A New Generation of Alkoxyl Radical Precursors – Preparation and Properties ofN-(Alkoxy)-4-arylthiazole-2(3H)-thiones

Abstract

N‐(Hydroxy)thiazole‐2(3H)‐thiones 6–10 have been prepared in a short and efficient synthesis from p‐substituted acetophenones. Alkylation of heterocycles 6–10 in the form of their potassium or tetraalkylammonium salts 11–15 affords N‐alkoxy‐4‐arylthiazole‐2(3H)‐thiones 16–20 in good to satisfactory yields. The hitherto unknown thiones 16–20 have been subjected to a detailed structural investigation (NMR spectroscopy and X‐ray crystallography) and furthermore to a mechanistic study in order to explore their utility as sources of oxygen‐centered radicals in solution. From the results of these studies, the following conclusions can be drawn: (i) X‐ray analyses of the p‐chlorophenyl‐substituted acid 9, of the O‐alkyl derivatives 19c, 19f, and of the O‐mixed anhydride 19k indicate short C–S bonds [C2–S2 = 1.637(5)–1.684(2) Å] and long N–O connectivities [N3–O1 = 1.369(3)–1.379(2) Å] in the thiohydroxamate functionalities. Furthermore, O‐alkyl‐ or O‐acyl substituents at O1 are twisted out of the thiazolethione plane by ca. 90°, which points to lone‐pair repulsion between nitrogen and oxygen atom as the underlying structural motif of the cyclic thiohydroxamate derivatives. (ii) Alkylation of ambidentate thiohydroxamate anions (salts 11–15; oxygen and sulfur nucleophiles) affords almost exclusively O‐esters 16–20 (alkylation at the oxygen atom). (iii) Based on the results of X‐ray diffraction studies and on the 1H‐ and 13C‐NMR spectra, guidelines for the characterization of N‐(alkoxy)thiazolethiones 16–20 and 2‐(alkylsulfanyl)thiazole N‐oxides 21–25, i.e. the products of S‐alkylation of thiohydroxamate salts 11–15, could be derived. (iv) Photolyses of substituted N‐(4‐pentenoxy)‐4‐arylthiazolethiones 16–20 in general and in particular of p‐chloro derivatives 19 were carried out in the presence of the hydrogen donor Bu3SnH, and afforded substituted tetrahydrofurans 31 or tetrahydropyrans 32 as major products in good yields. The observed stereo‐ and regioselectivities of ethers 31 and 32 point to alkoxyl radicals 30 as reactive intermediates, which add intramolecularly by selective 5‐exo‐trig or 6‐endo‐trig pathways to the olefinic double bonds. In terms of synthetic access and ease of handling of the radical precursors, the p‐chlorophenyl‐substituted thiazolethiones 9 and 19 exhibit significant advantages over all the other thiones used in this study and are considered as excellent substitutes for the pyridinethiones as efficient sources of free alkoxyl radicals. Consequently, the present compounds may be of use in both mechanistic and synthetic studies.

Stereoselective Construction of the Tetrahydrofuran Nucleus by Alkoxyl Radical Cyclizations

“…Ellipsoid graphics of single-crystal structure analyses of pyridinethione 34 and thiazolethione 35; ellipsoids are drawn at the 50% level, hydrogen atoms are depicted as circles of arbitrary radius, see ref. [21,50] Although the progress summarized in Schemes 2 and 3 helped to further study O-radical reactions, the instability of a number of thiones was unsatisfactory. [20] Compound 21, for example, when stored in a refrigerator, affords the heteroaromatic isomer 22 in quantitative yield within a few days.…”

The Barrier to Rotation around N−O Bonds in 4-Substituted N-Isopropoxythiazole-2(3H)-thiones and in N-Isopropoxy-2(1H)-pyridinethione

“…N-Isopropoxy-2(1H)-pyridinethione (1) [12,13] and 4-(pchlorophenyl)-N-isopropoxythiazole-2(3H)-thione (3) [14] were available from earlier studies. N-Isopropoxy-4-methylScheme 1.…”

“…For example, a doublet at δ ϭ 1.04 ( 1 H NMR) and a singlet at δ ϭ 19.0 ( 13 C NMR) were recorded for both CH 3 groups in 4-(p-chlorophenyl)-N-isopropoxythiazole-2(3H)-thione (3). [14] These signals broadened on cooling. Coalescence was observed at 233 K and well-separated resonances of the individual rotamers were observed at 200 K [3 ( 13 C NMR): δ ϭ 19.4, 19.0, Figure 2].…”

“…[3] The ground state geometry of N-isopropoxy-4-(p-chlorophenyl)thiazole-2(3H)-thione (3) in the solid state shows an almost orthogonal transposition of the N-alkoxy substituent with respect to the thiazolethione plane. [14] According to NOE experiments [12] and to theoretical investigations, [18] this geometry should also represent the most significantly populated conformer of N-alkoxypyridinethiones, for instance 1, and presumably of thiones 2 and 3, in solution. Thus, the change in position of the isopropoxy substituent caused by an NϪO rotation through the heterocyclic plane leads to higher energy conformers.…”

“…All solvents were distilled prior to use and purified according to standard procedures. [20] N-Isopropoxy-2(1H)-pyridinethione (1) [12,13] and 4-(p-chlorophenyl)-N-isopropoxythiazole-2(3H)-thione (3) [14] were prepared as reported previously.…”