A copper-catalyzed diastereoselective O-transfer reaction of: N -vinyl-α,β-unsaturated nitrones with ketenes into γ-lactones through [5 + 2] cycloaddition and N-O bond cleavage

Article abstract of DOI:10.1039/C9GC01811E

A general protocol for the construction of novel densely functionalized γ-lactones was developed in good to excellent yields with high diastereoselectivity from easily available N-vinyl-α,β-unsaturated nitrones and ketenes. The reaction involves copper-catalyzed [5 + 2] cycloaddition, N-O bond cleavage, 6π electron cyclization, and aromatization to afford various γ-(pyridin-2-yl)lactones over four step transformations in a single flask. The present method features mild reaction conditions, high atom economy, high regio- and diastereoselectivity, diversity of γ-lactones, and a new application of the O-transfer reaction.

Full text of DOI:10.1039/C9GC01811E

An article presented by Prof. Dong-Liang Mo et al. of the
Guangxi Normal University, People's Republic of China.
As featured in:
Volume 21 Number 24 21 December 2019 Pages 6517–6756
A copper-catalyzed diastereoselective O-transfer reaction of
N-vinyl-N,-unsaturated nitrones with ketenes into -lactones
through [5 + 2] cycloaddition and N–O bond cleavage
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A copper-catalyzed atom economic O-transfer reaction strategy
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O-lactones from N-vinyl-,-unsaturated nitrones and ketenes.
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A copper-catalyzed diastereoselective O-transfer
reaction of N-vinyl-α,β-unsaturated nitrones with
ketenes into γ-lactones through [5 + 2]
Cite this: Green Chem., 2019, 21,
6567
Received 31st May 2019,
Accepted 22nd September 2019
cycloaddition and N–O bond cleavage†
Jun-Yi Liao,‡a Qing-Yan Wu,‡a Xiuqiang Lu,b Ning Zou,a Cheng-Xue Pan,a
DOI: 10.1039/C9GC01811E
a
rsc.li/greenchem
Cui Liang,a Gui-Fa Su*a and Dong-Liang Mo
*
A general protocol for the construction of novel densely function- the preparation of densely functionalized γ-lactones would
alized γ-lactones was developed in good to excellent yields facilitate the study of biological activity of these compounds.
with high diastereoselectivity from easily available N-vinyl-
The transition-metal catalyzed O-transfer reaction of N–O
α,β-unsaturated nitrones and ketenes. The reaction involves bond compounds, such as pyridine N-oxides, nitrones, and
copper-catalyzed [5 + 2] cycloaddition, N–O bond cleavage, 6π oxime ethers, provides a good tool to introduce an oxygen
electron cyclization, and aromatization to afford various source into complex target molecules.9 However, the generated
γ-(pyridin-2-yl)lactones over four step transformations in a single N-heterocycles or imines from N-oxides or nitrones in most of
flask. The present method features mild reaction conditions, high these reactions usually did not participate in the reaction and
atom economy, high regio- and diastereoselectivity, diversity of were left as waste (Scheme 1-A). The atom economical reaction
γ-lactones, and a new application of the O-transfer reaction.
is one of the most important goals in green chemistry because
it does not produce additional waste and improves the syn-
thetic efficiency. Consequently, development of an atom econ-
omical O-transfer reaction is valuable. In 2013, Anderson
and coworker pioneered the development of a copper-catalyzed
γ-Lactones are valuable heterocycles that are not only found in
a large number of biologically active natural and unnatural
molecules but also serve as versatile synthetic intermediates
to access many important architectures, such as 1,4-diols,
γ-hydroxycarboxylic acids, and tetrahydrofurans.1 Naturally
occurring γ-lactones are often present in various pharmaceuti-
cals, foods and fruits and show interesting biological activi-
ties.2 Many elegant strategies for synthesizing γ-lactones have
been reported, including oxyfunctionalization of alkenes,3
dehydrogenative esterification,4 C–H activation,5 hydroacyla-
tion or hydrohydroxyalkylation,6 ring-opening and rearrange-
ment reactions,7 and other cascade transformations.8
Unfortunately, the corresponding methods for the preparation
of densely functionalized γ-lactones are sparse and no reported
strategy has been shown to construct γ-(pyridin-2-yl)lactones
containing pyridine and γ-lactone rings in a one pot reaction.
