N-Iodosuccinimide-Promoted Cascade Trifunctionalization of Alkynoates: Access to 1,1-Diiodoalkenes

Article abstract of DOI:10.1021/acs.orglett.5b03685

(Chemical Equation Presented). An efficient cascade trifunctioalization reaction of alkynoates with N-iodosuccinimide has been developed which proceeds through iodination, aryl migration, decarboxylation, and second iodination. This reaction represents an

Full text of DOI:10.1021/acs.orglett.5b03685

Letter
pubs.acs.org/OrgLett
N‑Iodosuccinimide-Promoted Cascade Trifunctionalization of
Alkynoates: Access to 1,1-Diiodoalkenes
Shengyang Ni,† Wanxing Sha,† Lijun 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: An efficient cascade trifunctioalization reaction of alkynoates with N-iodosuccinimide has been developed which
proceeds through iodination, aryl migration, decarboxylation, and second iodination. This reaction represents an example of 1,1-
difunctionalization of the acetylene bond and also provides a new strategy for the preparation of 1,1-diiodoalkenes.
Scheme 1. Reactions of Alkynoates
1,1-Dihaloalkenes belong to an important class of building
blocks in synthetic chemistry1 and have been employed for a
wide range of reactions, including metal-catalyzed cross-
coupling,2 construction of complex heterocycles,3 and other
useful conversions.4 Furthermore, such a structure motif is
found to exist in some natural products isolated from marine
sponges.5 Because of the high reactivity and versatility of
iodides, 1,1-diiodoalkene intermediates more easily to undergo
selective bond-forming reactions in organic synthesis and
photochemistry.6 Consequently, the development of new
methods for the preparation of 1,1-diiodoalkenes is of great
demand.7
Functionalization of aryl alkynoates has become an attractive
and powerful tool in organic synthesis, mainly because of the
existence of the valuable acetylene bond motif in aryl
alkynoates, which makes it easily derived from several
functional groups.8,9 Furthermore, cascade intramolecular
cyclization of aryl alkynoates renders this organic synthetic
intermediate more attractive due to the easy construction of
substituted heterocycles. In recent years, many approaches have
been explored on difunctionalization reactions of alkynoates
which generate new bonds as well as introduction of additional
functional groups (Scheme 1a). Cascade radical functionaliza-
tion of alkynoates and followed by intramolecular cyclization
with o-C(sp2) on the aromatic moiety afforded varieties of
functionalized coumarins.10 Several radical coupling partners,
such as α-keto acids,10a ethyl bromodifluoroacetate,10b
diorganyl diselenides,10d Togni’s reagent,10e dialkyl H-phos-
phonates,10f 2-oxoacetic acids,10g aldehydes,10j AgSCF3,
AgSCN,10k and others have been used for this transformation.
On the other hand, alkynoates could undergo transition-metal-
catalyzed oxidative ipso-cyclization reaction to afford
azaspiro[4.5]trienones derivatives.11 Further, we and other
groups have developed the cascade oxidative difunctionalization
reactions of alkynoates leading to substituted olefins.12 Other
types of difunctionalizations of alkynoates, such as [2 + 2]-
cycloaddition with ketene silyl acetals affording functionalized
Received: December 28, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b03685
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Organic Letters
Letter
cyclobutenediones, have also been reported.13 However, to the
best of our knowledge, trifunctionalization of alkynoates has
never been explored until now. There have been few examples
on halogenation initiating cascade functionalization of
alkynoates.11a Herein, we report an unprecedented iodination-
triggered cascade radical trifunctionalization reaction of
alkynoates, which proceeds through the sequence of iodination,
aryl migration, decarboxylation, and second iodination (Scheme
1b). This reaction could be carried out under simple conditions
with readily available N-iodosuccinimide (NIS) as the iodine
precursor,14 affording 1,1-diiodoalkenes as products. Further-
more, this process demonstrates a multistep radical reaction for
trifunctionalization of alkynoates and also represents a strategy
of the 1,1-difunctionalization of acetylene bonds.
