A Strategy to Aminate Pyridines, Diazines, and Pharmaceuticals via Heterocyclic Phosphonium Salts

Article abstract of DOI:10.1021/acs.orglett.8b00813

A straightforward process to aminate pyridines and diazines is presented by reacting phosphonium salt derivatives with sodium azide. The iminophosphorane products are versatile precursors to several nitrogen-containing functional groups, and the process can be applied to building block heterocycles, to drug-like fragments, and for late-stage functionalization of complex pharmaceuticals. Appealing features of this strategy include using C-H bonds as precursors, precise regioselectivity, and a distinct scope from other amination methods, particularly those relying on halogenated azaarenes.

Full text of DOI:10.1021/acs.orglett.8b00813

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
A Strategy to Aminate Pyridines, Diazines, and Pharmaceuticals via
Heterocyclic Phosphonium Salts
Chirag Patel, Margaret Mohnike, Michael C. Hilton, and Andrew McNally*
Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523, United States
S
* Supporting Information
ABSTRACT: A straightforward process to aminate pyridines and
diazines is presented by reacting phosphonium salt derivatives with
sodium azide. The iminophosphorane products are versatile
precursors to several nitrogen-containing functional groups, and the
process can be applied to building block heterocycles, to drug-like
fragments, and for late-stage functionalization of complex pharma-
ceuticals. Appealing features of this strategy include using C−H bonds
as precursors, precise regioselectivity, and a distinct scope from other amination methods, particularly those relying on
halogenated azaarenes.
xtensive efforts have been dedicated toward aminating
aromatic rings over the past several decades due to the
herein report that this phosphorus-mediated strategy can be
broadly applied to selectively aminate building block hetero-
cycles, drug-like fragments, and complex pharmaceuticals.
Iminophosphoranes are also versatile functional groups that
enable access to valuable nitrogen-containing derivatives.
E
widespread occurrence of aryl amines in pharmaceuticals,
agrochemicals, natural products, and materials.1 The most
widely applied methods are metal-catalyzed C−N cross-
coupling reactions, but several other distinct strategies have
emerged, including radical-based methods, reactions with
nitrogen electrophiles, nitroarene reduction processes, and
C−H amination reactions (eq 1).2−6 We became interested in
this field after noticing that (a) aminopyridines and diazines are
prominent in drug compounds (eq 2) and that (b) the number
of broadly effective methods to aminate these heterocycles is
considerably narrower than for benzene derivatives.7−10 The
classic Chichibabin reaction, which forms 2-aminopyridines
from C−H precursors, lacks generality due to the excessive
reactivity of NaNH2.11,12 Most methods rely on prehalogenated
substrates such as Buchwald−Hartwig reactions, recent Ni-
catalyzed cross-couplings, and SNAr reactions.2a,f,13 While these
are powerful approaches, they can be limited by the lack of
methods that can selectively install halides on more complex
pyridines and diazines. As such, an alternative approach that
produces a distinct set of aminated products would be valuable
to medicinal chemists.
We are engaged in a program aimed at selectively
transforming pyridine and diazine C−H bonds into phospho-
nium ions and then exploiting the reactivity of the C−P bond
to make useful heterocyclic derivatives. Ourselves and Anders
reported a single example of transforming the C−+PPh3 group
into an iminophosphorane using NaN3 as a nucleophile;
however, we did not know if this strategy would be general
across a range of pyridines and diazines.14,15 We were therefore
compelled to investigate this process further, as phosphonium
salts can be formed on azaarenes that are often outside of the
scope of current halogenation methods (eq 3). For example,
Hartwig’s AgF2-mediated pyridine fluorination can be used to
introduce amines at the 2-position,16 whereas phosphonium
salt formation is selective for the 4-position of the scaffold. We
Our first priority was to build on the preliminary result by
investigating reaction parameters to obtain a standard
amination protocol. We found that heating 2-phenyl
phosphonium salt in the presence of sodium azide in DMSO
at 120 °C was optimal, in terms of temperature and that
increasing the concentration of the reaction to 1.5 M also
increased the yield of the reaction. Although it is possible to use
Received: March 13, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00813
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
ab
,
Scheme 1. Scope of the Phosphorus-Mediated Amination Process
a
b
Isolated yields of products are shown with yields of phosphonium salts in parentheses. A red dot indicates the position of phosphonium salt
regioisomers. Iminophosphoranes are isolated as single regioisomers in all cases.
solvents other than DMSO as the reaction medium, the
reaction efficiency suffers (see Supporting Information (SI) for
further details). Small amounts of the corresponding C−H
heterocyclic precursor are obtained in the reaction, which can
be separated via column chromatography.
aminoquinoxaline 2j are obtained in reasonable yields.
Pyrimidines 2k and 2l work particularly well in the C−N
bond-forming step, and although the synthesis of pyrrolopyr-
imidine 2m was less efficient, it still gives access to a motif
found in drugs such as tofacitinib (eq 2).
With an optimized amination reaction in hand, we began
exploring the generality of this amination process. Starting with
pyridines, we selected scaffolds displaying a variety of
substitution patterns and functional groups. In all cases,
phosphonium salt formation and subsequent amination is
exclusively selective for the 4-position (Scheme 1A). Tetrahy-
droquinoline, bearing a 2,3-substitution pattern, is smoothly
aminated using this protocol (2a). Similarly, 2,5-disubstituted
pyridines bearing substituents, including trifluoromethyl,
thiomethyl, cyano groups, and aryl ethers, are effective (2b−
2d). Sterically hindered 3,5-disubstituted pyridines also see C−
N bond formation selectively occur at the 4-position (2e and
2f). If the 4-position is blocked, then the 2-position is aminated
instead, as shown for pyridine 2g and quinoline 2h. Diazines
are also compatible with this approach: aminopyrazine 2i and
Then, we turned our attention to drug-like fragments with
pyridines and diazines in their structures.17 These types of
molecules are abundant in pharmaceutical compound collec-
tions, and applying the amination protocol would result in
important amino derivatives. However, their structures are
often complex with other functional groups and basic nitrogen
atoms present, making C−N bond formation challenging.
Scheme 1B shows that a diverse set of representative drug
fragments can be converted into iminophosphoranes using this
two-step process. Iminophosphorane 2n, containing a tri-
(hetero)aryl methane motif, is formed in good overall yield.
Similarly, benzhydryl stereocenters are accommodated in
pyridine 2o, without interference from the piperidine moiety.
Distinct pyrimidine-containing fragments, such as 2p and 2q,
are particularly effective in this strategy. Finally, tri(hetero)aryl
B
DOI: 10.1021/acs.orglett.8b00813
Org. Lett. XXXX, XXX, XXX−XXX

