Efficient synthesis of 3-substituted indazoles using Pd-catalyzed intramolecular amination reaction of N-tosylhydrazones

Article abstract of DOI:10.1246/cl.2004.1026

The efficient method for the preparation of 3-substituted indazoles was developed using the palladium catalyzed intramolecular animation reaction of 2-bromophenyl hydrazone derivatives. Good functional group compatibility was observed under mild reaction

Full text of DOI:10.1246/cl.2004.1026

1026
Chemistry Letters Vol.33, No.8 (2004)
Efficient Synthesis of 3-Substituted Indazoles Using Pd-Catalyzed Intramolecular Amination
Reaction of N-Tosylhydrazones
Kiyofumi Inamoto, Mika Katsuno, Takashi Yoshino, Ikue Suzuki, Kou Hiroya, and Takao SakamotoÃ
Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba-ku, Sendai 980-8578
(Received June 9, 2004; CL-040660)
The efficient method for the preparation of 3-substituted in-
dazoles was developed using the palladium catalyzed intramo-
lecular amination reaction of 2-bromophenyl hydrazone deriva-
tives. Good functional group compatibility was observed under
mild reaction conditions and various 3-substituted indazoles
were obtained in moderate to excellent yield.
Table 1. Pd-catalyzed amination for indazoles synthesis
R1
R1
NHTs
base, catalyst
5
4
R2
N
N
R2
dioxane
conditions
N
X
Ts
1
1a : R1 = CO2tBu, R2 = H, X = Br 1e : R1 = Ph, R2 = 5-OMe, X = Br
1b : R1 = CONEt2, R2 = H, X = Br 1f : R1 = Ph, R2 = 4-Me, X = Br
1c : R1 = Ph, R2 = H, X = Br
1g : R1 = (4-OMe)C6H4, R2 = H, X = Br
The development of methods for the efficient construction of
aromatic heterocycles still attracts much attention due to their
numerous presence in natural products, their potent biological
activities, and specific material properties. Despite being not
abundant in nature, indazole derivatives are considered as im-
portant pharmacophores that have a broad range of biological ac-
tivities.1 Song et al. have reported the N-arylindazole synthesis
via the palladium-catalyzed amination reaction using hydrazine
derivatives as starting materials.2 However, gained indazoles are
not manifold and the yields are moderate. More recently, Cho et
al. have demonstrated that the reaction of arylhydrazines and 2-
bromobenzaldehydes gave the N-arylindazoles in the presence
of a palladium catalyst and a base.3 Though this one-pot indazole
synthesis is a novel method, the reaction conditions are some-
what harsh so the substituents compatible during the reaction
seem to be limited. Meanwhile, as compared with the prepara-
tion of N-substituted indazoles, the synthesis of 3-substituted in-
dazoles is much rarer.4,5 To overcome this restriction, we em-
ployed the palladium-catalyzed intramolecular amination
reaction6 of hydrazone derivatives (1) for the synthesis of 3-sub-
stituted indazoles.7
During the course of the optimization of the reaction condi-
tions, it was found that the use of dioxane as a solvent and
Cs2CO3 or NaOtBu as a base allowed the cyclization to proceed
efficiently under mild conditions (even at room temperature in
some cases).8
For example, 3-tert-butoxycarbonyl-N-tosylindazole was
obtained in 81% yield from the corresponding hydrazone 1a in
the presence of Pd2(dba)3 and P(2-Tol)3 along with Cs2CO3
(Table 1, Entry 1). The reaction proceeded smoothly at room
temperature and the desired indazole produced exclusively.
The reaction of hydrazone 1b possessing amide moiety also af-
forded the cyclized product in 72% yield without forming any
side reaction products (Table 1, Entry 2).
1d : R1 = Ph, R2 = 4-NO2, X = Br 1h : R1 = Ph, R2 = H, X = ONf
Entry Hydrazonea Base/Catalystb,c Conditions Yield/%
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
Cs2CO3/A
NaOtBu/B
Cs2CO3/C
Cs2CO3/B
NaOtBu/C
NaOtBu/B
NaOtBu/B
Cs2CO3/B
rt, 3 h
50 ꢀC, 12 h
50 ꢀC, 17 h
50 ꢀC, 12 h
50 ꢀC, 2 h
50 ꢀC, 15 h
rt, 8 h
81
72
83
74
56
66
94
96
1g
1h
rt, 2 h
a
Single isomer was used, which was a major product in hydra-
zone synthesis.
A; Pd2(dba)3, P(2-Tol)3, B; Pd(OAc)2, dppf, C; Pd(OAc)2,
b
dppp.
c
palladium; 10 mol %, phospine ligand; 15 mol %.
= ArOSO2(CF2)3CF3)9 was also employed as a substrate for this
process. The reaction of hydrazone 1h rapidly proceeded at room
temperature and gave the cyclized product in 96% yield (Table 1,
Entry 8).
Although employing the combination such as Cs2CO3 or
NaOtBu/dioxane provided mild cyclization of several hydra-
zones, not all types of substrates reacted effectively. When the
hydrazones possessing alkyl group as R3 in Table 2 were sub-
jected to the reaction under the conditions above, 3-alkylinda-
zoles produced in up to only 52% yield. However, a survey of
other reaction conditions indicated that the use of LiHMDS,
Pd2(dba)3, and P(2-Tol)3 in toluene could remarkably promote
the cyclization and the expected products were obtained in high
yield, albeit at relatively higher temperature (Table 2, Entries 1–
4). It is noteworthy that aryl chloride 1k also successfully react-
ed under this reaction condition to give 2-ethyl-N-tosylindazole
in 62% yield (Table 2, Entry 4).
In conclusion, efficient construction of 3-substituted inda-
zole derivatives was accomplished using the palladium-cata-
lyzed intramolecular amination reaction. The procedures intro-
duced here are practically useful and good functional group-
compatibility was observed under mild reaction conditions;
base-sensitive substituents such as ester and amide remained in-
tact during the reaction. In addition, we have confirmed that the
We next investigated the synthesis of 3-arylindazoles with
various substituents. As shown in Table 1, bidentate dppp or
dppf served as an excellent ligand for this reaction. 3-Phenyl-
N-tosylindazole was obtained in 83% yield from hydrazone 1c
(Table 1, Entry 3). Furthermore, substituents on the arene such
as -NO2, -OMe, and -Me were tolerated in this reaction, and a
variety of 3-arylindazoles were obtained in moderate to high
yield (Table 1, Entries 4–7). In addition, aryl nonaflate (ArONf
Copyright Ó 2004 The Chemical Society of Japan

