Improved synthesis of mono- and disubstituted 2-halonicotinonitriles from alkylidene malononitriles

Article abstract of DOI:10.1021/ol4025265

Pyridines with 2,3,4 and/or 5 substitution remain challenging to prepare. Existing strategies to form multisubstituted 2-halonicotinonitriles via enamines suffer from dimerization of the starting alkylidene malononitriles resulting in low yields. Through alteration of reaction conditions, a new high yielding method into enamines was realized by condensing DMF-DMA and alkylidene malononitriles in the presence of substoichiometric acetic anhydride. Cyclization of the resulting enamines under Pinner conditions provided 2-halonicotinonitriles in high overall yields.

Full text of DOI:10.1021/ol4025265

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Improved Synthesis of Mono- and
Disubstituted 2‑Halonicotinonitriles
from Alkylidene Malononitriles
Ashley R. Longstreet,† Brian S. Campbell,† B. Frank Gupton,‡ and D. Tyler McQuade*,†
Department of Chemistry and Biochemistry, Florida State University, Tallahassee,
Florida 32306, United States, and Department of Chemistry, Department of Chemical
and Life Science Engineering, Virginia Commonwealth University, Richmond,
Virginia 23284, United States
mcquade@chem.fsu.edu
Received September 2, 2013
ABSTRACT
Pyridines with 2,3,4 and/or 5 substitution remain challenging to prepare. Existing strategies to form multisubstituted 2-halonicotinonitriles via
enamines suffer from dimerization of the starting alkylidene malononitriles resulting in low yields. Through alteration of reaction conditions, a new
high yielding method into enamines was realized by condensing DMFÀDMA and alkylidene malononitriles in the presence of substoichiometric
acetic anhydride. Cyclization of the resulting enamines under Pinner conditions provided 2-halonicotinonitriles in high overall yields.
Pyridines are abundant in many molecules of interest,
including active pharmaceutical ingredients (APIs),1 natural
products,2 biological probes,3 and materials.4 Despite many
innovative approaches, high yielding syntheses of poly-
substituted and fused pyridines with broad substrate ap-
plications remain elusive. These valuable multifunctional
intermediates are synthesized using two major strategies:
(1) modification ofpyridineprecursors5 or(2) construction
of the pyridine by cycloadditions or cyclizations from
acyclic intermediates.6 Complete construction of the pyr-
idine has the promise of providing complex pyridines
† Florida State University.
‡ Virginia Commonwealth University.
(1) For a list of current APIs, see: Mack, D. J.; Wieinrich, M. L.;
Vitaku, E.; Njardarson, J. Top 200 Brand Name Drugs by total US
prescriptions in 2010. http://cbc.arizona.edu/njardarson/group/sites/
default/files/Top%20200%20Brand-name%20Drugs%20by%20Total%
20US%20Prescriptions%20in%202010sm_0.pdf (accessed July 22,
2013).
(2) (a) Aida, W.; Ohtsuki, T.; Li, X.; Ishibashi, M. Tetrahedron 2009,
65, 369. (b) Michael, J. P. Nat. Prod. Rep. 2005, 22, 627.
(3) (a) Ishizuka, T.; Kimoto, M.; Sato, A.; Hirao, I. Chem. Commun.
2012, 48, 10835. (b) Kimoto, M.; Mitsui, T.; Yamashige, R.; Sato, A.;
Yokoyama, S.; Hirao, I. J. Am. Chem. Soc. 2010, 132, 15418.
(4) (a) Lee, C. W.; Lee, J. Y. Chem. Commun. 2013, 49, 6185. (b) Luo,
X.-Z.; Jia, X.-J.; Deng, J.-H.; Zhong, J.-L.; Liu, H.-J.; Wang, K.-J.;
Zhong, D.-C. J. Am. Chem. Soc. 2013, 135, 11684. (c) Zhao, G.; Lu, M.
J. Phys. Org. Chem. 2013, 26, 211. (d) Su, S.-J.; Sasabe, H.; Takeda, T.;
Kido, J. Chem. Mater. 2008, 20, 1691. (e) Su, S.-J.; Chiba, T.; Takeda, T.;
Kido, J. Adv. Mater. 2008, 20, 2125.
(5) Recent examples introducing new functionalities to pyridines: (a)
Chen, Q.; du Jourdin, X. M.; Knochel, P. J. Am. Chem. Soc. 2013, 135,
4958. (b) Bull, J. A.; Mousseau, J. J.; Pelletier, G.; Charette, A. B. Chem.
Rev. 2012, 112, 2642. (c) Seiple, I. B.; Su, S.; Rodriguez, R. A.;
Gianatassio, R.; Fujiwara, Y.; Sobel, A. L.; Baran, P. S. J. Am. Chem.
