Oxidative difunctionalization of alkynoates via cascade radical addition, aryl migration, and decarboxylation

Article abstract of DOI:10.1016/j.tetlet.2015.12.092

A cascade radical oxidative difunctionalization of alkynoates with simple ethers for the construction of tri-substituted olefins is developed. The reaction undergoes cascade radical addition to C-C triple bond, 1,4-aryl migration, and decarboxylation to d

Full text of DOI:10.1016/j.tetlet.2015.12.092

Tetrahedron Letters xxx (2015) xxx–xxx
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Oxidative difunctionalization of alkynoates via cascade radical
addition, aryl migration, and decarboxylation
b
b,
Changduo Pan a,b, , Honglin Zhang , Chengjian Zhu
⇑
⇑
a School of Chemistry & Environmental Engineering, Jiangsu University of Technology, Changzhou 213001, PR China
b School of Chemistry and Chemical Engineering, State Key Laboratory of Coordination Chemistry, Nanjing University, Nanjing 210093, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A cascade radical oxidative difunctionalization of alkynoates with simple ethers for the construction of
tri-substituted olefins is developed. The reaction undergoes cascade radical addition to C–C triple bond,
1,4-aryl migration, and decarboxylation to deliver a variety of difunctionalized alkenes in moderate to
good yields. This procedure also represents a promising strategy for the direct functionalization of the
Received 6 November 2015
Revised 7 December 2015
Accepted 23 December 2015
Available online xxxx
a
-Csp3-H bonds in ether derivatives.
Ó 2015 Published by Elsevier Ltd.
Keywords:
Alkynoates
1,4-Aryl migration
Decarboxylation
Ether
Olefins
Introduction
them, the direct functionalization of Csp3-H bonds is an interesting
while challenging task for their relatively strong bond dissociation
energy (BDE) and the low polarity. Gratefully, radical reaction pro-
vides a promising avenue to the direct functionalization of inert
Csp3-H bonds, a lot of excellent results have been reported
recently.13 Simple ethers are important basic chemical feedstock
Direct difunctionalization of alkynes has emerged as a promising
and powerful approach for the construction of various valuable
organic compounds due to its high efficiency in the cascade
formation of carbon–carbon or carbon–heteroatom bonds.1 For
example, some excellent difunctionalization reactions such as
sulfonylation,2 oxysulfurization,3 halogenation,4 phosphorylation,5
trifluoromethylation,6 ispo-carboacylation,7 etc, catalyzed by transi-
tion-metals or reacted under metal-free conditions have been devel-
oped delivering a series of functional derivatives. In this field, the
difunctionalization of readily available alkynoates via cascade radi-
cal cyclization has been proved to be a fascinating strategy in the
construction of 3-functionalized coumarins. Through 6-endo/5-exo
cyclization, a variety of 3-phosphorated,8 sulfonylated,9 trifluo-
romethylated,6c thiocyanated,10 and acylated11 coumarins were
obtained in good yields with excellent selectivity (Scheme 1a).
Besides, alkynoates could also undergo radical oxidation-tandem
cyclization/dearomatization in the presence of Langlois’ reagent as
the CF3 radical source to synthesize 3-trifluoromethyl oxaspiro
[4.5]trienones (Scheme 1b).12a
and widely used solvents. Moreover, a-functionalized ether deriva-
tives frequently exist in numerous biologically active molecules
and natural products.14 Thus, the direct functionalization of ethers
becomes an urgent task. In other words, the
ethers are relatively weak and easy to generate
radicals under oxidative conditions.15 Here, we reported our recent
achievements in the -functionalization of simple ethers with
a
-C(sp3)-H bonds of
-carbon centered
a
a
alkynoates as the radical acceptors to access tri-substituted olefins.
Results and discussion
Initially, phenyl 3-phenylpropiolate (1a) was chosen as sub-
strate catalyzed by CuI in the presence of DTBP (di-tert-butyl per-
oxide) as the oxidant in THF under air at 110 °C to optimize the
reaction conditions. To our surprise, neither coumarin derivative
nor oxaspiro[4.5]trienone analogue was detected after 16 h, but
an unexpected oil compound 3aa was isolated in 62% yield. In fact,
after GCMS and NMR analysis, we found that the obtained product
was 2-diphenylvinyl tetrahydrofuran (3aa). Thus, the reaction
must undergo aryl migration and decarboxylation process. Encour-
aged by this exciting result, we further optimized the reaction
Construction of C–C bonds via direct C–H functionalization has
drawn great attention during the recent decade owing to its step-
and atom-economy with environmental sustainability. Among
⇑
Corresponding authors.
E-mail addresses: panchangduo@jsut.edu.cn (C. Pan), cjzhu@nju.edu.cn (C. Zhu).
http://dx.doi.org/10.1016/j.tetlet.2015.12.092
0040-4039/Ó 2015 Published by Elsevier Ltd.
Please cite this article in press as: Pan, C.; et al. Tetrahedron Lett. (2015), http://dx.doi.org/10.1016/j.tetlet.2015.12.092

