From Pyridine- N-oxides to 2-Functionalized Pyridines through Pyridyl Phosphonium Salts: An Umpolung Strategy

Article abstract of DOI:10.1021/acs.orglett.1c02165

The reactions of pyridine-N-oxides with Ph3P under the developed conditions provide an unprecedented route to (pyridine-2-yl)phosphonium salts. Upon activation with DABCO, these salts readily serve as functionalized 2-pyridyl nucleophile equivalents. This umpolung strategy allows for the selective C2 functionalization of the pyridine ring with electrophiles, avoiding the generation and use of unstable organometallic reagents. The protocol operates at ambient temperature and tolerates sensitive functional groups, enabling the synthesis of otherwise challenging compounds.

Full text of DOI:10.1021/acs.orglett.1c02165

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Letter
From Pyridine‑N‑oxides to 2‑Functionalized Pyridines through
Pyridyl Phosphonium Salts: An Umpolung Strategy
Dmitry I. Bugaenko,* Marina A. Yurovskaya, and Alexander V. Karchava*
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ABSTRACT: The reactions of pyridine-N-oxides with Ph3P under the developed conditions provide an unprecedented route to
(pyridine-2-yl)phosphonium salts. Upon activation with DABCO, these salts readily serve as functionalized 2-pyridyl nucleophile
equivalents. This umpolung strategy allows for the selective C2 functionalization of the pyridine ring with electrophiles, avoiding the
generation and use of unstable organometallic reagents. The protocol operates at ambient temperature and tolerates sensitive
functional groups, enabling the synthesis of otherwise challenging compounds.
Quaternary phosphonium salts are used as versatile arylating
agents for carbon−carbon and carbon−heteroatom bond-
forming reactions under transition metal-catalyzed conditions9
or via P(V) intermediates.10 However, their long-known ability
to undergo a Lewis base-initiated C−P bond cleavage,
delivering the most electronegative substituents as anions11
for reactions with electrophilic reagents, remains underex-
plored. Despite an intrinsic synthetic potential of this
chemistry, there have been only a few reports about the
generation of nucleophilic carbanion species from quaternary
phosphonium salts, followed by their trapping with electro-
philes.12
In this context, quaternary 2-pyridylphosphonium salts could
serve as in situ 2-pyridyl anion surrogates to replace the
challenging organometallic reagents (Scheme 1A). However,
the use of this strategy is currently hampered by the lack of a
general method for the preparation of 2-pyridyl phosphonium
salts. Thus far, these compounds have been prepared via either
SNAr or transition metal-catalyzed reactions of 2-halopyr-
idines.13 Both methods require high reaction temperatures,
which limits their applicability to substrates bearing sensitive
functional groups. The Anders and, more recently, McNally
groups have developed a selective route to 4-pyridyl
phosphonium salts via a C−H functionalization of N-Tf-
yridines with different substitution patterns are privileged
Pheterocyclic motifs most employed in medicinal chem-
istry.1 Notably, of 35 small molecule-based therapeutic agents
that were approved by the Food and Drug Administration in
2020, 15 (43%) contained a substituted or fused pyridine
ring.2 Pyridine derivatives are also frequently used as ligands.3
Within a vast and diverse family of pyridines, 2-substituted
pyridines are the most prevalent in pharmaceuticals and
ligands.1a,3
Because of the electron-deficient nature of pyridines, their 2-
functionalized derivatives are traditionally prepared by
nucleophilic substitution in 2-halopyridines or reactions of
preactivated pyridine-N-oxides4 or unfunctionalized pyridines5
with nucleophiles. Other transition metal-free strategies for
functionalizing pyridine at the C2 position are based on radical
reactions6 or metallomimetic main group chemistry.7
An umpolung approach, allowing 2-pyridyl nucleophilic
reagents to react with electrophiles, remains less common and
largely relies on the use of highly reactive 2-pyridyl lithium or
Grignard reagents.8 Due to a destabilizing effect of the lone
pair of the nitrogen atom, 2-pyridyl lithium species and other
organometallic intermediates are often stable only at low
temperatures and difficult to handle.8b The generation of 2-
metalated pyridines employs strong bases and/or organo-
metallic reagents, which often results in poor chemoselectivity.
