Oxidative Difunctionalization of Alkynoates through Alkylation and Migration Decarboxylative Arylation

Article abstract of DOI:10.1021/acs.orglett.5b02356

A cascade oxidative difunctionalization reaction of alkynoates for the construction of trisubstituted olefins has been developed. The process undergoes alkylation of a C-C triple bond, 1,4-aryl migration, and decarboxylation, which demonstrates a multistep radical cascade reaction for the difunctionalization of alkynoates and also represents a strategy of direct decarboxylation of esters.

Full text of DOI:10.1021/acs.orglett.5b02356

Letter
pubs.acs.org/OrgLett
Oxidative Difunctionalization of Alkynoates through Alkylation and
Migration Decarboxylative Arylation
Shengyang Ni,† Yu Zhang,† Chen Xie,† Haibo Mei,†,‡ Jianlin Han,*,†,‡ and Yi Pan†,‡
†School of Chemistry and Chemical Engineering, State Key laboratory of Coordination Chemistry, Nanjing University, Nanjing,
210093, China
‡MaAnShan High-Tech Research Institute of Nanjing University, MaAnShan, 238200, China
S
* Supporting Information
ABSTRACT: A cascade oxidative difunctionalization reaction
of alkynoates for the construction of trisubstituted olefins has
been developed. The process undergoes alkylation of a C−C
triple bond, 1,4-aryl migration, and decarboxylation, which
demonstrates a multistep radical cascade reaction for the
difunctionalization of alkynoates and also represents a strategy
of direct decarboxylation of esters.
Scheme 1. Reactions of Alkynoates
he development of efficient methodologies for the
Tconstruction of carbon−carbon bonds has become one
of the most active areas in modern organic chemistry.1 Radical-
mediated functionalization of the sp3 C−H bonds has been
demonstrated to be a powerful and versatile tool for carbon−
carbon formation to assemble molecules with a wide range of
structural varieties.2 In recent decades, significant achievements
have been made in the area of C(sp3)−H bond functionaliza-
tion. In particular, such reactions show advantages in the
synthesis of complex molecules, which may form multiple C−C
bonds in one process. Many ingenious applications of such
radical cascade reactions in the total synthesis of natural
products have been well explored.3
Aryl alkynoate represents an important and extremely
valuable synthetic block in organic synthesis. It is because
that acetylene bond is a privileged motif, which can easily react
with radical partners and allows the various introductions of
different functional groups.4,5 Furthermore, the site-specifically
generated reactive radical intermediates could undergo
cyclization reactions to construct functionalized heterocycles
via intramolecular cross-coupling with sp2 C of aromatic rings.
In recent years, several examples have been developed on the
related cascade reactions of aryl alkynoates. The first type,
which was most studied, was cascade functionalization of an
alkyne and subsequent cyclization with ortho-C(sp2) on an
aromatic moiety affording varieties of functionalized Coumarins
(Scheme 1a).6,7 Functionalization of an alkyne and ipso-
cyclization represented the other type of reaction on
alkynoates, which gave spiro compounds as target products
(Scheme 1b).8 Also, aryl alkynoates could undergo [2 + 2]-
cycloaddition with ketene silyl acetals to give polysubstituted
four-membered ring compounds with good yields.9 However,
to the best of our knowledge, alkylation of alkynoate triggers
migration and decarboxylation of the ester moiety to assemble
trisubstituted olefins has not been explored. Notably, Tunge
and co-workers explored the relevant Pd-catalyzed allylation via
decarboxylative coupling of ester.10 The Gooßen group
demonstrated the decarboxylative coupling of alcohols with
oxalate esters.11 Herein, we reported an unprecedented cascade
radical difunctionalization reaction of alkynoates, which
proceeds through alkylation with cycloalkanes, 1,4-aryl
migration, and decarboxylation to afford trisubstituted olefins
Received: August 14, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b02356
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Organic Letters
Letter
(Scheme 1c). This process contains one C−H, one C−O, and
two C−C bond cleavages, along with two new C−C bond
formations.
using various types of alkynoates to react with cyclohexane 2a.
As presented in Scheme 2, this radical reaction showed a broad
Our previous study showed that alkyl radicals could be easily
in situ generated from the reaction of oxidant DTBP and
alkanes.12 Thus, we selected phenyl 3-phenylpropiolate 1a and
cyclohexane 2a as model compounds to carry out the cascade
reaction in the presence of 3.0 equiv of DTBP with cyclohexane
(1.5 mL) as solvent at 120 °C for 24 h (entry 1, Table 1). The
Scheme 2. Reaction Scope of Aryl Alkynoates with
Cyclohexane 2a
a b
,
a
Table 1. Optimization of the Reaction Conditions
b
c
entry
oxidant (equiv)
temp (°C)
t (h)
yield (%)
1
2
3
4
5
6
7
8
9
DTBP (3.0)
TBHP (3.0)
TBPB (3.0)
K2S2O8 (3.0)
DCP (3.0)
120
120
120
120
120
120
120
120
120
120
120
140
120
120
24
24
24
24
24
24
24
24
48
24
24
24
24
24
43
9
34
trace
19
H2O2 (3.0)
DTBP (1.0)
DTBP (2.0)
DTBP (2.0)
DTBP (2.0)
DTBP (2.0)
DTBP (2.0)
DTBP (2.0)
DTBP (2.0)
N.R.
