Cu-catalyzed intermolecular oxyalkylation of styrenes under air: Access to diverse iminolactones

Article abstract of DOI:10.1039/c7ra07306b

A practical, simple, and efficient copper-catalyzed highly regioselective oxyalkylation of styrenes and readily available α-bromoacetamides under air is realized. This reaction exhibits a wide range of functional group tolerance in styrenes and α-bromoacetamides to afford iminolactones.

Full text of DOI:10.1039/c7ra07306b

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Cu-catalyzed intermolecular oxyalkylation of
styrenes under air: access to diverse iminolactones†
Cite this: RSC Adv., 2017, 7, 41723
*
Yunhe Lv,
Weiya Pu, Shukuan Mao, Xiaoran Ren, Yingtao Wu and Hao Cui
Received 2nd July 2017
Accepted 21st August 2017
A practical, simple, and efficient copper-catalyzed highly regioselective oxyalkylation of styrenes and readily
available a-bromoacetamides under air is realized. This reaction exhibits a wide range of functional group
tolerance in styrenes and a-bromoacetamides to afford iminolactones.
DOI: 10.1039/c7ra07306b
rsc.li/rsc-advances
Difunctionalization of alkenes is a powerful tool for the highly regioselective oxyalkylation of styrenes and readily
synthesis of heterocycles through tandem two same or available a-bromoacetamides under air.
different C–X (X ¼ C, N, O, etc.) bond formations in organic
We started our investigation by applying styrene 1a and 2-
synthesis. Although metal-free as well as transition-metal- bromo-2-methyl-N-phenylpropanamide 2a in a model reaction
catalyzed aminocarbonylation, aminoarylation, amino- to optimize the reaction conditions. To our delight, in the
vinylation, aminoalkynylation, and aminooxygenation reac- preliminary experiment of using 10 mol% of CuI as catalyst, the
tions of alkenes have been signicant developments in recent desired oxyalkylation proceeded to give the desired product 3a
decades,1 the selective oxyalkylation reactions of alkenes for in 45% yield in the presence of 1,10-phenanthroline (Phen) and
ꢀ
their efficiency in synthesizing different types of oxygen- K2CO3 at 100 C in CH3CN (Table 1, entry 1). Product 3a was
containing heterocycles remains challenging.2 N-Substituted obtained in 83% yield when acetone was employed as the
iminolactones, which can be easily converted to g-lactones, solvent (Table 1, entry 2). In contrast, other solvents such as
are prevalently used as antibacterial agents, aldosterone CH2Cl2, DMF, and EtOAc did not perform well (Table 1, entries
inhibitors, and proper precursors for the preparation of a wide 3–5). Further investigation on different copper salts revealed
spectrum of natural compounds.3 However, the selective oxy- that CuBr, CuCl and Cu(OTf)2 were also efficient catalyst for this
alkylation of alkenes for the synthesis of N-substituted imi- transformation, affording product 3a in a satisfying 80%, 79%
nolactones are still rare. In this context, Lei and coworkers and 81% yield, respectively (Table 1, entries 6–8). Other ligand
developed Ni-catalyzed cyclization of a-haloamides with such as PPh3 and 2,20-bipyridine (bipy) were less effective than
alkenes through carbon-centered radical addition to the Phen (Table 1, entries 9 and 10). Other bases such as NaOAc and
carbonyl oxygen of amides or esters (Scheme 1a).4 Recently, Et3N gave the desired product in lower yield (Table 1, entries 11
Nishikata and coworkers reported copper-catalyzed oxy- and 12). Control experiments demonstrated that CuI, Phen and
alkylation of alkenes to afford iminolactone by controlling the K2CO3 were all important (entries 13–15). In addition, trace
reactivity of the oxygen nucleophile of the amide group
(Scheme 1b).5 However, these methods require long reaction
time, anhydrous solvent, inert atmosphere protection and
sometimes even special apparatuses such as the glovebox to
manipulate the reactions. Therefore, a practical and simple
methodology towards effective intermolecular oxyalkylation of
alkenes is highly desirable. Recently, we developed selectuor-
mediated highly selective radical dioxygenation of alkenes and
metal-free catalyzed C–O bond formation reactions directly
from C–H bonds.6 As part of our ongoing study on difunc-
tionalization of alkenes6a,d and C–O bond formation reactions,
we present herein our recent progress in copper-catalyzed
College of Chemistry and Chemical Engineering, Anyang Normal University, Anyang,
455000, P. R. China. E-mail: luyh086@nenu.edu.cn; lvyunhe0217@163.com
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c7ra07306b
Scheme 1 Oxyalkylation of alkenes with a-bromoacetamides.
