A Bifunctional Reagent Designed for the Mild, Nucleophilic Functionalization of Pyridines

Article abstract of DOI:10.1021/jacs.7b05414

Herein is reported the design and application of a reagent for the direct functionalization of pyridines. These reactions occur under mild conditions and exhibit broad functional group tolerance, enabling the late-stage functionalization of drug-like molecules. The reagent can be easily prepared on large scale from inexpensive reagents, and reacts in the title reaction with acetonitrile, sodium chloride, and sodium methanesulfonate as the sole byproducts. Although this Communication focuses primarily on reactions with cyanide as nucleophile, preliminary experiments with other nucleophiles foreshadow the broad reaching synthetic utility of this approach.

Full text of DOI:10.1021/jacs.7b05414

Communication
pubs.acs.org/JACS
A Bifunctional Reagent Designed for the Mild, Nucleophilic
Functionalization of Pyridines
Patrick S. Fier*
Department of Process Research and Development, Merck & Co., Inc., Rahway, New Jersey 07065, United States
S
* Supporting Information
ABSTRACT: Herein is reported the design and applica-
tion of a reagent for the direct functionalization of
pyridines. These reactions occur under mild conditions
and exhibit broad functional group tolerance, enabling the
late-stage functionalization of drug-like molecules. The
reagent can be easily prepared on large scale from
inexpensive reagents, and reacts in the title reaction with
acetonitrile, sodium chloride, and sodium methanesulfo-
nate as the sole byproducts. Although this Communication
focuses primarily on reactions with cyanide as nucleophile,
preliminary experiments with other nucleophiles fore-
shadow the broad reaching synthetic utility of this
approach.
Figure 1. Nucleophilic functionalization of pyridines.
yridines are pervasive in synthetic chemistry as the most
Pprevalent heteroarenes in pharmaceuticals, and as structural
components of many natural products.1 The majority of
synthetic approaches to pyridine-containing targets largely rely
on the manipulation of prefunctionalized building blocks.2
However, methods that do not require prefunctionalization can
result in more streamlined syntheses and can enable the late-
stage diversification of complex molecules.3
To develop a new approach to pyridine functionalization, a
bifunctional reagent was conceptualized. First, the reagent would
act as an electrophilic activator to facilitate nucleophilic addition
to the pyridine ring (eq 1). Next, in the presence of a base, the
Two classes of reactions for the direct functionalization of
pyridines have become ingrained in organic synthesis. The first
comprise Minisci-type reactions in which radicals add to
pyridines under acidic and oxidizing conditions.4 Although this
approach has undergone extensive development, it remains
primarily limited to alkyl and acyl radicals.5
reagent would act as a two-electron oxidant to rearomatize the
dihydropyridine intermediate (eq 1).9 To be practical, the
reagent would need to be readily available and easily handled,
both steps would need to occur under mild conditions, and only
innocuous byproducts would be formed. With these criteria in
mind, a class of imine-based reagents containing a leaving group
at both the α-carbon and nitrogen were envisioned to promote
the direct functionalization of pyridines. More specifically, α-
chloro O-sulfonyl aldehyde oximes were targeted due to their
ease of synthesis from aldehyde oximes with inexpensive
reagents.10
A small library of air- and moisture-stable α-chloro O-
methanesulfonyl aldoximes were prepared (Scheme 1), and their
reactivity toward pyridine was investigated. However, in all cases
it was found that the formation of the intermediate pyridinium
chloride salt was thermodynamically unfavorable, with the
A second approach for pyridine functionalization involves
initial oxidation of pyridines to pyridine N-oxides, followed by
O-activation and nucleophilic substitution (Figure 1A).6
Although these reactions are useful in certain contexts, the
pyridine N-oxides need to be prepared and isolated in a separate
step.7 Pyridine N-oxides are highly polar, hygroscopic, and
generally water-soluble, which makes purification and handling
difficult. More significantly, the oxidants used to prepare
pyridine N-oxides can promote Baeyer−Villager oxidation of
ketones, epoxidation of olefins, and the oxidation of 5-
membered heterocycles, aldehydes, amines, and sulfides. Finally,
the activating reagents used to promote the nucleophilic
substitution step are highly reactive, and often exhibit modest
functional group compatibility. All of these limitations are
significant, and therefore the development of new reagents that
enable similar transformations of pyridines under mild
conditions would be of great synthetic value.8
Received: May 25, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.7b05414
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
a
crystalline solid in analytically pure form after an aqueous
workup.13
Scheme 1. Proof of Concept Studies
With large quantities of reagent 2b in hand, the direct
cyanation reaction was demonstrated on a range of function-
alized pyridines. In addition to being a simple protocol, the direct
functionalization procedure reported here offers several
advantages over related reactions with pyridine N-oxides.
