A-acetoxy

Mutagenicity. The AJ-nitrosamines, in general, induce mutations in standard bacterial-tester strains (117). As with carcinogenicity, enzymatic activation, typically with Hver microsomal preparations, is required. Certain substituted A/-nitrosamine derivatives (12) induce mutations without microsomal activation (31,33,34). Because the a-acetoxy derivatives can hydroly2e to the corresponding a-hydroxy compounds, this is consistent with the hypothesis that enzymatic oxidation leads to the formation of such unstable a-hydroxy intermediates (13) (118). However, for simple /V-nitrosamines, no systematic relationship has been found between carcinogenicity and mutagenicity (117,119—123). 

Metal-ammonia solutions reduce conjugated enones to saturated ketones and reductively cleave a-acetoxy ketones i.e. ketol acetates) to the unsubstituted ketones. In both cases the actual reduction product is the enolate salt of a saturated ketone this salt resists further reduction. If an alcohol is present in the reaction mixture, the enolate salt protonates and the resulting ketone is reduced further to a saturated alcohol. Linearly or cross-conjugated dienones are reduced to enones in the absence of a proton donor other than ammonia. The Birch reduction of unsaturated ketones to saturated alcohols was first reported by Wilds and Nelson using lithium as the reducing agent. This metal has been used almost exclusively by subsequent workers for the reduction of both unsaturated and saturated ketones. Calcium has been preferred for the reductive cleavage of ketol acetates. 

Reductions of unsaturated ketones and a-acetoxy ketones usually are effected with an excess of reducing agent. For optimum yields of saturated ketones, the intermediate enolate salt obviously must not become protonated while... 

A third type of reduction of a-substituted ketones is typified by the expulsion of the substituent and the reduction of the keto function to form an olefin. Wolff-Kishner reductions of a-hydroxy, a-acetoxy, " a-halo, °° and a-epoxy (see below) ketones are the most frequently encountered steroid examples of this general class. ... 

Ester functions are not saponified under these ring opening conditions. However, a trans-a-acetoxy function hinders the epoxide opening reaction and a noticeable decrease in yield is observed in comparison to the cw-a-acetoxy isomer. The ring opening reaction is also dependent on the concentration of sulfuric acid. Polymer formation results when the acid concentration is too low and the reaction is markedly slower with excessive concentrations of acid. A 0.5% (vol./vol.) concentration of acid in DMSO is satisfactory. Ring opening does not occur when ethanol, acetone, or dioxane are used as solvent. 

Acetoxypregna-5,16-dien-20-one, 211 3/3-Acetoxy-5a-pregnane-l 1,20-dione, 207 3 a-Acetoxy-5/3-pregnane-20-one, 178 3/3-Acetoxypregn-5-en-20-one, 71 3 /3-Acetoxypregn-5-en-20-one-[l 7 a, 16a-c]-A -pyrazoline, 106 3/3-Acetoxy-5a-pregn-9( 1 l)-en-20-one-[17a, 16a-c]-Ai-pyr azoline, 106, 107 17/3-Acetoxy-2,3-seco-5a-androstan-2,3-dioic acid, 409... 

A second paper161 describes the use of the same base in either THF or t-butanol for the elimination of a-acetoxy phenyl sulphones as outlined in equation (68), in essence a reaction sequence very similar to the Julia olefin synthesis (Section III.B.3) except in the method by which the sulphonyl group is finally removed. 

RCM of a dienyne was also a key step in Mori s recent total synthesis of the alkaloid erythrocarine (447) [183]. The tetracyclic framework of447 was elaborated in the penultimate step, by exposing the hydrochloride of metathesis precursor 445 (1 1 diastereomeric mixture at the carbinol center) to first-generation catalyst A. The tandem process occurred smoothly within 18 h at room temperature leading to tetracycles 446 (1 1 mixture) in quantitative yield. Deprotection of the a-acetoxy isomer 446a led to 447 (Scheme 88). 

Bei der Reduktion von a-Acetoxy-alkanon-N2-tosyl-hydrazonen mit Natriumboranat in Methanol werden in 70-80%iger Ausbeute Kohlenwasserstoffe und in 15-20%iger Ausbeute Aik oh ole erhalten1 ... 

