Synthesis of Highly Substituted Pyridines through Copper-Catalyzed Condensation of Oximes and α,β-Unsaturated Imines

Article abstract of DOI:10.1002/anie.201704378

A copper-catalyzed condensation reaction of oxime acetates and α,β-unsaturated ketimines to give pyridine derivatives is reported. The reaction features mild conditions, high functional-group compatibility, and high regioselectivity with respect to unsymmetrical oxime acetates, thus allowing the preparation of a wide range of polysubstituted pyridines, many of which are not readily accessible by conventional condensation methods.

Full text of DOI:10.1002/anie.201704378

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Accepted Article
Title: Synthesis of Highly Substituted Pyridines via Copper-Catalyzed
Condensation of Oximes and α,β-Unsaturated Imines
Authors: Wei Wen Tan, Yew Jin Ong, and Naohiko Yoshikai
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201704378
Angew. Chem. 10.1002/ange.201704378
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Synthesis of Highly Substituted Pyridines via Copper-Catalyzed
Condensation of Oximes and α,β-Unsaturated Imines**
Wei Wen Tan, Yew Jin Ong, and Naohiko Yoshikai*[a]
Abstract:
A
copper-catalyzed condensation reaction of oxime
activated Michael acceptor formed via carbonyl–amine
condensation or Knoevenagel condensation, and are attractive
for the preparation of unsymmetrically substituted pyridines.
However, this approach does not allow the use of ordinary
unactivated enones, which substantially limits the accessible
substitution patterns of pyridines. In fact, even a preformed
iminium salt derived from an enone failed to participate in our
previous pyridine-forming reaction (Scheme 1b). In our effort to
remove this limitation, we have developed a copper-catalyzed
pyridine synthesis from oxime acetates and α,β-unsaturated
ketimines, which is reported herein (Scheme 1c). The method
features simple and mild reaction conditions and allows
regioselective synthesis of a broad range of multisubstituted
pyridines, including those not readily accessible by conventional
condensation approaches.
acetates and α,β-unsaturated ketimines into pyridine derivatives is
reported. The reaction features mild conditions, high functional group
compatibility, and high regioselectivity with respect to unsymmetrical
oxime acetates, thus allowing for the preparation of a wide range of
polysubstituted pyridines, many of which are not readily accessible
by conventional condensation methods.
The pyridine ring frequently occurs as a core structural element
in natural products and synthetic pharmaceuticals and plays
pivotal role in coordination chemistry, catalysis and materials
science. Consequently, the development of methods for the
efficient and regioselective of this compound class has been
among significant tasks in heterocyclic chemistry.[1] Besides
conventional methods based on the condensation of carbonyl
compounds and amines, a number of alternative approaches,
those catalyzed by transition metals in particular, have been
actively pursued to date.[2-4]
In the above context, oxime derivatives have emerged as
readily accessible and versatile starting materials for transition
metal-catalyzed synthesis of pyridines[5,6] as well as many other
nitrogen-containing heterocycles owing to the ability of the oxime
functionality to undergo reductive N–O bond cleavage[7-9] and/or
to serve as a directing group for C–H activation.[10,11] While α,β-
unsaturated oxime derivatives have been employed as C3N1
units for pyridine synthesis using alkenylboronic acids,[5a]
alkynes,[5b-e] or alkenes[5f,g] as C2 reaction partners, oxime
acetates bearing α-protons have also found a use as C2N1 units
for pyridine synthesis (Scheme 1a).[6] Guan and coworkers
developed a series of metal-catalyzed pyridine-forming reactions
wherein two molecules of oxime acetates are condensed with a
C1 source such as aldehyde, dimethylformamide, and
dimethylaniline (Scheme 1a, a–c).[6a-c] Our group developed a [3
+ 3] pyridine synthesis from oxime acetates and α,β-unsaturated
aldehydes promoted synergistically by a copper catalyst and a
secondary amine (Scheme 1a, d).[6d] Later, Cui and Jiang
independently reported copper-catalyzed three-component
pyridine synthesis from oxime esters, aldehydes, and active
methylene compounds such as malononitrile or β-ketoesters
(Scheme 1a, e and f).[6e,f] The methods d–f are considered to
involve the reaction between a nucleophilic copper(II) enamide
formed via reduction of the oxime acetate by copper(I) and an
Scheme 1. Oximes as C2N1 units for pyridine synthesis.
[a]
W. W. Tan, Prof. N. Yoshikai
Division of Chemistry and Biological Chemistry, School of Physical
and Mathematical Sciences
Nanyang Technological University
Singapore 637371, Singapore
Given the failure of enones as substrates for the
copper/secondary amine catalytic system,[6d] the present study
initially focused on the exploration of enone equivalents for the
condensation with oxime acetates. Screening experiments along
this line led to the finding of clean transformation of
propiophenone oxime acetate (1a, 0.24 mmol, 1.2 equiv) and
E-mail: nyoshikai@ntu.edu.sg
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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chalcone N-tosyl imine (2a, 0.2 mmol) into the desired
functional groups such as methylthio, bromo, cyano, nitro, and
trifluoromethyl groups. The reaction also tolerated unsaturated
ketimines bearing furyl, thienyl, or alkyl substituents (see 3am–
3aq). A pentasubstituted pyridines 3ar and 3as could also be
synthesized via the condensation of 1a and the corresponding
α,β-disubstituted unsaturated ketimines.
tetrasubstituted
pyridine
3aa
in
the
presence
of
[Cu(MeCN)4][PF6] (5 mol%) and NaHSO3 (1 equiv) in DMSO at
60 °C (Table 1, entry 1). The same reaction could be performed
on a 5 mmol scale in 95% yield. Note also that the reaction
proceeded quantitatively even under air using undistilled DMSO.
