N-Heterocyclic Carbene Catalyzed Synthesis of Trisubstituted Epoxides via Tandem Amidation/Epoxidation Sequence

Article abstract of DOI:10.1021/acs.orglett.0c01017

A tandem amidation/epoxidation sequence between various substituted chalcones and N,N-dimethylformamide (DMF) for the synthesis of trisubstituted epoxides employing N-heterocyclic carbene catalysis was developed. This reaction was performed under metal-free conditions in the presence of tert-butyl hydroperoxide (TBHP) as the oxidant. Trisubstituted epoxides bearing a ketone and an amide functionality (N,N-dimethyl formyl group) were synthesized starting from a wide range of chalcones in moderate to good yields with excellent diastereoselectivity.

Full text of DOI:10.1021/acs.orglett.0c01017

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Letter
N‑Heterocyclic Carbene Catalyzed Synthesis of Trisubstituted
Epoxides via Tandem Amidation/Epoxidation Sequence
E. Sankari Devi, Thangavel Pavithra, A. Tamilselvi, Subbiah Nagarajan, Vellaisamy Sridharan,
and C. Uma Maheswari*
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ABSTRACT: A tandem amidation/epoxidation sequence between
various substituted chalcones and N,N-dimethylformamide (DMF)
for the synthesis of trisubstituted epoxides employing N-
heterocyclic carbene catalysis was developed. This reaction was
performed under metal-free conditions in the presence of tert-butyl
hydroperoxide (TBHP) as the oxidant. Trisubstituted epoxides
bearing a ketone and an amide functionality (N,N-dimethyl formyl group) were synthesized starting from a wide range of chalcones
in moderate to good yields with excellent diastereoselectivity.
mployment of small organic molecules as catalysts, notably
known as organocatalysis, gained widespread attention over
Scheme 1. Application of Thiazolium Derived NHCs as
Organocatalysts
E
the past two decades.1 Based on their mode of binding with
substrates, organocatalysts have been classified as covalent and
noncovalent catalysts. Among covalent catalysts, N-Hetero-
cyclic Carbenes (NHCs) attain greater significance due to their
wide range of applicability. Even though NHCs were
successfully isolated in the 1990s,2 the seminal work of Ukai
et al. in 1943 on coenzyme thiamine (vitamin B1), being used as
a thiazolium based NHC catalyst for benzoin condensation
reaction proved to be pioneering work in NHC catalysis.3 The
mechanism of this reaction was later proposed by Breslow which
involves an acylazolium intermediate commonly known as a
Breslow intermediate.4 Since then, several chemists tried to
explore thiamine as NHC for various transformations including
intermolecular cross-benzoin condensation.5 When compared
with transition-metal catalysts, NHCs show low toxicity, are
environmentally benign, are easy to handle, and are employed
for several transformations due to their umpolung reactivity
toward the carbonyl compounds.6 Among several classes of
NHCs, triazolium, imidazolium and thiazolium based N-
heterocyclic carbenes acts as more prominent organocatalysts
owing to their superior reactivity and wide range of trans-
formations.7
Among these organocatalysts, thiazolium based NHCs gained
importance due to it is historic significance and myriad synthetic
applications. A few important transformations include oxidative
lactonization for the synthesis of benzodioxepinone deriva-
tives,8a intermolecular Stetter reaction of linear and cyclic alkyl
α-diketones,8b synthesis of keto-amides from aldehydes and
acylimines,8c and oxidative esterification of aldehydes8d
(Scheme 1).
Likewise, various N-heterocycles including pyridinones, oxin-
doles, indole, and imidazoles were constructed via NHC
Received: March 20, 2020
Similarly, N-heterocyclic carbene catalysis was successfully
employed for the construction of O-heterocycles via C−O bond
formation to generate phthalimides, isocoumarins, and pyrans.9
https://dx.doi.org/10.1021/acs.orglett.0c01017
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

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Letter
catalyzed C−N bond formation.10 Among, O-heterocycles,
epoxides are privileged building blocks in organic synthesis.11 In
particular, epoxides derived from electron-deficient alkenes like
α,β-unsaturated carbonyl compounds possess various applica-
tions in the preparation of intermediates for pharmaceutics and
fine chemicals.12 Due to their chemical importance and its
myriad applications, various groups have reported the synthesis
of sterically hindered epoxides, which includes Rh catalyzed
synthesis of sterically hindered epoxypyrrolidines,13a rare earth
metal amides catalyzed epoxidation of α,β-unsaturated
ketones,13b TBAI catalyzed epoxidation of naphthaquinones,13c
and Ag-NHC complex catalyzed epoxidation of diazocarbonyl
compounds with aryl aldehydes.13d In continuation of our efforts
on NHC catalyzed oxidation reaction to access compounds of
biological significance,10e,14 herein, we report the synthesis of
trisubstituted epoxides bearing ketone and amide functionalities
starting from various substituted chalcones and N,N-dimethyl-
formamide (DMF) employing thiazolium NHC as the organo-
catalyst in the presence of tert-butyl hydroperoxide (70% aq.