2
C. Pan et al. / Tetrahedron Letters xxx (2015) xxx–xxx
Ar'
Table 2
Ar'
Scope of the alkynoatesa
R
6-endo or 5-exo cyclization
R'
R
(a)
R'
R1
R1
R1
R1
O
O
O
O
O
O
O
R = PO(R)2, SO2R, CF3, Acyl, SCN, etc
CuBr, DTBP
110 oC
O
Ar'
Ar'
R
R
Cu, TBHP
CF3SO2Na
CF3
O
O
2a
(b)
(c)
1
3
O
O
O
R1
F
Me
O
Ar'
O
Ar'
O
O
O
O
This work
-CO2
R1
H
F
Me
O
3aa, 78%
Cl
3ca, 74%
3ba
, 80%
Scheme 1. Radical difunctionalization of alkynoates.
CF3
Cl
O
conditions and some of them are listed in Table 1. The results
showed that, CuBr is a better catalyst than CuI, and 3aa could be
obtained in 78% yield. The reaction became sluggish if the amount
of oxidant was decreased (Table 1, entry 2). Copper(II) catalyst, as
Cu(OAc)2 was inferior to CuBr. Control experiment indicated that,
this aryl migration/decarboxylation process could proceed without
copper-catalyst while in a low yield (Table 1, entry 4). Other com-
mon peroxides, such as TBHP, delivered only traces of the corre-
sponding alkene (Table 1, entry 5) and the BPO resulted in lower
yield (Table 1, entry 6).
O
O
F3C
Cl
Cl
3ea, 66%
3fa, 69%
3da, 70%
F
Me
OMe
O
O
O
With the optimized reaction conditions in hand, the scope of
alkynoates was investigated as shown in Table 2. As expected, all
substrates ran smoothly under the standard procedure to produce
the corresponding tri-substituted alkenes in moderate to good
yields (3aa–3la, Table 2). Halogen substituents such as F, Cl, and
I could be well tolerated in this transformation to afford the
desired products in 66–81% yields, respectively (3ca, 3da, 3ea,
sia, 3ja, and 3ka, Table 2), providing more chance for further func-
tionalization or modification of these compounds. Particularly
noteworthy is the tolerance of iodo-in our procedure (3ka). Under
the limits of detection, no deiodination or other related by-prod-
ucts were found in the crude reaction mixtures. The reaction was
not sensitive to the electronic nature of the substituents on phe-
nyls, for alkynoates with either electron-withdrawing or elec-
tron-donating substituent reacting smoothly. The steric
hindrance has little influence on the reaction, for alkynoates with
meta-substituted aryls, the yields of corresponding products were
slightly lower than those with para-substituted ones (e.g., 3ea vs
3ga, 78%, E:Z = 1:1b 3ha, 51%, E:Z = 1:1b
Cl
3ia, 81%, E:Z = 1:1b
I
CF3
O
O
O
b
b
b
3ja
, 77%, E:Z = 1:1
3la
, 75%, E:Z = 1:1
3ka
, 74%, E:Z = 1:1
a
Reaction conditions:
1 (0.2 mmol), 2a (2 mL), CuBr (10 mol %) and DTBP
(4 equiv) at 110 °C for 16 h. Isolated yields.
b Determined by 1H NMR.
3da, Table 2). Finally, substrates bearing different aryls were also
employed to investigate the stereoselectivity of the reaction
(3ga–3la, Table 2). The results showed that the reactions of those
alkynoates afforded the corresponding stereoisomers mixtures,
with the E/Z ratios nearly 1:1, as determined by 1H NMR.
Table 1
Owing to the diversity of ether compounds, we next investi-
gated the applicability of various simple ether derivatives with dif-
ferent alkynoates in this transformation (Table 3). To our delight,