In O-Acetyl-enolen und a -Acetoxy-ketonen gelingt es mit Hilfe von Pentacarbonylei-sen die C-O-Bindung des Enols bzw. der Alkohol-Komponentezu Alkenen bzw. Keto-nen zu hydrogenolysieren3 ... 

These compounds are not isolated, but used directly in situ for conjugate addition reactions (15-24). Another method for the preparation of such reagents (but with Zn instead of Li) allows them to be made from a-acetoxy halides ... 

A more general route to 4-acetoxy-l,3-dioxanes utilizes the reductive acylation of l,3-dioxane-4-ones [46] (Scheme 21). l,3-Dioxane-4-ones 126 are prepared from the corresponding -hydroxy carboxylic acids. Low temperature reduction with DIBALH generates a diisobutylaluminum hemiacetal (127) which undergoes acylation in situ with AC2O in the presence of pyridine and DMAP. This method allows for the preparation of a wide range of 4-acetoxy-l,3-dioxanes, without the problem of a-epimerization. This method also represents a general approach to acylic a-acetoxy ethers, which are themselves useful synthetic intermediates [47,48]. 

Benzaldehyde dimethyl acetal 121 reacts, for example, with the silylated allylic alcohol 645, in the presence of SnCl2-MeCOCl, via an intermediate analogous to 641, to the 3-methylenetetrahydrofuran 646 and methoxytrimethylsilane 13 a [182], whereas benzaldehyde dimethyl acetal 121 reacts with the silylated homoallylalco-hol 640 in the presence of TMSOTf 20 to afford exclusively the ds 4-vinyltetrahy-drofuran 647 and 13 a [183]. A related cyclization of an a-acetoxy urethane 648 containing an allyltrimethylsilane moiety gives the 3-vinylpyrrohdine 649 in 88% yield and trimethylsilyl acetate 142 [184, 185]. Likewise, methyl 2-formylamido-2-trimethylsilyloxypropionate reacts with allyltrimethylsilane 82 or other allyltri-methylsilanes to give methyl 2-formamido-2-aUyl-propionate and some d -unsatu-rated amino acid esters and HMDSO 7 [186] (Scheme 5.56). 

Pyrroles are also formed from dipolarophiles such as a-acetoxy esters and a-chloroacrylonitrile that have potential leaving groups. 

Lead tetraacetate can effect oxidation of carbonyl groups, leading to formation of a-acetoxy ketones,215 but the yields are seldom high. Boron trifluoride can be used to catalyze these oxidations. It is presumed to function by catalyzing the formation of the enol, which is thought to be the reactive species.216 With unsymmetrical ketones, products from oxidation at both a-methylene groups are found.217... 

Introduction of oxygen a to a ketone function can also be carried out via the silyl enol ether. Lead tetraacetate gives the a-acetoxy ketone.219... 

The recombinantly expressed nitrilase from Pseudomonas fluorescens EBC 191 (PFNLase) was applied in a study aimed at understanding the selectivity for amide versus acid formation from a series of substituted 2-phenylacetonitriles, including a-methyl, a-chloro, a-hydroxy and a-acetoxy derivatives. Amide formation increased when the a-substituent was electron deficient and was also affected by chirality of the a- stereogenic center for example, 2-chloro-2-phenylacetonitrile afforded 89% amide while mandelonitrile afforded 11% amide from the (R)-enantiomer but 55% amide was formed from the (5)-enantiomer. Relative amounts of amide and carboxylic acid was also subject to pH and temperature effects [87,88]. 

Acyl nitronates (63) derived from primary AN are characterized by two types of such transformations the rearrangement into a-acetoxy aldoximes (219) and elimination of the corresponding carboxylic acids to form nitrile oxides (Scheme 3.63). 

From appraisal of their respective resonance stabilisation, arylnitrenium ions and alkoxynitrenium ions should form with similar facility. On account of the fact that A-acetoxy-A-acetyl arylamines 7 are penultimate carcinogens in the metabolism of aromatic amines, A-acyloxy-A-alkoxyamides 3 were designed to test their potential as DNA-damaging agents. 

