A copper-catalyzed three component reaction of aryl acetylene, sulfonyl azide and enaminone to form iminolactone via 6π electrocyclization

Article abstract of DOI:10.1039/c8cc06868b

We developed a copper-catalyzed three component reaction of aryl acetylene, enaminone and sulfonyl azide to construct iminolactone via a cascade process involving copper-catalyzed alkyne-azide cycloaddition (CuAAC), Michael addition of metalated ketenimin

Full text of DOI:10.1039/c8cc06868b

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A copper-catalyzed three component reaction of
aryl acetylene, sulfonyl azide and enaminone to
form iminolactone via 6p electrocyclization†
Cite this: Chem. Commun., 2018,
4, 13953
5
Received 23rd August 2018,
Accepted 19th November 2018
a
a
a
a
Jiarui Sun, Xiangsheng Cheng, John Kamanda Mansaray,
Weihong Fei,
b
a
Jieping Wan * and Weijun Yao
*
DOI: 10.1039/c8cc06868b
rsc.li/chemcomm
We developed a copper-catalyzed three component reaction of aryl and in situ generated metalated ynamide intermediates, a tautomer
1
0
11
acetylene, enaminone and sulfonyl azide to construct iminolactone of metalated ketenimine. In 2014, Zhang and co-workers
via a cascade process involving copper-catalyzed alkyne–azide disclosed an electrophilic addition of an immonium ion to
cycloaddition (CuAAC), Michael addition of metalated ketenimine copper ketenimine to deliver a,b-unsaturated amidine deriva-
followed by elimination and 6p electrocyclization.
tives. In this context, exploring new reactions of nucleophilic
ketenimine in situ generated from sulfonyl azides and terminal
1
Cascade multicomponent reactions (MCRs) have grown into a alkynes (Scheme 1) is still in demand and remains challenging.
12
powerful synthetic tool for the construction of complex mole-
Enaminone is a type of synthetically useful synthon and has
cular scaffolds through the formation of multiple carbon– been widely applied in a huge number of reactions towards fine
carbon and carbon–heteroatom bonds in one pot. Since the molecule synthesis. Herein, we document a novel copper-catalyzed
2
pioneering work of Chang, who discovered the first copper three component reaction of aryl acetylene, sulfonyl azide and
13
catalyzed three-component reaction involving in situ generated enaminone to form iminolactone via a cascade process involving
ketenimine, copper-catalyzed MCRs involving sulfonyl azides copper-catalyzed alkyne–azide cycloaddition (CuAAC), Michael
and terminal alkynes have attracted great attention from addition/elimination and 6p electrocyclization.
synthetic chemists. Generally, these MCRs are triggered by a
copper-catalyzed azide–alkyne cycloaddition (CuAAC) reaction (2a) and p-toluenesulfonyl azide (3a) as model substrates to
to form 1,2,3-triazoles A followed by the ring opening rearran- explore the feasibility of the reaction catalyzed by copper(I)
Initially, we chose p-tolyl enaminone (1a), phenylacetylene
3
gement to release a N , simultaneously, to generate metalated iodide (10 mol%) in the presence of triethylamine in dichloro-
2
ketenimine intermediate B. After protonation, ketenimine C is methane at room temperature under a nitrogen atmosphere. To
trapped by various nucleophiles to deliver diverse molecules. our delight, iminolactone 4a could be isolated in 52% yield
Due to its high reactivity and ready preparation in situ, the (Table 1, entry 1). Attempts to improve the yield by carrying out
4
electrophilic ketenimine C has been widely explored through solvent screening revealed that weak polarity solvents such as
5
6
nucleophilic addition, cascade reactions and cycloaddition dichloromethane, 1,2-dichloroethane, chloroform and toluene
7
reactions. However, compared with considerable progress of led to a moderate yield (Table 1, entries 1–4), while strong polar
electrophilic ketenimine C, there were few examples of the solvents (tetrahydrofuran, ethyl acetate and acetonitrile) restrained
8
transformation of the nucleophilic metalated ketenimine B. The
nucleophilic ketenimine with carbonyl compounds undergoing
[
2+2] cyclization and the subsequent ring opening was reported by
9
Ma’s group, and also they described an inverse electron-demand
hetero-Diels–Alder reaction of N-sulfonyl-1-aza-1,3-butadiene
a
Department of Chemistry, Zhejiang Sci-Tech University, Hangzhou, 310018,
P. R. China. E-mail: Orgywj@zstu.edu.cn
b
College of Chemistry and Chemical Engineering, Jiangxi Normal University,
Nanchang 330022, P. R. China. E-mail: wanjieping@jxnu.edu.cn
†
Electronic supplementary information (ESI) available: Experimental proce-
dures, analytical data and NMR spectra. CCDC 1859641 (4b). For ESI and
crystallographic data in CIF or other electronic format see DOI: 10.1039/
c8cc06868b
Scheme 1 Transformation of ketenimine from terminal alkyne and
sulfonyl azide.
