FeIII-Catalyzed Cross-Dehydrogenative Arylation (CDA) between Oxindoles and Arenes under an Air Atmosphere

Article abstract of DOI:10.1002/chem.201502519

An efficient Fe^III-catalyzed cross-dehydrogenative arylation (CDA) of 3-substituted oxindoles with activated arenes under an air atmosphere was developed to provide 3,3′-disubstituted oxindoles in good yields.

Full text of DOI:10.1002/chem.201502519

DOI: 10.1002/chem.201502519
Communication
&
CÀH Functionalization
FeIII-Catalyzed Cross-Dehydrogenative Arylation (CDA) between
Oxindoles and Arenes under an Air Atmosphere
Hong-Ru Wu,[a, b] Hong-Yan Huang,[a, b] Chuan-Li Ren,[a, b] Li Liu,*[a] Dong Wang,[a] and Chao-
Jun Li*[c]
Chem. Eur. J. 2015, 21, 16744 – 16748
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Abstract: An efficient FeIII-catalyzed cross-dehydrogena-
tive arylation (CDA) of 3-substituted oxindoles with acti-
vated arenes under an air atmosphere was developed to
provide 3,3’-disubstituted oxindoles in good yields.
Direct CÀH functionalization to construct CÀC bonds plays an
important role in synthetic organic chemistry.[1] Among the
methods employed, cross-dehydrogenative coupling (CDC)
through direct CÀH functionalization enhances synthetic effi-
ciency—an inherent endeavor of Green Chemistry.[2] Although,
the cross-coupling reaction often requires appropriate oxidants
and efficient transition-metal catalysts such as palladium,
ruthenium, and copper reagents.[2,3] Iron, being one of the
most abundant metals, is particularly attractive for such reac-
tions because of its low price, nontoxicity, and environmentally
benign character. Indeed a considerable effort has been direct-
ed towards iron-catalyzed cross-coupling reactions through CÀ
H bond functionalization.[4] On the other hand, the use of sacri-
ficial oxidants such as 2,3-dichloro-5,6-dicyano-1,4-benzoqui-
none (DDQ), Oxone, PhI(OAc)2, tert-tutyl hydroperoxide (TBHP)
generates unwanted waste.[2,3] Nevertheless, dioxygen is
a more economical and green oxidant because it produces
water as the only byproduct, and therefore has attracted much
attention in CDC reactions recently.[5]
Scheme 1. 3-Arylation of oxindoles.
To begin our study, we chose the reaction of N-methyl-3-
benzyl-2-oxindole (1a) with anisole (2a) in anisole as a model
reaction. The results are listed in Table 1. In the absence of any
oxidant under a nitrogen atmosphere, the cross-coupling prod-
uct 3a was obtained in 90% yield, but required 200 mol% of
the FeCl3 catalyst (Table 1, entry 1). When the catalyst loading
was decreased to 20 mol%, the yield of 3a also decreased to
20% (Table 1, entry 2). The addition of DDQ into the reaction
3,3’-Disubstituted oxindoles exist in a large number of natu-
ral products and biological compounds with pharmacological
activities.[6] The coupling of oxindole derivatives with various
aromatic compounds has become an important method to
prepare 3-aryloxindoles (Scheme 1). These include: 1) a palladi-
um-[7] or phase-transfer-agent[8]-catalyzed cross-coupling of 3-
aryl-2-oxindole with aryl halides [Eq. (1)]; 2) the Friedel–Crafts
reaction of 3-hydroxyl-oxindoles with activated arene mediated
by a strong base (1,8-diazabicyclo[5.4.0]undec-7-ene; DBU) or
catalyzed by Hg(ClO4)2·3H2O to afford 3-aryloxindoles[9]
[Eq. (2)]; 3) a laccase-catalyzed 3-arylation of 3-substituted ox-
indoles recently reported by Pietruszka and Wang,[10] in which
the arene employed was limited to catechols [Eq. (3)]. Herein,
we report an FeIII-catalyzed cross-dehydrogenative arylation
(CDA) between 3-substituted oxindoles and activated arenes
under an air atmosphere for the rapid synthesis of 3,3’-disub-
stituted oxindoles [Eq. (4)].