RSC Adv., 2017, 7, 41723–41726 | 41723
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Table 1 Optimization of the reaction conditionsa
Table 2 Reactions of alkenes 1 with 2aa,b
Entry
Metal
Ligand
Additive
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
CuI
CuI
CuI
CuI
Phen
Phen
Phen
Ph3P
Phen
Phen
Phen
Phen
PPh3
bipy
Phen
Phen
Phen
None
Phen
Phen
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
NaOAc
Et3N
CH3CN
Acetone
CH2Cl2
DMF
45
83
Trace
18
Trace
80
79
81
37
41
45
40
Trace
Trace
0
CuI
EtOAc
CuBr
CuCl
Cu(OTf)2
CuI
CuI
CuI
CuI
None
CuI
CuI
CuI
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
Acetone
9
10
11
12
13
14
15
16c
K2CO3
K2CO3
None
K2CO3
Trace
a
Reactions were carried out with 1a (0.45 mmol), 2a (0.3 mmol), metal
(10 mol%), ligand (10 mol%) and additive (2.0 equiv.) in 3 mL solvent
under air atmosphere at 100 ꢀC for 1.5 h, unless noted otherwise.
b
c
Yield of the isolated product. The reaction was performed at 70 ꢀC.
Phen ¼ 1,10-phenanthroline, Tf ¼ triuoromethanesulfonyl, bipy ¼
2,20-bipyridine.
amouꢀnts of 3a was obtained when the reaction was performed
at 70 C (Table 1, entry 16).
The scope of the oxyalkylation of styrenes was then investi-
gated under the optimized reaction conditions (Table 1, entry
5). As described in Table 2, a broad range of styrene derivatives
were investigated. Generally, styrene substrates bearing
electron-donating substituents provided higher yields than
those containing electron-withdrawing substituents on the
aromatic ring (3b–3h). Halo-substituted styrene derivatives (1b–
1d, 1i–1m) were tolerated in the oxyalkylation reaction of
styrenes, allowing for further functionalization through a cross-
coupling manifold. Starting from disubstituted styrene 1,4-
dimethyl-2-vinylbenzene, 3n was obtained in 71% yield. In
addition, the cyclic alkene substrates such as indene also
provided the desired oxyalkylation product 3o in 70% yield.
Notably, 1,1-disubstituted styrenes such as 1p–1r were also
effective to provide 3q–3s in 80–86% yields. In addition, starting
from methyl acrylate (1s), the corresponding product 3s could
be obtained in 78% yields. Remarkably, in all cases, the reac-
tions proceeded smoothly under air, and the desired imino-
lactones (3a–3r) were consistently obtained in 60–93% yields
with high regioselectivity.
a
Reactions were carried out with 1 (0.45 mmol), 2a (0.3 mmol), CuI
(10 mol%), Phen (10 mol%) and K2CO3 (2.0 equiv.) in acetone (3 mL)
under air atmosphere at 100 ꢀC for 1.5 h. b Yield of the isolated product.
methoxy, proceeded well with moderate to good yields. This
reaction trend is also consistent with the electronic effect
of styrenes. In addition, the steric hindrance on the aryl
ring also inuence the reaction. Slightly decreased
yields were achieved for ortho-substituted a-bromoaceta-
mides (2k–2n).
