Transition-metal-free synthesis of substituted pyridines via ring expansion of 2-allyl-2H-azirines

Article abstract of DOI:10.1021/ol501010k

A new strategy to open the 2-allyl-2H-azirines by 1,8-diazabicyclo[5.4.0] undec-7-ene (DBU) promotion in metal-free conditions affording 1-azatrienes that in situ electrocyclize to the pyridines in good to excellent yields is reported. The reaction displays a broad substrate scope and good tolerance to a variety of substituents including aryl, alkyl, and heterocyclic groups. In addition, one-pot synthesis of pyridines from oximes via in situ formation of 2H-azirines was achieved.

Full text of DOI:10.1021/ol501010k

Letter
pubs.acs.org/OrgLett
Transition-Metal-Free Synthesis of Substituted Pyridines via Ring
Expansion of 2‑Allyl‑2H-azirines
Yaojia Jiang,† Cheol-Min Park,*,§ and Teck-Peng Loh*,†,‡
†Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University,
Singapore 637616, Singapore
‡Department of Chemistry, University of Science and Technology of China, Hefei, Anhui 230026, P. R. China
§Department of Chemistry, UNIST (Ulsan National Institute of Science and Technology), UNIST-gil 50, Ulsan 689-798, Korea
S
* Supporting Information
ABSTRACT: A new strategy to open the 2-allyl-2H-azirines
by 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) promotion in
metal-free conditions affording 1-azatrienes that in situ electro-
cyclize to the pyridines in good to excellent yields is reported.
The reaction displays a broad substrate scope and good
tolerance to a variety of substituents including aryl, alkyl, and
heterocyclic groups. In addition, one-pot synthesis of pyridines
from oximes via in situ formation of 2H-azirines was achieved.
yridine moieties represent one of the most important
Pclasses of heterocycles found in many natural products,
pharmaceuticals, functional materials, and valuable ligands in
organic synthesis.1 A variety of methods have been developed
for the preparation of pyridines in the past few decades.2
While traditional methods employ condensation of carbonyl
compounds with ammonia,3 modern strategies largely rely on
transition-metal catalysis, C−H functionalization, and cyclo-
addition reactions.4 Despite this progress, it is still highly desir-
able to develop a more flexible, operationally simple method
with broad functional group tolerability.
Figure 1. Ring expansion of 2H-azirines to C−N bond construction.
2H-Azirines, the smallest nitrogen-containing unsaturated
heterocycles, have been extensively explored in synthetic and
substituted pyridines.11 In our continued efforts for the develop-
ment of N-hetercycle synthesis by an organic base,12 we report
herein the efficient synthesis of pyridines from 2-allyl-2H-
azirines by DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) promoted
electrocyclization13 (Figure 1, eq 2).
The substrate 2-allyl-2H-azirine 1a was easily prepared by
using the Neber reaction14 (see Supporting Information) and
was examined for pyridine formation under various conditions.
When treated with TMEDA in chlorobenzene at 130 °C, 1a
provided ethyl 2,6-diphenylnicotinate 2a in poor yield (Table 1,
entry 1). Attempts to improve the yield by employing other
bases turned out to be unsuccessful; the use of DMAP failed to
give any product (entry 2), while quinine, DABCO, and TEA
gave similar results as TMEDA (entries 3−5). Gratifyingly, the
yield could be improved to 95% when DBU was employed as
the base (entry 6). In contrast, no conversion was observed in
the absence of DBU ruling out the possibility of simple thermal
rearrangement (entry 7). Reduction of the amount of base or
biological applications.5 Due to their high ring strain, 2H-
azirines serve as a versatile source of nitrenes, electrophiles,
dienophiles, and dipolarophiles6 and are extensively used in the
construction of various N-heterocycles such as indoles, pyrroles,
isoxazoles, and pyrazolo[1,5-a]pyridines.7 Typically, 2-aryl-2H-
azirines and 2-vinyl-2H-azirines are believed to give indoles and
pyrroles via nitrene intermediates upon thermolysis and transi-
tion metal catalysis (Figure 1, eq 1, n = 0).8 However, unlike
aryl and vinyl-substituted azirines, few successful examples of
N-heterocycle synthesis involving 2-allyl-2H-azirines, which
contain remote double bonds, have been reported; Padwa and
co-workers reported in a limited number of examples that
thermal generation of nitrenes from 2-allyl-2H-azirines leads
to the formation of mixtures of pyridines, pyrroles, and indoles
(Figure 1, eq 1, n = 1).9 Ohe et al. reported palladium-mediated
decarboxylative aziridination of 4H-isoxazol-5-ones in which
selective formation of pyrroles have been achieved via
1-azabicyclo[3.1.0]hex-2-ene intermediates formed by the
addition of putative nitrene−metal complexes to pendant allyl
groups.10 Recently, Gagosz et al. reported the gold-activated
triple bonds of 2-propargyl-2H-azirines for synthesis of
Received: April 7, 2014
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ol501010k | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
,b
Table 1. Base Promoted Synthesis of Pyridines
