Synthesis of 3-aryl-1H-indazoles via iridium-catalysed C-H borylation and Suzuki-Miyaura coupling

Article abstract of DOI:10.1039/c4ra04235b

The regioselective iridium-catalysed C3-borylation of 1H-indazoles has been achieved. Subsequent Suzuki-Miyaura coupling of the boronate esters with aryl chlorides, bromides and iodides affords 3-aryl-1H-indazoles in good yields. This journal is the Partn

Full text of DOI:10.1039/c4ra04235b

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Synthesis of 3-aryl-1H-indazoles via iridium-
catalysed C–H borylation and Suzuki–Miyaura
coupling†
Cite this: RSC Adv., 2014, 4, 27726
Received 7th May 2014
Accepted 11th June 2014
*
Ben A. Egan and Paul M. Burton
DOI: 10.1039/c4ra04235b
www.rsc.org/advances
The regioselective iridium-catalysed C3-borylation of 1H-indazoles C–H arylation of 1H-indazoles with aryl iodides.9–11 However,
has been achieved. Subsequent Suzuki–Miyaura coupling of the bor- the conditions reported require high temperatures (up to
ꢀ
onate esters with aryl chlorides, bromides and iodides affords 3-aryl- 150 C) and they fail when the cheaper and more readily avail-
1H-indazoles in good yields.
able aryl chlorides are used as the coupling partner. Further-
more, the examples of aryl halides reported are limited to those
unsubstituted at the ortho positions.
Indazoles are rare in nature but are an important class of
heterocycles in medicinal and agrochemical discovery programs
due to their isosterism with indoles.1 In particular, 3-aryl-1H-
indazoles feature in the estrogen receptor agonist 1,2 the anti-
fungal agent 2 (ref. 3) and the antibiotic teloxantrone (3) (Fig. 1).
Previously reported approaches to 3-aryl-1H-indazoles
include the condensation of hydrazines with uorobenzo-
phenones,2–4 diazomethane cycloaddition with benzynes,5 C–H
amidation of aryl hydrazones6 or catalytic N–N bond formation.7
However, these methods all suffer from requiring the use of
either explosive or toxic reagents. In addition, the diversity of
substitution on both the indazole and the aryl group must be
introduced relatively early on in the synthetic sequence when
employing these conditions.
The synthesis of 3-aryl-1H-indazoles via the cross coupling of
1H-indazoles metalated in the 3-position to aryl halides is
particularly attractive from a discovery-chemistry viewpoint
because it enables the late-stage attachment of an indazole
moiety to an aryl halide intermediate, thus allowing the rapid
access to a variety of substitution patterns. However, this reac-
tion is hampered by the propensity of a 3-metallated, 1H-inda-
In an attempt to broaden the substrate-scope of 1H-indazole
C3-arylation to include both aryl chlorides and bromides and
also aryl halides that possess one or two ortho substituents, we
turned to the Ir-catalysed C–H borylation reaction,12 followed by
Suzuki–Miyaura cross coupling. The results of this investigation
are reported herein.
Our initial investigations were focussed on the borylation of
1-methyl-1H-indazole 6 employing the [Ir(OMe)(COD)]2/di-tert-
butyl bipyridine (dtbpy) catalyst system pioneered by Ishiyama,
Takagi, Hartwig and Miyaura and subsequently applied by other
researchers to the C–H borylation of a wide variety of aromatics
and heteroaromatics over the last decade.12–15 We were pleased
to observe that when employing 0.5 equivalents of bis(pinaco-
lato)diboron (B2Pin2) in tert-butyl methyl ether (TBME) at 55 ꢀC
for 1.5 h, selective borylation at the 3-position of 6 gave 7 in 50%
yield aer chromatographic purication (Scheme 2). Boronate 7
was stored in a freezer without evidence of degradation for 6
months. The high C3-regioselectivity can be attributed to a
zole
4 to undergo ring-opening to the corresponding
2-aminophenylnitrile 5 (Scheme 1).
Knochel and co-workers reported an elegant solution to this
problem in 2012 by zincation at the 3-position of 1-alkyl-1H-
indazoles employing TMPZnCl, followed by subsequent Negishi
cross-coupling with aryl iodides.8 Subsequent reports from the
Itami, Yu and Guillaumet groups have demonstrated the direct
Syngenta Ltd., Jealott's Hill International Research Centre, Bracknell, Berkshire, RG42
6EY, UK. E-mail: Paul.Burton@syngenta.com
† Electronic supplementary information (ESI) available: Experimental procedures