Functional groups prone to oxidation under the conditions
used to oxidize pyridines to pyridine N-oxides were well
tolerated, including electron-rich heterocycles, ketones, an
electron-rich aldehyde, olefins, sulfide, and even an arylboronate
ester. Amides and alcohols were well tolerated; this is
noteworthy because these functional groups can react with
typical activating agents used in pyridine N-oxide reactions (A-X,
Figure 1). The mild conditions of the cyanation step enabled
reactions to occur in the presence of an aryl fluoride susceptible
toward SNAr, an aldehyde prone to cyanide-catalyzed benzoin
condensation, an α,β-unsaturated carbonyl compounds reactive
a b c
, ,
Scheme 2. Substrate Scope for the Cyanation of Pyridines
a
For experimental details, see the Supporting Information. For clarity,
the triflate counterions have been removed from the crystal structure
images.
reaction equilibrium largely favoring the two starting materials.
To overcome this, a stoichiometric amount of NaOTf was added
to increase conversion to the pyridinium salt by the precipitation
of NaCl.11 Reagents 2a and 2b reacted with pyridine in nearly
quantitative yields under mild conditions.
The pyridinium salts formed from 2a and 2b were analyzed by
X-ray crystallography (Scheme 1B). Both contained a cis
orientation of the OMs and pyridinium groups. The preferred
orientation likely results from favorable orbital interactions of
the lone pair on the oxime nitrogen and the σ* orbital of the C
N (pyridinium) bond. In each case, the pyridinium ring was bent
∼56° out of plane relative to the CN bond of the oxime group.
For the nucleophilic substitution stage, reactions with cyanide
nucleophiles were investigated.12 Reactions with NaCN and
KCN occurred rapidly and formed 2-cyanopyridine in
comparable yields, with the identity of the auxiliary bases having
minimal impact. In each case, <1% of isomeric 4-cyanopyridine
was formed. The mass balance in each reaction was pyridine,
resulting from cyanide attack at the oxime carbon. Overall, the
novel reagent 2b was identified as the bifunctional reagent that
provided the highest yields, and is also the most atom-economic.
Reagent 2b was prepared on 400 mmol scale from
inexpensive, commercially available acetaldehyde oxime (eq 2).
a
The reactions were performed by sequential addition of the reagents
for the two stages, see the Supporting Information for details. Isolated
b
yields shown for reactions performed on 0.5 mmol scale. Assay yields
of volatile products were determined by HPLC against authentic
product standards. Reagent 2a was used in place of 2b. Ratios in
parentheses refer to isomeric 2,3- and 2,5-disubstituted pyridines
formed in the reaction, with the major product shown.
c
Acetaldehyde oxime was chlorinated with N-chlorosuccinimide
(NCS), and the crude material was treated with triethylamine
and MsCl to form reagent 2b as an air- and moisture-stable
B
DOI: 10.1021/jacs.7b05414
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
toward conjugate addition, and an epimerizable stereocenter.
For every example shown in Scheme 2, the mass balance
consisted of unreacted pyridine substrate, either from incom-
plete reaction with 2b, or via competitive attack of cyanide at the
oxime carbon of the intermediate pyridinium salt.
