A borylative cyclisation towards indole boronic esters

Article abstract of DOI:10.1039/c0cc03577g

2-Alkynylaniline borylative cyclisations provide a direct means to access indole 3-boronic esters from simple precursors. The Pd-catalysed cyclisation can be merged with cross-coupling processes in the same reaction vessel, moreover, the products can be e

Full text of DOI:10.1039/c0cc03577g

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A borylative cyclisation towards indole boronic estersw
Jianhui Huang,a Simon J. F. Macdonaldb and Joseph P. A. Harrity*a
Received 31st August 2010, Accepted 28th September 2010
DOI: 10.1039/c0cc03577g
2-Alkynylaniline borylative cyclisations provide a direct means
to access indole 3-boronic esters from simple precursors. The
Pd-catalysed cyclisation can be merged with cross-coupling
processes in the same reaction vessel, moreover, the products
can be exploited in C–N bond forming reactions.
can be accessed by Cu-catalysed cyclisations,9 or via electro-
philic iodination.10 Our specific goal was to investigate the
potential of boronate incorporation within the indole cyclisation
reaction. This technique would have the potential to generate
the heteroaromatic boronates in a single step from established
indole precursors, and would provide the opportunity to
generate azole boronates that are currently inaccessible by
alkyne benzannulation strategies, thereby representing a
powerful and complementary alternative. The traditional
and proposed approaches to indole boronic acid derivatives
are summarised in Fig. 1.
Increasing pressure on the Fine Chemicals Industry to produce
novel therapeutics with an efficacious clinical profile but within
a shorter timeframe has revolutionised medicinal chemistry
over the last decade, and has been significantly promoted by
the advent of high throughput synthesis techniques. A key
element of this drug discovery process is the availability of
starting compounds that bear useful functionality for further
elaboration, such that a systematic investigation of the bio-
logical and physiochemical properties can be made. In this
context, aromatic and heteroaromatic boronic acid derivatives
represent one of the most valuable classes of synthetic inter-
mediates in modern organic chemistry because they undergo
a large variety of functional group interconversions as well
as C–C bond forming reactions.1 Approaches towards the
synthesis of boronic acid derivatives largely falls into two
categories: (1) Functionalisation of a pre-formed (hetero)-
aromatic ring;2 (2) Benzannulation strategies, whereby the
boronate is installed by virtue of aromatic ring formation.3
In the context of this latter approach, alkynylboronates have
proven to be useful precursors to a range of heteroaromatic-
and benzene based boronic acid derivatives via metal promoted4
and pericyclic5 cycloaddition processes.
We initiated our studies by preparing the Ts-protected
o-alkynylaniline substrate 1,11 and investigated the Pd-catalysed
cyclisation in the presence of bis(pinacolato)diboron. Our
results are summarised in Table 1. We screened a series of
Pd(II) catalysts which are known to promote indole forming
cyclisations and subsequent electrophile trapping reactions.7a
In the event, whilst PdCl2 catalysis efficiently promoted
cyclisation at room temperature and provided the desired
product 2a, the major product of the reaction was the
C3-protonated indole 2b (entries 1 and 2). We next employed
low valent Pd-catalysts but again were disappointed to find
that desired product 2a was only a minor component of the
cyclised products (entries 3 and 4). In an effort to reduce reac-
tion times, we attempted the cyclisations at elevated tempera-
tures and were surprised to find an overall improvement in the
ratio of 2a : 2b (compare entries 4 and 5). Further optimi-
sation highlighted that DMA and Cs2CO3 gave marginal
improvement (entries 6–8) but significantly, the introduction
of Ph3As proved to promote the borative cyclisation, thereby
providing an effective means to deliver the desired 2-substituted
indole 3-boronic esters. The superior ability of Ph3As to
promote this formation of 2a over 2b is intriguing but mirrors
similar successes documented by Marinelli and co-workers.7c
In an effort to confirm that boronic ester formation occurred
during cyclisation rather than after indole formation, we
subjected 2b to the optimised reaction conditions over 16 h
and found o5% conversion to 2a (Scheme 1). Moreover, 2a
was found to be quite stable towards protodeboronation under
Although the alkynylboronate cycloaddition approach has
provided access to a reasonable selection of arylboronic ester
compounds, exclusive use of alkyne cycloadditions as a vehicle
for aromatic ring formation places an obvious limitation on
the type of scaffold that can be prepared. There is therefore a
clear need to expand the current paradigm beyond this method
and we therefore envisaged an alternative sequence that
employed a metal catalysed benzannulation process that was
