Tosyloxy ketones

When an aldehyde is used as the starting material in the Gewald reaction, a 5-alkyl-2-aminothiophene is the product isolated. For example, when 3-methylbutanal 25 was combined with ethylcyanoacetate 15 and sulfur in the presence of triethylamine, aminothiophene 26 is the only product observed in this reaction. However, when an a-tosyloxy-ketone 27 and sodium sulfide were employed in the reaction, the corresponding 4-alkyl-2-aminothiophene 28 was the sole reaction product. ... 

A solvent-free strategy for the synthesis of thiazoles involved mixing of thioamides with a-tosyloxy ketones in a clay-catalyzed reaction (Scheme 7). The typical procedure entailed mixing of thioamides and in situ produced a-tosyloxy ketones with montmorillonite K-10 clay in an open glass container. The reaction mixture was irradiated in a microwave oven for 2-5 min with intermittent irradiation and the product was extracted into ethyl acetate to afford 2-substituted thiazoles in 88-96% yields [8]. 

Varma, R.S., Kumar, D. and Liesen, P.J., Solid state synthesis of 2 arnvlbcnzn [ b ] fui.tns, thiazoles and 3-aryl-5,6-dihydroimidazo [2,1 fo] [ 1,3] thiazoles from a-tosyloxy ketones using microwave irradiation, /. Chem. Soc., Perkin Trans. 1, 1998,4093-4096. 

The installation of heteroatom groups based on elements other than oxygen can be readily achieved by a two-step (usually one-pot) sequence in which ketones are first converted to tosyloxy ketones with HTIB, and nucleophilic reagents are then introduced [6,8]. The nosylate analog 18 of HTIB can also be used for this purpose. Recent examples of C-S, C-Se, C-N, and C-I bond formation by this approach are shown in Scheme 28 [86 - 89]. 

The use of silyl enol ethers permitted the preparation of a-tosyloxy ketones with acid-sensitive or oxidizable ring systems, such as fiiran and pyridine. 

An alternative and complementary approach, also proceeding via a-nitrooximes, which has been used to generate furoxans of the sugar series but which should be more generally applicable, involves reaction of a-tosyloxy ketones with hydroxylamine hydrochloride in aqueous pyridine followed by treatment of the resulting oximinopyridine salt with sodium nitrite. The latter step is understood to proceed via nucleophilic displacement of the pyridine by nitrite ion, followed by cyclization of the nitrooxime (72CC1117). 

A similar reagent, [hydroxy(tosyloxy)iodo]benzene, has been used to prepare a-tosyloxy ketones, e.g. (14), from the corresponding ketones. A similar mechanism is thought to operate except that here the initially formed a-iodo species decomposes to the a-phenyliodonio ketone (the tosyloxy salt has been isolated in one case), which is displaced directly by tosyloxy anion. The yields are generally good for a range of substrates, including 3-dicarbonyl systems. 

Leaving groups other than halogens have been used on the C-C fragment. For example, the use of a-tosyloxy ketones offers an alternative to the lachrymatory a-haloketones. The MW-mediated reaction of several para-substituted a-tosyloxy acetophenones with ra-substituted thiobenzamides was accomplished in 88-96% yields with reaction times ranging from 2 to 4 min <1998J(P1)4093>. Cyclization has also been reported without a leaving... 

Selenazoles have been prepared by reactions using hypervalent iodine reagents. Condensation of a-tosyloxy-ketones with primary selenoamides affords 1,3-selenazoles in a one-pot process (Equation 7) <200081219, 2004CJI63>. Reactions of alkynyl(phenyl)iodonium salts with primary selenoamides give 1,3-selenazoles (Equation 8) <2001JHC503>. 

The first naturally occurring member of the class of fenestranes is the diterpene lauren-l-ene (27), isolated in 1979 from the essential oil of Dacrydium cupressinum. The intermediate (26) for Wender s stereocontrolled synthesis of (27) is readily accessible by attack of KOH on the tosyloxy ketone (25) to give, via fragmentation, a carboxylate anion which undergoes immediate ring closure to the lactone (26 Scheme 12). 

Thiazoles have been readily obtained from thioamides and a-tosyloxy-ketones, catalyzed by montmorillonite K-10 clay under MW irradiation, in excellent yields. These compounds are very difficult to synthesize under conventional heating conditions (Scheme 8.25). ... 

FIGURE 18 / 0 0 A heterocycle-release strategy was [433] applied to solid-supported a-tosyloxy ketones in the synthesis of a pentasubsti-tuted pyrrole. Sulfonic acid resin, prepared from commercially available sulfo-nyl chloride resin or polystyrene, was employed. 