NIS. Interestingly, decreasing the NIS substrate loading to 2.0
equiv afforded the best reaction outcome, and the highest yield
was obtained (79%, entry 11). Further attempts to improve the
yield by varying the reaction time were not successful (entries
14 and 15). Finally, other iodine reagents, such as iodine (entry
16) and the nucleophilic iodine reagent TBAI (entry 17), were
used for this reaction instead of NIS, and the results clearly
suggested that NIS should be considered as the best choice.
The next objective of this study focused on exploration of the
alkynoates’ structural generality by using NIS as the coupling
partner (Scheme 2). As shown in Scheme 2, aryl alkynoates
a,b
Scheme 2. Reaction Scope of Aryl Alkynoates with NIS
Initial studies focused on investigating the cascade reaction of
phenyl alkynoates 1a and 3.0 equiv of N-iodosuccinimide 2
with dichloroethane as the solvent. We were pleased that the
reaction proceeded at 120 °C, affording the desired 1,1-
diiodoalkenes product 3a in 21% chemical yield (entry 1, Table
1). When the solvent was switched to toluene (entry 2) or 1,4-
a
Table 1. Optimization of the Reaction Conditions
b
NIS
(equiv)
temp
(°C)
yield
(%)
entry
solvent (mL)
time (h)
1
DCE (2.0)
toluene (2.0)
DMF (2.0)
DMSO (2.0)
1,4-dioxane (2.0)
PhCl (2.0)
PhCl (2.0)
PhCl (2.0)
PhCl (1.5)
PhCl (2.5)
PhCl (2.5)
PhCl (2.5)
PhCl (2.5)
PhCl (2.5)
PhCl (2.5)
PhCl (2.5)
PhCl (2.5)
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
2.0
2.2
2.5
2.0
2.0
2.0
2.0
120
120
120
120
120
120
140
160
160
160
160
160
160
160
160
160
160
24
24
24
24
24
24
24
24
24
24
24
24
24
12
16
24
24
21
23
NR
NR
26
32
47
68
55
71
79
75
72
52
73
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
c
10
d
NR
a
Reaction conditions: 1a (0.2 mmol), NIS, solvent, under air.
Isolated yield based on 1a. I2 was used. TBAI was used.
b
c
d
dioxane (entry 5), no obvious improvement was found on the
reaction outcome. On the other hand, no reaction was found
when the DMSO or DMF was used as solvent (entries 3 and
4). A slightly higher chemical yield was obtained when the
reaction was performed in chlorobenzene (32%, entry 6).
Continuing the search for optimized conditions, we found that
the reaction efficiency can be noticeably improved by increasing
the reaction temperature (entries 7 and 8), affording product
3a with up to 68% yield. The concentration also has an obvious
effect on the reaction, and the results showed that 2.5 mL of
chlorobenzene was the best choice (0.08 mol/L, entries 9 and
10). We then investigated the effect of the loading amount of
a
Reaction conditions: 1 (0.2 mmol), NIS 2 (0.4 mmol),
b
chlorobenzene (2.5 mL) at 160 °C for 24 h. Isolated yields.
bearing different substituents on the aromatic ring of the ester
moiety, such as halo, phenyl, methyl, methoxyl, and
trifluoromethyl groups, were well tolerated, affording the
corresponding product in 60−88% isolated chemical yields
(3a−n). Of particular interest was that the position of
substituents on aromatic rings showed almost no effect on
the reaction efficiency. Most of the reactions could proceed
smoothly regardless of the electronic properties; even the
B
DOI: 10.1021/acs.orglett.5b03685
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Letter
substrates bearing strong electron-withdrawing groups were
well tolerated in this system (4-fluorophenyl 3-phenyl-
propiolate 1b and 4-(trifluoromethyl)phenyl 3-phenylpropio-
late 1f). We also presented an example of disubstituted
substrate 1n (2,6-dimethylphenyl 3-phenylpropiolate) contain-
ing two methyl groups in the ortho-position, which also gave
rise to the expected product 3n in 60% yield. We then carried
out another series of experiments using the substrates with
substituted phenylpropiolates under standard reaction con-
ditions (3o−t). Pleasingly, starting compounds containing
various substituents on the phenylpropiolates were acceptable,
resulting in the expected product with up to 96% chemical
yields (3s). Finally, an aliphatic substrate, with methyl-
substituted acetylenic acid 1u (phenyl but-2-ynoate), was
examined in the current reaction. It also showed good
applicability for this reaction to give the corresponding methyl,
phenyl-substituted 1,1-diiodoalkene (3u) with a lower yield
(52%).
observed (determined by ESI-MS analysis). The result indicates
that the transformation may proceed via a radical course.