Consequently, exploring a general and practical method for
aState Key Laboratory for Chemistry and Molecular Engineering of Medicinal
Resources, Ministry of Science and Technology of China; School of Chemistry and
Pharmaceutical Sciences, Guangxi Normal University, 15 Yu Cai Road, Guilin,
541004, China. E-mail: gfysglgx@163.com, moeastlight@mailbox.gxnu.edu.cn
bFuqing Branch of Fujian Normal University, Fuzhou, Fujian, 350300, China
†Electronic supplementary information (ESI) available: Experimental details and
characterization of all compounds and copies of 1H and 13C NMR for new com-
pounds. CCDC 1915597. For ESI and crystallographic data in CIF or other elec-
tronic format see DOI: 10.1039/C9GC01811E
Scheme 1 New application for the copper-catalyzed O-transfer reac-
tion of α,β-unsaturated nitrones to γ-lactones.
‡These authors contributed equally to this work.
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Table 1 Optimization of the reaction conditionsa
self O-transfer reaction of N-aryl-α,β-unsaturated nitrones to
prepare useful α,β-epoxyketimines and a plausible isoxazoline
intermediate was proposed (Scheme 1-B).10 This strategy
showed an efficient and atom economical O-transfer reaction
and demonstrated the distinct reactivity and powerful appli-
cation of N-aryl-α,β-unsaturated nitrones. But this self intra-
molecular O-transfer reaction still limited its application to
more complex motifs. N-Substituted-α,β-unsaturated nitrones
as useful organic building blocks have attracted much atten-
tion because the double bond of nitrones can participate in
many transformations to construct complex molecules.11 Since
the pioneering observations of [5 + 2] cycloaddition of N-aryl-
α,β-unsaturated nitrones with activated alkynes by the Yang
group,12 many cycloadditions of N-substituted-α,β-unsaturated
nitrones with various dipolarophiles to prepare complex
heterocycles were reported.13 However, most of these reactions
involved [3 + 2] cycloaddition instead of [5 + 2] cycloaddition.
The regioselectivity between [3 + 2] and [5 + 2] cycloaddition of
α,β-unsaturated nitrones with different dipolarophiles is still
unresolved and challenging.
Entry
Cat.
Solvent
Base
3aa, yieldb (%)
1
2
3
4
CuCl
THF
THF
THF
THF
NEt3
NEt3
NEt3
NEt3
5
Cu(OTf)2
Cu(NO3)2
Cu(OAc)2
FeCl3
67
64
82
49
<5
23
32
50
56c
79d
<5
41
72
5
THF
NEt3
6
7
8
9
10
11
12
13
14
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
MeCN
Toluene
DCM
Et2O
THF
THF
THF
NEt3
NEt3
NEt3
NEt3
NEt3
NEt3
Pyridine
TMEDA
NMMP
THF
THF
a Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol, 2.0 equiv.),
Cu(OAc)2 (20 mol%), base (2.0 equiv.), solvent (3.0 mL), 0 °C to 25 °C,
24–48 h. b Isolated yield. c 2a (1.5 equiv.). d 2a (3.0 equiv.).
Ketenes, generated from acyl chlorides or their equivalents,
are useful and important reactive intermediates in organic syn-
thesis and participate in various cycloadditions.14 However, to
date, the cycloaddition of nitrones with ketenes has usually
provided oxindoles and produced aldehyde as waste, showing FeCl3 only delivered 3aa in 49% yield (Table 1, entry 5). Solvent
that the cycloaddition of ketenes occurred at the CvO bond screening showed that THF gave better yield than MeCN,
(Scheme 1-C).15 To avoid these drawbacks, [3 + 2] cycloaddition toluene, DCM, and Et2O (Table 1, entries 6–9). Lower yields of
occurring at the CvO bond of ketenes should be inhibited. 3aa were obtained using either 1.5 equiv. or 3.0 equiv. of 2a
During studies of the preparation and cycloaddition of (Table 1, entries 10 and 11). The influence of the base was also
α,β-unsaturated nitrones in our group,16 recently, we have investigated. Pyridine did not afford 3aa while tetramethyl-
reported an iron(III) catalyst controlled selective cyclization of ethylenediamine (TMEDA) or N-methylmorpholine (NMMP)
N-vinyl-α,β-unsaturated nitrones to prepare polysubstituted delivered 3aa in 41% and 72% yields, respectively (Table 1,
pyridines and isoxazolines in good to excellent yields.16a Then, entries 12–14). Therefore, the optimal conditions for preparing
we proposed that using ketenes generated from acyl chlorides 3aa were Cu(OAc)2 (20 mol%), and NEt3 (2.0 equiv.) as a base
under base conditions as dipolarophiles in the cycloaddition in THF from 0 °C to 25 °C under air conditions.
