Silver-Catalyzed Intramolecular C-2 Selective Acylation of Indoles with Aldehydes: An Atom-Economical Entry to Indole-Indolone Scaffolds

Article abstract of DOI:10.1002/adsc.201600108

A direct annulation reaction of N-(2-formylaryl)indoles has been developed, which can provide a new entry to biologically and medicinally important indole-indolone scaffolds via a silver-catalyzed direct oxidative coupling between aldehyde C H and sp²C H bonds for the first time. Remarkably, this strategy displayed excellent functional group compatibilities, thereby suggesting its wide potential for applications in developing and synthesizing new drug-like compounds containing indole-indolone frameworks. (Figure presented.) .

Full text of DOI:10.1002/adsc.201600108

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DOI: 10.1002/adsc.201600108
Silver-Catalyzed Intramolecular C-2 Selective Acylation of
Indoles with Aldehydes: An Atom-Economical Entry to
Indole-Indolone Scaffolds
Xiaoxia Wang,+a Zhongfeng Li,+a Shengli Cao,a and Honghua Raoa,*
a
Department of Chemistry, Capital Normal University, Beijing 100048, Peopleꢀs Republic of China
Fax : (+86)-10-6890-2493; e-mail: honghua.rao@gmail.com
+
These authors contributed equally to this work.
Received: January 24, 2016; Revised: April 13, 2016; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201600108.
Abstract: A direct annulation reaction of N-(2-for-
mylaryl)indoles has been developed, which can pro-
vide a new entry to biologically and medicinally im-
portant indole-indolone scaffolds via a silver-cata-
inal chemists to pursue new drug-like compounds by
introducing chemical functional groups to the indole
or indolone core.[1c,4–6] In this context, a most promis-
ing strategy is to assemble these two biologically and
medicinally interesting substructures into one skeletal
structure, especially the indole fused indolone scaf-
fold.[7] In 2009, the Larock group thereby first pre-
sented a rapid synthesis of the indole-indolone hybrid
through [3+2] annulation of arynes with methyl
indole-2-carboxylates in moderate to good yields,[8]
which has been serving as the sole strategy for estab-
lishing this biologically important skeleton for a long
time (Figure 1a).[9] Only very recently, another strat-
egy via an HFIP-promoted intramolecular Friedel–
Crafts acylation was proposed for the construction of
the indole-indolone scaffold (but only one example
was given) (Figure 1b).[10]
lyzed direct oxidative coupling between aldehyde
2
À
À
C H and sp C H bonds for the first time. Remark-
ably, this strategy displayed excellent functional
group compatibilities, thereby suggesting its wide
potential for applications in developing and synthe-
sizing new drug-like compounds containing indole-
indolone frameworks.
À
Keywords: C H bond oxidative coupling; indole-in-
dolone hybrids; silver-catalyzed reaction; single-
electron-transfer process (SET); sulfate radical
anion
À
As is well-known, catalytic C H activations and
À
subsequent C C bond formations have witnessed
a meteoritic development during the past decades and
The indole moiety is a privileged structural constitu- are now routinely employed as a powerful tool in
ent of numerous natural products and pharmacologi- both academia and industry.[11] In particular, direct
cal entities.[1] In addition, the indolone motif is also couplings between C H bonds utilizing transition
À
embedded in several biologically active molecules, in- metal catalysis or organocatalysis can provide an un-
cluding the potent cholecystokinin antagonist asperli- precedented opportunity for the development of
cin[2] and the antifungal fumiquinazolines.[3] Conse- novel retrosynthetic disconnections, thus promising
quently, the diverse array of biological and medicinal the construction of useful molecular frameworks in an
activities has stimulated synthetic chemists and medic- atom-economical and straightforward manner from
Figure 1. Reported protocols for indole-indolone hybrid construction.
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less functionalized substrates.[12] Unfortunately, no the C-7 acylation process completely,[20] albeit afford-
such catalysis has been developed for establishing ing product 2a in diminished yield (entry 10). Like-
indole-indolone hybrids through direct coupling of al- wise, the use of different silver catalysts had a drastic
2
À
À
dehyde C H and sp C H bonds, even though direct impact in catalyzing this oxidative coupling reaction.
