Synthesis of 2-substituted-benzothiazoles by palladium-catalyzed intramolecular cyclization of o-bromophenylthioureas and o-bromophenylthioamides

Article abstract of DOI:10.1016/S0040-4039(03)01469-2

2-Amino-, and 2-alkyl-benzothiazoles have been efficiently prepared by palladium catalyzed cyclization of o-bromophenylthioureas and o-bromophenylthiamides. Results were best with the Pd₂(dba)₃/monophosphine catalytic system.

Full text of DOI:10.1016/S0040-4039(03)01469-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 6073–6077
Synthesis of 2-substituted-benzothiazoles by palladium-catalyzed
intramolecular cyclization of o-bromophenylthioureas
and o-bromophenylthioamides
Carolina Bened´ı,a Fernando Bravo,a Pedro Uriz,b Elena Ferna´ndez,b Carmen Claverb and
Sergio Castillo´na,*
aDepartament de Qu´ımica Anal´ıtica i Qu´ımica Orga`nica, Universitat Rovira i Virgili, Pl. Imperial Ta`rraco 1, 43005 Tarragona,
Spain
bDepartament de Qu´ımica F´ısica i Inorga`nica, Universitat Rovira i Virgili, Pl. Imperial Ta`rraco 1, 43005 Tarragona, Spain
Received 30 April 2003; revised 30 May 2003; accepted 12 June 2003
Abstract—2-Amino-, and 2-alkyl-benzothiazoles have been efficiently prepared by palladium catalyzed cyclization of o-bromo-
phenylthioureas and o-bromophenylthiamides. Results were best with the Pd2(dba)3/monophosphine catalytic system.
© 2003 Elsevier Ltd. All rights reserved.
Palladium-catalyzed arylꢀnitrogen bond forming
reactions1 are highly useful for synthesizing arylamines
and have found numerous applications in organic
synthesis. Intramolecular palladium-catalyzed N-
arylation reactions of aryl halides have been used to
prepare indoles,2 oxoindoles,3 2-aryl-2H-indazoles,4 1-
aryl-1H-indazoles,5 imidazoles,6 oxazepines and thiaze-
pines,7 indolines,8 and other heterocycles9 (Scheme
1).
halides with thiolates requires very drastic conditions,
(polar solvents and temperatures often over 150°C).10
The use of palladium for synthesizing arylthioether was
first reported by Murahashi11 and Migita,12 and
Hartwig13 subsequently studied the mechanism of the
reaction and increased the synthetic scope.14 General
methods for synthesizing arylthioethers starting from
aryltriflates,15
aryliodides,16
arylbromides17
and
arylchlorides18 have recently been reported. The synthe-
sis of bispyrimidine thioethers19 and the use of aryl
thiocyanates as starting material20 have also been
reported. Recently, copper catalysts have been shown
to be efficient in the synthesis of arylthioethers.21
In contrast, there are fewer studies on the correspond-
ing palladium-catalyzed arylꢀsulfur bond formation.
The direct nucleophilic substitution of inactivated aryl
Scheme 1.
* Corresponding author. E-mail: castillon@quimica.urv.es
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01469-2

