Direct arylations of 2H-Lndazoles on water

Article abstract of DOI:10.1021/ol902537d

(Figure presented) The efficient palladium-catalyzed synthesis of a range of substituted 2H-lndazoles via C-H arylation Is reported. Reactions are performed on water and provide a direct and mild route toward 2,3-diaryl Indazoles of widespread biological significance.

Full text of DOI:10.1021/ol902537d

ORGANIC
LETTERS
2010
Vol. 12, No. 2
224-226
Direct Arylations of 2H-Indazoles On
Water
Stephan A. Ohnmacht,† Andrew J. Culshaw,‡ and Michael F. Greaney*,†
UniVersity of Edinburgh, School of Chemistry, Joseph Black Building, King’s Buildings,
West Mains Rd., Edinburgh EH9 3JJ, U.K. and Global DiscoVery Chemistry, NoVartis
Horsham Research Centre, Wimblehurst Road, Horsham, West Sussex RH12 5AB, U.K.
michael.greaney@ed.ac.uk
Received November 2, 2009
ABSTRACT
The efficient palladium-catalyzed synthesis of a range of substituted 2H-Indazoles via C-H arylation is reported. Reactions are performed on
water and provide a direct and mild route toward 2,3-diaryl indazoles of widespread biological significance.
Direct arylation is a powerful approach to the synthesis of
functionalized arenes that offers an alternative to conven-
tional cross-coupling methods.1,2 The direct manipulation of
C-H bonds in catalytic C-C or C-X bond formation avoids
the preparation and use of stoichiometric organometallics,
conferring the strategic benefit of streamlined, operationally
simple synthesis with reduced byproduct formation.
A feature of current direct arylation methodology is the
high reaction temperatures required to effect C-C bond
formation, with relatively few systems being reported to date
that proceed below 100 °C.3 The development of new
systems that function at milder temperatures will significantly
enhance the scope and functional group tolerance of direct
arylation as a general method of sp2 C-C bond formation.
We are addressing this issue through the development of
direct arylation chemistry that works on water.4 We have
found that on water conditions, where substrate and catalyst
system form a heterogeneous mixture in pure water, can be
extremely effective for high yielding direct arylations under
mild conditions.5 We now wish to report our results on the
application of on water arylation to the indazole substrate.
Although rare in nature, the indazole heterocycle has vast
application in medicinal chemistry, particularly in the field of
kinase inhibition.6 Direct arylation at the C3 position would
significantly simplify synthetic routes to this important class of
heteroarene. Catalytic direct arylation of indazoles has received
little attention, a single elegant study from Lautens on the
synthesis of annulated 2H-indazoles via intramolecular direct
arylation being the only extant report in the literature.7
Figure 1. 1H- and 2H-indazoles.
We began by examining the regioisomeric 1- and 2-phe-
nylindazoles as substrates (Figure 1). The C3 position is known
to be markedly less reactive toward substitution in the 1H-series,
and this was manifested in our direct arylation studies, with 1
undergoing no arylation on water under the mild conditions
we were looking to develop. 2-Phenylindazole,8 by contrast,
proved an excellent substrate, undergoing clean on water
† University of Edinburgh.
‡ Novartis Horsham Research Centre.
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Acc. Chem. Res. 2009, 42, 1074–1086. (c) Chen, X.; Engle, K. M.; Wang,
D.-H.; Yu, J.-Q. Angew. Chem., Int. Ed. 2009, 48, 5094–5115
.
10.1021/ol902537d  2010 American Chemical Society
Published on Web 12/16/2009

