An efficient iodine pentoxide-triggered iodocarbocyclization for the synthesis of iodooxindoles in water

Article abstract of DOI:10.1039/c8ob01130c

An efficient iodocarbocyclization of alkenes for the synthesis of iodooxindoles has been developed. This reaction proceeds in a chemoselective manner and shows excellent tolerance of various functional groups, including a chemosensitive hydroxymethyl grou

Full text of DOI:10.1039/c8ob01130c

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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
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An efficient iodine pentoxide-triggered iodocarbocyclizations for
the synthesis of iodooxindoles in water
MingꢀZhong Zhang,*a Xin Wang,a MingꢀYing Gong,a LinꢀChen,a WenꢀBing Shi,*a ShuꢀHua He,a
Yong Jianga and Tieqiao Chen*b
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
An efficient iodocarbocyclization of alkenes for the synthesis of iodooxindoles has been developed. This reaction proceeds
in a chemoselective manner and shows excellent tolerance of various functional groups, including a chemosensitive
hydroxymethyl group. Nonmetal inorganic iodine pentoxide was used as both the oxidant and iodine source, making this
protocol very practical. On the basis of experimental observations, a plausible electrophilic reaction mechanism was
proposed.
www.rsc.org/
organic waste (e.g., iodobenzene), which lowers the overall
atom efficiency of the reaction. In 2014, Guo et al. reported a
metalꢀfree (NH4)2S2O8ꢀmediated halocarbocyclization for the
Introduction
Iodocyclization reactions are very important reactions in
organic chemistry, since they can play an important role in
building carbocycles, heterocycles and natural products.1 In
addition, some of the iodocyclized products are bioactive.2
Thus, in recent years, cyclizations involving iodoniumꢀinduced
activation of prefunctionalized alkyne and alkene substrates
have gained significant prominence. These reactions generally
allow the generation of polysubstituted molecules (e.g., indoles,
isoquinolines, isocoumarins, quinolones, oxazolones, and
furans, etc.) from simple skeletons in one step, providing the
chance for further functionalization via crossꢀcoupling.3ꢀ8
3,3’ꢀDisubstituted oxindoles, bearing a functional group at
the C3ꢀposition, are an important class of heterocycles that can
be used for synthesizing biologically active molecules.9,10
Traditional procedures for their preparation rely on a radical Cꢀ
H functionalization process, whereas these radical reactions
have their advantages and disadvantages.11 The introduction of
an iodine atom was shown to induce the cyclization of activated
alkenes, involving the simultaneous formation of both CꢀI and
CꢀC bonds, thus arising as a fascinating strategy for producing
3,3’ꢀdisubstituted oxindoles. In 2011, a phenyliodine diacetate
(PIDA)ꢀpromoted iodocarbocyclization of alkenes leading to
iodinated oxindoles was reported.12 Using organohypervalent
iodine reagent as an oxidant faces the drawback of generating
synthesis of halogenated oxindoles by using NH4X (X = Cl, Br,
I) as the halide source.13 This report was followed by Ye et al.
by using K2S2O8/KX (X = Cl, Br, I) as a similar oxidative
halogenation system.14 Although some advances have been
made, these oxidative methods suffered from the following
drawbacks: (1) narrow substrate scope and/or limited functional
group tolerance, were exposed in iodocarbocyclization; (2)
large amounts of organic byꢀproducts and environmentally
deleterious waste (e.g., SO42ꢀ) were frequently brought about
when stoichiometric amounts of strong oxidants, i.e.,
persulfates, were used. Therefore, developing a new oxidative
iodination system to accomplish a similar transformation that
can exploit more efficient and sustainable approaches to
iodooxindoles would be highly desirable.
