Acyloxy amides

When an isocyanide is treated with a carboxylic acid and an aldehyde or ketone, an a-acyloxy amide is prepared. This is called the Passerini reaction. The following mechanism has been postulated ... 

Imperial Chemical Industries (ICI) chemists " prepared a novel series of spirocyclic 2,4-oxazolidinediones 243 derived from 7-substituted isatins (Scheme 6.54). The key intermediate a-acyloxy amides 242 were readily prepared from 241 in three steps. Base-catalyzed cyclization of 242 then afforded the target compounds that were reported to be potent inhibitors of aldose reductase. Pfizer chemists approached 5-substituted isatin spirocyclic analogues 243 via a-hydroxy esters 244 that were converted to the corresponding a-carbamyloxy esters 245 in good yield using chlorosulfonyl isocyanate. Cyclization of 245 with potassium ferf-butoxide then produced 243 in acceptable yield (Scheme 6.54 Table 6.10, Fig. 6.20). 

Diastereofacial selectivity in the a-allylation of cyclic a-acyloxy amides 259 derived from succinic or phthalic anhydride can be controlled by the Lewis acid. Thus, while TiCLt gives 260, allylation promoted by SnCLt affords 261393. No rationalization has been offered. 

Since anodically prepared a-formyloxy-A / -dimethylformamide has successfully been used as an electrophilic reagent, and it has been found that the a-methoxylation of the carbamates of a variety of higher aliphatic amines and alicyclic amines can be readily performed, extensive studies have been carried out to utilize the anodically synthesized a-methoxy- or a-acyloxy-amides and -carbamates as electrophiles in organic synthesis. One example is shown in equation (51). ... 

A few years later Passerini, developed a new 3CR towards a-acyloxy amides 9 which are formed by reacting an aldehyde or ketone 6, a carboxylic acid 8 and an isocyanide 7 (Scheme 2) ([25] and see for review [26]). Since the first synthesis of isocyanides (formerly known as isonitriles [27]) in 1858, the Passerini 3-component reaction (P-3CR) was the first MCR involving these reactive species. It has become one of the renowned examples of an important subclass of MCRs, the isocyanide-based MCRs (IMCRs). Especially important for the Passerini reaction, but also for a lot of other IMCRs, is the ability of isocyanides to form a-adducts, by reacting with nucleophiles and electrophiles (at the carbon atom). The nucleophilic... 

Initially, a loosely bound hydrogen bonded adduct 10 is formed, from the carboxyhc acid 8 and the carbonyl compound 6. The next step is the formation of the a-adduct 11 by reaction of the isocyanide with the nucleophilic carboxylate and the electrophilic protonated carbonyl compound. a-Adduct 11 then rearranges to give oc-acyloxy amide 9. 

Novel a-carboranyl-a-acyloxy amides were prepared as potential BNCT agents utilizing a three-component Passerini reaction (Jonnalagadda et al. 2009). Cytotoxicity of the representative compounds on brain tumor cell lines showed no effect on cell viability, an essential requirement for utility as potential BNCT agents. Novel classes of structurally different boronated quinazolines bearing 22-37 wt% B were designed for BNCT by Genady (2009). 

Jonnalagadda, S. C., J. S. Cruz, R. J. Connell, P. M. Scott, and V. R. Mereddy. 2009. Synthesis of a-carboranyl-a-acyloxy-amides as potential BNCT agents. Tetrahedron Lett. 50 4314 317. 

Recently, some other boron carriers were used to deliver polyhedral boranes into tumor cells. One of the most interesting and new direction is developments in the BNCT driven by nanotechnology [142-147]. This subject will not be discussed here since a special chapter is planned in this book. Carboranylquinazolines [148], carboranyl aminoalcohols [149], carboranyl-a-acyloxy-amides [150], carboranyl glycophosphonates [151], conjugates of icosahedral dicarboranes with cobalt bis(dicarbollide) [152], and platinum complexes containing carborane [153] have been obtained as potential candidates for BNCT. 

The aryl radical thus formed attacks the substrate to give the intermediate 1 (p. 898), from which the radical 26 abstracts hydrogen to give the product. N-Nitroso amides probably rearrange to N-acyloxy compounds, which cleave to give aryl radicals ... 

Two heterocyclic ring systems that have found some use in the formation of amides under mild conditions are lV-alkyl-5-arylisoxazolium salts (16A) and lV-acyloxy-2-alkoxydihydroquinolines (16B). 

This review will cover the structural, physical, spectroscopic, chemical and biological properties of the most widely studied class of these anomeric amides, the A-acyloxy-A-alkoxyamides 3. 

A-Acyloxy-A-butoxyamides 29, with variable amide and acyloxyl side chains... 

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

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 ... 

A -Acyloxy-A -alkoxyamides are characterised by two high frequency double bond absorptions corresponding to the stretching modes of the ester and amide carbonyls. 

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. 

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 ... 

These results clearly indicate that barriers to all isomerisation processes are at least less than about 8kcalmol 1. In /V-benzyloxy-7V-chlorobenzamide 44 the amide isomerisation was not observable but the anomeric overlap resulted in diastereotopic benzylic hydrogens, which at coalescence afforded a barrier for rotation about the N-OBn bond of around 10.3 kcalmol-1.32 Like its /V-chloro analogue, the amide isomerisation barrier in 43 is too low to be observed by 3H NMR and even though there is definitive X-ray and theoretical evidence for anomeric effects in /V-acyloxy-/Y-alkoxyamidcs, the barrier to isomerisation about the N-OBn bond must be lower than 10.3 kcalmol-1. The n0-CN ci anomeric interaction in 44 is predicted to be stronger than the n0-CN OAc interaction in 43 on purturbation arguments.32... 

V-Acyloxy-/V-alkoxyamides are intrinsically reactive at the amide nitrogen. Three... 

Bimolecular reactions of aniline with /V-acyloxy-/V-alkoxyamides are model Sn2 processes in which reactivity is dictated by a transition state that resembles normal Sn2 processes at carbon. Electronic influences of substituents support a non-synchronous process which has strong charge separation at the transition state and which is subject to steric effects around the reactive centre, at the nucleophile but not on the leaving group. The sp3 character of nitrogen and disconnection between the amino group and the amide carbonyl renders these reactions analogous to the displacement of halides in a-haloketones. 

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