Friedel-Crafts reaction of indoles with vicinal tricarbonyl compounds generated in situ from 1,3-dicarbonyl compounds and TEMPO: highly selective synthesis of tertiary alcohols

Article abstract of DOI:10.1039/c5ra17383c

A novel Friedel-Crafts reaction of indoles with vicinal tricarbonyl compounds generated in situ from 1,3-dicarbonyl compounds, which produces indole substituted tertiary alcohols in good to excellent yields and with good functional group tolerance, has be

Full text of DOI:10.1039/c5ra17383c

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Friedel–Crafts reaction of indoles with vicinal
tricarbonyl compounds generated in situ from 1,3-
dicarbonyl compounds and TEMPO: highly
selective synthesis of tertiary alcohols†
a
Cite this: RSC Adv., 2015, 5, 89906
Received 27th August 2015
Accepted 15th October 2015
Jianwei Yan, Tianjun Ni,b Fulin Yan,a Jixia Zhanga and Fangfang Zhuanga
*
DOI: 10.1039/c5ra17383c
www.rsc.org/advances
A novel Friedel–Crafts reaction of indoles with vicinal tricarbonyl materials. Numerous efforts conducted to develop processes of
compounds generated in situ from 1,3-dicarbonyl compounds, which this type have resulted in new preparative methods involving
produces indole substituted tertiary alcohols in good to excellent cross-dehydrogenative coupling of indoles with tetrahy-
yields and with good functional group tolerance, has been developed. droisoquinolines4 and tertiary amines,5 and reactions of indoles
The mechanistic pathway for this process involves the initial dispro- with methyl ketones,6 a-amino carbonyl compounds,7 and
portionation of TEMPO, a-oxyamination of the 1,3-dicarbonyl secondary and tertiary amine.8 Recently, Pihko and co-workers
compound followed by N–O bond cleavage to form the tricarbonyl described a palladium-catalyzed dehydrogenative b0-function-
intermediate. Addition of indole to this intermediate then generates alization reaction of cyclic b-ketoesters with indoles9 and
the tertiary alcohol product. This method can also be used for the Gribble and co-workers devised a Mn(III)-mediated radical
synthesis of pyrrole-containing tertiary alcohols. Further efforts aimed addition reaction of 2-nitroindole and 2-cyanoindole with acti-
at elucidating the mechanism of the reaction and boardening the vated methylene compounds such as malonates.10
substrate scope of this process are ongoing.
The 2,2,6,6-tetramethylpiperidine-N-oxyl radical (TEMPO),
has been broadly used as a stoichiometric and catalytic oxidant
in organic reactions.11 In the past several years, TEMPO also
been used as an oxidant in novel, transition metal-catalyzed,
C–C bond forming reactions12 and the a-C–H activation of
carbonyl compounds.13 In addition, TEMPO was also applied in
the a-oxygenation of 1,3-dicarbonyl compounds.14 We envisaged
that TEMPO would promote the formation of C–C bonds
between the C-3 position of indoles and the a-position of 1,3-
dicarbonyl compounds, to form novel molecular scaffold. In
order to test this proposal, a mixture of indole (1a), ethyl ace-
toacetate (2a) (1.1 equiv.), and TEMPO (2.0 equiv.) in acetic acid
was stirred at ambient temperatures open to air for 30 h (eqn
(1)). Under these conditions, efficient (81%) reaction took place
to generate the tertiary alcohol 3aa, whose structure was
unambiguously assigned using X-ray crystallographic analysis
(Fig. 1).15
Introduction
The indole ring system is the core structure of over 3000 natural
products and dozens of pharmaceutical agents.1 Owing to their
ubiquitous nature, functionalized indoles have been the focus
of numerous synthetic studies. A large effort has been given
recently to the development of new indole C–H activation
processes that can be used to prepare indole derivatives.2 Over
the past several decades, great advances have been made in
devising transition metal-catalyzed C(2)–H or C(3)–H function-
alization reactions of indoles3 owing to their broad functional
group tolerance, these processes have played signicant roles in
the synthesis and modication of indole containing medicinal
agents. Direct double C–H functionalization reactions between
indoles and substrates containing C(sp3)–H bonds, leading to
formation of C(sp2)–C(sp3) bonds have potent application in
synthetic organic chemistry owing to unique advantages asso-
ciated with simplicity and the accessibilities of starting
aSchool of Pharmacy, Xinxiang Medical University, Xinxiang, Henan 453003, P. R.