À
activation of aldehyde C H bonds has been realized By using AgOMs as the catalyst, product 2a was ob-
via either oxidative insertion of Rh[13] or Pd cata- tained in 87% yield, together with only 3% of C-7
lysts[14] to aldehyde C H bonds (generating acyl- acylation product (entry 15). Other silver catalysts
À
metal moieties) or direct hydrogen abstraction from having difÀferent counterions (such as SO42À, OTfÀ,
[15]
À
Fe catalysts,[16] BF4 , NO3 , or OAcÀ) exhibited much lower catalytic
À
aldehyde C H bonds utilizing Cu,
quaternary ammonium salts,[17,18] or even under simple activities and selectivities than AgOMs (entries 6, 16–
oxidative conditions (generating acyl radicals).[19] Fol- 19). Interestingly, a trace amount or 21% of the de-
lowing this tendency and regarding to retrosynthetic sired product 2a was obtained without either oxidant
analysis of indole-indolone motif, we herein report or catalyst, respectively (entries 20 and 21). Neverthe-
the design of a variety of N-(2-formylaryl)indoles that less, when a substrate with an electron-donating
can efficiently and highly selectively deliver the groups, such as 5-methoxy group on indole ring, was
indole fused indolone scaffolds via a silver-catalyzed subjected to the above optimized reaction conditions
À
aldehyde C H bond activation (Scheme 1). This strat- (p-dioxane as solvent, 5.0 mol% of AgOMs as cata-
egy accommodates a broad range of catalytically reac- lyst, and 2.0 equiv. of oxone as oxidant), it afforded
tive functional groups, and to the best of our knowl- only 75% of the C-2 selective acylation product 2o,
edge, can serve as a new entry to indole-indolone hy- with 10% of C-7 acylation product (entry 22). Further
brids.
optimizations were hence conducted, and the results
Our study commenced by subjecting N-(2-formyl- revealed that p-dioxane/DCE (10:1 v/v ratio) as co-
phenyl)indole (1a) to the TBAX/TBHP organocata- solvent and 4.0 mol% of AgOMs as catalyst are cru-
lytic system, which was previously developed by our cial to the obtention of exclusive C-2 acylation prod-
group to realize the intramolecular oxidative coupling uct for substrates with electron-donating groups
2
[17]
À
between sp C H bonds. However, it only leads to (entry 23; see Table S1 in the Supporting Informa-
the consumption of 1a without any detection of the tion), while p-dioxane/DCE (8:1, v/v ratio) as co-sol-
desired acylation product 2a (Table 1, entry 1). Cu[15] vent, 7.5 mol% of AgOMs as catalyst and 3.0 equiv.
or Fe catalysis[16] that has been developed for cross- of oxone as oxidant are required for substrates with
coupling of aldehyde C H and sp C H bonds afford- electron-withdrawing groups (entry 24; see Table S2
ed only trace amounts of 2a (Table 1, entry 2). Fortu- in the Supporting Information).
2
À
À
nately, use of Ag2SO4 as the catalyst, K2S2O8 as the
With the optimized reaction conditions in hand, we
oxidant, and p-dioxane as the solvent can deliver probed the substrate scope at 1008C under a nitrogen
product 2a in 39% yield (entry 5). Among the oxi- atmosphere by using AgOMs (4.0–7.5 mol%) as the
dants examined, oxone provided the best yield (66%) catalyst, oxone (2.0–3.0 equiv.) as the oxidant. As
of the desired product 2a, and 10% of the undesired summarized in Scheme 2, the AgOMs-catalyzed intra-
À
C-7 acylation product (entries 3–6). To improve the molecular oxidative cross-coupling between C H
yield of C-2 acylation product 2a, as well as to sup- bonds displays broad substrate capacity and is toler-
press the C-7 acylation process, a series of different ant of a range of substituents in different positions of
solvents and catalysts were thereby screened. Re- the indole ring. On the other hand, the presence of
markably, the reaction efficiency and selectivity show various substituents with different electronic proper-
a strong dependency on the solvent: when the reac- ties results in drastic reactivity and selectivity differ-
tion was carried out in THF, DME, or CH3CN, the ences. For example, substrates bearing electron-with-
yield of desired product 2a was slightly reduced by drawing groups permit exclusive C-2 acylation on the
approximately 10% (entries 6–9), but decreased dra- indole ring (2b–j), although higher catalyst loading
matically in (n-Bu)2O, t-BuOH, toluene or DMF (en- (7.5 mol% AgOMs) and longer reaction time (36 h)
tries 11–14); notably, DCE as solvent nearly inhibited are required to achieve higher reaction efficiency
(comparing the yields of 2b under conditions A and
C). In contrast, electron-sufficient substrates (e.g., re-
actant 1o) can facilitate higher conversions of the
starting materials, but afford considerable yields of
the undesired C-7 acylation byproducts under condi-
tions A. Gratifyingly, when reactions of substrates
with electron-donating groups are conducted in the
previously optimized reaction conditions B, the corre-
sponding C-2 acylation products are obtained in good
to excellent yields with nearly no detection of the C-7
Scheme 1. Indole-indolone hybrid formation via silver-cata-
lyzed intramolecular C-2 selective acylation of indoles with
aldehydes.
