Copper-Catalyzed Ring-Expansion Cascade of Azirines with Alkynes: Synthesis of Multisubstituted Pyridines at Room Temperature

Article abstract of DOI:10.1021/acs.orglett.8b01090

The first intermolecular ring-expansion cascade of azirines with alkynes for the synthesis of pyridines, enabled by a copper/triethylamine catalytic system via simultaneous generation and utilization of yne-enamine and skipped-yne-imine intermediates, is reported. Experimental as well as computational mechanistic studies revealed that the role of triethylamine is crucial in deciding the reaction pathway toward the pyridine products. This process offers a novel, one-step, direct, and practical strategy for the rapid construction of highly substituted pyridines under exceedingly mild conditions, and an installed alkyne functionality.

Full text of DOI:10.1021/acs.orglett.8b01090

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Copper-Catalyzed Ring-Expansion Cascade of Azirines with Alkynes:
Synthesis of Multisubstituted Pyridines at Room Temperature
Chandragiri Sujatha,† Chandra Shekar Bhatt,‡ Mahesh Kumar Ravva,‡ Anil K. Suresh,‡
and Kayambu Namitharan*,†,‡
†Organic Synthesis and Catalysis Laboratory, SRM Research Institute, SRM Institute of Science and Technology, Chennai-603203,
India
‡SRM University-AP, Amaravati-522502, India
S
* Supporting Information
ABSTRACT: The first intermolecular ring-expansion cascade
of azirines with alkynes for the synthesis of pyridines, enabled
by a copper/triethylamine catalytic system via simultaneous
generation and utilization of yne-enamine and skipped-yne-
imine intermediates, is reported. Experimental as well as
computational mechanistic studies revealed that the role of
triethylamine is crucial in deciding the reaction pathway
toward the pyridine products. This process offers a novel, one-
step, direct, and practical strategy for the rapid construction of highly substituted pyridines under exceedingly mild conditions,
and an installed alkyne functionality.
he pyridine1 skeleton is a privileged scaffold in medicinal
Tchemistry, because of its vital occurrence in numerous
natural and unnatural compounds with significant biological
activities.2 Recently, the pyridine skeleton has also been
successfully utilized as organocatalysts and ligands for a variety
of transition-metal catalyzed reactions.3 In addition, pyridine
derivatives have also found applications in materials science as
organic-light-emitting diodes4 and fluorescent sensors.5 On the
other hand, three-membered cyclic-imines, azirines, have been
extensively utilized in a variety of addition and cycloaddition
reactions,6 in particular, ring-expansion reactions that are
considered highly powerful due to their ability to give direct
access to higher analogues of azacyclic compounds.6,7 However,
the majority of the ring-expansion reactions of azirines are
limited to the synthesis of five-membered structures and,
primarily, methods that deliver six-membered azacyclic struc-
tures such as pyridines are scarce (Figure 1).
In 2013, Park’s group reported the synthesis of pyridines from
2H-azirines with vinyl carbenoids and a subsequent DDQ
oxidation for the first time.8 The following year, the same group
Figure 1. Ring expansion reactions of azirines.
Notably, this represents the first example of an intermolecular
ring-expansion reaction of azirines and alkynes for the synthesis
of pyridines and is strictly in contrast to the earlier reports, where
five-membered pyrrole structures were commonly observed for
the ring-expansion reactions of azirines with alkynes (Figure
1b).11−14 This methodology includes the following salient
features: (1) utilization of a base-metal catalyst for the synthesis
of highly substituted pyridines from azirines; (2) direct
construction of rare alkynylpyridines, an important core found
described an intramolecular approach, activating azirines toward
alkenes for the synthesis of pyridines, however, under much
harsher conditions (130 °C and long reaction times).9 Similarly,
Gagosz and co-workers have accomplished a gold-catalyzed
intramolecular ring expansion of azirines with alkynes to
synthesize pyridines.10 Nevertheless, these reports suffer from
the following drawbacks: requirement of expensive metal
catalysts, predesigned starting materials, strict inert conditions,
high temperatures, and longer reaction times. Herein, we disclose
a mild and efficient reaction strategy for the synthesis of highly
substituted pyridines at room temperature via a copper-catalyzed
ring-expansion cascade of azirines with alkynes (Figure 1c).
Received: April 9, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01090
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Organic Letters
Letter
in many bioactive compounds;15 (3) reaction capability to
proceed at room temperature and complete within 30 min.