Chemistry Letters Vol.33, No.8 (2004)
1027
Table 2. 3-Alkylindazoles synthesis
Chem. Commun., 2004, 104.
4
5
a) A. Alberti, N. Bedogni, R. Leardini, D. Nanni, G. F.
Pedulli, A. Tundo, and G. Zanardi, J. Org. Chem., 57, 607
(1992). b) C. Dell’Erba, M. Novi, G. Petrillo, and C. Tavani,
Tetrahedron, 50, 3529 (1994).
For cross-coupling reactions of 3-haloindazoles, see: a) V.
Collot, P. Dallemagne, P. R. Bovy, and S. Rault, Tetrahe-
dron, 55, 6917 (1999). b) V. Collot, D. Varlet, and S. Rault,
Tetrahedron Lett., 41, 4363 (2000). c) A. Arnautu, V.
Copllot, J. C. Ros, C. Alayrac, B. Witulski, and S. Rault,
Tetrahedron Lett., 43, 2695 (2002).
For reviews, see: a) J. P. Wolfe, S. Wagaw, J.-F. Marcoux,
and S. L. Buchwald, Acc. Chem. Res., 31, 805 (1998). b)
J. F. Hartwig, Angew. Chem., Int. Ed., 37, 2046 (1998). c)
B. H. Yang and S. L. Buchwald, J. Organomet. Chem.,
576, 125 (1999).
General procedure for hydrazones syntheses was as follows:
A mixture of ketone (1.0 mmol), NH2NHTs (1.2–2.0 mmol),
and AcOH or AcCl (cat.) in EtOH (5 mL) was heated under
reflux for 4–24 h. The reaction mixture was treated with sat-
urated aqueous NaHCO3 (10 mL) followerd by extraction
with AcOEt (20 mL Â 3). The combined organic layer was
washed with saturated aqueous NaCl (20 mL), and the organ-
ic layer was dried over MgSO4. The organic solvent was re-
moved under reduced pressure and the residue was purified
by SiO2 column chromatography to give hydrazones 1a–
1k as single isomers or mixtures of E- and Z-isomers, which
were separable by recrystallization or flush column chroma-
tography. Not all of the geometries of hydrazones were de-
termined. In the case of hydrazones 1b, 1c, 1d, and 1e, the
major product was used for next cyclization. In the case of
hydrazones 1i–1k, geometries of both isomers were deter-
mined by 1H HMR, 13C NMR (steric effect), HMQC, and
NOESY. 1a; 65% (single isomer), 1b; 96% (1.3:1), 1c;
70% (5:1), 1d; 36% (6:1), 1e; 35% (6:1), 1f; 80% (single iso-
mer), 1g; 99% (single isomer), 1h; 73% (single isomer), 1i;
81% (E:Z = 4:1), 1j; 48% (E:Z = 1:8), 1k; 99% (E:Z = 1:1).
General procedure for cyclizations was as follows: Under Ar
atmosphere, a mixture of a hydrazone (1.0 mmol), a base
(1.5 mmol), a palladium catalyst (10 mol %), a phosphine li-
gand (15 mol %) and a solvent (10 mL) was stirred. The reac-
tion mixture was filtered through Celite and the solvent was
removed under reduced pressure. The residue was purified
by SiO2 column chromatography to give the indazoles.
For Pd-catalyzed amination reaction of aryl nonaflates, see:
K. W. Anderson, M. Mendez-Perez, J. Priego, and S. L.
Buchwald, J. Org. Chem., 68, 9563 (2003).
LiHMDS
R3
R3
N
N
Ts
Pd2(dba)3 (10 mol %)
NHTs
P(2-Tol)3 (15 mol %)
N
toluene
100 °C, time
X
1
1i : R3 = Me, X = Br 1k : R3 = Et, X = Cl
1j : R3 = Et, X = Br
Entry
Hydrazone
Time/h
Yield/%
1
2
3
4
1i (E)
1i (Z)
1j (Z)
1k (Z)
4
1
3
15
68
91
84
62
6
7
detosylation of the indazoles effectively proceeded to give the
deprotected indazoles (Scheme 1). It may offer the possibility
of the further functionalization of 3-substituted indazoles by
the subsequent transformation such as N-arylation and N-alkyla-
tion. Continuous studies to extend the scope of the substrates and
to apply this method for natural product synthesis are underway.
R4
N
R4
N
conditions
N
Ts
N
H
t
conditions : for R4 = CO2 Bu ; TBAF, THF, 50 °C, 24 h : >99%
for R4 = Me ; Mg, MeOH, rt, 1.5 h : 87%
Scheme 1. Detosylation of indazoles.
References and Notes
1
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L. M. Werbel, D. F. Worth, E. F. Elslager, W. R. Leopald,
and J. L. Shillis, J. Med. Chem., 31, 1527 (1988). c) J. D.
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8
9
2
3
Published on the web (Advance View) July 12, 2004; DOI 10.1246/cl.2004.1026