China. E-mail: jwyansimm@163.com
bDepartment of Chemistry, Xinxiang Medical University, Xinxiang, Henan 453003, P.
R. China
† Electronic supplementary information (ESI) available: Experimental details and
characterization. CCDC 1056685. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c5ra17383c
Fig. 1 ORTEP plot of 3aa shown with ellipsoids at the 30% level.
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Table 2 Indole scope of tertiary alcohol formation reactiona
To date, the preparation method of indole-containing
tertiary alcohol mainly through the Friedel–Cras reaction of
indoles with ethyl triuoropyruvate,16 2-oxomalonate17 and
other a-ketoesters.18 The general method for the synthesis of
indole-containing is still needed. Below, we describe the results
a thorough study of this one-pot process for the preparation of
indole-containing tertiary alcohol.
Results and discussion
In the rst phase of this effort, studies were carried out to
determine optimal conditions for the tertiary alcohol forming
reaction between indole and ethyl acetoacetate. Increasing the
temperature to 50 ꢀC enabled the alcohol forming reaction to be
completed in 8 h (Table 1, entry 3), whereas further increasing
the temperature to 80 ꢀC led to a obviously reduced yield (Table
1, entry 5). Importantly, when the amount of TEMPO was
increased from 2.0 to 3.0 equivalents, the reaction generated
3aa in a 85% yield (Table 1, entry 3), while decreasing the
amount of TEMPO to 1.1 equivalents resulted in a signicantly
decreased yield (Table 1, entry 4). The results of screening
carboxylic acid solvents showed that the domino process is
sensitive to the acidity of the medium. Specically, reaction in
formic acid was observed to produce a complicated product
mixture (Table 1, entry 6), whereas when acetic (optimal), pro-
pionic, butyric and valeric acid are used as solvents the tandem
process proceeded efficiently (Table 1, entries 7–9). In addition,
reaction conducted under an argon atmosphere took place with
a decreased yield (Table 1, entry 10). The combined results show
that optimal conditions for reaction of indole (1 equiv.) with
ethyl acetoacetate (1.1 equiv.) involve the use of 3.0 equivalents
ꢀ
TEMPO, acetic acid as solvent, a temperature of 50 C and an
exposure to air for 1 h.
Table 1 Optimization of the three component reaction of indole with
ethyl acetoacetate and TEMPOa
Entry
Solvent
TEMPO
Temp/time
Yieldb
1
2
3
4
5
6
7
8
MeCO2H
MeCO2H
MeCO2H
MeCO2H
MeCO2H
HCO2H
EtCO2H
PrCO2H
BuCO2H
MeCO2H
2.0 equiv.
2.0 equiv.
3.0 equiv.
1.1 equiv.
3.0 equiv.
3.0 equiv.
3.0 equiv.
3.0 equiv.
3.0 equiv.
3.0 equiv.
r.t./30 h
81%
78%
85%
52%
71%
Mess
81%
69%
69%
76%
50 ꢀC/8 h
50 ꢀC/1 h
50 ꢀC/48 h
80 ꢀC/0.5 h
r.t./0.5 h
50 ꢀC/8 h
50 ꢀC/16 h
50 ꢀC/24 h
50 ꢀC/1 h
9
10c
a
All reaction were run under optimized conditions, unless otherwise
b
a
noted. Isolated yields aer column chromatography. 4.0 equiv.
Reaction conditions: a mixture of indole 1a (1.0 mmol), ethyl
acetoacetate 2a (1.1 mmol) and TEMPO in the designated solvent was
stirred at the indicated temperatures for the times indicated open to
air. b Isolated yields. c Under Ar.
c
TEMPO were used for reaction at 80 ꢀC for 12 h. reaction at 50 ꢀC
for 8 h.