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systems 2r and 2s are noteworthy due to the potential isomeric
mixtures of iminophosphoranes between the different pyridine
rings; a single regio- and site-selective outcome was observed in
each case.
Scheme 2. Derivatizations of Iminophosphoranes
Late-stage functionalization of pharmaceuticals is being
intensively investigated at present, although strategies to
aminate complex pyridines and diazines are limited.18 Outside
of Hartwig’s 2-fluorination reaction, iridium-catalyzed boryla-
tion is the most promising strategy for aminating azaarenes, as
the C−B bond can be used as a coupling handle to introduce an
amine.16,19 Our previous studies have shown that complex
pharmaceuticals can be converted into phosphonium salts with
excellent regio- and site-selectivity;14a,b successfully applying
the subsequent azide coupling reaction would therefore
represent an important method for late-stage amination.
Scheme 1C shows that the two-step sequence is straightforward
to apply to a set of structurally diverse pharmaceuticals.
Chlorphenamine, a common antihistamine, is converted into
iminophosphorane 2t with exclusive regioselectivity over two
steps. The C−N bond-forming step for loratadine occurs with
lower yield, but in quantities that would be usable for medicinal
chemists (2u). Benzyl-protected varenicline (2v), containing a
quinoxaline ring, can also be aminated via this strategy. The
site-selectivity issues in etoricoxib and imatinib are overcome
using this phosphorus-mediated approach; the C−P bond is
formed exclusively at the 4-position of the 2,5-disubstituted
pyridine in etoricoxib and with 20:1 selectivity for pyridine
versus pyrimidine in imatinib. Subsequent iminophosphorane
formation proceeds efficiently, resulting in etoricoxib derivative
2w. When the corresponding gleevec salt was aminated, we
observed that appreciable amounts of the iminophosphorane
hydrolyze under the reaction conditions. After consumption of
the salt, water was added to the reaction mixture, and stirring at
room temperature results in aniline derivative 2x. In general,
hydrolysis under the reaction conditions is a minor pathway in
a small number of cases in this study; we believe that the
adjacent aminopyrimidine ring in gleevec and conformation
effects are responsible for this outcome.
Scheme 1D indicates some of the limitations of the C−N
bond-forming reaction. Halogenated pyridines, in both the 2-
and 3-positions, can undergo competitive SNAr processes, and
the corresponding organoazides are detected by LCMS analysis.
Methoxy-substituted pyridines can undergo dealkylation
reactions with NaN3 that diminish the yields of the reaction.
Pyridines substituted with amines are also challenging
substrates; we attribute this deficiency to the electron-donating
nature of these groups that slow down the coupling process.
We next derivatized the iminophosphorane within 2a to
show that this versatile functional group can give access to
useful nitrogen-containing products (Scheme 2). Hydrolysis to
the heteroaryl aniline, 3aa, occurs by heating under neutral
aqueous conditions.20 Stirring the iminophosphorane in carbon
disulfide forms isothiocyanate 3ab in reasonable yield and is
another versatile functional group that can be used to access
carbonyl derivatives and heterocycles.21 Finally, combining the
iminophosphoranes with alkyl halides, followed by stirring in
acidic protic media, is a simple protocol to obtain alkylated
derivatives (3ac).22
a
Isolated yields of products are shown.
Scheme 3. Mechanistic Pathways and Evidence of an
Organoazide Intermediate
C−N bond.23 Second, a SNAr reaction where NaN3 reacts at
the ipso carbon and forms a Meisenheimer complex that then