Nonmetal inorganic iodine pentoxide (I2O5) is widely used as
a reliable singleꢀelectron oxidant in radical reactions due to its
safe, clean, and environmental friendly characters.15 For
example, in 2014, Liu group pioneeringly employed I2O5 as an
initiator to realize the radical trifluoromethylation/cyclization of
alkenes
with
Langlois
reagent
for
producing
trifluoromethylated 3,3’ꢀdisubstituted oxindoles.16,17 Almost at
the same time, Liu demonstrated that I2O5 can be both a radical
promoter and an iodine source for generating
βꢀCF3
alkyl/alkenyl iodides.18 Inspired by these findings, we
envisaged that the iodocarbocyclization of alkenes to yield
valuable iodinated 3,3’ꢀdisubstituted oxindoles could be
potentially realized by using I2O5 as an iodine source. Herein,
we communicate an efficient iodine pentoxideꢀtriggered
iodocarbocyclization (Scheme 1). This reaction proceeds via an
electrophilic process and produces O2 and H2O as the green byꢀ
products. Most importantly, under the reaction conditions,
various functional groups, including these electronꢀwithdrawing
and chemosensitive ones, were wellꢀtolerated, leading to the
a.School of Chemistry and Chemical Engineering, Yangtze Normal University,
Chongqing 408100, China; E-mail: mingzhongzhang2010@126.com;
wenbingshi@hotmail.com
b.State Key Laboratory of Marine Resource Utilization in South China Sea, College of
Materials and Chemical Engineering, Hainan University, Haikou 570100, China;
chentieqiao@hnu.edu.cn
† Footnotes relaꢀng to the ꢀtle and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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Table 1. Optimization studiesa
generation of the corresponding iodooxindoles in good to
excellent yields (up to 98% yields). Moreover, the reaction can
be carried out on large scales to produce the desired
iodooxindoles without significant decrease of the efficiency.
Preliminary mechanistic studies reveal that iodine pentoxide
plays a dual role (both the oxidant and iodine source) in this
iodocarbocyclization, which is mechanistically distinct from
other oxidative ones. The present protocol provides an efficient
and practical method for creating the synthetically useful
halooxindoles.9
I2O5
Entry (equiv)
Additive
(equiv)
Temp (oC)
/Time (h)
Yieldb (%)
2a
2a’
1
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
2.5
2.2
2.0
1.5
2.2
2.2
2.2
2.2
2.2
2.2
2.2
2.2
None
60/24
60/24
60/24
80/24
100/10
80/24
80/24
60/24
RT/24
80/12
80/12
80/12
80/12
80/12
80/12
80/12
80/12
80/12
Trace 12
2c
3d
4
None
Trace Trace
Trace Trace
R3
None
H
I
R3
O
I
I2O5/KI
O2
H2O
None
19
20
55
83
75
60
85
87
90
86
75
50
92
91
89
85
87
83
86
24
R1
R1
O
+
H2O, 80 o
C
N
R2
N
R2
5
None
25
6
KI (0.2)
KI (1.0)
KI (1.0)
KI (1.0)
KI (1.0)
KI (1.0)
KI (1.0)
KI (1.0)
KI (1.0)
KI (0.5)
KI (1.2)
KI (1.5)
NaI (1.2)
9
> 20 examples
up to 98% yields
I2O5 triggered green process:
7
0
O2
8
Trace
H
R3
HIO3
9
5
R1
HOI
10
11
12
13
14
15
16
17
18
19
20
21e
0
N
R2
O
''I+''
0
I2
0
I2O5
0
Trace
Scheme 1. An efficient iodine pentoxideꢀtriggered
iodocarbocyclization.
31
0
Results and discussion
0
We commenced our study by investigating the reactivity of
Nꢀ
0
arylacrylamide 1a, and the obtained results were compiled in
Table 1. An initial experiment employing 3.0 equiv of I2O5 as
the iodine source, H2O as the solvent, and the reaction provided
the cyclic product 2a’ in 12% yield (entry 1). Changing the
solvent to H2OꢀCH3CN or H2OꢀDCE produced only a trace
amount of the mixed products 2a and 2a’ (entries 2 and 3).
