A practical method for the reduction of 2,1,3-benzothiadiazoles to 1,2-benzenediamines with magnesium and methanol

Article abstract of DOI:10.1016/S0040-4039(01)00163-0

A new and practical method for the reduction of 2,1,3-benzothiadiazoles to 1,2-benzenediamines with magnesium and methanol is described. Sensitive functional groups such as bromo, chloro, cyano, and ester are well tolerated under these new conditions.

Full text of DOI:10.1016/S0040-4039(01)00163-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 2277–2279
A practical method for the reduction of 2,1,3-benzothiadiazoles
to 1,2-benzenediamines with magnesium and methanol
Mahavir Prashad,* Yugang Liu and Oljan Repicˇ
Process Research and Development, Chemical and Analytical Development, Novartis Institute for Biomedical Research,
59 Route 10, East Hanover, NJ 07936, USA
Received 12 December 2000; revised 16 January 2001; accepted 17 January 2001
Abstract—A new and practical method for the reduction of 2,1,3-benzothiadiazoles to 1,2-benzenediamines with magnesium and
methanol is described. Sensitive functional groups such as bromo, chloro, cyano, and ester are well tolerated under these new
conditions. © 2001 Elsevier Science Ltd. All rights reserved.
Substituted 1,2-benzenediamines are important com-
pounds for the synthesis of agrochemical and pharma-
ceutical intermediates.1 Because these diamines are very
sensitive to a variety of reaction conditions and difficult
to handle, they are often protected as 2,1,3-benzothiadi-
azoles.2 Additionally, the resulting 2,1,3-benzothiadia-
zole system enables regioselective functionalization of
the parent aromatic ring.3 However, unraveling the
diamine functionality can sometimes pose significant
challenges and may be substrate dependent. Several
methods have been reported in the literature for the
reduction of 2,1,3-benzothiadiazoles to 1,2-benzenedi-
amines, e.g. lithium aluminum hydride,2c Sn/HCl,4a,b
SnCl2/HCl,4c sodium borohydride2a,4d,e and H2/Raney-
Ni.4f All these methods have limitations. Sodium boro-
hydride is the least reactive and reduces only electron
deficient 2,1,3-benzothiadiazoles. Lithium aluminum
hydride is a strong reducing agent, and heteroatoms
such as bromo,5 chloro,5 cyano and ester groups are
also reduced under these conditions. Tin is a toxic
metal and is not amenable to scale-up due to safety
reasons. In addition, tight specifications on toxic
metals, e.g. tin, and total heavy metal content in active
pharmaceutical ingredients also makes this method less
desirable. Thus, we needed to develop a method for the
reduction of 2,1,3-benzothiadiazoles that is safer, eco-
logically cleaner, and does not involve heavy metals. In
this communication, we wish to report a new and
practical method for the reduction of 2,1,3-benzothiadi-
azoles to 1,2-benzenediamines using magnesium turn-
ings in methanol.
Magnesium in methanol is a known method for the
reduction of a,b-unsaturated nitriles,6a amides,6b,c and
esters.6d We rationalized that this method might be
suitable for the reduction of 2,1,3-benzothiadiazoles to
1,2-benzenediamines. Indeed, magnesium in methanol
reduced 2,1,3-benzothiadiazoles smoothly. This method
is unique in that it works only in methanol. No reduc-
tion was observed when ethanol was used as the sol-
vent, and the starting material was recovered. Only
slow destruction of magnesium metal by the solvent
occurred. The exact reason for such a difference
between methanol and ethanol is not understood, but
solvent polarity might play an important role in this
electron transfer process. The reduction of 2,1,3-benzo-
thiadiazoles is exothermic and is carried out safely by a
slow addition of magnesium turnings to a solution of
the substrate in methanol which was pre-heated to
45–50°C. Several substrates containing different func-
tional groups were successfully reduced to correspond-
ing 1,2-benzenediamines using this method (Scheme 1),
and the results are summarized in Table 1.7 As is
evident from entries 1–4, methyl substituted 2,1,3-benzo-
thiadiazoles (1a–d) were successfully reduced in excel-
lent yields. 7-Bromo-4-methyl-2,1,3-benzothiadiazole
(1e) reduced exclusively to the corresponding diamine
2e in 82% yield. Less than 2% of the debrominated
product was detected. Compound 1f, which contained a
* Corresponding author.
Scheme 1.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00163-0

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M. Prashad et al. / Tetrahedron Letters 42 (2001) 2277–2279
Table 1. Reduction of 2,1,3-benzothiadiazoles with Mg/methanol
In summary, a new and practical method for the reduc-
tion of 2,1,3-benzothiadiazoles to 1,2-benzenediamines
with magnesium and methanol is described. Sensitive
functional groups such as bromo, chloro, cyano, and
ester are well tolerated under these conditions.
chlorine substituent, was also reduced satisfactorily and
in excellent yield under these conditions. No dechlori-
nated derivative of 2f was observed. Substrates 1g,
containing an electron-donating amino group, and 1h
and 1i, containing an electron-withdrawing cyano or
ester group, were also reduced to the corresponding
triamine 2g and diamines 2h and 2i, respectively, in
high yields. These results clearly demonstrate the gen-
eral synthetic utility of this new method.
Acknowledgements
We thank Dr. Tao He for mass spectra.

M. Prashad et al. / Tetrahedron Letters 42 (2001) 2277–2279
2279
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Data for selected compounds 2e–i: 2e: mp: 54–55°C; 1H
NMR (CDCl3, 300 MHz): l 6.87 (1H, d, J=8.82 Hz), 6.45
(1H, d, J=8.82 Hz), 3.55 (4H, bs), 2.12 (3H, s); MS (ESI):
m/z 201.3, 203.3 (MH+). 2f: mp: 75–76°C; 1H NMR
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1
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1
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.
.