Co/Mn-mediated oxidative cross-coupling of indoles with β-keto esters via dioxygen activation: An efficient access to ketonization-olefination of indoles

Article abstract of DOI:10.1039/c1cc10545k

The Co/Mn-mediated oxidative cross-coupling of indoles with β-keto esters via dioxygen activation under mild conditions leads to ketonization-olefination of indoles. This reaction furnishes the highly functionalized products with excellent selectivity in good yields. The Royal Society of Chemistry 2011.

Full text of DOI:10.1039/c1cc10545k

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COMMUNICATION
Co/Mn-mediated oxidative cross-coupling of indoles with b-keto esters
via dioxygen activation: an efficient access to ketonization–olefination of
indolesw
Wenliang Wu, Jing Xu, Shijun Huang and Weiping Su*
Received 27th January 2011, Accepted 3rd March 2011
DOI: 10.1039/c1cc10545k
The Co/Mn-mediated oxidative cross-coupling of indoles with
b-keto esters via dioxygen activation under mild conditions leads
to ketonization–olefination of indoles. This reaction furnishes
the highly functionalized products with excellent selectivity in
good yields.
To the best of our knowledge, this reaction represents the first
example of the C–C double bond formation accompanied by
oxygen-atom transfer via dioxygen activation and multiple
C–H bond cleavages.
Initially, we observed the formation of (Z)-ethyl 3-oxo-2-
(3-oxoindolin-2-ylidene)-3-phenylpropanoate (3a) in the reaction
of indole (1a) and ethyl benzoylacetate (2a) in the presence
of Co(OAc)2 under aerobic conditions. The structure of 3a
was elucidated by NMR studies and confirmed by X-ray
crystallography (see Supporting Informationw). Being highly
functionalized, 3a would find applications in organic synthesis.10
The data in Table 1 illustrates the impact of various parameters
on this reaction. The reaction of 1a with equimolar 2a carried
out in the presence of stoichiometric amount of Co(OAc)2
under an atmosphere of oxygen (1 atm) gave the product 3a in
14% yield in the distilled DMF (entry 1). Reducing the loading
of Co(OAc)2 resulted in a decrease in yield. For example, use
of 15 mol% of Co(OAc)2 gave only a trace of 3a, indicating
that stoichiometric amount of Co(OAc)2 was required for this
transformation (entry 2). Increasing the amount of 2a relative
to 1a and introducing pivalic acid into the reaction system
improved the conversion of 1a (entry 9, Table 1). Pivalic acid
may inhibit decomposition of indoles under these conditions.3c
Although the replacement of Co(OAc)2 with Mn(OAc)2
afforded only a trace of 3a, the combined use of Mn(OAc)2
(0.25 equiv.) and Co(OAc)2 (1 equiv.) led to a significant
increase in yield (entry 13). The synergistic effect of Co and
Mn salts has also been observed in the aerobic oxidation of
alkylbenzenes.11 The reaction conducted in a mixed solvent of
DMSO (10%, v/v) in DMF gave a higher yield than that in
DMF (entry 14 vs. entry 13). N-hydroxyphthalimide (NHPI) is
known to serve as a co-catalyst for Co-catalyzed aerobic
oxidation of alkanes.12 Indeed, the addition of 0.15 equiv. of
NHPI to this reaction system resulted in the further improvement
on yield (entry 15). Thus, the combination of Co(OAc)2
(1 equiv.), Mn(OAc)2 (0.25 equiv.) and NHPI (0.15 equiv.)
constitutes an effective system to effect oxidative cross-
coupling of free (NH) indole with b-keto ester (entry 15).
When the undistilled solvents (DMF and DMSO) and
Co(OAc)2ꢀ4H2O were used, the reaction under otherwise
identical conditions afforded the yield (65%) comparable to
that with distilled solvents, which indicated that this reaction is
not sensitive to moisture (entry 16).13
Owing to the prevalence of the indole nucleus in biologically
active molecules and medicinally relevant structures, indole
chemistry has been and continues to be a very active area of
research.1–3 Among transformation of indoles, oxidative
difunctionalization of indole at the C2–C3 double bond offers
a rapid entry into various indole derivatives, as exemplified by
the recently reported Pd-catalyzed carboaminoxylation2d of
indoles and Rh-catalyzed oxyamidation2e of indoles.