Other copper salts could be used in place of the cationic catalyst,
albeit with somewhat lower yields of 3aa (entries 2–4). The yield
of 3aa dropped significantly in the absence of NaHSO3 (entry
5).[12] The reaction became sluggish when using DMF instead of
DMSO as the solvent (entry 6). Notably, chalcone N-PMP (p-
methoxyphenyl) imine (2a') also participated in the condensation
with 1a under otherwise identical conditions to afford 3aa, albeit
in a moderate yield (entry 7). This reaction was further improved
by increasing the catalyst loading and the reaction temperature
to 10 mol% and 90 °C, respectively (entry 8). In contrast, the
reaction using parent chalcone (2a'') afforded only a trace
amount of 3aa (entry 9). Note that the reaction of 2a', when
performed using a large excess (> 2 equiv) of 1a, was
accompanied by homocoupling of 1a to produce 2,5-diphenyl-
3,4-dimethylpyrrole as a byproduct,[9c] while this homocoupling
was not observed at all in the optimized reaction systems
(entries 1 and 8).
Table 2. Condensation of 1a with various α,β-unsaturated ketimines.[a]
Table 1. Effect of reaction conditions.[a]
Entry
X
Deviation from standard conditions
None
Yield [%][b]
1
2
3
4
5
6
7
8
9
NTs
NTs
NTs
NTs
NTs
NTs
NPMP
NPMP
O
99 (95)[c]
84
CuCl instead of [Cu(MeCN)4][PF6]
CuBr instead of [Cu(MeCN)4][PF6]
CuI instead of [Cu(MeCN)4][PF6]
NaHSO3 omitted
85
84
10
[a] Unless otherwise noted, the reaction was performed under the conditions in
Table 1, entry 1. [b] N-PMP imine was employed, and the reaction was
performed under the conditions in Table 1, entry 8. [c] The reaction was
performed at 90 °C.
DMF instead of DMSO
None
68
75
10 mol% catalyst, T = 90 °C
None
87
Next, we examined the reaction of various oxime acetates
bearing only one type of enolizable α-position, using 2a as the
reaction partner (Table 3). The reaction of acetophenone-
derived oxime acetate 1b was somewhat sluggish under the
conditions optimized for 1a, affording 2,4,6-triphenylpyridine
(3ba) in 76% yield. Nevertheless, the reaction could be
improved by increasing the equivalence of 1b (1.6 equiv) and
the reaction temperature (90 °C), resulting in the formation of
3ba in near quantitative yield. This modified set of conditions
proved highly reliable for efficient preparation of a series of
2,4,6-triarylpyridines using oximes derived from aryl methyl
ketones (see 3ba–3na). Aryl alkyl oximes derived from tetralone,
2-phenylacetophenone, and phenyl 3-butenyl ketone smoothly
took part in the reaction with 2a under the original conditions,
< 5
[a] The reaction was performed using 0.24 mmol (1.2 equiv) of 1a and 0.2
mmol of 2a under N2 atmosphere. [b] Determined by GC using n-tridecane as
an internal standard. [c] Isolated yield. The result for a 5 mmol-scale reaction
is shown in the parentheses.
Having identified the viable enone equivalent and the optimal
reaction conditions, we explored the scope of the present
pyridine synthesis. Table
2
summarizes the results of
condensation of 1a with a variety of unsaturated ketimines.
Unsaturated imines derived from substituted chalcones smoothly
participated in the reaction with 1a, affording the desired
pyridines 3ab–3al in good to excellent yields with tolerance of
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affording the desired products 3oa–3qa in excellent yields.
Interestingly, oxime derived from isobutyrophenone afforded 3,4-
dihydorpyridine derivative 3ra as a result of C–C bond formation
at the tertiary carbon center, albeit in a modest yield. Besides
the aryl alkyl oximes, oximes derived from acetone, pinacolone,
ethyl pyruvate, and cycloalkanones were all amenable to the
present condensation (see 3sa–3wa). A bis-oxime derived from
1,3-diacetylbenzene participated in twofold condensation with 2a
to afford the pyridine product 3xa albeit in a low yield.
ketone produced 2,4,6-trisubstituted pyridine 3aba via C–C bond
formation at the methyl group. The regioselectivity observed in
these reactions may be associated with the thermodynamic
stability of the copper enamide intermediates (vide infra). On the
other hand, oxime derived from cyclohexyl ethyl ketone afforded
tetrasubstituted pyridine 3aca in good yield via regioselective C–
C bond formation at the ethyl group.
