An efficient synthesis of 5-bromopyridine-2-carbonitrile

Article abstract of DOI:10.1081/SCC-120023985

5-Bromopyridine-2-carbonitrile was efficiently synthesized in two steps from 2,5-dibromopyridine with an overall yield of 75%.

Full text of DOI:10.1081/SCC-120023985

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An Efficient Synthesis of 5-Bromopyridine-2-
carbonitrile
David Y. Markevitch a , Miroslav Rapta a , Scott J. Hecker a & Thomas E. Renau a
a Essential Therapeutics Inc. , Mountain View, California, USA
Published online: 15 Aug 2006.
To cite this article: David Y. Markevitch , Miroslav Rapta , Scott J. Hecker & Thomas E. Renau (2003) An Efficient Synthesis of
5-Bromopyridine-2-carbonitrile, Synthetic Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 33:19, 3285-3289
To link to this article: http://dx.doi.org/10.1081/SCC-120023985
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SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 19, pp. 3285–3289, 2003
An Efficient Synthesis of
5-Bromopyridine-2-carbonitrile
David Y. Markevitch,Miroslav Rapta,
Scott J. Hecker,and Thomas E. Renau
*
Essential Therapeutics Inc.,
Mountain View, California, USA
ABSTRACT
5-Bromopyridine-2-carbonitrile was efficiently synthesized in two
steps from 2,5-dibromopyridine with an overall yield of 75%.
Key Words: Acid catalyzed amide dehydration; Pd(0)-catalyzed
cross coupling; Nucleophilic aromatic substitution.
As part of a discovery effort to identify novel anti-bacterial agents
we required an efficient and reliable synthesis of 5-bromopyridine-2-
carbonitrile (1). A literature survey revealed that although the synthesis
of 1 had previously been reported,[1] it was only recovered as a minor
*Correspondence: Thomas E. Renau, Roche Pharmaceuticals, 3401 Hillview
Ave., Palo Alto, California 94304-1397, USA; E-mail: thomas.renau@roche.com.
3285
DOI: 10.1081/SCC-120023985
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com

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3286
Markevitch et al.
Scheme 1.
by-product during the cyanation of 3-substituted pyridine N-oxides with
Me3SiCN.
Our initial route to prepare 1 was relatively straightforward,
involving the displacement of fluoride from 5-bromo-2-fluoropyridine
(2) with NaCN or KCN in DMF at 150ꢀC (Sch. 1). While this route
afforded 1, the yields were typically only 10–15%; starting material and
by-products attributable to polymerization were also recovered. Attempts
to optimize the procedure by changing the temperature, reaction time,
or concentration of reagents afforded similarly poor results. Likewise,
alternative solvents (DMF, DMSO, NMP, DME, toluene) gave no
improvement.
We next evaluated a method involving Pd(0)-catalyzed cross-
coupling of cyanide salts with halopyridines (Sch. 1). This was based
on the recently-reported work of Maligres et al.[2] describing the
syntheses of pyridinecarbonitriles via the treatment of bromopyridines
with Zn(CN)2 and Pd(0) with diphenylphosphine ferrocene (dppf ) as a
ligand. In a similar report, Song and Yee[3] reported the regioselective
synthesis of 5-bromopyridine-2-carboxylic acid methyl ester from 2,5-
dihalopyridines via palladium-catalyzed carbonylation in the presence
of MeOH. Combining various aspects of these published methods, we
attempted the synthesis of 1 from both 2,5-dibromopyridine (3) and
5-bromo-2-iodopyridine (4), prepared in one step from 3 following the
procedure outlined in Ref.[3] In either case, the use of dppf did not furnish
the expected product. Use of Pd(PPh3)4 in NMP did furnish the desired 1;
however, the numerous by-products generated during the course of this
reaction, a problematic purification and irreproducible results placed
serious constraints on the scale-up effort.
We next considered applying an approach developed by Wang et al.[4]
that involved the regio-selective monolithiation of compound 3 (Sch. 1).

