Thiolactams

Scheme 19 Formation of (3-thiolactams from thioketenes and imines...

Sordo et al. [79] investigated computationally the reaction between thioketenes (79) and imines to yield (3-thiolactams (80) (Scheme 19), a reaction investigated experimentally by Schaumann [80]. 

In this reaction, achiral A-methacryloylthiobenzanilide 39 gave chiral crystals by spontaneous crystallization, and absolute asymmetric synthesis was performed by the solid-state photoreaction leading to optically active thietane-fused 3-thiolactam. The reaction mechanism for the cyclization was elucidated on the basis of the correlation between the absolute structures of both the prochiral starting monothioimide and the photoproduct. 

Crystal-to-Crystal Solid-State Photochemistry Absolute Asymmetric (3-Thiolactam Synthesis from an Achiral a,(3-Unsatur ated Thioamide, J. Am. Chem. Soc. 118, 10664-10665. (b) Sakamoto, M., Takahashi, M., Arai, W., Mino, T., Yamaguchi, K., Watanabe, S., and Fujita, T. (2000) Solid-State Photochemistry Absolute Asymmetric (3-Thiolactam Synthesis from Achiral N,N-Dibenzyl-a,6-unsaturated Thioamides, Tetrahedron, 56, 6795-6804. (c) Hosoya, T., Ohhara, T., Uekusa, H., and Ohashi, Y. (2002) Crystalline-state... 

Alknyl silyl sulfides, R C=CSSiR 3, which are readily obtained by silylation of anions (39), react as thioketene equivalents. Thus, (3-thiolactams are formed in the reaction with C=N systems (c/. Volume 5, (Chapter 2.2) and thioamides on addition of amines equation (18) shows a typical example. This approach has great promise for the thioacylation of very sensitive natural products. 

Cyclic amidinium salts (71) are obtained by [2 + 2] cycloaddition of ketenimmonium compounds (69) to Schiff bases (70 R = H, Ph, MeOaC) or thioimidates (70 R = SBn) their thiolysis provides an elegant access to 3-thiolactams (72 equation 32). ... 

Photolysis of crystals of 67 gave the spiro (3-thiolactam 68 with high ce and is the first example of an absolute asymmetric synthesis involving hydrogen abstraction by an alkenyl carbon atom <96JAI0664>. 

A diversity of thiolactams has been prepared from the corresponding lactams by use of LR or of the modified reagent (13). Monobactam analogs, e.g., the weakly antibacterial -thiolactam (93), have been prepared by thionation of suitably protected optically active /3-lactams with LR or Davy s reagent (2,4-bis (methylthio)-l,3,2,4-dithiadiphosphetane disulfide), deprotection and subsequent introduction of the side chain. Very recently, an efficient solid-phase synthesis of 1,3,4-trisubstituted /3-thiolactams has been described. The y-thiolactam (94) has been prepared as an intermediate for the synthesis of analogs of the acetylcholinesterase inhibitor huperzine B. Transformation of the quinoline alkaloid cytisine into its thio analog (95) enhanced its biological activity. ... 

The [2+2] cycloaddition of thioketenes to the C=N bond in azomethines is also observed . In this reaction /3-thiolactam, resulting from addition across the C=C bond of the thioketene group, is obtained. For example, from 29 and 30 the [2+2] cycloadduct 31 is obtained in 43 % yield... 

When aldothioketenes are generated in the thermolysis of 4-mono substituted 1,2,3-thiadiazoles in excess of the imines /3-thiolactams are also obtained in 37-79 % yields . 

In the generation of t-butyl(cyano)thioketene at low temperature in the presence of imines, addition across the C=S bond occurs to give thiazetidine derivatives, while at higher temperatures /3-thiolactams are obtained . 

Carbodiimides react with bis-trifluoromethylthioketene to give the /3-thiolactam cycloadducts 47 . 