Reactions with 3-substituted pyridines were investigated in
order to probe the site-selectivity of cyanation. Substrates
containing halogen and oxygen substituents in the 3-position
formed the 2-cyano-3-substituted pyridines with >95:5
selectivity. Isoquinoline substrates underwent cyanation ex-
clusively at the 1-position. These observations are consistent
with nucleophilic addition occurring at the most electrophilic
carbon of the pyridinium intermediate, and is in-line with the
selectivity observed with other reported nucleophilic addition
reactions to activated pyridines.6 Substrates containing bulkier or
less-polar groups formed mixtures of two isomers. 4-
cyanopyridine products were not observed in any case.
bond vs a CH bond.15 Under the standard cyanation
conditions, a 1:1 ratio of deuterio- and protio-products was
formed (Scheme 4B), consistent with irreversible cyanide
addition occurring prior to deprotonation. Irreversible cyanide
addition is also consistent with the observation that reactions of
3-phenylpyridine with various bases formed the isomeric
cyanopyridine products in approximately the same ratio
(Scheme 4C).16 This is consistent with the product-determining
step in the cyanation reaction of 3-substituted pyridines being
controlled by the relative rates of cyanide attacking the pyridine
ring at the isomeric 2-positions.
Finally, the impact of the cyanide source on site-selectivity was
investigated with pyridine as the substrate (Scheme 4D).
Scheme 4. Investigating the Reaction Mechanism
To demonstrate the application of this method in the context
of late-stage functionalization, the direct cyanation was carried
out on 1w, a mixed progesterone agonist/antagonist (Scheme
3).14 This compound contains two electrophilic ketones: one
Scheme 3. Gram-Scale Cyanation of a Mixed Progesterone
Agonist/Antagonist
bearing an epimerizable stereocenter, the other conjugated to a
diene. Of particular note, these functionalities are reactive
toward the oxidants used to form pyridine N-oxides,7 as well as
typical radicals used in Minisci-type reactions.4 The pyridine
cyanation procedure was performed under the standard
conditions with 1.0 g of 1w to form a 2.5:1 mixture of 2-
cyanopyridine products in 80% combined yield. The isomers
were readily separated on silica gel, and the mass balance
consisted of unreacted starting material.
Although this method allows for the direct cyanation of a
wide-range of functionalized pyridines, there are two limitations
that need to be mentioned. First, because of the modest
electrophilicity of reagent 2b, diazines and 2-substituted
pyridines exhibit poor reactivity in the current protocol. Second,
although certain nucleophilic functional groups are tolerated,
side-reactions were observed with substrates bearing unhindered
alcohols and amines.
Although both NaCN and KCN formed 2-cyanopyridine as
the sole product, Zn(CN)2 formed 4-cyanopyridine as the major
product, albeit in modest yield. These observations are
consistent with site-selectivity being controlled by the
nucleophilic addition step.
Taken together, the results from the above-mentioned
experiments are consistent with the mechanism illustrated in
Scheme 4E. The intermediate pyridinium salt has been
characterized by X-ray crystallography, the irreversibility of the
cyanide addition step has been validated, and the byproducts
from the elimination/rearomatization step have been observed.
Finally, to demonstrate that this concept for pyridine
functionalization extends beyond cyanation, preliminary experi-
ments with other nucleophiles were conducted (Scheme 5).
With minimal screening, proof of concept was obtained showing
Having demonstrated the cyanation reaction on a broad range
of substrates, experiments were designed in order to gain a
deeper understanding of the reaction mechanism. First, a
reaction with pyridine was carried out in deuterated solvents. At
1
the end of the reaction, H NMR spectroscopy of the crude
mixture revealed an equimolar amount of CH3CN, methanesul-
fonate anion, and 2-cyanopyridine (Scheme 4A), consistent with
the nitrile-forming rearomatization step proposed above.
To probe the reversibility of nucleophilic addition of cyanide,
4-phenylpyridine containing a deuterium atom at the 2-position
was subjected to the reaction conditions. If cyanide addition is
reversible, a higher percentage of the deuterated product would
be expected due to the slower rate of deprotonation of a CD
C
DOI: 10.1021/jacs.7b05414
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
(4) (a) Minisci, F.; Vismara, E.; Fontana, F. Heterocycles 1989, 28, 489.
(b) Duncton, M. A. J. MedChemComm 2011, 2, 1135. (c) Fujiwara, Y.;
Dixon, J. A.; O’Hara, F.; Funder, E. D.; Dixon, D. D.; Rodriguez, R. A.;
Scheme 5. Preliminary Results with Other Nucleophiles
́
Baxter, R. D.; Herle, B.; Sach, N.; Collins, M. R.; Ishihara, Y.; Baran, P. S.
