Michael nitroolefins

The enantioselective Michael reaction of malonates to nitroolefins catalysed by bifunctional amino-thioureas has recently been reported by Take-moto [161]. Excellent ee (75-93%) were obtained with diethylmalonate after solvent optimisation, toluene being the best solvent both for the activity and for the selectivity. Substituted malonates were then reacted with various nitroolefins under the same conditions. Excellent enantioselectivities were observed (Scheme 45). 

This bifunctionnal amino-thiourea organocatalyst led to high selectivity because it was activating both the nitrone and the malonate, in its enol form, due to the acidic hydrogen atoms of the thiourea. Thus, the amino-thiourea catalyst promoted the Michael reaction of malonates to various nitroolefins... 

Some particular features should be mentioned. Instead of Michael additions, a-nitroolefins are reported to yield allyl sulfones under Pd catalysis (equation 21). Halogenated acceptor-olefins can substitute halogen P to the acceptor by ipso-substitution with sulfinate (equation 22 , equation 23 ) or can lose halogen a to the acceptor in the course of a secondary elimination occurring P to the introduced sulfonyl groups (equation 24). On the other hand, the use of hydrated sodium sulfinates can lead to cleavage at the C=C double bond (equation 25). 

Bifunctional thiourea-catalysed enantioselective Michael reaction has been achieved. The thiourea moiety and an amino group of the catalyst activated a nitroolefin and a 1,3-dicarbonyl compound, respectively afford the Michael adduct with high enantioselectivity.177,178 Thioureas work as one of the most effective and general enantioselective nitro-Mannich reaction and carbonyl cyanation catalyst.179,180... 

Nitroolefins are good Michael acceptors and their reactivity toward diethylzinc is different depending on the presence or absence of Lewis acids. Since the nitro group can be further transformed to a variety of useful containing functionalities,76,7641 the asymmetric 1,4-additions of nitroolefins may provide an easily accessible pathway to highly versatile optically active synthons. 

This sequence involves a Henry reaction of 41 with nitromethane followed by a dehydration of the resulting acyclic D-heptitol derivative 42 and a Michael intramolecular addition of the resulting nitroolefin 43. 

Addition of the lithium salt of tris(triphenylthio)methane to the D-glyceraldehyde-derived nitroolefin 80 resulted in a stereoselective Michael addition leading to adduct 81, which was then converted into the novel... 

Another recent example of a Michael addition of organometallic reagents to sugar nitroolefins consists of the addition of vinyl magnesium bromide to nitroolefin 83, that afforded nitro sugar 84 (Scheme 27).64... 

A Michael addition-Nef reaction sequence was used in a synthesis of disaccharides. Addition of the sodium salt of 1-thio-D-glucose to sugar nitroolefin 112 gave a mixture of isomers 113. The subsequent deacetylation, followed by a Nef reaction, afforded the S -disaccharides 114 and 115 (Scheme 35).82... 

Recently, a synthesis of tetrodotoxin from D-glucose was described (Scheme 36). After a Michael addition of the lithium salt of bis(phenylthio)-methane to the nitroolefin 116, the major component (117b) of the resulting epimeric mixture 117a + 117b was subjected to a reaction sequence that involved an intramolecular nitroaldol reaction, to give the complex nitro cyclohexane derivative 118. 

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 Michael reaction of malonates to nitroolefins and the aza-Henry reaction of nitroalkanes to Al-phosphinoylimines are catalyzed by thiourea derivative 5a to provide the respective products in good and moderate enantioselectivities. Thiourea... 

For Michael addition to nitroolefins, the lithio or titanium derivatives have been found to be useful [87AG(E)480], Hydrolysis gives a-amino--y-nitrocarboxylate esters (Scheme 69). 

Thus, the 1,4-addition of the lactams 72 to nitroolefins provided access to the Michael adducts 73 with good stereoselectivities, which could be improved by recrystallization or chromatography. After reduction and protection of the amino group the y-butyrolactams 74 were converted to the corresponding a-substituted lactams 75 in good overall yields (37-65%) and excellent diastereo- and enantio-... 

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). 

Nitroolefins are excellent Michael acceptors which react with a broad range of nucleophiles in a Michael fashion. The resulting functionalized nitroalkanes can be readily converted into amines by reduction reactions or to carbonyl compounds by a Nef reaction . The addition of nucleophiles to nitroolefins is complicated by the subsequent addition of the resulting nitronate to remaining nitroolefin. Whereas such a side-reaction is quite fast for lithium and magnesium nitronates. it is slow for zinc... 

Using l-(2-nitrovinyl)pyrrolidines 108 or 111 as Michael acceptors, the addition of the Reformatsky reagent is followed by amine elimination. A formal vinylic substitution ensues, which can take advantage of the presence of stereocenters in the pyrrolidine moiety, affording new chiral nitroolefins 110151 and 113152, as reported in equations 64 and 65, respectively. In both cases, zinc enolates 109 and 112 are prepared by lithia-tion/transmetallation of the parent ester. 

J.-M. Lassaletta and R. FemSndez, Michael addition of formaldehyde dimethyl-hydrazone to nitroolefins. A new formyl anion equivalent, Tetrahedron Lett. 33 3691 (1992). 

Nitroolefins are good Michael acceptors and have been used as such in the carbohydrate series. One advantage of this approach would be the subsequent transformation into branched-chain amino sugars after reduction of the nitro group. Baer has reported the... 

The enantioselective aldol and Michael additions of achiral enolates with achiral nitroolefins and achiral aldehydes, in the presence of chiral lithium amides and amines, was recently reviewed354. The amides and amines are auxiliary molecules which are released on work-up (equation 90 shows an example of such a reaction). 

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). 

Michael-adducts obtained by Barbas and Betancort (ref. 42) from aldehydes and nitroolefins, using 20 mol-% of 53 as catalyst in THF at ambient temperature... 

Michael-adducts obtained by Takemoto et al. (ref. 45) from the addition of malonates to nitroolefins... 

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. 

As early as 1977 Pracejus et al. investigated alkaloid-catalyzed addition of thiols to a-phthalimido acrylates, methylene azlactones, and nitroolefins [56a]. In the former approach, protected cysteine derivatives were obtained with up to 54% ee. Mukaiyama and Yamashita found that addition of thiophenol to diisopropyl mal-eate in the presence of cinchonine (10 mol%) proceeds in 95% yield and that the product, (S)-phenylthiosuccinate, was formed with 81% ee [56b]. The latter Michael adduct was used as starting material for preparation of (R)-(+)-3,4-epoxy-1-butanol. In the course of an asymmetric total synthesis of (+)-thienamycin Ike-gami et al. studied the substitution of the phenylsulfonyl substituent in the azetidi-none 69 by thiophenol in the presence of cinchonidine (Scheme 4.34) [56c]. This substitution probably proceeds via the azetinone 70. In this reaction the phenyl-thioazetidinone 71 was obtained in 96% yield and 54% ee. Upon crystallization, the optically pure substitution product 71 was obtained from the mother liquor... 

The same experimental procedure can be used with alkylidenemalonate and other related Michael-acceptors, as well as nitroolefins.26 However, under these reaction conditions only one of the two R groups of R2Zn is transferred to the enone. This problem can be solved by using mixed diorganozincs of the... 

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]. 

Scheme 2.48 The Michael addition of aldehydes on nitroolefins, catalyzed by 45a and 45b.

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