would inhibit the self O-transfer reaction of α,β-unsaturated
With the optimized conditions in hand, we turned our
nitrones due to their high reactivity to be attacked fast by the efforts to investigate the scope of substrates. As shown in
O-atom of nitrones. And the metal-catalyst subsequently co- Table 2, a variety of dibenzylidene-acetone-derived N-vinyl-
ordinated to the double bond would facilitate [5 + 2] cyclo- α,β-unsaturated nitrones 1 reacting with 2-phenylacetyl chlor-
addition instead of [3 + 2] cycloaddition to afford new hetero- ide 2a smoothly afforded the corresponding γ-(pyridin-2-yl)
cyclic scaffolds through subsequent metal-catalyzed N–O bond lactones 3aa–3ha in moderate to good yields with high diastereo-
cleavage (Scheme 1-D). Herein, we describe our design for a selectivity. The diastereoselectivity of these compounds was
1
new application of the O-transfer reaction through copper-cata- determined by H NMR of the crude mixtures. Both electron-
lyzed [5 + 2] cycloaddition of N-vinyl-α,β-unsaturated nitrones donating and electron-withdrawing styrenyl functional groups
with ketenes to prepare a variety of γ-(pyridin-2-yl)lactones and with ortho, meta, and para substituents were well tolerated to
γ-ketolactones in good to excellent yields over four step trans- afford γ-(pyridin-2-yl)lactones 3aa–3ga, but that with an elec-
formations in a one-pot reaction under air conditions.
tron-withdrawing group gave better yield than that with an
Our investigations started with N-vinyl-α,β-unsaturated electron-donating group (3ba vs. 3ea). Interestingly, when the
nitrone 1a and 2-phenylacetyl chloride 2a as model substrates. styrenyl group of nitrone 1g with an ortho-bromo group was
As shown in Table 1, CuCl used as a catalyst only provided subjected to the optimal conditions, product 3ga was obtained
desired product 3aa in 5% yield, while good yields of 3aa were in 40% yield with a 1 : 1 dr of atropisomer. Thiophene-substi-
obtained using Cu(OTf)2 or Cu(NO3)2 and NEt3 as a base in tuted nitrone 1h afforded desired product 3ha containing four
THF under air (Table 1, entries 1–3).17 The structure and rela- heterocycles in 81% yield. In addition to the styrenyl func-
tive configuration of 3aa were further determined by X-ray tional groups, the N-vinyl substituent was varied to determine
diffraction analysis.18 The yield of 3aa was further improved to its effect on the formation of γ-(pyridin-2-yl)lactones. The R3
82% when Cu(OAc)2 was used as a catalyst (Table 1, entry 4). and R4 groups could be present with aryl, alkyl, and cyclic
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Table 2 Substrate scope of N-vinyl nitrones 1 to prepare γ-(pyridin-2-
yl)lactones 3a,b
Table 3 Substrate scope of acyl chlorides 2 to prepare γ-(pyridin-2-yl)
lactones 3a,b
a Reaction conditions: 1a (0.2 mmol), 2 (0.4 mmol, 2.0 equiv.),
Cu(OAc)2 (20 mol%), NEt3 (2.0 equiv.), THF (3.0 mL), 0 °C to 25 °C,
24–48 h. b Isolated yield.
Its configuration was determined by its NOESY spectrum,
showing that the proton connected with the Ph group had cor-
relations with the Et group.
The chalcone-derived N-vinyl-α,β-unsaturated nitrones were
also tested under the standard conditions. As shown in
Scheme 2, when nitrones 1m and 1n were subjected to the
standard conditions, γ-ketolactones 4ma and 4na were
obtained in 91% and 90% yields, respectively (Scheme 2-1).
Similarly, N-phenyl-α,β-unsaturated nitrone 1o and N-methyl-
α,β-unsaturated nitrone 1p were subjected to the optimal con-
ditions both affording γ-ketolactone 4oa in 95% and 90%
yields, respectively (Scheme 2-2). γ-Ketolactones are one impor-
tant class of heterocycles and extensively exist in biologically
a Reaction conditions: 1 (0.2 mmol), 2a (0.4 mmol, 2.0 equiv.),
Cu(OAc)2 (20 mol%), NEt3 (2.0 equiv.), THF (3.0 mL), 0 °C to 25 °C,
24–48 h. b Isolated yield.
groups (3ia–3la). Nitrones 1j and 1k with six- and seven-mem-
bered rings provided products 3ja and 3ka in 90% and 71%
yields, respectively. We were pleased to observe that nitrone 1l
with an acetal group on the six-membered ring was compatible
with the reaction conditions, since this substituent further
enhanced the potential synthetic utility of these compounds
by simple deprotection.