Table 1. The dehydrogenative arylation of 1a with 2a.[a]
Entry
Catalyst
(mol%)
Oxidant
T
t
[h]
Yield
[%][b]
[oC]
[c]
1
2
3
4
5
FeCl3 (200)
FeCl3 (20)
FeCl3(20)
FeCl3 (20)
FeCl3 (20)
FeBr3(20)
–
120
120
120
120
120
120
120
120
120
120
120
120
120
120
100
80
5
3
1.5
8
8
8
90
20
72[e]
56
78
80
89
29
59
0
53
51
88
80
87
80
[c]
–
DDQ[d]
O2
air
O2
6
7
FeBr3(20)
air
3
8
9
Fe2(SO4)3 (20)
FeCl2 (20)
Ce(SO4)2 (20)
Cu(OTf)2 (20)
CuBr2(20)
FeBr3 (10)
FeBr3 (5)
air
air
air
air
air
air
air
air
24
24
24
6
[a] H.-R. Wu, H.-Y. Huang, Dr. C.-L. Ren, Prof. Dr. L. Liu, Prof. D. Wang
Beijing National Laboratory for Molecular Sciences (BNLMS)
CAS Key Laboratory of Molecular Recognition and Function
Institute of Chemistry, Chinese Academy of Sciences
Beijing 100190 (P. R. China)
10
11
12
13
14
15
16
24
4.5
E-mail: lliu@iccas.ac.cn
8
18
40
[b] H.-R. Wu, H.-Y. Huang, Dr. C.-L. Ren
FeBr3(20)
FeBr3(20)
University of Chinese Academy of Sciences, Beijing 100049 (P. R. China)
air
[c] Prof. Dr. C.-J. Li
[a] The reaction of 1 (0.2 mmol) in the presence of a catalyst in anisole
(3 mL) at given temperature. [b] Yield was determined by 1H NMR spec-
troscopy with 1,3,5-trimethoxybenzene as an internal standard. [c] Under
an N2 atmosphere. [d] 200 mol%. [e] The b-hydrogen elimination product
4 was detected (28%).
Department of Chemistry, McGill University
801 Sherbrooke Street West, Montreal, PQ, H3A 0B8 (Canada)
E-mail: cj.li@mcgill.ca
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201502519.
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afforded 3a in 72% yield together with the compound 4 in
28% (Table 1, entry 3).
that the N-substituents had little effect on the product yields.
For example, both the N-methyl- and N-benzyl-substituted ox-
indoles gave the corresponding products, 3a and 3b, in
a range of 80–85% yield. Unsubstituted 2-oxindole also
worked to give 3c in a good yield.
Treatment of 1a in the presence of 20 mol% of FeCl3 in ani-
sole (3 mL) at 1208C for 8 h under an oxygen atmosphere led
to the desired product 3a in 56% yield (Table 1, entry 4). Grati-
fyingly, the yield of 3a increased significantly to 78% when
the reaction was performed under air (Table 1, entry 5). Replac-
ing the FeCl3 catalyst by FeBr3 gave better results; the yield of
3a rose to 80% and 89%, under an oxygen atmosphere and
under air, respectively (Table 1, entries 6 and 7). Interestingly,
although there are two possible reaction sites, namely the
para- and ortho-positions of the phenyl group of anisole, the
product 3a shows an exclusive para-regioselectivity (see the
Supporting Information for X-ray crystal structure analysis).
After examining a series of iron and copper salts it was
found that FeBr3 was the most effective (Table 1, entries 8–12).
Further studies revealed that varying the amount of FeBr3 used
had little effect on the product yields of 3a and the optimum
results were obtained when the reaction was conducted at
1208C (Table 1, entry 7 versus 13–16).
Next we investigated the scope of the 3-substituted N-
methyl oxindoles (Scheme 2). N-Methyl-3-methyl-oxindole gave
the desired product 3d in 54% yield. However, when 3-methyl
was replaced with a phenyl group the reactivity increased and
3e was obtained in 86% yield. Electron-donating substituents
at the para-position of the 3-phenyl ring (R2 =4-CH3Ph (3g;
97%) and CH3OPh (3h; 92%)) gave higher yields compared
with an electron-withdrawing substituent (R2 =4-ClPh (3 f;
83%). For the cases where R2 is a benzyl group with different
substituents at the ortho-, meta-, and para-positions of the
phenyl ring, the products 3i–3m were obtained in good yields
(70–81%). N-Methyl-2-oxindole (R2 =H) (1n) was also compati-
ble under the reaction conditions, albeit giving the disubstitut-
ed product 3h in lower yield (42%). When the cyclic ketone, 8-
benzylbicyclo[4.2.0]octa-1,3,5-trien-7-one, was used instead of
oxindole, no reaction occurred. The X-ray crystal structure of
3j is shown in Figure 1.[13]
Under the optimal conditions, several 2-oxindoles with dif-
ferent N-substituents were allowed to react with 2a to give
the corresponding products 3a–c (Scheme 2). It was noted
Figure 1. X-ray crystal structure of compound 3j.