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a
Table 1 Optimization of the three-component reaction
b
Entry Catalyst
Ligand
Base
Solvent Yield (%)
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuCl
CuBr
CuCN
—
—
—
—
—
—
—
TEA
TEA
TEA
TEA
TEA
TEA
TEA
CH
(CH
CH
Toluene 44
THF
EtOAc
3
CH CN Trace
2
Cl
Cl)
Cl
2
52
57
36
2
2
3
Trace
Trace
1,10-Phenanthroline TEA
(CH
(CH
(CH
(CH
(CH
(CH
(CH
(CH
(CH
(CH
(CH
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
Cl)
2
Cl)
2
Cl)
2
Cl)
2
Cl)
2
Cl)
2
Cl)
2
Cl)
2
Cl)
2
Cl)
2
Cl)
2
Cl)
2
Cl)
2
Cl)
2
Cl)
2
48
Proline
TEMED
Dppe
PPh
PPh
PPh
PPh
PPh
PPh
S PPh
PPh
PPh
TEA
TEA
TEA
TEA
TEA
TEA
TEA
TEA
TEA
TEA
Trace
Trace
46
71
38
0
1
2
3
4
5
6
7
8
9
0
1
2
3
3
3
3
3
3
3
3
3
3
3
47
Trace
Trace
Trace
20
Trace
27
Cu
2
O
a,b a
Scheme 2 Substrate scope of enaminone 1.
1 (0.4 mmol), 2a (1 mmol), TsN
(0.08 mmol) and CuI (0.04 mmol) in (CH Cl)2 (2 mL). Isolated yield.
Conditions: enaminone
CuBr
2
CuBrꢀMe
2
3 3
3a (1 mmol), TEA (0.2 mmol), PPh
b
CuI
DABCO (CH
DBU (CH
DIPEA (CH
Cs CO (CH
2
CuI
CuI
CuI
PPh
PPh
58
62
2
3
Encouraged by these results, we turn our attention to exocyclic
enaminones. 1-Indanone and a-tetralone derived 1m and 1n
a
Conditions: enaminone 1a (0.2 mmol), phenylacetylene 2a (0.5 mmol),
p-toluenesulfonyl azide TsN
3
3a (0.5 mmol), base (0.1 mmol), solvent could also be employed in the copper catalyzed tandem reaction
(
2 mL), ligand (0.02 mmol, if optional) under a nitrogen atmosphere.
Isolated yield. dppe = 1,2-bis(diphenylphosphino)ethane; TEA = triethyl
to provide moderate to good yields of the corresponding products
Scheme 3, eqn (a)). Meanwhile, 1o from cyclopentanone partici-
b
(
amine; DABCO = 1,4-diazabicyclo[2.2.2]octane; DBU = 1,8-diazabicyclo-
0 0
[
5.4.0]undec-7-ene; DIPEA = diisopropylethylamine. TEMED = N,N,N ,N - pated well in this three component reaction despite the yield of 5d
tetramethylethylenediamine.
decreasing to 46% (Scheme 3, eqn (b)).
Next, a variety of aryl acetylenes was investigated to extend
the reaction (Table 1, entries 5–7). Common ligands (Table 1, substrate diversity. As shown in Scheme 4, due to the steric
entries 8–12) were also investigated and triphenylphosphine hindrance, o-methyl phenylacetylene led to a lower yield of 4o,
was the best choice to increase the yield to 71% (Table 1, entry 12). while m-methyl phenylacetylene and p-methyl phenylacetylene
The screening of copper catalysts (Table 1, entries 12–18) shows afforded the corresponding products 4n and 4m in 54% and
that CuI performed the best and CuBr, CuCl and CuBrꢀMe S show 52% yield, respectively. Other substituted phenylacetylenes,
2
2 2
poor catalysis, while CuCN, Cu O and CuBr almost didn’t work 2-ethynylnaphthalene and 3-ethynylthiophene, were also tolerated
at all. We examined several bases simply and found that triethyl- in this reaction to achieve the product in moderate yield. However,
amine was better than the others.
