Preparation of polyfunctional indazoles and heteroarylazo compounds using highly functionalized zinc reagents

Article abstract of DOI:10.1021/ol901585k

Readily available 2-chloromethylarylzinc reagents react with functionalized aryldiazonlum tetrafluoroborates providing polyfunctional indazoles. Selective metalations of these 2-aryl-2H-indazoles afford new polycyclic aromatlcs. The performance of a chemo

Full text of DOI:10.1021/ol901585k

ORGANIC
LETTERS
2009
Vol. 11, No. 19
4270-4273
Preparation of Polyfunctional Indazoles
and Heteroarylazo Compounds Using
Highly Functionalized Zinc Reagents
Benjamin Haag, Zhihua Peng, and Paul Knochel*
Department Chemie und Biochemie, Ludwig-Maximilians-UniVersita¨t,
Butenandtstrasse 5-13, 81377 Munich, Germany
paul.knochel@cup.uni-muenchen.de
Received July 11, 2009
ABSTRACT
Readily available 2-chloromethylarylzinc reagents react with functionalized aryldiazonium tetrafluoroborates providing polyfunctional indazoles.
Selective metalations of these 2-aryl-2H-indazoles afford new polycyclic aromatics. The performance of a chemoselective addition of
diheteroarylzincs to aryldiazonium salts allows an efficient preparation of new heterocyclic azo compounds.
Heterocyclic compounds and in particular indazoles have found
numerous applications as pharmaceuticals, agrochemicals, and
polymers.1,2 Some indazoles act as dopamine antagonists,
anti-inflammatory, analgesic, or antipyretic agents.2a,3 For
the preparation of complex heterocycles, the use of organo-
metallics as key intermediates has proven to be very useful.4
Especially, organozinc compounds are of high importance
due to their exceptional functional group tolerance and
satisfactory reactivity in the presence of appropriate cata-
lysts.5 The compatibility of organozinc compounds with
nitrogen functionalities at high oxidation degree such as nitro
groups, azides, and triazenes is a remarkable feature.6
Diphenylzinc has been reported to react with diazonium salts
providing azo compounds.7 Herein, we report the reaction
of functionalized 2-chloromethylarylzinc reagents of type 1
with various aryldiazonium tetrafluoroborate salts of type 2
leading to a new general synthesis of 2-aryl-2H-indazoles
of type 3 (Scheme 1).8,9 Furthermore, we also report a useful
Scheme 1. Synthesis of Aryl-2H-indazole Derivatives of Type 3
preparation of heterocyclic azo compounds using heterocyclic
zinc reagents.
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10.1021/ol901585k CCC: $40.75
Published on Web 08/31/2009
 2009 American Chemical Society

Thus, the treatment of 2-iodobenzyl chloride (4a) with
i-PrMgCl·LiCl (1.05 equiv, -20 °C, 30 min) furnishes
2-chloromethylphenylmagnesium chloride.10 Transmetalation
with ZnBr2·LiCl (0.55 equiv, -20 to 25 °C, 20 min) provides
the diarylzinc 1a.11 This zinc reagent was then added to
phenyldiazonium tetrafluoroborate in a 1:1 THF:NMP mix-
ture (NMP ) N-methyl-2-pyrrolidone) at -40 °C.9c After
stirring the reaction mixture at 25 °C (30 min) and warming
the solution to 50 °C for 1 h, 2-phenyl-2H-indazole (3a) was
isolated in 98% yield (entry 1 of Table 1).
Table 1. Aryl-2H-indazole Synthesis by the Reaction of
Di(2-chloromethylaryl) Zinc with Aryldiazonium Tetrafluoroborate
We envisioned that the diarylzinc reagent 1 chemoselec-
tively adds to the diazonium salt 2 yielding the 2-chloro-
methylarylazo compound 5. Intramolecular nucleophilic
substitution at the benzylic carbon leads to the cyclic
intermediate 6. Subsequent proton abstraction furnishes the
indazole 3 (Scheme 2).
Scheme 2. Tentative Mechanism of the Indazole Synthesis
This reaction displays a remarkable functional group
tolerance. Thus, a great variety of diazonium tetrafluoroborate
salts and di(2-chloromethylaryl)zinc reagents can be prepared
and used for the synthesis of 2-aryl-2H-indazole derivatives
(3a-r) bearing sensitive functional groups such as halo,
ester, ketone, cyano, methoxy, and nitro groups (Table 1).
As an application, a highly selective ligand for the estrogen
receptor ꢀ (7) was prepared.3 In the key step, the diarylzinc
Scheme 3
.
Synthesis of a Selective Ligand for Estrogen
Receptor ꢀ (7)
a Yield of analytically pure product. b With ZnBr2·LiCl (0.55 equiv), a
transmetalation was performed.
Org. Lett., Vol. 11, No. 19, 2009
4271