TBHP) as the oxidant. In the final product, the N,N-dimethyl
formyl group was introduced and the resulting epoxide was
obtained via the tandem amidation/epoxidation sequence
diastereoselectively.
Table 1. Optimization of the Reaction Conditions for the
NHC-Catalyzed Construction of 2-Benzoyl-N,N-dimethyl-3-
a
phenyloxirane-2-carboxamide
b
Entry
Base
Et3N
t-BuOK
Cs2CO3
K2CO3
DBU
Piperidine
Morpholine
(i-Pr)2NH
DIPEA
DABCO
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Oxidant
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP in decane
Other peroxides
TBHP
TBHP
TBHP
TBHP
TBHP
Yield (%)
1
2
3
4
5
6
7
8
73
54
46
41
15
47
45
24
55
23
54
9
10
11
12
13
14
15
16
17
18
c
−
d
56
30
f
e
In order to identify the suitable reaction conditions for the
synthesis of trisubstituted epoxides from chalcones and DMF,
initial optimization studies were performed with chalcone 1a as
the model substrate. The role of various NHC salt precursors
A−K were investigated for the formation of an epoxide, 2-
benzoyl-N,N-dimethyl-3-phenyloxirane-2-carboxamide 2a, em-
ploying Et3N as base and aq. TBHP as oxidant in DMF at 120 °C
(Figure 1). Among the various NHC precatalysts employed, the
−
g
32
68
57
h
i
TBHP
a
Reaction conditions: Chalcone 1a (1.0 mmol), NHC precatalyst K
(10 mol %), Base (10 mol %), Oxidant (3.0 equiv), DMF (2.0 mL),
b
c
120 °C, 1.5 h. Isolated yield. DTBP, DCP, BPO, TBPB, H2O2.
d
e
f
g
Reaction at 100 °C. Reaction at 80 °C. Reaction at rt. 5 mol % of
base. 15 mol % of base. 2.0 equiv of oxidant.
h
i
the various inorganic bases screened (entries 2−4), t-BuOK was
found to be the best one furnishing 54% of the epoxide. Next,
several organic bases were tested (entries 1, 5−10), and among
them, Et3N produced the desired epoxide with optimal yield
(entry 1). A screening of oxidants was carried out, and when
TBHP in decane was used as the oxidant instead of 70% aq.
TBHP, the yield of the product decreased significantly from 73%
to 54% (entry 11). Other peroxides, di-tert-butyl peroxide
(DTBP), dicumyl peroxide (DCP), benzoyl peroxide (BPO) or
tert-butyl peroxybenzoate (TBPB) and hydrogen peroxide (30%
aq. H2O2), did not work for this reaction (entry 12), and the
effect of temperature on the product formation was also studied
subsequently. It was observed that the product yield decreased
when the reaction temperature was reduced from 120 °C
(entries 13 and 14), and the reaction failed completely when it
was performed at room temperature (entry 15). When the
amount of base required to generate the free carbene was
decreased from 10 mol % to 5 mol %, the yield decreased
drastically from 73% to 32% (entry 16) and a further increase in
the base from 10 mol % to 15 mol % did not increase the product
formation (entry 17). Decreasing the oxidant from 3.0 equiv to
2.0 equiv led to a decrease in the yield of the product (entry 18).
Consequently, we set entry 1 (10 mol % of NHC precatalyst K,
10 mol % of Et3N, 3.0 equiv of aq. TBHP in DMF at 120 °C) as
the optimized reaction conditions for further experiments.
