Metal-free site selective cross-coupling of pyridines with secondary phosphine chalcogenides using acylacetylenes as oxidants

Article abstract of DOI:10.1039/c8cc01155a

Pyridines undergo site selective cross-coupling with secondary phosphine chalcogenides (oxides, sulfides, and selenides) in the presence of acylphenylacetylenes under metal-free mild conditions (70-75 °C, MeCN) to afford 4-chalcogenophosphoryl pyridines in up to 71% yield. In this new type of S_N^HAr reaction acylacetylenes act as oxidants, being stereoselectively reduced to the corresponding olefins of the E-configuration.

Full text of DOI:10.1039/c8cc01155a

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DOI: 10.1039/C8CC01155A
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Metal‐free site selective cross‐coupling of pyridines with
secondary phosphine chalcogenides using acylacetylenes as
oxidants
Received 00th January 20xx,
Accepted 00th January 20xx
Nina K. Gusarova,a Pavel A. Volkov,a Kseniya O. Khrapova,a Anton A. Telezhkin,a Nina I. Ivanova,a Alexander I. Albanov,a Oleg
N. Chupakhinb and Boris A. Trofimov*a
DOI: 10.1039/x0xx00000x
www.rsc.org/
Pyridines undergo site selective cross‐coupling with secondary phosphine chalcogenides (oxides, sulfides, and selenides) in
the presence of acylphenylacetylenes under metal‐free mild conditions (70–75 °С, MeCN) to afford 4‐
chalcogenophosphoryl pyridines in up to 71% yield. In this SNHAr new type reaction acylacetylenes act as oxidants, being
stereoselectively reduced to the corresponding olefins of E‐configuration.
Chalcogenophosphoryl pyridines and their precursors,
phosphinopyridines, represent in‐demand ligands forming a
number of biologically active complexes with a variety of
metals.1,2
However, assortment of available pyridines bearing
phosphoryl or phosphine moieties is limited mainly to
diphenylphosphinopyridines.1‐3 This is mostly due to certain
difficulties with syntheses of other chalcogenophosphoryl and
phosphinopyridines requiring hazardous and hardly accessible
(in case of other than phenyl substituents) secondary
phosphine halides, which are then involved into the BuLi‐
assisted reactions with bromopyridines.3 For this purpose, the Scheme 1 Vinylation/phosphorylation of pyridines by alkyl
propiolate/secondary phosphine chalcogenide pairs.
cross‐coupling of halopyridines with secondary phosphine
chalcogenides in the presence of Ni and Pd complex was also
employed.4 To follow the trend in organic chemistry with
emphasis on safe ecology and pot, atom, and step economy
(PASE paradigm5), it would be desirable to develop a synthesis
of chalcogenophosphoryl pyridines, which does not require
transition metals and halopyridines and having a larger
substrate scope.
In this communication, we report on the oxidative cross‐
coupling reaction between pyridines 1a,b and secondary
phosphine chalcogenides 2a‐j in the presence of
acylphenylacetylenes 3a‐d as the oxidants, MeCN being used
as a solvent. We have encountered with this SNHAr reaction of
new type during our on‐going investigation of reductive
When we replaced alkyl propiolates
by
acylphenylacetylenes, this reaction took absolutely
unexpected direction: instead of the above reductive
vinylation/phosphorylation of the pyridine nucleus (Scheme 1),
the oxidative cross‐coupling between pyridine and secondary
phosphine chalcogenides along with reduction of acetylene to
the corresponding E‐ethene was observed (Table 1). This
reaction can be referred to oxidative metal‐free nucleophilic
substitution of hydrogen in (hetero)arenes SNHAr, which now
draws a growing attention.7
Table 1 illustrates influence of the acetylene structures on
the reaction time and yields of the cross‐coupling products.
The reaction was monitored by 31P NMR to follow
disappearance of signals in the region 17.2 ppm belonging to
the starting phosphine oxides and appearance of signals of the
target products in the region 27.6 ppm. As seen from Table 1,
acetylenes 3с,d with phenyl and furyl substituents (Ph, 2‐Fu) at
the carbonyl group appear to be better oxidizers than those
with the alkyl groups 3a,b (entries 3, 4 cf 1, 2), evidently owing
to a lower electrophilicity of the triple bond in the latter. The
synthesis was carried out up to the complete conversion of
phosphine oxide.
vinylation/phosphorylation
of
pyridines
by
alkyl
propiolate/secondary phosphine chalcogenide pairs to yield 1‐
alkoxycarbonylethenyl dihydropyridines (Scheme 1).6
a. A.E. Favorsky Irkutsk Institute of Chemistry, Siberian Branch of the Russian
Academy of Sciences, 1 Favorsky St., Irkutsk 664033, Russian Federation.
