Iron-catalyzed cross-dehydrogenative coupling of indolin-2-ones with active methylenes for direct carbon-carbon double bond formation

Article abstract of DOI:10.1039/c9gc03639c

The iron-catalyzed cross-dehydrogenative coupling (CDC) of C(sp³)-H/C(sp³)-H bonds to afford olefins by 4H elimination is described. This method employs air (molecular oxygen) as an ideal oxidant, and is performed under mild, ligand-free and base-free conditions. H₂O is the only byproduct. Good tolerance of functional groups and high yields have also been achieved. Preliminary mechanistic investigations suggest that the present transformation involves a radical process.

Full text of DOI:10.1039/c9gc03639c

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Iron-catalyzed cross-dehydrogenative coupling of
indolin-2-ones with active methylenes for direct
carbon–carbon double bond formation†
Cite this: DOI: 10.1039/c9gc03639c
Received 23rd October 2019,
Accepted 11th December 2019
Zhi-Yu Tan,‡ Ke-Xin Wu,‡ Lu-Shan Huang, Run-Shi Wu, Zheng-Yu Du and
DOI: 10.1039/c9gc03639c
Da-Zhen Xu
*
rsc.li/greenchem
The iron-catalyzed cross-dehydrogenative coupling (CDC) of
Iron is the second most abundant metal in the Earth’s
C(sp3)–H/C(sp3)–H bonds to afford olefins by 4H elimination is crust. Iron salts are cheap and incorporated into biological
described. This method employs air (molecular oxygen) as an ideal systems. The characteristic of low toxicity is especially important
oxidant, and is performed under mild, ligand-free and base-free in the pharmaceutical and food industry. These advantages
conditions. H2O is the only byproduct. Good tolerance of func- make iron salts highly attractive catalysts or reagents in chemical
tional groups and high yields have also been achieved. Preliminary transformations.12 Iron salts are considered as the ideal material
mechanistic investigations suggest that the present transformation for catalyst development. Notable achievements have been made
involves a radical process.
recently with iron salts for direct transformations of inert C–H
bonds into C–C and C–X (X = heteroatom) bonds, which were
often promoted by rare and expensive transition metal catalysts,
such as Ru, Rh, and Pd (Scheme 1a).13,14 However, iron-catalyzed
direct coupling of two unactivated C(sp3)–H alkyl groups to form
a new CvC bond is unprecedented.
On the other hand, with the increasing interest in the devel-
opment of green or sustainable chemistry, clean and environ-
mentally benign technologies have attracted significant atten-
tion. Oxidation reactions using chemical oxidants are often
expensive and cause secondary pollution, which may limit
their applications in industrial production. Air is cheap and
easily available. The use of air instead of chemical oxidants is
considered to be an ideal oxidation process due to its econ-
omic and environmental benefits.15 Herein, we report an iron-
catalyzed cross-dehydrogenative coupling reaction (CDC)
between two C(sp3)–H bonds to form C–C double bonds
Carbon–carbon double bonds have a central importance in
organic chemistry. They can be directly transformed into any
desirable functional groups.1 Some very important organic reac-
tions, such as the Heck reaction,2 olefin metathesis3 and
Sharpless epoxidation,4 are all based on olefins. Molecules with
carbon–carbon double bonds are widespread in natural com-
pounds; they constitute key intermediates for pharmaceuticals,
agrochemicals, functional materials and bulk chemicals.5 In the
past few decades, a number of typical classic olefination method-
ologies have been established, such as the Wittig reaction,6
Peterson olefination,7 McMurry coupling,8 and Julia olefination.9
And very recently, some alternative methods for the synthesis of
alkenes have been developed, such as carbene dimerization10
and a three-membered ring for carbonyl olefination.11 However,
these reactions are based on substrates with specific unsaturated
functional groups, and/or require extensive prefunctionalization
of reactants. A large amount of waste was often generated due to
the involvement of a stoichiometric amount of toxic reagents.
Hence, the development of new catalytic methods for the con-
struction of carbon–carbon double bonds from readily available
starting materials is still a significant challenge.
National Engineering Research Center of Pesticide (Tianjin), State Key Laboratory
and Institute of Elemento-Organic Chemistry, College of Chemistry, Nankai
University, Tianjin 300071, People’s Republic of China.
E-mail: xudazhen@nankai.edu.cn; Fax: (+86) 22 2350 5948
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c9gc03639c
‡These authors contributed equally to this work.