30
58
55
d
10
44
e
11
68
e
12
46
e
f
13
trace
e
g
14
48
a
Reaction conditions: 1a (0.2 mmol), cyclohexane 2a (1.5 mL),
b
oxidant under air. DTBP: di-tert-butyl peroxide; H2O2: 30% aqueous
solution; TBHP: tert-butyl hydroperoxide 5.5 M in decane; TBPB:
tert-butyl peroxybenzoate; DCP: dicumyl peroxide. Isolated yields
c
d
e
based on 1a. 1 mL of cyclohexane used. 2 mL of cyclohexane used.
f
g
20 mol % Pd(OAc)2 was added. 20 mmol % Cu(OAc)2·H2O was
added.
reaction could happen and afford the desired product 3aa in
43% yield. To find the best oxidant, the reactions performed in
the presence of different oxidants other than DTBP were
investigated. Application of other oxidants, such as TBHP,
TBPB, and DCP (entries 2, 3 and 5), was rather unsuccessful,
as no improved yields were obtained. Even no desired product
was found at all when K2S2O8 or H2O2 was used for this
reaction (entries 4 and 6). To further optimize the reaction
conditions, the amount of cyclohexane, reaction time, and
temperature were examined. Noticeably, 2.0 equiv of DTBP
were sufficient for the completion of this reaction with
increased yield (58%, entry 8). The results in entries 10 and
11 disclosed that 2 mL of cyclohexane were needed, and the
best result was obtained (68% yield). It did not result in any
improvement of the yield when prolonging the reaction time to
48 h or increasing the temperature to 140 °C (entries 9 and
12). Finally, the attempts to use metal catalysts, such as
Pd(OAc)2 (entry 13) and Cu(OAc)2 (entry 14), were also
unsuccessful. Even almost no product was detected when
Pd(OAc)2 was used.
a
Reaction conditions: 1 (0.2 mmol), cyclohexane 2a (2.0 mL), DTBP
b
c
(2.0 equiv), at 120 °C under air for 24 h. Isolated yields. Determined
by H NMR.
1
substrate scope, and halo, methyl, and methoxyl groups could
be well tolerated in this reaction to afford the expected
substituted olefins with up to 68% chemical yield. The position
of substituents on aromatic rings had an obvious effect on the
results of the reactions, as the substrates with para and meta
substituents gave the same level of yields (3ea and 3ja, 52% and
54% respectively) while a dramatically lower yield was obtained
from the substrate bearing an ortho-substituted aromatic ring
(3oa, 25%). In general, the alkynoates with electron-with-
drawing groups gave slightly better results (3da, 3fa, 3ha)
compared with the alkynoates associated with electron-
donating groups (3ba, 3ca). Substrates bearing different
aromatic rings were also employed to investigate the stereo-
selectivity of the reaction (3pa, 3qa). Reactions of 3pa and 3qa
afforded the products as a 1:1 mixture of stereoisomers. Finally,
With the optimized conditions in hand, we then set out to
investigate the substrate generality of this radical reaction by
B
DOI: 10.1021/acs.orglett.5b02356
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Letter
it should be mentioned that the starting materials remained in
most cases of these reactions.
Scheme 4. Investigation of the Reaction Mechanism
We then carried out the study of another line of substrate
generality by using various cycloalkanes 2 (Scheme 3). Several
Scheme 3. Reaction Scope of Cycloalkane with Aryl
a b
,
Alkynoates
Scheme 5. Proposed Mechanism
a
Reaction conditions: 1 (0.2 mmol), cycloalkane 2 (2.0 mL), DTBP
b
(2.0 equiv), at 120 °C under air for 24 h. Isolated yields.
cycloalkanes have been employed to react with phenyl 3-
phenylpropiolate 1a. These radical reactions could afford the
corresponding product 3 bearing five- (3ab) and seven-
membered (3ac) rings with up to 65% yield. It is noteworthy
that cyclopentane could also react smoothly with electron-rich
(1b and 1c) or electron-poor (1f) alkynoates to afford the
expected products. Unfortunately, the yield decreased dramat-
ically when the larger cycloalkanes were used as substrates, and
almost no product was obtained at all in the case of
cyclododecane (2e). The reaction also showed poor
regioselectivity when the coupling partner cycloalkane contains
several potential reaction sites (2f), and a mixture of
regioisomers was obtained (3af, the ratio of mixture = 4:1.8:1).