The high nucleophilicity of sulfur atoms is preserved, even if it is bound to electron withdrawing carbonyl groups. Thiocarboxylales, for example, substitute bromine, e.g. of a-bromo ketones. In the presence of bases the or-acylthio ketones deprotonate and rearrange to episulfides. After desulfurization with triphenylphosphine, 1,3-diketones are formed in good yield. Thiolactams react in the same way, and A. Eschenmoser (1970) has used this sequence in his vitamin B]2 synthesis (p. 261). 

Ethylenethiourea reacts to form monosulftde cross-links (117). A number of alternative curatives have been proposed to avoid use of ethylene thiourea. These iaclude polyhydric phenols (118), hydroxyphenyl and mercapto substituted tria2oles (119), thiolactams (120), thia2o1idinethiones as Vulkacit CRV (121), and alkanethioamides (122). Among these, Vulkacit CRV is the most widely used. An accelerator is ordinarily used ia combination with a retarder to control premature cross-linking. Tetramethylthiuram disulfide [137-26-8] is ordinarily used for this purpose when the accelerator is either ethylenethiourea [96-45-7] or a thia2o1idinethione. 

The TJV spectra were measured for practically all the numerous derivatives. Beside the analytical application of these to demonstrate the position of the substituent no detailed interpretation was attempted, however. On the whole, they are similar to the spectra of analogous purine derivatives and also display a similar dependence on Despite the fact that the question of structure with regard to the lactim-lactam (or thiolactim-thiolactam) tautomerism has not been studied in detail, it can be assumed that oxygen and sulfur derivatives, at variance with the conventional way of writing the formulas, possess a lactam or thiolactam structure. This is in agreement with the views on the analogous purine derivatives. 

Methylations—lactams, thiolactams, amino compounds, and enols. 

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. 

Schemes 15 and 16 summarize the syntheses of intermediates that represent rings A and D of vitamin Bi2 by the Eschenmoser group. Treatment of lactam/lactone 51, the precursor to B-ring intermediate 8 (whose synthesis has already been described, see Scheme 8), with potassium cyanide in methanol induces cleavage of the y-lac-tone ring and furnishes intermediate 76 after esterification of the newly formed acetic acid chain with diazomethane. Intermediate 76 is produced as a mixture of diastereomers, epimeric at the newly formed stereocenter, in a yield exceeding 95%. Selective conversion of the lactam carbonyl in 76 into the corresponding thiolactam...

Although neither of the two carbonyl groups in 18 is immune to the action of Lawesson s reagent,11 it is possible to bring about the selective conversion of the more Lewis-basic lactam carbonyl to the corresponding thiocarbonyl. Thus, treatment of 18 with Lawesson s reagent results in the formation of thiolactam 19 in 85% overall yield from 13. 

To set the stage for the crucial aza-Robinson annulation, a reaction in which the nucleophilic character of the newly introduced thiolactam function is expected to play an important role, it is necessary to manipulate the methyl propionate side chain in 19. To this end, alkaline hydrolysis of the methyl ester in 19, followed by treatment of the resulting carboxylic acid with isobutyl chlorofor-mate, provides a mixed anhydride. The latter substance is a reactive acylating agent that combines smoothly with diazomethane to give diazo ketone 12 (77 % overall yield from 19). 

In the context of 12, the diazo keto function and the thiolactam are in proximity. This circumstance would seem to favor any process leading to the union of these two groupings. It is conceivable that decomposition of the diazo function in 12 with rhodium(n) acetate would furnish a transitory electron-deficient carbene which would be rapidly intercepted by the proximal thiolactam sulfur atom (see 20, Scheme 4). After spontaneous ring contraction of the... 

Benzazepin-2-amines can be obtained by nucleophilic displacement reactions on a variety of substrates. For example, the benzazepin-2-amine 22 is formed by treating the thiolactam 21, obtained from the benzazepinone 20 with phosphorus pentasulfide in pyridine or triethylamine solution, with ammonia.61... 

