The Henry Nitroaldol Reaction

The asymmetric Henry reaction has been reviewed, and a survey of organocat- 0 alytic enantioselective versions includes recent advances in the emergent domino Michael/Henry protocol. 0 

New chiral organocatalysts have been prepared by condensation of menthylamine with a range of substituted imidazole carbaldehydes reduction of the imines yields 

A library of 16 C2-symmetric modular chiral BINOL-oxazoline Schiff base cop-per(II) complex catalysts have been generated in situ in a one-pot, three-component manner. Yields and ee of up to 98% were obtained in a Henry reaction under mild conditions.  

A mild Lewis-acid-catalysed enantioselective Henry reaction has been carried out in water at 0 °C, using copper(II) bromide and a prolinol with a pendant phenol (69) yields and ee up to 99% were obtained.  

Aryl glyoxals, ArCOCHO, or their hydrates, ARCOCH(OH)2, as well as their aliphatic analogues, typically react with nucleophiles at the aldehyde carbon, but a chiral copper(II)-iminopyridine catalyst switches the reactivity, allowing Henry reaction at the ketone, and with high ee, giving a quaternary stereocentre in the product, without any specific protection of the aldehyde.  

The scope, limitations and mechanisms of asymmetric Henry reactions catalysed by transition metal complexes have been reviewed.  

A green one-pot preparation of nitroalkenes has been developed for example, ben-zaldehyde and nitromethane give pure nitrostyrene in 95% isolated yield in toluene, after 4h reflux (or 79% without toluene). A dual-catalyst system of iron trichloride and piperidine (both 10 mol%) simultaneously activates electro- and nucleophiles, without affecting many sensitive groups. The one-pot conditions can be extended by the addition of, for example, indole to give 3-alkylindole (74) via Michael addition of the initial nitrostyrene product. Similar one-pot tandem approaches yield 3-nitrochromenes and A-arylpyrroles. 

A Henry reaction in aqueous media gives iyn- 0-nitroalcohols under very mild conditions reactions take a day or two, using phosphate buffer at neutral pH and ambient temperature.Aromatic aldehydes work with comparable yields to aliphatics. 

Three closely related phenanthrolinylquinine ligands were tested for their ability to coordinate copper(II).i One did not form a complex, another gave an unexpected five-coordinate mode and the third catalysed a Henry reaction in high ee, being able to activate both aldehyde and nitroalkane. 

Stereoselective synthesis of highly functionalized azatricycles (e.g., 75) has been achieved by copper-catalysed Henry reaction of enals with nitromethane, zinc reduction of the nitro group and subsequent tosylation, followed by iodocyclization. The iodine is easily removed afterwards by hydrogenation, or can be used to introduce other functionality, such as by epoxidation of the adjacent alcohol. 

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The Henry (nitroaldol) reaction was reported under very mild reaction conditions, in aqueous media using a stoichiometric amount of a nitroalkane and an aldehyde, in NaOH 0.025 M and in the presence of cetyltrimethylammonium chloride (CTAC1) as cationic surfactant (Eq. 8.94) 240 Good to excellent yields of (i-nitroalkanol are obtained. Under these conditions several functionalities are preserved, and side-reactions such as retro-aldol reaction or dehydration of 2-nitroalcohols are avoided. 

Rosini, G. 1991. The Henry (nitroaldol) reaction. In Comprehensive Organic Synthesis. Trost, B.M., ed. Pergamon Press, Oxford, vol. 2, pp. 321 0. 

For more references to Michael Addition, see section titled The Henry (Nitroaldol) Reaction . 

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