and all spectra of compounds synthesised. See DOI: 10.1039/c4ra04235b
Fig. 1 Bioactive 3-aryl-1H-indazoles.
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Table 1 Suzuki–Miyaura coupling of boryl-indazole 7b
Scheme 1 Fragmentation of 3-metallated 1H-indazoles.
Entry
1
Ar–X
Product
Yielda (%)
Scheme 2 Borylation of 1-Me-1H-indazole with B2Pin2.
72 (A), 74 (B)
combination of steric factors and the C–H acidity at this posi-
tion.16 To the best of our knowledge, 3-boronic esters of 1-alkyl-
1H-indazoles have not previously been reported in the
literature.17
2
3
9
9
71 (A), 66 (B)
86 (A), 68 (B)
A short screen of conditions for the Suzuki–Miyaura aryla-
tion of boronic ester 7 was concluded with the discovery that the
Buchwald second-generation XPhos precatalyst 8 in TBME and
aqueous potassium phosphate effects the cross coupling with
most of the aryl halides we tried (Table 1).18 This cross coupling
4
5
63 (A), 97 (B)
90 (B)
ꢀ
could be performed thermally (55 C for 16 h, conditions A) or
under microwave irradiation (100 ꢀC for 20 min, conditions B).
As shown in Table 1, aryl iodides, chlorides and bromides all
react in good yields (entries 1–3). The coupling is tolerant of
electron donating substituents (entries 6 and 7). Highly
hindered electrophiles such as 2,6-diethylphenyl bromide also
perform well (entry 5). The reaction is also tolerant of free
alcohols (entry 8) and will work on 2-pyridinyl and 2-pyrimidyl
halides (entries 9 and 10).
6
7
76 (B)
91 (B)
We next turned our attention to combining the indazole
borylation and Suzuki–Miyaura coupling into a one-pot proce-
dure.19 We were pleased to nd that this was possible without a
work-up or solvent swap.20 It was possible to simply monitor the
borylation by GCMS and, once this indicated the consumption
of starting material, the palladium precatalyst 8, the aryl halide,
potassium phosphate and water could be added to the reaction
mixture (Scheme 3).
We next investigated varying the substitution on the indazole
employing this one-pot procedure (Table 2). The commercially
available indazole bearing a methyl ester at the 5-position (entry
1) was smoothly borylated using the conditions described in
Scheme 3. When using more highly functionalised indoles, we
found it preferential to use 1 equivalent of B2Pin2 for the
borylation, as doing so increased the reaction rate (entries 1, 2, 3
and 5). When a methyl ester is in the 4-position, borylation is
instead directed to the 6-position (entry 5), presumably due to
the steric bulk of the 4-substituent. 1N-methoxymethyl pro-
tected indazole also performs well in the 3-borylation-Suzuki
sequence (entries 2 and 3). Furthermore, the azaindazole in
entry 4 is well tolerated.21
8
9
84 (B)
87 (B)
97 (B)
10
a
b
Isolated yields aer chromatography.
Reaction conditions: a
solution of the aryl halide (1.0 eq., typically 0.50 mmol), 7 (1.3 eq.),
XPhos-Pd-G2 (0.015 eq.) and K3PO4 (2.0 eq.) in TBME–H2O (10 : 1,
typically 0.1 M) was heated in a RBF at 55 ꢀC for 16 h (conditions A)
or in a microwave reactor at 100 ꢀC for 20 min (conditions B).
Finally, the borylation of the isomeric 2-methyl-2H-indazole
22 was attempted (Scheme 4). Despite smooth borylation at the
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3-position, the resulting pinacol boronate 23 proved to be
unstable in our hands. All attempts to employ it in a Suzuki–
Miyaura reaction employing either the Pd–XPhos precatalyst or
other standard catalysts for this reaction (e.g. PdCl2(dppf)/CsF
or Pd(OAc)2/SPhos/K3PO4) resulted in proto-deborylation and
no desired product formation.
In conclusion, we have demonstrated a novel route to 3-aryl-
1H-indazoles employing Ir-catalysed C–H borylation at the 3-
position, followed by Suzuki–Miyaura coupling with aryl
halides. In particular, the wide substrate scope of the aryl halide
coupling partner in combination with the high yielding and
operationally simple procedure allows a diverse selection of 3-
aryl-1H-indazoles to be rapidly furnished as part of a discovery
chemistry program.
Scheme 3 One pot borylation/Suzuki sequence.
Table 2 One-pot indazole borylation and Suzuki–Miyaura coupling
Notes and references
Entry
1
Indazole
Ar–Xa
Product
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