A metal free domino synthesis of 3-aroylindoles via two sp3 C-H activation

Article abstract of DOI:10.1039/c4cc04407j

A metal free synthesis of 3-aroylindole involving two sp³ C-H activation has been achieved starting from o-alkynyl-N,N-dialkylamines using catalyst TBAI and oxidant TBHP. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4cc04407j

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A metal free domino synthesis of 3-aroylindoles
via two sp3 C–H activation†
Cite this: Chem. Commun., 2014,
50, 10445
Anupal Gogoi, Anju Modi, Srimanta Guin, Saroj Kumar Rout, Debapratim Das and
Bhisma K. Patel*
Received 10th June 2014,
Accepted 18th July 2014
DOI: 10.1039/c4cc04407j
www.rsc.org/chemcomm
A metal free synthesis of 3-aroylindole involving two sp3 C–H activation they provide alternate routes to other functionalised indoles
has been achieved starting from o-alkynyl-N,N-dialkylamines using because of easy manipulation of their carbonyl groups.8 As an
catalyst TBAI and oxidant TBHP.
obvious consequence, development of a straightforward method
for the synthesis of 3-aroylindoles has been of great significance.
This motivation led to our Cu catalysed synthesis of 3-aroylindole
from 2-alkynyl-N,N-dialkylamine via cascade C–C and C–O bond
forming pathways following the above-mentioned intra-molecular
CDC strategy (path-a, Scheme 1).5 Exactly the same strategy has
been reported by the Liang group using a Pd–Cu catalytic system
instead of a simple Cu catalyst.6 Prior to these reports, several other
unconventional methods (via C–H activation) for their synthesis
have been developed using transition metal catalysts.8g,9
Although transition metal catalysed processes are advant-
ageous they are invariably associated with high cost and dif-
ficulties in removal of residual metals from the final product
which limits their utility in pharmaceutical industries. Further-
more, for a copper catalysed reaction often doubt arises
whether it is the real catalyst or a co-catalyst due to the traces
of Pd present in commercial grade Cu salts. There are instances
where the metal impurities present even in traces in commercial
grade salts are the actual catalyst.10
To overcome some of the disadvantages associated with
metal catalysts recently photo-catalysts11 and molecular iodine
or organo-iodide12 such as tetrabutylammonium iodide (TBAI)
in combination with an external oxidant are appropriate sub-
stitutes.11,12 The use of designer ligands and at times metals are
unavoidable in any photo-catalytic process, thereby making the
overall method expensive when applied to large scale reactions.
Thus, we envisaged that instead of using metal catalysts the
In modern organic synthesis, C–H functionalisation strategies
have brought about atom and step-economy by streamlining
various arduous synthetic processes.1 However, in this forum,
much of the attention has been focused on functionalisations
of sp and sp2 C–H bonds.2 In contrast high pKa’s (430–35) as
well as large bond dissociation energies (4104 kcal molꢀ1) of
various sp3 C–H bonds make their selective activation a for-
midable challenge. The solutions to these challenges led to the
evolution of various sp3 C–H activation strategies, one of them
being the cross dehydrogenative coupling (CDC). In most cases,
functionalisations of sp3 C–H bonds a to heteroatoms are
attained by the CDC strategy using transition metal catalysts.3
The heteroatoms present in precursors are invariably N- or
O- that generate iminium or oxonium ion intermediates
in situ.3,4 These reactive intermediates are formed by a single
electron transfer from the heteroatoms to the metal centre that
forms a radical cation. This is then followed by a loss of a
hydrogen radical from the adjacent carbon generating either an
iminium or an oxonium ion which is amenable for the con-
struction of C–C or C–heteroatom bonds by an inter- or an
intramolecular nucleophilic attack. For precursors like tertiary
amines, a variety of transition metal catalysts in combination
with organic peroxides are conducive for the formation of
reactive intermediates.3,4a–c Noteworthily, an intramolecular
nucleophilic attack at these iminium ions can generate various
nitrogen containing heterocycles.4a,5,6
Among nitrogenous heterocycles, the indole ring system finds
wide applications in materials chemistry and pharmaceuticals.7
In particular, 3-aroylindoles have gained more importance as
Department of Chemistry, Indian Institute of Technology Guwahati, 781 039,
Assam, India. E-mail: patel@iitg.ernet.in; Fax: +91-3612690762
† Electronic supplementary information (ESI) available. CCDC 1006843. For ESI
and crystallographic data in CIF or other electronic format see DOI: 10.1039/
c4cc04407j
Scheme 1 Synthesis of 3-aroylindole via sp3 C–H activation.
Chem. Commun., 2014, 50, 10445--10447 | 10445
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domino transformation of 2-alkynyl-N,N-dialkylamines to
3-aroyl indoles could be realised under metal free conditions
using TBAI. With this inspiration in mind our initial investigation
began by treating N,N-dimethyl-2-(2-phenylethynyl)benzenamine
(1a) (1 equiv.) with TBAI (20 mol%) and 70% aq. TBHP (3 equiv.)
