A-Thioiminium salts

In addition to its basicity, the structural nature of the base can affect the course of the reaction. For example, a sterically imposing base such as diisopropylethylamine was prevented from abstracting proton (Ha) residing in a congested environment of the a-thioiminium salt (23 Scheme 6) Instead, a less-hindered hydrogen (Hb) was abstracted, leading to formation of a proposed S,N-ketene acetal (24), which underwent rearrangement to yield the a-alkylated thioamide (25) as the major product. A less... 

The role of the thiophile is to assist extrusion of the sulfur atom from the episulfide intermediate to produce the unsaturated product. Studies have established that the presence of a thiophile affects the rate as well as the yield of the sulfur-extrusion reaction. This participation was observed by measuring the difference in reaction rates and yields upon inverting the order of addition of the base and thiophile to a given a-thioiminium salt. Better results were obtained when the thiophile was allowed to stand in the presence of the a-thioiminium salt prior to addition of base. Presumably a sulfur-phosphine complex is established that enhances the acidity of the a-proton slated for abstraction and results in shorter reaction times and better yields. 

In another example, a-bromo ketone (34) was used to alkylate the thioamide (33) in hopes of obtaining directly the vinylogous amide (35 Scheme 8). However, abstraction of an undesired proton in the a-thioiminium salt formed the S,N-ketene acetal as in a previously described example. This proposed intermediate then rearranged and dehydrated to produce the thiophene (36) as the major product. 

Table 2 Reactions of a-Thioiminium Salts with Active Methylene Compounds (Scheme 10)- ...

Warming the above a-thioiminium salt in the presence of the thiophile and base was critical in order to accomplish the sulfide-contraction process. At ambient temperature, work-up of the same reaction mixture produced the oxolactam analog of (102) as the major product (74%) along with a small amount (12%) of vinylogous carbamate (103). In order to better understand the underlying mechanism that prevailed under ambient versus elevated temperatures, NMR studies were conducted on the a-thioiminium salt (107). This intermediate, when dissolved in deuterated chloroform at ambient temperature in the presence of DBU, was converted immediately to a proposed S,N-ketene acetal (108 Scheme 23). Triphenylphosphine had no effect on the iminium salt. Aqueous work-up yielded the lactam (109), which is consistent with formation of the S,N-ketene acetal. However, wanning the intermediate (107) in the presence of the base and thiophile allowed the reaction to eventually proceed via the sulfur-extrusion pathway, due to the reversibility of the S,N-ketene acetal formation. 

To implement the Knoevenagel-based modiHcation, the p-diketone derivative (137) was treated with methyl iodide to yield a white solid, presumed to be the a-thioiminium salt. Upon treatment of the salt with base, the expected cyclized product (142) was isolated in excellent yield. Likewise, the diketone (137) was treated with an equivalent of bromine to produce the same product. The bromine-based cycli-zation is believed to occur by formation of the oi-bromo 3-diketone and closure via the Eschenmoser-based mechanism. A mechanism involving bromination at the sulfur atom also would be consistent with the results. 

The mitomycins are a class of antitumor antibiotics that has been the target of numerous synthetic efforts. The Eschenmoser reaction was a key coupling step in the synthesis of a mitomycin intermediate, apomitomycin (153). Thiopyrrolidinone (149) was alkylated with the aryl bromoacetate (150), and the intermediate a-thioiminium salt was heated with DBU (Scheme 32). The desired condensation product (151) was obtained in excellent yield, although epimerization about the pyrrolidine ring had occurred to produce a 1 1 mixture of the cis and trans substituted diastereomers. Note that, in contrast to a-alkyl-substituted electrophiles, which require conversion to triflates for complete thioamide alkylation, the more reactive benzylic bromide in (150) gave efficient alkylation. The key intermediate (151) was cy-clized in the presence of sodium hydride and copper(I) bromide to yield a single product (152) in nearly quantitative yield. Epimerization to the more stable trans isomer occurred under the cyclization conditions. This intermediate was readily converted to the final product (153). 

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