One-pot oxidative hydrolysis-oxidative cleavage of 7-borylindoles enables access to: O -amidophenols and 4-acylbenzoxazoles

Article abstract of DOI:10.1039/c9cc09807k

7-Borylindoles undergo a one-pot oxidative-hydrolysis of the arylboronate and oxidative cleavage of the indole C2-C3 double bond to afford o-amidophenol derivatives. Subsequent cyclisation delivers benzoxazoles bearing an acyl group at C4, a substitution pattern common to fungal-derived benzoxazole alkaloids. Using 7-borylindoles as substrates to access functionalised o-amidophenols circumvents the difficult preparation of these compounds from arenes, streamlining access to substituted 4-acylbenzoxazoles in the process.

Full text of DOI:10.1039/c9cc09807k

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One-pot oxidative hydrolysis-oxidative cleavage
of 7-borylindoles enables access to
Cite this:DOI: 10.1039/c9cc09807k
o-amidophenols and 4-acylbenzoxazoles†
Received 18th December 2019,
Accepted 20th February 2020
Kirsty Anderson,
Andrew S. Eastabrook
and Jonathan Sperry
*
DOI: 10.1039/c9cc09807k
rsc.li/chemcomm
7-Borylindoles undergo a one-pot oxidative-hydrolysis of the aryl-
boronate and oxidative cleavage of the indole C2–C3 double bond to
afford o-amidophenol derivatives. Subsequent cyclisation delivers
benzoxazoles bearing an acyl group at C4, a substitution pattern
common to fungal-derived benzoxazole alkaloids. Using 7-borylindoles
as substrates to access functionalised o-amidophenols circumvents the
difficult preparation of these compounds from arenes, streamlining
access to substituted 4-acylbenzoxazoles in the process.
Benzoxazole natural products derived from fungi display a wide
range of structural diversity and biological properties. Due to
their common biosynthesis from 3-hydroxyanthranilic acid
(3-HANA) via the shikimate pathway, these alkaloids always
possess an acyl group at the benzoxazole C4 position (Scheme 1A).1,2
Moreover, a number of 4-substituted benzoxazoles have also been
isolated from both plant and marine sources (Scheme 1B).1,2
Most synthetic approaches to 4-acylbenzoxazoles mimic the
biosynthesis and involve the condensation of an o-aminophenol
bearing an acyl substituent with an aldehyde or ester (or
equivalent),1–3 a straightforward process when the 4-acylbenz-
oxazole does not possess any additional substituents. However,
accessing substituted 4-acylbenzoxazoles such as many of those
Scheme 1 (A) Fungal benzoxazole natural products and their general
biosynthesis (3-HANA = 3-hydroxyanthranilic acid; DHHA = trans-2,3-
dihydro-3-hydroxyanthranilic acid); (B) non-fungal benzoxazole alkaloids
with a substituent at C4.
shown in Scheme 1, or for medicinal chemistry studies, 7-borylindole 2. A one-pot oxidation-hydrolysis of the arylboronate
requires access to densely functionalised o-aminophenols, sub- and oxidative cleavage of the indole 2,3-bond8,9 would generate
strates that are not readily attainable. For example, procedures the o-amidophenol 3 that upon cyclisation would give the
for the synthesis of substituted 3-HANA’s are quite rare and are 4-acylbenzoxazole 4, the common heteroaromatic unit found
generally limited to the derivatisation of 3-HANA.4,5 Similarly, in the fungal benzoxazoles shown in Scheme 1. Given that
facile synthetic routes to substituted 2-amino-3-hydroxy- substituted indoles are easy to prepare and a vast number are
benzaldehydes and 2-amino-3-hydroxyacetophenones are also commercially available, this methodology should enable access
few in number.6
to 4-acylbenzoxazoles bearing a variety of different substituents
A proposal for a distinct route to substituted 4-acylbenz- that would be otherwise cumbersome to prepare using existing
oxazoles that circumvent these issues is shown in Scheme 2. methods.
Iridium-catalysed C7–H borylation7 of indole 1 would give the
We initially examined if a 2,3-disubstituted indole could
proceed through the route outlined in Scheme 2. 2,3-Dimethyl-
indole (5) underwent facile iridium-catalysed C–H borylation
to give the 7-borylindole 6,10 setting up the pivotal step in
the proposed route; the simultaneous oxidative cleavage of the
indole C2–C3 double bond and oxidative hydrolysis of the
School of Chemical Sciences, University of Auckland, 23 Symonds Street, Auckland,
New Zealand. E-mail: j.sperry@auckland.ac.nz
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
c9cc09807k
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Scheme 3 Initial proof of concept.