We have shown keen interest in exploring base-metal catalysis
for developing new synthetic methods16 and have recently
reported a copper-catalyzed multicomponent cascade reaction of
2H-azirines with sulfonyl azides and alkynes for the direct
synthesis of triazolopyrimidines.16a During the course of our
investigation on further reactions of azirines, we were pleased to
isolate a highly substituted alkynylpyridine17 as the major
product (3a, 56%) along with 12% of the homocoupling product
when azirine 1a was reacted in the presence of alkyne 2a, CuI
(0.1 equiv), and DIPEA (2 equiv) in DCM at room temperature
(25 °C) for 6 h (Table 1, entry 1). Interestingly, switching the
examined as an additive with more homocoupling product
(Table 1, entry 3). No improvement in the products yields was
witnessed (32% and 45%, respectively) using other nitrogen
based additives such as pyridine and DMAP. In contrast, with
inorganic additives such as K2CO3, KtOBu, and Cs2CO3, the
reactions did not yield any pyridine products, and only
homocoupling products were isolated (entries 6−8). This
observation suggests that the nitrogen-based additives are acting
not only as a base but also as a ligand in delivering the desired
product. To confirm this, additives that can act as both ligand and
base were examined (entries 9−12). With ethylene diamine
(EDA) and bypyridine as additives, product 3a was isolated in
47% and 11% yields. When different phosphine-based additives
were tried, the reaction afforded only trace amounts of the
desired product with PPh3 and a 27% yield while using PBu3.
When the reaction was performed at a slightly higher
temperature of 45 °C, product 3a was obtained in a relatively
lesser yield of 65%, along with the formation of the
homocoupling product at a yield of 18% (entry 13). Also,
reduction in the yield of 3a was detected when 1 equiv of TEA
was used (entry 14). Pleasingly, when the reaction duration was
reduced to 30 min, the cascade reaction was relatively clean and
proceeded quite efficiently with a maximum yield of 90% (entry
15). Therefore, we evaluated a variety of copper salts as catalysts,
CuI, CuBr, CuCl, Cu(SO4)2·H2O, and Cu(OAc)2·H2O, among
which CuI was proven to be the optimal catalyst (entries 15−19).
Subsequently, a solvent screen was also undertaken; besides
DCM, other solvents such as DCE, ACN, toluene, THF, CHCl3,
DMF, and dioxane were tested. No significant improvement in
the yields was observed.
With the optimized reaction conditions, the scope of the
copper-catalyzed ring-expansion reaction was studied, as
illustrated in Figure 2. Generally, the reaction efficiency was
not very sensitive to the electronic properties of the substituents
on the aryl ring of the azirine moiety, as the substrates bearing
both electron-donating (3b−d, 85%−90%) and electron-with-
drawing groups (3e−g, 80%− 88%) worked very well with good
to excellent yields. The scope of the reaction with respect to
various alkynes was also examined and was found to proceed
smoothly in all the cases (3h−s). Notably, the substrate with an
n-pentyl substituent or bulky tert-butyl was also well tolerated
affording the corresponding products 3j and 3k in good yields
(74% and 80%, respectively). Excitingly, an aromatic alkyne
bearing a strong electron-withdrawing substituent such as
fluorine could also be efficiently transformed into the desired
product (3m, 79%). When aliphatic alkynes were employed in
the cascade reaction, the reaction proceeded as efficiently as
aromatic alkynes and delivered products in good to high yields
(3n−s). Most importantly, the cascade reaction was successfully
applied for the gram-scale synthesis of alkynylpyridines. The
alkynylpyridine 3a was isolated in a marginally lesser yield of 88%
(see SI). In order to further expand the scope of this novel ring-
expansion process, a one-pot sequential reaction starting from
vinyl azides was investigated (see SI). This new sequential
process allowed the efficient one-pot synthesis of the
alkynylpyridines beginning from vinyl azides derived from the
isolation of intermediate azirines.
a
Table 1. Optimization Conditions
3a, yield
1,3-diyne, yield
b
b
entry
catalyst
CuI
additive
solvent
(%)
(%)
1
DIPEA
TEA
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
56
86
15
32
45
−
12
−
27
15
22
6
2
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuBr
CuCl
3
DBU
pyridine
DMAP
K2CO3
KtOBu
Cs2CO3
EDA
4
5
6
7
−
−
11
9
8
9
47
11
trace
27
65
59
90
77
24
trace
−
−
−
−
18
trace
−
−
−
10
11
12
Bi-Py
PPh3
PBu3
c
13
TEA
d
14
TEA
e
15
TEA
16
17
18
TEA
TEA
Cu(SO4)2·
H2O
TEA
−
19
Cu(OAc)2·
H2O
TEA
DCM
trace
−
20
21
22
23
24
CuI
CuI
CuI
CuI
CuI
TEA
TEA
TEA
TEA
TEA
DCE
27
15
10
30
12
12
47
−
−
33
toluene
CHCl3
DMF
dioxane
a
Conditions: 1a (0.85 mmol), 2a (0.93 mmol), base (1.7 mmol),
b
solvent (3 mL), and catalyst (0.085 mmol), at 25 °C, 6 h. Isolated
yield. At 45 °C. Base (0.85 mmol). Reaction was performed for 30
c
d
e
min.
additive to TEA resulted in a much better yield of 86%, and also
the homocoupling product, 1,3-diyne, was completely sup-
pressed (entry 2). The structure of alkynylated pyridine 3a was
unambiguously established by spectroscopic analyses and single
crystal X-ray studies (Supporting Information (SI), Figure S1),
which confirmed the presence of a pyridine ring and alkyne
functionality in the product.
