Nitroketone cyclization

This class was first reported in 1924 and was formed 62HC(17)l) by cyclization of a-bromo-/3-aryl-y-nitroketones. The direct synthesis by oxygenation of 2-isoxazolines has not been reported. To date only 3-substituted derivatives have been prepared. Aryl-nitromethanes react with nitrostilbene to form isoxazoline A-oxide by a nitrile ion displacement (Scheme 138) <62HC(17)1, 68TL3375). 

Formation of the d bond by the reductive cyclization of a,oj- nitroketones (68CRV747, p. 778), -cyanoketones and -cyanoesters (74MIP51800) has been used in the preparation of both 1,4- and 1,5-benzodiazepines. 

The reduction of a nitroketone with H2 and Raney nickel in EtOH directly provided the bridged myosmine (42) (76%), presumably via an intermediate amino ketone which undergoes an intramolecular Schiff base cyclization (Equation (17)) <83JOC492>. 

Examples of such three-carbon synthons are 2-nitro-2-propen-l-yl acetates and piva-lates, which have been developed by Seebach and coworkers57,58 as reagents for [3 + 3] cyclizations with cyclic and acyclic ketone enamines. After workup these reactions give 4-nitrocyclohexanones. With enamines from prolinol methyl ether and cyclic ketones, enantiomerically pure compounds were obtained58. An example of such a [3 + 3] cyclization is the synthesis of bicyclic nitroketone 99 from nitroallylic ester 97 and enamine 98 (equation 18). 

Oxidative cyclization of o-aminoacylbenzenes is a much less common process for the synthesis of anthranils than the reductive cyclizations discussed in the previous section, mainly because the o-aminoketones are in many instances best prepared by reductive ring opening of anthranils (see Section III,C,3). Nevertheless, a few examples have been recorded. Oxidation of o-aminobenzophenones to the nitroketones using peroxytrifluoro-acetic acid, permaleic acid, or persulfuric acid proceed via the 3-phenyl-anthranil which occasionally is isolable.168 Caro s acid is also a useful oxidant.169... 

A third major global health problem are parasitic protozoa that cause myriad diseases and afflictions in humans and animals. A serious problem in the poultry industry is coccidiosis, caused by the parasites Eimeria tenella, E. acervulina, E. mitis, and E. maxima, which invade the avian intestinal hning [202], leading to illness and death [202]. A new potential set of coccidiostats are 2,3-diarylui-doles such as 91, which has excellent in vitro (ICj 0.5 nM) and in vivo activity [203]. These indoles were prepared either via a Fischer indohzation between arylhydrazines and a-arylacetophenones or via a reductive cyclization of a nitroketone, which is presented in a later chapter. 

Diones are important intermediates in a number of syntheses of cyclopent-2-enones by aldol cyclization, and several routes to them have been published (see Review section). An attractive new approach involves the Michael addition of silyl enol ethers to nitro-olefins catalysed by Lewis acids, which leads directly to the 1,4-dione without isolation of nitroketone or related intermediates (Scheme 15). A feature of the method is that it is highly regiospecific in the selective formation of 1,4-diones with no double-bond migration in the silyl enol ether. 

A number of routes can be envisioned for the preparation of polysubstituted pyrrolidines, and the intramolecular addition of a silyl ketene acetal to an oxime ether has been employed in the synthesis of ABT-627 (4). However, the reductive cyclization of a nitroketone, which could be obtained via the conjugate addition of a ketoester to a nitrostyrene, was viewed as being the most direct, convergent approach to ABT-546. In this approach, the nitro functionality is reduced to generate the cyclic imine, which is then further reduced to the trisubstituted pyrrolidine (Figure 2). As the trans-trans isomer is thermodynamically favored, both it and the cis-cis isomer are usable intermediates. 

With this encouraging precedent, a similar approach was investigated in the Hrst-generation synthesis of ABT-546 (Figure 4). The Michael addition was again carried out in the presence of catalytic base. The reductive cyclization of nitroketone 9 was carried out employing modified conditions to yield directly the trans-trans pyrrolidine, 10. However, despite significant effort, only tartaric acid was found to resolve this pyrrolidine, and then the optically enriched product was obtained with low recovery. 

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