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Literature Report
Shi, F. et al. Org. Lett. 2011, ASAP
Reporter: De-Yang ZhangChecker: Chang-Bin Yu
Synthesis of 3-Substituted Indazolesfrom Arynes and N-Tosylhydrazones
2011-6-21
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1. Introduction
NH
N
NH
N
HN
O
NH CMe3
ABT-102
NH
N
X
X = BrX = Cl
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2. Synthesis of 1H-Indazoles from Arynes and N-Tosylhydrazones
Shi, F. et al. Org. Lett. 2011, ASAP
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Proposed Mechanisms
R NNH
Ts CsF R NN
Ts
Cs
Path B
R NN
Ts
R NN
Ts
Phside product
R N
NN
R
-Ts
NN
R
Ts
NH
N
R
desired product
Path A
N
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2. Common Synthetic Routes
Diazotization of 2-alkyl anilinesNitrosation of the N-acetyl derivatives of 2-alkyl anilines Condensation of ortho-substituted benzaldehydes with hydrazine
The reaction conditions of these methods are fairly harsh!Usually strong acids or high temperatures are required!
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Diazotization of 2-Alkyl Anilines
a) Rüchardt, C. Synthesis 1972, 375.b) Stadlbauer, W. Sci. Synth. 2002, 12, 227.
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Mechanisms
R
NH2
NH
N
R
NaNO2
H /H2O
R
N N
NN
R
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Nitrosation of N-Acetyl 2-Alkyl Anilines
a) Jacobson, P. et al. Ber. Dtsch. Chem. Ges. 1908, 41, 660.b) Rüchardt, C. et al. Leibigs Ann. Chem. 1980, 908.c) Yoshida, T. et al. Heterocycles 1996, 43, 2701.
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Mechanisms
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Condensation of Ortho-Substituted Benzaldehydeswith Hydrazine
a) Caron, S. et al. Synthesis 1999, 588.b) Lukin, K. et al. J. Org. Chem. 2006, 71, 8166.
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Mechanisms
NH2NH2
R
X
O
X = F, Cl, OMs
R
X
NNH2
NH
N
R
Base
Heat
NH2NH2
R
NH
NNH2
NH2 NH
NH
NHNH2R
-NH2NH2
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4. Other Synthesis of 1H-Indazoles Utilizing Aryne[3+2] Dipolar Cycloaddition Reactions
R2R1
N
NN
N
R1
R2
R1 = H, C(O)R, CO2R
NN
R1
R2
Yamamoto and Larock
Moses
R1Cl
NHN
R2
baseN
R1
N
R2
NN
R1
R2
The reaction can proceed well under very mild conditions!
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Arynes with Diazomethane Derivatives
Yamamoto, Y. et al. Angew. Chem. Int. Ed. 2007, 46, 3323.
TMS
OTf
R1 R2CHN2KF/[18]-crown-6
THF, RTNH
N
R2
R1
F
R2
N
H
N
[3+2]
NN
R2H
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Arynes with Ethyl Diazoacetate
Larock, R. C. et al. J. Org. Chem. 2008, 73, 219.
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Proposed Mechanisms
TMS
OTf
F
O
OEt
N
H
N
[3+2]
NN
CO2EtH
NH
N
CO2Et
NHN
CO2Et
NH
N
CO2Et
NN
CO2Et
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Arynes with Nitrile Imides
Moses, J. E. et al. Org. Lett. 2010, 12, 3368.
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5. Synthesis of 2H-Indazoles by the [3 + 2] Cycloaddition of Arynes and Sydnones
Shi, F. et al. Org. Lett. 2010, 12, 2234.
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Proposed Mechanisms
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6. Summary
R2
NH2
NaNO2
H
R2
NHAc
RONOHeat
R2
X
NH2NH2
Heat
O
X = F, Cl, OMs
TMS
OTf
R1
R2CHN2
NNHTs
HR2
R2
NH
N R3
Cl
N2CHCO2Et
NH
N
R2
R1
KF, RT
CsF, RT
TBAF, RT
CsF, 70 oC
R1
R1
R1
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The indazole unit constitutes a key structural moiety in pharmaceutically relevant structures that exhibits a broad range of bioactivities. Synthesis of the indazolesystem has therefore attracted much attention from the synthetic organic chemistry community. Recently, new and effective routes for the synthesis of indazolesutilizing aryne [3+2] dipolar cycloaddition reactions have been developed. We and Yamamoto reported the dipolar cycloaddition of arynes with diazo compounds to be an effective route to indazoles, and Moses disclosed the [3+2] dipolar cycloaddition of arynes with in situ generated nitrile imides.
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In summary, we have developed a method for the preparation of 3-arylindazoles starting from arynes and readily available, bench stable, inexpensive N-tosylhydrazones. The reaction appears to involve in situ formation of a diazo compound and eliminates the problem of preparing and isolating such unstable and hazardous intermediates. Thus, it extends our previous aryne-diazo cycloaddition route to indazoles.
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Thank you !