Elevating the temperature to 80 °C improved the efficiency of
the reaction (entry 4); however, we noted that a further rise in
the temperature failed in improving the reaction efficiency,
whereas some unknown byꢀproducts were produced within a
relatively short reaction time (10 h, entry 5). To our delight, the
main product 2a was produced in 55% yield with the addition
of 20 mol% of KI in the present reaction system (entry 6).
Encouraged by this result, we expected to obtain
diiodooxindole 2a as a single product. Satisfyingly, when the
reaction was performed with 1.0 equiv of KI in I2O5/H2O
system, the single product 2a was produced in 83% yield (entry
7). Further attempts to improve the yields by lowering the
reaction temperature were futile (entries 8 and 9). However, a
decrease of reaction time lead to a clean reaction, and the
desired product 2a was isolated in 85% yield (12 h, entry 10).
Both the loadings of I2O5 and KI were systematically optimized,
and the experimental results revealed that a combination of 2.2
equiv of I2O5 and 1.2 equiv of KI gave the highest yield of 2a
(92%, entry 16 vs entries 11ꢀ15 and entry 17). Subsequently,
other iodine anion sources such as NaI and NH4I were tested,
the results showed that KI was the best choice for this reaction
(entry 16 vs entries 18 and 19). It should be noted that when the
NH4I (1.2) 80/12
0
I2 (1.2)
KI (1.2)
KI (1.2)
80/12
80/16
80/24
0
0
22f
a
0
General reaction conditions: 1a (0.2 mmol), H2O (1 mL); RT
b
c
=
Room temperature.
Isolated yields based on 1a.
H2O/CH3CN (1:1, 1 mL). H2O/DCE (1:1, 1 mL). e 1a (0.35g,
2 mmol) and H2O (10 mL). f 1a (1 g, 5.7 mmol) and H2O (15
mL).
d
reaction was performed using 1.2 equiv of I2 as an iodine
source in the presence of I2O5, 87% yield of 2a was produced
(entry 20).19 Therefore, the optimal reaction conditions were
found to be 2.2 equiv of I2O5 and KI (1.2 equiv), using H2O as
the solvent at 80 C for 12 h. To demostrate the feasibility of
the optimized I2O5ꢀtriggered protocol, we performed the model
o
iodocarbocyclization of Nꢀarylacrylamide 1a on large scales. At
first, a 2ꢀmmol scale iodocarbocyclization of 1a is successfully
performed with I2O5 and KI, giving the desired product 2a in
satisfactory yield (16 h, entry 21). Moreover, treatment of 1 g
(5.7 mmol) of 1a with 2.2 equiv of I2O5 and 1.2 equiv of KI in
H2O at 80 oC afforded the single product 2a in 86% yield (24 h,
entry 22). Obviously, the present iodine pentoxideꢀtriggered
system leads to the highly efficient and chemoselective
2 | J. Name., 2012, 00, 1-3
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Table 2. Substrate scope for iodine pentoxideꢀtriggered formation of the diiodooxindoles.
iodocarbocyclizationa,b
With the optimized protocol in hand, the substrate scope of
this iodocarbocyclization was explored. As shown in Table 2,
substrates with haloꢀsubstituents (Cl, Br, and I) on the paraꢀ
position of the aromatic ring served well, delivering the
iodooxindoles in good to high yields. The paraꢀNO2ꢀsubstituted
substrate did not work in this reaction. Other substrates with the
R3
I
R3
I
KI (1.2 equiv)
I2O5 (2.2 equiv)
R1
R1
O
H2O (1 mL), 80 o
C
N
N
O
R2
Me
R2
1
2
strong electronꢀwithdrawing groups, as exemplified by para
ꢀ
Me
Me
I
I
CF3 and paraꢀCN substituted derivatives, underwent
cyclization readily under the reaction conditions, yielding the
desired products 2e and 2f in 68% and 72% yields, respectively.