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Table 1. Screening of the reaction conditions.[a]
Entry
Cat. (mol%)
[O] (equiv.)
Solvent
Yield [%][b]
2a
C-7
1
2
3
TBAX (10.0)
“Cu” or “Fe”
Ag2SO4 (5.0)
Ag2SO4 (5.0)
Ag2SO4 (5.0)
Ag2SO4 (5.0)
Ag2SO4 (5.0)
Ag2SO4 (5.0)
Ag2SO4 (5.0)
Ag2SO4 (5.0)
Ag2SO4 (5.0)
Ag2SO4 (5.0)
Ag2SO4 (5.0)
Ag2SO4 (5.0)
AgOMs (5.0)
AgOTf (5.0)
AgBF4 (5.0)
AgNO3 (5.0)
AgOAc (5.0)
AgOMs (5.0)
–
TBHP (2.0)
TBHP (2.0)
Na2S2O8 (2.0)
CH3CN
CH3CN
0
0
0
0
0
12
10
16
14
15
3
17
0
0
0
3
0
10
15
16
0
trace
trace
trace
39
66
53
59
52
45
38
30
19
0
87
33
55
28
51
p-dioxane
p-dioxane
p-dioxane
p-dioxane
THF
DME
CH3CN
DCE
nBu2O
4
(NH4)2S2O8 (2.0)
K2S2O8 (2.0)
oxone (2.0)
oxone (2.0)
oxone (2.0)
oxone (2.0)
oxone (2.0)
oxone (2.0)
oxone (2.0)
oxone (2.0)
oxone (2.0)
oxone (2.0)
oxone (2.0)
oxone (2.0)
oxone (2.0)
oxone (2.0)
–
5c
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22[c]
23[c,d]
24[e,f]
tBuOH
toluene
DMF
p-dioxane
p-dioxane
p-dioxane
p-dioxane
p-dioxane
p-dioxane
p-dioxane
p-dioxane
p-dioxane/DCE (10:1)
p-dioxane/DCE (8:1)
trace
21
75
84
74
oxone (2.0)
oxone (2.0)
oxone (2.0)
oxone (3.0)
0
AgOMs (5.0)
AgOMs (4.0)
AgOMs (7.5)
10
<1
<1
[a]
Reaction conditions: 1a (0.10 mmol), [O] (2.0 equiv.), solvent (2.0 mL), 1008C, under nitrogen for 24 h unless otherwise
noted.
[b]
[c]
[d]
[e]
[f]
Yield determined by 1H NMR spectroscopy with mesitylene as the internal standard.
N-(2-Formylphenyl)-5-methoxyindole (2o) as the substrate.
AgOMs (4.0 mol%), p-dioxane/DCE (2.0 mL; 10:1, v/v ratio).
N-(2-Formylphenyl)-6-chloroindole (2f) as the substrate.
AgOMs (7.5 mol%), oxone (3.0 equiv.), p-dioxane/DCE (2.0 mL; 8:1, v/v ratio), 36 h. [O]=oxidant, TBAX=(n-Bu)4NI
or (n-Bu)4Br, TBHP=tert-butyl hydroperoxide, THF=tetrahydrofuran, DME=1,2-dimethoxyethane, DCE=1,2-di-
chloroethane, DMF=N,N-dimethylforamide, Tf=trifluoroacyl, Ms=methanesulfonyl.
acylation by-products (2k–p). To expand the substrate tion; these examples demonstrate that the silver-cata-
À
scope, the benzaldehyde units bearing either electron- lyzed intramolecular C H cross-coupling provides
donating groups (e.g., methoxy group; 2q–s) or elec- a complementary platform for further elaboration of
tron-withdrawing groups (e.g., chloro group; 2t–x) the indole-indolone hybrid via transition metal-cata-
were tested, and all of them readily produce the de- lyzed or even traditional chemical functional group
sired C-2 acylation products in reasonable to excellent transformations.