Next, various acyl chlorides 2 were evaluated. As shown in
Table 3, acyl chlorides with electron-donating and electron-
withdrawing groups at the ortho, meta, and para positions
afforded the desired γ-(pyridin-2-yl)lactones 3ab–3ak in good
to excellent yields. The R5 and R6 substituents of acyl chlorides
tolerated aryl or heteroaryl groups, and alkyl groups. The steric
hindrance of substituents in acyl chlorides had little effect on
the yield of γ-(pyridin-2-yl)lactones (3ai vs. 3aj). We are pleased
to find that when the R5 and R6 groups of acyl chloride 2k
were Ph and Et groups, desired product 3ak with a quaternary
carbon center was obtained in 49% yield as a single isomer. Scheme 2 Testing various chalcone-derived N-substituted nitrones.
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active natural products, such as phentatic acid B, cytospora-
none A, and A. strictum lactone.19 This method provides a good
approach to prepare γ-ketolactones in excellent yields or
related analogs by further reduction of γ-ketolactones from
chalcone-derived N-substituted-α,β-unsaturated nitrones with
ketenes. These results suggested that γ-ketolactone 4 was
formed by hydrolysis of the imine intermediate because these
substrates did not undergo 6π electron cyclization to form a
pyridine ring. The results of nitrones 1o and 1p also indicated
that the self O-transfer reaction and [3 + 2] cycloaddition
can be inhibited by using ketenes and N-substituted-
α,β-unsaturated nitrones under a copper catalyst because the
epoxyketimines reported by the Anderson group10 were not
observed under these similar conditions.
We are also interested in the electronic effect on the regio-
selectivity of cycloaddition for unsymmetrical nitrones
(Scheme 3). When a 1 : 1 E/Z mixture of nitrone 1q with a
methoxy on the styrenyl group was subjected to the standard
conditions, product 3qa was obtained in 43% yield with a
1.5 : 1 ratio (Scheme 3-1). However, a 1 : 1 E/Z mixture of
nitrone 1r with CF3 on the styrenyl group delivered product 3ra
in 75% yield with only one isomer (Scheme 3-2). The structure
of 3ra was determined by its 2D NMR spectra. These results
suggested that the styrenyl groups of nitrones with an electron-
withdrawing group facilitated [5 + 2] cycloaddition and both
Scheme 4 Mechanistic studies.
the E/Z isomers were converted to a desired product because allenoate 6a in 90% yield (Scheme 4-3). We prepared ketene-
there are existing balance and conversion between E and Z THF solution under NEt3 conditions by removing the pro-
isomers of nitrones under 20 mol% copper catalyst and duced HNEt3Cl solid (Scheme 4-4). Then, the prepared ketene-
1.0 equiv. of NEt3 at room temperature.20
THF solution was transferred to the mixture of nitrone 1a and
To better understand the formation of γ-(pyridin-2-yl) Cu(OAc)2 without adding NEt3. 3aa with a yield of 69% was
lactones 3, control experiments were performed. When epoxy- obtained as only one isomer (Scheme 4-5). But no reaction
pyridine 5a prepared by the self O-transfer reaction16a was sub- occurred without adding Cu(OAc)2 and only nitrone 1a was
jected to the standard conditions, 3aa was not observed, recovered (Scheme 4-6). These results indicated that ketenes
suggesting that epoxypyridine 5a was not an intermediate for were the real reactant under the standard conditions and the
the formation of 3aa (Scheme 4-1). Addition of TEMPO to copper catalyst played important roles in the simple addition
the standard conditions still afforded 3aa in 62% yield and cycloaddition.
(Scheme 4-2).21 Treatment of 2a with NEt3 in THF at 0 °C for
30 min, and then quenching with phosphorus ylide delivered a plausible mechanism for the cycloaddition of nitrone 1
with acyl chloride into γ-(pyridin-2-yl)lactones and
Based on the experimental results and previous literature,10
2
3
γ-ketolactones 4 is illustrated in Scheme 5-1. An initial addition
of nitrone 1 to ketenes generated from acyl chlorides 2 under
base conditions formed intermediate A. Coordination of the
copper catalyst to the double bond of A gives intermediate B,
which undergoes intramolecular addition of the generated
E-enolate to the styrenyl groups to furnish intermediate C.22,23
Then, C undergoes N–O bond cleavage to give intermediate D.
