Thioamide intermediate

Chemical modification via thioamide intermediates and conformation-activity relationships of an antitumor bicyclic hexapeptide 04YGK993. 

Pyridoisothiazolones and the corresponding thiones were prepared according to Method R and used for evaluations in vitro of mti-micobacterium activity. 3H-l,2-Dithiol-[3,4-fo]pyridin-3-thione (326) was transformed into the corresponding 0x0 compound 337 (98%) with Hg(OAc)2 in AcOH [108]. The reaction of 336 with hexylamine gave the thioamide intermediate, which was then oxidised with I2 in basic conditions affording 338, which equiU-brates to 338 in different solvents such as DMSO, DMF, acetone and H2O. From 337, N-hexylisothiazolo[5,4-fo]pyridine-3-(2H)-one (339) (36%) was prepared using the sequence shown above (Scheme 83) [109]. 

It has been tentatively suggested that one mechanism underlies the Willgerodt reaction and the Kindler modification of it. A labile intermediate is first formed which has a carbon—carbon bond in the side chain. The scheme is indicated below it postulates a series of steps involving the addition of ammonia or amine (R = H or alkyl), elimination of water, re addition and eUmination of ammonia or amine until the unsaturation appears at the end of the chain then an irreversible oxidation between sulphur and the nitrogen compound may occur to produce a thioamide. 

Similarly, 5-thiazole alkanoic acids and their salts are obtained from thioamides and /3-halo -y-keto acids (695). Thus thioarylamides condensed with 3-aroyl-3-bromopropionic acid (88) in isopropanolic solution in the presence of Na COs give first 4-hydroxy-2-aryl-A-2-thiazoline-5-acetic acid intermediates (89), which were dehydrated in toluene with catalytic amounts of p-toluene sulfonic acid to 2,4-diaryl-5-thiazole acetic acid (90) (Scheme 39) (657), with R = H or Me Ar = Ph, o-, m- or p-tolyl, o-, m-, or P-CIC6H4, 0-, m-, or p-MeOC(iH4, P-CF3C6H4, a-thienyl, a-naphthyl (657). 

The use of a reagent bearing a basic center or the addition of a base to the reaction mixture was recognized as necessary to prevent the acid-catalyzed elimination of the elements of water from the intermediates. Since the publication of this work, a number of similar intermediates have been isolated from thioamides and a-halogeno carbonyl compounds (608, 609, 619, 739, 754, 801), and as a result of kinetic studies, the exact mechanism of this reaction has been well established (739, 821). 

But the reaction with aliphatic a-halocarbonyl compounds is usually complex, and a variety of compounds can be formed depending on the reactants and the reaction conditions. With chloroacetone in neutral medium (alcohol) the acyclic intermediate (144) analogous to those obtained with thiourea and thioamides was isolated (Scheme 70). 

By condensing the salts or the esters of either dithioformic (207) or dithiophenacetic acids with a-aminonitriles (206) 5-aminothiazoles (209), in which R] = hydrogen, benzyl and Rj = phenyl, carbethoxy, or car-bophenoxy, were obtained in fairly good yields (Scheme 108) (271). These reactions were carried out in aqueous ethereal solution at room temperature. Acyclic thioamides as intermediates in this reaction have been isolated in some cases (208). 

The action of thioamides (1) on a-haloacids or esters gives the same products (230) in moderate yields (20 to 30%) through intermediates analogous to 229. In 230, Ri is phenyl, benzyl, or -pyridyl, Rj is methyl or hydrogen (287, 324). 

Reaction of 2,5-dimethylisoxazoline-3-thione with thiophenol produced a ring-opened thioamide, while pyrolysis gave two products via a thiocyclopropene intermediate (Scheme 76) (80CPB103). 

In the oxidative Eschenmoser sulfide contraction (Scheme 11), thioamide 59 is oxidized by benzoyl peroxide to give either a symmetrical disulfide or the O-benzoate of the thiolactam-S-oxide. In any event, the once-nucleophilic thioamide sulfur atom is now forced to adopt the role of electrophile a reactivity umpolung has, in effect, been achieved.13 The nucleophilic enamide 65 attacks the sulfur atom leading to the formation of sulfur-bridged intermediate 66. The action of a phosphine or a phosphite thiophile on the putative episulfide then gives vinylogous amidine 67. 

Beside thioamides, dithioesters are the most stable and accessible thiocarbonyl compounds. Their specific reactivity, in particular towards nucleophiUc reagents and their apphcations to the formation of carbon-carbon bonds, have already been reviewed [8]. However, as shown below, the presence of a phosphonate function alpha or beta to the thiocarbonyl group in phosphonodithioformates and phosphonodithioacetates makes these difunctional compounds very versatile building blocks. Moreover, for the phosphonodithioacetates, the substitution of the methylenic hydrogen atoms by fluorine increases again their potential as intermediates for the synthesis of modified natural and bioactive phosphorylated structures. 

A recent total synthesis of tubulysin U and V makes use of a one-pot, three-component reaction to form 2-acyloxymethylthiazoles <06AG(E)7235>. Treatment of isonitrile 25, Boc-protected Z-homovaline aldehyde 26, and thioacetic acid with boron trifluoride etherate gives a 3 1 mixture of two diastereomers 30. The reaction pathway involves transacylation of the initial adduct 27 to give thioamide 28. This amide is in equilibrium with its mercaptoimine tautomer 29, which undergoes intramolecular Michael addition followed by elimination of dimethylamine to afford thiazole 30. The major diastereomer serves as an intermediate in the synthesis of tubulysin U and V. 

The thiophene synthesis described herein is related to the synthesis in solution reported by Laliberte, and Medawar4 but differs in some aspects from the procedure in homogeneous phase. Laliberte and Medawar succeeded in obtaining aminothio-phenes in a one-pot reaction from acceptor-substituted acetonitriles, isothiocyanates, a-haloketones, and sodium ethoxide. In contrast to their procedure, solid-phase S-alkylation of the intermediate thioamides under basic conditions led to the formation of product mixtures. We obtained pure aminothio-phenes only when conducting the S-alkylation under neutral or slightly acidic conditions. 

The formation of thioamides from amines (methylamine, dimethylamine and morpholine) and dithioester sulphines, prepared from dithio esters and peracids, is thought to proceed via the intermediates shown in equation 102325. 

The aldol condensation of benzaldehyde with the thioacetamide carbanion (RCHCSNRV), derived from the desilylation of the silyl-thioether with tetra-/i-buty-lammonium fluoride, is stereoselective at—80°C producing the erythro isomer of the p-hydroxy thioamide preferentially (Scheme 6.18, R = Me, erythro threo 95 5) via a conformationally mobile intermediate. However, when R is bulky, a greater amount of the threo isomer is formed. Predictably, as the reaction temperature is raised, so the stereoselectively decreases. This procedure contrasts with the corresponding condensation catalysed by titanium salts, where the complexed intermediate produces the threo isomer [47, 48],... 

---