Hydroxamic esters

To synthesize the monoxacetam stmctures (Fig. 6), alkylation of A/-protected 1-hydroxyazetidinones (46) with the appropriate haloacetic acid derivatives provided (47). Alternatively, (47) could be prepared from the acycHc hydroxamate ester (48). Deprotection of (47) furnished the zwitterionic intermediate (49) [90849-16-4] CgH2QN204, which subsequendy underwent acylation using the C-3 aminothiazole oxime side chain to afford SQ 82,291 (45) also known as oximonam (37). 

In a nonelectrolytic reaction, which is limited to R = primary alkyl, the thio-hydroxamic esters 29 give dimers when irradiated at -64°C in an argon atmosphere ... 

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 ... 

Thus the impact of hydroxamic ester substitution through nitrogen at the ester oxygen is to raise the acyloxyl carbonyls into the range for acid chlorides and acid anhydrides.128... 

Table 2 Infrared carbonyl absorption frequencies (CHC13), 13C and selected 15N chemical shiftsa (CDC13) for 7V-acyloxy-7V-alkoxyamides (R1ON(OCOR2)COR3) and precursor hydroxamic esters... 

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... 

C NMR spectroscopy. 13C NMR resonances for both carbonyls of the TV-acyloxy-V-alkoxyamides and that of the parent hydroxamic ester are given for most compounds in Table 2. 

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 ... 

The role of steric effects is unclear but the anomeric effect could also contribute to an increase in electron density at nitrogen. X-ray data for the two TV-acyloxy-TV-alkoxyamides, a urea and a carbamate outlined above show clear evidence, both from bond lengths and conformations, of an anomeric interaction RO-N bonds are short when compared to alkoxyamines. This interaction is responsible for SN1, SN2, homolytic and rearrangement reactions of /V-acyloxy-TV-alkoxyamides (vide infra) and has also been supported computationally. Acyloxylation of the hydroxamic esters results in both pyramidalisation as well as anomeric donation from the... 

A number of A-acyloxy-A-alkoxybenzamides 100 have been shown to decompose in mesitylene at temperatures above 100°C giving a complex mixture of products including the A-alkyl adduct 106, the corresponding alkyl ester 108, anhydride 101 and a product (up to 60% yield in cases), which was characterised as 1,4,2-di-oxazoline 104 (Scheme 21). Minor products included hydroxamic ester 105 and mesitylene adduct 109. 

UNUSUAL CHARACTERISTICS OF V-HETEROATOM-SUBSTITUTED HYDROXAMIC ESTERS. 842... 

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. 

II. UNUSUAL CHARACTERISTICS OF A/-HETEROATOM-SUBSTITUTED HYDROXAMIC ESTERS... 

A-Heteroatom-substituted hydroxamic esters can be expected to have different properties to those displayed by simple hydroxamic esters in two respects. On the one hand, bisheteroatom substitution at nitrogen impacts strongly upon the nitrogen hybridization... 

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 ... 

This chapter will address the synthesis, theoretical and physical properties and reactivity of a number of different classes of anomeric hydroxamic esters. Principal categories include A-aUtoxy-A-haloamides (XNO systems), A-acyloxy-A-alkoxyamides and A,A-dialkoxyamides (ONO systems), A-alkoxy-Al-aminoamides (ONN systems) and N-... 

A-Chlorohydroxamic esters (2) are universally synthesized from the parent hydroxamic esters (4) using the positive halogenation source, tert-butyl hypochlorite " . Reactions are... 

---