Nitration of tert-butyloxycarbonylated aniline and 1,3,5-triaminobenzene by acetyl nitrate

Article abstract of DOI:10.1016/j.tetlet.2012.05.139

Acetyl nitrate was found to be an effective reagent for aromatic mono- and dinitration of Boc-protected aminobenzenes. The method was used in a new synthesis of 1,3,5-triamino-2,4-dinitrobenzene in two steps with 63% yield.

Full text of DOI:10.1016/j.tetlet.2012.05.139

Tetrahedron Letters 53 (2012) 4154–4155
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Tetrahedron Letters
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Nitration of tert-butyloxycarbonylated aniline and 1,3,5-triaminobenzene
by acetyl nitrate
⇑
Matthew C. Davis , Thomas J. Groshens
Chemistry & Materials Division, Naval Air Warfare Center, China Lake, CA 93555, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Acetyl nitrate was found to be an effective reagent for aromatic mono- and dinitration of Boc-protected
aminobenzenes. The method was used in a new synthesis of 1,3,5-triamino-2,4-dinitrobenzene in two
steps with 63% yield.
Received 13 April 2012
Revised 25 May 2012
Accepted 29 May 2012
Available online 9 June 2012
Published by Elsevier Ltd.
Keywords:
Aromatic nitration
Acetyl nitrate
Aniline
Boc-protection
The aromatic nitration of aniline is difficult owing to its inher-
ent sensitivity to oxidation as well as deactivation toward electro-
philic substitution through formation of its ammonium salt by the
acidic conditions typically employed.1 For best results, a protecting
group for the amine should be employed that is both convenient to
install and later remove. Carboxyl-2 and sulfonylamides3 as well as
alkyl carbamate (methyl and ethyl)4 have been used for this pur-
pose but they often require harsh treatment for subsequent re-
moval (hot sulfuric acid).5 The benzyloxycarbonyl (Cbz) was
considered but it was thought that it would not work in the pres-
ent case since further complications would occur such as nitration
of the benzyl ring as well as concomitant nitro reduction during
typical removal conditions of hydrogenolysis.6 The tert-butyloxy-
carbonyl (Boc) group, pioneered by Carpino,7 may be the premier
amine protecting group in use today. There are only a few reports
of nitration in the presence of Boc-protected amines, which is not
surprising due to their acid-lability.8 It was hypothesized that mild
or non-acidic nitration conditions such as mixed anhydrides (RCO2-
NO2),9a,9b dinitrogen pentoxide (N2O5),9c N-nitropyridinium salts9d
or similar might be selective enough to accomplish C-nitration
without Boc-deprotection. Herein we describe preliminary studies
on the nitration of Boc-protected aniline and 1,3,5-triaminoben-
zene by acetyl nitrate.
yl nitrate (Scheme 1). Allowing 1 to react with a previously pre-
pared solution of two equivalents of acetyl nitrate in excess
acetic anhydride at ice bath temperature gave, after a cold aqueous
work-up, a good yield of a mixture of mono-nitro compounds 2
and 3 in an ortho/para ratio of 3:1. This ratio is close to that ob-
tained by Lynch et al.10 who nitrated acetanilide similarly (o/
p = 4.5). With four equivalents nitrating agent Boc-protected 2,4-
dinitroaniline (4) was obtained, albeit in low yield. The single crys-
tal X-ray structure of 4 is shown in Figure 1.11 In contrast to previ-
ous work with the ethyl carbamate of aniline,12 allowing 1 to react
with further quantities of acetyl nitrate did not yield a trinitro
derivative.
Encouraged by these results, similar nitration of fully Boc-pro-
tected 1,3,5-triaminobenzene (5) was conducted (Scheme 2). Here,
the nitration reaction was started out at À78 °C and care was again
taken during work-up to keep the temperature near 0 °C. With
slightly more than one equivalent of acetyl nitrate the unreported
mononitro 6 was isolated in modest yield (not optimized). How-
Initial concerns were centered around the sensitivity of nitro
derivatives of Boc-aniline (1) during aqueous work-up at which
time they would be exposed to an acidic environment created by
the hydrolysis of both the acetic anhydride as well as residual acet-
⇑
Corresponding author. Tel.: +1 760 939 0196; fax: +1 760 939 1617.
E-mail address: matthew.davis@navy.mil (M.C. Davis).
Scheme 1. Nitration of compound 1 by acetyl nitrate.
0040-4039/$ - see front matter Published by Elsevier Ltd.
http://dx.doi.org/10.1016/j.tetlet.2012.05.139

M. C. Davis, T. J. Groshens / Tetrahedron Letters 53 (2012) 4154–4155
4155
Figure 1. Crystal structures of new dinitro compounds 4 and 7.
Acknowledgments
Financial support through an In-house Laboratory Independent
Research award from the Office of Naval Research is gratefully
acknowledged.
Supplementary data
Supplementary data associated with this article can be found, in
the
online
version,
at
http://dx.doi.org/10.1016/
j.tetlet.2012.05.139.
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