When the R1 group was a styrenyl group, D would undergo 6π
electron cyclization to afford intermediate E.24 Finally, aerobic
oxidation of E afforded aromatic γ-(pyridin-2-yl)lactone 3.25
Alternatively, when the R1 group was an aryl, hydrolysis of D
would provide γ-ketolactone 4 due to the inhibition of 6π elec-
tron cyclization. As shown in Scheme 5-2, we assume that the
high dr was obtained because of minimization of steric inter-
actions as the attack of the generated E-enolate occurs via a
twist chair transition state of a seven-membered ring (TS1) from
B, which favors having R5 and the proton at C4 on the same
Scheme 3 Study of regioselectivity of [5 + 2] cycloaddition.
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α,β-unsaturated nitrones with ketenes. This reaction tolerates a
broad range of N-vinyl-α,β-unsaturated nitrones and acyl chlor-
ides, to furnish useful and densely functionalized γ-(pyridin-2-
yl)lactone structures. In addition, the reaction could also
furnish γ-ketolactones in excellent yields and a privileged
1,4-diol motif through simple reduction of γ-(pyridin-2-yl)
lactones. Direct and easy access to the densely functionalized
γ-lactones will enable their use in biological activity studies.
More importantly, we have devised a general and practical plat-
form for the new application of the O-transfer reaction for
N-substituted-α,β-unsaturated nitrones with ketenes and will
provide a further design for other dipolarophiles in a new reac-
tion mode.
Conflicts of interest
There are no conflicts of interest to declare.
Scheme 5 Proposed mechanism.
Acknowledgements
Financial support from the National Natural Science
Foundation of China (21562005 and 21602037), the Natural
Science Foundation of Guangxi (2016GXNSFFA380005), the
State Key Laboratory for Chemistry and Molecular Engineering
of Medicinal Resources (CMEMR2017-A01), the Ministry of
Education (IRT_16R15), the Student Innovation Training
Program (201810602057), the “Overseas 100 Talents Program”
of Guangxi Higher Education, and the “One Thousand Young
and Middle-Aged College and University Backbone Teachers
Cultivation Program” of Guangxi is greatly appreciated.
Scheme 6 The applications of compound 3aa.
Notes and references
face, rather than R5 and R2, to afford C. Then, the carbanion
connected with copper of C attacks oxygen of the N–O bond
from the upside to provide D with high diastereoselectivity. The
copper(II) catalyst likely acts as a Lewis acid to promote cycliza-
tion of the generated E-enolate and the N–O bond cleavage.14c
To demonstrate the advantages of the current approach
for preparing γ-(pyridin-2-yl)lactones, a gram scale preparation
of γ-(pyridin-2-yl)lactone 3aa was performed. When 1.2 g of
nitrone 1a was reacted with 2a under the standard
conditions, 1.2 g of compound 3aa was obtained in 72% yield
(Scheme 6-1). Oxidation of 3aa with m-CPBA afforded
γ-(pyridin-2-yl)lactone N-oxide 7 in quantitative yield and
reduction of 3aa with LiAlH4 afforded linear 1,4-diol 8 in
57% yield with maintenance of stereochemical integrity
(Scheme 6-2), which provides an approach to access linear 1,4-
diol with three chiral carbon centers.
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achieve copper-catalyzed [5 + 2] cycloaddition of N-vinyl-
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20 We studied the isomerization of N-vinyl chalcone nitrone 23 A mechanism of [3 + 2] cycloaddition and sequential [3,3]-
1m. It showed that the E and Z isomers of 1m could be con-
verted to each other under 20 mol% of Cu(OAc)2 and 1.0
equiv. of NEt3 in THF. Please see more detailed studies of
E/Z isomer transformations of N-vinyl nitrone 1m in ESI.†
21 We also tested the influence of the formation of 3aa by
other radical trapping reagents under the standard con-
ditions. The yields of 3aa are listed as: n-Bu3SnH (70%),
benzoquinone (79%) and DPPH (65%).
22 Selected examples of copper-promoted addition of eno-
lates, see: (a) P. A. Evans and M. J. Lawler, J. Am. Chem.
Soc., 2004, 126, 8642; (b) X. Wei, S. Shi, X. Xie, Y. Shimizu
and M. Kanai, ACS Catal., 2016, 6, 6718.
rearrangement to form intermediate D under copper was
also possible, see more details of another proposed mecha-
nism in the ESI.†
24 Selected examples of 6π electron cyclization to form a pyri-
dine ring, see: (a) S. Liu and L. S. Liebeskind, J. Am. Chem.
Soc., 2008, 130, 6918; (b) I. Nakamura, D. Zhang and
M. Terada, J. Am. Chem. Soc., 2010, 132, 7884.
25 Examples of oxidation to aromatization by air, see:
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Org. Biomol. Chem., 2016, 14, 7455; (b) C. Wang,
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This journal is © The Royal Society of Chemistry 2019
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