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5-Bromopyridine-2-carbonitrile
3287
These authors had shown that treatment of 2,5-dibromopyridine
with n-butyl lithium over 2 h afforded the thermodynamic product,
5-bromo-2-lithiopyridine (5). They further demonstrated that quenching
5 with various electrophiles afforded 2-substituted-5-bromopyridines. We
hypothesized that quenching 5 with an electrophilic form of CN would, by
analogy, furnish the desired 1; however, our initial attempts to prepare
1 via the treatment of 5 with p-tosylcyanide or cyanogen bromide were
not successful. In both cases, 3-bromopyridine was recovered upon
workup.
Since using a suitable electrophilic cyano equivalent proved to be
inadequate for direct introduction of the cyano group, we next explored
an alternate approach that we postulated would lead, in one additional
step, to 1 (Sch. 2). The key to this sequence would initially involve the
synthesis of the t-butylamide 6 from 5 followed by the subsequent
conversion to the desired 1. Indeed, treatment of compound 5 with
t-butyl isocyanate at ꢁ78ꢀC in toluene cleanly and quantitatively fur-
nished 5-bromopyridine-2-carboxylic acid tert-butylamide (6), which
was converted smoothly to 1 following a modified literature procedure[5]
that involved the dehydration of the amide in POCl3 and toluene at
110ꢀC. The structural identity of 1 was confirmed by comparing our
analytical data with that reported previously for the compound.[1]
In summary, the title compound 1 was efficiently prepared from
commercially available 2,5-dibromopyridine in a two-step yield of
75%. One attractive feature of the sequence is that it introduces the
cyano functionality without the use of toxic metal cyanides.
5-Bromopyridine-2-carboxylic acid tert-butylamide (6). 2,5-Dibromo-
pyridine (1.3 g, 5.5 mmol) was dissolved in toluene (65 mL), and the
Scheme 2.

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3288
Markevitch et al.
mixture was purged with N2 (g) and cooled to ꢁ78ꢀC. A solution
of n-BuLi (6.5 mmol) in hexanes was added dropwise, and the mixture
was stirred at this temperature for 2 h. A solution of t-butyl isocyanate
(850 mL, 7.2 mmol) in 2.5 mL of toluene was added dropwise, and the
reaction mixture was stirred for 1 h. The mixture was allowed to warm
to ꢁ10ꢀC, and was quenched with aqueous NH4Cl (130 mL) and stirred
for 30 min. The layers were separated and the toluene layer was dried
over Na2SO4, filtered, and concentrated to dryness to furnish 1.4 g (99%)
1
of crude 6, which was judged to be 90–95% pure by H NMR: 1H NMR
(300 MHz, CD3OD): ꢀ 8.66 (d, 1H, J ¼ 1.2), 8.12 (d, 1H, J ¼ 6.3), 7.94
(d, 1H, J ¼ 6.3), 1.44 (s, 9H).
5-Bromopyridine-2-carbonitrile (1). Crude 6 (1.4 g) was dissolved in a
mixture of toluene (5 mL) and POCl3 (5 mL). The resulting solution was
stirred at 110ꢀC for 5 h. The reaction was cooled to room temperature
and poured into a flask containing ice cold H2O (80 mL). The pH of the
resulting solution was adjusted to ꢂ12 by the slow addition of aqueous
2 N NaOH. The product was extracted from the aqueous layer using
EtOAc (50 mL Â 2). The organic layers were collected, dried over
Na2SO4, and concentrated to dryness. Compound 1 (734 mg, 75% two
1
step yield) was estimated to be 95% pure by H NMR and was subse-
quently used in additional reactions without further purification. A small
sample was recrystallized from hexanes to afford the analytical sample:
Rf ¼ 0.50 (hexanes:EtOAc ¼ 4:1 v/v). 1H NMR (300 MHz, CDCl3): ꢀ 8.79
(d, 1H, J ¼ 2.1), 7.99 (d, 1H, J ¼ 2.1, 8.4), 7.59 (d, 1H, J ¼ 8.4). IR (NaCl,
neat, cmꢁ1): 2232. LC-MS: M þ CH3CN 224, retention time 2.22 min,
purity 98.4% (method: Phenomenex Synergi 4 m Hydro-RP column;
2 mL/min flow rate, 5ꢁ100% CH3CN gradient in 0.1% formic acid).
M.p.: 128–129ꢀC (Lit. m.p. 100–110ꢀC, 3 mmHg).
ACKNOWLEDGMENTS
The authors thank William J. Watkins and Constantine G. Boojamra
for reviewing the manuscript.
REFERENCES
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selectivity in the cyanation of 3-substituted pyridine 1-oxides with
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565–571.

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5-Bromopyridine-2-carbonitrile
3289
2. Maligres, P.E.; Waters, M.S.; Fleitz, F.; Askin, D. A highly catalytic
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Received in the USA March 12, 2003

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