A general and mild palladium-catalyzed domino reaction for the synthesis of 2H-indazoles

Full text of DOI:10.1002/anie.200902323

Angewandte
Chemie
DOI: 10.1002/anie.200902323
Heterocycles
A General and Mild Palladium-Catalyzed Domino Reaction for the
Synthesis of 2H-Indazoles**
Nis Halland,* Marc Nazarꢀ, Omar Rꢁkyek, Jorge Alonso, Matthias Urmann, and
Andreas Lindenschmidt*
Indazoles play an increasingly important role in drug discov-
ery. They act as an efficient isostere for privileged structures
such as indoles and benzimidazoles. Furthermore, this impor-
tant scaffold is able to interact with a variety of diverse
targets, as highlighted by the growing number of reports of
biologically active indazole derivatives.[1] However, only a
limited number of approaches for the regioselective synthesis
of N-substituted indazoles are available today. Most
approaches afford the thermodynamically favored 1H-inda-
zole or mixtures of 1H- and 2H-indazoles, whereas the
regioselective formation of 2H-indazoles remains a very
challenging task. The lack of a direct, efficient, and regiose-
lective synthetic procedure for the construction of 2H-
indazoles prevents their broader application in, for example,
medicinal chemistry.[2] Thus, there is an unmet need for the
development of a simple and general synthesis of 2H-
indazoles from readily available precursors. Herein we
report a straightforward domino reaction sequence consisting
Scheme 1. Proposed synthesis of 2H-indazoles.
of a regioselective coupling of monosubstituted hydrazines 2
with 2-halophenylacetylenes 1, followed by an intramolecular
hydroamination through a 5-exo-dig cyclization and subse-
quent isomerization of the exocyclic double bond to give the
regioselective.[4d] A second challenge in the development of
our proposed strategy was the control of the hydroamination/
cyclization step to form the 1,2-dihydroindazole 5, as other
possible cyclization pathways lead to other products, such as
1,2-dihydrocinnolines and N-azaindoles.[5] The isomerization
of the exocyclic double bond in dihydro-2H-indazole 5 to give
the aromatic 2H-indazole 3 was expected to occur sponta-
neously under the reaction conditions and thus not to pose
any problems.
We initiated our investigation by screening for reaction
conditions under which the coupling of 1-chloro-2-phenyl-
ethynylbenzene (1a) and phenylhydrazine (2a) would pro-
ceed efficiently to give the N,N’-diaryl hydrazine 4. Upon
optimization of the reaction parameters (the transition metal,
metal salt, ligand, base, solvent, and temperature), the desired
coupling was found to proceed cleanly within just a few hours
and with complete regioselectivity when the catalyst system
[Pd2(dba)3]/PtBu3 (1:2) was used in toluene at 808C with
NaOtBu as the base (dba = dibenzylideneacetone). This
reaction is to our knowledge the first regioselective transi-
tion-metal-catalyzed coupling of monosubstituted hydrazines
to give N,N’-disubstituted hydrazine products.[6]
aromatic 2H-indazole (Scheme 1).[3]
The first challenge in this strategy was the development of
a regioselective transition-metal-catalyzed coupling of mono-
substituted hydrazines 2 with 2-halophenylacetylenes 1 to
afford the required N,N’-disubstituted hydrazines 4. Although
a number of transition-metal-catalyzed coupling reactions of
aryl halides with amides, amines, hydrazides, and hydrazones
are known, only a few coupling reactions of hydrazines have
been reported,[4] and only one of the reported hydrazine
couplings, for the formation of N,N-diaryl hydrazines, is
[*] Dr. N. Halland, Dr. M. Nazarꢀ, Dr. O. R’kyek, Dr. J. Alonso,
Dr. M. Urmann
Sanofi-Aventis Deutschland GmbH, Industriepark Hꢁchst
Building G875, 65926 Frankfurt am Main (Germany)
Fax: (+49)69-305-21618
E-mail: nis.halland@sanofi-aventis.com
Dr. A. Lindenschmidt
Sanofi-Aventis Deutschland GmbH, Industriepark Hꢁchst
TD Thrombosis and Angiogenesis
Building G838, 65926 Frankfurt am Main (Germany)
E-mail: andreas.lindenschmidt@sanofi-aventis.com
We further optimized the reaction parameters to identify
conditions that would promote the complete domino reaction
of 1a with 2a as a one-pot reaction (Table 1).[7] We found that
the use of polar solvents, such as DMF, NMP, or DMA, in
combination with Cs2CO3 led to the formation of the desired
2H-indazole 3a in good yield (Table 1, entries 2–4), whereas
[**] We thank D. I. W. Heyse, H. Schweitzer, and Dr. N. Nagel for solving
the X-ray crystal structure. This research was supported by the
European Community through a Marie Curie Host Fellowship for
the Transfer of Knowledge (HCTMCR).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200902323.