common simple ethers such as 1,4-dioxane, tetrahydropyrane,
1,3-dioxolane, and diethyl ether all reacted smoothly with alkyno-
ates to generate the corresponding alkenes in moderate to good
yields (52–80% yields) (3ab–3ae, Table 3).
The optimization of reaction conditions
Ph
Ph
O
O
Ph
Ph
O
O
3aa
2a
1a
To gain some insights into the mechanism of the reaction, con-
trol experiments were carried out as shown in Scheme 2. When the
radical scavenger, 2,6,6-tetramethyl-1-piperidinyloxy (TEMPO)
was added under the standard conditions, the reaction was obvi-
ously inhibited, which suggests a radical intermediate is involved
(Scheme 2). Thus, the proposed reaction mechanism is outlined
in Scheme 3. Firstly, copper(I)-promoted homolytic cleavage of
Entry
Catalyst
Oxidant
Yielda (%)
1
2
3
4
5
6
CuI
DTBP
DTBP
DTBP
DTBP
TBHP
BPO
62
CuBr
Cu(OAc)2
—
CuBr
CuBr
78(52)b
58
32(39)c
Trace
55
DTBP gives tert-butoxyl radical,15d,16 which abstracts one
a-H from
a
Reaction conditions: 1a (0.2 mmol), 2a (2 mL), catalyst (10 mol %) and oxidant
(4 equiv) at 110 °C for 16 h. Isolated yields.
THF to generate radical intermediate A. Then the addition of radical
A to the triple bond of alkynoate 1a forms radical intermediate B.
Next, the ipso-cyclization of B gives a spiro intermediate C.12 Sub-
b
DTBP (3 equiv).
40 h.
c
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C. Pan et al. / Tetrahedron Letters xxx (2015) xxx–xxx
3
Table 3
E. Finally, hydrogen abstraction of 2a by intermediate E produces
the product 3aa together with a radical intermediate A for the next
cycle.
Scope of the ethersa
R'
R'
O
CuBr, DTBP
110 oC
O
Conclusions
H
R
R
O
O
In summary, we have developed a radical cascade difunctional-
ization reaction of aryl alkynoates with ethers to access tri-substi-
tuted olefins through radical addition, aryl migration, and
decarboxylation processes.17 Different substituted alkynoates and
various simple ethers all reacted well, leading to the corresponding
tri-substituted olefins in moderate to good yields. This procedure
2
3
1
O
O
O
O
3ac, 77%
gives a new avenue to the direct functionalization of the
a-C
3aa
3ab, 69%
, 78%
(sp3)-H bonds in ether derivatives.
F
Acknowledgments
O
O
O
O
We gratefully acknowledge the National Natural Science Foun-
dation of China (21172106, 21372114) for their financial support.
F
3af, 79%
3ae, 80%
CF3
3ad, 52%
Cl
Supplementary data
Cl
Supplementary data (experimental details and the characteriza-
tion data) associated with this article can be found, in the online
version, at http://dx.doi.org/10.1016/j.tetlet.2015.12.092.
O
O
O
Cl
F3C
Cl
3ag,
77%
3ah
3ai
, 73%
, 69%
References and notes
a
Reaction conditions:
1
(0.2 mmol),
2
(2 mL), CuBr (10 mol %), and DTBP
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Scheme 3. Proposed mechanism.
sequent 1,4-migration of the aryl group on the ester moiety results
in carboxyl radical D, which is ready to undergo the decarboxyla-
tive process with the release of CO2 to afford radical intermediate
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