Scheme 1 Iron-catalyzed cross-dehydrogenative coupling reactions.
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(Scheme 1b). The notable features of this process include (1) a
readily available iron salt as a catalyst under ligand-free and
base-free conditions, (2) air as a green and sustainable
oxidant, and (3) low reaction temperature (50 °C).
At the outset of the project, various reaction conditions
were investigated for the model reaction between indolin-2-one
(1a) and malononitrile (2) with air as the oxidant to optimize
and identify the reaction parameters (see Table 1, and
Table S1 in the ESI†).16 The effect of different solvents was
evaluated in the presence of 10 mol% FeCl3·6H2O under open
air. To our delight, the corresponding alkene (3a) was obtained
in 91% yield within 5 h in DMF (Table 1, entry 3). However,
under the same reaction conditions, other metal salts such as
indium, ytterbium, and scandium salts fell short in affording
the desired alkene product 3a (Table 1, entries 4–7). These
results indicate that the iron catalysis of FeCl3·6H2O has
unique power in the oxidative coupling reaction for the con-
struction of alkene, even at a reduced catalyst loading (Table 1,
entries 8 and 9). To further improve the reaction conditions,
different iron salts were tested, but no better results were
obtained (Table 1, entries 10–14). Furthermore, no product
was formed under the conditions without any catalyst
(Table 1, entry 15).
With the optimized conditions in hand, we next examined
the versatility with various substituted indolin-2-ones to
explore the scope for the iron-catalyzed oxidative coupling ole-
fination reaction. As is shown in Scheme 2, the reactions of
indolin-2-ones with electron-donating and electron-withdraw-
ing groups all proceeded smoothly to deliver the desired
alkenes in good yields (3a–g). Indolin-2-ones with substituted
Scheme 2 Substrate scopes of indolin-2-ones with nitriles. Unless
otherwise noted, the reactions were performed on a 0.5 mmol scale
under the standard reaction conditions, see Table 1, entry 9. [a]
FeCl3·6H2O (10 mol%). [b] DMSO was used as the solvent. [c]
Determined by 1H NMR.
Table 1 Optimization of the iron-catalyzed oxidative coupling
groups at the 4-, 6-, and 7-positions were well tolerated, provid-
ing the corresponding alkenes in high yields (3h–k). Even the
sterically hindered substrate 4-chloroindolin-2-one reacted
smoothly to afford the desired product 3h in a good yield of
88%. Indolin-2-ones possessing N-protecting groups, such as
phenyl, allyl, methyl, n-butyl and benzyl, were found to be par-
ticularly compatible with this reaction (3l–q). Moreover, mul-
tiple substituted indolin-2-ones were also efficiently converted
into the corresponding products (3r–u). Having demonstrated
that the dehydrogenative process is compatible with various
substituted indolin-2-ones, we investigated other nitriles. It
was found that benzoylacetonitrile (2b) and ethyl cyanoacetate
(2c) were less reactive, and the alkene products were isolated
in moderate yields (3v–3aa). However, 2-benzofuranone could
not be employed successfully (3ab).
To demonstrate the further synthetic utility of this protocol,
a gram-scale reaction was carried out and 1.03 g of 3a was
obtained in 88% yield (Scheme 3). Then several transform-
ations were carried out. The double bond of 3a could be
reduced by treatment with the Hantzsch 1,4-dihydropyridine
ester, affording the product 4 in 85% yield (Scheme 3i).
Michael addition processes with 2-methylquinoline and
diethyl phosphate were also explored, delivering the products
reactiona
Entry
Cat. (10 mol%)
Solvent
Yieldb (%)
1
2
3
4
5
6
FeCl3·6H2O
FeCl3·6H2O
FeCl3·6H2O
InCl3
In(OTf)3
Yb(OTf)3
Sc(OTf)3
FeCl3·6H2O
FeCl3·6H2O
FeBr3
Fe(NO3)3·9H2O
Fe2(SO4)3·xH2O
FeCl2·4H2O
Fe(OAc)2
DMSO
DCE
78
—
91
—
—
—
—
91
91
90
82
77
—
37
—
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
7
8c
9d
10d
11d
12d
13d
14d
15
—
a Reaction conditions: 1a (0.5 mmol, 1.0 equiv.), 2 (0.6 mmol, 1.2
equiv.), catalyst (10 mol%), DMF (0.5 mL), 50 °C, under open air, 5 h.
b Isolated yield. c With 5 mol% catalyst. d With 3 mol% catalyst.