Soc. 2010, 132, 13194. (d) Berman, A. M.; Lewis, J. C.; Bergman, R. G.;
Ellman, J. A. J. Am. Chem. Soc. 2008, 130, 14926.
(6) Examples for syntheses of polysubstituted pyridines including
cycloadditions and cyclizations from acyclic precursers: (a) Allais, C.;
ꢀ
Lieby-Muller, F.; Rodriguez, J.; Constantieux, T. Eur. J. Org. Chem.
2013, 2013, 4131. (b) Lei, C.-H.; Wang, D.-X.; Zhao, L.; Zhu, J.; Wang,
M.-X. J. Am. Chem. Soc. 2013, 135, 4708. (c) Yamamoto, S.-i.; Okamoto,
K.; Murakoso, M.; Kuninobu, Y.; Takai, K. Org. Lett. 2012, 14, 3182. (d)
Anderson, E. D.;Boger, D. L. J. Am. Chem. Soc. 2011, 133, 12285. (e) Rizk,
T.; Bilodeau, E. J. F.; Beauchemin, A. M. Angew. Chem., Int. Ed. 2009, 48,
8325. (f) Trost, B. M.; Gutierrez, A. C. Org. Lett. 2007, 9, 1473. (g) Boger,
D. L. Chem. Rev. 1986, 86, 781.
(7) (a) Lehmann, J.; Alzieu, T.; Martin, R. E.; Britton, R. Org. Lett.
2013, 15, 3550. (b) Wei, Y.; Yoshikai, N. J. Am. Chem. Soc. 2013, 135,
3756. (c) Nakamura, I.; Zhang, D.; Terada, M. J. Am. Chem. Soc. 2010,
132, 7884. (d) Catozzi, N.; Edwards, M. G.; Raw, S. A.; Wasnaire, P.;
Taylor, R. J. K. J. Org. Chem. 2009, 74, 8343. (e) Colby, D. A.; Bergman,
R. G.; Ellman, J. A. J. Am. Chem. Soc. 2008, 130, 3645. (f) Liu, S.;
Liebeskind, L. S. J. Am. Chem. Soc. 2008, 130, 6918. (g) Winter, A.;
Risch, N. Synlett 2003, 2003, 1959. (h) Katritzky, A. R.; Denisenko, A.;
Arend, M. J. Org. Chem. 1999, 64, 6076.
r
10.1021/ol4025265
XXXX American Chemical Society

otherwise difficult to obtain. To date however, high yield-
ing strategies into 2,3,4- or 2,3,4,5-substituted pyridines are
limited.7
Table 2. Synthesis of 2-Bromonicotinonitriles from Various
Alkylidene Malononitrilesa
Early studies by Baldwin, Raab, and Ponticello at-
tempted to reach 2-bromonicotinonitriles from alkylidene
malononitriles using either triethyl orthoformate or N,N-
dimethylformamide dimethyl acetal (DMFÀDMA) as a
C1 source (Scheme 1).8 Using triethyl orthoformate led to
modest yields of the corresponding diethylacetal or enol
ether but demonstrated a limited substrate scope. In addi-
tion, cyclization of the acetal or enol ether under Pinner
conditions to the 2-bromonicotinonitriles was low yield-
ing. Alternatively, when DMFÀDMA wasused, low yields
of the corresponding enamine resulted due to dimerization
of the alkylidene malononitriles.
Scheme 1. The Baldwin, Raab, and Poticello Strategy for
Synthesizing Substituted 2-Bromonicotinonitriles
Table 1. Reducing the Addition of Ac2Oa
entry
Ac2O (mol %)
DMFÀDMA equiv
yield (%)b
a Performed at 5 mmol scale using anhydrous DCM. b Isolated yields
from the corresponding alkylidene malononitrile. Samples contained
residual AcOH (<1 wt %). c Performed at 20 mmol scale with alter-
native workup (see Supporting Information for details).
1
2
3
4
5
6
7
8
0
1
44
84
86
88
89
89
90
>99
200
100
50
25
20
10
20
1
1
1
can be derived from inexpensive aldehydes or ketones and
malononitrile. Additionally, the 2-bromo-3,4,5-tetrasub-
stituted pyridines are primed for further modification.9
Despite these positive attributes, the low overall yields of
1
1
1
1.2
a Performed at a 0.5 mmol scale using anhydrous DCM. b Calibrated
yields determined by GC using mesitylene as the internal standard.
(9) Examples of transition metal couplings with 2-bromopyridines
and quinolines: (a) Hoecker, J.; Gademann, K. Org. Lett. 2013, 15, 670.
