Nitronates, silyl Henry reaction

In the presence of a catalytic amount of tetrabutylammonium fluoride, either freshly dried over molecular sieves22 or as the trihydrate16, silylnitronates 2 derived from primary nitroalkanes react readily at — 78 C or below, via their in situ generated nitronates. with aromatic and aliphatic aldehydes to give the silyl-protected (/J, S )-nitroaldol adducts 3 in excellent yield4,22-24-26,27. Silylnitronates, derived from secondary nitroalkanes. afford the adducts in 30 40% overall yield24. In contrast to the classical Henry reaction (vide supra), the addition of silylnitronates to aldehydes is irreversible. Ketones are unreaetive under such conditions. 

Silyl Nitronates in Henry Reactions Topologically, condensations of SENAs with carbonyl and nitroso groups, as well as with an imino fragment, belongs to Henry reactions. 

The classical Henry reaction conditions (base catalyzed addition) have some drawbacks sometimes the nitro alcohols are obtained in low yields and diastereoselectivities are not always high. To improve these results, a number of modifications were introduced. One of them is the Seebach s silyl nitronate method,25 that involves a reaction between an aldehyde with a silyl nitronate prepared by metalation of the corresponding nitro alkane with LDA, followed by reaction of the resulting nitronate with tert-butyldimethylsilyl chloride.26... 

The total synthesis of (+)-cyclophellitol containing a fully oxygenated cyclohexane ring was accomplished by T. Ishikawa and co-workers. The synthetic strategy was based on the intramolecular silyl nitronate [3+2] cycloaddition reaction. The cycloaddition precursor was prepared by the Henry reaction starting from a D-glucose-derived aldehyde. 

Significant improvements to the Henry reaction have been achieved by using silyl nitronates and catalytic amounts of fluoride ion or, alternatively, a,a doubly deprotonated primary nitroalkanes. Both of these procedures, discovered by the Seebach group, have proved to be useful for the stereoselective preparation of vicinal amino alcohols. 

TBDMSCl-Assisted Reactions. Nitro aldol (Henry) reactions have been reported to be promoted by TBDMSCl. To a THF solution of tetra-n-butylammonium fluoride is added sequentially equimolar amounts of the nitro compound, aldehyde, and EtsN, followed by an excess of TBDMSCl (eq 11). Substitution of TMSCl for TBDMSCl reduces the yield of nitro aldol product. The authors speculate that TBDMSCl is responsible for activation of the aldehyde while n-Bu4NF activates the nitro compound. In a related method, primary and secondary nitro alkanes were treated with LDA in THF followed by addition of TBDMSCl to give the corresponding silyl nitronates. The silyl nitronates reacted with a variety of aliphatic and aromatic aldehydes which gave vicinal nitro TBDMS aldol products. ... 

Miscellaneous. An asymmetric Henry reaction involving combination of an aldehyde with a silyl nitronate, catalyzed by Cu(OTf)2 in the presence of TBAT and a chiral BOX ligand, gives the nitroaldol products in moderate yield and stereoselectivity. TBAT is effective in triggering desilylation of certain functionalized silyloximes, resulting in concomitant cyclization and nitrone formation (eq 9) ... 

The second most important synthetic application of silyl nitronates in C-C bond-forming reactions is their fluoride-mediated addition to aldehydes. Silyl nitronates from secondary nitroalkanes lead to free nitro aldols such as (4), while those from primary nitro alkanes give silylated products. In contrast to the classical Henry reaction, the silyl variant is highly diastereose-lective with aldehydes, furnishing e yfAro-0-silylated nitro aldols (e.g. 5). It is important that the reaction temperature does not rise above 0 °C, otherwise threo/erythro equilibration takes place. The same erythro-nitio aldol derivatives are available by diastere-oselective protonation of silyloxy nitronates (eq 3) (usually the dr is >20 1), while the nonsilylated fAreo-epimers (R = H, dr = 7 3-20 1) are formed by kinetic protonation of lithioxy lithio nitronates in THF/DMPU (eq 4). Other recent modifications of the nitroaldol addition using titanium nitronates or ClSiRs in situ are less selective. It should also be mentioned that there are recent reports about the enantioselective addition of nitromethane to aldehydes in the presence of rare earth binaphthol complexes. 

Sterochemical control in the Henry reaction had been essentially neglected until lithionitronates, doubly-lithiated nitronates and silylnitronates methodologies were explored. Treatment of nitropropane with -BuLi furnishes nitronate 57, which then reacts with 4-nitrobenzaldehyde in the presence of Ti(/-OPr)Cl3 in THF to provide nitroalcohol 55 in high erythro anti) selectivity. Silyl nitronates in the presence of fluorides also prefers erythro (anti) products " while dilithiated nitronates reacts with aldehydes to afford 2-nitroalcohols in high threo syn) selectivity. ... 

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