Cu(i) mediated Kinugasa reactions of α,β-unsaturated nitrones: A facile, diastereoselective route to 3-(hydroxy/bromo)methyl-1-aryl-4-(-styryl)azetidin-2-ones

Article abstract of DOI:10.1039/c6nj01747a

The manuscript describes a facile and highly diastereoselective synthesis of cis-3-(hydroxy/bromo)methyl-1-aryl-4-(-styryl)azetidin-2-ones via copper(i) mediated Kinugasa reactions of previously unexplored functionalized α,β-unsaturated nitrones. A variety of functionalized acetylenes and α,β-unsaturated nitrones were studied to yield cis-3-(hydroxy/bromo)methyl-1-aryl-4-(-styryl)azetidin-2-ones in good yields (82%).

Full text of DOI:10.1039/c6nj01747a

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DOI: 10.1039/C6NJ01747A
Journal Name
ARTICLE
Cu(I) mediated Kinugasa Reactions of -unsaturated Nitrones: A
Facile, Diastereoselective Route to 3-(Hydroxy/bromo)methyl-1-
aryl-4-(-styryl)azetidin-2-ones
Received 00th January 20xx,
Accepted 00th January 20xx
Yogesh Kumar,a Prabhpreet Singhb and Gaurav Bhargavaa*
DOI: 10.1039/x0xx00000x
www.rsc.org/
The manuscript describes a facile and highly diastereoselective lactam includes ketene-imine [2+2] cycloaddition reactions10
synthesis of
cis-3-(Hydroxy/bromo)methyl-1-aryl-4-(- and metallo-ester enolate-imine cyclocondensations.11
styryl)azetidin-2-ones by copper (I) mediated Kinugasa reactions However, these traditional synthetic routes are mostly
of previously unexplored functionalized unsaturated intolerant to acid or base sensitive moieties. After the advent
nitrones.
A variety of functionalized acetylenes and - of Kinugasa reaction, functionalized lactams were synthesized
unsaturated nitrones were studied to yield cis-3- which were previously in-accessible using traditional synthetic
(hydroxy/bromo)methyl-1-aryl-4-(-styryl)azetidin-2-ones in good methodologies.12 The Kinugasa reactions use readily available
yields (82%).
substrates viz. nitrones and acetylenes, and are mild and can
tolerate different functional groups (Figure 1).13 Kinugasa

-lactams are widely recognized as one of the most significant
heterocyclic scaffold1 and has maintained a high level of
curiosity, both in academia and in industry. The -lactam ring
is the common structural characteristic of number of broad
spectrum -lactam antibiotics, such as penicillin,
cascade provides an access to numerous -lactam compounds
with distinct configuration and potential biological activity.14


cephalosporins, carbapenems, nocardicins, monobactams,
clavulanic acid as well as inhibitors of HIV-1 protease.2 In
recent years, renewed interests has been paying attention on
the synthesis and modification of lactam ring to obtain
compounds with different pharmacological activities like
cholesterol absorption inhibitory activity, human tryptase,
thrombin and chymase inhibitory activity, vasopressin V1a
antagonist activity, antimalarial, antidiabetic, antitubercular,
Figure 1. A: Previous work on Kinugasa reactions; B: Present work on Kinugasa
reactions of α,β-unsaturated nitrones
anti-inflammatory, anti-parkinsonian and anti-HIV activity.3-4 
lactams are also increasingly being used as useful synthon for
-
the synthesis of variety of natural products via
-lactam
An early investigation by different research groups on Kinugasa
reactions examined the generation of functionalized -lactams
using aliphatic or aromatic substituted nitrones. These
Kinugasa reactions are initiated by [3+2] cycloadditions of
nitrones with Cu acetylide. These [3+2] cycloadducts (I) usually
follow two different pathways: pathway A17 and pathway B12b
synthon methodology.5 The lactam have also been explored as
well recognized for the variety of non-protein amino acids,
oligopeptides, peptidomimetics, and nitrogen-heterocycles,6,7
as well as biologically active natural and unnatural products of
medicinal interest. 8, 9
The common methodologies for synthesis of functionalized -
(Figure 1). Both pathways
intermediates -aminoketene
respectively, which eventually, collapse to cis/trans-
The Kinugasa reactions generally afford -lactams as mixtures
A
&
B
have revealed the presence
II) oxaziridinium III)
-lactams.

