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D. Hedou et al. / Tetrahedron 70 (2014) 5541e5549
expected compounds. Carboxylic acid should also be converted into
an ester analogue (e.g., methyl, ethyl); (b) Regioselective bromi-
nation and/or nitrogen insertion (e.g., nitration) of anthranilic and
2-aminonicotinic acid derivatives are crucial steps of the synthesis
for the proper orientation of the thiazole ring; (c) benzo[d]thiazole
or thiazolo[5,4-b]pyridine ring and concomitant carbonitrile for-
mation is best achieved via Appel salt chemistry and copper(I)-
mediated cyclization. The generated carbonitrile function may be
further converted (e.g., amidines, amides, imidates, esters or acids)
or cleaved (e.g., hydrolysis and decarboxylation).
both trifluoroacetamide and methyl ester into an original structure:
7-trifluoromethylthiazolobenzoxazinone (11) in 89% yield (Scheme
3). This side-cyclisation is most likely the result of an attack of the
activated carbonyl of the trifluoroacetamide function on the methyl
ester followed by methanol release.
Failure to obtain selectively the expected thiazoloanthranilic
ester 12 encouraged us to study the deprotection of the tri-
fluoroacetamide prior to the cyclization of the aryliminodithiazole.
Unfortunately, no efficient method led to the clean deprotection of
the acetamide function without degrading the iminodithiazole.
Scheme 1. Retrosynthetic pathway and access to novel linear methyl 6-amino-2-cyanobenzo[d]thiazole-5-carboxylate (1) and methyl 5-amino-2-cyanothiazolo[5,4-b]pyridine-6-
carboxylate (2) from methyl anthranilate derivatives 3 and 4 and 2-aminonicotinic acid 5.
In order to obtain intermediate B of anthranilic series, 5-
nitroanthranilic acid (3) was first used as starting material. De-
spite our efforts and regardless of the synthetic method we were
never able to isolate the desired compound from 3. Instead, the
synthesis was alternatively conceived from methyl 4-
bromoanthranilate (4).
Direct nitration of 4 in usual conditions (concentrated sulfuric
acidþpotassium nitrate) was infructuous and incited us to first
protect the amino group. Methyl ester 4 was treated with tri-
fluoroacetic anhydride (TFAA) in tetrahydrofuran (THF) at room
temperature for 2 h to give the trifluoroacylated derivative 6
quantitatively. Its nitration was carried out with a mixture of po-
tassium nitrate and sulfuric acid to give the desired methyl 5-nitro-
2-(2,2,2-trifluoroacetamido)benzoate (7) in a good 82% yield along
with the 3-nitro isomer 8 in 10% yield. Compound 7 was then re-
duced with iron powder in a refluxing mixture of methanol and
acetic acid into its amino-derivative 9 (80%). Addition of Appel salt
and pyridine to a solution of 9 in methylene chloride gave the ex-
pected N-aryliminodithiazole 10 in good yield (74%) (Scheme 2).
Consequently, we investigated smoother conditions for the aryli-
minodithiazole cyclization. Microwave irradiation of 10 with cop-
per(I) iodide (1 equiv), pyridine (1 equiv) in dry N,N-
dimethylformamide (DMF) at 105 ꢀC provided adduct 12 in good
85% yield. Noticeably, the result of this cyclization was time and
scale-dependant, and a short investigation of the reaction time
showed that a longer heating (e.g., 30 min instead of 15 min) was
sufficient to hydrolyze the carbonitrile-bearing product 12 into its
carboxamide derivative 13 (Scheme 3).
At this stage of the synthesis, deprotection of the amino group
was studied in order to generate the target product 1. Usual con-
ditions (e.g., methanolysis, reduction with sodium borohydride)
were experimented but none allowed the cleavage of the tri-
fluoroacetamido group without modifying the carbonitrile func-
tion. Thus, methanolysis of 12 led to the methyl carboximidate
adduct 14 in quantitative yield. After unsuccessful trials, we found
out that refluxing compound 11 and p-toluenesulfonic acid (PTSA)
in methanol gave the desired methyl 6-aminobenzo[d]thiazole-5-
carboxylate (1) in good 76% yield. In contrast with its cyanated
Scheme 2. Optimized synthetic pathway and access to trifluoroacetylated (Z)-methyl 2-amino-4-bromo-5-(4-chloro-5H-1,2,3-dithiazol-5-ylideneamino)benzoate (10) from methyl
2-amino-4-bromobenzoate (4).
Iminodithiazole 10 was subjected to copper(I)-mediated cycli-
sation8 in order to obtain the thiazole moiety. Unexpectedly,
microwave-assisted irradiation of 10 in the presence of copper(I)
iodide in pyridine at 115 ꢀC not only led to the rapid formation of
the thiazole ring but also provoked the concomitant cyclisation of
analogue 12, compound 13 was quantitatively converted into the
adduct 15 by treatment of with potassium carbonate in methanol at
room temperature in 2 h.
Upon scale-up, the problems encountered during deprotection
of 12, and the growing appearance of product 13 (and incidentally
Hédou, Damien
