Regioselective Three-Component Reaction of Pyridine N-Oxides, Acyl Chlorides, and Cyclic Ethers

Article abstract of DOI:10.1021/acs.orglett.7b01481

A novel three-component reaction of pyridine N-oxides, acyl chlorides, and cyclic ethers is described. Treatment of an electron-deficient pyridine N-oxide with an acyl chloride in the presence of a cyclic ether at 25-50 °C leads to a substituted pyridine as a single regioisomer in up to 58% isolated yield. Isotopic-labeling experiments and substrate scope support the reaction proceeding through a carbene intermediate.

Full text of DOI:10.1021/acs.orglett.7b01481

Letter
pubs.acs.org/OrgLett
Regioselective Three-Component Reaction of Pyridine N‑Oxides,
Acyl Chlorides, and Cyclic Ethers
D. Heulyn Jones, Steven T. Kay, Jayde A. McLellan, Alan R. Kennedy, and Nicholas C. O. Tomkinson*
WestCHEM, Department of Pure and Applied Chemistry, Thomas Graham Building, University of Strathclyde, 295 Cathedral Street,
Glasgow G1 1XL, United Kingdom
S
* Supporting Information
ABSTRACT: A novel three-component reaction of pyridine N-oxides, acyl chlorides, and cyclic ethers is described. Treatment
of an electron-deficient pyridine N-oxide with an acyl chloride in the presence of a cyclic ether at 25−50 °C leads to a substituted
pyridine as a single regioisomer in up to 58% isolated yield. Isotopic-labeling experiments and substrate scope support the
reaction proceeding through a carbene intermediate.
he pyridine ring is a fundamental heterocycle1 that is
present in over 100 marketed drugs including the block
busters esomeprazole and etoricoxib (Figure 1). The prevalence
transformations were occurring within this process: first, the
expected heterocyclization procedure resulting in an oxadiazole
heterocycle,5 and second, and more interestingly, a reaction
between a pyridine N-oxide, an acyl chloride, and a molecule of
THF. This represented a novel multicomponent reaction
(MCR) and presented an intriguing method for the function-
alization of a pyridine ring.
T
MCRs are important processes in which three or more starting
materials react to form a single product.6 These reactions are of
particular relevance to discovery research by enabling diverse
structures to be generated rapidly through a single process.7
MCRs that generate pyridine and its saturated derivatives are
established and include the Hantzsch dihydropyridine synthesis8
and the Bagley−Bohlmann−Rahtz pyridine synthesis9 along
with more recent transition-metal-catalyzed processes.10 MCRs
that functionalize a pre-existing pyridine ring are less developed
yet represent an intriguing alternative strategy by which to
prepare diverse structures of this important heterocycle. Curious
about the overall process highlighted in Scheme 1 and the
potential to develop a novel MCR, we set about investigating the
procedure further. Within this paper, we describe the optimi-
zation of the reaction, explore the scope and limitations of each
component, and present a series of experiments to aid under-
standing of the reaction mechanism.
Figure 1. Drug molecules containing a pyridine group.
of the pyridine core in both pharmaceuticals and agrochemicals2
means that new methods for the synthesis and functionalization
of this privileged structure are of great interest and represents an
exciting area of contemporary research.3
During the course of our investigations to realize new chemical
probes for discovery research,4 a curious product was isolated
from an acylation/heterocyclization sequence (Scheme 1).
Scheme 1. Unusual Three-Component Reaction of Pyridine
N-Oxide, Acyl Chloride, and THF
As a starting point to understanding the reaction, we perfor-
med the transformation on the commercially available 3-cyano-
pyridine N-oxide 3 (Table 1). Confirmation that the coupling
procedure was independent of the N-hydroxyamidine function-
ality present in substrate 1 or the Bu4NOH came from treatment
of 3 with 4-toluoyl chloride (2.2 equiv) and NEt3 (2.2 equiv),
which led to the three-component product 4 in 35% conversion
Treatment of the pyridine N-oxide derivative 1 with 3 equiv of
both 4-toluoyl chloride and triethylamine at room temperature
overnight followed by stirring the crude reaction mixture with
tetra-n-butyl ammonium hydroxide in THF gave the unexpected
product 2 in 4% isolated yield. It appeared that two separate
1
by H NMR spectroscopic analysis (entry 1). Performing the
Received: May 16, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01481
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Letter
a
a
Table 1. Reaction Optimization
Table 2. Scope of Acyl Chloride and Pyridine N-Oxide
b
4-TolCOCl
(equiv)
NEt3
time
(h)
entry
Ar
R
product
yield (%)
b
entry
(equiv)
temp (°C)
conv (%)
1
4-OMeC6H4
4-MeC6H4
C6H5
3-CN
3-CN
3-CN
3-CN
3-CN
3-CN
4-CN
2-CN
3-Cl
6
17
25
33
34
40
48
40
22
46
38
33
0
1
2
3
4
5
6
2.2
2.2
2.2
2.2
2.2
1.0
2.2
2.2
2.2
2.2
2.2
3.0
1.0
2.2
2.2
2.2
25
18
8
35
33
2
4
−78 to +25
3
7
c
50
50
50
50
50
50
18
18
18
18
18
18
33 (25)
4
C6F5
8
34
0
5
4-CF3C6H4
4-NO2C6H4
4-NO2C6H4
4-NO2C6H4
4-NO2C6H4
4-NO2C6H4
4-NO2C6H4
4-NO2C6H4
9
6
10
11
12
13
14
15
16
29
31
32
7
d
7
e
8
8
9
a
Reactions carried out at 0.2 M concentration unless otherwise stated.