After identifying the optimal reaction conditions, we
investigated the scope and limitations of this NHC catalyzed
tandem amidation/epoxidation sequence for the synthesis of
trisubstituted 2-aroyl-N,N-dimethyl-3-aryloxirane-2-carboxa-
mides employing various substituted α,β-unsaturated carbonyl
Figure 1. N-Heterocyclic carbenes used for the synthesis of
trisubstituted epoxides.
yield of the desired epoxide 2a was found to be optimum with
thiazolium NHC salt precursors J and K and comparatively
better yields were obtained with thiamine hydrochloride K as
catalyst (Vitamin B1, 73%). After identifying the suitable NHC
precatalyst for this tandem amidation/epoxidation reaction, the
effect of base, temperature, and oxidant were studied, and the
results are summarized in Table 1.
Changing the base has a drastic effect on the product yield
which was observed by varying several organic and inorganic
bases in the presence of NHC precatalyst K at 120 °C. Among
B
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a
Scheme 2. Scope and Limitations for NHC Catalyzed Synthesis of 2-Aroyl-N,N-dimethyl-3-aryloxirane-2-carboxamides
a
Reaction conditions: 1 (1.0 mmol), NHC precatalyst K (10 mol %), Et3N (10 mol %), aq. TBHP (3.0 equiv), DMF (2.0 mL), 120 °C. Isolated
yields are reported.
compounds (Scheme 2). The reaction was tolerant to the
electronic nature of substituents (R1) at the para position of α,β-
unsaturated carbonyl compounds, as both electron-donating
and -withdrawing groups worked well to deliver the correspond-
ing epoxides in good yields (2b−e). The steric factor had a
minimal effect on this transformation, as the at ortho substituted
(E)-1,3-diphenylprop-2-en-1-ones furnished the corresponding
products in good yields (2g, h). Similarly, naphthyl substituted
chalcone gave the corresponding product in good yield (65%,
2i). The reaction of heteroaromatic (E)-1-phenyl-3-(thiophen-
2-yl)prop-2-en-1-one under the optimized reaction conditions
furnished the corresponding product in trace amount (2j) even
after a prolonged reaction time. When the substituent at another
aryl ring (R2) of (E)-1,3-diphenylprop-2-en-1-one was varied, it
was observed that the position and electronic effect of the
substituents have minimal effect on product yields and delivered
the corresponding products in moderate to good yields (2k−p).
Furthermore, reaction of (E)-1-(naphthalen-2-yl)-3-phenyl-
prop-2-en-1-one under optimized conditions gave only trace
amount of product 2q after 6 h. Finally, we tested the variation at
both aryl rings (R1 and R2) of (E)-1,3-diphenylprop-2-en-1-one,
and the electronic nature of the substituent did not have any
effect on the reaction on product yield (2r−v). When the
reaction was performed with (E)-1-(benzo[d][1,3]dioxol-5-yl)-
3-phenylprop-2-en-1-one, the corresponding epoxide was
obtained in trace amount even after prolonging the reaction
time (2w). In addition, instead of DMF, when the reaction was
performed with N-methylformamide as solvent, the correspond-
ing product 2-benzoyl-N-methyl-3-phenyloxirane-2-carboxa-
mide 2x was obtained in 55% yield. When the reaction was
performed with N,N-dimethylacetamide, the reaction failed to
deliver the corresponding product completely. Similarly, when
aliphatic α,β-unsaturated carbonyl compounds like (E)-4-
phenylbut-3-en-2-one and (E)-1-cyclopropyl-3-phenylprop-2-
C
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en-1-one were employed as the substrates, the reaction failed to
produce the desired products 2y and 2z. When we extended the
scope of the reaction to other aldehydes like benzaldehyde and
iso-butyraldehyde instead of DMF, the desired epoxide was not
observed.
To understand the mechanism of the NHC catalyzed tandem
amidation/epoxidation sequence for the synthesis of 2-aroyl-
N,N-dimethyl-3-aryloxirane-2-carboxamides, we carried out a
set of control experiments employing chalcone 1a as the model
substrate as shown in Scheme 3. In the absence of either catalyst
reactions, we can ascertain the role of catalyst, oxidant, and DMF
for the formation of epoxide 2a. When the reaction was
performed with chlorobenzene, a simple epoxide, phenyl(3-
phenyloxiran-2-yl)methanone 2a′, was obtained as the major
product (81%, entry 4). When epoxide 2a′ was taken as the
substrate instead of 1a, under the optimized reaction conditions,
the desired product 2a was not observed from which we can infer
that the epoxide 2a′ cannot be the intermediate for the
formation of 2a (entry 5). Finally, when the reaction was carried
out in the presence of 2,2,6,6-tetramethylpiperidin-1-yl)oxyl
(TEMPO), as radical scavenger, the desired epoxide 2a was not
observed, which confirms the existence of a radical intermediate
in the catalytic cycle (entry 6).
