A trans diacyloxylation of indoles

Article abstract of DOI:10.1039/c2cc17815j

A trans diacyloxylation of indoles is accomplished by employing PhI(OAc)₂ as the oxidant. A broad range of functional groups are well tolerated. Both the electronic properties of the N-protecting groups of indoles and the acidity of the reaction media play important roles in the selectivity of indole acyloxylation reactions. The Royal Society of Chemistry 2012.

Full text of DOI:10.1039/c2cc17815j

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A trans diacyloxylation of indolesw
Qiang Liu,a Qing Yong Zhao,a Jie Liu,a Pan Wu,a Hong Yia and Aiwen Lei*ab
Received 14th December 2011, Accepted 2nd February 2012
DOI: 10.1039/c2cc17815j
A trans diacyloxylation of indoles is accomplished by employing
PhI(OAc)2 as the oxidant. A broad range of functional groups are
well tolerated. Both the electronic properties of the N-protecting
groups of indoles and the acidity of the reaction media play
important roles in the selectivity of indole acyloxylation reactions.
explore powerful transition-metal-free procedures is an important
direction.12 Moreover, the stereo-selective dioxygenation of olefins
is still challenging. The syn dioxygenate is usually the major
product. Hence it is a significant task to achieve the anti
dioxygenation of olefins.13 A traditional method to synthesize
anti-diols from alkenes is Prevost reaction, which suffers from
´
the usage of a stoichiometric amount of silver salt.14 Last but
not the least, the dioxygenation of enamines and heterocycles
containing enamine substructures has been rarely reported. All
in all, this trans diacyloxylation of indoles reaction meets all the
above-mentioned requirements for the further development of
olefin dioxygenation reactions.
Indolines are structural scaffolds frequently found in important
pharmaceuticals and biologically active natural compounds.1
Inspired by Nature’s efficiency of selective indole oxidation2
and as part of our efforts in developing efficient methodologies
for the functionalization of indoles,3 we aimed to discover
a convenient and versatile method towards the synthesis of
2,3-disubstituted indolines directly from the oxidation of
widely available indole derivatives.4 In this work, we describe
a PhI(OAc)2 promoted stereoselective diacyloxylation of indoles
bearing electron deficient N-protecting groups. Notably, only trans
diacyloxylated indolines were obtained (Scheme 1). N-Acetyl-2,3-
diacetoxylindolines have been previously synthesized via electro-
chemical synthesis from indolines.5 We report herein the organic
synthesis of these important compounds via one-step diacyloxyl-
ation of indole derivatives.
We started this study by choosing 1-(1H-indol-1-yl)ethanone
(R = Ac, R0 = H, Scheme 1) 1a and PhI(OAc)2 2 as the model
substrates to explore the behaviour of indoles bearing electron
deficient N-protected groups in oxidative acetoxylation reactions.
Noteworthily, a new product was isolated after 1 hour in 68%
yield when acetic acid was used as the solvent at 70 1C. From the
NMR and HRMS results, we preliminarily assigned it as the trans-
diacetoxylated product of indole derivatives 1a. A very similar
result was also obtained for tert-butyl 5-methyl-1H-indole-1-
carboxylate 1b, and the isolated yield of the corresponding
diacetoxylated product was 82% (Table 1, 3b). Subsequently,
the X-ray single crystal structures of 3a and 3b were obtained,
which further unambiguously confirmed the structures and
stereo-configuration of these products (Fig. S1, ESIw).
For this diacetoxylation reaction, the reaction conversion
was dramatically influenced by acidity of the reaction media
(Table S1, ESIw). The best result was obtained by using acetic
acid as the sole solvent. Apart from the solvents, the N-protecting
groups of indoles should be electron deficient groups, which was
another key factor for the success of this reaction. Both indoles
without any N-protecting groups and indoles bearing electron
donating N-protecting groups were decomposed into unknown
side-products under the standard conditions as shown in Table 1.
We then evaluated the scope of different N-Boc and N-Ac
protected indoles, and the reactions of various substituted N-Boc
and N-Ac protected indoles were investigated (Table 1). Regard-
less of the substituents, all of the reactions were carried out
efficiently to afford the desired diacetoxylated indolines in good
yields. The isolated yield for substrate 1g was up to 96%.
Functional groups such as chloro, bromo, methyl, benzyloxy
and methoxy were well tolerated under the optimized reaction
conditions (Table 1, 3a–3l). It was worth mentioning that only
trans diacetate products were isolated in these reactions.
Moreover, the reactions of indoles bearing electron-donating
Actually, dioxygenation of alkenes is an attractive transforma-
tion to make valuable compounds from widely available starting
materials, among which OsO4 catalyzed dihydroxylation is the
most famous protocol.6 During the past decade, remarkable
progress has been made in the metal-facilitated olefin dioxygena-
tion reactions including Pd,7 Cu,8 Ru,9 Fe10 and Mn.11 However,
the use of precious and/or toxic metal catalysts as well as the
generation of high levels of inorganic wastes hindered the further
application of these metal catalyzed processes. As a result, to
Scheme 1 Trans diacyloxylation of indoles.
a College of Chemistry and Molecular Sciences, Wuhan University,
Wuhan, 430072, P. R. China. E-mail: aiwenlei@whu.edu.cn;
Fax: +86-27-68754672; Tel: +86-27-68754672
b State Key Laboratory for Oxo Synthesis and Selective Oxidation,
Lanzhou Institute of Chemical Physics, Chinese Academy of
Sciences, 730000, Lanzhou, P. R. China
w Electronic supplementary information (ESI) available: General
procedures, spectral data and other supplementary information.
CCDC 822881 & 822882. For ESI and crystallographic data in CIF
or other electronic format see DOI: 10.1039/c2cc17815j
c
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Chem. Commun., 2012, 48, 3239–3241 3239

