Copper-Catalyzed Mild and Efficient Entry to 1-Substituted Indazolones

Abstract

A variety of 1-alkyl- and aryl-substituted indazolones were synthesized easily starting from commercially available 2-halobenzoic acids and hydrazines via the copper-catalyzed intramolecular C-N bond formation of 2-halobenzohydrazides under mild conditions.

indazolone - copper - proline - coupling - hydrazide

References and Notes

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<A NAME="RU03708ST-12A">12a</A> For a recent example for copper-catalyzed intramolecular C-N coupling reaction, see: Lu H. Li C. Org. Lett.  2006,  8:  5365 

<A NAME="RU03708ST-12B">12b</A> During the preparation of this manuscript, Zhu and co-workers disclosed their studies on the synthesis of 2-aryl-2H-indazoles via copper(I)-catalyzed intramolecular amination reaction of N′-aryl-N′-(o-bromobenzyl) acetyl-hydrazines, but the reaction need higher reaction tempera-ture (100-105 ˚C) and long reaction time (20 h) in a pressure tube. See: Liu R. Zhu Y. Qin L. Ji S. Katayama S. Heterocycles  2007,  71:  1755 

<A NAME="RU03708ST-13">13</A>

The acid hydrazides were synthesized from corresponding acid chloride with hydrazine or the condensation of
2-halobenzoic acid with hydrazine using EDC.

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<A NAME="RU03708ST-17">17</A> Xie X. Chen Y. Ma D. J. Am. Chem. Soc.  2006,  128:  16050 

<A NAME="RU03708ST-18">18</A>

Typical Experimental Procedure - Synthesis of 1- tert -butyl-1,2-dihydroindazol-3-one
The mixture of 2-iodobenzoic acid N′-tert-butylhydrazide (0.32 g, 1.0 mmol), CuI (19 mg, 0.10 mmol, 10 mol%), l-proline (23 mg, 0.20 mmol, 20 mol%), and K₂CO₃ (0.28 g, 2.0 mmol) in DMSO (10 mL) was stirred at r.t. for 3 h under nitrogen atmosphere. The mixture was treated with H₂O and the mixture was extracted three times with EtOAc. The combined organic layer was washed with H₂O and brine, and dried over MgSO₄. After filtration, solvent was evaporated in vacuo to ca. 1 mL and crystallization afforded 1-tert-butyl-1,2-dihydroindazole-3-one (0.19 g, 97%) as white crystals. R _f  = 0.36 (hexane-EtOAc, 1:1); mp 115-117 ˚C. IR (KBr): 2979 (NH), 1648 (C=O), 1538, 1209, 748 cm^-¹. ^¹H NMR (400 MHz, DMSO): δ = 10.47 (br s, 1 H, NH), 7.61 (d, 1 H, J = 8.5 Hz, C-4), 7.59 (d, 1 H, J = 7.8 Hz, C-7), 7.26 (dd, 1 H, J = 6.8, 8.5, Hz, C-5), 6.96 (dd, 1 H, J = 6.8, 7.8 Hz, C-6), 1.60 (s, 9 H, t-Bu). ^¹³C NMR (136 MHz, DMSO): δ = 152.8, 139.5, 126.4, 120.1, 118.2, 113.9, 111.9, 58.3, 29.3 (3 × C). ESI-HRMS: m/z calcd for C₁₁H₁₄N₂O 191.1179; found: 191.1182.

<A NAME="RU03708ST-19">19</A>

Acid hydrazide derived from 2,4,6-trichlorophenyl-hydrazine, tert-butylcarbazide, benzoylhydrazine, and
p-toluenesulfonylhydrazine did not afford the corresponding indazolone to recover the starting material even at heating conditions (>100 ˚C).

<A NAME="RU03708ST-20">20</A> Gordon DW. Synlett  1998,  1065 

<A NAME="RU03708ST-21">21</A>

A variety of compounds possessing pharmaceutical profile have been prepared from indazolone derivatives, see ref. 15.