(b) Isik, M.; Tanyeli, C. J. Org. Chem. 2013, 78, 1604. (c) Leon, B.; Fong,
J. C. N.; Peach, K. C.; Wong, W. R.; Yildiz, F. H.; Linington, R. G. Org.
Lett. 2013, 15, 1234. (d) Xiong, X.; Jiang, Y.; Ma, D. Org. Lett. 2012, 14,
2552. (e) Kuzmina, O. M.; Steib, A. K.; Flubacher, D.; Knochel, P. Org.
Lett. 2012, 14, 4818. (f) Oberli, M. A.; Buchwald, S. L. Org. Lett. 2012,
14, 4606. (g) Kim, Y.; Kumar, M. R.; Park, N.; Heo, Y.; Lee, S. J. Org.
Chem. 2011, 76, 9577.
ꢀ
The BaldwinÀRaabÀPonticello synthesis is an attractive
route to substituted pyridines because the acyclic precursors
(8) Baldwin, J. J.; Raab, A. W.; Ponticello, G. S. J. Org. Chem. 1978,
43, 2529.
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 3. Temperature Screen for the Enamine Formationa
Table 4. Synthesis of 2-Bromonicotinonitriles at 1 M Reaction
Concentration for the Enamine Formationa
entry
temp (°C)
yield (%)b
1
2
3
4
rt
81
90
94
78
35
45
60
a Reactions performed at 20 mmol scale using anhydrous toluene.
b Isolated yields.
their process have limited wide application. We hypothesized
that an alternative set of conditions, using DMFÀDMA,
would provide a high yielding route to bifunctional enamines
(2). Furthermore, we predicted the cyclization under Pinner
conditions with these enamines would provide higher yields
than those observed with the acetal or enol ether. Herein, we
describe an alteration to the method that allows the corre-
sponding enamines and 2-halonicotinonitriles to be obtained
in high yield.
Initially, we applied the reaction conditions reported
by Deng et al.10 whereby dilute alkylidene malononitrile
(1a; DCM) was combined with DMFÀDMA. While these
conditions provided the enamine (2a) in yields higher
(44%) than those reported by Baldwin, Raab, and Ponti-
cello (0%), 1H NMR spectroscopy showed primarily dimer-
ized 1a. To improve the yield of 2a further, we system-
atically surveyed reaction conditions that would suppress
dimer formation.
We hypothesized that the methanol released from the
DMFÀDMA was catalyzing the dimer formation. To test
our hypothesis, we measured the yield of 2a as as function
of added MeOH scavengers: acetic anhydride, trimethylsi-
˚
lyl chloride (TMSCl), and molecular sieves (5 A). Of these
scavengers, only Ac2O provided measurable quantities of
the desired product.
The scavenger hypothesis was examined in more detail
1
by analyzing the reaction mixtures by H NMR. If the
scavenger hypothesis was valid, formation of methyl acet-
ate would be observed. To our surprise, only small quan-
tities of methyl acetate formed prompting us to reduce the
amount of Ac2O. As shown in Table 1 (entries 4À7), Ac2O
loadings as low as 10 mol % provided improved yields.
Though 10 mol % provided significant yield improve-
ment, a small amount of dimer remained, making purifica-
tion difficult. Therefore, we elected to employ Ac2O at the
20 mol % level. Further optimization studies demon-
strated that increasing the equivalents of DMFÀDMA
to 1.2 gave quantitative yields of the desired enamine,
prompting us to examine the cyclization and the reaction
scope generally.
a Reaction performed at 5 mmol scale using anhydrous toluene.
b Isolated yields from the corresponding alkylidene malononitrile. Sam-
ples still contained some AcOH (<1 wt %). c Yield improved to 83%
upon scaling to 20 mmol. d Contains <1 wt % of the 2-bromo-4,5-
dimethylnicotinonitrile isomer. e Contains 2 wt % of starting alkylidene
malononitrile. f Solvent DCM (0.1 M) and 1 equiv of Ac2O was used.
We proceeded to focus on enamine cyclization under
Pinner conditions. We hypothesized that the enamines
would provide high yields of the desired pyradines com-
pared to similar acetals or enol ethers, because HBr reacts
with acetals and enol ethers through multiple manifolds,
whereas enamines can only cyclize. To our gratification,
we were able to synthesize 2-bromo-4-methylnicotinonitrile
(5a) in 91% yield in two steps (Table 2, entry 1). The method
(10) (a) Xue, D.; Li, J.; Zhang, Z.-T.; Deng, J.-G. J. Org. Chem. 2007,
72, 5443. (b) Xue, D.; Chen, Y.-C.; Wang, Q.-W.; Cun, L.-F.; Zhu, J.;
Deng, J.-G. Org. Lett. 2005, 7, 5293.
