A-hydroxymethyl amides

A-Hydroxymethyl amides are potential acylimines152-154 and react in a strongly acid medium (usually acetic and sulfuric acids) at ca. 10°C, probably as a carbonium-immonium ion ... 

However, an exception must be made for those A-hydroxymethyl amides that derive from antimicrobial effective compounds having an amide configuration in the molecule, e.g. a-halogen-amides (introduction of a second toxophoric group into the molecule). 

AT-[(Acyloxy)methyl] derivatives of active amines and amides have the general formula RK N-CHR O-COR " where R" = H or Me (or an even larger substituent) and COR" is the acyl group. Activation of these derivatives occurs in two steps as depicted in Fig. 8.20, by analogy with the biotransformation of 0-[(acyloxy)methyl] derivatives of phenols (Sect. 8.5.6) [62], The first step is enzymatic or nonenzymatic cleavage of the ester bridge (Fig. 8.20,a), followed by chemical breakdown of the A-(hydroxymethyl) intermediate (see also Chapt. 5 in [81]). Here, again, liberation of toxic formaldehyde, i. e., where R" = H, should be avoided whenever possible by substitution of, e.g., Me at R"... 

Several reaction mechanisms are possible for the cleavage of A-(hydroxy-methyl) intermediates [214], In the case of derivatives of amides and imines, the reaction is base-catalyzed, with the rate-limiting step being deprotonation of the A-(hydroxymethyl) compound (which has a pKa of ca. 13 Fig. 

Rajagopal et al. (1984) used numerous compounds to develop a proposed pathway of degradation of aldicarb in soil. These compounds included aldicarb oxime, A-hydroxymethyl aldicarb, A-hydroxymethyl aldicarb sulfoxide, A-demethyl aldicarb sulfoxide, A-demethyl aldicarb sulfone, aldicarb sulfoxide, aldicarb sulfone, A-hydroxymethyl aldicarb sulfone, aldicarb oxime sulfone, aldicarb sulfone aldehyde, aldicarb sulfone alcohol, aldicarb nitrile sulfone, aldicarb sulfone amide, aldicarb sulfone acid, aldicarb oxime sulfoxide, aldicarb sulfoxide aldehyde, aldicarb sulfoxide alcohol, aldicarb nitrile sulfoxide, aldicarb sulfoxide amide, aldicarb sulfoxide acid, elemental sulfur, carbon dioxide, and water. Mineralization was more rapid in aerobic surface soils than in either aerobic or anaerobic subsurface soils. In surface soils (30 cm depth) under aerobic conditions, half-lives ranged from 20 to 361 d. In subsurface soils (20 and 183 cm depths), half-lives under aerobic and anaerobic conditions were 131-233 and 223-1,130 d, respectively (Ou et al, 1985). The reported half-lives in soil ranged from approximately 70 d (Jury et ah, 1987) to several months (Jones et al, 1986). Bromilow et al. (1980) reported the half-life for aldicarb in soil to be 9.9 d at 15 °C and pH 6.34-7.0. 

Structures 3.3-3.10 possess two potential handles for their support on SP. The obvious choice is the carboxylic function, which could be linked either to a chlo-romethyl or to a hydroxymethyl PS resin through an ester bond. The insertion of a commercially available acid-labile linker, possibly already supported onto the resin, would allow the release of the target into solution under mild conditions. Different functionalities could be released by cleaving the acid-labile linker with, for example, TFA (free acid) and amines (amides). Another possible handle is the secondary amine, which could be anchored to resin-bound carboxylates or halides and finally released as an A-acyl or A-aUcyl moiety. For both handles the protection of the other functional... 

Tropicamide. N-Ethyl-a-(hydroxymethyl)-N-(4-pyridinytmethylibenzeneaceta mide N-ethyt-2-phenyl-N-(4-pyridylmethyl)hydracrylamide Af-ethy I -N-(y-picolyl)trop-amide Mydiiacyl. C(7Ha sl1Oj mol wt 284.35. C 71.80%, H 7.09%. N 9.85%, O 11.25%. Prepn Rey-Ballet, Spiegel -berg, U-S. pat. 2,726,245 (1955 to Hoffmann-La Roche). Comprehensive description K. W. Blesse) el al. in Analytical Profiles of Drug Substances vol. 3, K. Florey, Ed. (Aca -demic Press, New York, 1974) pp 565-580. 

Formaldehyde plus a nitrile may replace the (hydroxymethyl) amides the resulting reaction ... 

Dressman et a/. described an alternative solid-phase synthesis in which the amino acids were N-terminally linked to a hydroxymethyl resin through a carbamate linker. Amide formation gave products 273 which, after treatment with base cyclised to yield hydantoins of typ>e 274 Scheme 4.4.6). 

Rajagopal et al. (1989) used numerous compounds to develop a proposed pathway of degradation of aldicarb in soil. These componnds inclnded aldicarb oxime, A-hydroxym-ethyl aldicarb, A-hydroxymethyl aldicarb snUbxide, A-demethyl aldicarb sulfoxide, A-demethyl aldicarb sulfone, aldicarb snUbxide, aldicarb sirlfone, A-hydroxymethyl aldicarb sulfone, aldicarb oxime snUbne, aldicarb snUbne aldehyde, aldicarb snUbne alcohol, aldicarb nitrile sulfone, aldicarb snUbne amide, aldicarb snUone acid, aldicarb oxime suUoxide, aldicarb suUoxide aldehyde, aldicarb suUoxide alcohol, aldicarb nitrile snUoxide, aldicarb... 

Dioxo-imidazolidines, also called hydantoins, also include the carbonamide structure, and therefore the corresponding A-hydroxymethyl compounds are listed among the reaction products of amides and formaldehyde. 

The heterocyclic N,S compounds Dazomet (Section 3.3.16) and Taurolin (Section 3.5.2.) can be regarded as formaldehyde releasing compounds therefore they are listed in Section 3. The A -hydroxymethyl derivative of 2-mercaptobenzothiazole (Section 3.4.10.2) is a formaldehyde releasing compound too and is described under Section 3.4, Reaction products of amides and formaldehydes . 

A Claisen-type condensation of ethyl retinoate (24) with the a-hydroxymethyl ketone (641) in the presence of lithium amide in tetrahydrofuran led to the enolized diketone (642), which when treated with an acid, underwent cyclization to give the butenolide (643) (Ito et aL, 1979b). 

Leznoff and Goldwasser (1977) used a hydroxymethylated polymer for monoblocking of symmetrical diacid chlorides. The unblocked acid chloride group was then converted to an amide and the polymer-bound derivatives were cleaved from the polymer and characterized as monoamide monoesters (Scheme 9-11). The functionalized products were obtained in high yield and in pure state, indicating that there was no observable double binding of the acids on polymer support. It was stressed that proper choice of the reaction conditions can alter the ability of the polymer to undergo interresin reactions. 

The OBO ester (2,6,7-trioxabicyclo[2.2.2]octyl ester) can also be prepared from a secondary or tertiary amide (Tf20, CH2CI2, Pyr then 2,2-bis(hydroxymethyl)-l-propanol, 10-88% yield). ... 

Yet another nonsedating zwitterionic H-1 antihistamine consists of the product from metabolism of the terminal hydroxyl of the potent antihistamine hydroxyzine terminating in hydroxymethyl instead of a carboxylic acid. This compound, cetirzine (123), can be obtained in straightforward fashion by alkylation of the monosubstituted piperazine 120 with halide 121, via the amide 122 [27]. 

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