Substrates containing electronꢀdonating groups exhibited
excellent reactivity in this reaction. For instance, paraꢀmethyl
and paraꢀmethoxy reactants gave excellent yields of 97% and
98%, respectively (products 2g and 2h). Worth noting is that
the paraꢀmethoxyꢀsubstituted alkene furnished the product with
phenyl ring C6ꢀposition being iodinated exclusively, which is in
sharp contrast to an iodobenzene diacetateꢀmediated reaction
with lower chemoselectivity.12 A substrate bearing a methyl
group on the metaꢀposition of phenyl ring could also be
cyclized to produce the corresponding product in an excellent
yield although with inevitable regioisomers (2i/2i’ in a ratio of
1.66:1). The steric hindrance seemed to have an unfavorable
impact on the conversion since the orthoꢀmethylꢀsubstituted
substrate produced the desired 2j with a decreased yield.
Naphthylanilides also underwent cyclization in this system to
selectively provide the iodinated oxindoles in excellent yields.
The substituent effect at the N atom (R2) was also investigated.
I
Cl
I
Br
O
O
O
N
N
Me
N
Me
Me
2b: 76% (24 h)
2c: 82% (24 h)
2a: 92%
Me
Me
Me
I
I
I
I
O2N
F3C
O
O
O
N
N
N
Me
Me
Me
p-I, 2a: 89% (24 h)
2d: 0% (24 h)
2e: 68% (24 h)
Me
Me
Me
N
I
I
5
6
I
C
Me
MeO
O
O
O
N
N
N
I
Me
Me
Me
2f: 72% (24 h)
2g: 97%
2h: 98%
Me
Me
Me
Me
5
I
I
I
I
I
It was found that except for a
alkene, other ꢀsubstituted substrates with phenyl, benzyl, ethyl,
ꢀbutyl, and isopropyl all proved to be productive partners.
Particularly worth noting is that when the paraꢀposition of one
benzene ring in ꢀarylacrylamide was occupied with a methyl
group, the reaction proceeded smoothly to deliver the cyclic
products 2o and 2o’ in 97% yield (the ratio of 2o 2o’ was ca.
Nꢀhydrogen atom substituted
I
O
+
O
N
O
N
N
N
n
Me
Me
Me
Me
Me
N
2j: 61%
2i + 2i': 93% (1.66:1)
Me
/
Me
Me
I
I
I
I
I
2.68:1), and a small amount of pure 2o’ could be separated
from its mixture. In addition, a tetrahydroquinoline derivative
was also compatible with the reaction conditions and provided
the desired product 2t in 85% yield. To our satisfaction, the
monosubstituted olefin (R3 position) with a chemosensitive
hydroxymethyl group also showed good reactivity in this
reaction (2u, 72%).
To understand the mechanism of this transformation, some
information has been gathered. First, the reaction proceeded
well in the presence of 2.0 equiv of radical scavengers such as
TEMPO (2,2,6,6ꢀtetramethylꢀ1ꢀpiperidinyloxy) and BHT (2,6ꢀ
diꢀtertꢀbutylꢀ4ꢀmethylphenol), which may exclude a radical
mechanism for this transformation (Scheme 2a). Second, when
O
O
O
N
N
N
Me
H
Me
2k: 97%
2l: 90%
Me
2m: trace
Me
Me
I
I
I
I
Me
Me
O
+
O
O
N
N
N
Ph
2n: 98%
2o +2o': 97% (2.68:1)c
I
paraꢀfluoroꢀsubstituted alkene
3
was employed as a substrate,
the iodohydroxylated product
5, which was produced from the
Me
Me
N
Me
I
I
classic electrophilic addition mechanism, was isolated in 64%
yield (Scheme 2b, for details, see the Supporting Information).
Similarly, with the addition of 2.0 equiv of etheneꢀ1,1ꢀ
I
I
I
I
O
O
O
N
Bn
N
diyldibenzene
6
under the standard conditions, apart from 2a
,
n-Bu
2r: 96%
Et
28% yield of the iodohydroxylated product
7
was also obtained
2p: 92%
2q: 94%
(Scheme 2c, for details, see the Supporting Information). The
above results clearly suggested that the reaction should be an
electrophilic process. Third, under the standard reaction
conditions, monoiodinated product 2a’ was converted to the
corresponding 2a with excellent yield (99%, Scheme 2d),
implying that the cyclization process probably occurred prior to
the substitution of the aromatic ring.
OH
Me
Me
I
I
I
I
I
I
O
O
O
N
N
N
i-Pr
Me
2s: 90%
2t: 85%
2u: 72%
a
General reaction conditions:
1
(0.2 mmol), I2O5 (2.2 equiv),
Since the formation of molecular iodine was confirmed by
KI (1.2 equiv) and H2O (1 mL) at 80 C for 12 h. Isolated observing the color changes of the reaction mixture (Figure S1),
yields. conversion, 100%; yield was determined by TLC we further conducted a series of control experiments to verify
o
b
c
analyse; the ratio of 2o and 2o’ was determined by 1H NMR.
the potential activated iodine species and iodine sources in our
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reaction system. Replacement of I2O5 and KI with 2.2 equiv of Scheme 2. Experiments for mechanistic studies.
I2 gave a 33% yield of the mixture products 2a and 2a’
(Scheme 3a; Conditions A). Moreover, when 5.0 equiv of I2O5
was employed to react with 1a in the absence of KI, in addition
to excellent yield of 2a was obtained (Scheme 3a; Conditions
B), the solid iodine could also be observed from the reaction
tube (Figure S1).20 The above results coupled with previous
optimization studies using 3.0 equiv of I2O5 (Table 1, entries 4
and 5), suggesting that I2O5 can be an iodine source and the
molecular iodine is presumably an activated iodine species in
this reaction. It should be noted that when readily available
HIO3, which was known as a hydrated form of I2O5,21 was used
as an iodine source instead of I2O5 and KI under otherwise
identical reaction conditions, products 2a and 2a’ were isolated
in 49% total yield; however, addition of 2.2 equiv of KIO3 to
replace HIO3 completely quenched the reaction (Scheme 3b, c).
The above results suggested that this reaction presumably
Scheme 3. The potential activated iodine species and iodine
sources verification experiments.
proceeded via HIO3 as another activated iodine species.
To further probe the mechanism, an additional competition
experiment was also performed. As shown in Scheme 4, when
0.6 equiv of both KBr and KI were used as the halide source,
the reaction gave a 95% yield of an inseparable mixture of
diiodooxindole 2a and iodobromooxindole 2b (the ratio of
2a/2b was ca. 1:1.1), implying that I2O5 could be an oxidant for
the generation of I2 in this iodocarbocyclization.22
Scheme 4. Competition experiment using KBr and KI.
Based on our experimental results as well as other reports, a
plausible reaction mechanism was proposed and shown in
Scheme 5. The oxidation of the iodine ion with iodine
pentoxide (I2O5) generates molecular iodine, which is further
transformed in water into HOI and HI reversiblely.22 Since I2O5
can be easily hydrated into iodic acid (HIO3) in water, we
propose the activated HOI could also be generated from HIO3
through a decomposition process and released O2.23 Once this
unstable species (HOI) is formed, it will be captured by the Π
electron of alkene 1a to produce an iodonium ion intermediate
A 24
trapping by water using alkenes
.
Further evidence was provided by the nucleophilic
3
and (products and ).
6
5
7
Reasonably, similar electrophilic process can also be directly
engaged by molecular iodine, since the reaction rate constant
between iodine and water is very small. The subsequent
intramolecular electrophilic cyclization and proton elimination
processes occurred successively, generating the monoiodinated
product 2a’. Finally, electrophilic iodination on the aromatic
ring in intermediate 2a’ by an activated iodine species take
place to yield the desired diiodooxindoles 2a
. For the
iodocarbocyclization reaction studied in the present
contribution, we assumed the I2O5ꢀtriggered mechanism
involving the generation of O2 and H2O as the green appendants.
4 | J. Name., 2012, 00, 1-3
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Me
Me
I
I
I
"I+"
O
O
Electrophilic
substitution
N
N
Me
Me
2a
2a'
OH
H2O
H
Me
H
I
O2
O
H2O
HIO3
HO
I
N
Me
B
or
OH
I
HI
Me
N
HI
"I+"
I
I2O5
O
H2O
H2O
Me
O
Me
A
HO
N
I- (KI)
R1
I2
Observed
Me
1a
R2
and
I
5
7
Scheme 5. Proposed mechanism.
Rubio and J. M. González, Angew. Chem. Int. Ed., 2003, 42,
2406; (e) Z. Chen, G. Huang, H. Jiang, H. Huang and X. Pan,
J. Org. Chem., 2011, 76, 1134; (f) Z. Wang, J. Zhong, C.
Zheng and R. Fan, Org. Chem. Front., 2017, 4, 1005; (g) T.
Conclusions
Aggarwal, S. Kumar and A. K. Verma, Org. Biomol. Chem.
,
2016, 14, 7639; (h) D. R. Garud, A. D. Sonawane, J. B. Auti,
N. D. Rode, V. R. Ranpise, R. R. Joshi and R. A. Joshi, New
J. Chem., 2015, 39, 9422; (i) H.ꢀT. Zhu, X. Dong, L.ꢀJ.
Wang, M.ꢀJ. Zhong, X.ꢀY. Liu and Y.ꢀM. Liang, Chem.
Commun., 2012, 48, 10748; (j) D. R. Siegel and S. J.
Danishefsky, J. Am. Chem. Soc., 2006, 128, 1048; (k) J. S.
Yadav, M. R. Pattanayak, P. P. Das and D. K. Mohapatra,
Org. Lett., 2011, 13, 1710; (l) X. Yang, W. Liu, L. Li, W.
Wei and C.ꢀJ. Li, Chem.ꢀEur. J., 2016, 22, 15252; (m) D. A.
In summary, we have developed a highly efficient iodine
pentoxideꢀtriggered iodocarbocyclization. This transformation
proceeded via an electrophilic process under transition metalꢀ
free conditions, realizing CꢀH activation, CꢀI and CꢀC bonds
formation in one pot to produce the synthetically useful
iodinated oxindoles. The use of readily available I2O5 as both
the oxidant and iodine source succeeded in avoiding the
generation of environmentally deleterious wastes. Valuable
functional groups such as halo (Cl, Br and I), methoxy,
trifluoromethyl, and even the chemosensitive hydroxymethyl
group were well tolerated. The gramꢀscale iodocarbocyclization
well demonstrated the potential synthetic application of this
highly efficient method in organic synthesis. Further studies on
the mechanism and applications are ongoing in our laboratory.
Petrone, M. Lischka and M. Lautens, Angew. Chem. Int. Ed.
2013, 52, 10635.
,
2
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Acknowledgements
This work was supported by the Natural Science Foundation of
China (No. 21275021), Program for Innovation Team Building
at Institutions of Higher Education in Chongqing
(No.CXTDX201601039), and Scientific and Technological
Research Program of Chongqing Municipal Education
Commission (KJ1601202).
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20 The thermal decomposition of I2O5 to give I2 and O2 seems
unlikely in this reaction, since it usually occurs at a much
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22 It’s known that the electronegativity of bromine is stronger
than that of iodine. Actually, the oxidation of Brꢀ with I2O5 for
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Table of contents
highly efficient iodine pentoxideꢀtriggered iodocarbocyclizations
for the synthesis of iodooxindoles has been established
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