; A. Van
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64, 2986–2987.
Entry R1R2N
R3
H
(%)b
(%)c
(%)b
(%)c
1
2
BnNH
84
95
> 98
quant.
( > 98) (quant.) ( > 98) (quant.)
H
90
86
95
70
85
90
3
4
H
H
85
59
> 98
> 98
90
80
(95)
(94)
( > 98) (quant.)
5
6
H
H
> 98
52
> 98
86
> 98
94
> 98
98
( > 98) (quant.) ( > 98) (quant.)
> 98 87 > 98 94
7
H
( > 98) (quant.) ( > 98) (quant.)
8
9
H
H
> 98
> 98
94
89
> 98
> 98
87
quant.
10
11
H
H
> 98
> 98
86
84
> 98
> 98
93
84
MeN(CH2)2CN
( > 98) (93)
( > 98) (quant.)
12
13
14
15
a
BnNH
BnNH
BnNH
BnNH
4-F
4-Me
90
80
93
71
88
90
90
69
97
89
78
> 98
> 98
> 98
6 C. Palomo, M. Oiarbide, R. Lopez and E. Gomez-Bengoa, Tetrahedron
Lett., 2000, 41, 1283–1286.
4-Me-6-Br > 98
5-CF3 > 98
7 C. G. Bates, R. K. Gujadhur and D. Venkataraman, Org. Lett., 2002, 4,
2803–2806.
Reaction times not optimized.b Conversion determined by 1H NMR.
Conversions shown in brackets are those derived from the corresponding
iodide substrate. c Yields after silica gel column chromatography. Yields
shown in brackets are those derived from the corresponding iodide
substrate.
8 F. Y. Kwong and S. L. Buchwald, Org. Lett., 2003, 4, 3517–3520.
9 J. Garin, E. Melendez, F. L. Merchan, D. Ortiz and T. Tejero, Synthesis,
1987, 368–370; J. Garin, E. Melendez, F. L. Merchan, P. Merino, J.
Orduna and T. Tejero, J. Heterocycl. Chem., 1990, 27, 321–326; J.
Garin, E. Melendez, F. L. Merchan, P. Merino, J. Orduna and T. Tejero,
Synth. Commun., 1990, 20, 2327–2334.
10 An analogous Pd-catalyzed variant has recently been reported: C.
Benedí, F. Bravo, P. Uriz, E. Fernández, C. Claver and S. Castillón,
Tetrahedron Lett., 2003, 44, 6073–6077.
11 General synthetic procedure. To a mixture of thiourea (0.5 mmol),
Cs2CO3 (1.0 mmol, 2 equiv.), and Pd(PPh3)4 (0.025 mmol, 5 mol%), or
CuI (0.025 mmol, 5 mol%) and 1,10-phenanthroline (0.05 mmol, 10
mol%), was added reagent grade dimethoxyethane (4 mL). The reaction
mixture was heated at 80 °C for 16–24 h under nitrogen, and
subsequently diluted with EtOAc (50 mL) and washed with H2O (2 3
50 mL) and brine (1 3 50 mL). The organic layer was dried over
MgSO4, the solvent removed in vacuo, and the crude product purified
using silica gel column chromatography.
12 Confirmation that cyclization occurred through S, rather than N, was
established by comparison of the isolated product 2a (R1 = Bn, R2, R3
= H) with a sample independently synthesized by the nucleophilic
displacement reaction of benzylamine with 2-chlorobenzothiazole.
Scheme 3 Reagents and conditions: BnNH2, MeCN, rt, 1 h; then Cs2CO3
with CuI (5 mol%) and 1,10-phenanthroline (10 mol%), or Pd(PPh3)4 (5
mol%), reflux, 24 h.
formation with the cyclization reaction. These results further
underscore the recent trend of replacing Pd-mediated carbon–
heteroatom formation reactions by the more cost effective Cu-
catalyzed processes.
This work was supported by the Natural Sciences and Engineer-
ing Research Council of Canada (NSERC). L. L. J. thanks NSERC
C h e m . C o m m u n . , 2 0 0 4 , 4 4 6 – 4 4 7
447