Nitroaldol reaction

The Henry reaction, and Kamlet reaction or Nitroaldol called, is a name of reaction in organic chemistry. Characteristic of this reaction is the coupling of an α - carbon atom of an aliphatic nitro compound with a carbonyl compound to a β -nitro alcohol to form a C- C bond.

Henry's reaction is usually used as a reaction intermediate step in the synthesis of complex organic molecules. It is carried out under relatively mild reaction conditions and with the formation of β -nitro alcohol provides a functionalized starting compound for further transformations such as oxidations, reductions or the Nef reaction.

Because of the mild reaction conditions also labile protecting groups and functional groups remain intact.

Mechanism

The reaction mechanism of the Henry reaction is the aldol reaction very similar, which is why it is also referred to frequently as Nitroaldol. The difference from the aldol reaction is that in the Henry reaction, the CH-acidic carbonyl compound was replaced by a nitro - compound.

Aliphatic nitro compounds, which have an α -hydrogen atom, are very acidic CH and can be depretoniert by strong bases and forms a nitronate ion. The carbonyl compound may be activated by a metal cation coordination to the oxygen atom ( Lewis acid-base complex). The nitronate ion can then attack the carbonyl compound, with its negative charge on the carbon atom at the carbonyl carbon atom, and the anion of the β -nitro alcohol is formed, which can eventually be further protonated nitro compounds.

Stereochemistry

When Henry reaction a chiral compound are usually manufactured from a prochiral aldehyde or ketone by reaction with the nitro nation. An exception is the use of symmetric carbonyl compounds such as for example acetone, because these compounds are prochiral and therefore no stereogenic center is formed. The same applies to the nitro component. With the use of nitromethane, also there is no new stereocenter.

In a newly formed stereocenter one obtains a two possible enantiomers. In two stereocenters newly formed is obtained, however, four possible connections - two Enantiomerpaare and two Diastereomerpaare. Wherein the pairs of diastereomers, a distinction (derived from threose and erythrose ) between the threo- and erythro- form. If both substituents in the Fischer projection on one side, there is this to be the erythro form, both substituents are on the opposite side, is it the threo form.

Are all compounds involved in the reaction are achiral or as a mixture of stereoisomers before, then in the Henry reaction, as is generally preferably formed in such reactions, no stereoisomer, and that means you always get a uniform mixture of all possible enantiomers. The situation is different in the Diastereomerpaaren, the result of steric effects, even in the absence of enanatiomer - enriched compound which may also have a preference, which is why you often here the ratio threo: erythro determined to make statements about the selectivity of a reaction.

A rather complicated case, one has available, if in one or both substrates already stereocenters are included ( eg, sugars or aldehydes derived from amino acids), since more combinations of enantiomers and Diastereomerpaaren are conceivable and the stereocenters and the selectivities own influence.

Catalysts

Henry reaction can be catalyzed by a variety of catalysts and reaction conditions. Organic bases, inorganic bases, quaternary ammonium salts, protic and unprotische solvent and solvent-free conditions were applied successfully. Wherein the reaction conditions of the substrates can be adjusted in terms of, for example, protecting groups, solubility and instability of the functional groups.

The first catalysts used in the Henry reaction, were both alkoxides and hydroxides in alcoholic or aqueous solvents. A later development was the use of 1,1,3,3- tetramethylguanidine (TMG ) as a catalyst which has frequently found application.

On this basis then bicyclic and even bound to polymeric resins guanidines were used.

Vekaden then developed Proazaphosphatane as effective catalysts for the reaction in the Henry reaction of nitroalkanes with aldehydes and ketones.

When using ketones as carbonyl component, the condensation of ketones with each other ( aldol condensation ) is the major side reaction. By using the Proazaphosphatane this side reaction can be suppressed effectively. For optimum conditions magnesium sulfate is used as a Lewis acid in the reagent system of Vekaden.

With lithium aluminum hydride as the catalyst many nitroaldol reactions between aromatic and aliphatic aldehydes and nitromethane, nitroethane and nitropropane are published.

By R. Ballini the ion exchanger Amberlyst A-21 was introduced under solvent-free conditions in the production of Nitrodiolen by reaction of aldehydes with 4-nitro -butanol. From the same group, the application of phase transfer catalyst cetyltrimethylammonium chloride comes in water and in the presence of sodium hydroxide.