10
11
12
4-Cl
b
c
d
1
Determined by H NMR analysis. Isolated yield. Reaction carried
3-NO2
H
e
out at 0.1 M concentration. Reaction performed in the presence of
4 Å molecular sieves.
a
Reactions carried out at 0.2 M concentration with 2.2 equiv of aroyl
b
chloride. Isolated yield.
Table 3. Scope of Cyclic Ether
Figure 2. Single-crystal X-ray structure of 4 and the coproduct 5.
mixing of reagents at low temperature followed by warming
(entry 2) or carrying out the reaction at 50 °C (entry 3) made no
difference to the overall outcome. Reducing the amount of NEt3
to 1 equiv caused the reaction to shut down (entry 5), suggesting
the base had an important role beyond the acylation process
whereas reducing the amount of acyl chloride had little impact
(entry 6). Reduction of reaction concentration (entry 7) or
performing the reaction under strictly anhydrous conditions and
in the presence of molecular sieves also made no impact on the
transformation (entry 8). Overall, the reaction appeared to be
robust and could deliver the three-component reaction product 4
in a reliable manner.
Confirmation of the structure of the product 4 came through
single-crystal X-ray analysis (Figure 2). This clearly showed
substitution of the pyridine ring at the 2-position and confirmed
the regioselectivity of the procedure alongside the introduction
of a four-carbon unit from the THF group linking the pyridine to
the 4-toluoyl benzoate. In addition to the three-component
product observed within the process, the ester 5 was also isolated
from the optimized reaction (2.2 equiv of 4-TolCOCl, 2.2 equiv
of NEt3, THF, 50 °C, 18 h) and whose structure was also
confirmed through X-ray analysis. Selectivity for substitution at
the 2-position suggested that 4 and 5 could arise through a
common intermediate and prompted further investigation of the
reaction mechanism.
Having established optimal conditions for the reaction of
3-cyanopyridine N-oxide, 4-toluoyl chloride, and THF, we went
on to examine alternative acyl chloride and pyridine N-oxide
substrates (Table 2). The presence of electron-withdrawing
groups on the acyl chloride greatly enhanced the efficiency of the
process (entries 1−6). For example, reaction of 4-methox-
ybenzoyl chloride with 3-cyanopyridine N-oxide gave the three-
component product 6 in 17% yield (entry 1), whereas the use of
4-nitrobenzoyl chloride delivered the product 10 in a much
improved 48% isolated yield (entry 6). On the basis of these
observations, 4-nitrobenzoyl chloride was used in subsequent
a
1
Complex mixture of products observed by H NMR spectroscopy.
Product isolated as an inseparable 1:1 mixture of regioisomers.
b
transformations (entries 7−12). The reaction proceeded effecti-
vely with 3- (entry 6; 48%) and 4-substituted (entry 7; 40%)
pyridine N-oxide substrates. Although less efficient, 2-substituted
substrates also delivered the expected three-component product
(entry 8; 22%). Alternative electron-withdrawing groups were
also tolerated on the pyridine N-oxide ring including chloro
(entries 9 and 10) and nitro substituents (entry 11; 33%). An
electron-withdrawing group on the pyridine N-oxide substrate
was essential to bring about the transformation with the unsub-
stituted pyridine N-oxide failing to deliver the three-component
product 16 (entry 12; 0%).
We then went on to examine the reactivity of alternative cyclic
ethers (Table 3). The reaction of cyclohexene oxide (entry 1)
and oxetane (entry 2) under the optimized conditions led to a
complex mixture of products with no clear indication of the
three-component product in the 1H NMR spectrum of the crude
reaction mixture. This suggests the process is not viable for highly
strained cyclic ethers. Increasing the ether ring size led to signifi-
cantly greater success for the transformation (entries 3−7).
B
DOI: 10.1021/acs.orglett.7b01481
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Letter
procedure.11 Reaction of this acid chloride with 3-cyanopyridine
N-oxide 3 in the presence of THF led to the products 23 and 24
which showed an 88% incorporation of the 18O label by mass
spectrometry. Treatment of the mixture of 23 and 24 with
methylamine showed 47% incorporation of the 18O label in the
N-methylbenzamide product 27 and a 38% 18O incorporation in
the pyridyl product 25, indicating scrambling of the isotopic label
(Scheme 2).