at 80 1C. To our delight aroylindole (10a) was isolated in 52% yield
(entry 1, Table S1, ESI†). To the best of our knowledge this is the
first metal free synthesis of 3-aroylindole involving two sp3 C–H
activation (path-b, Scheme 1).
Encouraged by this metal-free cascade synthesis of 3-aroyl
indole, other reaction parameters such as catalysts, oxidants
and solvents were varied to attain the best possible yield.
Increasing the amount of TBHP from 3 equiv. to 4 equiv. and
5 equiv. resulted in an improved yield of 59% and 74%
respectively (entries 2 and 3, Table S1, ESI†). The use of other
halogen analogues such as KI, I2, and tetrabutylammonium
bromide (TBAB), instead of TBAI, was found to be less effective
(entries 4–6, Table S1, ESI†). A decane solution of TBHP (5–6 M)
(5 equiv.) in lieu of its aqueous solution (70%) gave a compar-
able yield of 69%, however, other peroxides such as di-tert-butyl
peroxide (DTBP) or aq. H2O2 (50%) failed to give satisfactory
yield of the product (entries 7–9, Table S1, ESI†). Furthermore,
the use of other solvents such as DMF (62%), toluene (46%),
1,4-dioxane (54%), DCE (37%) was found to be less productive
than DMSO (entries 10–13, Table S1, ESI†). The yield dropped
to 56% when the catalyst loading was reduced to 15 mol%
(entry 14, Table S1, ESI†). Neither TBAI nor TBHP alone were
capable of triggering this domino transformation, suggesting
an essential requirement of their combination (entries 15 and 16,
Table S1, ESI†). Thus, catalyst TBAI (20 mol%), and aqueous
TBHP (5 equiv.) in DMSO at 80 1C were found to be the ideal
conditions for this transformation (entry 3, Table S1, ESI†).
After achieving the optimised conditions, this methodology
was applied to different o-alkynyl-N,N-dialkylamines to afford
their respective 3-aroylindoles. As shown in Schemes 2 and 3, a
series of aroylindoles could be obtained in moderate to excellent
yields from their aminoalkyne precursors. At first, effects of
substituents on the aryl ring of the alkynes were examined.
The electron-donating substituents viz. m-Me (1b), p-tBu (1c)
and p-OMe (1d) when present in the aryl ring of the alkyne had a
positive impact on the product (10b–10d) yields (in the range of
76–78%). However, when the aryl ring contains electron-
withdrawing groups such as p-Br (1e) and m-F (1f), the reactions
Scheme 2 Substrate scope of 3-aroylindoles. Reaction conditions: o-alkynyl-
N,N-dialkylamine (0.25 mmol), TBAI (0.05 mmol), TBHP (1.25 mmol) DMSO
(1 mL) at 80 1C. Isolated yields.
proceeded sluggishly to afford their corresponding aroylindoles Scheme 3 Substrate scope of 3-aroylindoles. Reaction conditions: o-alkynyl-
(10e) and (10f) in slightly lesser yields (in the range 67–69%).
N,N-dialkylamine (0.25 mmol), TBAI (0.05 mmol), TBHP (1.25 mmol) DMSO
(1 mL) at 80 1C. Isolated yields.
When the amine bearing aryl rings of the o-alkynylamines are
substituted with weakly electron-donating groups such as p-Me
and the other aryl ring being unsubstituted (2a) or substituted
with an electron-withdrawing group (2f), good yields of the annular tertiary amines. The o-alkynyl amine precursors with a
products were achieved. An excellent yield of 81% was obtained six- or a five-membered ring provided their corresponding
when both the rings contain electron-donating groups as found aroylindoles under the optimised reaction conditions as demon-
for (20d). A moderately electron-withdrawing group such as p-Cl strated by the synthesis of (40a), (40d), (40e) (50a) and (50g).
present in the aryl ring bearing the tertiary amine group resulted However, the yields were moderate which may be due to the
in comparatively lesser yields regardless of the nature of the ring strain associated with the resulting fused aroylindoles. The
substituents on the other ring as exemplified for (30a), (30g) and structure of the aroylindole (50g) was confirmed by X-ray crystallo-
(30e). The scope of this methodology was next extended to graphy (Fig. S1, see ESI†).
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nism has been proposed for this transformation. An aminyl radical
cation (A) is formed by a single electron transfer (SET) process
from the nitrogen atom of the o-alkynyl-N,N-dialkylamine. Abstrac-
tion of a hydrogen radical a to the nitrogen atom gives an iminium
intermediate (B). The intermediate (B) then undergoes annulation
by an intramolecular nucleophilic attack of the alkynyl group at
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18
of 20 equivalent of H2 O afforded aroylindole (10a) without any
18O incorporation indicating TBHP as the possible oxygen source.
Ketonisation of (C) provides 3-aroylindoline (D) which is finally
oxidised/aromatised to its 3-aroylindole (Scheme 4).
In conclusion, we have developed a metal free method for the
synthesis of 3-aroylindoles from o-alkynyl-N,N-dialkylamine through
a TBAI catalysed intramolecular oxidative coupling pathway using
TBHP as the oxidant. This protocol simultaneously installs C–C and
C–O bonds at the expense of two sp3 C–H bonds. The use of an
inexpensive and environmentally benign catalytic system and rela-
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