M. J. Shibasaki published catalysts based on rare earths. Here special mention because it provides the basis for the chiral catalysts is Samariumtrihexamethylsilazid [ Sm ( HMDS ) 3], which is easy to manufacture of samarium (III ) chloride ( SmCl3 ) and sodium hexamethyldisilazide ( NaHMDS ).

Asymmetric Catalysis

The aim of the asymmetric catalysis is to enable the highest possible proportion of one enantiomer can be synthesized. Since most drugs in vivo have a different effect, it is to obtain for large-scale synthesis of great interest as selective as possible synthetic methods at hand.

The first catalytic asymmetric Henry reaction was established in 1992 by H. Shibasaki et al. published. The experiences that have been made with the catalysts of rare earth came to use and lanthanum it was first used as a metal. As a chiral auxiliary or ligand here enantiomerically pure β - binaphthol was used. In a later publication, the synthesis of the catalyst system is simplified, and instead of Lanthanquelle Trilanthanhepta tert-butoxide is easier to handle, lanthanum ( III) chloride was used as the lanthanum source now. The achieved enantiomeric excess was given as 79-91 %.

Also moderate to high enantiomeric excesses ( 70-95 %) were achieved with a use of samarium as the metal, and also here binaphthol as the chiral ligand.

Based on previous experience with binaphthol as a chiral ligand and the guanidines as achiral Ligenaden it was obvious based on this work to optimize the ligand on. In this work, a variety of chiral guanidines were used.

Exemplary two asymmetric syntheses are shown by means of an asymmetrically catalyzed Henry reaction as partial synthesis of pharmacologically interesting compounds in the following.

Variations of the Henry reaction

Nitronate condensation

If a nitroalkane is reacted with n- butyllithium, the result is a Lithioalkylnitronat, which can be in the presence of isopropyloxytitanium with many aldehydes under very mild conditions (THF, -78 ° C) to implement the corresponding β - amino alkanols. The in - situ formation of a Dichlorisopropylnitronats supports the high diastereoselectivity of the Nitroalkanol products ( erythro: threo = 7:1).

From Seebach and Eyer comes a variant in which a dilithiated nitronate is used as active nitronate species in a Henry reaction. The potential of this method has been demonstrated in a number of reactants, such as benzyl, or dimethyl carbonate as the carbonyl component. As an example, a tetrahydropyranyl -protected nitroethanol above, which is treated with a two- fold excess of n-butyllithium in THF / HMPT, to obtain the nitronate. In the nitronate is a unintramolekular - chelated Nitronatdianion. This was reacted with a series of aldehydes and after acid treatment (Amberlyst ) one obtains the Dihydroxynitroalkane. It was found that it is preferred that the threo series, the reaction products. After removal of the THP protecting group and the pure diastereomers could be obtained by Kristallisiation.

Retro - Henry Reaction

In analogy to the related aldol Henry reaction is a reversible reaction. This can be used when preparing in a different way than a Henry reaction a β - Hydroxnitro connection and then subjected to a retro - Henry reaction. For this purpose are especially β - nitro ketones, which is converted by reaction with Grignard reagents under CC- link in such a β - Hydroxnitro connection.

Michael - Henry reaction

The Michael reaction is a vinylogous aldol reaction. By analogy, it is also a Michael - Henry reaction ( nitro -Michael reaction ). Here, the α - β -unsaturated nitro group as Michael acceptor react in the Michael reaction.

Intramolecular Henry reaction

The Henry reaction, as many other organic reactions are carried out intramolecularly. In this case, the nitro moiety and the carbonyl component present within the same molecule and the Henry reaction leads to a ring-closing reaction. Generally, either the nitro - moiety or carbonyl component manufactured in a Triggered and this compound then subjected to a cyclization reaction. Here is an example from the natural product synthesis was performed. The carbonyl component is obtained from an ester by DIBAL reduction ( DIBAL -H) to give the aldehyde. The cyclization is then initiated by alumina.

A similar structure may be constructed by a combination of a Henry -Michael reaction and Henry reaction.

In a variant of the intramolecular Henry reaction active species of carbonyl components and nitro components is constituted by a first intermolecularly Henry reaction. For this purpose, a dicarbonyl compound is required, which is accessible by oxidation of a diol or from olefins by oxidation to glycol and subsequent periodate cleavage or directly by ozonolysis. Reacting a nitroalkane with leads to a compound containing a nitro group and a carbonyl group in the molecule and the intramolecular Henry reaction may be subjected.