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C. Bened´ı et al. / Tetrahedron Letters 44 (2003) 6073–6077
Scheme 2.
The above-mentioned procedures for synthesizing hete-
rocycles by creating carbonꢀnitrogen and carbonꢀsulfur
bonds usually involve simple amino and thiol function-
alities. We hypothesize that a thiocarbonyl group is
nucleophilic enough to be used in the reaction (Scheme
2). Here we report a new procedure for synthesizing
benzothiazole derivatives22 by a palladium-catalyzed
intramolecular cyclization of o-bromoarylthioureas and
o-bromoarylthioamides.
Thioureas 2a–d23 were easily prepared in excellent
yields from o-bromophenylisothiocyanate (1) by reac-
tion with methylamine, aniline, dimethylamine and
morpholine, respectively (Scheme 3). Amides 6a–d were
prepared from o-bromoaniline (5) by reaction with acyl
chlorides, and were then efficiently transformed into the
corresponding thioamides 7a–d by reaction with the
Lawesson reagent. For the sake of comparison, we also
prepared ureas 4a,c by reacting o-bromophenyliso-
cyanate (3)24 with methylamine, aniline, and
dimethylamine.
We studied the effect of the ligand on the reaction
starting from the thiourea 2a and using Pd2dba3 as
palladium precursor. The diphosphine dppf has been
used efficiently in several palladium catalyzed amina-
tions.25 When the reaction was performed in dioxane
with Pd2dba3/dppf and Kt-BuO as the base we
obtained 87% of the benzothiazole 8a (entry 1, Table
1).26 We tried the monophosphine o-biphenylP(t-Bu)2
27
(entry 2) and it also provided a very active catalytic
system, which afforded the benzothiazole in very high
yield. The synthesis of benzothiazole from o-bro-
mophenylthioureas by nucleophilic substitution has
been reported, although it requires very drastic condi-
tions.28 In order to discard the substitution reaction we
carried out the reaction in the standard conditions and
in the absence of the palladium catalytic system, and we
recovered the starting material unaltered, proving that
the palladium catalyst is necessary to drive the reaction
(entry 3).
Scheme 3.
Then we explored the reaction of urea 2c, which has a
disubstituted amine. In this case, the use of dppf gave a
very low yield (entry 7), although it was improved by
using Cs2CO3 as base (entry 8). However, the
monophosphine o-biphenylP(t-Bu)3 provided excellent
yields of the benzothiazole 8c (entry 9). We also tried
the monophosphines P(t-Bu)3 and n-BuPAd2 which
also gave excellent yields at shorter reaction times
(entries 10 and 11).
Unexpectedly, the thiourea 2b did not give the benzo-
thiazole derivative: rather mass spectrometry and 1H
NMR identified compound 9 as the main product
(entries 4 and 5). Since isothiocyanate, o-bromoisothio-
cyanate, aniline, and o-bromoaniline were also iden-
tified in the reaction mixture, we believe that the initial
reaction involves the nitrogen and that the imidazolone
obtained reacts further with the isothiocyanate present
in the medium. In fact, the compound is also formed in
the absence of catalyst (entry 6), at lower temperatures
and in the presence of other bases.
29
30
The morpholino derivative 2d was cyclized by using
Pd/o-biphenylP(t-Bu)3 to give the benzothiazole 8d but
in this case the yield was moderate (entry 12).