The p-thiolactams 50 are obtained by the action of Lawesson s or Davy s reagent on 3-substituted 1-methoxy- or 1-benzyloxy-azetidinones followed by reductive N-deprotection. The simple P-thiolactam can be modified to give the thiolactam analogues of monobactams <96LA141>. 

Structural characterization of many quinolizidine derivatives has been established by X-ray diffraction. For example, this technique, in combination with spectroscopic methods, showed that (+)-2-thionosparteine 21 and (+)-2,17-dithionospartine 22 are conformationally rigid and have their lactam and thiolactam groups close to planarity, with the exception of the lactam group in 21, and that rings A and C adopt distorted sofa conformations <2005JST75>. 

Thiolactams 622 treated with carbon suboxide provide mesoionic compounds 623. Their 1,4-dipolar cycloaddition reaction with highly reactive PTAD gives compounds 624, formed by the cycloaddition followed by extrusion of COS, in quantitative yield (Scheme 100) <1995T6651, 1995H(41)1631>. 

Chlorination of amide or lactam using oxalyl chloride gives the chloro-iminium salts in situ. They react with tetrathiomolybdate to afford the corresponding thioamides and thiolactams in short-time and at low temperature in high yields. This method affords high yields of secondary or tertiary thioamides on the other hand it gives low yield of primary thioamide (17% yield) (Scheme 12).3 3... 

Acyl thioamides react with lithium diisopropylamide (LDA) to give p-thiolactams (Scheme 30).57... 

Padwa et al. <20010L1781, 2004JOG33> succeeded in constructing the saturated pyrrolizinones 125 by photo-chemical-promoted intramolecular cyclization of thiolactams 123 leading to 124. Treatment of the latter with Raney-Ni in ethanol afforded compound 125a, while treatment with dimethyl(methylthio)sulfonium tetrafluoroborate (DMTSF) followed by Raney-Ni leads to bicyclic hexahydropyrrolizin-3-ones 125b (Scheme 21). 

The tri-(/erf-butyl) ester (511) was prepared in 40% yield when the thiolactam (510) was first treated with di-rm-butyl malonate and DBU and then with triphenylhosphine and DBU in boiling toluene (85CC583). 

When the solid sample of 24a was irradiated at 0 °C, the crystals gradually changed to amorphous. At this point, the generation of 25a was not observed (Scheme 14 and Table 9, entry 1), and only a mixture of (E) and (Z) isomers (Z/ =1.5) was obtained [47,48]. Prolonged irradiation gave P-thiolactam 25a in 54% yield (entry 2). 

In the solid-state photoreaction of 24c, a more chemoselective reaction occurred and only p-thiolactam 25c was obtained almost quantitatively. Of particular importance is the finding that the solid-state photoreaction of 24c involves a crystal-to-crystal nature where the optically active p-thiolactam 25c is formed in specific yield. Furthermore, the X-ray crystallographic analysis revealed that the crystals of 24c are chiral, and the space group is P2j. Irradiation of crystals at 0 °C exclusively gave optically active P-thiolactam 25c, in 81% yield at 100% conversion (entry 5). As expected, the thiolactam 25c showed optical activity (81% ee). This reaction exhibited good enantioselectivity throughout the whole reaction, where a small difference was observed in the ee value from 97 to 81% ee with increasing conversion from 20 to 100% (entries 5 and 6). The solid-state photoreaction also proceeded without phase separation even after 100% reaction conversion. The crystal-to-crystal nature of the transformation was confirmed by X-ray diffraction spectroscopy. 

Photolysis of cycloheptenecarbothioamide 24d in the solid state also gave the corresponding p-thiolactam in specific yield (entry 7). As the X-ray crystallographic analysis revealed, the crystal is racemic (Fig. 9), and the isolated p-thiolactam was obtained as racemate. 

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