Ketones nitroolefins

The following section presents the energetic details of the formation of such activated substrates as well as how the stereoselectivity is imparted in the subsequent step of the reaction. The illustrations generally revolve around simple amines, pyrroUdines, and proline. Though a broad range of substrates has been considered, to maintain some degree of uniformity the substrates described here are generally simple aldehydes, ketones, nitroolefins, and other activated olefins. 

Electrophiles The most used classes of electrophiles in asymmetric organocata-lyzed F-C reactions are a,P-imsaturated aldehydes or ketones, nitroolefins, carbonyl compoimds, and imines (see next section) (Figure 35.4). 

In general, copper-zinc compounds, unlike organolithium-derived organocopper reagents, undergo clean addition reactions to nitroolefins. After Michael addition, the resulting zinc nitronates can be oxidatively converted into polyfunctional ketones, such as 117 (Scheme 2.45) [96]. 

The pure ketone has a 1.5240 and a boiling point of 128-130°/14 mm., 150°/30 mm. Insufficient removal of o-meth-oxybenzaldehyde will cause the refractive index to be high to the extent of about 0.0003 for each per cent present. The use of distilled nitroolefin eliminates the aldehyde, but this advantage is offset by the distillation hazard and slightly lower over-all yields. 

This topological rule readily explained the reaction product 211 (>90% stereoselectivity) of open-chain nitroolefins 209 with open-chain enamines 210. Seebach and Golinski have further pointed out that several condensation reactions can also be rationalized by using this approach (a) cyclopropane formation from olefin and carbene, (b) Wittig reaction with aldehydes yielding cis olefins, (c) trans-dialkyl oxirane from alkylidene triphenylarsane and aldehydes, (d) ketenes and cyclopentadiene 2+2-addition, le) (E)-silyl-nitronate and aldehydes, (f) syn and anti-Li and B-enolates of ketones, esters, amides and aldehydes, (g) Z-allylboranes and aldehydes, (h) E-alkyl-borane or E-allylchromium derivatives and aldehydes, (i) enamine from cyclohexanone and cinnamic aldehyde, (j) E-enamines and E-nitroolefins and finally, (k) enamines from cycloalkanones and styryl sulfone. 

Whereas the examples discussed so far proceed according to the iminium ion mechanism (A), amine-catalyzed additions of, e.g., ketones to nitroolefins are effected by intermediate enamine formation (B). List et al. were the first to report that L-proline catalyzes the addition of several ketones to nitroolefins (Scheme 4.23). Whereas both the yields and diastereoselectivity were high in DMSO as solvent, the ee did not exceed 23% [38]. A related study of this process by Enders and Seki resulted in identification of methanol as a superior solvent, and enantioselec-tivity up to 76% was achieved (Scheme 4.23) [39]. 

W/cbae/-adducts obtained by List et al. (ref. 38) from ketones and nitroolefins, using 15 mol-% of L-proline as catalyst in DMSO at ambient temperature... 

N-terminal L-proline, again in DMSO as solvent [40], In this study the maximum ee in the addition of acetone to trans-2-nitrostyrene was 31%. Alexakis and Andrey successfully employed the bis-pyrrolidine 52 as catalyst for the addition of aldehydes and ketones to trans-fi-nitrostyrene [41], whereas Barbas and Betancort [42] were able to perform the Michael addition of unprotected aldehydes to nitroolefins using the pyrrolidine derivative 53 as catalyst (Scheme 4.24). 

Several iodine-catalyzed organic transformations have been reported. Iodine-catalyzed reactions are acid-induced processes. Molecular iodine has received considerable attention because it is an inexpensive, nontoxic and readily available catalyst for various organic transformations under mild and convenient conditions. Michael additions of indoles with unsaturated ketones were achieved in the presence of catalytic amounts of iodine under both solvent-free conditions and in anhydrous EtOH (Scheme 19) [85,86]. l2-catalyzed Michael addition of indole and pyrrole to nitroolefins was also reported (Scheme 20) [87]. 

Aluminum salen complexes have been identified as effective catalysts for asymmetric conjugate addition reactions of indoles [113-115]. The chiral Al(salen)Cl complex 128, which is commercially available, in the presence of additives such as aniline, pyridine and 2,6-lutidine, effectively catalyzed the enantioselective Michael-type addition of indoles to ( )-arylcrolyl ketones [115]. Interestingly, this catalyst system was used for the stereoselective Michael addition of indoles to aromatic nitroolefins in moderate enantiose-lectivity (Scheme 36). The Michael addition product 130 was easily reduced to the optically active tryptamine 131 with lithium aluminum hydride and without racemization during the process. This process provides a valuable protocol for the production of potential biologically active, enantiomerically enriched tryptamine precursors [116]. 

Addition of Ketones to Nitroolefins and Alkylidene Malonates 2.3.3.1 Proline... 

Alanine 20 and alanine-containing small oligopeptides showed good stereocontrol in the addition of ketones to nitroolefins (Scheme 2.41) [24]. The i-ala-r-ala dipeptide 21 was more selective than the monomer 20, while the hybrid derivative 22, mediated the addition, with an ee-value of 93% [25]. 

Diamine-Catalyzed Addition of Unmodified Ketones to Nitroolefins [28] (p. 81)... 