Org. Lett., Vol. XX, No. XX, XXXX
C

The substrate 1g, despite its similarity to 1a, is not high
yielding (entry 2) because the 2-bromo-4,5-dimethylnico-
tinonitrile isomer is also produced (structure not shown).
The reaction conditions do not work well with substrates
formed from aldehydes (1m) (entry 8). Using the alter-
native dilute conditions with DCM and a higher concen-
tration of Ac2O improved the yield of 1m to 36% (see
Supporting Information for details).
Scheme 2. Synthesis of 2-Bromo, 2-Chloro, and
2-Iodo-4-methylonicotinonitrilesa
Finally, to further expand the access to alternative
2-halonicotinonitriles, we investigated synthesizing both
2-chloro and 2-iodo dervatives from the enamine (2a)
(Scheme 2). Upon treatment with HCl (g), the slurry of
enamine 2a in AcOH was transformed into 2-chloro-4-
methylnicotinonitrile (8), the precursor to a starting mate-
rial to nevirapine,12 2-chloro-3-amino-4-picoline (CAPIC).
In addition, the enamine (2a) slurry treated with trimethyl-
silyl iodide (TMSI) and water to produce HI in situ pro-
duced 2-iodo-4-methylnicotinonitrile, an ideal substrate for
difficult metal insertions.
In conclusion, we have developed an efficient method to
produce 4-substituted and 4,5-disubstituted 2-halonicoti-
nonitriles. The substoichiometric addition of Ac2O has a
major impact on the viability of this approach, allowing
access to 4-substituted and 4,5-disubstituted 2-halonicotino-
nitriles. However, the role of the acetic anhydride has yet to
be determined. Rate enhancement occurs upon addition of
Ac2O, but the dependency of Ac2O appears complex.13 This
process provides a window of opportunity for chemists to
reach a variety of multisubstituted pyridines that were pre-
viously either unattainable or only attainable in low yields.
a Yields of isolated product. See Supporting Information for details.
was then applied to several substrates obtained from acet-
ophenone and acetophenone derivatives (entries 2À6).
Although this initial process provided high overall yields
(>87%), we sought to refine the route by removing the
use of DCM while increasing the overall concentration. Of
the solvents we examined, toluene was the most attractive
because pure enamine product (2a) precipitated from the
reaction and also enabled a 10-fold increase in concentration.
Product precipitation drives the reaction forward and sim-
plifies workup to merely filtration. Despite these benefits, the
reaction at room temperature produced 2a in only 81% yield
(Table 3, entry 1). Further optimization revealed heating to
45 °C improved the yield (Table 3, entry 3). Temperatures
higher than 45 °C led to lower yields (Table 3, entry 4).
We applied the improved method to various substrates
with the goal of producing both 2-bromo-4-substituted
and 2-bromo-4,5-disubstituted nicotinonitriles. The method
works well with substrates derived from ketones, including
substrates leading to bi- and tricyclic compounds (5h, 5i,
5k) (Table 4). These compounds can potentially be trans-
formed into different isoquinoline, 2-azaphenanthrene, and
other fused pyridine derivatives after functionalizing the
nitrile and/or halogen that followed upon oxidation or
halogenation followed by elimination.11 Furthermore, yields
improve upon scaling as shown with substrate 5a (entry 1; 5
to 20 mmol scale).
Acknowledgment. The authors thank the Clinton Health
Access Initiative and Corning Glass, Inc. for support.
In addition, ARL, BSC, and DTM thank the NSF
(CHE-1152020) and FSU.
Supporting Information Available. Experimental pro-
cedures, characterization, and prelimary kinetic data of
reaction products. This information is available free of
charge via the Internet at http://pubs.acs.org.
(12) (a) Boswell, R. F.; Gupton, B. F.; Lo, Y. S. Method for Making
Nevirapine. U.S. Patent 6,680,383, Jan 20, 2004. (b) Gupton, B. F. Process
for making 3-amino-2-chloro-4-methylpyridine. U.S. Patent 6,399,781,
Jun 4, 2002.
(11) (a) Zou, Y.; Young, D. D.; Cruz-Montanez, A.; Deiters, A. Org.
Lett. 2008, 10, 4661. (b) Anzini, M.; Cappelli, A.; Vomero, S.; Giorgi, G.;
Langer, T.; Hamon, M.; Merahi, N.; Emerit, B. M.; Cagnotto, A.;
Skorupska, M.; Mennini, T.; Pinto, J. C. J. Med. Chem. 1995, 38, 2692.
(13) For preliminary kinetic data, see Supporting Information.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX