A Metal-free Approach to 3-Aryl-3-hydroxy-2-oxindoles by Treatment of 3-Acyloxy-2-oxindoles with Diaryliodonium Salts

Article abstract of DOI:10.1002/asia.201500854

A mild, metal-free approach has been realized for the facile construction of highly valuable 3-(hetero)aryl-3-hydroxy-2-oxindoles. Direct arylations of 3-acyloxy-2-oxindoles with diaryliodonium salts as arylation reagents are implemented in the presence o

Full text of DOI:10.1002/asia.201500854

DOI: 10.1002/asia.201500854
Communication
Arylation
A Metal-free Approach to 3-Aryl-3-hydroxy-2-oxindoles by
Treatment of 3-Acyloxy-2-oxindoles with Diaryliodonium Salts
Xiaokang Li,[a] Wei Ni,[a] Fei Mao,[a] Wei Wang,*[a, b] and Jian Li*[a]
tins as electrophilic reagents in their transformations,[4,5] we de-
Abstract: A mild, metal-free approach has been realized
signed electronically reversal 3-acyloxy-2-oxindoles as nucleo-
for the facile construction of highly valuable 3-(hetero)ar-
philes for the reaction with diaryliodonium salts[7] (Scheme 1).
yl-3-hydroxy-2-oxindoles. Direct arylations of 3-acyloxy-2-
The lesson we have learned from the study is that the 3-hy-
oxindoles with diaryliodonium salts as arylation reagents
droxy-2-oxindoles, readily obtained from the reduction of 3-
are implemented in the presence of K2CO3 at room tem-
keto group of isatins, show remarkable acidity for the negative
perature without using an organometallic promoter to de-
induction effect at the C3 position and hence reveals high nu-
liver an array of 3-(hetero)aryl-3-hydroxy-2-oxindoles in
cleophilicity[8] in the presence of a weak base.
good yields.
Diaryliodonium salts have become new popular electrophilic
arylation reagents because of their high stability, low toxicity,[9]
3-Hydroxy-2-oxindoles are featured in numerous nat-
ural products and pharmaceutically active com-
pounds with a broad spectrum of biological activi-
ties.[1] Among them, 3-aryl-3-hydroxy-2-oxindoles are
particularly important structures[1c,2] and display
promising therapeutic effects in several drug candi-
dates.[3] Therefore, the quest of efficient methods for
their synthesis is in high demand. In this context,
a number of synthetic methods have been devel-
oped. It is noted that they mainly rely on organome-
tallics as promoters for the processes of intermolecu-
lar[4] and intramolecular[5] nucleophilic addition to isa-
tins, and direct hydroxylation[6] of 3-aryl oxindoles
(Scheme 1).[7]
Herein, we wish to describe a new alternative syn-
thetic strategy to access diverse 3-(hetero)aryl-3-hy-
droxy-2-oxindoles. Notably, a mild metal-free protocol
has been realized for the first time. In the presence
of simple base K2CO3, the direct reaction of readily
available 3-acyloxy-2-oxindoles with diaryliodonium
salts as direct electrophilic arylation reagents gives
rise to the products in good yields. Furthermore, dif-
Scheme 1. Synthetic strategy of 3-aryl-3-hydroxy-2-oxindoles.
ferent from these reported methods that generally employ isa-
and easy preparation.[10] They have been widely used in organ-
ic synthesis.[11] It is noted that these arylation reactions are
generally carried out in the presence of organometallic cata-
lysts. We envisioned that easily deprotonated highly nucleo-
philic 3-hydroxyl or acetylated 2-oxindoles may be good candi-
dates for the reaction with electrophilic diaryliodonium salts.
To probe the feasibility, we performed a model reaction be-
tween 1 and diphenyliodonium salt 2a at room temperature
(Table 1).
[a] X. Li, W. Ni, F. Mao, W. Wang, J. Li
Shanghai Key Laboratory of New Drug Design
School of Pharmacy
East China University of Science and Technology
130 Meilong Road, Shanghai 200237 (China)
E-mail: jianli@ecust.edu.cn
[b] W. Wang
Department of Chemistry and Chemical Biology
University of New Mexico
Albuquerque, NM 87131-0001 (USA)
E-mail: wwang@unm.edu
Regrettably, the reactions did not afford the desired 3-aryl-
substituted target molecule in the absence of base (Table 1,
entry 1 and also see Table S1 in the Supporting Information).
However, encouraging results came from the reactions in the
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/asia.201500854.
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Table 1. Optimization of the Reaction Conditions.[a]
Table 2. Effect of the Counteranions.[a]
Entry
R1
R2
Solvent
Base
Yield [%][b]
Entry
XÀ
Yield [%][b]
1
H
H
H
H
H
Ac
Bn
Ac
Ac
THF
THF
THF
THF
THF
THF
THF
–
–
1
2
3
4c
Cl
73
56
74
72
2[c]
3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
<5
56
69
<5
48
73
OTf
PF6
PF6
Ac
Ac
H
Ac
Ac
4
5
6[d]
7[e]
[a] Unless specified, all reactions were carried out using 1a (0.2 mmol), 2
(0.24 mmol), K2CO3 (0.3 mmol), THF (2 mL) at 258C for 24 h. [b] Yields of
isolated products.[c] Extended reaction time to 36 h.
[a] Reaction conditions:
1 (0.2 mmol), 2a (0.24 mmol), and base
(0.24 mmol) in 2 mL solvent at 258C for 48 h. [b] Yields of isolated prod-
ucts. [c] A complicated mixture of products, as monitored by TLC.
[d] 508C. [e] With 1.5 equiv of base and 24 h reaction time.
Table 3. Scope of Substituted 3-acetoxy-2-oxindoles 1.[a]
presence of K2CO3 (Table 1, entries 2–4 and Table S1 in the
Supporting Information). Furthermore, among different pro-
tected forms for “O” and “N” atoms in 1, the N,O-diacetyl
substrate 1a provided the best yield of 69% (Table 1,
entry 4 and Table S1), this could be due to the more easily
produced deprotonated nucleophilic species at the C3 posi-
tion.[12] However, the reaction performed badly when O-un-
protected substrates were employed (Table 1, entries 2 and
5). This result might be due to the complex mutability of
the O-unprotected substrates under alkaline conditions.[9a,13]
Next, we chose the N,O-diacetylated 3-hydroxy-2-oxindole
as the substrate to further optimize the reaction conditions
by probing reaction media (see Table S1 in the Supporting
Information). Tetrahydrofuran (THF) was found optimal
(Table 1, entry 4). We also investigated the effect of different
bases on the reaction, and found K2CO3 to be the most suit-
able (see Table S1 in the Supporting Information). When the
reaction was conducted at 508C, the isolated yield of 3 de-
clined significantly (Table 1, entry 6). Moreover, increasing
the amount of K2CO3 accelerated the reaction rate and
shortened the reaction time while giving a higher yield of 3
(73%, Table 1, entry 7).
[a] All reactions were carried out using 1 (0.2 mmol), 2b (0.24 mmol), K2CO3
(0.3 mmol), THF (2 mL) at 258C; yields of isolated products.
Finally, we examined the effect of the counteranions[14] of
salts 2, satisfactory results were obtained with chloride and
hexafluorophosphate (Table 2, entries 1–3), however, ex-
tended reaction times did not enhance the reaction yield
(Table 2, entry 4).
Having demonstrated the preparative power of the arylation
reaction with simple symmetrical diphenyliodonium hexafluor-
ophosphate, we attempted to extend to unsymmetrical ones.
The aryl-mesityl-iodonium salts were found to be selective ary-
lation reagents,[15] and this enables the preferential transfer of
the less sterically hindered aromatic moiety.[16] Under the
above-established optimal reaction conditions, 3bc was ob-
tained in poor yield (Table 4, entry 1) Therefore, we optimized
the reaction conditions. The results from the studies showed
that CH2Cl2 was the optimal solvent and K2CO3 was the choice
of base (Table 4, entry 5). The yield decreased slightly at higher
With optimized reaction conditions in hand (see Table 2,
entry 3), we probed the scope of metal-free direct arylations of
different substituted 3-acetoxy-2-oxindoles (1a–1m) with di-
phenyliodonium hexafluorophosphate (2b). Electron-withdraw-
ing halogenated substrates reacted smoothly to deliver the
products in high yields (Table 3, 3ab–3af). It appears that the
substitution pattern is inert to the process. A similar trend is
observed with other electron-withdrawing substrates (3al and
3am). Furthermore, electron-donating groups can also effi-
ciently participate in the process (3ah–3ak).
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Table 4. Optimization of Reaction Conditions for Unsymmetrical Diarylio-
donium Salt 2c as Arylation Reagent.[a]
Table 5. Scope of Unsymmetrical Diaryliodonium Salts in the Arylation.[a]
Entry
Solvent
Base
Yield [%][b]
1[c]
2
3
4
5
6
7
8
THF
DMF
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
NaHCO3
Cs2CO3
NaOH
Et3N
32
39
45
33
47
52
38
30
49
37
34
48
54
1,4-Dioxane
Acetone
CH3CN
CH2Cl2
EA
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
9
10
11
12[d]
13[e]
K2CO3
K2CO3
[a] Unless specified, all reactions were carried out using 1a (0.3 mmol), 2c
(0.36 mmol), base (0.45 mmol), solvent (3 mL) at 258C for 24 h. [b] Yields
of isolated products. [c] Optimized reaction conditions for symmetrical di-
aryliodonium salts. [d] 358C. [e] With 1.5 mL of solvent.
temperatures (Table 4, entry 12), but decreasing the amount of
solvent was beneficial (Table 4, entry 13).
Optimal reaction conditions identified for the unsymmetrical
diaryliodonium salt 2c serve as a general protocol for the
preparation of structurally diverse 3-acyloxy-3-aryl 2-oxindoles
(Table 5). Significant structure variation can be tolerated. The
phenyl rings bearing electron-neutral (3bc), electron-donating
(3bf–3bg) and electron-withdrawing (3bd–3be, 3bh, and 3bi)
groups can effectively participate in the process. Notably, the
electronic effect has a significant impact on the reaction yield.
It seems that the halogen and electron donating-substituents
give lower yields, while the electron-withdrawing substituents
give higher yields. In addition to simple arenes, heteroaromatic
benzofuran (3bj), thiophene (3bn), fused aromatics (3bk and
3bl), and biphenyl (3bm) can also deliver the desired products
(Table 5).
[a] All reactions were carried out using 1a (0.3 mmol), 2c–2n (0.36 mmol),
K2CO3 (0.45 mmol), CH2Cl2 (1.5 mL); yields of isolated products.
The acylated 3-hydroxy-2-oxindoles provide higher necessary
activity for the arylation reaction. We found that the acyl
group can be readily removed by treatment with K2CO3 or
LiOH to give high yielding 3-hydroxy-3-phenyl-2-oxindole 4a
(Scheme 2).[17]
On the basis of previous studies,[7a,c,11b,18] a plausible mecha-
nism was proposed (Scheme 3). The base promotes formation
of enolate A from 3-acyloxy-2-oxindoles 1. The generated nu-
cloephilic species react with electrophilic diaryliodonium salts
2 to give key intermediate B. The intramolecular [2,3]-rear-
rangement delivers products 3 and byproducts Ar’I.
In conclusion, we have developed a simple and efficient
method for direct arylation of 3-acyloxy-2-oxindoles. The mild
and metal-free reaction conditions enable structurally diverse
diaryliodonium salts to participate in this process and deliver
Scheme 2. Transformation of 3aa to known hydroxyoxindole 4a.
synthetically and medicinally valuable 3-hydroxy-3-aryl-2-oxin-
doles. To our knowledge, this study represents the first exam-
ple for the preparation of this class of compounds without
using organometallics as catalysts. Although we have attempt-
ed to achieve the enantioselective version of the process, we
have not identified the protocol. Continuing efforts are under-
way in our laboratories.
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Scheme 3. Proposed mechanism.
Experimental Section
General Procedures for the Preparation of Substituted 3-
Aryl-3-hydroxy-2-oxindoles (3aa–3am) with Symmetrical Di-
aryliodonium Salt 2b
Solutions of substituted 3-hydroxy-2-oxindoles 1a–1m (0.2 mmol),
diaryliodonium salt 2b (0.24 mmol), K2CO3 (0.3 mmol) in THF
(2.0 mL) were stirred for 24 h at 258C. After the reaction was com-
pleted, the solvents were concentrated, H2O (15 mL) was added,
and the reaction mixture was extracted with EtOAc (3”15 mL). The
combined organic layers were washed with brine, dried over
Na2SO4, and concentrated in vacuo. The remaining residues were
purified by column chromatography on silica (petroleum ether/
EtOAc 20:1!15:1) to yield 3aa–3am (62%–82%) as colorless
solids.
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General Procedures for the Preparation of Substituted 3-
Aryl-3-hydroxy-2-oxindoles (3bc–3bn) with Unsymmetrical
Diaryliodonium Salt 2c–2n
Solutions of substituted 3-hydroxy-2-oxindoles 1a (0.3 mmol), dia-
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Financial support of this research provided by the National
Natural Science Foundation of China (Grants 21222211,
21372001, 91313303 and 21372073), the Program for New Cen-
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Keywords: 3-acyloxy-2-oxindoles
oxindole · arylation · diaryliodonium salt · metal-free
·
3-aryl-3-hydroxy-2-
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Manuscript received: August 16, 2015
Accepted Article published: October 20, 2015
Final Article published: November 3, 2015
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