Moreover, this process requires a directing group, a special
reagent, or a halogen atom to ensure C2 regioselectivity, thus
limiting its scope.8 Consequently, alternative umpolung
strategies for producing 2-substituted pyridines with a broader
scope and functional group tolerance are still very interesting.
Received: June 29, 2021
Published: July 16, 2021
https://doi.org/10.1021/acs.orglett.1c02165
© 2021 American Chemical Society
Org. Lett. 2021, 23, 6099−6104
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a
Scheme 1. (A) Umpolung Strategies for 2-Substituted
Pyridines and (B) Orthogonal Site Selectivities in the
Synthesis of Pyridyl Phosphonium Salts
Scheme 2. Selected Optimization Results
pyridinium triflates with Ph3P (Scheme 1B).14 Although the
formation of small amounts of 2-isomers is often observed in
the reaction, the exclusive 2-selectivity can be achieved only
when the 4-position is blocked. Clearly, developing a practical
method for the selective preparation of (pyridine-2-yl)-
phosphonium salts with enhanced scope is highly desirable.
Addressing this issue, we turned to the N-oxide-based
methodology for C−H functionalization of the pyridine ring,
which represents a powerful platform for the preparation of
functionalized pyridines.4 Although many different nucleo-
philes are amenable to the methodology, reactions of pyridine-
N-oxides with tertiary phosphines have never been revealed. As
a continuation of our previous studies of the functionalization
of pyridine-N-oxides,15 herein we describe for the first time the
transition metal-free deoxygenative C−H phosphination of
pyridine- and quinoline-N-oxides with tertiary phosphines to
furnish quaternary (pyridine-2-yl)- and (quinoline-2-yl)-
phosphonium salts (Scheme 1B) and their use for 2-
functionalization of the pyridine ring employing electrophilic
reagents.
We began our studies by optimizing the reaction between 2-
chloropyridine-N-oxide (1a) and Ph3P. After an extensive
survey of the reaction conditions, we found that when N-oxide
1a reacted with 1.5 equiv of Ph3P in CH2Cl2 in the presence of
trifluoroacetic anhydride (TFAA, 1.5 equiv) as an activator,
isomeric (6-chloropyridine-2-yl)- (3a) and (2-chloropyridin-4-
yl)triphenylphosphonium trifluoroacetates (3b) were obtained
in a combined yield of 88% and in a ratio of 3:1 [standard
conditions (Scheme 2)]. Using <1.5 equiv of both Ph3P and
TFAA resulted in decreasing yields (entries 2 and 3,
respectively). Unlike many other deoxygenative transforma-
tions of pyridine-N-oxides,4 this reaction proceeds unexpect-
edly more smoothly and with a higher yield in the absence of
any base (entry 1 vs entry 4). Other activators and solvents
were also examined yet with no improvements (entries 5 and
6). Notably, C−H phosphination proceeds without compet-
itive SNAr displacement of the 2-chloro substituent in N-oxide
1a. Performing the reaction at −60 °C had no positive effect
on regioselectivity (entry 7). However, we were pleased to find
that (6-chloropyridine-2-yl)triphenylphosphoniun bromide
(2a) could be isolated as a single regioisomer in 43% yield
after a counteranion exchange step, readily occurring during
a
Yields and ratios of regioisomers were determined by 1H NMR using
an internal standard. For further details, see the Supporting
Information.
aqueous workup, followed by single recrystallization (Scheme
2). Unlike highly hygroscopic trifluoroacetates, the isolated
bromide 2a is stable, easy to handle, and substantially soluble
in organic solvents.
Our protocol was effective across a diverse range of
substituted pyridine- and quinoline-N-oxides (Scheme 3).
Pyridinium salts containing either electron-withdrawing (2c−e
and 2h−j) or electron-donating (2g, 2k, and 2l) groups were
synthesized in 36−91% yields. Although reactions of 2,4-
unsubstituted pyridines led to the formation of a mixture of
regioisomers in all cases, the major 2-isomers were isolated in a
pure form as bromides 2a−f after the counteranion exchange.