that were found to be capable of converting 6 into 7 were
m-CPBA11 and ozone,12 with the former giving a slightly better
yield in this instance. Cyclisation of 7 with TFA gave 4-acetyl-2-
methylbenzoxazole (8) in good overall yield.
Scheme 2 Proposed route to 4-acylbenzoxazoles from indoles.
With the example shown in Scheme 3 successful, we sub-
jected a variety of 2-substituted indoles to this process
(Scheme 4). By using 2,3-disubstituted indoles, benzoxazoles
harbouring a ketone at C4 are readily attainable, exemplified by
heteroarylboronate at C7. Subjecting 6 to a wide variety of
different oxidants including NaIO4, VO(acac)2, CrO3, salcomine,
RuCl3 and CuCl2 was met with universal failure, with the
desired o-amidophenol 7 not observed. The only two oxidants
Scheme 4 Synthesis of 4-acylbenzoxazoles from 2-substituted indoles.
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Subjecting 23 to ozone led to the o-amidophenol 24 in acceptable
yield. Facile cleavage of the formamide in 24 gave 20-amino-30-
hydroxyacetophenone (25), which could also be obtained in one-
pot from 23 by ozonolysis followed by acidic workup. Interestingly,
25 was directly attainable from the 2,7-diborylindole 22 by ozono-
lysis followed by acidic workup. Treatment of 25 with trimethyl
orthoformate and trimethyl orthobutyrate gave the 4-acetylbenz-
oxazoles 2614 and 27, respectively. 5-Benzyloxyskatole (28) and
6-fluoroskatole (29) both proceeded through this sequence, afford-
ing the o-aminophenols 30 and 31, that upon heteroannulation
with trimethyl orthoformate gave the benzoxazoles 32 and 33,
respectively (Scheme 5B).
Finally, the methodology was used to access a benzoxazole
related to the natural product calcimycin (Scheme 6). 2-Methyl-
4-nitroindole (34)15 underwent the established sequence to give
the benzoxazole 35, which itself is structurally related to the
calcimycin benzoxazole. Moreover, the 2,4-disubstituted indole
34 harbours a substitution pattern that complements the
examples shown in Schemes 4 and 5.
Indoles serve as readily available substrates for the synthesis
of substituted o-amidophenols and hence a range of 4-acylbenz-
oxazoles. Iridium-catalysed C–H borylation of the indole gives a
7-borylindole that undergoes a one-pot oxidative hydrolysis and
oxidative cleavage in the presence of either m-CPBA or ozone.
The resulting o-amidophenol derivatives undergo cyclisation to
give the desired 4-acylbenzoxazoles bearing a variety of different
substituents. A variety of substituents tolerate this process, and the
final cyclisation in TFA is compatible with aldehydes, ketones,
halogens and the nitro group. The use of 7-borylindoles as
templates to access functionalised o-aminophenol derivatives
circumvents the difficulty in preparing these compounds, simulta-
neously streamlining access to substituted 4-acylbenzoxazoles in
the process.
Scheme 5 (A) Preparation of benzoxazoles 26 and 27 from skatole (21);
(B) synthesis of the 6-benzyloxybenzoxazole 32 and the 7-fluorobenzoxazole
33 from commercially available skatole derivatives.
We are indebted to the Royal Society of New Zealand for a
Rutherford Discovery Fellowship (A. S. E., J. S.) and the Uni-
versity of Auckland for a doctoral scholarship (K. A.).
Scheme 6 Application of the methodology towards the calcimycin
benzoxazole.
Conflicts of interest
There are no conflicts to declare.
the synthesis of 4-acylbenzoxazoles 8–12. Next, a series of
2-substituted indoles with a vacant C3 site were trialled;
2-methylindole, 2-phenylindole and 2-(4-fluorophenyl)indole
all proceeded through the sequence smoothly, affording the
4-formylbenzoxazoles 13–15. 2,5-Disubstituted indoles also work
well in this process, enabling access to 4-acylbenzoxazoles bearing
a variety of substituents on the benzenoid ring, including nitro
(16), methyl (17) and a variety of halogens (18–20).
With a series of mono- and disubstituted indoles bearing a
C2-substituent successfully transformed into their corresponding
o-amidophenols and hence 4-acylbenzoxazoles, attention turned to
incorporating 3-substituted indoles into this process. 3-Substituted
indoles present a challenge as the vacant C2-position will undergo
C–H borylation along with the C7-site. Iridium-catalysed diboryla-
tion of skatole 21 gave the 2,7-diborylindole 22 that upon selective
protodeborylation at C213 gave the 7-borylindole 23 (Scheme 5A).
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