E‐mail: boris_trofimov@irioch.irk.ru
b. I.Ya. Postovsky Institute of Organic Synthesis, Ural Branch of the Russian
Academy of Sciences, 22/20 S. Kovalevskoi/Akademicheskaya St.,
Ekaterinburg 620219, Russian Federation.
†
Electronic
Supplementary
Information
(ESI)
available.
See
DOI: 10.1039/x0xx00000x
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Table 1 Cross‐coupling of pyridine 1a with diphenylphosphine
oxide 2a in the presence of acylacetylenes 3a
Isolated
yield 4a (%)
Acylacetylene
Time
(h)
Entry
3a‐d
Scheme
3
Cross‐coupling of 3‐methylpyridine 1b with
secondary phosphine oxides 2a‐d in the presence of
benzoylphenylacetylene 3c
1
2
3
4
28
35
24
26
50
36
57
53
.
3a
3b
The reaction of perdeuteropyridine (pyridine‐d5) with
phosphine sulfide 2f and acetylene 3c afforded the
corresponding isotopically labelled cross‐coupling product, 4‐
bis(2‐phenylethyl)thiophosphorylpyridine‐d4, in 42% yield (for
50 h).
3c
The lower yield and longer reaction time compared to
those for non‐deuterated pyridine (71%, 35h, Scheme 2) are
expected to be due to deuterium kinetic isotope effect.
Notably, 3‐fluoropyridine appeared unable to undergo the
above cross‐coupling, obviously because of its lower
basicity/nucleophilicity (electron‐acceptor effect of fluorine
atom).
3d
aConditions: 1a (1.1 mmol), 2a (1 mmol), 3a‐d (1.1 mmol), MeCN (3
ml), 70–75 °C.
Further, we have studied the scope of phosphine
chalcogenides suitable for this synthesis (Scheme 2). As follows
from Scheme 2, the reaction tolerates a quite representative
number of structurally diverse secondary phosphine
chalcogenides (oxides, sulfides and selenides) having both
aromatic and alkylaromatic substituents.
As for substituted pyridines, 3‐methylpyridine 1b was
found to be also able of cross‐coupling with secondary
phosphine oxides 2a‐d to give the corresponding
phosphorylated pyridines 6a‐d in 42–64% yield (Scheme 3). At
the same time, we failed to find the reaction conditions,
appropriate for the cross‐coupling of pyridine 1b with any
other phosphine chalcogenides studied.
H
In accordance with SN nature of the reaction, the second
products of the cross‐coupling were reduced starting
acylphenylacetylenes, ethenes
5, which were formed in
approximately equivalent quantities as phosphorylated
pyridines (according to 1H NMR spectra of the reaction
mixture). Usually, the samples of E‐ethenes were
contaminated by small admixtures of the starting acetylenes. If
necessary, E‐ethenes
state. For instance, in the cases of benzoyl and 2‐
furoylacetylenes 3c
(R3 = Ph and 2‐Furyl), the corresponding
E‐ethenes were purified chromatographically (SiO2 column),
the yields being 35 and 45%, respectively
5 can be isolated in isomerically pure
,
d
.
The low yields of the cross‐coupling products with
phosphine selenides 2i,j (Scheme 2) are resulted from the side
selenylation of the starting acetylenes to furnish the
corresponding divinyl selenides
7
(Scheme 4).9 The selenium
transfer involves trace water from the solvent (MeCN).
The structures of the synthesized compounds were proved
by spectral data (1H, 13C, 15N, 31P, 77Se NMR, IR‐spectroscopy
and elemental analysis, see supporting).
Scheme 2 Scope of secondary phosphine chalcogenides 2a‐j
.
Scheme 4 Selenylation of the acylphenylacetylenes by
secondary phosphine selenides.
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The mechanism of the cross‐coupling likely includes the nucleophilic, should generate 1,3‐dipole intermediate
A in a
reversible formation of 1,3‐dipole (intermediate ) resulted higher concentration. In view of the suggested mechanism, it is
A
from nucleophilic addition of the pyridine to acetylenes
(Scheme 5).