Of particular use is the reaction of [hydroxy(tosyloxy)iodo]benzene (HUB, also known as Koser s reagent) with ketones leading to a-tosyloxyketones [185-187], This is a highly chemoselective reaction different functional groups, aromatic rings and carbon-carbon double bonds are well tolerated under the reaction conditions [188], Scheme 3.59 shows a representative example of synthetic application of HUB for the functionalization of the azabicyclic alkaloid anatoxin-a, which is one of the most potent nicotinic antagonists. Specifically, the reaction of A-Boc anatoxin-a 140 with HTIB is the method of choice for the preparation of the synthetically versatile a-tosyloxy ketone 141 (Scheme 3.59) [189],... 

Based on the oxidation-tosyloxylation sequence, Togo and coworkers have developed the preparation of a-tosyloxy ketones and aldehydes 146 in good yields from alcohols 145 by treatment with iodosylbenzene and p-toluenesulfonic acid monohydrate (Scheme 3.61) [206]. This method can also be used for the direct preparation of thiazoles (147, X = S), imidazoles (147, X = NH) and imidazo[l,2-a]pyridines 148 from alcohols in good to moderate yields by successive treatment with iodosylbenzene and p-toluenesulfonic acid monohydrate, followed by thioamides, benzamidine and 2-aminopyridine, respectively (Scheme 3.61) [206]. 

A one-pot procedure for the a-tosyloxylation of ketones by the reaction of ketones with mCPBA and TsOH H2O in the presence of catalytic amounts of NH4I and benzene in a mixture of MeCN and trifluo-roethanol (8 2) has been reported (Scheme 4.67) [110]. This method has some advantages, such as mild reaction conditions with a simple procedure and it is suitable for preparing not only a-tosyloxy ketones but also other a-sulfonyloxy ketones. It has been suggested that [hydroxyl(tosyloxy)iodo]benzene, generated by the reaction of iodide anion with mCPBA, benzene and TsOH, serves as the active species in this reaction [110]. 

This reaction was first reported by Hantzsch and Weber in 1887. It is the formation of thiazole derivatives by means of condensation of a-haloketones (or aldehydes) and thioamides. Therefore, it is generally known as the Hantzsch thiazole synthesis. In addition, other names, including the Hantzsch synthesis, Hantzsch reaction, and Hantzsch thiazole reaction are also used from time to time. Besides thioamides, other thio-ketone derivatives such as thiourea, dithiocarbamates, and ketone thiosemicarbazone can also condense with a-halo ketones (or aldehydes) to form thiazoles. This reaction occurs because of the strong nucleophilicity of the sulfur atom in thioamides or thioureas, and normally gives excellent yields for simple thiazoles but low yields for some substituted thiazoles, as of dehalogenation. This reaction has been proven to be a multistep reaction, and the intermediates have been isolated at low temperatures, in which the dehydration of cyclic intermediates seems to be the slow step. It is found that a variety of reaction conditions might result in the racemized thiazoles that contain an enolizable proton at their chiral center, and it is the intermediate not the final product that is involved in the racemization. Therefore, some modifications have been made to reduce or even eliminate the epimeriza-tion upon thiazole formation. In addition, this reaction has been modified using a-tosyloxy ketones to replace a-haloketones. ... 

This reaction has been modified to reduce the epimerization upon the formation of thiazole. In addition, a-tosyloxy ketones have been used to replace a-haloketones for such reactions. ... 

An alternative procedure for the preparation of dialkyl-1,2-epoxyalkylphosphonates includes reaction of diethyl H-phosphonate in methanol with ot-tosyloxy ketones in the presence of DBU (l,8-diazobicyclo[5.4.0]undec-7-ene) [256]. 

Aqueous PEG 400 was also used in the formation of 1-aroylmethyl-l,2,3-triazoles 82 from phenacyl bromides, sodium azide, and terminal alk5mes under the copper(II) sulfate/sodium ascorbate catalysis [75]. Similar conditions (room temperature, 30 min) were applied to the syndesis of a variety of 1-substituted 4-aryl-l,2,3-triazoles with yield of 75-90% using the copper(II) sulfate/sodium ascorbate catal5dic system in aqueous PEG 400 [76]. a-Tosyloxy ketones 83, including cyclic, were also successfully adopted as substrates for this reaction (Scheme 49) [77,78]. It was demonstrated that copper(I) iodide could be replaced by the copper(II) sulfate/sodium ascorbate system. Some of the products 84 were reported [78] to inhibit Src kinase, a valid target for the therapy of cancer, acute ischemic stroke, and other diseases. 

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