Synthesis of 3-acylated indoles through iron-catalyzed oxidative coupling of indoles with α-amino carbonyl compounds

Article abstract of DOI:10.1080/00397911.2017.1364767

A novel iron-catalyzed oxidative coupling of indoles with α-amino carbonyl compounds has been developed. The transformation provides an attractive approach to the synthesis of 3-acylindoles, with the advantages of easily available starting materials and high functional group tolerance. Furthermore, control experiments imply that a radical process maybe involved in this reaction.

Full text of DOI:10.1080/00397911.2017.1364767

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
Synthesis of 3-acylated indoles via iron-catalyzed
oxidative coupling of indoles with α-amino
carbonyl compounds
Niannian Yi, Jinxia Li, Hao Zhang, Ruijia Wang, Jun Jiang, Wei Deng, Zebing
Zeng & Jiannan Xiang
To cite this article: Niannian Yi, Jinxia Li, Hao Zhang, Ruijia Wang, Jun Jiang, Wei Deng,
Zebing Zeng & Jiannan Xiang (2017): Synthesis of 3-acylated indoles via iron-catalyzed oxidative
coupling of indoles with α-amino carbonyl compounds, Synthetic Communications, DOI:
10.1080/00397911.2017.1364767
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Date: 11 August 2017, At: 17:08

Synthesis of 3-acylated Indoles via iron-catalyzed oxidative
coupling of indoles with α-amino carbonyl compounds
Niannian Yi†
State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and
Chemical Engineering, Hunan University, Changsha, P. R. China
Jinxia Li†
State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and
Chemical Engineering, Hunan University, Changsha, P. R. China
Hao Zhang
State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and
Chemical Engineering, Hunan University, Changsha, P. R. China
Ruijia Wang
State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and
Chemical Engineering, Hunan University, Changsha, P. R. China
Jun Jiang
1

State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and
Chemical Engineering, Hunan University, Changsha, P. R. China
Wei Deng
State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and
Chemical Engineering, Hunan University, Changsha, P. R. China
Zebing Zeng
State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and
Chemical Engineering, Hunan University, Changsha, P. R. China
Jiannan Xiang
State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and
Chemical Engineering, Hunan University, Changsha, P. R. China
Address correspondence to Jiannan Xiang, State Key Laboratory of Chemo/Biosensing and
Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha,
410082, P. R. China. E-mail: jnxiang@hnu.edu.cn
Address correspondence to Wei Deng, State Key Laboratory of Chemo/Biosensing and
Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha,
410082, P. R. China. E-mail: weideng@hnu.edu.cn
2

†These authors contributed equally to this work.
Supplemental data (experimental data, 1H NMR and 13C NMR spectra of compounds 3a-3v) for
this article can be access on the publisher’s website.<TQ: The publisher’s website will be a live
link.>
ABSTRACT
A novel iron-catalyzed oxidative coupling of indoles with α-amino carbonyl compounds
has been developed. The transformation provides an attractive approach to the synthesis of
3-acylindoles, with the advantages of easily available starting materials and high functional
group tolerance. Furthermore, control experiments imply that a radical process maybe involved
in this reaction.
GRAPHICAL ABSTRACT
KEYWORDS: 3-acylindoles, iron, oxidative coupling, Α-amino carbonyl compound
Introduction
As one of the most important parts of heterocyclic nitrogen compounds, indoles, are
ubiquitous in natural products, bioactive molecules, and are used as valuable starting materials in
3

organic synthesis.[1,2] Therefore, finding new methods for their synthesis are important and
meaningful, particularly for the synthesis of 3-acylindoles due to wide applications of their
carbonyl group in the synthesis of other indole derivatives.[3] Traditionally, Friedel−Crafts
acylations,[4] Vilsmeier−Haack acylations,[5] and the reactions of indole salts with acyl
chlorides[6] are used for the synthesis of 3-acylindoles. However, these methods suffer from the
shortcomings of harsh reaction conditions (e.g., strict exclusion of moisture), environmentally
unfriendly POCl3, and poor functional group tolerance, respectively.
Recently, Su’s group reported a mild and convenient method for the synthesis of
3-acylindoles via Ru- or Fe-catalyzed oxidative coupling of indoles with anilines (Scheme 1,
reaction 1).[7] Then, Li’s group developed a novel and mild route to the synthesis of
2-(1H-indol-3-yl)-2-oxo-carbonyls via Cu-catalyzed oxidative coupling of indoles with α-amino
carbonyl compounds in the presence of tert-butyl hydroperoxide (TBHP) (Scheme 1, reaction
2).[8] Recently, we found that 2-(1H-indol-3-yl)-2-oxo-carbonyls could generate from indoles and
α-amino carbonyl compounds under the conditions of Pd(OAc)2, Cu(OAc)2, and HOAc (Scheme
1, reaction 3).[9] However, the expensive palladium catalyst shouldn’t be involved in such a
developed method.
Based on our continuous research of synthesizing α-functionalized carbonyl
compounds[10], herein we describe a route to the synthesis of 2-(1H-indol-3-yl)-2-oxo-carbonyls
via iron-catalyzed oxidative coupling of indoles with α-amino carbonyl compounds in the
4