terminated by a boration reaction. In this context, the metal
catalyzed cyclisation of o-alkynylaniline derivatives has be-
come a well established method for the synthesis of indoles.6
The substrates for this transformation are easily prepared by
Sonogashira coupling of an appropriate alkyne and o-haloaniline.
As well as providing 2-substituted indoles, Pd-catalysis allows
this strategy to be expanded to permit the incorporation of
substituents at the 3-position by additional metal catalysed
coupling reactions.7,8 Moreover, 3-halo- and 3-cyanoindoles
a Department of Chemistry, University of Sheffield, Sheffield, S3 7HF,
UK. E-mail: j.harrity@sheffield.ac.uk
b GlaxoSmithKline, Stevenage, Hertfordshire, SG1 2NY, UK
w Electronic supplementary information (ESI) available: Experimental
procedures and spectroscopic data for all new compounds. See DOI:
10.1039/c0cc03577g
Fig. 1 Metal catalysed benzannulation–borylation sequence.
c
8770 Chem. Commun., 2010, 46, 8770–8772
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Table 1 Optimisation of the borylative cyclisation
Entry
Catalyst (mol%)
Base (2 equiv.)
Conditions
Yield % (2a : 2b)
1
2
3
4
5
6
7
8
PdCl2 (10)
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
Cs2CO3
Cs2CO3
DMF, rt, 16 h
DMF, rt, 16 h
DMF, rt, 16 h
DMF, rt, 16 h
DMF, 60 1C, 0.5 h
DMA, 60 1C, 0.5 h
DMA, 60 1C, 0.5 h
DMA, 60 1C, 0.5 h
83 (1 : 4.5)
78 (1 : 3)
76 (1 : 6)
92 (1 : 5.5)
91 (1 : 2)
81 (1 : 1)
88 (3.5 : 1)
92 (3.5 : 1)
(PPh3)2 PdCl2 (10)
Pd(PPh3)4 (10)
Pd2(dba)3 (5)
Pd2(dba)3 (5)
Pd2(dba)3 (5), PPh3 (20)
Pd2(dba)3 (5), AsPh3 (20)
Pd2(dba)3 (5), AsPh3 (10)
dba: dibenzylideneacetone.
yield. Finally, we found this methodology to be applicable to
the synthesis of azaindoles and compound 10 was prepared in
51% yield.
In order to demonstrate the synthetic potential of these
scaffolds we undertook some representative functionalisation
reactions, these are highlighted in Scheme 3. We began these
investigations with a Suzuki–Miyaura coupling reaction, as it
represents the most heavily utilised synthetic manipulation of
boronic acid derivatives.12 Moreover, given that the indole
boronic ester formation employs Pd-catalysis, we believed
there to be an opportunity to conduct the cross-coupling reac-
tion after benzannulation, thereby using a single Pd-catalyst
to promote sequential cyclisation and C–C bond forming
processes in situ. In the event, borative cyclisation of 11
followed by addition of 4-fluoro iodobenzene provided
cross-coupled product 12 upon treatment with TBAF.13 Com-
pound 12 represents the core indole motif of fluvastatin, used
in the treatment of hypercholesterolemia.14 Boronic acid
derivatives also offer the potential to construct carbon–
heteroatom bonds and we explored the Cu-catalysed azide
formation from 2.15 Pleasingly, compound 13 was generated in
93% yield, moreover, this procedure was found to be compatible
with a one-pot azidation/click reaction and biheteroaryl product
14 was generated in good yield.
Scheme 1
the reaction conditions, undergoing only 5–10% debory-
lation to 2b over this extended period.
We next turned our attention to exploring the scope of the
borative cyclisation and our results are depicted in Scheme 2.
The methodology was found to be successful over a small
series of sulfonamide based substrates (2–4), although all
attempts to cyclise anilines bearing N-Boc or N-Bn substituents
failed and starting material was returned in these cases. The
chemistry was found to be tolerant of alkyl substituents (5–7),
and bifunctional indoles 8 and 9 were also prepared in good
Scheme 3 Reagents and conditions: (a) 5% Pd2(dba)3, 10% Ph3As,
Cs2CO3, B2Pin2, DMA, 60 1C, 0.5 h; 4-IC6H4F, DMA : H2O (1 : 1),
60 1C, 16 h; TBAF, 60 1C , 6 h. (b) NaN3, 10% CuSO4, MeOH, rt, 2 h.
(c) NaN3, 10% CuSO4, MeOH, rt, 2 h; phenylacetylene, sodium
ascorbate, CH2Cl2 : H2O (1 : 1).
Scheme 2 aReaction conducted with 10% Pd2dba3, 40% Ph3As.
bReaction conducted with 10% Pd2dba3, 20% Ph3As.
c
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In conclusion, we have developed a borative cyclisation
strategy to indole 3-boronic esters. This technique employs
readily available o-alkynylanilines whereby simply adding
commercially available B2Pin2 to a typical catalyst mixture
employed in indole formation, allows direct synthesis of the
corresponding indole boronic esters, that would otherwise be
generated after additional functionalisation steps. This process
is amenable to one-pot cyclisation/cross-coupling protocols
providing a versatile means for generating compound diversity
in a practical manner. Studies towards investigating the scope
of this technique for the synthesis of other heteroaromatic
systems are underway and will be reported in due course.
We are grateful to GlaxoSmithKline and the University of
Sheffield for financial support, and Johnson-Matthey for the
loan of palladium salts.
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8772 Chem. Commun., 2010, 46, 8770–8772
This journal is The Royal Society of Chemistry 2010