Then two control experiments were carried out to gain
insight into the reaction mechanism. First, a reaction of 1a and
2a with the addition of radical-trapping reagent 2,2,6,6-
tetramethyl-1-piperidinyloxy (TEMPO) under the standard
conditions was performed, and the formation of desired
product 3aa was suppressed (Scheme 4a). This suggests the
reaction might be a radical process. Interestingly, the reaction
with aryl alkynoate with an ortho-occupied aromatic ring (1r)
could also work well in this system to afford the expected
product 3ra in 45% yield (Scheme 4b), which implies that no
neighboring group participation happens during the migration
of the aryl group.
cyclization to give spiro intermediate D.8 Subsequent migration
of the aryl group on the ester moiety gives the carboxyl radical
E, which is ready to undergo the decarboxylative process with
release of the CO2 to afford intermediate F. Finally, hydrogen
abstraction of cyclohexane 2a by the radical intermediate F
gives the desired product 3aa and cyclohexane radical
intermediate B for next cycle.
In summary, we have explored an unexpected radical cascade
difunctionalization reaction of aryl alkynoates which proceeded
through cleavage of the sp3 C−H bond of cycloalkanes,
alkylation of alkynoates, 1,4-aryl migration, and decarboxyla-
tion. This complex radical process tolerated a wide range of
substrates, affording trisubstituted olefins with moderate
chemical yields. It is worth noting that this process involves
one C−H, one C−O, and two C−C bond cleavages, along with
two new C−C bond formations. This reaction also could be
viewed as the direct decarboxylation of ester, which enriches
the content of decarboxylative reactions. Further studies
directed toward the development of new radical precursors
for this system are currently underway in our laboratory.
Based on the above experimental results and the previous
reports,7 a possible mechanism for the cascade radical reaction
was proposed in Scheme 5. Initially, homolysis of DTBP
generates tert-butoxy radical intermediate A under heating.
Subsequent hydrogen abstraction of cyclohexane 2a by a tert-
butoxy radical affords cyclohexane radical intermediate B,12
which adds to the C−C triple bond of alkynoates resulting in
intermediate C.7 Then, intermediate C undergoes ipso-
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b02356.
C
DOI: 10.1021/acs.orglett.5b02356
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(8) (a) Tang, B. X.; Tang, D. J.; Tang, S.; Yu, Q. F.; Zhang, Y. H.;
Liang, Y.; Zhong, P.; Li, J. H. Org. Lett. 2008, 10, 1063−1066. (b) Hua,
H. L.; He, Y. T.; Qiu, Y. F.; Li, Y. X.; Song, B.; Gao, P.; Song, X. R.;
Guo, D. H.; Liu, X. Y.; Liang, Y. M. Chem. - Eur. J. 2015, 21, 1468−
1473. (c) Wei, W. T.; Song, R. J.; Ouyang, X. H.; Li, Y.; Li, H. B.; Li, J.
H. Org. Chem. Front. 2014, 1, 484−489.
Experimental procedures, full spectroscopic data for
compounds 3, copies of 1H NMR and 13C NMR spectra
(PDF)
AUTHOR INFORMATION
Corresponding Author
■
(9) (a) Hamura, T.; Iwata, S.; Suzuki, K. Chem. Commun. 2011, 47,
6891−6893. (b) Iwata, S.; Hamura, T.; Suzuki, K. Chem. Commun.
2010, 46, 5316−5318.
*E-mail: hanjl@nju.edu.cn.
Notes
(10) (a) Rayabarapu, D. K.; Tunge, J. A. J. Am. Chem. Soc. 2005, 127,
13510−13511. (b) Lang, S. B.; O’Nele, K. M.; Tunge, J. A. J. Am.
Chem. Soc. 2014, 136, 13606−13609.
The authors declare no competing financial interest.
(11) Grunberg, M. F.; Gooßen, L. J. Chem. - Eur. J. 2013, 19, 7334−
̈
ACKNOWLEDGMENTS
■
7337.
We gratefully acknowledge the financial support from the
National Natural Science Foundation of China (Nos. 21102071
and 21472082) and the Fundamental Research Funds for the
Central Universities (020514380018).
(12) (a) Zhou, W.; Ni, S. Y.; Mei, H. B.; Han, J. L.; Pan, Y. Org. Lett.
2015, 17, 2724−2727. (b) Zhou, W.; Qian, P.; Zhao, J. C.; Fang, H.;
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Fang, H.; song, R. C.; Zhou, J.; Han, J. L.; Pan, Y. Chem. Commun.
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DOI: 10.1021/acs.orglett.5b02356
Org. Lett. XXXX, XXX, XXX−XXX