presence of TBHP and trimethylacetic acid (PivOH) (Scheme 1, reaction 4). Compared to
previous works, this work uses the unexpensive iron catalyst, and is suitable for a wider range of
substrates.
Results and discussion
We began our investigation with
the use of indole (1a) and
1-phenyl-2-(phenylamino)ethanone (2a) as the model reaction (Table 1). The desired product 3a
was obtained in 52% yield under the conditions of FeCl3 (10molꢀ %), TBHP (5 equiv), PivOH
(1 equiv) and DMSO (2mLꢀ) in a sealed tube at 50 °C for 15hꢀ (entry 1). Subsequently, a
variety of iron catalysts were examined, and the results were shown in entries 2-6. Among the
iron catalysts tested, Fe(OTf)3 performed better than other catalysts, with the yield of 80%. The
reactions with other oxidants, including tert-butyl peroxide (DTBP), H2O2, mCPBA and K2S2O8,
gave products in low yields (entries 7–10). Then, different solvents were examined, and the
results indicated that DMSO was the best choice (entries 11–14). The reaction did become
sluggish when the temperature decreased to 25 °C, and it was meaningless to elevate the
temperature to 80°C (entries 15 and 16). Meanwhile, further exploration suggested that
iron-catalyst, TBHP and PivOH were necessary for the reaction, and O2 had almost no effect on
the reaction (entries 17–20).
With the optimal conditions in hand, the scope of both indoles (1) and α-amino carbonyl
compounds (2) was then investigated (Scheme 2). Initial screening on α-amino ketones revealed
5

that several substituents, including Me, MeO, Ph, F, Cl, CF3, and CN groups, on the aromatic
ring of the 1-arylethanone moiety were well-tolerated (products 3b-3l). In general, the reactive
order is electron-withdrawing groups > electron-donating groups. It was notable that the
substrates having groups at meta and ortho positions of the aromatic ring could also give the
corresponding products smoothly under the optimal conditions, but the yields of 3k and 3l were
about 65%, likely due to the steric effect of substituents on aromatic ring. Ethyl
2-(phenylamino)acetate was also a suitable substrate, giving the desired product 3n in 54% yield.
Unfortunately, when 1-(phenylamino)propan-2-one was chosen as a substrate, we couldn’t get
the desired product, which implied that α-amino aliphatic ketones were not applicable to the
reaction.
To further explore the generality of this catalytic reaction, a wide range of indoles were
then investigated (products 3o-3v). For example, indoles with substituents such as Me, MeO, Cl,
Br, and CN at the 5 position underwent the reaction with 2a providing the corresponding
products 3o-3s in moderate to good yields under the conditions of Fe(OTf)3, TBHP, PivOH and
DMSO. It was noteworthy that indoles with substituents (Me or Ph) at the 2 position gave the
desired products 3t and 3u smoothly, but 3-methyl indole was an unsuitable substrate. The
product 3v was obtained in 60% yield when 1-methyl indole was used as a substrate.
6

We also explored the reactivity of the Fe(OTf)3 catalyzed oxidative coupling reaction for
large-scale synthesis of 3a (Scheme 3). The reaction of indole (1a, 5 mmol) and α-amino ketone
(2a, 7.5 mmol) gave the desired product 3a in 78% yield under the optimal conditions.
Control experiments were carried out in order to elucidate the reaction mechanism
(Scheme 4). When the radical inhibitor 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) was
added to the reaction of 1a with 2a under the optimal conditions, the formation of 3a was
completely inhibited (Scheme 4, reaction 1), which implies that a radical process may be
involved
in
this
reaction.
Surprisingly,
substrate
4
[2-(methyl(phenyl)amino)-1-phenylethan-1-one] was not viable for the reaction and the desired
product 3a was not detected (Scheme 4, reaction 2). Then, the compound 5
[1-phenyl-2-(phenylimino)ethanone] was used as a substrate to react with 1a under the optimal
conditions, and the desired product 3a was obtained in 73% yield (Scheme 4, reaction 3).
Interestingly, the compound 6 was converted into 3a in 86% yield under the optimal conditions
(Scheme 4, reaction 4).
Based on our experimental results and previous reports,[8,11,12] a possible reaction
mechanism was proposed in Scheme 5. Firstly, 2a is oxidized to intermediate 5 by the
TBHP.[8,11] Then, the intermediate 5 reacts with 1a to generate intermediate 6 via Friedel-Crafts
alkylation.[8] Finally, the intermediate 6 is hydrolyzed by H2O to afford the product 3a.[8,12]
Experimental section
7

