1-Alkyl-1-nitroolefins

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. ... 

Nitroolefins also offer the possibilities of 1,2 cycloaddition (37,57) or simple alkylation (57-59) products when they are allowed to react with enamines. The reaction of nitroethylene with the morpholine enamine of cyclohexanone led primarily to a cyclobutane adduct in nonpolar solvents and to a simple alkylated product in polar solvents (57). These products are evidently formed from kinetically controlled reactions since they cannot be converted to the other product under the conditions in which the other... 

The alkylation of enamines with nitroolefins, which gives intermediates for reductive cyclization (6S2), also provided an example of a stable cycliza-tion product derived from attack of the intermediate imonium function by the nitro anion (683). A previously claimed tetrasubstituted enamine, which was obtained from addition of a vinylsulfone to morpholinocyclohexene (314), was shown to be the corresponding cyclobutane (684). Perfluoro-olefins also gave alkylation products with enamines (685). Reactions of enamines with diazodicarboxylate (683,686) have been used diagnostically for 6-substituted cyclohexenamines. In a reaction of 2-penten-4-one with a substituted vinylogous amide, stereochemical direction was seen to depend on solvent polarity (687). 

Since the trapping of the lactam enolate with electrophiles should not be limited to nitroolefins, extension to conjugate additions to alkenylsulfones, the ring opening of N-tosylaziridines, alkylation with functionalized halides, and silylation with chlorotrimethylsilane were explored. 

Based on this gathered experience the diastereoselective alkylation of enantio-pure a-lithiated sulfonates was extended to the Michael addition with aliphatic nitroolefins [95]. Thus the Michael adducts 118 could be achieved in excellent yields (84-99%) with high diastereoselectivities de of 80-88% (84 to >98% after recrystallization or chromatography). Cleavage of the chiral auxiliary and treatment with diazomethane furnished the anti-configured a,j3-disubstituted y-nitro-methyl sulfonates 119 in overall yields of 41-70% and with excellent de- and ee-values (Scheme 1.1.32). 

As with epoxides, carbanions can add in a 1,4 fashion to enones or nitrosugars. Nitromethane anion has been used [64], Dithiane anion has been successfully used in the addition to nitroolefins [65] and to enones [66], Accordingly, C-5 branched-chain glucose derivatives 47 and 48 have been prepared from nitroolefin 46 (Scheme 20) [67,68], Sugar-derived enones have been also used as acceptors in free radical reactions to trap alkyl radicals as well as anomeric radicals (see Schemes 29 and 30). 

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. 

In the presence of 10 mol% of this catalyst, the malonates 56 could be added to several nitroolefins 57 with up to 93% ee. Apolar solvents such as toluene are crucial for high ee values. It is also noteworthy that (i) good ee can be achieved with catalyst 55 even in the absence of solvents, i.e. with a mixture of the neat starting materials 56 and 57, and that (ii) the range of Michael donors/acceptors includes aryl- and alkyl-substituted nitroolefins and 2-alkylated malonates. 

Chiral bis-sulfonamides 162-163 are a new group of organo catalysts for the enantioselective Friedel-Crafts alkylation of indoles to nitroolefins. The hy-... 

Due to the increased reactivity of the aldehyde, alkyl-substituted nitroolefins can also be used as substrates. Nevertheless, these reactions are usually low-yielding and afford moderate selectivity. Alexakis has shown, however, that the bispyrrolidine 5-catalyzed additions may be used in multistep synthesis. The addition of propionaldehyde 34 to nitroolefin 33 resulted an approximate 2 3 mixture of anti/syn isomers in 92% yield and in high ee (93%), allowing the asymmetric synthesis of (—)-botryodiplodin (Scheme 2.46) [23b]. 

The bifunctional pyrrolidine sulfonamide catalyst, 38, having basic pyrrolidine nitrogen and Bronsted acidic sulfonamide function, mediates the addition of aldehydes to nitrostyrenes in high yield and selectivity (Scheme 2.47) [34]. Alkyl-substituted nitroolefins afford, however, product in low yield and in low selectivity. 

The diphenylprolinol silyl ether 45a catalyst was developed by the Hayashfs group for the addition of a-unbranched aldehydes to aryl and alkyl substituted nitroolefins [35]. This catalyst, as well as the perfluoroalkyl derivative 45b [36],... 

Jorgensen and co-workers employed chiral bis-sulfonamide catalyst 27, a proven ligand for metal-based asymmetric catalysis, for the Friedel-Crafts alkylations of N-methylindoles (24) using -substituted nitroolefins [52]. Using optimized conditions, 2 mol% 27 gave the desired indole alkylation products of substituted aryl and heteroaryl nitroolefins in moderate to high yields (20-91%) and moderate enantiopurities (13-63% ee Scheme 6.3). Aliphatic -substitution... 

On the other hand, 2-naphthols have been used with different success as Michael donors in conjugate Friedel Crafts reactions with nitroalkenes and related substrates (Scheme 4.53). For example, cinchonine-derived thiourea 72b was identified as an excellent promoter for the reaction of a wide variety of 2-naphthols and nitroolefins, providing excellent yields and enantioselectivities. Remarkably, the more challenging p-alkyl substituted nitroalkenes were also found to undergo the reaction in a highly stereoselective way and with comparable yields to those obtained when nitrostyrene derivatives were employed. 

Regarding substrate scope, catalysts 22a, 30,37, and 40-44 (Fig. 2.4) are efficient promoters for the Michael addition of aldehydes to p-alkyl substituted nitrooleflns. Taken advantage of the good activity exhibited by catalyst 30 in this process, Alexakis et al. have achieved the total synthesis of the mycotoxin (-)-botryodiplodin [73], process which involves an attractive Michael addition between an aldehyde and an a-substituted nitroolefin (Scheme 2.21). 

Michael adducts from p-aryl- and P-alkyl substituted nitroolefins in high yields (68-97%), good diastereoselectivities (dr 3/1 to >20/1), and excellent enantioselec-tivities (88-99% ee). This novel organocatalytic approach has been used in the formal synthesis of the alkaloid (-H)-physostigmine (Scheme 2.92). Catalyst 168 was... 

The oxygen of the nitro moiety can also be involved in the formation of the C-O bond. In this context, Mamoka et al. [52] recently disclosed an asymmetric organo-catalytic synthesis of various isoxazoline-A -oxides by phase-transfer conjugate addition of bromomalonate to nitroolefins and subsequent ring-closing 0-alkylation (Scheme 16.26). 

A BINAP-derived bifunctional thiophosphoramide gives >98% del>99% ee in Michael addition of cyclohexanones to both aryl- and alkyl-substituted nitroolefins. Imidazolylmethyl ketones undergo one-pot Michael-aldol cascade reactions with Q ,/3-unsaturated aldehydes in DCM at 20 °C using the simple organocatalyst, prolinol... 

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