arylation with a variety of aryl halides at just 50 °C on water.
A catalyst system of Pd(dppf)Cl2/PPh3 or Pd(dppb)Cl2/PPh3 in
the presence of an equivalent of Ag2CO3 produced good to
excellent yields of 2,3-diarylindazoles on water. The reaction
was generally effective for both aryl iodides and bromides, an
advance over our previous on water studies of azole heterocycles
which were restricted to aryl iodides (Table 1).
Table 1. Palladium-Catalyzed Direct Arylation of
2-Phenylindazolec
Functional group tolerance was good, with halo (entries
2, 5, and 7), electron withdrawing (entries 4, 8, 11, and 12),
and electron donating (entries 3, 6, and 9) groups being
tolerated at both para and meta positions. A single ortho-
functionalized aryl iodide was productive, but in a diminished
49% yield (entry 6). Heterocyclic 2-chloro-4-iodopyridine
produced functionalized indazole 4j in 95% yield, featuring
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a X-ray structure of product. b Reaction run at 60 °C. c Conditions:
Ag2CO3 (1 equiv), PPh3 (10 mol %), Pd(dppf)Cl2·DCM (5 mol %). Aryl
iodide (1.1 equiv), 2-phenylindazole (1 equiv), water, 50 °C, 16 h. Isolated
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the highly versatile 2-chloropyridine functionality for further
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and purifysa feature of on water chemistry. The catalyst
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of water, with good mixing being crucial for successful
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Org. Lett., Vol. 12, No. 2, 2010
225

To fully establish the scope of the arylation we prepared
a series of N2 substituted indazoles and subjected them to
on water arylation (Table 2).
to examine the possibility of intramolecular cyclopentannu-
lation via direct arylation. This intramolecular reaction proved
ineffective under the conditionsswhen 4-chloroiodobenzene
was added in a competition experiment the intermolecular
arylation product was isolated in moderate yield. Functional
handles could be incorporated into the indazole ring with
the 5-chloro- and 7-methoxyindazole compounds being
excellent substrates. Indazoles 4s and 4t previously have been
prepared in 5 steps as inhibitors of liver X receptor-mediated
cardiovascular disease.9
Table 2. Direct Arylation of Various 2H-Substituted Indazolesb
The combination of a silver salt and on water conditions
was essential for successful arylation. Replacing Ag2CO3
with common inorganic bases such as alkali metal carbonates
proved completely ineffective with water as solvent. Cor-
respondingly, using acetonitrile in place of water under our
reaction conditions gave poor yields of arylated indazoles
(12% yield of 4o, with 80% of starting indazole recovered).
Sequestration of halide from the palladium catalytic cycle
by Ag+ appears pivotal to achieving arylation at 50 °C on
water.
In summary, we have reported the first study of intermo-
lecular direct arylation of indazoles. Using on water reaction
conditions, a simple and efficient protocol has been devel-
oped that produces diverse C3-arylated indazoles under
notably mild conditions.
Acknowledgment. We thank Novartis, The EU (Marie
Curie scholarship for S.O.), and the EPSRC (Leadership
Fellowship to M.F.G.) for funding. We also thank the EPSRC
mass spectrometry service at the University of Swansea and
Dr. Fraser White (School of Chemistry, University of
Edinburgh) for assistance with X-ray crystallography. Mr.
Didier Pintori (School of Chemistry, University of Edin-
burgh) is thanked for additional experiments.
a Reaction run at 60 °C. b Conditions: Ag2CO3 (1 equiv), PPh3 (10 mol
%), Pd(dppf)Cl2·DCM (5 mol %). Aryl iodide (1.1 equiv), 2-phenylindazole
(1 equiv), water, 50 °C, 16 h. Isolated yields after SiO2 chromatography.
Supporting Information Available: Experimental pro-
cedures and characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
The SEM protecting group proved stable to the arylation
conditions, with the versatile 2-SEM protected indazole 4m
being formed in high yield. Alkyl-substituted indazoles were
good substrates, as were 2-p- and o-tolylindazoles 4o and
4p. The 2-iodobenzylindazole starting material was prepared
OL902537D
(9) Steffan, R. J.; Matelan, E. M.; Bowen, S. M.; Ullrich, J. W.; Wrobel,
J. E.; Zamaratski, E.; Kruger, L.; Olsen Hedemyr, A. L.; Cheng, A.;
Hansson, T.; Unwalla, R. J.; Miller, C. P.; Rhonnstad, P. P. U.S. Pat. Appl.
Publ. US 2006030612 A1 20060209, 2006; Chem. Abstr. 2006, 144, 212770.
226
Org. Lett., Vol. 12, No. 2, 2010