O2 activation at a metal center is of tremendous importance
in chemistry,4 as well as in biology.5 As an inexpensive,
abundant, and environmentally benign oxidant, O2 has
successfully been utilized in the transition-metal catalyzed
oxidative cross-coupling reactions.6 Substantial studies on
the transition-metal-mediated aerobic oxidation of indole have
been performed to provide mechanistic insight into enzyme-
catalyzed dioxygen oxidation of indole in the catabolism of
tryptophan.7 However, application of aerobic oxidation of an
indole to the efficient transformation remains a challenge since
an indole readily undergoes oxidative decomposition into a
complex mixture under dioxygen atmosphere.8 Herein, we
report the Co/Mn-mediated aerobic oxidative cross-coupling
of free (NH)-indoles with b-keto esters that leads to
ketonization–olefination of indoles by converting the C2–C3
double bond of indoles into an enone motif (eqn (1)).9
ð1Þ
State Key Laboratory of Structural Chemistry, Fujian Institute of
Research on the Structure of Matter, Chinese Academy of Sciences,
Fuzhou, Fujian 350002, China. E-mail: wpsu@fjirsm.ac.cn;
Fax: +86 591 8377 1575; Tel: +86 591 8377 1575
w Electronic supplementary information (ESI) available: Experimental
procedures and analytical data are provided. See DOI: 10.1039/
c1cc10545k
c
9660 Chem. Commun., 2011, 47, 9660–9662
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Table 1 Screening results for Co/Mn mediated oxidative coupling of indole with ethyl benzoylacetatea
Entry
2a (equiv.)
Additive (equiv.)
Acid (equiv.)
Solvent
Yield (%)b
1
1
1
1
1
1
1
5
1
5
5
5
5
5
5
5
5
—
—
—
—
—
—
—
—
—
—
—
DMF
DMF
DMSO
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
10% DMSO–DMF
10% DMSO–DMF
10% DMSO–DMF
14
o5
10
0
2c
3
4d
5e
6d
7
8
9
10
11
12
13
14
15
16f
—
Mn(OAc)2 (1.0)
—
—
—
—
—
—
Mn(OAc)2 (0.25)
Mn(OAc)2 (0.25)
Mn(OAc)2 (0.25), NHPl (0.15)
Mn(OAc)2 (0.25) NHPl (0.15)
0
o5
13
15
26
33
23
25
52
63
70
65
PivOH (20)
PivOH (20)
PivOH (30)
AcOH (30)
EtCOOH (30)
PivOH (30)
PivOH (30)
PivOH (30)
PivOH (30)
a
b
Reaction conditions: 0.125 mmol scale, Co(OAc)2 (1.0 equiv.), DMF (1 mL, 0.125 M), 1 atm of O2. Isolated yields. Co(OAc)2
c
d
e
f
(0.15 equiv.). In the absence of Co(OAc)2. N2 atmosphere. Undistilled solvents (DMF and DMSO), Co(OAc)2ꢀ4H2O were used.
With the optimized reaction conditions in hand (entry 15,
Table 1), we next evaluated the substrate scope of this reaction
(Table 2). With regard to b-keto esters, this reaction was
compatible with a range of substituents on the aromatic ring
of ethyl benzoylacetate with varied electronic and steric properties
(3b–3k). Notably, C–Cl and C–Br bonds were tolerated,
providing a complementary platform for further elaboration
of products. Methyl, isopropyl and benzyl benzoylacetates
afforded comparable yields to ethyl benzoylacetate (3l–3n).