a
Scheme 3. Control Experiments
On the basis of these control experiments, we propose a
plausible mechanism for the formation of epoxide 2a from
chalcone 1a (Scheme 4). Free carbene A was generated by the
action of base, Et3N, on thiamine hydrochloride K, which
undergoes conjugate addition with 1a to generate azolium
enolate (tetrahedral intermediate) I1. This enolate intermediate
undergoes a proton transfer to form the enamine intermediate
(deoxy-Breslow intermediate) I2.15 Nucleophilic attack of I1 on
the carbonyl group of DMF generates the intermediate I3, where
the less bulky aryl group (in comparison with NHC) and N,N-
dimethyl formyl group were present in a sterically less hindered
position (cis), thus accounting for the diastereoselectivity of the
product formation, which was further confirmed by single crystal
structures. The tertiary carbon of I3 can be attacked by a free
radical generated from tert-butyl hydroperoxide (tBuOO·),16 to
form intermediate I4, which, on reorganization, generates the
intermediate I5 along with the free carbene A. The trisubstituted
epoxide 2a was obtained from intermediate I5 via a hydride shift
along with t-BuOH as the byproduct.
a
Reaction conditions: 1a (1.0 mmol), NHC precatalyst K (10 mol
b
%), Et3N (10 mol %), aq. TBHP (3.0 equiv) 120 °C, 1.5 h. Isolated
c
yield. Phenyl(3-phenyloxiran-2-yl)methanone 2a′ was observed
d
(81%). 2a′ was treated with DMF under optimized condition
e
instead of 1a. TEMPO was used as a radical scavenger.
In conclusion, we have established a novel synthetic strategy
for the synthesis of trisubstituted epoxides from a wide variety of
chalcones and N,N-dimethylformamide via a tandem amida-
tion/epoxidation sequence. The reaction takes place in the
or oxidant, we could not observe the desired product (entries 1
and 2). In the absence of DMF as solvent and a coupling partner,
there was no product formation (entry 3). From the aforesaid
Scheme 4. Plausible Mechanism for the Synthesis of 2a from 1a
D
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presence of thiamine hydrochloride as thiazolium NHC
precatalyst, an environmentally benign catalyst in the presence
of Et3N as base and aq. TBHP as oxidant. This metal-free
strategy was successfully employed for the synthesis of
trisubstituted epoxides in moderate to good yields with excellent
diastereoselectivity. Based on the control experiments, a
plausible mechanism for this epoxidation was proposed which
involves tandem amidation/epoxidation reaction.
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AUTHOR INFORMATION
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Corresponding Author
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V.; Maheswari, C. U. Catal. Commun. 2019, 125, 26−31.
C. Uma Maheswari − Department of Chemistry, School of
Chemical and Biotechnology, SASTRA Deemed University,
Thanjavur 613401, India; orcid.org/0000-0002-7855-
2193; Email: umamaheswaric@scbt.sastra.edu, uma.cchem@
gmail.com
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E. Sankari Devi − Department of Chemistry, School of Chemical
and Biotechnology, SASTRA Deemed University, Thanjavur
613401, India
Thangavel Pavithra − Department of Chemistry, School of
Chemical and Biotechnology, SASTRA Deemed University,
Thanjavur 613401, India
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A. Tamilselvi − Department of Chemistry, Thiagarajar College,
Madurai 625009, India
Subbiah Nagarajan − Department of Chemistry, National
Institute of Technology-Warangal, Warangal 506004, India;
orcid.org/0000-0003-2233-4872
Vellaisamy Sridharan − Department of Chemistry and Chemical
Sciences, Central University of Jammu, Jammu 181143, India;
orcid.org/0000-0002-3099-4734
Complete contact information is available at:
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Notes
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from Science and Engineering Research Board
(SERB), DST, New Delhi for the award of Extramural research
grant (No. EMR/2016/002485/OC) and Council of Scientific
and Industrial Research, CSIR [No. 09/1095(0032)/18-EMR-
I] are gratefully acknowledged.
E
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