1-ethynyl-1-cyclohexene only resulted in a trace product and
With the optimal conditions in hand, we applied this three- 1-hexyne didn’t work at all. Furthermore, 4-fluorobenzenesulfonyl
component cascade reaction to other enaminone substrates. As azide 3b, methanesulfonyl azide 3c and 2-nitrobenzenesulfonyl
shown in Scheme 2, the substituents on the benzene ring impart azide 3d were chosen to extend the scope of this three
some effects on the reaction. The substrate with a donating group
could achieve good yield from 64% to 79% (4a–4d). A halogen
substituted (F, Cl, and Br) substrate only gave the products in
moderate yield from 43% to 52% (4e, 4f and 4g). The substrate with
a nitro group only afforded a trace product which is not shown here.
2
-Naphthyl substituted enaminone 1h and 4-biphenyl substituted 1i
could also be tolerated in this process to deliver the desired products
h and 4i in 51% and 57% yield, respectively. Additionally, hetero-
4
aromatic 2j with a 2-thiophenyl group works well to give the target
product 4j in 60% yield. Moreover, the styryl enaminone 2k pro-
ceeded smoothly to form product 4k in 61% yield; while alkynyl
substituted 2l was suitable in this reaction despite the yield dropping
to 41%. What’s more, the structure of 4b was further confirmed by
14
X-ray crystal structure analysis.
Scheme 3 Reactions of exocyclic enaminones.
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Scheme 7 Transformation of iminolactones 4a and 5b.
Scheme 4 Substrate scope of aryl acetylene.
Scheme 8 Control experiments.
Scheme 5 Simple screening of sulfonyl azide.
Scheme 9 Proposed mechanism.
Scheme 6 Gram scale synthesis of iminolactones 4b and 5b.
ketenimine I was coordinated with enaminone 1b to give transition
1
8
state II, followed by oxidation addition and elimination to
generate ketenimine IV that subsequently underwent 6p
electrocyclization to furnish iminolactone 4.
In conclusion, we have developed a novel copper catalyzed three
component cascade reaction, in which the metalated ketenimine
in situ generated from copper-catalyzed alkyne–azide cycloaddition
component reaction, and the target products were obtained
successfully in moderate yield (Scheme 5). Notably, this copper
catalyzed cascade reaction could be commenced in a gram scale
for 4b and 5b with the yield maintained (Scheme 6).
In addition, the protection group Ts of 4a could be removed
in hydrobromic acid solution in acetic acid (33%) to get imine
hydrobromide 6 in 65% yield, the analog of iminocoumarin,
19
(CuAAC) attacked enaminone followed by 6p electrocyclization to
construct iminolactone efficiently. A wide variety of aryl acetylenes
and aryl enaminones could be employed to react with sulphonyl
azide to deliver the desired products under mild reaction condi-
tions. Notably, the exocyclic enaminones were also suitable in this
methodology to furnish the analog of iminocoumarin. Moreover,
p-toluenesulfonyl azide could be easily removed under mild
conditions to yield imine hydrobromide.
We are grateful to the National Natural Science Foundation
of China (Grant No. 21702185) and the Science Foundation of
Zhejiang Sci-Tech University (Grant No. 16062189-Y).
1
5
which is used as an antitumor agent,
a luminescence
1
6
17
indicator and dye. The imine hydrobromide 6 was not stable
on a silica gel or alumina during flash column chromatography
and it was transformed to ketone 7. Meanwhile, iminolactone 5b
could be oxidized by 2,3-dicyano-5,6-dichlorobenzoquinone
(DDQ) in acetonitrile at room temperature to afford 8, which
could be hydrolysed to coumarin 9 (Scheme 7).
To understand this reaction better, control experiments were
carried out (Scheme 8). Chalcone 10 didn’t take part in this process
at all, neither did 3-chloroenone 11 even if it contains a leaving
group. A plausible mechanism for the present copper catalyzed
three-component cascade reaction is shown in Scheme 9. Firstly, in
the presence of base, copper-catalyzed alkyne–azide cycloaddition
Conflicts of interest
(CuAAC) took place to form metalated ketenimine I. The cooper in There are no conflicts to declare.
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