Base-promoted domino radical cyclization of 1,6-enynes

Article abstract of DOI:10.1039/c9ob01550g

A good regioselective, high atom-economical and transition-metal-free method for the synthesis of α-functionalized ether derivatives via the domino radical cyclization of 1,6-enynes is described. A series of α-functionalized ether derivatives could be eas

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COMMUNICATION
Base-Promoted Domino Radical Cyclization of 1,6-Enynes
Le-Han Gao,a Jun-Yao Zhang,a Si-Zhe Song,a Ting-Ting Cao,a Guo-Ping Ge,a Qiang Li,b and Wen-Ting
Wei*a
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
A good regioselective, high atom-economical and transition-
metal-free method for the synthesis of α-functionalized ether
derivatives via domino radical cyclization of 1,6-enynes is
described. A series of α-functionalized ether derivatives could
10 be easily obtained in good yields with wide functional groups
tolerance by using low-toxicity and inexpensive Cs2CO3 as a
base. The control experiments results show that the reaction
involves
a radical process. This strategy provides a
regioselective way toward the formation of dual C−C bonds in
15 one step.
Introduction
α-Functionalized ether derivatives are prevalent in many
pharmaceuticals, natural products and agrochemicals.1 Selected
examples are shown in Figure 1 and they show diverse biological
20 activities. Therefore, the direct radical α-C–H functionalization of
abundant readily available ethers leads to the synthesis of the
aforementioned core unit has been highly anticipated.2 In recent
years, considerable research efforts have been paid to the reaction
between ethers with ketones,3 carboxylic acids,4 amines,5 aromatic
25 hydrocarbons,6 heteroarenes,7 alkenes,8 alkynes9 and enynes,10 etc.
under this trend. Among these, particular attention focused on
domino radical cyclization of enynes is driven by its concise and
efficient nature. In 2015, Li group achieved an unprecedented
radical [2+2+1] carbocyclization of enynes with ethers in the
30 presence of tert-butyl peroxybenzoate (TBPB) at 110 oC (Scheme
1a).10a Subsequently, Hao, Jiang and co-workers reported an Ag-
50 Figure 1. Selected Biologically Active Ether Derivatives.
Although two examples have been developed in the field of
domino ether radical cyclization of enynes.10 However, transition-
metal catalyst (AgNO3) or high reaction temperature (110 C) is
o
still necessary in the above reaction processes. Hence,
55 establishing
a mild and simple route for the α-C–H
functionalization of ethers will be imperative from the
viewpoint of environmental protection. Herein we disclose a
base-promoted domino radical cyclization of 1,6-enynes
without the use of transition-metal catalyst at mild reaction
60 temperature to meet the demands of green chemistry (Scheme
catalyzed
bicyclization
of
1,7-enynes
with
acid
2,3-
dihydrobenzo[b][1,4]
dioxine-2-carboxylic
via
decarboxylative functionalization using K2S2O8 as an oxidant
35 (Scheme 1b).10b In light of our ongoing interest in regioselective