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Next, the generality of this process was examined (Table 2). the presence of TEMPO to form the coupling products in high
The results demonstrated that the domino multicomponent yields (Table 2, entries 16–17). 2-Phenyl indole (1r), containing
reaction is applicable to a wide range of indoles and, as a result, a bulky C-2 substituent, also reacts to form the corresponding
it enables ready synthetic access to diverse indole derivatives alcohol 3ra in moderate yield (Table 2, entry 18). It should be
containing a-hydroxy-ketoester groups at their b-positions. pointed out is that this product (3ra) consists of two atro-
Specically, indoles possessing a variety of electronically pisomers due to the presence of the phenyl group limits free
different substituents, including halogen, alkyl, alkoxy, cyano rotation about the C–C bond connecting the indole and
and methoxy carbonyl groups at different positions on the arene hydroxyacetoacetate group (1H and 13C NMR spectra in ESI†).
ring undergo reaction to produce the corresponding substituted
b-Ketoesters, containing sterically different substituents,
indoles in good to excellent yields (Table 2, entries 1–15). N- were also used to explore the scope of the new tandem reaction,
Methyl- and N-benzyl-indole also react with ethyl acetoacetate in conducted under optimized conditions. The results (Table 3)
show that nature of the ester alkoxy group has only a moderate
effect on the efficiency of this process (entries 1–3). Moreover, b-
Table
3 b-Ketoester and b-diketone scope for tertiary alcohol
ketoester substrates containing ethyl and phenyl ketone moie-
ties also react with indole to generate the corresponding alcohol
products in moderate yields (Table 3, entries 4–5). Finally,
tertiary alcohols are produced in moderate yields in TEMPO
promoted reactions between indole and 1,3-diketones such as
acetyl acetone and benzoylacetone (Table 3, entries 6–7).
The feasibility of extending the scope of the new TEMPO
promoted reactions to other heterocycles was explored. The
results of this effort showed that pyrrole and N-methyl pyrrole
also participate in the process to produce the corresponding a-
substituted pyrroles 6aa and 6ba in 40% and 56% yield,
respectively (Scheme 1).
formationa
To gain preliminary insight into the mechanism of the new
indole-tertiary alcohol forming reaction, we synthesized the
TEMPO–ethyl acetoacetate adduct B14d (Scheme 2) and investigated
Scheme
1 TEMPO promoted reaction of pyrroles with ethyl
acetoacetate.
a
Reaction conditions: indole 1a (117 mmol, 1.0 mmol), 1,3-dicarbonyl
compounds 2 (1.1 mmol), and TEMPO (468 mg, 3.0 equiv.) in acetic
acids (5.0 mL) open to air 50 ꢀC, 1–3 h.
Scheme 2 Experimental verification of the mechanism.
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Notes and references
1 J. C. Badenock and G. W. Gribble, Heterocyclic Scaffolds II:
Reactions and Applications of Indoles, Springer Science &
Business Media, 2010, vol. 2, p. 2.
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Scheme 3 Proposed mechanism for the TEMPO promoted reaction.
its reaction with indole. We observed that stirring a solution of
indole (1.0 mmol) and B (1.0 equiv.) at 50 ꢀC for 30 min results in
the formation of 3aa in 85% yield. Ethyl benzoylacetate (2f) reacted
with TEMPO affording tricarbonyl compound Cf in 82% isolated
yield. The 3af was obtained rapidly through the F–C reaction of
indole and Cf by using acetic acid as solvent (Scheme 2).
This result suggests that a plausible mechanism for this
process (Scheme 3) involves a pathway in which TEMPO dispro-
portionation reaction, generating the N-oxopiperidinium ion A
and N-hydroxypiperidine (TEMPOH), under acidic conditions,
takes place initially. Accordingly, reaction between the active
methylene compound and N-oxopiperidinium ion produces
adduct B,19 which then undergoes loss of tetramethylpiperidine
(TEMPH),14d,19 by a acidic elimination by the protonation route to
form ethyl 2,3-dioxobutanoate C. Finally, in presence of acetic
acid, through the Friedel–Cras reaction of indole and vicinal
tricarbonyl compounds C result in the adduct 3aa.17
In conclusion, a novel Friedel–Cras reaction of indoles with
vicinal tricarbonyl compounds generated in situ from 1,3-dicar-
bonyl compounds has been developed for direct preparation of
indole and pyrrole substituted tertiary alcohols. The process,
involving the disproportionation of TEMPO/a-aminoxylation of
1,3-dicarbonyl compounds/N–O bond cleavage to form the tri-
carbonyl intermediate/addition with indoles (C-3 position) or
pyrroles (C-2 position), leads to the formation of indole-
containing and pyrrole-containing tertiary alcohols in a domino
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synthesis of tertiary alcohols that contain multiple functional
groups. Further investigations are now underway to probe further
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Acknowledgements
This work was supported by the key project of Henan Provincial
Department of Education (14A350006) and post-doctoral
research projects of Henan Province (2013039).
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