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Table 1: Formation of 2-phenyl-3-benzyl-2H-indazole (3a) under various
Table 2: One-pot domino synthesis of various 2H-indazoles.[a]
reaction conditions.[a]
Entry
1[c]
R
Product
Yield
[%][b]
Entry Pd source (mol% Pd) Solvent Base (equiv)
t
Yield
[h] [%][b]
1
2
3
4
[Pd2(dba)3] (10)
[Pd2(dba)3] (10)
[Pd2(dba)3] (10)
[Pd2(dba)3] (10)
PdCl2 (5)
toluene NaOtBu (1.5) 20 <10
Ph
3a 79
DMF
DMA
NMP
Cs2CO3 (1.5)
Cs2CO3 (1.5)
Cs2CO3 (1.5)
20
20
20
6
20
4
74
72
76
<10
75
77
81
79
71
74
5
toluene Cs2CO3 (1.4)
2
3
4
5
2-pyridyl
3b 90
3c 83
3d 86
3e 70
6
7
PdCl2 (10)
[Pd2(dba)3] (10)
PdCl2 (5)
PdCl2 (5)
PdCl2 (5)
DMF
NMP
DMF
DMF
DMF
DMF
Cs2CO3 (1.5)
Cs2CO3 (1.5)
Cs2CO3 (1.4)
Cs2CO3 (1.4)
Cs2CO3 (1.4)
Cs2CO3 (1.4)
8
3
3
3
3
9[c]
4-CF3C6H4
10
11
PdCl2 (2)
[a] All reactions were performed with 1a (0.5 mmol) and 2a (1.4 equiv)
at 110–1308C. [b] Yield of the isolated product after flash chromatog-
raphy on silica gel. [c] The reaction was performed with 1-bromo-2-
phenylethynylbenzene (1b) instead of 1a. DMF=N,N-dimethylforma-
mide, DMA=N,N-dimethylacetamide, NMP=1-methyl-2-pyrrolidone.
4-MeOC6H4
6-MeO-2-naphthyl
only a trace amount of the 2H-indazole was formed in unpolar
solvents, such as toluene (Table 1, entry 5).[8] The structure of
the 2H-indazoles was confirmed by single-crystal X-ray
structure analysis of 2H-indazole 3r (Table 3; see the
Supporting Information). The palladium source only
seemed to have a minor effect on the outcome of the
reaction: [Pd2(dba)3], PdCl2, PdBr2, and PdI2 all performed
similarly. We therefore chose to use stable and cheap PdCl2
(Table 1, entries 2 and 6). Furthermore, the catalyst loading
could be decreased to 2 mol% Pd without any significant
drop in the yield of the isolated product (Table 1, entries 6, 8,
and 11). As expected, 2-phenyl-3-benzyl-2H-indazole (3a)
was formed in essentially the same yield from 1-bromo-2-
phenylethynylbenzene (1b) as from the corresponding aryl
chloride 1a (Table 1, entries 8 and 9).
Having optimized the reaction conditions, we prepared a
variety of (2-chlorophenyl)acetylenes 1 with different acety-
lene substituents[9] and explored the scope and generality of
this domino reaction sequence. Acetylenes with aromatic
substituents containing electron-withdrawing or electron-
donating groups, as well as the corresponding 2-pyridyl-
substituted acetylene, were transformed into 2-phenyl-2H-
indazoles in 70–90% yield (Table 2, entries 1–5). The reaction
proceeds equally well when the hydrazine salt is used as with
the free hydrazine base (Table 2, entry 1). This result is of
great practical importance, as most commercially available
hydrazines are sold as their more stable hydrochloride salts;
thus, the need to liberate and handle the free hydrazine bases
is eliminated. (2-Chlorophenyl)acetylenes 1 with electron-
withdrawing groups, such as amide, ester, or diacetal sub-
stituents, on the acetylene moiety reacted well with phenyl-
hydrazine (2a) to provide 2-phenyl-2H-indazoles 3 f–h in
good to excellent yields (Table 2, entries 6–8). When more-
electron-donating substituents, such a cyclopropyl or amino-
6
7
C(O)NiPr2
CO2tBu
3 f 63
3g 93
8
9[d]
10
CH(OEt)2
cyclopropyl
CH2NEt2
3h 55
3i 47
3j 30
[a] All reactions were performed with 1 (0.5 mmol), 2a (1.4 equiv), the Pd
catalyst (5 mol%), and Cs2CO3 (1.4 equiv) in DMF at 110–1308C for 3 h.
[b] Yield of the isolated product after flash chromatography on silica gel.
[c] The reaction was performed with PhNHNH2HCl and Cs2CO3
(2.7 equiv). [d] The reaction was performed with 3-chloro-4-cyclopropyl-
ethynylbenzoic acid tert-butyl ester (1c).
methyl group, were present on the alkyne, the 2-phenyl-2H-
indazoles were generally formed in only moderate yields
(Table 2, entries 9 and 10).