General information
Commercially available reagents were of reagent grade (AR grade) and were used
without further purification. Reactions were monitored by thin layer chromatography (TLC)
using silicycle pre-coated silica gel plates. Flash column chromatography was performed over
silica gel (200-300 mesh). 1H NMR and 13C NMR spectra were recorded on 400MHzꢀ NMR plus
spectrometer using residue solvent peaks as internal standards. Infrared spectra were recorded
with IR spectrometer and are reported in reciprocal centimeter (cm-1). High resolution mass
spectra were obtained using GCT-TOF instrument with ESI source.
General procedure for the synthesis of 3
Indole 1 (0.3 mmol), α-amino carbonyl compound 2 (0.45 mmol), Fe(OTf)3 (10mol %),
PivOH (1 equiv), TBHP (5 equiv) and DMSO (2mL) were added to a sealed tube. Then the
reaction mixture was stirred at 50 °C for 15h. After the reaction was complete, the resulting
mixture was diluted with dichloromethane and washed with water. The separated aqueous phase
was washed with CH2Cl2. Then the combined organic extract was washed with brine, dried over
sodium sulfate, filtered, and concentrated under vacuo. The residue was purified by
chromatography on silica gel with petroleum ether/ethyl acetate as eluent to afford the
corresponding product 3.
Spectral characterization of 3a
8

1-(1H-indol-3-yl)-2-phenylethane-1,2-dione (3a) 8, 9: Brown solid, 80% yield (60mgꢀ);
1H NMR (400MHzꢀ, DMSO-d6) δ 12.42 (brs, 1H), 8.24-8.22 (m, 1H), 8.18 (s, 1H), 7.97 (d, J =
8.0Hzꢀ, 2H), 7.74 (t, J = 7.2Hzꢀ, 1H), 7.61-7.55 (m, 3H), 7.32-7.30 (m, 2H); 13Cꢀ NMR
(100MHzꢀ, DMSO-d6) δ 194.5, 189.0, 138.4, 137.5, 135.1, 133.5, 130.2, 129.6, 125.5, 124.3,
123.3, 121.7, 113.2, 113.1.
Conclusion
In summary, we have demonstrated
a
novel route to the synthesis of
2-(1H-indol-3-yl)-2-oxo-carbonyls via iron-catalyzed oxidative coupling of indoles with α-amino
carbonyl compounds in the presence of TBHP and PivOH, with the advantages of easily
available starting materials and high functional group tolerance. Further study for explore
reaction mechanism and for synthetic applications to other bioactive molecules by this oxidative
coupling reaction is currently underway.
Acknowledgments
We are grateful to the National Natural Science Foundation of China (Nos. 21502049 and
51573040), the Planned Science and Technology Project of Hunan Province, China (No.
2015WK3003), and Hunan Provincial Innovation Foundation for Postgraduate (No.
CX2015B076).
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Table 1. Optimization of the reaction conditionsa
Entry
1
Catalyst
FeCl3
Oxidant
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
DTBP
H2O2
Solvent
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
Yield (%)b
52
2
FeBr3
55
3
FeCl2
64
4
Fe(OAc)2
Fe(OTf)2
Fe(OTf)3
Fe(OTf)3
Fe(OTf)3
Fe(OTf)3
Fe(OTf)3
Fe(OTf)3
Fe(OTf)3
Fe(OTf)3
Fe(OTf)3
Fe(OTf)3
18
5
68
6
80
7
trace
15
8
9
mCPBA
K2S2O8
TBHP
TBHP
TBHP
TBHP
TBHP
trace
11
10
11
12
13
14
15c
13
CH3CN
DCE
10
8
dioxane
DMSO
trace
58
12

16d
17
Fe(OTf)3
TBHP
TBHP
DMSO
DMSO
DMSO
DMSO
DMSO
76
0
18
Fe(OTf)3
Fe(OTf)3
Fe(OTf)3
trace
14
19e
20f
TBHP
TBHP
75
aReaction conditions: 1a (0.3 mmol), 2a (0.45 mmol), catalyst (10mol %), oxidant (1.5 mmol), PivOH (0.3 mmol), solvent (2mL) in
a sealed tube at 50 °C for 15h. b Isolated yields. cAt 25 °C. d At 80 °C. e No PivOH. f Under N2 atmosphere. TBHP (70% in water).
13

Scheme 1. Synthesis of 3-acylindoles.
14

Scheme 2. Reaction scope.a,b
15

Scheme 3. Large-scale synthesis of 3a.
16

Scheme 4. Control experiments.
17

Scheme 5. Possible mechanism.
18