Scheme 3
Scheme 4
Bromination Step
From the literature, access to a 2-halopyridine can be
accomplished in a number of ways, including: a diazotization
8
reaction from the appropriate amine, a related reaction of
the amino compound with a brominating agent, substitution
of suitable starting pyridines. Others have also had need to
access 4 for pharmacological studies. One approach has been
9
,10
of a pyridinium salt,
use of an N-pyridyl palladium
6
1
1
12
complex, or bromination of a pyridine either directly or
to react ammonia with 5-halo-2-cyanopyridines to effect a
1
3
through the N-oxide. Conversion of a 2-hydroxypyridine
to the corresponding 2-bromo derivative has been ac-
complished with a dehydrating agent, such as phosphorus
7
substitution, which is related to our final method in that a
substitution reaction is involved. However, all of these
preparations were laboratory-scale syntheses.
1
4
pentoxide, and a bromide source or NBS in the presence
One method we investigated took advantage of the
availability of nicotinamide. The introduction of the cyano
group could be achieved through the N-oxide in a manner
analgous to that illustrated in Scheme 2. Our focus, therefore,
was on the conversions of the carboxylic acid group to an
amine. Rather than perform a Curtius rearrangement, we
looked at a Hoffman degradation with a variety of reagents.
In an alcoholic solvent, such as ethanol, the use of chlorine
or bleach led to reaction at the nitrile moiety. The Hoffman
degradation could be achieved in ∼70% yield by reaction
of the amide with chlorine in acetonitrile; other solvents gave
inferior yields. The N-chloro compound then underwent the
degradation by the addition of potassium carbonate. Good
conversions could only be achieved if the N-chloro com-
pound was isolated and this was considered to be a major
safety issue for large-scale work and this approach was
dropped.
1
5
of triphenylphosphine. These methods all have a disad-
vantage be it a low yield, obnoxious reagent, harsh condi-
tions, a multistep sequence to access the substrate, or
combinations thereof. To us, the best approach seemed to
be a displacement reaction on either 2-amino- or 2-hydroxy-
5
-nitropyridine. As the starting material for the preparation
of 2-hydroxy-5-nitropyridine (10) is 2-amino-5-nitropyridine
by a Sandmeyer reaction with water acting as the nucleophile,
the literature report for the direct conversion of 2-amino-5-
nitropyridine (8) to 2-bromo-5-nitropyridine (9) looked
8
encouraging. In our hands, copious amounts of bromine and
nitrogen oxides were evolved during the reaction. Removal
of these noxious byproducts was not simple, and this
approach was dropped.
A variety of methods were tried for the conversion of
the hydroxy compound 10 to the bromide 9. In most cases,
the yields were low or the reaction failed completely. For
example, use of phosphorus tribromide in a variety of
solvents resulted in failure. 2-Hydroxy-5-nitropyridine (10)
One method that did provide some promise is outlined in
a retrosynthetic sense in Scheme 3. It was thought that the
amine could be obtained by reduction of the nitro compound
16
can exist as the 2-pyridone tautomer 11 (Scheme 4). NMR
8
even though this would mean reduction in the presence of
1
7
and IR spectroscopic evidence suggests that the hydroxy
compound is the major contributor in a variety of solvents.
In nonpolar solvents intermolecular hydrogen-bonding can
also be discerned. The presence of the tautomer, as well as
the hydrogen-bonding, could be the reason the conversion
to the desired bromo compound was very sluggish. This was
the nitrile group. As pyridines are susceptible to nucleophilic
additions at the 2-position, a substitution reaction aided by
the para nitro group seemed feasible. Although Aldrich does
list 2-bromo-5-nitropyridine (9) in their catalogue, it is very
expensive (ca. $5/g). Thus, as the hydroxy compound 10 is
available in bulk, this was considered as our starting material.
In some listings the hydroxy compound 10 is given as the
tautomeric pyridinone 11 (vide infra). Although other halogen
derivatives might be considered as alternatives, as the
discussion below indicates, the bromo compound 8 provided
the cleanest methodology in the following cyanide displace-
ment reaction.
1
6
in line with other workers’ observations.
Phosphorus pentabromide did perform the desired reac-
tion, but only at higher temperatures (Scheme 5). When
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5
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(
2
(17) See the Aldrich Catalogue.
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