Amides, alkoxylation

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. 

The generally accepted mechanism for anodic amide alkoxylation involves the formation and further reaction of an intermediate acylimmonium ion with a nucleophile. The oxidation of Af-methyl-2-hydroxyethylcarbamate was utilized in the synthesis of a 1,3-oxazolidine derivative in 60% yield.117... 

Aromatic ethers and furans undergo alkoxylation by addition upon electrolysis in an alcohol containing a suitable electrolyte.Other compounds such as aromatic hydrocarbons, alkenes, A -alkyl amides, and ethers lead to alkoxylated products by substitution. Two mechanisms for these electrochemical alkoxylations are currently discussed. The first one consists of direct oxidation of the substrate to give the radical cation which reacts with the alcohol, followed by reoxidation of the intermediate radical and either alcoholysis or elimination of a proton to the final product. In the second mechanism the primary step is the oxidation of the alcoholate to give an alkoxyl radical which then reacts with the substrate, the consequent steps then being the same as above. The formation of quinone acetals in particular seems to proceed via the second mechanism. ... 

A-Acyloxy-A-alkoxyamides 34 and 35 where two amide groups are tethered by alkoxyl or acyl chains... 

The situation with 7V-acyloxy-/V-alkoxyureas and carbamates is similar although infrared data were mostly determined by liquid film or condensed phase (KBr/nujol mull).52,131 However, the limited data for V-acyloxy-TV-alkoxyureas (Table 2, entries 69-72) give amide carbonyl frequencies ca. 1730 cm-1 that are raised by some 37-40 cm-1 by acyloxylation. Values for carbamates (Table 2, entries 73-77) are higher (mostly 1780 cm-1) but are raised to a lesser extent (10-20 cm-1) relative to their parent carbamates. Clearly, carbonyl vibrational frequencies will be influenced strongly by the adjacent amino or alkoxyl group in both analogues. 

These rearrangement processes are characterised by a transition state in which the alkoxyl group migrates from the amide nitrogen to the carbonyl carbon (Fig. 17a) and therefore involves HEteroatom Rearrangements On Nitrogen the HERON... 

Notably, A-(2,6-dimethylbenzyloxy)-A-acetoxybenzamide 37a and N-acetoxy-A-butoxy-3,5-dimethylbenzamide 29u (Fig. 34, black squares, Table 17, entries 39 and 40) were well modelled by QSAR (4). The difference between predicted and observed activities for 37a (—0.03) and A -acetoxy-TV-isopropoxybenzamide 25f (0.04) (Table 17, entry 4) suggests that steric effects proximate to the reactive nitrogen but on the alkoxyl side chain are less important in terms of reactivity with DNA. This is most probably a consequence of the greater flexibility in this side chain relative to the acyloxyl or amide groups. 

The physical and spectroscopic properties of /V-acyloxy-A-alkoxyamides confirm pyramidality at nitrogen and the disconnection of the nitrogen lone pair from the amide carbonyl. The presence of an acyloxyl and an alkoxyl group at nitrogen also results in an anomeric interaction between the oxygens, which is facilitated by the sp3-hybridised nitrogen. Experimental observations, including X-ray analysis are fully supported by results from computational chemistry. 

Other functional groups which have a heteroatom rather than a hydroxyl group capable of directing the hydrogenation include alkoxyl, alkoxycarbonyl, carboxylate, amide, carbamate, and sulfoxide. The alkoxy unit efficiently coordinates to cationic iridium or rhodium complexes, and high diastereoselectivity is induced in the reactions of cyclic substrates (Table 21.3, entries 11-13) [25, 28]. An acetal affords much lower selectivity than the corresponding unsaturated ketone (Table 21.3, entries 14 and 15) [25]. 

Scheme 55, Eq. 55a) [119]. A plausible mechanism is depicted in Scheme 55 and involves radical addition of the 2-tetrahydrofuryl radical to the aldehyde followed by a rapid reaction of the alkoxyl radical with Et3B. Triethylborane has a crucial role since by reacting with the alkoxyl radical it favors the formation of the condensation product relative to the -fragmentation process (back reaction). A similar reaction with tertiary amines, amides and urea is also possible (Eq. 55b) [120]. 