Furthermore, a sequential one-pot two-step tandem reaction
for efficient synthesis of g-lactones was investigated (Table 4).
For example, the g-lactone 5a was obtained in 78% yield when
the reaction system of 1a with 2a was quenched in situ by HCl
(2 M aqueous solution). Starting from 1c and 1f, the corre-
sponding compounds 5b and 5c could be obtained in 75% and
80% yields, respectively. In addition, 1,1-disubstituted styrenes
such as prop-1-en-2-ylbenzene 1p was also effective to provide
5d in 76% yield. The present method was applied to citronellol
derivatives 3,7-dimethyloct-6-en-1-yl acrylate 6, and the corre-
sponding product 7 was obtained in 56% yield [eqn (1)].
This oxyalkylation of styrenes was further expanded to
a range of a-bromoacetamides, and the results are shown in
Table 3. The results indicate that reactions of a-bromoace-
tamides with different substituents on the aromatic ring,
such as F, Cl, Br, nitryl, methyl, ethyl, tert-butyl, and
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a,b
Table 3 Reactions of styrene 1a with a-bromoacetamides 2
Scheme 2 Proposed mechanism.
(3)
a
Reactions were carried out with 1a (0.45 mmol), 2 (0.3 mmol), CuI
(10 mol%), Phen (10 mol%) and K2CO3 (2.0 equiv.) in acetone (3 mL)
under air atmosphere at 100 ꢀC for 1.5 h. b Yield of the isolated product.
Some mechanistic experiments have been investigated to
probe the mechanism of this transformation. When the radical
scavenger such as 2,2,6,6-tetramethylpiperidine N-oxide
(TEMPO, 2.0 equiv.) and 2,6-di-tert-butyl-4-methylphenol (BHT,
2.0 equiv.) were added to the oxyalkylation reaction of 1a under
the optimal conditions, no desired products were isolated [eqn
(2)]. These results indicate that a radical pathway may be
involved under the catalytic system. Further evidence for
a radical mechanism was demonstrated by the radical clock
experiment with (1-cyclopropylvinyl)benzene as the substrate.
The reaction of (1-cyclopropylvinyl)benzene with 2h under the
standard reaction conditions produced the ring-expanded
products 8 in 31% yield [eqn (3)].7
Table 4 Direct synthesis of g-lactones from styrenes 1 and 2a a,b
On the basis of the present experimental results, a possible
mechanism was proposed in Scheme 2. The CuI catalyst reacts
with 2a to generate a tertiary-alkyl radical species A 8 and a CuII
species.9 Then, addition of A to styrene takes place to give benzyl
radical B.9a,b,10 The intramolecular addition of benzyl radical to
a carbonyl group of amide produces C,11 which then undergoes
radical oxidation and deprotonation to give the oxyalkylation
product 3a and regenerate CuI in the presence of CuII and
K2CO3. According to the hard and so acid and base theory
(HSAB), highly selective C–O bond formation may be due to an
easier amide oxygen attack under weakly basic conditions in
so acid solvents acetone.12
a
Reactions conditions: (1) 1 (0.45 mmol), 2a (0.3 mmol), CuI (10 mol%),
Phen (10 mol%), K2CO3 (2.0 equiv.) and acetone (3 mL), air, 100 ꢀC,
b
1.5 h; (2) HCl (2 M), air, 60 ꢀC, 5 h. Yield of the isolated product.
(1)
Conclusions
In conclusion, a novel copper-catalyzed intermolecular oxy-
alkylation of styrenes and readily available a-bromoacetamides
has been reported. This work provided an efficient route to
synthesize iminolactones, which can be conveniently converted
into g-lactones. Moreover, this reaction features high regiose-
lectivity, excellent functional-group tolerance, no extra oxidant,
(2)
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