Scheme 2. Isotopic-Labeling Experiments
Hamana has shown that reaction of pyridine N-oxide 29
with benzoyl chloride in acetonitrile under basic conditions
leads to the acetamide 33 in 4% isolated yield (Scheme 3).12
It was proposed that this reaction proceeded through
O-acylation followed by deprotonation to give the carbene 30.
Addition of acetonitrile followed by elimination of benzoate
led to 31 which on readdition of benzoate and O → N acyl
migration gave the product 33. Within this report it was also
disclosed that solvent participation was not apparent when the
reaction was carried out in THF. This is consistent with our
results in Table 2 where the pyridine N-oxide substrate needs to
be electron deficient in order for the transformation to occur
successfully.13
Scheme 3. Reaction of Pyridine N-Oxide and Benzoyl
Chloride in Acetonitrile
Based upon the labeling studies (Scheme 2), together with
the report of Hamana,12 a potential mechanism for the trans-
formation is outlined in Scheme 4. O-Acylation of pyridine
N-oxide 3 under the basic reaction conditions leads to the
intermediate 34. Subsequent deprotonation of 34 with triethyl-
amine provides the carbene 35. Direct reaction of 35 with
benzoate 39 followed by restoration of aromaticity gives the ester
5. Reaction of the carbene 35 with THF followed by elimination
of benzoate would lead to the oxonium ion 38. Finally, ring
opening of this oxonium ion with benzoate 39 leads to the
observed reaction product 4. The results from the isotopic-
labeling experiments are consistent with this mechanistic
proposal and suggest the loss of benzoate 39 and its subsequent
readdition occurs in a stepwise rather than a concerted manner.
With the data available, it is not possible to establish the precise
order of events with regard to addition of the THF and elimination
of benzoate; however, the proposed mechanism is consistent with
the data presented.
Reaction of 5- (entry 3; 48%), 6- (entry 4; 31%), and 7-mem-
bered cyclic ethers (entry 5; 38%) led to the expected pyridine
derivatives 10, 19, and 20. Substituted ethers were also tolerated
within the reaction (entries 6 and 7). Reaction of 2-methyl THF
gave the substituted pyridine 21 in 36% isolated yield as an
inseparable 1:1 mixture of isomers, showing no regioselectivity
in the opening of the THF ring. 1,4-Dioxane proved to be an
outstanding substrate leading to the three-component reaction
product 22 in an excellent 58% isolated yield.
The complete regioselectivity observed represents a powerful
aspect of the transformation. To probe this further, we examined
two nonsymmetrical 3,5-disubstituted pyridine N-oxide sub-
strates 40 and 41 (Scheme 5). Reaction of 3-cyano-5-methyl-
pyridine N-oxide 40 under the standard reaction conditions gave
the 2-substituted pyridine product 42 exclusively in an excellent
Isotopically labeled benzoyl chloride was prepared from α,α,α-
trichlorotoluene and 18O-labeled water via a two-step literature
Scheme 4. Potential Mechanism for the Formation of Three-Component Product 4
C
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Scheme 5. Selectivity Using Nonsymmetrical Substrates
ACKNOWLEDGMENTS
We thank the EPSRC Mass Spectrometry Service, Swansea, for
high-resolution spectra.
■
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56% isolated yield with none of the alternative regioisomer 43
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product. The architecture generated through this three-
component procedure has been prepared previously through
a multistep reaction sequence providing structures 46 that
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The inherent ability to introduce this functionality directly
from readily accessible building blocks suggests this trans-
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ASSOCIATED CONTENT
* Supporting Information
■
S
(13) For recent examples of reactions involving carbenes derived from
pyridine N-oxides, see: (a) Bugaenko, D. I.; Yurovskaya, M. A.;
Karchava, A. V. J. Org. Chem. 2017, 82, 2136. (b) Chen, Y.; Huang, J.;
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Said, S. A.; Haikal, A. E-F. Z.; Abu-El-Halawa, R.; El Kader, R. T. A.
Nucleosides, Nucleotides Nucleic Acids 2014, 33, 111. (c) Moustafa, A. H.;
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The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b01481.
Analytical data, experimental procedures, and NMR
spectra for all compounds (PDF)
X-ray data for compounds 4 and 5 (CIF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: nicholas.tomkinson@strath.ac.uk.
ORCID
Alan R. Kennedy: 0000-0003-3652-6015
Nicholas C. O. Tomkinson: 0000-0002-5509-0133
Notes
The authors declare no competing financial interest.
D
DOI: 10.1021/acs.orglett.7b01481
Org. Lett. XXXX, XXX, XXX−XXX