Efficient solid phase synthesis of benzo[1,2,3]thiadiazoles and related structures

Article abstract of DOI:10.1039/b504900h

The first solid-phase synthesis of benzo[1,2,3]thiadiazoles was achieved by starting from resin bound ortho bromo or iodo triazenes and using a functionalization on cleavage. Two different synergistic methods including an anionic approach and a cross-coupling approach were used for the synthesis. The resulting diazonium compounds readily underwent electrophilic cyclization yielding benzothiadiazoles, when cleaving the arenethiol resins. Cleavage from the resin with diluted trifluoroacetic acid resulted spontaneously in the desired cyclization reaction.

Full text of DOI:10.1039/b504900h

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C O M M U N I C A T I O N
Efficient solid phase synthesis of benzo[1,2,3]thiadiazoles and related
structures†
Michael Kreis, Carl F. Nising, Maarten Schroen, Kerstin Knepper and Stefan Bra¨se*
Institut fu¨r Organische Chemie, Universita¨t Karlsruhe (TH), Fritz-Haber-Weg 6, D-76131,
Karlsruhe, Germany. E-mail: braese@ioc.uka.de; Fax: + 49-721-6088581;
Tel: + 49-721-6082903
Received 7th April 2005, Accepted 7th April 2005
First published as an Advance Article on the web 19th April 2005
The first solid-phase synthesis of benzo[1,2,3]thiadiazoles
was achieved by starting from resin bound ortho bromo or
iodo triazenes and using a functionalisation on cleavage.
1,2,3-Thiadiazoles are heterocycles of great practical and the-
oretical interest.1 Especially derivatives of benzo[1,2,3]thiadi-
azoles are important in industry and agriculture.2 They have
been recognised as the first synthetic chemical plant activators,
which can induce disease resistance in plants, the so-called
systemic acquired resistance (SAR).3
The S-methyl ester of benzo[1,2,3]thiadiazole-7-thiocarb-
oxyclic acid (Acibenzolar-S-methylester) (Fig. 1) was introduced
R
R
as Bionꢀ or Actigardꢀ, respectively, as the first commercial
product of this type by Novartis.4 It has been shown that
Acibenzolar-S-methylester induces disease resistance in wheat,5
tobacco,6 Arabidopsis,7 melons8 and maize.9 It can be used as
a substitute for antibacterial and antiviral compounds as well
as for fungicides. Brisset et al.10 have found that Acibenzolar-
S-methylester induces the accumulation of defence-related en-
zymes in apples and thereby protects them efficiently against
Fig. 2 Bromo- and iodo-anilines used for heterocycle syntheses.
triazene bromo- or iodo aryl resins 3a–i were prepared on a
multigram scale (1–10 g) in medium (52%) to full conversion.
The resulting triazene aryl halide resins 3a–i could then be
converted to the corresponding triazene thiol or selenol resins
by two alternative methods. Method A (Scheme 1) starts with
a halide–lithium exchange with n-BuLi and TMEDA, followed
by treatment with elemental sulfur or elemental selenium.
R
fire blight. Bionꢀ is commercially used as a pesticide on
wheat, radish, lettuce and spinach.11 While there are synthetical
approaches towards benzo[1,2,3]thiadiazoles in solution, mainly
via the Wolff method and the Hurd–Mori reaction,12 they mainly
suffer from their lack of compatibility with functional groups as
well as poor availability of starting materials. Furthermore, the
synthesis of benzo[1,2,3]thiadiazoles on solid support has, to
our knowledge, not been achieved so far.
Fig. 1 Structure of Acibenzolar-S-methylester (BionꢀR ).
We herein report the first synthesis of a variety of benzo[1,2,3]-
thiadiazoles and related structures on solid support, employing
two different, synergetic methods: An anionic approach, via a
halide metal exchange13 and a cross-coupling approach, via an
innovative palladium catalysed C–S bond forming reaction.14
We first became interested in the synthesis of benzo[1,2,3]-
thiadiazoles during our synthetic studies of the triazene linker
system (T1).15 By then, we realised that sulfur electrophiles
could easily be reacted with resin-bound haloarenes, using n-
butyllithium or a palladium-based protocol developed in our
group.16 When cleaving the arenethiol resins, the resulting dia-
zonium compounds readily underwent electrophilic cyclisation
yielding benzothiadiazoles.
Scheme 1 Synthesis of benzo[1,2,3]thia- and selenadiazoles. Method
A: 1) n-BuLi, TMEDA, THF, −40 ◦C, 1 h; 2) S8, THF, rt (E = S) or grey
Selen (E = Se); Method B: 1) TIPSSH, Cs2CO3, 15 mol% Pd(OAc)2,
PPh3, toluene, 85 ◦C, 16 h; 2) TBAF, THF, rt, 2 h.
Method B (Scheme 1) uses a palladium-catalysed cross-
coupling reaction protocol with triisopropylsilylthiol (TIPSSH),
followed by deprotection with tetrabutylammonium fluoride
(TBAF) in THF. The results are summarised in Table 1.
By diazotation of the anilines 1a–i (Fig. 2) with tert-butyl
nitrite and subsequent coupling to the piperazine resin 2,
Cleavage from the resin with diluted trifluoroacetic acid
resulted spontaneously in the desired cyclisation reaction,
† Electronic supplementary information (ESI) available: Experimental
details and data. See http://www.rsc.org/suppdata/ob/b5/b504900h/
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 5
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 8 3 5 – 1 8 3 7
1 8 3 5
©

