Copper(II)-Catalyzed Room Temperature Aerobic Oxidation of Hydroxamic Acids and Hydrazides to Acyl-Nitroso and Azo Intermediates, and Their Diels–Alder Trapping

Abstract

CuCl(2), in the presence of a 2-ethyl-2-oxazoline ligand, is an effective catalyst for the room temperature, aerobic oxidation of hydroxamic acids and hydrazides, to acyl-nitroso and azo dienophiles respectively, which are efficiently trapped in situ via both inter- and intramolecular hetero-Diels-Alder reactions with dienes. Both inter- and intramolecular variants of the Diels-Alder reaction are suitable under the reaction conditions using a variety of solvents. Under the same conditions, an acyl hydrazide was also oxidized to give an acyl-azo dienophile which was trapped intramolecularly by a diene.

An Experimental and Computational Approach to Understanding the Reactions of Acyl Nitroso Compounds in [4 + 2] Cycloadditions

“…The identities of 42, 43, 51 and 52 were determined on the basis of similar cycloadducts reported elsewhere. 8 The cycloadducts reported herein were all characterized by 1 H NMR, 13 C NMR, IR spectroscopies and mass spectrometry (Figures S14-S45 for NMR spectra). While most adducts showed only one conformer in solution from NMR studies at ambient temperature, the bicyclic oxazaoctene 22 existed as a pair of rotamers ( Figure 1).…”

“…4H),1H),5.99 (d,J = 8.0 Hz,1H),1H),2H),3.87 (dt,J = 19.8,9.9 Hz, 2H), 1.71 -1.64 (m, 3H), 1.61 -1.56 (m, 3H), 1.52 (d, J = 6.9 Hz, 3H); 13 C{ 1 H} NMR (101 MHz, CDCl 3 ) δ 157. 8,143.9,128.6,128.6,127.2,126.1,122.7,122.6,72.0,49.2,48.2,22.5,15.5,13.7;FTIR (thin B) The reaction was performed according to GP2, using (R)-1-hydroxy-3-(1-phenylethyl)urea 3 (64 mg, 0.36 mmol), 2,3-dimethyl-1,3-butadiene (58 mg, 0.71 mmol), CuCl 2 (5 mg, 0.04 mmol) and 2-ethyl-2-oxazoline (7 mg, 0.07 mmol), the resulting solution was stirred at room temperature in air. The reaction was complete in 6 h. The product 26 was obtained as a colorless oil (92 mg, 99%).…”

“…7 Even though peroxides are less toxic, the yields depend upon the substrate, oxidant and catalyst. 7 We recently reported the use of a Cu(II)-catalyzed, air-based, in situ hydroxamic acid oxidation reaction, as shown in Scheme 1,8 which was particularly clean and efficient, and related reactions have been widely used in synthesis. 3,4,[9][10][11] During these studies, it is clear that both the regiochemistry of nitroso-Diels-Alder (NDA) reactions, and often the chemoselectivity of the acyl nitroso species is not always predictable, and is difficult to control.…”

“…3,4,[9][10][11] During these studies, it is clear that both the regiochemistry of nitroso-Diels-Alder (NDA) reactions, and often the chemoselectivity of the acyl nitroso species is not always predictable, and is difficult to control. [8][9][10][11] As a consequence, we undertook to study systematically this reaction both experimentally and theoretically, in order to develop an understanding of the principles which govern the reactivity of acyl nitroso compounds of different types with variously substituted dienes, and herein, we discuss our findings.…”

“…Four reported geometries were of conformer A with -COOCH 2 Ph groups, 8,20 a -CO-camphoryl 21 and a -COCH(OH)Ph 22 group at the bicyclic nitrogen. For bicyclic oxaazaoctenes structurally characterized to date, the -COOR and -COPh groups at the bicyclic nitrogen atom adopted the anti-conformer A or the syn-conformer B whereas others, with -COR groups at the bicyclic nitrogen atom, adopted the anti conformer A.…”