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Table 1 Dearomatization/regio-selective diacetoxylation of indoles
with PhI(OAc)2
a
Scheme 3 Direct C3-acetoxylation of 1g.
Scheme 4 Control experiments of 1o and 1p.
the acids as the coupling components are in large excess to 2.
However, the sterically hindered acid such as pivalic acid led
to a lower yield. (Scheme 2, entry 3).
We also found that 1g could efficiently generate trans
diacetated product 3g in 1 hour (Table 1, 3g), but it was
converted to C3-acetoxylated indole 4g after 20 hours in 75%
yield under the same conditions (Scheme 3, eqn (1)). When
diacetate indoline 3g was heated to 70 1C in acetic acid for
13 hours, 62% mono-acetate indole 4g was isolated along with
27% recovered starting material (Scheme 3, eqn (2)). We
therefore speculated that the thermodynamically favoured
product 4g was generated via elimination of acetic acid from
the diacetate intermediate 3g.
a
Reaction conditions: 1 (0.5 mmol), 2 (1 mmol) in 2 mL of HOAc at 70 1C.
trans/cis 4 99 : 1 for all the products determined by NMR. b 17%
1-benzoyl-5-methyl-1H-indol-3-yl acetate 4m was also produced with
c
7% starting material recovered. 20% starting material recovered.
groups led to completion within 1 hour (Table 1, 3a–3h), while
those with electron-withdrawing groups required more than
12 hours (Table 1, 3i–3l). As well as the N-Boc and N-Ac
protected indoles, the reactions of both N-Bz and N-Ts
protected indoles 1m and 1n all proceeded smoothly under
the standard conditions. No cis diacetated products were
observed for the reactions of 1m and 1n either.
Control experiments were then performed to figure out which
position (C2 or C3) on the indole ring was the initial reaction site
(Scheme 4). 1o reacted rapidly and efficiently to afford the C3-
acetoxylated indole 4o in 82% isolated yield (Scheme 4, eqn (1)).
However, there was no diacetoxylation reaction upon treating 1p
under the same reaction conditions (Scheme 4, eqn (2)). The
above results clarified that the reaction started by nucleophilic
attack of the C3 position of indole to PhI(OAc)2, which was
facilitated by the acid. Very recently, Gade and Kang also
reported that the proton was the catalytically active species in
olefin dioxygenation with PhI(OAc)2.12c
Besides, diversified diacyloxylated indoles were prepared by
simply changing the solvent from acetic acid to other acids.
Employing n-propionic acid and n-octanoic acid would result
in the corresponding trans diacylated products with the yields
63% and 50%, respectively (Scheme 2, entries 1 and 2).
Interestingly, diacetoxylated indoles were not isolated because
We propose the reaction pathways as shown in Scheme 5.
Initially, intermediate A is generated via the nucleophilic
attack of 1a towards 2 promoted by the proton and further
converted to the iodonium salt B via intramolecular nucleophilic
attack of iodine. The acetate attacks C3 position of iodine B to
afford trans intermediate D. The acetoxyl group attached to the
iodine is then protonated and undergoes intramolecular nucleo-
philic attack to generate cis oxygen cation intermediate F, which
determines the trans-selectivity of this diacetoxylation reaction. The
acetate anion finally attacks from the opposite site of oxygen atoms
of cis intermediate F to afford trans diacetated indoline 3a.
According to the proposed mechanism, indoles bearing the
electron donating N-protecting groups, which are more electron
Scheme 2 Diacyloxylation of 1-(1H-indol-1-yl)ethanone 1a. Reaction
conditions: 1b (0.5 mmol), 2 (1 mmol) in 2 mL of RCOOH (R = Et,
C7H15 and tBu) at 70 1C. trans/cis 4 99 : 1 for all the products
determined by NMR.
c
3240 Chem. Commun., 2012, 48, 3239–3241
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diacyloxylation of indoles and other heterocycles are under-
way in our laboratory.
This work was supported by Program for Changjiang
Scholars and Innovative Research Team in University
(IRT1030) and National Natural Science Foundation of China
(20972118 and 20832003) and financial support from Wuhan
University. We also thank Dr Andrew Crawford for his kind
help in revising this manuscript.
Notes and references
Scheme 5 Direct C3-acetoxylation of 1g.
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Scheme 6 Direct C3-acetoxylation of 1q.
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rich, should undergo this process more readily. With this idea
in mind, we treated 1q with PhI(OAc)2 2 in a mixture of acetic
acid and acetonitrile (1 : 1). The reaction was complete within
2 minutes at 0 1C to afford the C3-acetoxylated indole 4q in
30% yield (Scheme 6, eqn (1)). In fact, no diacetoxylated
product of 1q was observed in this reaction. We rationalized
the reaction selectivity as shown in Scheme 6. When an electron-
withdrawing group was attached to the N-atom of indole
(Scheme 6, Path B), the intramolecular nucleophilic addition
of intermediate E0 was preferred to generate the oxygen cation F0,
which could be converted to diacetoxylated indoline finally
(refer to Scheme 5). When the intermediate E0 bears the electron
donating N-protecting group (Scheme 6, Path A), the inter-
molecular deprotonation could be favoured, which produced
the more stable aromatic mono-acetoxylated product 4q.
In conclusion, we developed an efficient diacyloxylation of
indoles with PhI(OAc)2 as the oxidant in the presence of carboxylic
acid as the solvent. Interestingly, only trans diacyloxylated indolines
were obtained, revealing a high stereo-selectivity. Moreover, a
broad range of functional groups were well tolerated under these
reaction conditions. On the basis of our observations, it is clear that
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c
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Chem. Commun., 2012, 48, 3239–3241 3241