4-Substituted pyridines were transformed into corresponding
salts 2g−m in high yields, regardless of the electronic nature of
the substituent. 2,6-Lutidine-1-oxide under the developed
conditions gave salt 2n in 84% yield, thus allowing us to
overcome the limitations of the Anders−McNally protocol,
which is unproductive for substrates with the sterically
crowded nitrogen atom.7b
Unlike pyridine-N-oxides, N-oxides of 2,4-unsubstituted
quinolines reacted under standard conditions with exclusive
C2 regioselectivity, affording (quinoline-2)phosphonium salts
2o−r and 2x as single isomers in 82−93% yields. Meanwhile,
the reaction of 2-methylquinoline-1-oxide led to 4-substituted
phosphonium salts 2w. Notably, the only reported reaction of
unsubstituted quinoline with Ph3P under the Anders−McNally
conditions proceeded with low selectivity.14a Quinoxaline-N-
oxide was also converted to salt 2z with excellent yield;
however, when N-oxides of isoquinoline and 5-bromopyr-
imidine were used, inseparable mixtures of regioisomers were
obtained. Furthermore, expected salts 2bb and 2cc were
isolated in high yields when (pyridine-2-yl)Ph2P and n-Bu3P
were used instead of Ph3P. On the contrary, sterically
congested (o-Tol)3P was totally unproductive under the
same conditions. The reaction could be easily scaled up to
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a
a
Scheme 3. Deoxygenative Phosphination
Scheme 4. (A) Deuteration and (B) Postulated Mechanism
for the Activation of Phosphonium Salts with DABCO
a
b
Isolated yields are reported. Performed in THF (0.1 M) with D2O
(5 equiv).
Highly nucleophilic yet weakly basic DABCO [N (MeCN)
= 18.80; pKa (H2O) = 8.47]16 is preferred over the previously
used alkali metal hydroxides and carbonates.12,13 Notably,
functional groups sensitive to hydrolysis (e.g., CO2Me in 4b)
can survive under these conditions. Furthermore, the reaction
of salt 2d derived from 2,6-lutidine afforded monodeuterated
product 4d in 86% yield without sign of a competitive D/H
exchange at the CH-acidic methyl groups. Under the same
conditions, however, no reaction was observed for salt 2cc
derived from Bu3P, with the starting material being completely
recovered.
Although the activation of quaternary phosphonium salts
with DABCO was unprecedented until this report, we
envisioned that the reversible interaction between phospho-
nium salt 1 (a Lewis acid) and DABCO (a Lewis base) would
afford in situ a P(V) intermediate A (a Lewis pair),11b,17 which
in turn would be able to dissociate to form a reactive pyridine-
1
2-yl anion (Scheme 4B). Unfortunately, neither H nor 31P
NMR spectra recorded in a wide range of low temperatures
provided any evidence for the formation of A.
a
Isolated yields are reported.
We anticipated that this novel method for the activation of
phosphonium salts would be equally effective in both aqueous
and non-aqueous media. Employing DABCO as the activator,
the synthetic potential of pyridine-2-yl phosphonium bromides
was further assessed in their reactions with various carbonyl
compounds to furnish 2-substituted pyridines (Scheme 5).
Several 2-functionalized pyridines were successfully prepared
in good yields by the reactions with benzaldehydes (5a−g),
phenyl N-tosylimine (5k), and aliphatic (5h) and aromatic (5i
and 5j) ketones (Scheme 5A). A reaction of salt 2b with 4-
chlorobenzaldehyde afforded alcohol 5g in 75% isolated yield
at ambient temperature. Notably, pyridine 5g serves as a
starting material for the synthesis of carbinoxamine, an
gram quantities (2k, 2o, and 2t) without a considerable
decrease in yield or selectivity.
The synthetic potential of newly synthesized phosphonium
salts in the synthesis of 2-functionalized pyridines and
quinolines was then investigated using electrophilic reagents.
First, we examined the synthesis of 2-deuterated heterocycles.
We found that DABCO (2 equiv) as a Lewis base and D2O as
a deuterium source were highly effective for producing the
deuterated pyridines 4a−d and quinolines 4e−i in high yields
and free from any possible deuterated isomers and
dideuterated products (Scheme 4A). When scaled up to 3.5
mmol, quinoline 4i was obtained with only a small loss in yield.