(
&
(

a.I. K. Gujral Punjab Technical University, Kapurthala, Punjab-144603, India
(Formerly known as Punjab Technical University, Kapurthala) Fax: Tel.: (+91)-
1822-255504, E-mail: gaurav@ptu.ac.in.

of racemic diastereoisomers, however, various stereoselective
variants of such transformation with an appropriate chiral
auxiliaries or chiral Cu(I) ligands have been reported.13,14
b.Department of Chemistry, Guru Nanak Dev University, Amritsar, Punjab 143005,
India..
† Footnotes relating to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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DOI: 10.1039/C6NJ01747A
Scheme 2. Kinugasa reaction of α,β-unsaturated nitrone 3.
Figure 2. Proposed mechanisms for Kinugasa reaction. Path A: via -aminoketene
intermediate II; Path B: via oxaziridinium intermediate III.
Table 1. Optimization of reaction conditions for Kinugasa reaction.
Entry
Solventa
DMSO
DMF
MeCN
THF
Base
NEt3
NEt3
NEt3
NEt3
Catalyst
CuI
CuI
CuI
CuI
-
Yieldsb (%)
traces
82
35
20
0
0
0
traces
0
1
2
3
4
5
Although, in principle, Kinugasa reaction would provide
efficient access to styryl substituted lactam at the C-4 position,
to the best of our knowledge no examples of such a process
have been reported (Figure 1). In view of previous reports and
our ongoing interests in heterocyclic chemistry,15 we have
turned our attention to the exploration of Kinugasa reactions,
ideally with -unsaturated nitrones derived from variety of
-unsaturated cinnamaldehydes. Herein we demonstrate a
copper catalyst mediated Kinugasa reactions for the synthesis
of lactams containing diverse substituents at the C4-
position with very good stereoselectivity.
DMF
NEt3
MeCN
THF
NEt3
NEt3
-
-
6
7
DMF
MeCN
THF
DIPEA
DIPEA
DIPEA
K2CO3
CuI
CuI
CuI
CuI
8
9
10
11
0
DMF
traces
aReactions was conducted under Argon, bIsolated yields after purification
The starting α,β-unsaturated nitrones
reactions were prepared by reported methods16 using
nitrobenzene and different conjugated aldehydes viz.
cinnamaldehyde, -methyl- cinnamaldehyde and p-methoxy-
3 used in Kinugasa
After the optimization of the reaction conditions, these
variedly substituted α,β-unsaturated nitrones
3
were
1
2
investigated for their Kinugasa reactions using CuI in DMF. The
reactions were carried out under inert atmosphere to avoid
the competitive Glaser coupling. The reactions led to the
formation of regio- and diastereomerically pure 3-methyl-1-
aryl-4-(-styryl)azetidin-2-one in good yields (Scheme-3).