yields. Surprisingly, 3-methylindole (2y) and 7-azain-
When investigating the mechanism for this silver-
À
dole (2z) display poor reactivities under the optimized catalyzed direct oxidative coupling between C H
reaction conditions. Particularly noteworthy is the tol- bonds, the single-electron-transfer (SET) process is
erance toward a range of functionally diverse sub- a favorable consideration because it has already been
stituents in both indole and benzaldehyde units, such proved that silver(II) species, formed from the oxida-
as halogen (2b–h and 2s–x), ester (2i and 2w), cyano tion of silver(I) salts with peroxydisulfate, may facili-
(2j), methyl (2k–m and 2r), and methoxy groups (2n– tate a hydrogen-abstraction process to generate the
s and 2u), which remain unaffected during the reac- reactive carbon-centered radical.[21] Therefore, a radi-
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Scheme 2. Silver-catalyzed indole-indolone scaffold formation. General reaction conditions: 1 (0.10 mmol), 1008C, under ni-
trogen atmosphere. Conditions A: AgOMs (5.0 mol%), oxone (2.0 equiv.), p-dioxane (2.0 mL), 24 h. Conditions B: AgOMs
(4.0 mol%), oxone (2.0 equiv.), p-dioxane/DCE (2.0 mL, 10:1 v/v ratio), 24 h. Conditions C: AgOMs (7.5 mol%), oxone
(3.0 equiv.), p-dioxane/DCE (2.0 mL, 8:1 v/v ratio), 36 h. Average isolated yields of two runs are given.
cal-trapping experiment was carried out by introduc- this transformation most likely involves a radical in-
ing TEMPO (2,2,6,6-tetramethylpiperidine 1-oxyl) termediate (for reaction details in the presence of
into the standard reaction conditions. The desired re- TEMPO and the exclusion of intramolecular C-2 ad-
action did not occur (Scheme 3), thus indicating that dition to aldehyde, please refer to the Supporting In-
formation, pp S3–S5).
Based on the above result, a tentative mechanism
for this silver-catalyzed intramolecular cross-coupling
À
reaction between C H bonds is proposed in
Scheme 4. In the first step, peroxymonosulfate anion
disproportionates into a hydroxide anion and a sulfate
radical anion in the presence of silver(I) salt; mean-
Scheme 3. Investigation of the reaction mechanism.
while, the silver(I) salt is oxidized to silver(II) species
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1008C. After 24 h, the resulting mixture was cooled to room
temperature, filtered through a short silica gel pad and
washed with ethyl acetate. The above solution was evaporat-
ed under vacuum, and the residue was purified by silica gel
column with petroleum ether/ethyl acetate as the eluent to
give the analytically pure product 2a.
Acknowledgements
Financial support from The National Natural Science Foun-
dation of China (21402128), Beijing Natural Science Founda-
tion (2144045), Beijing Municipal Education Commission
Foundation (KM201410028007), Scientific Research Base
Development Program of the Beijing Municipal Commission
of Education, and Capital Normal University is greatly ap-
preciated. We thank Huimin Su and Xue Liu for reproducing
the results of 2a and 2o.
Scheme 4. Plausible mechanism for this AgOMs-catalyzed
indole-indolone hybrid construction.
(Scheme 4a).[22] After oxidizing the aldehyde C H
À
References
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(Scheme 4b).
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2
À
À
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Typical Procedure
An oven-dried round-bottom reaction vessel was charged
with AgOMs (1.01 mg, 0.005 mmol, 5.0 mol%), 1a
(0.1 mmol) and oxone (61.5 mg, 0.2 mmol, 2.0 equiv.). After
the vessel was filled with nitrogen, dry p-dioxane (2.0 mL)
was added by syringe under nitrogen, and the reaction mix-
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vessel was sealed, placed into an oil bath and heated to
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Adv. Synth. Catal. 0000, 000, 0 – 0
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asc.wiley-vch.de
Guo, X. Zhang, P. Tang, Angew. Chem. 2015, 127, 4137;
Angew. Chem. Int. Ed. 2015, 54, 4065.
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3
À
[23] For examples on the oxidation of sp C H bonds with
silver(II) species, see ref.[20]
Adv. Synth. Catal. 0000, 000, 0 – 0
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8 Silver-Catalyzed Intramolecular C-2 Selective Acylation of
Indoles with Aldehydes: An Atom-Economical Entry to
Indole-Indolone Scaffolds
Adv. Synth. Catal. 2016, 358, 1 – 8
Xiaoxia Wang, Zhongfeng Li, Shengli Cao, Honghua Rao*
Adv. Synth. Catal. 0000, 000, 0 – 0
8
ꢁ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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These are not the final page numbers!