3
understandable why 2‐ and 4‐methylpyridines and 3‐
fluoropyridine do not undergo the above cross‐coupling with
secondary phosphine chalcogenides: the position 6 is sterically
screened by the bulky substituted ethenyl moiety, while the
position 2 and 4 are occupied by the methyl group, and
fluorine atom as an electron acceptor decreases
nucleophilicity of the pyridine ring. Also, the slow‐down of the
reaction rate and low yield of the target products in the case of
pyridine‐d5 are in consistence with the expected deuterium
kinetic isotope effect associated with the above hydrogen
transfer steps.
Also, in support of Scheme 5, the intermediate
dihydropyridine
the corresponding pyridine 4i, when pyridine 1a reacted (room
temperature, MeCN, 4 h) with terminal furoylacetylene
9
was fixed in a mixture (1H and 31P NMR) with
8
(having no phenyl substituent in the position 2) and phosphine
selenide 2i (Scheme 6). This result additionally confirms the
importance of 2‐phenyl substituents in acetylenes 3a‐d to
complete the elimination of substituted ethenes 5a‐d from the
Scheme 5 A plausible reaction pathway.
intermediate dihydropyridine C (Scheme 5).
The carbanionic site of the intermediate
proton of the phosphine chalcogenides and the P‐centered
anion, thus released, attacks position 4 of the pyridine ring,
affording intermediate dihydropyridine The selective
A is quenched by
2
B
.
attachment of the anion to position 4, avoiding position 2, is
probably due to the steric screening of both alpha‐positions of
the pyridine ring by the phenyl substituent from one side and
by acylethenyl group from the other one. The elimination of E‐
acylphenylethenes
intermediate
elimination process may have a concerted character: cleavage
of the C‐N‐bond in the intermediate is accompanied by
5
from prototropically isomerized
B
C
affords the cross‐coupling products . The
4
Scheme
furoylacetylene 8.
6 Reaction of pyridine, phosphine selenide 2i and
C
simultaneous transfer of the hydride anion from the position 2
of the dihydropyridine ring to emerging carbocation in the
four‐membered transition state. Although the four‐membered
transition state is not as favourable as five or six ones, it is
The selenophosphorylpyridine 4i has been quantitatively
reduced to the corresponding phosphine 10 (Scheme 7). This
result implies that the cross‐coupling might open a simple
access to the related phosphines, prospective ligands for new
metal complexes for drug design and catalysis.
quite common for C‐H activation 10
By virtue, this cross‐
.
coupling reaction represents regioselective nucleophilic
substitution of hydrogen in the pyridine ring by the P‐centred
anion (this SNHAr reaction is now at its height7). The driving
force of the elimination should be a higher thermodynamic
stability of the final products (phosphorylated pyridines and
conjugated functionalized ethenes) as compared to
intermediate dihydropyridines
B
C. Kinetically, it might be
Scheme 7 Synthesis of 4‐pyridyl‐bis(2‐phenylethyl)phosphine.
initiated by the known stability of the benzylic type
carbocationic species originated from the C‐N‐bond cleavage.
The assumed mechanism is supported by the faster
reactions of phosphine sulfides (Scheme 2, for examples 4a
and 4e) in comparison with the corresponding phosphine
oxides, since the former are more acidic11 and, hence, the
proton transfer to carbanionic center of intermediate
be more facile.
The Scheme 5 is also in keeping with a higher reactivity of
3‐methylpyridine 1b as compared to unsubstituted pyridine
1a. In fact, 3‐methylpyridine 1b, being more basic than
pyridine 1a (pKa 5.68 and 5.25, respectively12) and likely more
In conclusion, pyridines are easily cross‐coupled with
secondary phosphine chalcogenides in the presence of
acylphenylacetylenes under mild conditions (70–75 °C) to
afford 4‐chalcogenophosphorylpyridines in up to 71% yield.
This metal‐, halogen‐free regioselective cross‐coupling
represents a new type of nucleophilic substitution of hydrogen
in heteroaromatic ring, when electron‐deficient acetylene
A should
plays
a
role of an oxidant, being simultaneously
stereoselectively reduced to the corresponding functionalized
ethenes of the E‐configuration.
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Conflicts of interest
The authors declare no competing financial interest.
Acknowledgements
The main results were obtained using the equipment of Baikal
analytical center of collective using SB RAS.
Notes and references
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