decomposes to release PPh3. We favor an SNAr process, given
that polar solvents are most suitable and that the reaction is
most effective on pyridines with electron-withdrawing sub-
stituents and diazine systems.24 Scheme 3B provides evidence
of a discrete organoazide intermediate. When 2-phenyl
phosphonium salt was subjected to standard conditions in the
presence of 1 equiv of PTol3, a mixture of two iminophosphor-
anes is observed in the crude LCMS and 31P NMR, indicating
that the organoazide intermediate can be intercepted by an
external nucleophile.
In summary, we have developed a simple and broadly
applicable strategy to aminate pyridines and diazines. The
heterocycle is first converted into a phosphonium salt and then
heated with sodium azide to form useful iminophosphorane
derivatives. The reaction is exclusively regioselective in almost
every case and can be applied on drug-like fragments and as a
tool for late-stage functionalization of pharmaceuticals. The
iminophosphorane is a versatile handle providing access to
other important nitrogen-containing molecules, making this
strategy particularly valuable for medicinal chemists.
Two mechanisms can be envisioned to form the
iminophosphorane products that both proceed via an organo-
azide intermediate, followed by a Staudinger reaction (Scheme
3A). First, sodium azide adds to the phosphonium ion, and the
resulting phosphorane undergoes ligand coupling to form the
C
DOI: 10.1021/acs.orglett.8b00813
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(10) Al-Bari, M. A. A. J. Antimicrob. Chemother. 2015, 70, 1608.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b00813.
■
(11) McGill, C. K.; Rappa, A. Adv. Heterocycl. Chem. 1988, 44, 1.
(12) Yin, J.; Xiang, B.; Huffman, M. A.; Raab, C. E.; Davies, I. W. J.
Org. Chem. 2007, 72, 4554.
S
(13) Smith, M. B.; March, J. Advanced Organic Chemistry, 5th ed.;
Wiley-Interscience: New York, NY, 2001.
(14) (a) Hilton, M. C.; Dolewski, R. D.; McNally, A. J. Am. Chem.
Soc. 2016, 138, 13806. (b) Zhang, X.; McNally, A. Angew. Chem., Int.
Ed. 2017, 56, 9833. (c) Koniarczyk, J. L.; Hesk, D.; Overgard, I.;
Davies, I. W.; McNally, A. J. Am. Chem. Soc. 2018, 140, 1990.
(d) Anders, E.; Markus, F. Tetrahedron Lett. 1987, 28, 2675.
(e) Anders, E.; Markus, F. Chem. Ber. 1989, 122, 113. (f) Anders,
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Experimental procedures and spectral data (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: andy.mcnally@colostate.edu.
ORCID
(15) For a review on functionalizing activated pyridines and recent
examples, see: (a) Bull, J. A.; Mousseau, J. J.; Pelletier, G.; Charette, A.
B. Chem. Rev. 2012, 112, 2642. (b) Fier, P. S. J. Am. Chem. Soc. 2017,
139, 9499. (c) Elbert, B. L.; Farley, A. J. M.; Gorman, T. W.; Johnson,
T. C.; Genicot, C.; Lallemand, B.; Pasau, P.; Flasz, J.; Castro, J. L.;
MacCoss, M.; Paton, R. S.; Schofield, C. J.; Smith, M. D.; Willis, M. C.;
Dixon, D. J. Chem. - Eur. J. 2017, 23, 14733.
(16) Fier, P. S.; Hartwig, J. F. J. Am. Chem. Soc. 2014, 136, 10139.
(17) (a) Erlanson, D. A.; Fesik, S. W.; Hubbard, R. E.; Jahnke, W.;
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Rees, D. C. Nat. Chem. 2009, 1, 187.
Andrew McNally: 0000-0002-8651-1631
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by start-up funds from Colorado
State University and The National Institutes of Health under
award number R01 GM124094-01.
(18) Cernak, T.; Dykstra, K. D.; Tyagarajan, S.; Vachal, P.; Krska, S.
W. Chem. Soc. Rev. 2016, 45, 546.
(19) Larsen, M. A.; Hartwig, J. F. J. Am. Chem. Soc. 2014, 136, 4287.
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DOI: 10.1021/acs.orglett.8b00813
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