Nitroketone approach

Another approach used in the empirical characterization of liquid polarity is the study of the outcome of a chemical reaction. Earle et al. [216] report a preliminary study of the keto-enol tautomerization of pentane-2,4-dione, and create an empirical correlation between the degree of tautomerization and the dielectric constant of molecular liquids. They then predict dielectric constants for a series of ILs based on the observed keto-enol equilibrium the values range from 40 to 50, slightly higher than those of short-chain alcohols. A more detailed study by Angelini et al. [217] considers the tautomerization of a nitroketone complex in a series of five imidazolium-based ILs. The results, parameterized as a linear free energy analysis of the behavior of the equilibrium constant, indicates an overall polarity comparable to that of acetonitrile, consistent with the partitioning and spectroscopic studies referenced above. 

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. 

In fact, as shown in Figure 3, this approach has been employed in the synthesis of ABT-627. The coupling of ketoester 1 with nitrostyrene 2 was accomplished with a catalytic quantity of KOtAm. Product nitroketone 3 was reduced over Raney nickel to prepare cyclic imine 4, which was further reduced on addition of TFA to produce Ae cis-cis pyrrolidine 5 with good selectivity. Following epimerization with DBU, trans-trans pyrrolidine 6 was resolved with good efficiency as the mandelate salt. 

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. 

This approach also allows a very efficient synthesis of different y-nitroketones containing quaternary stereogenic centers starting from cyclic as weU as selected acyclic P,P-disubstituted enones and cinchonine-based primary amine catalyst (Figure 21.4). The reaction is also possible with more demanding 2-nitropropane and nitroethane. In most cases, under lOkbar pressure and in the presence of 1-5 mol% of the simple chiral primary amine catalyst, good yields and good to excellent enantioselectivities were obtained. 

---