Nature 2012, 492, 95. (d) Ma, X.; Dang, H.; Rose, J. A.; Rablen, P.;
Herzon, S. B. J. Am. Chem. Soc. 2017, 139, 5998.
(5) For Minisci-type reactions with aryl or nitrogen radicals, see:
(a) 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. (b) Foo, K.;
́
Sella, E.; Thome, I.; Eastgate, M. D.; Baran, P. S. J. Am. Chem. Soc. 2014,
136, 5279. (c) Allen, L. J.; Cabrera, P. J.; Lee, M.; Sanford, M. S. J. Am.
Chem. Soc. 2014, 136, 5607. (d) Kim, H.; Kim, T.; Lee, D. G.; Roh, S.
W.; Lee, C. Chem. Commun. 2014, 50, 9273.
that alkoxide, Grignard, organozinc, and malonate nucleophiles
react to form a diverse set of functionalized pyridines.
Furthermore, these results, along with those shown in Scheme
4D, reveal that changing the identity of the nucleophile leads to
the selective functionalization at either the 2- or 4-position.
Follow-up studies to investigate further reaction conditions with
a wide array of nucleophiles are ongoing and will be reported in
due course.
In summary, a novel bifunctional reagent has been designed
for the direct functionalization of pyridines. The reagent acts to
promote nucleophilic addition to pyridine, and as a mild two-
electron oxidant in the presence of a weak base. The utility of the
method is highlighted by the ability to carry out the cyanation of
pyridines bearing functional groups sensitive toward acid, base,
and oxidation. Preliminary results with other nucleophiles reveal
that this approach to pyridine functionalization will be broad
reaching. Work is ongoing to expand the scope to other
nucleophiles, and to explore further the application of these
bifunctional reagents in the development of new reactions.
(6) (a) Bull, J. A.; Mousseau, J. J.; Pelletier, G.; Charette, A. B. Chem.
Rev. 2012, 112, 2642. For representative exmples, see: (b) Farrell, R. P.;
Elipe, M. V. S.; Bartberger, M. D.; Tedrow, J. S.; Vounatsos, F. Org. Lett.
2013, 15, 168. (c) Keith, J. M. J. Org. Chem. 2008, 73, 327. (d) Yin, J. J.;
Xiang, B. P.; Huffman, M. A.; Raab, C. E.; Davies, I. W. J. Org. Chem.
2007, 72, 4554. (e) Londregan, A. T.; Jennings, S.; Wei, L. Q. Org. Lett.
2011, 13, 1840. (f) Wengryniuk, S. E.; Weickgenannt, A.; Reiher, C.;
Strotman, N. A.; Chen, K.; Eastgate, M. D.; Baran, P. S. Org. Lett. 2013,
15, 792.
(7) Katritzky, A. R.; Lam, J. N. Heterocycles 1992, 33, 1011.
(8) For selected examples of other methods to functionalize pyridines,
see: (a) Fier, P. S.; Hartwig, J. F. Science 2013, 342, 956. (b) Fier, P. S.;
Hartwig, J. F. J. Am. Chem. Soc. 2014, 136, 10139. (c) Hilton, M. C.;
Dolewski, R. D.; McNally, A. J. Am. Chem. Soc. 2016, 138, 13806.
(d) Alberico, D.; Scott, M. E.; Lautens, M. Chem. Rev. 2007, 107, 174.
(e) Seregin, I. V.; Gevorgyan, V. Chem. Soc. Rev. 2007, 36, 1173.
(f) Murakami, K.; Yamada, S.; Kaneda, T.; Itami, K. Chem. Rev. 2017,
DOI: 10.1021/acs.chemrev.7b00021.
(9) Formally, triflic anhydride has been shown to act in this manner
with the formation of triflinate anion. (a) Anders, E.; Markus, F. Chem.
Ber. 1989, 122, 113. (b) Anders, E.; Markus, F. Chem. Ber. 1989, 122,
119. (c) Haase, M.; Goerls, H.; Anders, E. Synthesis 1998, 1998, 195.
(d) Katritzky, A. R.; Zhang, S.; Kurz, T.; Wang, M.; Steel, P. J. Org. Lett.
2001, 3, 2807. (e) Corey, E. J.; Tian, Y. Org. Lett. 2005, 7, 5535 Also see
reference 8c..