Table 3. Condensation of various oxime acetates with 2a.[a]
Scheme 2. Regioselective formation of pyridine derivatives from oximes
bearing two distinct α-positions. See the Supporting Information for the detail
of the reaction conditions.
To gain mechanistic insight, competition and control
experiments were performed (Scheme 3). First, a competition
between propiophenone oxime 1a and acetophenone oxime 1b
toward 2a resulted in preferential reaction of 1a (Scheme 3a).
This observation is in line with the milder reaction conditions
required for 1a than that required for 1b. Second, a competition
experiment was performed using N-Ts imine 4 and N-PMP imine
5, which were derived from electronically similar chalcone
derivatives (Scheme 3b). On the contrary to the better reactivity
of N-Ts imine in individual reactions (Table 1), the competition
resulted in the formation of the pyridine products 6 and 7 in a
near 1:1 ratio. Lastly, the reaction of 1a with 2a was largely
suppressed by the addition of TEMPO, while the addition of 1,1-
diphenylethylene did not interfere with the pyridine formation
(Scheme 3c). This may suggest that electron transfer processes
involving the copper catalyst (vide infra) are inhibited by
TEMPO,[13] but not by 1,1-diphenylethylene.
[a] Unless otherwise noted, the reaction was performed under the conditions
shown in Table 1, entry 1. [b] The reaction was performed using 1.6 equiv of
oxime at 90 °C. [c] Oxime acetate derived from isobutyrophenone was used.
[d] Oxime acetate derived from 1,3-diacetylbenzene and 2 equiv of 2a were
used at 90 °C.
To further clarify the scope of the present pyridine synthesis,
we examined the reaction of a series of oxime acetates that
have two distinct enolizable α-positions (Scheme 2). The
reaction of oxime derived from 2-hexanone with 2a resulted in
C–C bond formation at the α-position of the butyl group to afford
tetrasubstituted pyridine 3ya in 53% yield, while formation of the
other possible regioisomer was not detected. Likewise, oximes
derived from phenylacetone and methoxyacetone also
underwent regioselective C–C bond formation at the methylene
position to afford the corresponding products 3za and 3aaa,
respectively, while the one derived from cyclopropyl methyl
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Scheme 4. Proposed reaction pathways.
Scheme 3. Competition and control experiments. The yields were determined
by GC analysis.
In summary, we have developed
a copper-catalyzed
condensation reaction of oxime acetates and α,β-unsaturated
ketimines for the regioselective synthesis of highly substituted
pyridines. The scope of the reaction covers a particularly broad
range of oxime acetates, derived from aryl alkyl- and dialkyl,
acyclic and cyclic ketones, thus allowing access to various
multisubstituted pyridines including those not readily accessible
by conventional condensation methods such as the Kröhnke
synthesis and its variants.
On the basis of previous studies on copper catalysis of
oximes[5a,6,7b,9] and the above observations, we are tempted to
propose reaction pathways shown in Scheme 4. Sequential
single-electron reduction with two equivalents of CuI would
convert the oxime 1 to an iminyl radical A and then to an
iminylcopper(II) species B. The species B would tautomerize to
generate a copper(II) enamide C.[6,14] Conjugate addition of C to
the unsaturated N-Ts imine 2 and subsequent intramolecular
cyclization would liberate TsNH2 and give a dihydropyridine
intermediate F (cf. product 3ra in Table 3), which would be
oxidized by CuII to furnish the pyridine product 3. While low-lying
LUMO of the Michael acceptor appears essential for the
previously developed oxime/enal and oxime/aldehyde/ketoester
condensations (Scheme 1a), we speculate that coordination of
the imine nitrogen to copper assists the C–C bond-forming step
of the present pyridine synthesis (see TSC-D). This may also
account for the competence of N-PMP imine, which features
less electrophilic β-position and more coordinating nitrogen, as a
Michael acceptor for the present reaction (cf. Table 1 and
Scheme 3b). Besides the ionic pathway for the C–C bond
formation, we may not exclude an alternative pathway involving
an α-imino radical C', which can be formed via homolytic N–Cu
cleavage of C. Note that the radical C' and its dimerization were
Acknowledgements
This work was supported by the Singapore Ministry of Education
(RG3/15, RG114/15) and Nanyang Technological University.
Keywords: pyridines • synthetic methods • condensation •
oximes • copper
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Entry for the Table of Contents (Please choose one layout)
Layout 2:
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Wei Wen Tan, Yew Jin Ong, Naohiko
Yoshikai*
Page No. – Page No.
Synthesis of Highly Substituted
Pyridines via Copper-Catalyzed
Condensation of Oximes and α,β-
Unsaturated Imines
A copper-catalyzed condensation reaction of oxime acetates and α,β-unsaturated
ketimines into pyridine derivatives is reported. The reaction features mild
conditions, high functional group compatibility, and high regioselectivity with respect
to unsymmetrical oxime acetates, thus allowing for the preparation of a wide range
of polysubstituted pyridines, many of which are not readily accessible by
conventional condensation methods.
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