Synthesis of 3-Substituted Indazoles from Arynes …In summary, we have developed a method for the...

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

1. Introduction

NH

N

NH

N

HN

O

NH CMe3

ABT-102

NH

N

X

X = BrX = Cl

2. Synthesis of 1H-Indazoles from Arynes and N-Tosylhydrazones

Shi, F. et al. Org. Lett. 2011, ASAP

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

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!

Diazotization of 2-Alkyl Anilines

a) Rüchardt, C. Synthesis 1972, 375.b) Stadlbauer, W. Sci. Synth. 2002, 12, 227.

Mechanisms

R

NH2

NH

N

R

NaNO2

H /H2O

R

N N

NN

R

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.

Mechanisms

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.

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

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!

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

Arynes with Ethyl Diazoacetate

Larock, R. C. et al. J. Org. Chem. 2008, 73, 219.

Proposed Mechanisms

TMS

OTf

F

O

OEt

N

H

N

[3+2]

NN

CO2EtH

NH

N

CO2Et

NHN

CO2Et

NH

N

CO2Et

NN

CO2Et

Arynes with Nitrile Imides

Moses, J. E. et al. Org. Lett. 2010, 12, 3368.

5. Synthesis of 2H-Indazoles by the [3 + 2] Cycloaddition of Arynes and Sydnones

Shi, F. et al. Org. Lett. 2010, 12, 2234.

Proposed Mechanisms

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

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.

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.

Thank you !