(10) (a) Truce, W. E.; Naik, A. R. Can. J. Chem. 1966, 44, 297.
(b) Rajagopalan, P.; Talaty, C. N. Tetrahedron Lett. 1966, 7, 2101.
(c) Yamamoto, Y.; Mizuno, H.; Tsuritani, T.; Mase, T. J. Org. Chem.
2009, 74, 1394. (d) Yamamoto, Y.; Mizuno, H.; Tsuritani, T.; Mase, T.
Tetrahedron Lett. 2009, 50, 5813.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.7b05414.
■
S
Data for pyridinium salts from 2a (CIF)
Data for pyridinium salts from 2b (CIF)
Experimental details and characterization data for new
compounds (PDF)
(11) For related anion exchange reactions, see: (a) Pabel, J.; Hosl, C.
E.; Maurus, M.; Ege, M.; Wanner, K. T. J. Org. Chem. 2000, 65, 9272.
(b) Yamaguchi, R.; Hatano, B.; Nakayasu, T.; Kozima, S. Tetrahedron
Lett. 1997, 38, 403. (c) Yamaguchi, R.; Omoto, Y.; Miyake, M.; Fujita,
K. Chem. Lett. 1998, 27, 547.
AUTHOR INFORMATION
Corresponding Author
*patrick.fier@merck.com
ORCID
Patrick S. Fier: 0000-0002-6102-815X
Notes
The author declares no competing financial interest.
■
(12) (a) Feely, W. E.; Beavers, E. M. J. Am. Chem. Soc. 1959, 81, 4004.
(b) Fife, W. K. J. Org. Chem. 1983, 48, 1375. (c) Vorbruggen, H.;
̈
Krolikiewicz, K. Synthesis 1983, 1983, 316. (d) Okamoto, T.; Tani, H.
Chem. Pharm. Bull. 1959, 7, 130. (e) Harusawa, S.; Hamada, Y.; Shioiri,
T. Heterocycles 1981, 15, 981. (f) Fife, W. K. Heterocycles 1984, 22, 93.
(g) Yamaguchi, K.; Xu, N.; Jin, X.; Suzuki, K.; Mizuno, N. Chem.
Commun. 2015, 51, 10034.
ACKNOWLEDGMENTS
■
(13) Reagent 2b was stored and handled on the benchtop without
precautions toward air or moisture. No degradation was observed over
the span of 2 months. Melting point, 84 °C; decomposition onset
temperature, 222 °C.
I thank Kevin Maloney, L. C. Campeau, and Ian Davies (all at
Merck) for their feedback. I thank Andy Brunskill (Merck) for
obtaining the crystal structures.
(14) Rewinkel, J.; Enthoven, M.; Golstein, I.; van der Rijst, M.;
Scholten, A.; van Tilborg, M.; de Weys, D.; Wisse, J.; Hamersma, H.
Bioorg. Med. Chem. 2008, 16, 2753.
(15) (a) Anslyn, E. V.; Dougherty, D. A. Modern Physical Organic
Chemistry; University Science Books, 2006. (b) Simmons, E. M.;
Hartwig, J. F. Angew. Chem., Int. Ed. 2012, 51, 3066.
REFERENCES
■
(1) (a) Vitaku, E.; Smith, D. T.; Njardarson, J. T. J. Med. Chem. 2014,
57, 10257. (b) Substructure search of pyridine, Dictionary of Natural
Products; Taylor & Francis Group.
(2) (a) Joule, J. A.; Mills, K. Heterocyclic Chemistry, 5th ed.; Wiley, 2010.
(b) Eicher, T.; Hauptmann, S.; Speicher, A. The Chemistry of
Heterocycles, 3rd ed.; Wiley-VCH, 2012.
(16) An alternative explanation is that cyanide acts as the base to
deprotonate the C-2 position of the dihydropyridine intermediate.
(3) (a) Newhouse, T.; Baran, P. S.; Hoffmann, R. W. Chem. Soc. Rev.
2009, 38, 3010. (b) Gutekunst, W. R.; Baran, P. S. Chem. Soc. Rev. 2011,
40, 1976.
D
DOI: 10.1021/jacs.7b05414
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX