Synthesis of hydroxyl-containing oxindoles and 3,4-dihydroquinolin-2-ones through oxone-mediated cascade arylhydroxylation of activated alkenes

Article abstract of DOI:10.1039/d0gc02205e

Hydroxyl-containing compounds are highly value-Added organic molecules, and the establishment of novel methodologies for their elaboration is a long-standing challenge in organic synthesis. Here the first oxone-mediated direct arylhydroxylation of activat

Full text of DOI:10.1039/d0gc02205e

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DOI: 10.1039/D0GC02205E
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PAPER
Synthesis of Hydroxyl-Containing Oxindoles and 3,4-
Dihydroquinolin-2-ones through Oxone-Mediated Cascade
Arylhydroxylation of Activated Alkenes
Received 00th January 20xx,
Accepted 00th January 20xx
Ming-Zhong Zhang,*a Long Liu,b Quan Gou,a Qi Wang,a Yi Li,a Wan-Ting Li,a Fei Luo,a Min Yuan,a
DOI: 10.1039/x0xx00000x
Tieqiao Chen*b and Wei-Min He*c
Hydroxyl-containing compounds are highly value-added organic molecules, and the establishment of novel methodologies
for their elaboration is
a long-standing challenge in organic synthesis. Here the first oxone-mediated direct
arylhydroxylation of activated alkenes was developed for the synthesis of valuable hydroxyl-containing oxindoles and 3,4-
dihydroquinolin-2-ones. The products were controlled by adjusting the structure of the starting alkenes. Moreover, the
reaction was operated under simple conditions without any external additives or catalysts. Primary mechanistic studies
showed that this reaction was a tandem process involving epoxidation and subsequent Friedel-Crafts alkylation, and oxone
played a dual role (both the oxidant and proton source) in this process.
Me
Me
OH
R
ref. 2-6
Introduction
NMe
Ar
O
N
N
H
3,3-Disubstituted 2-oxindoles exist extensively in a variety of
bioactive molecules as one kind of important five-membered fused
nitrogen-heterocycles.1 Among them, the quaternary 3-
hydroxymethyl-2-oxindoles are particularly attractive, because they
are very valuable for the synthesis of natural product esermethole
and physostigmine.2-6 As illustrated in Scheme 1, a number of
multistep reactions have been developed for the production of 3-
hydroxymethyl-2-oxindoles, but these approaches usually suffer
from low atom economy and require poisonous reagents or
expensive metal catalysts (Scheme 1a).2,3 In 2015, the Pd-catalyzed
Heck/borylation of N-(2-iodophenyl)acrylamides was demonstrated
as an indirect approach for producing 3-hydroxymethyl-2-oxindoles
(Scheme 1b).4 Recently, we reported an oxidative radical
aminooxyarylation of activated alkenes, affording products that
could be further converted into 3-hydroxymethyl-2-oxindoles in an
aqueous acetonitrile solution (Scheme 1c).5 An oxidative
rearrangement strategy was also developed for the direct assembly
Me
Key intermediates for natural products
Me
R = OMe, esermethole
R = OCONHMe, physostigmine
(a)
R2
Me
COOMe
COOMe
OH
At least five steps (ref. 2)
Three steps (ref. 3)
O
O
N
N
or
etc.
Cl
R1
Me
R1 = Boc, H et al
R2 = H, Me et al
(b) Two steps (ref. 4)
O
B
Me
Me
I
OH
Me
Pd cat.
B2pin2
Oxone
O
O
O
Acetone/H2O
N
Me
N
N
O
Me
Me
(c) Two steps (ref. 5)
Me
Me
OH
PINO
Me
NHPI
K2S2O8/TBAI
Mo(CO)6
O
O
CH3CN/H2O
N
N
Me
N
O
Me
Me
of 3-hydroxymethyl-2-oxindoles, the reaction relied on
a
(d) One step operation from prefunctionalized substrates (ref. 6)
Me
prefunctionalized 2-hydroxymethylindole substrate and needed to
use the environmentally unfriendly organic fluorine reagent as the
oxidant (Scheme 1d).6 Thus, more economical, practical and eco-
Me
OH
OH
Selectfluor (1.2 equiv.)
O
N
N
Me
Me
Scheme 1 Preparation of 3-hydroxymethyl-2-oxindoles
a. School of Chemistry and Chemical Engineering, Yangtze Normal University,
Chongqing, 408100 China. E-mail: mzzhang@yznu.edu.cn.
friendly synthetic strategies for 3,3-disubstituted 2-oxindoles are
highly desirable.
b. Key Laboratory of Ministry of Education for Advanced Materials in Tropical Island
Resources, Hainan Provincial Key Lab of Fine Chem, Hainan University, Haikou,
570228, China. E-mail: chentieqiao@hnu.edu.cn.
The 1,2-difunctionalization of alkenes can incorporate two
functional groups into a molecule in one pot with high atom- and
step-economic efficiency and thus is recognized as a powerful
method for building the highly value-added molecules.7 During the
past decades, much effort has been devoted to this field, and many
c. Department of Chemistry, Hunan University of Science and Engineering, Yongzhou
425100, China. E-mail: weiminhe2016@yeah.net.
†Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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transition metal-catalyzed and metal-free methods have been Table 1. Optimization of the arylhydroxylation of activated alkene 1aa
View Article Online
Me
DOI: 10.1039/D0GC02205E
developed,
achieving
dicarbofunctionalization,8
OH
Me
carboheterofunctionalization9 and diheterofunctionalization.10 The
direct arylhydroxylation of alkenes is an important method for the
synthesis of hydroxyl compounds. However, only few examples
were reported. In 2013, Jiao’s group described that phenyl
hydrazines could oxidatively couple with styrenes to produce the
corresponding arylhydroxylating products.11 Three years later, a
similar arylhydroxylation reaction was accomplished by Heinrich’s
group using aryldiazonium salts as a radical source under thermal
induced conditions.12 In 2018, Buchwald et al. reported a new
version of arylhydroxylation reaction of dehydroalanine with
Oxone
Solvent, Temp (oC)
O
N
N
O
24 h
Me
Me
1a
2a
Yield (%)b
55
Entry
1
2
3
4c
5
6
7c
8c
Oxone (equiv.)
Solvent
MeCN
DCE
Benzene
DMSO
DMF
EtOAc
THF
PhCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
Tem. (oC)
80
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
1.5
1.2
2.0
2.0
2.0
80
80
80
80
80
80
80
90
trace
trace
N.R.
trace
trace
N.R.
N.R.
74
aryldiazonium salts through
ferrocene.13
a catalytic redox process using
9
R2
One-step to precious molecules from easily
accessible alkenes
10
11
12
13d
14e
15f
100
90
63
70
OH
Ar
O
90
61
N
R1
R3
O
R2
R3
R2
90
57
R1
N
R1
N
R3 = H
R3
Oxone
H+
90
71
H
-K SO4
Ar
Ar
90
74
O
a Reaction conditions: a mixture of 1a (0.3 mmol), oxone in solvent (3.0
mL) was heated at the indicated reaction temperature under the air
atmosphere for 24 h. b Isolated yield. c N.R. = no reaction. d 12 h. e 30 h. f
Under N2 atmosphere.
OH
O
Via
Ar
Dual role of oxone, external-catalyst-free
Controllable cyclization
Overall: 37 examples, up to 91% yields
N
R1
O
R2 = H
Heating the mixture of activated terminal alkene 1a, oxone (2
equiv.) in MeCN at 80 C for 24 h under air atmosphere resulted in
Scheme 2 Oxone-mediated intra-molecular direct arylhydroxylation
of activated alkenes
o
the formation of the desired 3-hydroxymethyl-2-oxindole 2a in 55%
yield (Table 1, entry 1). Next, a series of solvents were investigated.
MeCN seemed to be essential to this reaction, since no or only a
trace amount of product could be detected in other solvents such
as DCE, benzene, DMSO, DMF, EtOAc, THF and PhCN (entries 2-8).
When the reaction was carried out at 90 oC, the yield of 2a
increased to 74% (entry 9); however, further elevating the reaction
temperature to 100 oC lead to slight decrease of the yield (entry 10).
To our satisfaction, a good yield (70%) was also achieved by
reducing the amount of oxone to 1.5 equiv. (entry 11); however,
when 1.2 equiv. of oxone was used, the yield of 2a decreased to
61% (entry 12). The reaction time was also screened with 24 h
being suitable for this reaction (entries 9, 13 and 14). Finally, the
same yield of 2a was obtained under N2 atmosphere (entry 15).
With the optimal reaction conditions in hand, the substrate scope
was subsequently investigated. As shown in Table 2, this reaction
showed relatively high functional group tolerance. For example, F,
Cl, Br, CF3, MeO and Me all were compatible under the reaction
conditions (2b-2g). It should be noted that the yield was affected by
the electron density of benzene ring. When the electron-deficient
substrates were used, the yield decreased. Prolonging the reaction
time could improve the yields to some extent. The results were
consistent with the proposed mechanism as described below,
because the Friedel-Crafts alkylation took place more readily at the
electron-rich benzene. In the cases of the N-methyl-N-
phenylmethacrylamides bearing strong electron-withdrawing fluoro
or trifluoromethyl substituent on the phenyl ring (1b or 1e), the
epoxides 2b’ and 2e’ were formed in 26% and 40% yield,
respectively. The steric hindrance also affected the reaction. For
example, when ortho-methyl derivative was used under the
Oxone is a cheap, stable, easy to handle and nontoxic inorganic
oxidant.14 The oxidation reactions with oxone as the oxidant have
been extensively studied over the past years. However, to the best
of our knowledge, the dual role of oxone in organic transformations
has rarely been reported.15 We herein reported an intra-molecular
arylhydroxylation16 reaction (Principle 8, Reduce Derivatives) for the
synthesis of hydroxyl-containing heterocycles with oxone as the
sole oxidant under the transition-metal-free conditions (Principle 3,
Less Hazardous Chemical Syntheses). This reaction was a cascade
epoxidation/Friedel-Crafts alkylation process. In the reaction, the
oxone not only acted as an oxidant for the epoxidation of alkenes
but also served as the proton source for the subsequent ring-
opening Friedel-Crafts alkylation (Principle 1, Prevention). This
reaction provided a versatile and simple platform for the selective
construction of 3-hydroxymethyl-2-oxindoles and 3-hydroxy-3,4-
dihydroquinolin-2-ones17 with step- and atom-economy (100% with
respect to N-arylacrylamides, Principle 2, Atom Economy). It should
be noted that the halocarbocyclizations of N-arylacrylamides with
halogenation reagents in the presence of a large excess of oxidants
have been developed for the construction of 3-halomethyl-2-
oxindoles18 and analogues.19 These products might be further
transformed into the corresponding hydroxyl derivatives via extra
reaction procedures. However, the requirement of stoichiometric
halogenation reagents not only increased the manufacturing cost
but also led to producing copious halide waste. Mechanistic studies
showed that halonium ions were the key intermediates in these
reactions.
Results and discussion
2 | J. Name., 2012, 00, 1-3
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standard conditions, the corresponding cyclizing product (2h) was (2r and 2s). A series of heteroaromatic substratVeisewwAreticrlee Oanllisnoe
given in 45% yield; the epoxide 2h’ was also isolated in 38% yield. explored under the standard conditions. However, the
DOI: 10.1039/D0GC0220N5E-
When the substrates bearing meta-group were used, a mixture of heteroaromatic substrates failed to produce the desired products,
regioisomers were generated with the cyclization preferentially which might be caused by the formation of heteroaromatic onium
occurring at the para-position of meta-group (2i and 2j).20 The N- salt between N-heteroaromatic substrates and potassium bisulfate.
substituent was subsequently investigated, and all selected The O-heterocycles gave
a complex mixture of unidentified
derivatives could be converted into the expected arylhydroxylated products. As demonstrated in Table 1, the reaction of 1a with 1.5
products in good to high yields (2k-2q). As expected, a mixture of equiv. of oxone could also provide a satisfactory yield (entry 11).
regioisomers was given when the substrate bearing two N-aryl We also evaluated the reaction efficiency of several well performed
groups (2o) was applied. Worth noting is that a three cyclic product substrates under the reaction conditions, and the results were
was produced in a good yield when the tetrahydroquinoline listed under the corresponding products (2f, 2g, 2m, 2r and 2s) in
derivative was used under the reaction conditions (2q). The Table 2.
substituent effect at the α-position of the acrylamide moiety was
also investigated. It was found that both ethylacrylamide and five-membered cyclic oxindoles, but the six-membered cyclic 3,4-
We then investigated the internal alkenes.21 Interestingly, not the
phenylacrylamide showed high reactivity in this arylhydroxylation
dihydroquinolin-2-ones were produced under the reaction
conditions. As illustrated in Table 3, a variety of six-membered cyclic
hydroxyl-containing products including those with functional groups
were generated in good to high yields (4a-4o). The studies on the
Table 2. Direct arylhydroxylation of activated terminal alkenesa,b
R3
R3
OH
Oxone (2 equiv.)
R1
R1
O
MeCN, 90 oC, 24 h
N
R2
N
R2
O
Table 3. Direct arylhydroxylation of activated internal alkenesa,b,c
1
2
R
R
OH
Me
Me
Me
Me
Oxone (1.5 equiv.)
MeCN, 90 oC, 24 h
R1
OH
R1
OH
OH
OH
Cl
F
Br
N
R2
O
N
R2
O
O
O
O
O
N
N
Me
, 74%
N
N
4
3
Me
Me
Me
c,d
c
2a
2b
2c
2d
, 53%
, 62%
, 66%
Me
Me
Me
Me
OH
OH
OH
OH
OH
OH
MeO
OH
CF3
OH
Me
Me
MeO
O
O
O
O
N
N
N
N
N
O
N
O
N
O
N
O
Me
Me
Me
Me
Me
Me Me
Me
Me
Me
e,f
g
g
h
2e
, 12% (34%
)
2g
, 81% (73% )
2f
, 85% (76% )
2h
, 45%
Me
4a
, 69%
4b
4c, 79%
, 74%
4d
, 63%
Me
Me
Cl
Me
Me
Me
OH
OH
OH
OH
O
N
Me
+
O
+
O
O
OH
Br
OH
N
Me
Cl
N
Me
N
Me
OH
Me
OH
N
O
N
O
2i + 2i',
2j 2j',
+
77% (1.91:1)
Me
60% (2:1)
Me
N
O
Me
4e
, 65%
N
O
Me
Me
Me
Me
Me
OH
OH
4f
OH
OH
, 84%
F
4g
, 91%
Cl
4h
, 73%
O
O
O
O
OMe
N
N
N
Et
N
Cl
Ph
n-Bu
i-Pr
g
2m
, 82% (77% )
2k
2l
2n
, 78%
, 87%
, 69%
OH
OH
OH
OH
Me
Me
Me
OH
OH
Me
Me
O
OH
N
O
N
O
N
O
N
Me
, 57%
O
O
O
HO
+
Me
Me
Me
4kd, 68%
O
N
N
N
N
4j
4l, 61%
4i
, 88%
Bn
2p
, 73%
2q
, 61%
Me
Cl
Me
2o 2o',
+
80% (1.17:1)
Ph
Me Me
OH
OH
OH
OH
Et
N
Unsuccessful substrates
OH
OH
N
O
N
O
N
O
N
O
O
Me Me
N
Me Me
O
Me
Me
Me
Me
N
Me
N
Me
4n
, 66%
4m
4o
, 64%
, 71%
4p
, 63%
O
O
N
N
g
g
2r
, 79% (71% )
1t
2s
1u
, 86% (80% )
n-Pr
O
Me
O
Me
OH
O
OH
Me
N
O
N
Ph
OH
Ph
N
Me
N
O
N
O
N
O
Me
O
Me
N
Me
Me
Me
1v
O
1w
1x
4q
, 71%
4s
,0%
4r
, 88%
a
Reaction conditions: a mixture of 1 (0.3 mmol), oxone (2 equiv.) in
a
MeCN (3.0 mL) was heated at 90 oC under air atmosphere for 24 h.
b
Reaction conditions: a mixture of 3 (0.3 mmol), oxone (1.5 equiv.) in
MeCN (3.0 mL) was heated at 90 oC under air atmosphere for 24 h.
Isolated yields. c Only trans isomers were observed. d The trans isomer of
4k was confirmed by single-crystal X-ray diffraction analysis.
b
Isolated yields. c 30 h. d Epoxide 2b’ was also isolated in 26% yield. e 40 h. f
Epoxide 2e’ was also isolated in 40% yield. g Using 1.5 equiv. of oxone.
h
Epoxide 2h’ was also isolated in 38% yield.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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N-substituent effect showed that both ethyl and n-butyl groups
On the basis of these results and previous related literatures,14a,23
View Article Online
DOI: 10.1039/D0GC02205E
promoted this reaction (4f and 4g). Again, the heavier the electron the arylhydroxylation of activated alkenes would take place through
density is, the easier Friedel-Crafts alkylation occurs. The electron a tandem process involving epoxidation and subsequent Friedel-
effect on the aryl group connected with the carbon-carbon double Crafts alkylation, and oxone acted as a dual role mediator in this
bond was also studied and showed that higher yields were obtained tandem process (Scheme 4). It should be noted that the ring-
with the electron-rich substrates (4h-4o). It was deduced that the opening Friedel-Crafts alkylation of arenes with epoxides
electron-rich aryl group could promote the cleavage of C-O bond determined the regioselectivity to produce either five-membered
during the ring-opening Friedel-Crafts alkylation, and thus cyclic hydroxyl-containing oxindole or six-membered cyclic
enhanced the yield. Acrylamide substrates with alkyl substituents hydroxyl-containing 3,4-dihydroquinolin-2-ones.
on the β-position of vinyl group gave the desired products (4p and
4q) in good yields. N-Methyl-N-phenyl-4,5-dihydrofuran-3-
carboxamide also produced the expected cyclizing product 3,4-
dihydroquinolin-2-one product (4r) in 88% yield. Unluckily,
acrylamide bearing methyl groups on both α- and β-position of vinyl
group afforded a complex mixture of unidentified products under
the reaction conditions (4s).
As shown in Figure 1, the structure of product 4k was confirmed
by single-crystal X-ray diffraction analysis, clearly showing that
phenyl and hydroxyl groups were not on the same side of ring
(CCDC 2012568; for details, see the ESI†). The result indicated that
this reaction exhibited high trans-selectivity in the ring-opening
Friedel-Crafts alkylation.
R2
R2
H
Oxone (KHSO5)
Me
N
Me
N
K
O
S
O
R1
R1
Ph
O
O
Ph
H
K
SO4
O
O
O
or
1
3
+
R1
R1
OH
H
OH
OH
R1
+
R2 = H
O
O
N
N
N
O
H+
Me
Me
Me
R2
2
H+
Me
N
O
R1
Ph
R2
R2
R2
+
O
H
OH
OH
OH
+
R1 = H
N
O
N
O
N
O
H+
Me
Me
Me
4
Scheme 4 Proposed mechanism
Conclusions
In summary, we have described for the first time an oxone-
mediated cascade arylhydroxylation of activated alkenes, and
both the valuable hydroxyl-containing oxindoles and 3,4-
dihydroquinolin-2-ones could be readily prepared by adjusting
the structure of the starting alkenes. The efficiency and
practicality of this new methodology were well demonstrated
with (1) 37 examples, (2) wide functional group tolerance and
generally good yields (up to 91%), and (3) successful
integration of epoxidation and ring-opening Friedel-Crafts
alkylation as a one-pot reaction, achieving one step synthesis
of high value-added molecules, especially 3-hydroxymethyl-2-
oxindoles, from easily accessible alkenes. The present method
is of great value from the viewpoint of green chemistry and
organic synthesis because of using cheap and non-toxic oxone
as a dual role mediator under additional additives- and
catalysts-free conditions.
Figure 1 Molecular structure of product 4k (one crystal water is
attached).
In order to gain some mechanistic information, several control
experiments were conducted (Scheme 3). During the reaction
process, epoxide product 2a’ was detected by GC-MS (for details,
see the ESI†). Previous work has showed that oxone is an effective
oxidant for the epoxidation of alkenes.14a Therefore, combining
with the electron effect described above, it was deduced that
epoxides might be the key intermediate in this reaction. We also
synthesized compound 2a’22 and found that it indeed could be
converted into the corresponding oxindole 2a under the current
reaction conditions (Scheme 3a). This reaction could also take place
readily with oxone or oxalic acid (1 equiv.) (Scheme 3b and 3c).
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
Me
O
We gratefully acknowledge financial support from the Project
for Basic Research and Frontier Exploration of Science and
Technology Commission of Chongqing (no. cstc2018jcyjAX0419
and cstc2019jcyj-msxm1275), the Science and Technology
Research Program of Chongqing Municipal Education
Commission (no. KJ1601202 and KJQN201901422), the Natural
OH
Me
Oxone or acid
MeCN (3.0 mL), 90 oC, 24 h
O
N
N
O
Me
Me
(a)
(b)
(c)
oxone (2 equiv.)
oxone (1 equiv.)
oxalic acid (1 equiv.)
82%
80%
65%
2a'
2a
Scheme 3 Control experiments
4 | J. Name., 2012, 00, 1-3
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21, 1480; (e) A. D. Manick, G. Duret, D. N. Tran,VFie.wBAertrichlealOanlninde
G. Prestat, Org. Chem. Front., 2014, 1,D1O0I5: 810..1039/D0GC02205E
11 Y. Su, X. Sun, G. Wu and N. Jiao, Angew. Chem., Int. Ed.,
2013, 52, 9808.
Science Foundation of Hainan Province (no. 219MS005), and
the Nature Science Foundation of China (no. 21871070).
12 S. Kindt, K. Wicht and M. R. Heinrich, Angew. Chem., Int. Ed.,
2016, 55, 8744.
13 R. K. M. Khan, Y. Zhao, T. D. Scully and S. L. Buchwald, Chem.-
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14 (a) H. Hussain, I. R. Green and I. Ahmed, Chem. Rev., 2013,
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15 J. N. Moorthy and K. N. Parida, J. Org. Chem., 2014, 79,
11431.
16 For an unsuccessful example on intra-molecular
arylhydroxylation starting from aryl borons through a radical
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17 3,4-Dihydroquinolin-2-ones are another important class of N-
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K. Shen, X. Liu, W. Wang, G. Wang, W. Cao, W. Li, X. Hu, L. Lin
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2-Hydroxymethylindoles
are
prepared
from
the
corresponding ethyl esters that are usually uneasy to get,
see: X. Jiang, J. Yang, F. Zhang, P. Yu, P. Yi, Y. Sun and Y.
Wang, Org. Lett., 2016, 18, 3154.
7
For selected reviews, see: (a) Z.-L. Li, G.-C. Fang, Q.-S. Gu and
X.-Y. Liu, Chem. Soc. Rev., 2020, 49, 32; (b) J. Lin, R.-J. Song,
M. Hu and J.-H. Li, Chem. Rec., 2019, 19, 440; (c) G. Yin, X.
Mu and G. Liu, Acc. Chem. Res., 2016, 49, 2413; (d) E. Merino
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For selected examples, see: (a) R. Beniazza, V. Liautard, C.
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20 Similar regio-selectivity can also be found in radical
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8
21 We found that with 1.5 equiv. of oxone is better for the
reaction of internal alkenes.
22 Compound 2a’ was prepared in 70% yield by treating 1a with
m-CPBA (2 equiv.) in MeCN at 80 oC for 24 h, for the
characterization data and the NMR spectra of epoxide 2a’,
see the ESI†. In addition, we noticed that the ring-opening
product 2a was not produced in this reaction. A few reports
showed that m-CPBA could also be a dual role reagent in the
oxidation of olefins, but the reaction usually occurred at
room temperature; the reason may be due to the easy
decomposability of m-CPBA under heating conditions. For
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Cao, K. Gao, C. Niu and H. Yang, J. Org. Chem., 2013, 78,
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9
10 For selected examples, see: (a) Y. Yang, R.-J. Song, X.-H.
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Marcos, C. Rodríguez-Escrich, C. I. Herrerías and M. A.
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