To a solution of pyrrolidine catalyst (0.05 mmol, 15 mol%) in CHCI3 (3 mL) was added at r.t. the ketone (3.35 mmol) and the nitroolefin (0.335 mmol). The evolution of the reaction was monitored by TLC. The solution was then hydrolyzed with 1 M HCl (2 mL). The layers were separated and the aqueous phase was extracted with CH2CI2 (2 x 3 mL). The combined organic phases were dried over MgS04, filtered, concentrated and purified by flash column chromatography on silica gel using a mixture of cyclohexane and ethyl acetate as eluent. 

Thiourea-Mediated Michael Addition of Ketones to Nitroolefins [29] (pp. 82-83)... 

To a stirred solution of catalyst (0.15 equiv) in toluene (0.5 mL) and ketone (10 equiv) at r.t., was added water (2 equiv) and, after 5 min, nitroolefin (1 equiv). The reaction mixture was stirred at r.t. for the appropriate time. The solvent was evaporated and the residue purified by TLC or chromatography on silica gel (hexane ethyl acetate, 1 1) to afford the desired product. 

Oxidation always accompanies nitration, resulting in the formation of nitro compounds and a mixture of acids, aldehydes, ketones, alcohols, nitrites, nitroso compounds, nitroolefins, polymers, carbon monoxide and carbon dioxide. Catalysts such as copper, iron, platinum oxide, etc., accelerate oxidation rather than nitration. 

The mechanism of this cyclization involves a conjugate addition of the enamine (100) to the nitroallyl ester (101) to give 102, which on elimination produced 103. The immonium salt 103 undergoes proton transfer to give enamino nitro olefin 104, which cyclizes to an enamine (107) via 105 and 106. Hydrolysis of 107 produces the ketone (108). Depending on the reaction conditions and the structure of the enamine and nitroolefin components employed, intermediates can be isolated (equation 19). 

As reported in Figure 2.5, nitroolefins (26), easily obtained by nitroaldol condensation between 5-nitro ketones (24) and aldehydes (25), are converted directly into the spiroketals (29) by reduction with sodium boronhydride in methanol. The one-pot reduction-spiroketalization of nitroalkenes (26) probably proceeds via the nitronate (27) that by acidification is converted into carbonyl derivatives, which spontaneously cyclize to emiketals (28). Removal of the tetrahydropyranyl group, by heating the acidic mixture during the workup, affords, in a one-pot reaction from (26), the desired spiroketals in 64-66% overall yields. The spiroketalization of (26)-(29b) proceeds in high ( )-diastereoselectivity. 

The nitroparaffins are condensed with aldehydes to yield nitro alcohols (70-80%), which on acetylation and treatment with an aqueous methanolic solution of sodium bicarbonate are converted to nitroolefins (80-84%). These compounds are reduced to the corresponding ketoximes by zinc and acetic acid (50-60%). Reduction with iron and dilute hydrochloric acid gives good yields of either ketones or ketoximes, depending upon the amount of hydrochloric acid used. The ketoximes can be hydrolyzed to ketones by refluxing with dilute sulfuric acid in the presence of formalin, which acts as a hydroxylamine acceptor (80%). The over-all yields from the nitroolefins are 40-60%. In this manner, certain otherwise difficultly obtainable ketones are prepared. Semicarbazones have been converted to ketones by treatment with sodium nitrite in glacial acetic acid, with aqueous oxalic acid, or with phthalic anhydride. ... 

The synthesis of the bisbenzannelated spiroketal core of the y-rubromycins was achieved by the research team of C.B. de Koning." The key step was the Nef reaction of a nitroolefin, which was prepared by the Henry reaction between an aromatic aldehyde and a nitroalkane. The nitroolefin was a mixture of two stereoisomers, and it was subjected to catalytic hydrogenation in the presence of hydrochloric acid. The hydrogenation accomplished two different tasks it first converted the nitroalkene to the corresponding oxime and removed the benzyl protecting groups. The oxime intermediate was hydrolyzed to a ketone that underwent spontaneous spirocyclization to afford the desired spiroketal product. 

With chiral diamine 24, in the form of a trifluoroacetate salt, the classic aqueous biphasic protocol has been successfully applied to the asymmetric Michael reaction of ketones with both aryl and alkyl nitroolefins. Brine is used as the aqueous phase. ... 

The thiourea functionality, inserted on the most frequently used chiral pyrrolidine scalTold, works excellently as reactivity and enantioselectivity control co-factor by chelating the nitro group of the acceptor. This solution, adopted in 25, provides a family of robust catalysts that afford high yields (up to 98%) and great stereoselectivities (up to 99 1 dr and 99% ee) in direct Michael additions of ketones to various nitroolefins in water. ... 

Seebach and Golinski further examined the Michael addition of the enamines derived from ketones and morpholine to nitroolefins, as shown in Scheme 16 and Table 4 (33,35,36). The structure of the major product of entry 1 (Table 4) was assigned by chemical correlation. The remaining structures were assigned by analogy to entry 1. High levels of syn selectivity were uniformly observed. Control experiments revealed that the geometry of neither the enamine nor the nitroolefin influences the stereochemistry. Indeed, observation of the reaction of isomeric nitrostyrenes and the morpholine... 

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