chemistry,11 we specifically focus on the site-selective cyclization
of enynes. Thus, method development by regioselectively
introducing the ether radical into enynes will be highly desirable.
1c). Most importantly, this study demonstrates
regioselectivity cyclization manner and uses inexpensive
Cs2CO312 as the base.
a high
Results and discussion
65 We initiated our study by choosing N-phenyl-N-(prop-2-yn-1-
yl)methacrylamide 1a as a model substrate for this domino radical
cyclization with tetrahydrofuran 2a. The reaction was firstly
carried out in the presence of 4.0 equiv TBPB and 1.2 equiv
Cs2CO3 at 85 C. To our delight, the reaction proceeded well,
70 leading to the formation of desired product 3aa in 78% yield (Table
40 a School of Materials Science and Chemical Engineering, Ningbo
University, Ningbo 315211, China. Fax: +86(0574)87600784; E-mail:
weiwenting@nbu.edu.cn.
b Institution of Functional Organic Molecules and Materials, School of
Chemistry and Chemical Engineering, Liaocheng University, Liaocheng,
45 252059, China.
o
† Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See DOI:
10.1039/b000000x/
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the role of base is unclear, it might speed up the formation
of α-oxo radical. Increasing the amount of Cs2CO3 to 2.0 equiv
remained effective, but had no further improvement on the yield
25 (Table 1, entry 15). A brief screening of the reaction temperatures
showed that lowering (60 oC) or raising (100 oC) the temperature
both had a negative effect (Table 1, entries 16-17).
With the optimal reaction conditions in hand, the substrate scope
regarding the ethers was investigated (Table 2). Common cyclic
30 ethers such as tetrahydrofuran 2a, tetrahydro-2H-pyran 2b and 1,4-
dioxane 2c all reacted smoothly with 1a to afford the
corresponding products 3aa-3ac in good yields (61−78%). To our
delight, linear ethers ethoxyethane 2d and 1,2-dimethoxyethane 2e,
were tolerated by the base-promoted system, and proceeded
35 regioselectivity at the CH2 position (3ad-3ae). In addition, this
transformation was also efficient with α-C(sp3)−H bonds in
diethylsulfane 2f, giving the desired product 3af in 71% yield.
Scheme 1. Domino Ether Radical Cyclization of Enynes.
1, entry 1). Control experiments implied that both oxidant and base
were necessary for this transformation and the absence of base only
resulted in 23% yield (Table 1, entries 2–3). Then, a variety of
oxidants, including DTBP, BPO, TBHP, H2O2 and PhI(OAc)2 did
not provide higher yields (Table 1, entries 4–8). While reducing
loading of TBPB (3.0 equiv) decreased the yield of 3aa (Table 1,
entry 9), raising its loading (5.0 equiv) had no improvement of the
Table 2 Scope of Ethers.a
5
10 yield compared with the result at 4.0 equiv (Table 1, entry 10). The
domino radical cyclization also proceeds with other bases such as
Na2CO3, NaOAc, DBU and Et3N (Table 1, entries 11-14). While
Table 1 Optimization of Reaction Conditionsa
a Reaction conditions: 1a (0.2 mmol), TBPB (4.0 equiv) and Cs2CO3 (1.2
equiv) used 2 (0.5 mL) as solvent sealed in air at 85 oC for 20 h.
[O]
(4.0 equiv)
TBPB

