A Simple and Efficient Preparation of Novel Formaldehyde Derivatives

Abstract

New formaldehyde derivatives were prepared in good yields by a short and versatile route. Several crystal structures of corresponding thioacetic acid esters and thiols were determined. The thioacetates were cleaved under acidic or basic conditions affording the thiols in high yield, thus introducing the new substance classes of N-mercaptomethyl-alkylcarboxamides, N-mercaptomethylsulfonamides, and alkoxymethanethiols.The reactivity of formaldehyde is outstanding among aldehydes making it difficult to obtain the pure substance. With traces of water formaldehyde immediately suffers from nucleophilic attack rendering polymeric formaldehyde. This extraordinary reactivity is due to the lack of electron-donating alkyl groups, which stabilize the carbonyl group of larger homologues by the inductive effect.For our syntheses 1 of orally active carbapenems we searched for formaldehyde-derived N-mercaptomethylalkylcarboxamides and HS/O-acetals. Surprisingly, the former compounds have not been prepared yet, whereas the latter could not be prepared by a route proposed in 1912. 2 We wish to report here the synthesis of the following three novel types of formaldehyde derivatives. As they contain a reactive SH group they are versatile C 1 -building blocks in organic synthesis.N-Mercaptomethylcarboxamides represent a first novel class of thiols, prepared by a four-step synthesis starting from carboxamides and formaldehyde according to Scheme 1. The mildest method to prepare N-hydroxymethyl compounds 2 uses an aqueous formaldehyde solution with a catalytic amount of K 2 CO 3 , a reaction first described by Einhorn. 3 Accordingly, amides 1 reacted easily in high yields. However, our attempts to purify the products 2 by column chromatography or recrystallization failed in most cases. The hydroxymethyl group was cleaved, leaving only starting material 1 and formaldehyde. Adduct 2c could be recrystallized from toluene, yielding pure product. The adducts 2 were converted to chlorides 3 using thionyl chloride or oxalyl chloride. The reaction of chlorides 3 with potassium thioacetate produced the desired 4 using a method developed in our group. 1 Acidic or basic cleavage of the thioacetates delivered the corresponding thiols 5 in good yields. Thioacetate 4b was prepared by direct reaction of 2b with thioacetic acid in 64% yield.Scheme 1 General reaction sequence used to prepare 5Starting with pyrrolidin-2-one (1e) the intermediate lactams 2e-4e and the cyclic thiol 5e were produced. Alternatively from the known 4 3-chloromethyl-1,3,4-oxadiazol-2(3H)-ones 3f,g and from 1,3,4-thiadiazol-2(3H)-ones 1h 5 and 1i 5 the cyclic thiols 5f-i were synthesized.Pyrrolidin-2-one (1e) did not easily react with aqueous formaldehyde, so we had to deviate from the standard route. In a modified procedure, 6 a mixture of paraformaldehyde and 1e was heated to 180°C to give 2e, which was chlorinated immediately affording 3e in 40% overall yield after distillation. Crystal structures of thioacetates 4b,i as well as of thiols 5d,g,h,i could be determined. 7 The ...

Synthesis and crystal structure studies of 5-(trifluoromethyl)-1,3,4-thiadiazol-2(3H)-one at 180 K

“…A few other crystal structures of compounds related to 5-TMD-2-one include MAZZIX and NIYDOO01 (Boechat et al, 2006), 1,3,4-thiadiazolium-2-thiolate (Hu et al, 2006) and 3-(mercaptomethyl)-1,3,4-thiadiazol-2(3H)-one (HORZAQ; Hartung et al, 2009).…”