Encouraged by these results, we undertook a systematic
optimization study, the results of which are summarized in Table
1. A substantial drop in the yield was observed when DBU was
Next, we explored the synthetic utility of the obtained
alkynylpyridines to more useful derivatives, because of their
significant pharmaceutical properties (Scheme 1). Benzylic
oxidation proceeded well with molecular oxygen under reflux
conditions and delivered aryl alkynylpyridyl ketones in good
yields (Scheme 1, 4a−c). Moreover, a selective alkyne reduction
B
DOI: 10.1021/acs.orglett.8b01090
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Letter
Scheme 1. Synthetic Elaboration
was also achieved using molecular hydrogen as the reductant
with Pd/C in methanol to give the corresponding cis-3-
alkenylpyridines (Scheme 1, 5a and 5b).
A plausible mechanistic pathway for our ring-expansion
reaction cascade is depicted in Scheme 2. Initially, the reaction
Scheme 2. Plausible Mechanistic Pathway for the Ring-
Expansion Cascade Synthesis of Pyridines
of an alkyne with copper as a catalyst, in the presence of TEA,
gives copper acetylide I. This would then undergo a ring-opening
reaction with azirine 1 to provide a skipped-yne-imine
intermediate II, which can further give rise to a highly
nucleophilic yne-enamine intermediate IV. This intermediate
can proceed through either of two pathways. Path A includes
undergoing an intramolecular hydroamination or reacting with
the starting azirine to give pyrrole structures; Path B includes
reacting with the initially formed skipped-yne-imine II to give the
intermediate V. The latter can only be possible when the relative
population of these two key intermediates II and IV are high, a
very crucial factor in deciding the reaction pathway. For instance,
if the ring-opening process is rapid and effective, at any given
point of time, the population of these intermediates will be
Figure 2. Scope of the reaction. Conditions: 1 (0.85 mmol), 2 (0.93
mmol), TEA (1.7 mmol), solvent (3 mL), and CuI (0.085 mmol), at 25
°C, 30 min. Yields are those of isolated products. IC50 is the half maximal
inhibitory concentration.
C
DOI: 10.1021/acs.orglett.8b01090
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Organic Letters
Letter
greater than that of the starting azirines, and vice versa. Based on
our optimization studies, we believe that TEA is not only acting
as a base in generating copper acetylide I but also as a ligand in
accelerating the copper-catalyzed ring-opening process to obtain
higher concentrations of these key intermediates II and III. To
gain more insight into the mechanism, we performed density
functional theory calculations to study the role of TEA in the
reaction between azirine and copper acetylide. As expected, the
energy barrier for the reaction was ∼4 kcal/mol lower in the
presence of TEA (SI, Figure S2), which clearly explains the role
of TEA in the ring-opening process to access the intermediates at
high concentrations. When the concentrations of II and IV are
critically high, IV can readily undergo a copper-assisted
hydroalkylation with II to produce intermediate V. Subse-
quently, spontaneous cyclization of intermediate V would
provide an aminal VI, which would then eliminate ammonia
and undergo tautomerization to yield product 3.
As per our interest and expertise in exploring nanoparticles/
small molecules for biomedical applications,18 we evaluated the
in vitro cytotoxicity of selected products (3a, 3b, and 3h) against
oral cancer KB cell lines (KERATIN-forming tumor cells) using
an MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium
bromide) assay (SI, Figure S4). The half maximal inhibitory
concentration (IC50) values were determined to be 62.32, 59.28,
and 53.98 μM for the samples 3a, 3b, and 3h.
In summary, we have discovered and developed the interesting
reactivity of yne-enamine and skipped-yne-imine intermediates
generated in situ from the copper-catalyzed ring-expansion
reaction of azirines and alkynes for the synthesis of highly
substituted 3-alkynylpyridines, with potent anticancerous activity
against oral cancerous cells. This transformation features
inexpensive base-metal catalysts, proceeds at room temperature,
is operationally simple, and generates high-valued products. In
addition, the reaction is certainly scalable, and the products thus
obtained can be easily derivatized further to more functional
pyridines. Novel reactions of these unique intermediates and
investigation of alkynylpyridine derivatives for biological
activities are being explored in our laboratory.
ACKNOWLEDGMENTS
■
The authors acknowledge financial support from the Depart-
ment of Science and Technology (DST), New Delhi, India under
a DST-INSPIRE faculty scheme (DST/INSPIRE/04/2015/
001003). We thank Prof. M. Sasidharan, SRM University for
providing laboratory facilities.
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The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.8b01090.
Experimental procedures and characterization of all new
compounds, including 1H, and 13C NMR spectra (PDF)
Accession Codes
CCDC 1570536 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_
request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; fax: +44 1223 336033.
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail namitharan.k@res.srmuniv.ac.in.
ORCID
Kayambu Namitharan: 0000-0002-4283-1895
Notes
The authors declare no competing financial interest.
D
DOI: 10.1021/acs.orglett.8b01090
Org. Lett. XXXX, XXX, XXX−XXX