C. Bened´ı et al. / Tetrahedron Letters 44 (2003) 6073–6077
6075
Table 1. Cyclization reaction of 2-bromophenylthioureas 2a–d catalyzed by Pd2dba3/liganda (see Ref. 31)
Entry
Substrate
Ligand
Base
Time (h)
Product
Yield (%)b
1
2
3
4
5
6
7
8
2a
2a
2a
2b
2b
2b
2c
2c
2c
2c
2c
2d
dppf
Kt-BuO
Kt-BuO
Kt-BuO
Kt-BuO
Kt-BuO
Kt-BuO
Kt-BuO
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Kt-BuO
18
18
18
18
18
18
18
18
18
2
8a
8a
–
9
9
87
88
–
o-BiphenylP(t-Bu)2
c
–
dppf
100d
100d
34d
17
o-BiphenylP(t-Bu)2
c
–
9
dppf
dppf
8c
8c
8c
8c
8c
8d
52
90
92
97
9
o-BiphenylP(t-Bu)2
P(t-Bu)3
n-BuPAd2
o-BiphenylP(t-Bu)2
10
11
12
1
18
55
a Conditions: Substrate (1 mmol), dioxane (4 ml), Pd2dba3 (0.05 mmol), ligand (0.055 mmol), base (1.5 mmol), temperature 80°C.
b Isolated yield.
c In the absence of Pd2dba3.
d Conversion, yield not determined.
Table 2. Cyclization reaction of 2-bromophenylthioamide
Afterwards, we explored the synthesis of 2-alkylbenzo-
thiazole derivatives by palladium-catalyzed intramolec-
ular cyclization of o-bromophenylthioureas (Table 2).
We selected Pd2dba3/o-biphenylP(t-Bu)3 as the catalytic
system, using Cs2CO3 as the base and dioxane as the
solvent. In order to test the efficiency of the procedure
we selected both simple thioamide derivatives, such as
7a and 6b, and the more hindered 7c and 7d. Yields
were good to excellent in all cases, and the formation of
tert-butyl and adamantyl derivatives 10c–d (entries 3
and 4, Table 2), and benzothiazole 10b are especially
remarkable (entry 2).
a
7a–d catalyzed by Pd2dba3/o-biphenylP(t-Bu)2
Entry
Substrate
Product
Yield (%)b
In order to check the scope of the reaction, we also
explored the reaction of the amide 6a and ureas 4a,c in
the conditions previously optimized. No reaction was
observed in the case of amide 6a, but the behavior of
ureas 4a and 4b was more interesting: cyclization
involved the nitrogen to give corresponding benzoimi-
dazolones 11a,b. Results were best when diphosphines
were used (Table 3), whilst monophosphines provided
very low conversions. The dimethylamino derivative 4c
did not react even in drastic conditions. These results
are in agreement with those previously reported by
Buchwald.8
1
2
3
4
7a
7b
7c
7d
10a
10b
10c
10d
77
100
88
68
a Conditions: Substrate (1 mmol), dioxane (4 ml), Pd2dba3 (0.05
mmol), o-biphenylP(t-Bu)2 (0.055 mmol), Cs2CO3 (1.5 mmol), tem-
perature 80°C, time 18 h.
b Isolated yield.
phenylthioamides is a direct and efficient procedure for
synthesizing 2-substituted benzothiazoles. Highly hin-
dered alkyl monophosphines proved to be the most
efficient ligands.
In conclusion, the palladium-catalyzed intramolecular
cyclization of o-bromophenylthioureas and o-bromo-

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C. Bened´ı et al. / Tetrahedron Letters 44 (2003) 6073–6077
Table 3. Cyclization reaction of 4a,c catalyzed by
hedron 1996, 52, 7525–7546; (b) Yang, B. H.; Buchwald,
S. L. Org. Lett. 1999, 1, 35–37.
palladiuma
9. (a) Peat, A. J.; Buchwald, S. L. J. Am. Chem. Soc. 1996,
118, 1028–1030; (b) Yang, B. H.; Buchwald, S. L. J.
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12. (a) Kosugi, M.; Shimizu, T.; Migita, T. Chem. Lett. 1978,
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Entry
Substrate
Product
Yield (%)b
1
2
3
4a
4b
4c
11a
11b
11c
70
32
0
a Conditions: Substrate (1 mmol), dioxane (4 ml), Pd2dba3 (0.05
mmol), dppf (0.055 mmol), Kt-BuO (1.5 mmol), temperature 80°C,
time 18 h.
b Isolated yield
Acknowledgements
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Financial support from DGESIC BQU2002-01188
(Ministerio de Ciencia y Tecnolog´ıa, Spain) is acknowl-
edged. F.B. thanks CIRIT (Generalitat de Catalunya)
for a grant. Technical assistance from the Servei de
Recursos Cientifics (URV) is acknowledged. The
authors thank Dr. M. Beller (Rostock University, Ger-
many) for generously providing the phosphine n-
BuPAd2.
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C. Bened´ı et al. / Tetrahedron Letters 44 (2003) 6073–6077
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argon, Pd2(dba)3 (0.05 mmol), dppf (0.075 mol), and
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ing solution was heated to 80°C until the starting mate-
rial had disappeared. The reaction mixture was then
cooled, filtered over Celite, evaporated to dryness and
purified by column chromatography.