reagent 1f reacted with the diazonium salt 2j affording the
indazole derivative 3r. Selective chlorination of 3r with
N-chlorosuccinimide (NCS) using microwave irradiation and
subsequent deprotection of the hydroxyl groups furnished
the indazole derivative 7 in 78% yield (Scheme 3). Further
functionalization of the indazole scaffold can be achieved
by using TMP-derived bases.12-14
Scheme 6. Heterocyclic Organozinc Mediated Azo Coupling
Selective zincation of the indazole 3b was achieved using
TMP2Zn·2MgCl2·2LiCl.12b Subsequent trapping with iodine
furnished 2-(2,6-diiodophenyl)-3-iodo-2H-indazole (8b) in
73% yield (Scheme 4). Also, the treatment of 3b with ZnCl2
Additionally, we have examined the synthesis of hetero-
cyclic azo compounds since they are not easily accessible
by conventional methods. Thus, the reaction of heteroaryl-
zincs of type 13 with aryldiazonium tetrafluoroborate 2c leads
to various functionalized azo compounds (Scheme 6).
The required diarylzincs (13a-f) were obtained by halogen/
magnesium exchange from the corresponding heteroaryl iodides
or bromides followed by transmetalation with ZnBr2·LiCl (-20
to 25 °C, 20 min). Reaction of these zinc, organometallics with
aryldiazonium tetrafluoroborate salt 2c in THF:NMP mixture
Scheme 4. Direct Metalation of Indazole 3b
(1.0 equiv) followed by the addition of TMPMgCl·LiCl (1.1
equiv) led to a selective monozincated indazole.13,14 After
iodolysis, the diiodoindazole 8a is obtained in 83% yield.
Table 2. Reaction of Heterocyclic Diarylzinc with
Aryldiazonium Tetrafluoroborate Salt Leading to Heteroarylazo
Compounds
Scheme 5. Domino Cross-Coupling Affording the Formation of
Heterocyclic Isomeric Indazole Structures of Type 9b and 10b
Polycyclic heteroaromatics bearing an indazole unit were
prepared using domino cross-coupling15 (Scheme 5). Thus,
Pd-catalyzed cross-coupling (Pd(PPh3)4 (4 mol %), THF, 50
°C, 6 h) with 2- and 3-zincated benzofuran derivatives (11
and 12) gave in quantitative yields the structures 9a and 10a.
Treatment of indazole 9a with Pd(OAc)2 (20 mol %) and
dppf (20 mol %) in a 8:1:1 DMF:H2O:Et3N mixture at 150
°C for 1 h provided the cyclized indazole 9b.16 Bismetalation
of indazole 10a with TMP2Zn·2MgCl2·2LiCl (1.1 equiv, 80
°C, 30 min, microwave irradiation) followed by transmeta-
lation with CuCN·2LiCl and addition of chloranil furnished
the isomeric polycyclic heterocycle 10b in 63% yield
(Scheme 5).12a,17
a Yield of analytically pure product.
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Org. Lett., Vol. 11, No. 19, 2009

(4:1) at -40 to -20 °C for 2 h furnishes the azo compounds
(14a-f) in 65-94% yield (Table 2).
BASF SE (Ludwigshafen), and W. C. Heraeus GmbH
(Hanau) for financial support.
In summary, we have reported a short and convenient
synthetic route to 2-aryl-2H-indazoles using highly func-
tionalized arylzinc reagents. As an application, we have
prepared a highly selective binding ligand for the estrogen
receptor ꢀ (7). Finally, new heterocyclic azo compounds were
also reported. Extensions of this method to material relevant
molecules are currently underway in our laboratories.
Supporting Information Available: Experimental pro-
cedures and full characterization of all compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL901585K
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Acknowledgment. We thank the DFG, the European
Research Council (ERC), Chemetall GmbH (Frankfurt),
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