Scheme 2. Substrate Scope
a
bc
,
entry
base
sovlent
yield (%)
1
2
3
4
5
6
7
8
9
TMEDA
DMAP
DABCO
quinine
TEA
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCH3
DCE
PhCl
PhCl
PhCl
17
0
17
16
13
95
0
DBU
−
DBU
77
26
75
23
25
DBU
d
10
DBU
e
11
FeBr2
f
12
Rh2(OAc)4
a
Unless otherwise noted, reactions were performed using 1a (0.1 mmol),
base (0.3 mmol) in solvent (0.1 M, 1 mL) at 130 °C for 48 h under
b
a nitrogen atmosphere. Yields determined by NMR vs standard.
c
d
e
The remaining materials were 1a. 2.2 equiv of DBU. 20 mol % FeBr2.
f
2 mol % Rh2(OAc)4. TMEDA = Tetramethylethylenediamine,
DMAP = 4-Dimethylaminopyridine, DABCO = 1,4-diazabicyclo-
[2.2.2]octane, DBU = 1,8-Diazabicyclo[5.4.0]undec-7-ene.
a
reaction temperature resulted in decreased yields (entries 8−10).
Interestingly, metal complexes commonly employed for the
generation of nitrenes gave 2a in poor yields (entries 11−12).15
Encouraged by the results, we investigated the substrate
scope of the reaction (Scheme 2). In general, the reaction
tolerated a broad range of substitution to give trisubstituted
pyridines in good to excellent yields. To examine the electronic
effect on the R1 substituent, substrates with aryl groups bearing
electron-donating and -withdrawing groups were subjected to
the reaction conditions. Whereas those with phenyl and
electron-rich aryl groups provided excellent yields of pyridines
(2a and 2b, respectively), a competing reaction providing a
mixture of regioisomers 2c and 2c′ was observed with a
substrate bearing an electron-deficient aryl group. We reasoned
that the formation of the minor product 2c′ proceeds through
1,3-dipolar cycloaddition of the nitrile ylide intermediate arising
from C−C bond cleavage of the azirine ring (Scheme 1).9
Unless otherwise noted, reactions were carried out using 1 (0.2 mmol),
DBU (0.6 mmol) in chlorobenzene (0.1 M, 2 mL) at 130 °C for 48 h
under nitrogen atmosphere. bIsolated yields. c2c′ = ethyl 6-(4-
nitrophenyl)-5-phenylpicolinate (38%); 2d′ = ethyl 6-(furan-2-yl)-5-
phenylpicolinate (32%); 2e′ = ethyl 5-phenyl-6-(thiophen-2-yl)-
picolinate (23%). dReactions were carried out using 1 (1.0 mmol),
DBU (3.0 mmol) in chlorobenzene (0.1 M, 10 mL) at 130 °C for 48 h
under nitrogen atmosphere.
presumably due to the isomerization of the alkene into the
dihydropyridine.16
Next, we turned our attention to examine the influence of
the substituents at the 2-position of 2H-azirines (Scheme 3).
Unlike the substitution at R1, substrates with both electron-rich
and -deficient aryl groups at the terminal position of the allyl
groups (R4) proceeded smoothly to give single regioisomers
(2m and 2n). However, replacement of the aryl groups at R4
with a methyl group resulted in a mixture of 2o and 2o′
resulting from the competing nitrile ylide pathway. Likewise, 1p
bearing an unsubstituted allyl group gave a regioisomeric
mixture. Interestingly, introduction of a methyl group at R3
(1q) also promoted the nitrile ylide pathway, even in the
presence of an aryl substituent at R4. In addition to the ester
group, we also examined different functional groups for R2.
Thus, 1s bearing a phenyl group reacted well to provide 2s in
excellent yield. Elimination is favored over oxidation to give
3-unsubstituted pyridine 2t′ in 92% yield when the phosphonate
group was employed for R2.
Since the preparation of substrates in the Neber reaction
employs DBU, we reasoned that one-pot synthesis of pyridines
from oximes via in situ formation of 2H-azirines could be
achieved. To our delight, 2a was formed in 85% yield from
oxime 3 by using 3 equiv of DBU (Scheme 4).
In summary, we have developed a novel method for the
synthesis of highly substituted pyridines through DBU-mediated
Scheme 1. Proposed Pathway for Pyridines
Likewise, a similar competing reaction was observed with
heteroaryl-substituted substrates 1d and 1e. In contrast, the
competing nitrile ylide pathway was completely suppressed
with alkyl-substituted substrates providing single regioisomers
in excellent yields (2f−k, Scheme 2). Substituents such as cyclo-
propyl and vinyl groups remained intact during the reaction
(2k and 2l); However, styryl substitution led to an unexpected
product 2h in which the alkenyl moiety was saturated,
B
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Unless otherwise noted, reactions were carried out using 1 (0.2 mmol),
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Scheme 4. One-Pot Synthesis of Pyridine
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ASSOCIATED CONTENT
* Supporting Information
■
S
Detailed experimental procedures and characterization data.
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: teckpeng@ntu.edu.sg.
*E-mail: cmpark@unist.ac.kr.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the Nanyang Technological
University and the Singapore Ministry of Education Academic
Research Fund Tier 2: MOE2011-T2-1-013 for TPL and
MOE2012-T2-1-014 for SC, and the National Environment
Agency (NEA-ETRP Project Ref. No. 1002 111), and
University of Science and Technology of China.
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