The anodic a-alkoxylation of amides [10-12, 62-65] has been used extensively... 

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. 

The AgBp4 method was extended to cyclizations onto the alkoxyl side chain. Novel heterocycles A-acyl-3,4-dihydro-lP -2,l-benzoxazines (25) and A-acyl-4,5-dihydro-l//,3//-2,1-benzoxazepines (26) were synthesized by the treatment of open-chain A-chloro-A-(2-phenylethyloxy)- and A-chloro-A-(3-phenylpropyloxy)amides (24, n = 2, 3) with silver tetrafluoroborate in benzene (Scheme 2). Optimal yields of 25 were ultimately obtained with AgBp4 in ether or TPIP. ... 

Geometries of all four amides in the solid state indicate a preference for a conformation in which the alkoxyl oxygen p-type lone pair, noR, is largely collinear with the bond. Dihedral angles C(2) - 0(2) - 0(3) in Table 4 are all close to 90°. This anomeric... 

Thus, Af-acyloxyl-A-alkoxyl substitution in these anomeric amides significantly impacts upon their biological activity in two ways Inversely by affecting the ease of their nucleophilic reactivity towards intracellular bionucleophiles and hence their intracellular survival, and directly by controlling their ability to undergo Si 2 reactions once ultimately bound in the major groove of DNA. 

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... 

Ethers can be converted to acetals, and acetals to ortho esters, by anodic oxidation in an alcohol as solvent.194 Yields are moderate. In a similar reaction, certain amides, carbamates, and sulfonamides can be alkoxylated a to the nitrogen, e.g., MeS02NMe2 — Me-S02N(Me)CH20CH3.195 OS VII, 307. 

The pigment properties of chromium oxides can be modified by precipitation of hydroxides (e.g., of titanium or aluminum), and subsequent calcining. This treatment changes the color to yellow-green, and decreases the flocculation tendency [3.54], Aftertreatment with organic compounds (e.g., alkoxylated alkylsulfon-amides) is also used [3.55]. 

Frequently the configuration of the hydroxyamino acid component of the peptide alkaloid could be deduced with the aid of NMR studies. The coupling constants, JaB, of several a-amino-j8-hydroxyamino acids as well as their A,iV-dimethyl derivatives and their methyl ethers were determined by Marchand et al. (34). They showed that only the N,N-dimethyl derivatives yielded JaB values of configurational significance and that the conversion of the hydroxyl to alkoxyl exerted virtually no influence. The Ja0 value of Ar,A-dimethyl-j3(p-tolyloxy)leucine in the threo form was 8.5 Hz whereas that in the erythro form was 2.5 Hz. Wenkert et al. studied frangulanine (10), discarine-A (6), and discarine-B (7) whose amide protons had been replaced by deuterium (22). The a- and jS-methine signals of hydroxyleucine occurred at 84,40 and 4.77, respectively, as a doublet with JaB = 8 Hz and as a double... 

The nature of alkyl halide and the environment of the phosphorus atom make a substantial contribution to the direction of the reaction. Thus, cyclic phosphites [108], like trialkyl phosphites [110], react with preservation of the coordination of the P(III) phosphorus atom (126-132 ppm). If the alkoxyl group is substituted by amide, alkyl, or aryl, the nucleophilicity of the phosphorus atom in the corresponding amidophosphite (phosphonite) increases in comparison with the trialkyl phosphite. This probably promotes attack by 1 -haloalkyl-2-pyrrolidone at the phosphorus atom and not the oxygen, and this was confirmed experimentally. As a result of the investigated reactions amidophosphonates or ethyl phenyl phosphinates llOa-c were isolated compounds with P(III) were not detected in these cases. 

A radical substitution path is assumed for the alkoxylation or acetoxylation of the methyl group in N,N-dimethylbenzamide, -acetamide or -formamide to the corresponding N-alkoxy- or N-acetoxymethyl derivatives 193-. An alternative path via radical cations has been proposed for the acyloxylation of amides on the basis of polarographic measurements and controlled potential electrolysis (Eq. (93) )48 ... 

---