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Scheme 5 Proposed reaction mechanism.
were added in the reaction under the standard conditions, the
present transformation was completely inhibited, suggesting
that a radical intermediate might be involved in this trans-
formation (Scheme 4a). On the other hand, we observed that
only a trace amount of 3a was obtained when the reaction was
performed under an argon atmosphere (Scheme 4b). This
result signifies the importance of air (molecular oxygen).
Moreover, a mixture of isatin (10) and the oxidative coupling
product (11) was obtained in the absence of malononitrile (2a)
(Scheme 4c). This result suggests that a radical intermediate
might be generated from indolin-2-one (1a) in the presence of
FeCl3 via a single-electron transfer (SET). In addition, com-
pound 11 could be reacted with malononitrile (2) to afford 3a
in 96% yield under the standard conditions (Scheme 4d).
Based on the above control experiments and previous
reports,13c,17 a tentative mechanism is illustrated in Scheme 5.
Initially, in the presence of Fe(III), indolin-2-one (1a) could be
easily converted into the corresponding radical A via a single
electron transfer (SET) and loss of H+. In this step, the sub-
strate 1a acts as an auxiliary ligand with Fe(III) leading to a
chelate Fe complex 1a′ which may play a key role in the oxi-
dation step of 1a to A. Then, indolin-2-one radicals (A) abstract
hydrogen atoms from methylene nitriles to afford radical B,
which may react with A to afford intermediate C. Finally, C was
oxidized to provide the product via two single electron trans-
fers (SET) and loss of two H+.
Scheme 3 Gram-scale synthesis and synthetic manipulations.
Conditions: (i) Hantzsch 1,4-dihydropyridine ester (1.05 equiv.), ethanol,
r.t., 15 min, 85% yield. (ii) 2-Methylquinoline (1.05 equiv.), H2O, 100 °C,
2 h, 88% yield. (iii) Diethyl phosphate (1.05 equiv.), [DABCO-H]AcO
(10 mol%), THF, r.t., 30 min, 97% yield. (iv) Dimethyl acetylenedicarboxy-
late (1.05 equiv.), 4-bromoaniline (1.0 equiv.), [DABCO-H]AcO (10 mol%),
ethanol, 40 °C,
5 h, 85% yield. (v) 1,3-Indanedione (1.05 equiv.),
[DABCO-H]Cl (10 mol%), ethanol, 50 °C, 91% yield. (vi) Hantzsch 1,4-
dihydropyridine ester (0.5 equiv.), InCl3 (20 mol%), ethanol, r.t., 2 h, 67%
yield.
in good yields of 88% and 97% respectively (Scheme 3ii and
iii). Furthermore, spiro 1,4-dihydropyridine (7) and spiro 4H-
pyran (8) could be obtained in one step from 3a (Scheme 3iv
and v). Moreover, the reductive self-coupling cyclization
product 9 could be obtained catalyzed by InCl3 in the presence
of the Hantzsch 1,4-dihydropyridine ester (Scheme 3vi).
To gain more insights into the reaction pathway, a few
control experiments were performed as shown in Scheme 4.
Firstly, when radical trapping reagents such as TEMPO
(2,2,6,6-tetramethyl-1-piperidinyloxy) or 1,1-diphenylethylene
Conclusions
In summary, we have developed an iron-catalyzed oxidative
coupling reaction between two different C(sp3)–H bonds to
access carbon–carbon double bonds under ligand-free and
base-free conditions. The use of iron salts as catalysts in the
cross-dehydrogenative coupling reaction to construct olefins
has not been described previously. Notably, this protocol
employed air as a green and sustainable oxidant, and H2O is
the only byproduct. Two readily available methylene com-
pounds directly lost four Hs to from a carbon–carbon double
bond under mild conditions, providing a new way to access
olefins. A wide range of substituted indolin-2-ones and nitriles
could be well tolerated in the current catalytic system. We
Scheme 4 Control experiments.
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anticipate that this work will highlight the iron-catalyzed
cross-dehydrogenative coupling (CDC) reactions. Further
studies on the application of the cross-dehydrogenative coup-
ling reaction are currently underway in our laboratory.
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This work was financially supported by the National Training
Programs of Innovation and Entrepreneurship for
Undergraduates (No. 201810055095, 201910055087). We also
thank the Chemistry College of Nankai University for support.
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