O-Alkylation of N-hydroxythiazole-2(3H)-thiones (TTOHs) provides N-alkoxy derivatives, which are valuable alkoxyl radical precursors for photobiological, mechanistic, and synthetic purposes.^2,3,4 Chemical reactivity of the N-alkoxythiazole-2(3H)-thiones (TTORs) is controlled by the thiohydroxamic acid functional group that is embedded in a cross-conjugated heterocyclic π-electron system.^5,67 Breaking of the thiohydroxamate nitrogen-oxygen bond in TTORs allows the heterocyclic fragment to gain aromatic stabilization, which is the reason for the molecules to liberate oxygen-centered radicals under comparatively mild conditions.

Systematic exploration of O-alkyl thiohydroxamate-based O-radical precursors started with the N-alkoxypyridine-2(1H)-thiones.^8,9,10 Experimental difficulties associated with synthesis and storage of the reagents stimulated development of the N-alkoxy-4-(p-chlorophenyl)thiazole-2(3H)-thiones (CPTTORs). The latter compounds have shelf-lives from months to years,^11,12 but selectively liberate oxygen radicals if photochemically or thermally excited.⁴ Problems remaining unsolved in CPTTOR-chemistry, such as synthesis of tertiary O-alkyl derivatives, were successfully addressed by introducing N-hydroxy-5-(p-methoxyphenyl)-4-methylthiazole-2(3H)-thione (MAnTTOH) as next generation alkoxyl radical progenitor.^3,13,14

CPTTOH is an acid of similar strength to acetic acid and forms primary and secondary O-esters in 50-70% yield, if converted into the derived tetraalkylammonium salt and treated with a hard alkylating reagent. The largest body of chemical reactivity data compiled for the CPTTORs relate to photochemically or thermally initiated reactions with typical mediators for conducting radical chain reactions, such as tributylstannane, tris(trimethylsilyl)silane, O-ethyl cysteine, or bromotrichloromethane.^5,15,16,17 In a supplementary project, the propensity of O-acyl- and O-alkyl-derivatives of CPTTOH to crystallize was used to study the until then unexplored solid state chemistry of the thiohydroxamates. The results from this study show that the molecules tolerate a significant degree of steric congestion at the thiohydroxamate oxygen, because strain effects are absorbed by structural changes across the whole thiohydroxamte group.¹⁸

In addition to radical reactions and solid state chemistry, new ground state reactivity of CPTTORs was discovered, such as a shift of the methyl group from oxygen to sulfur, fragmentation of secondary benzylic esters leading a thiolactam and a ketone, and 4-pentenoxy rearrangements occuring specifically in the solid state (Figure 1).^19,20

From a structure-reactivity study it became apparent that a substituent attached in position 5 shifts electronic absorptions of the thiazole-2(3H)-thione nucleus stronger than the same group does in position 4. Synthesis of 5-substituted N-hydroxy-4-methylthiazole-2(3H)-thiones (Figure 2) starts from constitutionally dissymmetric ketones. Arylpropanones that are not commercially available can be prepared from underlying arylcarbaldehydes and nitroethane via intermediate β-nitrostyrenes. Hydrolysis of nitrostyrenes in acidic aqueous solutions containing iron-powder furnishes the required ketones, which are chlorinated by sulfuryl chloride at the higher substituted α-carbon. Methods of O-ethyl xanthogenate- and oxime-synthesis follow the protocol of the original CPTTOH-synthesis (Figure 2). For the final step, potassium hydroxide in an equimolar volume of dichloromethane and water is the more efficient reagent to mediate the thiazolethione ring closure compared to anhydrous zinc chloride in diethyl ether, which is the recommended reagent for the final step of CPTTOH-synthesis.³

N-Hydroxy-5-(p-methoxyphenyl)-4-methylthiazole-2(3H)-thione (MAnTTOH) was developed as successor of CPTTOR, to improve photochemical properties of alkoxyl radical progenitors, raise yields of O-alkylation products, and prepare tert-O-alkyl thiohydroxamates which until then were not available in yields higher than 5%. MAnTTORs show a longest wavelength of absorption at around 334 nm that gives some of the compounds a yellow color and allows photochemical excitation with visible light or 350 nm-light from a Rayonet^®-photoreactor. MAnTTOH-derived thiohydroxamate salts show an unusual propensity to form products of O-alkylation (MAnTTORs), if treated with alkyl tosylates, alkyl chlorides, or even alkyl iodides (top graphic of Figure 3).²⁰ The majority of MAnTTORs are solids that crystallize by adding an excess of methanol to crude reaction mixtures. Alkylation at sulfur, which consumes the major fraction of alkylation reagent in N-alkoxypyridine-2(1H)-thione-synthesis, is restricted to comparably few instances, such the reaction between the MAnTTOH-tetraethylammonium salt and methyl iodide (46%; bottom graphic of Figure 3).

Alternative methods for thiohydroxamate O-alkylation are the Mitsunobu-reaction, cyclic sulfate-opening, and O-alkyl isourea-chemistry (Figure 4). The former two methods proceed via an inversion of configuration at the attacked carbon,²¹ and the latter is the only method available so far to prepare tertiary O-alkyl thiohydroxamates.²²

The advantage of N-alkoxythiazole-2(3H)-thiones compared to alternative alkoxyl radical precursors is their ability to liberate alkoxyl radicals in a propagating step of a chain reaction. Nitrogen-oxygen bond homolysis thereby occurs after addition of a chain propagating radical, such as a carbon-, silicon-, or tin-radical, to the thione-sulfur (Figure 5).¹⁴ Alkoxyl radicals are highly reactive intermediates, their selectivities are, however, predictable in a straightforward manner on the basis of kinetic and thermochemical data. Additions and hydrogen-atom abstractions, two of the main alkoxyl radical reactions, are irreversible and therefore controlled by kinetic effects (Figure 6, top and center). Selectivity of β-carbon-carbon fragmentation for synthesis of carbonyl compounds (Figure 6, bottom), and alkoxyl radical rearrangements are guided by radical stabilizing effects and therefore are thermodynamically controlled.^2,20,23

Since the radical oxygen is electrophilic and the hydroxyl oxygen nucleophilic, additions of alkoxyl radicals and alcohols to polar carbon-carbon double bonds occur with complementary selectivity (Figure 7).^7,25,26,27

Alkoxyl radical generation from N-alkoxythiazolethiones occurs under pH-neutral, non-oxidative conditions and therefore may be used for transformations that are not attainable by other alkoxyl radical-generating methods. Substituted 5-hexenyloxyl radicals, for example, cyclize onto π-bonds having two methyl groups attached at the terminal alkene carbon. The reaction stereoselectively provides tetrahydropyranylmethyl radicals, which are trapped by bromotrichlormethane to furnish bromocyclized products (Figure 8).^28,29 Polar bromocyclization of the underlying 5-hexenols provide oxepans as major products.

The thiohydroxamate method also applies to prepare vicinal bromohydrin ethers from intermolecular alkoxyl radical addition to alkenes (Figure 9). O-Alkyl thiohydroxamates thus were used to synthesize norbornene-derived vicinal bromohydrin ethers, which have interesting biological properties but are difficult to prepare from ionic reactions due to complications imposed by non-classical carbocation formation.^22,30

Besides adding benefits to organic synthesis, MAnTTORs are excellent tools for conducting kinetic studies on alkoxyl radical elementary reactions.²² Kinetic data are the basis for application of alkoxyl radicals in synthesis of ethers , for complementing selectivity that for more than a century has been restricted to nucleophilic carbon-oxygen bond formation.