To further expand the scope of the reaction, we treated
several (2-chlorophenyl)acetylenes 1 substituted with elec-
tron-withdrawing (CF3, F, CO2H, or CO2tBu) or electron-
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Table 3: (Continued)
donating groups (Me or MeO) in various positions with
phenylhydrazine (2a) under the standard conditions. The
corresponding 2-phenyl-2H-indazoles 3k–q were formed in
moderate to good yields (Table 3, entries 1–7). We then
turned our attention to the hydrazine component. The use of
Entry
Product
Yield [%][b]
50
15
3y
3z
16[c,d]
55
Table 3: One-pot domino synthesis of substituted 2H-indazoles.[a]
Entry
Product
Yield [%][b]
[a] All reactions were performed with
1 (0.5 mmol), hydrazine 3
(1.4 equiv), the Pd catalyst (5 mol%), and Cs2CO3 (1.4 equiv) in DMF
at 110–1308C for 3–6 h. [b] Yield of the isolated product after flash
chromatography on silica gel. [c] Reaction time: 20 h. [d] The reaction
was performed with the hydrazine hydrochloride salt and Cs2CO3
(2.7 equiv). [e] See the Supporting Information for the X-ray crystal
structure of 3r.
1[c]
3k
3l
61
2[c]
43
64
aryl and heteroaryl hydrazines with electron-withdrawing or
electron-donating functionalities afforded 2-aryl-3-benzyl-
2H-indazoles 3r–u in excellent yields (Table 3, entries 8–11).
Thus, the electronic nature of the aryl hydrazine does not
significantly influence the outcome of the reaction. The 2H-
indazole 3v was formed in almost quantitative yield when
4-pyridylhydrazine was used (Table 3, entry 12), whereas the
reaction of (thiophen-2-ylmethyl)hydrazine afforded 3w in
only very moderate yield (Table 3, entry 13). Alkyl hydra-
zines, such as methylhydrazine, isopropylhydrazine, and
phenethylhydrazine, reacted readily with 1a to provide the
desired 2-alkyl 3-benzyl-2H-indazoles in reasonable yields
and with higher than 10:1 regioselectivity, as determined by
1H NMR spectroscopy of the crude reaction mixture (Table 3,
entries 14–16). These results demonstrate the high versatility,
mildness, and high functional-group tolerance of this novel
domino reaction.
3
3m
4
5
6
3n
3o
3p
73
63
46
7
3q
69
In summary, we have developed a practical and general
one-pot procedure for the synthesis of 2H-indazoles from
readily available 2-halophenylacetylenes and hydrazines. The
method involves the first regioselective coupling of aryl
halides with monosubstituted hydrazines, which undergo
reaction at the unsubstituted N atom, and the incorporation
of this reaction into a domino coupling/cyclization/isomer-
ization sequence. This practical and highly versatile one-pot
procedure is a completely novel approach to the formation of
2H-indazoles and thus closes a gap in current synthetic
methodology.
8[d,e]
3r
81
85
9[d]
3s
10[d]
3t
81
11[d]
12[d]
3u
3v
93
94
Experimental Section
General procedure: PdCl2 (5 mol%), tBu3PHBF4 (10 mol%), Cs2CO3
(1.4 equiv), and anhydrous DMF (2.5 mL) were placed in an oven-
dried Schlenk tube with a magnetic stirring bar, and the resulting
mixture was stirred under argon at ambient temperature for 30 min.
The (2-chlorophenyl)acetylene 1 (0.5 mmol) and the hydrazine
(1.4 equiv) were then added, and the mixture was heated at 1308C
for 3 h. The reaction mixture was then cooled, diluted with water, and
extracted twice with EtOAc. The organic phase was dried over
Na2SO4 and concentrated, and the crude product was purified by flash
13[d]
3w
3x
36
63
14
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chromatography on silica gel with EtOAc/heptane or EtOAc/CH2Cl2
as the eluent.
[3] A part of this research has been patented: N. Halland, M. Nazarꢀ,
A. Lindenschmidt, J. Alonso, O. R’kyek, M. Urmann,
WO2009000411, 2009.
[4] a) S. Cacchi, G. Fabrizi, A. Goggiamani, E. Licandro, S. Maiorana,
D. Perdicchia, Org. lett. 2005, 7, 1497 – 1500; b) T. A. Prikhodko,
S. F. Vasilevsky, Russ. Chem. Bull. Int. Ed. 2001, 50, 1268 – 1273;
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WO9943643, 1999.
[5] According to the Baldwin rules, 6-endo-dig and 5-exo-dig
cyclizations to give 1,2-dihydrocinnolines and N-azaindoles,
respectively, are also allowed.
Received: April 30, 2009
Revised: July 10, 2009
Published online: August 13, 2009
Keywords: alkynes · domino reactions · homogeneous catalysis ·
.
nitrogen heterocycles · palladium
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rearrangement.
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synthesis of 2H-indazoles 3 and the associated costs.
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rate-determining (see Figure 2 in the Supporting Information).
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