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the participation of the CH-acidic methyl group, whereas the
direct lithiation of 4-picoline at the C2 position is normally
complicated by the side-chain proton abstraction.19
Scheme 5. Reactions with (A) Carbonyl Compounds and
(B) N-Acylimidazoles
a
To further demonstrate the synthetic utility of our method,
we developed a semi-one-pot telescoped procedure for the
rapid assembly of the valuable 2,2′-bipyridine scaffold starting
from pyridine-N-oxides (Scheme 6).3 Initially, N-oxides
a
Scheme 6. Semi-One-Pot Synthesis of 2,2′-Bipyridines
a
Isolated yields are reported.
reacted with (pyridine-2-yl)Ph2P under the developed
conditions and then the resulting bis(pyridine-2-yl)-
phosphonium salts, after removal of the solvent, underwent a
ligand coupling under the McNally conditions,7b delivering
functionalized 2,2′-bipyridines.
In summary, we have developed, for the first time, a method
for the selective deoxygenative C−H phosphination of azine-
N-oxides with tertiary phosphines to obtain quaternary
(pyridine-2-yl)- and (quinoline-2-yl)phosphonium bromides.
We have also shown that after treatment with DABCO at
ambient temperature, these phosphonium salts release
functionalized 2-pyridyl and 2-quinolyl nucleophiles, which
can be intercepted by electrophiles, resulting in the formation
of 2-substituted pyridines and quinolines. Thus, functionaliza-
tion of the pyridine ring at the innately electrophilic C2
position can be accomplished employing electrophilic reagents
while avoiding the use of highly reactive and intrinsically
unstable organometallic compounds.
a
b
Isolated yields are reported. Using Cs2CO3 (3 equiv) instead of
DABCO under otherwise identical conditions.
ASSOCIATED CONTENT
* Supporting Information
■
sı
antihistaminic drug, and is normally prepared using organo-
metallic reagents at low temperatures.18
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c02165.
Next, we extended our protocol using readily available N-
acylimidazoles as electrophilic partners (Scheme 5B). The
transfer of the substituted pyridine-2-yl moieties proceeded
selectively under the standard setup, affording pyridine-2-yl
ketones 6a−h in 54−75% yields, including those derived from
quinoxyfen (6f), L-proline (6g), and naproxen (6h). Overall,
nucleophile-sensitive functional groups such as an ester (5d), a
cyano (5c and 6e), a nitro (5e), an amide (5j and 5k), a Boc
(5h and 6g), a CF3 (5i), and halogens (5f, 5g, 6d, and 6f)
were well tolerated in this method. Notably, these functional
groups are not always totally compatible with organolithium
and organomagnesium chemistry. Furthermore, the reaction of
salt 2k, derived from 4-picoline, proceeded smoothly
producing compounds 5a, 5h, 5j, 5k, 6b, 6g, and 6h without
Detailed experimental procedures and compound
characterization data and NMR spectra of all com-
pounds (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
Dmitry I. Bugaenko − Department of Chemistry, Moscow
State University, Moscow 119992, Russia; orcid.org/
0000-0002-5028-7244; Email: bugaenko@
org.chem.msu.ru
Alexander V. Karchava − Department of Chemistry, Moscow
State University, Moscow 119992, Russia; orcid.org/
6102
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0000-0001-9008-644X; Email: karchava@
pubs.acs.org/OrgLett
Letter
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Pyridylsulfonium Salts and Their Application in the Formation of
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Azine Biaryls from Chloroazines: A Strategy Using Phosphorus
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org.chem.msu.ru
Author
†Marina A. Yurovskaya − Department of Chemistry, Moscow
State University, Moscow 119992, Russia
(c) Balkenhohl, M.; Franco̧ is, C.; Sustac Roman, D.; Quinio, P.;
Knochel, P. Transition-Metal-Free Amination of Pyridine-2-sulfonyl
Chloride and Related N-Heterocycles Using Magnesium Amides. Org.
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Complete contact information is available at:
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Author Contributions
D.I.B. optimized reaction conditions and expanded the
substrate scope. D.I.B. and M.A.Y. analyzed the data and
wrote the Supporting Information. D.I.B. and A.V.K. wrote the
manuscript. A.V.K. directed the project.
Notes
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The authors declare no competing financial interest.
†Deceased May 21, 2021.
ACKNOWLEDGMENTS
■
This work was financially supported by the Russian
Foundation for Basic Research (20-03-00456).
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