TBPB
DTBP
BPO
Base
(1.2 equiv)
Cs2CO3
Cs2CO3

Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Na2CO3
NaOAc
DBU
Yield
(%)
78
Entry
T (oC)
40 The scope of 1,6-enynes was subsequently explored using 2a as
the reaction partner (Table 3). A series of N-aryl substituted 1,6-
enynes (1b-1j) could successfully undergo the domino radical
cyclization and gave corresponding products 3ba-3ja in 71-84%
yields. The reaction tolerated both electron-donating (-OMe, -Me
45 and t-Bu) and electron-withdrawing substituents (-F, -Cl, -Br and
-CF3) on the aryl ring. For example, N-(4-methoxyphenyl)-N-
(prop-2-yn-1-yl)methacrylamide 1b could react with 2a and
provided the desired product 3ba in 84% yield. Unfortunately, the
domino radical cyclization was not compatible with N-benzyl
50 substituted 1,6-enyne 1k, and >90% of starting material was
recovered. 1,6-Enyne 1l bearing a methyl group at the alkynyl
position afforded 3la in 63% yield. However, when N-phenyl-N-
(prop-2-yn-1-yl)acrylamide 1m was used to test this reaction, trace
amount of target product 3ma was detected. When 2-benzyl-N-
55 phenyl-N-(prop-2-yn-1-yl)acrylamide 1n and N,2-diphenyl-N-
(prop-2-yn-1-yl)acrylamide 1o were applied to the optimal
conditions, products 3na and 3oa were isolated in 60% and 67%
yields, respectively. When using 1,7-enyne 1p as reaction substrate,
the corresponding product 3pa was not detected, and a small
60 amount of 1p decomposed.
1
85
85
85
85
85
85
85
85
85
85
85
85
85
85
85
60
100
2b
3c
4
0
23
5
5
18
6
TBHP
H2O2
32
7
Trace
12
8
PhI(OAc)2
TBPB
TBPB
TBPB
TBPB
TBPB
TBPB
TBPB
TBPB
TBPB
9d
10e
11
12
13
14
15f
16g
17
51
78
71
49
72
Et3N
45
Cs2CO3
Cs2CO3
Cs2CO3
79
23
67
15 a Reaction conditions: 1a (0.2 mmol), 2a (0.5 mL), oxidant (4.0 equiv) and
base (1.2 equiv) sealed in air for 20 h. DTBP = di-tert-butyl peroxide. BPO
= benzoyl peroxide. TBHP = tert-butyl hydroperoxide. DBU = 1, 8-
diazabicyclo (5, 4, 0) undec-7-ene. The d. r. of 3aa was about 5.7:1. b 91%
of 1a was recovered. c 68% of 1a was recovered. d TBPB (0.6 mmol, 3.0
20 equiv). TBPB (1.0 mmol, 5.0 equiv). Cs2CO3 (0.4 mmol, 2.0 equiv). g
e
f
57% of 1a was recovered.
2
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Table 3 Scope of 1,6-Enynes a
to form a vinyl radical III.10, 14 Lastly, hydrogen abstraction of
radical III from solvent or water offers product 3aa.11a, 15
25
Scheme 3 Plausible Mechanism
Conclusions
In conclusion, an environmental-friendly and high regioselectivity
base-promoted domino radical cyclization has been developed for
30 the rapid synthesis of biologically important α-functionalized ether
derivatives. A series of 1,6-enynes can react with a wide range of
ethers to furnish α-functionalized ether derivatives in moderate to
good yields under transition-metal-free conditions. Plausible
radical mechanism of the method has been proposed. Further
35 applications of this novel strategy are under current study in our
laboratory.
[a] Reaction conditions: 1 (0.2 mmol), 2a (0.5 mL), TBPB (4.0 equiv) and
Cs2CO3 (1.2 equiv) sealed in air at 85 oC for 20 h. [b] At 100 oC for 36 h.
Experimental
Typical experimental procedure for the regioselective radical
cyclization:
40 To a Schlenk tube were added 1,6-enynes 1 (0.2 mmol), ethers 2
(0.5 mL), TBPB (4.0 equiv) and Cs2CO3 (1.2 equiv). Then the tube
was stirred at 85 oC sealed in air for the indicated time until
complete consumption of starting material as monitored by TLC
analysis. After the reaction was finished, the solution was
45 concentrated under reduced pressure, and the mixture was purified
by flash column chromatography over silica gel (hexane/ethyl
acetate) to afford the desired products 3.
In order to support our original description of this domino
radical cyclization, two control experiments have been
conducted as shown in Scheme 2. Firstly, the deuterated
experiment between THF 2a and THF-d8 2a-d8 (kH/kD = 1.5)
supports the cleavage of α-C(sp3)–H bonds of THF constitutes
a rate-limiting step.9d, 9f Furthermore, adding radical scavengers
2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) or butylated
5
10 hydroxytoluene
(BHT)
completely
inhibited
the
transformation, and the radical-trapping product 4a was
obtained in 73% yield (Scheme 2b), which provided evidence
of the generation of α-oxo radical in this reaction.
Acknowledgment
We thank the National Natural Science Foundation of China
50 (Grants 21801142), the Natural Science Foundation of Zhejiang
Province (No. LQ18B020002), the Ningbo Municipal Natural
Science Foundation (No. 2018A610242), and the K. C. Wong
Magna Fund in Ningbo University for financial support.
15
Scheme 2 Control Experiments
Notes and references
On the basis of these investigations above and literature
precedents,8f, 9e, 10, 11a, 13-15 a possible mechanism accounting for the
formation of 3aa is proposed in Scheme 3. First, α-oxo radical I is
generated by hydrogen abstraction of 2a in the presence of TBPB
20 and Cs2CO3 under heating. 8f, 9e, 13 Then, the radical I undergoes
intermolecular addition to the C−C double bond of 1a to produce
an alkyl radical II, which goes through further radical cyclization
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R2
R3
DOI: 10.1039/C9OB01550G
R2
n
TBPB (4.0 equiv)
R1 N
O
R3
n
+
Y
N
Cs2CO3 (1.2 equiv)
Y
R1
R4
85 oC
Y = O, S
R4
O
n = 1, 2
Transition-metal-free
High regioselectivity
C(sp3)-H functionalization
Dual C-C bonds formation