Michaela Schwarz

On the Selective O-Alkylation of Ambident Nucleophiles – The Synthesis of Thiohydroxamic Acid O-Esters by Phase-Transfer Reactions

O-Alkylation of cyclic thiohydroxamic acids 1 and 3–5 has been studied with a view to developing an efficient method for the synthesis of N-(alkoxy)pyridine-2(1H)-thiones and N-(alkoxy)thiazole-2(3H)-thiones. Four issues have been addressed and the following conclusions can be drawn: (i) Thiones 1 and 5 exist as O–H acids in the solid state. (ii) According to NMR investigations (1H, 13C), the thione structures should be largely retained in CDCl3, [D6]DMSO, and CD3OD solutions of acids 1, 3–5, as is also the case for pyridinethione salts 2a–h. (iii) O-Alkylation of pyridinethione salts occurs in competition with S-alkylation. Selective O-alkylation is however possible, if thiohydroxamate salts with large countercations, such as M = NBu4, are treated with hard alkylating reagents in polar aprotic media. (iv) As tetrabutylammonium thiohydroxamates, such as 2f, are highly useful in the synthesis of cyclic thiohydroxamic acid O-esters, we have developed an efficient protocol for the preparation of N-(alkoxy)pyridine-2(1H)-thiones directly from acid 1 using phase-transfer conditions (alkyl halide or sulfonic acid ester, CH3CN, K2CO3, Bu4NHSO4). This method has proved particularly successful for the synthesis of N-(alkoxy)thiazole-2(3H)-thiones 11, 20–28, which were obtained in yields of up to 87%.

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

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) A] and long N–O connectivities [N3–O1 = 1.369(3)–1.379(2) A] 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.

4-(4-Chlorophenyl)-3-(4-phenylpent-4-enyloxy)-1,3-thiazole-2(3H)-thione.

The title compound, C(20)H(18)ClNOS(2), is a thiazole-derived thiohydroxamic acid O-ester. The value of Z is 3 and the asymmetric unit comprises three molecules of identical helicity along the N-O bond. Two of these show an anti and the third a syn arrangement of substituents attached in positions 3 and 4 to the 1,3-thiazole nucleus.

Uncovering stereochemical relations in a compound with a stereogenic N-O axis: methyl 2-(4-methyl-2-thioxo-2,3-dihydrothiazol-3-yloxy)propanoate.

The geometry of racemic methyl 2-(4-methyl-2-thioxo-2,3-dihydrothiazol-3-yloxy)propanoate, C(8)H(11)NO(3)S(2), (I), is characterized by a distorted heterocyclic five-membered ring and an enantiomorphic N-alkoxy substituent, which is inclined at an angle of -68.8 degrees to the thiazolethione plane in (M)-(I). The unit cell consists of a 1:1 ratio of R,P- and S,M-configured molecules of (I). The combination of a P configuration at the N-O axis and an R configuration at the asymmetric propanoate C(beta) atom on one side, and an S,M configuration on the other side, is considered to originate from steric interactions. The largest substituent at the asymmetric propanoate C(beta) atom, i.e. the methoxycarbonyl group, resides above the methyl substituent; the medium-sized propanoate gamma-methyl substituent points in the opposite direction with respect to the N-O bond, whereas the H atom is located above the C=S double bond of the thiazolethione subunit.