Importantly, these transformations exhibited excellent geometric
selectivity in favor of Z-isomer with the exception of the
reaction involving ethyl (2-methylbenzoyl)acetate that yielded
a mixture of Z and E isomers with a 4 : 1 Z/E ratio (3d). With
regard to the substituents on the indole core, both electron-
donating and -withdrawing substituents can be tolerated
(3o–3w). Interestingly, the labile C–I bond was also unaffected
by this reaction, further highlighting the compatibility of this
reaction with the functional group (3t). Compared with electron-
donating groups, electron-withdrawing groups afforded
slightly lower yields. The position of the substitutent on the
indole core also affected the reaction outcomes, as illustrated
by the reactions of two isomers of methyl-substituted indole
(3u vs. 3v). Under the standard reaction conditions, the reaction
of free (NH)-indole with methyl cyanoacetate furnished the
corresponding product in 50% yield (3x). Removing
Mn(OAc)2 from the catalyst system and increasing the amount
of NHPI to 0.5 equivalents, the standard reaction conditions
can also be applied to the reactions of free (NH)-indole with
benzoylacetone or ethyl acetylacetate. The corresponding
products were obtained from benzoylacetone and ethyl
acetylacetate in 45% (3y) and 40% (3z) yields, respectively.
The former produced exclusively E-isomer whereas the latter
formed a mixture of E and Z isomers (E/Z = 3.6 : 1).
Obviously, there is a difference in reactivity between ethyl
acetylacetate or benzoylacetone and ethyl benzoylacetate,
which is reminiscent of the previous report that the catalytic
activity of [(1.3-diketonato)2Co(II)] in the aerobic oxidation
of olefins depends on the electronic effect of 1,3-diketone
ligands.14
To probe the mechanism of this reaction, a free-radical trap
test was investigated. We observed that introducing one
equiv. of 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO), a
free-radical trap, to the reaction system completely inhibited
the oxidation of indoles and that addition of N-phenyl-1-
naphthylamine, another free-radical trap, to the reaction
system inhibited formation of the desired product but gave
several unknown products from the indole. These observations
suggested that reaction likely involves radical intermediates.
Under 18O2 atmosphere 18O-labeled product was detected by
high-resolution MS while in the presence of H218O (10 equiv.
relative to indole), no 18O-labeled product was observed (see
Supporting Information Labeling Experiments Sectionw). The
18O-labeled experiments clearly showed that the oxygen atom
in the indolone carbonyl originated from O2.
On the basis of the above results, a hypothesized mechanism
of this oxidative transformation is shown in Scheme 1. Initially,
oxidation of 2a mediated by NHPI/Co(OAc)2/O2 formed free
radical beta-keto ester 4. Then, free radical 4 added to the
2-position of indole 1a to give 5. The resulting radical was
trapped by O2 to generate a peroxide 6 which converted into
an indolin-3-one intermediate 7. It has been reported that
NHPI/Co(OAc)2/O2-mediated reactions that involve the addition
of alkyl radicals to alkenes generate other alkyl radicals which
were trapped by O2 to form ketones.15 Finally, oxidative
dehydrogenation of 7 afforded the corresponding product 3a.
In conclusion, we have developed the Co/Mn-mediated
oxidative coupling reaction of indoles with b-keto esters
via dioxygen activation under mild conditions that leads to
c
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Table 2 Scope of Co/Mn mediated oxidative coupling of indoles with
b-Keto estersa
Notes and references
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a
Reaction conditions: 1 (1 equiv., 0.125 mmol), 2 (5 equiv.),
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NHPI (0.15 equiv.), DMF (1 mL, 0.125 M), DMSO (0.1 mL), 1 atm of
b
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¨
Scheme 1 The proposed mechanism for the transformation.
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ketonization–olefination of indoles. This reaction features the
high functional-group compatibility and the formation of
densely functionalized products, providing a good starting
point for the synthesis of complex molecules containing an
indole framework.
We wish to thank Prof. Ning Jiao for his help with
18O-labeled experiments.
c
9662 Chem. Commun., 2011, 47, 9660–9662
This journal is The Royal Society of Chemistry 2011