Amides hydroxamic esters

Scheme 3 outlines synthetic strategies for the introduction of a range of substituents on the amide, alkoxyl and acyloxyl side chains. Hydroxamic esters 23 are readily synthesised from potassium salts of hydroxamic acids 21 according to Cooley et al.7 8 9 or by condensation of the corresponding acid chloride 24 with an alkoxyamine. 

Carbonyl stretch frequencies, carbonyl 13C and amide 15N chemical shifts for a wide range of A-acyloxy-A-alkoxyamides are listed in Table 2 together with those of the precursor hydroxamic esters. Spectroscopically, mutagens can be categorised into six types ... 

Amide v (cm ) ( 13C) [S15N] Ester v (cm ) (S13C) [S15N] Hydroxamic ester v (cm-1) (S13C) [S15N]... 

Steric effects on both the amide and the acyloxyl side chain are similar. Tert-butyl and adamantyl groups on the amide side chain in 29v, 29x, 29c, and 29e (Table 2 entries 53 and 54, 63 and 65) result in lower stretch frequencies that, on average, are only 40 cm-1 higher than their precurser hydroxamic esters. Streck and coworkers have suggested that such changes in dialkyl ketones can be ascribed to destabilisation of resonance form II through steric hindrance to solvation which, in the case of tert-butyl counteracts the inductive stabilisation.127... 

With the exception of para-substituted benzyloxy-/V-acyloxy-V-alkoxyamides, amide carbonyl 13C NMR values of 56 congeners differ from those of their precursor hydroxamic esters by on average +8.0( + 0.6)ppm. Steric and electronic effects influence hydroxamic esters and N- a c y 1 o x y - A- - a 1 k o x y a m i dc s similarly. This includes substrates with branching a to the amide carbonyl. Two classes of A -acy 1 o x y- A -a 1 koxyamides are worthy of mention ... 

A. Amide Properties in V-Heteroatom-substituted Hydroxamic Esters. . . 843... 

FIGURE 2. (a) A stericaUy twisted amide (b) an angularly constrained amide (c) a twisted lactam (d) an angularly constrained hydroxamic ester... 

This chapter will cover the synthesis, structure and chemical reactivity of various N-heteroatom-substituted hydroxamic esters, anomeric amides in which at least one of the heteroatom substituents at nitrogen is an alkoxyl group. Throughout this review, these will either be referred to as A-substituted hydroxamic esters or as A-substituted-A-alkoxy amides. 

Some of the properties of bisheteroatom-substituted hydroxamic esters were described in an earlier review and this chapter will further focus attention on the unique characteristics and reactivity patterns that this configuration imparts to such amides. In short, they display quite different physical and chemical properties to normal hydroxamic esters. 

The barrier to inversion at nitrogen in A-heteroatom-substituted hydroxamic esters should be greater than that found for hydroxamic esters or simple amides. However, it is likely to be substantially reduced in anomeric amides relative to amines since the planar transition state in which nitrogen is sp hybridized, can benefit from jr-overlap with the carbonyl (Figure 3b) and this has been verified experimenfally Rudchenko has measured an inversion barrier for A,A-dialkoxyureas af AG = 9-11 kcalmoH and fhose of acyclic dialkoxyamines fypicaUy af AG = 20-22 kcalmoH ... 

Amide carbonyl vibrational frequencies for the series behave similarly while those of the hydroxamic esters in this subset vary between 1678 and 1698 cm , the V-acyloxy-V-alkoxyamide carbonyl frequencies span only six wave numbers. 

Following the trend towards lower carbonyl IR stretch frequencies, branching alpha to the amide carbonyl (Table 5, entries 53, 54, 62, 63 and 65) affects the shifts for mutagens and hydroxamic esters similarly and causes a marked downfield shift of up to 6 ppm relative to the acetamide substrate (Table 5, entry 60). These effects, as well as the smaller than expected downfield shift with ferf-butyl and neopentyl side chains are, as with the Ai-chlorohydroxamic esters, due to the combined influence of a stabilizing alkyl inductive effect together with destabilizing desolvation of the polar form of the amide carbonyl ". 

Af,Af-Dialkoxyamides (Ic) are the least studied class of stable A-heteroatom-substituted hydroxamic esters. The combined electronegativity of two alkoxyl oxygen atoms is less than that of acyloxyl and alkoxyl oxygen in A-acyloxy compounds but properties are largely typical of anomeric amides. There is good spectroscopic evidence that the nitrogen... 

Limited carbonyl NMR data are available for these anomeric amides. However, carbonyl shifts for hydrazines 217 and 218 were on average 3 ppm higher than their hydroxamic ester precursors. This reflects a higher degree of residual amide resonance in the hydrazines relative to A-acyloxy-iV-alkoxyamides where the difference was closer to 8.0 ppm. As reported for A-acyloxy-A-alkoxyamides (see Section IV.B.2), analysis of variance in the hydrazine and hydroxamic ester shifts indicates that substituents affect the hydroxamic ester carbonyl shifts ( 2.6) more than those of the hydrazines ( 1.3 ppm). 

---