Next, various aromatic compounds were tested in the reac-
tion with 1a or 1 f, and the resulting CDA products are shown
in Scheme 3. Surprisingly, when toluene was used as an arene
substrate the desired product 3r was obtained in only 46%
isolated yield, albeit using 200 mol% of FeCl3. With the para-
position of the phenyl ring blocked by a methyl group, an ex-
cellent ortho-regioselectivity was observed in the case of the
products 3n and 3s. More electron-rich heteroaromatic com-
pounds also gave the CDA products 3u–3x in good yields
with PhCl as the solvent. Moreover, the reaction temperature
could be lowered to 508C in a few cases. When dichloroben-
zene was used as a solvent, the amount of aromatic com-
pound required could be reduced. The reaction of 1a
(0.2 mmol) with 2-methylthiophene (2k) (0.4 mmol) in 1,2-di-
chlorobenzene (3 mL) provided the coupling product 3w in
82% yield. When benzene or chlorobenzene was used as the
arene substrate, the coupling product was not obtained. It is
clear that increasing the electron density on the aromatic ring
is beneficial for the reaction, which showed Friedel–Crafts type
features. To gain a better understanding of the reaction mech-
anism, some control experiments were performed. When 1a
was treated in chlorobenzene at 1208C in the presence of
FeBr3 (20 mol%), the dimeric product 5 was isolated in 26%
Scheme 2. Scope of oxindoles; yields reported are of isolated products;
[a] yield reported in parentheses was obtained from the reaction of N-
methyl-2-oxindole (R2 =H; 1n) with anisole.
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while at the same time FeII is formed.[4,11,12] Then radical A and
FeII are oxidized to the cation species B and FeIII, respectively,
by air or FeIII under a N2 atmosphere. Air can be considered as
a diluted oxygen, which may be better than oxygen in the re-
action, thus avoiding side-reactions. The attack of intermediate
B at anisole (2a) provides cation intermediate C, which follow-
ing the loss of H+ affords the desired CDA product 3a.
In summary, we have developed a new and efficient iron-
catalyzed cross-dehydrogenative arylation of 3-substituted ox-
indoles with electron-rich aromatic and heteroaromatic com-
pounds by using aerobic oxygen as an oxidant source. We an-
ticipate that this cross-coupling will find more useful applica-
tions in organic synthesis.
Experimental Section
General procedure for the cross-dehydrogenative arylation of N-
methyl-3-substituted-2-oxindole with anisole: A mixture of N-
methyl-3-substituted-2-oxindole (0.2 mmol) and FeBr3 (0.04 mmol)
in anisole (3 mL) was stirred at 1208C for 3 h. The mixture was
cooled to room temperature, and the anisole was removed under
reduced pressure. The residue was purified by flash column chro-
matography by using ethyl acetate/petroleum ether to afford the
desired product.
Scheme 3. Scope of arenes; [a] arene substrate (3 mL) as a solvent; [b] tolu-
ene (3 mL) as a solvent and FeCl3 (200 mol%); [c] 1 f (0.2 mmol) in PhCl
(3 mL) and arene substrate (2 mmol); [d] 1 f (0.2 mmol) in 1,2-dichloroben-
zene (3 mL) and arene substrate (0.4 mmol).
General procedure for the cross-dehydrogenative arylation of N-
methyl-3-substituted-2-oxindole with aromatic and heteroaro-
matic compounds: A mixture of N-methyl-3-substituted-2-oxindole
1a or 1 f (0.2 mmol) and FeBr3 (0.04 mmol) in arene substrates 2b–
2h (3 mL) was stirred at 1208C for 3 h, while 2i–2l (2 mmol) in
PhCl (3 mL) were stirred at 808C, 1008C, 1008C, and 508C, respec-
tively. The mixture was cooled to room temperature, and the aro-
matic or heteroaromatic compounds were removed under reduced
pressure. The residue was purified by flash column chromatogra-
phy by using ethyl acetate/petroleum ether to afford the desired
product.
yield, but no CDA product was detected (Scheme 4). Based on
these findings, a tentative mechanism is proposed (Figure 2).
First, the oxindole substrate 1a tautomerizes to its enol form
1a’ in the presence of FeIIIX3, which is easily oxidized to the
corresponding radical A via a single-electron-transfer (SET),
Acknowledgements
We thank the National Natural Science Foundation of China
(Nos. 21420102003, 21372224, and 21232008), the Ministry
of Science and Technology of China (973 Program
2011CB808600), Shandong Province Independent Innovation
Scheme 4. Control experiment.
and
Achievements
Transformation
Major
Project
(2014XGC06001), and the Chinese Academy of Sciences for fi-
nancial support.
Keywords: air · arenes · CH activation · cross-dehydrogenative
arylation · iron · oxindoles
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Received: June 29, 2015
Published online on September 16, 2015
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