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Table 1 Synthesis of benzo[1,2,3]thiadiazoles and benzo[1,2,3]selena-
and ortho-iodo anilines giving approximately the same results
diazole
(entries 1 and 6). While the lithiation protocol failed for anilines
bearing functional groups such as nitro (entry 3) and ester groups
(entry 4), we were delighted to find that the palladium-catalysed
methodology succeeded in converting these more demanding
substrates into the desired products in good yields and purities.
Even the sterically hindered Acibenzolar-O-methylester, with
two substituents in the ortho-position could be synthesised in
only slightly lower yields (entry 9). This conversion gives com-
binatorial access towards benzo[1,2,3]thiadiazole-7-carboxyclic
acid derivatives, as a substance class of chemical plant activators
Entry
1
Product
Yielda
R
like Bionꢀ.
53%b
62%c
Considering our success with benzo[1,2,3]thiadiazoles, we em-
ployed our strategy in the synthesis of benzo[1,2,3]selenadiazole,
which could be synthesised by the lithiation protocol in a
good yield (63%) and purity. Benzo[1,2,3]selenadiazoles are only
scarcely found in literature17 and show antioxidative as well as
antibacterial activities.18
2
10%c
While the advantages of the first methodology are the lower
costs and the ecological harmlessness of the waste, the second
methodology performs better as regards to functional group
tolerance and gives rise to a potential combinatorial approach
towards benzo[1,2,3]thiadiazoles.
With these results at hand, we envisioned that this strategy
could also give access to other heterocyclic systems, simply by
reacting the thiol resins with various electrophiles followed by
cleavage (Scheme 2).
3
4
37%c
34%c
5
41%c
6
7
45%b
42%c
56%b
8
9
Tracesb
Tracesc
Scheme 2 Synthesis of 4H-[1,2,3]-triazolo[5,1-c][1,4]benzothiazine.
Therefore, thiol resin 4a was reacted with propargyl bromide
to give thiopropargylether resin 6. In order to apply our
functionalisation on cleavage strategy, the diazonium compound
resulting from cleavage of 6 was converted into the correspond-
ing aryl azide, a method which has been used previously.19 On
heating, this azide underwent [3 + 2]-cycloaddition to yield
4H-[1,2,3]-triazolo[5,1-c][1,4]benzothiazine in 14% overall yield
(4 steps).20 A library access to this class of compounds by
Sonogashira coupling of thiopropargylether resins is currently
being performed in our laboratory.
15%c
63%b
10
In summary, we have accomplished the first solid phase
synthesis of benzo[1,2,3]thiadiazoles. The T1-triazene linker
system was used for a functionalisation on cleavage. By em-
ploying two synergetic methodologies, we were able to syn-
thesise a wide range of substituted benzo[1,2,3]thiadiazoles.
Among these, Acibenzolar-O-methylester possesses a prominent
position, being a precursor for a class of chemical plant
a Isolated yield after chromatography. b Lithiation protocol: 1) 1.0 g
resin, TMEDA (5.4 mmol), n-BuLi (5.4 mmol) in THF under argon at
−40 ◦C to rt, then S8. 2) TFA in CH2Cl2 at rt. c Palladium-catalysed
protocol: 1) 1.0 g resin, Pd(OAc)2 (0.15 mmol), PPh3 (0.60 mmol),
Cs2CO3 (4.0 mmol), TIPSSH (2.5 mmol) at 85 ◦C in toluene under
argon. 2) TBAF (2.5 mmol) in THF at rt. 3) TFA in CH2Cl2 at rt.
R
activators like Bionꢀ. Furthermore we were able to realise
the synthesis of more complex heterocycles like 4H-[1,2,3]-
triazolo[5,1-c][1,4]benzothiazine.
yielding benzo[1,2,3]thiadiazoles in good yields. Both, ortho-
bromo and ortho-iodo anilines are excellent substrates for the
synthesis of benzo[1,2,3]thiadiazoles. Both electron rich (entry
6 and 7) as well as electron poor (entry 2, 3, 4, 5 and 9) halo-
anilines achieved good results. Both methodologies are equally
effective for unsubstituted and methyl substituted ortho-bromo
Acknowledgements
We acknowledge the support by the DFG (BR 1750/2) and the
Fonds der Chemischen Industrie (Fellowship for C. F. N.).
1 8 3 6
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 8 3 5 – 1 8 3 7

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