Another experiment was conducted with methyl alkynoate 1v
as starting material under the standard conditions (Scheme 4b).
No reaction was found, and almost all of the starting material
1v was recovered. This result cleanly suggests that the
migration proceeds through the cyclic transition state instead
of direct group shift.
On the basis of our experimental observations and previous
reports,12 we proposed a mechanistic pathway, as depicted in
Scheme 5, for this cascade radical reaction. The first step of this
Scheme 5. Proposed Mechanism
After NIS was examined in this reaction, we then turned our
attention to other similar halo sources. Thus, the reactions
using commercially available N-halosuccinimide substrates were
carried out (Scheme 3). N-Bromosuccinimide (NBS) was
Scheme 3. Reaction of Aryl Alkynoates with NBS and
a,b
NCS
a
Reaction conditions: 1a (0.2 mmol), NBS or NCS (0.4 mmol),
b
chlorobenzene (2.5 mL) at 160 °C for 24 h. Isolated yields.
reaction is the generation of iodine radical A from NIS under
heating. The second step is the iodination of phenyl alkynoate
1a through the iodine radical A addition to the C−C triple
bond of alkynoate resulting in intermediate B. Subsequently,
the intermediate B proceeds through intramolecular cyclization
to afford the spiro intermediate C, which undergoes the aryl
migration via cleavage of C−O bond to give the carboxyl radical
D. Subsequent decarboxylation of carboxyl radical D generates
intermediate E with release of CO2. Finally, the intermediate
alkene radical E reacts with iodine radical to complete the
second iodination, affording the final 1,1-diiodoalkene product
3a.
In conclusion, we have developed an unprecedented NIS-
promoted trifunctionalization reaction of aryl alkynoates under
simple conditions. This reaction proceeds through the
sequence of iodination, aryl migration, decarboxylation, and
second iodination via one C−O and two C−C bond cleavages,
along with one C−C bond and two C−I bond formations. The
reaction tolerates a wide range of substrates affording the
corresponding 1,1-diiodoalkene product in good to excellent
yields. This reaction could be viewed as 1,1-difunctionalization
of the acetylene bond, and it represents a new strategy for the
preparation of 1,1-diiodoalkenes. Further studies on the
reactions of aryl alkynoates with iodine radical are underway
in our laboratory.
found to react well with phenyl alkynoates under standard
conditions, affording the expected 1,1-dibromoalkene product
4a in 66% isolated yield, which was a little bit lower compared
with the yield from NIS (3a, 79% yield). Unfortunately, no
reaction was observed when N-chlorosuccinimide was used as
chloro source, and most of the starting material 1a was
remained.
The final portion of this involved the elucidation of the
observed reaction outcome and the proposal of the possible
reaction mechanism. A control experiment of phenyl alkynoates
1a and NIS 2 in the presence of the radical-trapping reagent
2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) was carried out
(Scheme 4a). As expected, the formation of desired product 3a
was suppressed, and only TEMPO−iodine adduct was
Scheme 4. Investigation of the Reaction Mechanism
C
DOI: 10.1021/acs.orglett.5b03685
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b03685.
■
S
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Experimental procedures; full spectroscopic data for
1
compounds 3 and 4a; H NMR and 13C NMR spectra
(PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: hanjl@nju.edu.cn.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
We gratefully acknowledge financial support from the National
Natural Science Foundation of China (Nos. 21102071 and
21472082) and the Fundamental Research Funds for the
Central Universities (020514380018). The Jiangsu 333
program (Y.P.) and Changzhou Jin-Feng-Huang program
(J.H.) are also acknowledged.
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