A-Acyloxy-A-alkoxyamidcs 20 are synthesised from A-chlorohydroxamic esters 22 by replacement of chlorine by a carboxyl group (Scheme 3). Initially we employed silver acetate in anhydrous ether to make A-acetoxy derivatives.47 However, most have been made using sodium carboxylates in dry acetone by analogy with Finkelstein chemistry.5,38 40>42,43,46,48,49,i05 reacti0ns can be monitored conveniently by thin layer chromatography and A-acyloxy-A-alkoxyamides generally... 

A-Acetoxy-A-alkoxybenzamides 25, with variation in the alkoxyl side chain... 

A-Acetoxy-A-butoxyarylamides 26, with variation on the benzamide ring... 

A-Acetoxy-A-arylmethyloxybenzamides 27, with variation on the benzyloxyl side chain... 

A-Benzoyloxy- and A-acetoxy-A-benzyloxybenzamides 31-33, bearing one or more para-tert-butyl substituents... 

Both AMI calculations on A-acetoxy-A-methoxybenzamide38 and ab initio 6-31G calculations on A-formyloxy-A-methoxyformamide 405 45 predict a strongly pyramidal nitrogen. Its lowest energy conformation at HF/6-31G is depicted in Fig. 5a while structural data are provided in Table 1 together with that for A-methoxyformamide 41. 

The first indication that A-acyloxy-A-alkoxyamidcs reacted by an acid-catalysed process came from preliminary H NMR investigations in a homogeneous D20/ CD3CN mixture, which indicated that A-acetoxy-A-butoxybenzamide 25c reacted slowly in aqueous acetonitrile by an autocatalytic process according to Scheme 4 (.k is the unimolecular or pseudo unimolecular rate constant, K the dissociation constant of acetic acid and K the pre-equilibrium constant for protonation of 25c).38... 

Upon addition of a solution of sulfuric acid in D20 the reaction of A-acetoxy-A-alkoxyamides obeys pseudo-unimolecular kinetics consistent with a rapid reversible protonation of the substrate followed by a slow decomposition to acetic acid and products according to Scheme 5. Here k is the unimolecular or pseudo unimolecular rate constant and K the pre-equilibrium constant for protonation of 25c. Since under these conditions water (D20) was in a relatively small excess compared with dilute aqueous solutions, the rate expression could be represented by the following equation ... 

Table 4 Arrhenius and rate data for acid-catalysed solvolysis of A-acetoxy-A-alkoxybenzamides (25, 26, 2738 39 and 2840)a,b...

The products resulting from acid-catalysed solvolysis of A-acetoxy-A-butoxy-benzamides 26 in acetonitrile-water mixtures, as illustrated in Scheme 7, are... 

Initially, a reaction of A-acetoxy-A-butoxybenzamide 25c with A-methyl aniline 61 in butyl benzoate 63(R = Bu) and acetic acid. Close examination of these highly coloured reaction mixtures indicated the presence of crystals of A,A-dimethyl-A,A-diphenyltetrazene 65 (Scheme 11, R = Bu). The reaction is promoted by polar solvents as reactants are unchanged in pure acetonitrile. A crossover experiment using a mixture of /V- a ce t o x y - A-- b u t o x y - to 1 u a m i d e 26d and A-acetoxy-A-ethoxybenz-amide 25a afforded clean yields of butyl /Moluatc and ethyl benzoate thus pointing to an intramolecular rearrangement.41... 

Table 5 Arrhenius activation energies, entropies of activation and rate constants at 308 K for reaction of A-acetoxy-A-alkoxybenzamides 25, iV-acetoxy-iV-butoxybenzamides 26, iV-benzoyloxy-iV-benzyloxybenzamides 2842,43 and other iV-acyloxy-iV-alkoxyamides with A-methylaniline in d4-methanol...

Fig. 19 Ground state and transition state geometries for the bimolecular reaction of Af-methylaniline and A -acetoxy-A -alkoxyamides.

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