cinnamaldehyde. (Scheme-1)
Scheme 3. Kinugasa reaction of α,β-unsaturated nitrones 3.
Scheme 1. Preparation of α,β-unsaturated nitrones 3.
The reaction of nitrones 3a and 3c gave comparatively better
yield of 3-methyl-1-aryl-4-(-styryl)azetidin-2-ones 5 (Table 2,
entries 1 and 3). However, the nitrones 3d and 3f gave
The α,β-unsaturated nitrones 3, were, initially, investigated for
the Kinugasa reactions in different solvents viz. dimethyl
sulfoxide (DMSO), N,N-dimethylformamide (DMF), MeCN and
THF (Scheme 2). The reaction gave best yield and selectivity of
product in DMF as solvent using CuI (3.3 eq.) and triethylamine
(3.3 eq.). In acetonitrile, the formation of lactam was
significantly low. When the Kinugasa reaction was attempted
in DMSO, only traces of the product were formed (Table 1).
These reactions were also tested in different bases viz.
triethylamine, DIPEA and K2CO3. But, only traces of product
were observed when DIPEA and K2CO3 were used as base in
these Kinugasa reactions.
comparatively
less
yield
of
cis-3-methyl-1-aryl-4-(-
styryl)azetidin-2-ones (Entries 4 & 6). The reactions were also
studied with propargyl bromide, however, yield was
comparatively low and there was not much change in the yield
of 5g-j with the change in the nitrones 3. The reactions of
nitrone with methyl propiolate and propiolaldehyde did not
succeed even using high amount of Cu(I) or use of different
base. Moreover, the kinugasa reactions of -unsaturated
nitrones derived form 2-nitro cinnamaldehyde were not
successful even under different reaction conditions. It was
worth noting that the complete cis selection was observed
during the synthesis of 
-lactams 5a-j.18, 19
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Table 2. Percentage yield of cis-3-methyl-1-aryl-4-(-styryl)azetidin-2-ones 5
The
diastereomerically
pure,
functionalized
View ArticlecOisn-li3ne-
DOI: 10.1039/C6NJ01747A
Producta
Yieldsb (%)
(hydroxyl/bromo)methyl-1-aryl-4-(-styryl)azetidin-2-one
5
Entry
1
Nitrone
Alkyne
(Figure 3), thus obtained was characterized on the basis of
analytical data and spectral evidences. The detailed
information is described in supporting information while the
salient features are discussed here. The compound, cis-3-
82
(hydroxymethyl)-1-phenyl-4-styrylazetidin-2-one
example, analyzed for C18H17NO2, mass spectrum showed
molecualr peaks at 280 (M+1). The high resolution H NMR
5a
for
2
3
1
75
80
(500MHz) spectrum showed
a characteristic doublet of
doublet at δ 4.86 having J = 6.0, 8.5 Hz corresponding to H4,
multiplet at δ 6.03 corresponding to H3, a doublet at δ 6.84 (J =
16.0 Hz) assigned to H6, and a doublet of doublet at δ 6.53 (J =
8.5, 16.0 Hz) assigned to H4. The 13C NMR has shown the
presence of one carbonyl carbon at δ 165.4 and at δ 57.9
corresponding to CH2 of the side chain at C-3 position. The cis
stereochemistry at CH3-CH4 of 5a was also confirmed by NOE
studies.18,19
4
5
6
70
65
Figure 3. 3-(Hydroxymethyl)-1-phenyl-4-styrylazetidin-2-one 5a.
70
45
45
40
42
0c
In conclusion, we have explored a highly diastereoselective
Kinugasa reactions of a variety of α,β-unsaturated nitrones
with
different
acetylenes
to
produce
cis-3-
7
8
(hyroxy/bromo)methyl-1-aryl-4-(-styryl)azetidin-2-ones
in
good yields. The methodology provides a new route to 3-
substituted-styryl lactams from variedly substituted α,β-
unsaturated nitrones which are exigent to access by traditional
methods. The reactions are highly diastereoselective and only
cis-3-(hyroxy/bromo)methyl-1-aryl-4-(-styryl)azetidin-2-ones
were observed. The current methodology for the formation of
cis-3-(hyroxy/bromo)methyl-1-aryl-4-(-styryl)azetidin-2-ones is
an important in terms of their potential biological application
as well as their usefulness as organic synthon.
9
Acknowledgements
The financial support from Board of Research in Nuclear
Sciences (BRNS), India (Scheme No. 2013/37C/11/BRNS/198)
and Department of Science and Technology (DST), New Delhi,
under Scheme No:- SB/FT/CS-079/2012 is highly
acknowledged. Mr. Yogesh Kumar gratefully acknowledge the
UGC Scheme RGNF (Award No:- F1-17.1/2011-12/RGNF-SC-
PUN-2309/(SA-III/Website)). I. K. Gujral Punjab Technical
University (PTU), Kapurthala is acknowledged for providing
research facilities.
10
11
Notes and references
aReaction time 18-24 hrs, bIsolated yields after purification, cStarting was
consumed but no useful product was isolated
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Palomo, J. M. Aizpurua, I. Ganboa, M. Oiarbide, Eur. J. Org.
Chem. 1999, 3223. (c) F. H. Van Der Steen, G. Van Koten,
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Cu (I) mediated Kinugasa Reactions of α,β−unsaturated Nitrones: A Facile,
Diastereoselective Route to 3-(Hydroxy/bromo)methyl-1-aryl-4-(-styryl)azetidin-2-ones
Yogesh Kumara, Prabhpreet Singhb, Gaurav Bhargavaa*
aDepartment of Applied Sciences, I. K. Gujral Punjab Technical University, Kapurthala, Punjab-144603,
India
Fax: Tel.: (+91)-1822-255504, E-mail: gaurav@ptu.ac.in.
bDepartment of Chemistry, Guru Nanak Dev University, Amritsar, Punjab 143005, India
Abstract: The manuscript describes a facile and highly diastereoselective synthesis of cis-3-
(hydroxyl/bromo)methyl-1-aryl-4-(-styryl)azetidin-2-ones by copper (I) mediated Kinugasa reactions of
previously unexplored functionalized
and -unsaturated nitrones were studied to yield cis-3-(hydroxyl/bromo)methyl-1-aryl-4-(-
styryl)azetidin-2-ones in good yields (82%).
α,β−unsaturated nitrones. A variety of functionalized acetylenes
α, β