Intramolecular Henry reaction

Chiu et al. developed the first example of a reductive intramolecular Henry reaction induced by Stryker s reagent (Scheme 30) [53]. The conjugate reduction of keto-nitroalkenes with [Ph3PCuH]6 (150 mol%) triggers spontaneous nitro-aldol reaction at - 40 °C to produce (f-hydroxy nitro compounds in moderate yield. 

Scheme 30 Reductive intramolecular Henry reaction, nitroaldol reaction, mediated by Cu H...

The stereoselective intramolecular Henry reactions have been reported by Seebach. The Michael addition of doubly deprotonated acetyl acetaldehyde to l-methylenedioxyphenyl-2-nitroethene followed by subsequent intramolecular nitro-aldol cyclization leads to the diastereomerically pure cyclohexanone derivative, where the nitro and OH groups are cis as shown in Eq. 3.73.114 This reaction is applied to the synthesis of l-desoxy-2-lycorinone as shown in Eq. 3.74.115... 

In fact, cyclization (16 5b) is an intramolecular modification of the classical Henry reaction. It should be noted that the Henry reaction generally occurs as C,C-coupling (path (b)), but the reaction can be forced to proceed by path (a) due to steric hindrance or other factors. 

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. 

Intramolecular nitroaldol reactions are a useful choice for the conversion of sugars into polyhydroxylated nitro cyclopentanes, nitro cyclohexanes and their derivatives.46 Baer et al. in the course of their studies on the cyclization of 6-deoxy-6-nitrohexoses under kinetic and thermodynamic control,47 established the reaction pathway involved in the formation of nitroinositols mediated by intramolecular Henry reactions. Firstly, a nitronate is formed and then, under thermodynamic control conditions, an epimerization occurs before cyclization. But, under kinetic controlled conditions, the cyclization occurs first.48... 

Intramolecular Henry reactions of nitro sugars are usually diastereo-selective sometimes a single isomer results from an epimeric mixture, on account of the reversivility of the Henry reaction, which allows equilibration through open chain intermediates.49 A recent example involving the D-glucose derived nitro acid ester 26 is shown in Scheme 22. 

Another recent example supporting the influence of the nature of the base in intramolecular Henry reactions in nitro sugars is depicted in Scheme 23. The intramolecular nitroaldol cyclization of compound 67 using alkoxides, hydroxides or carbonates gave unsatisfactory results, but when this compound and DABCO (3 eq.) were refluxed in benzene, surprisingly, only... 

In a recent application of this strategy, nitrocyclohexane 143 (prepared from nitrosugar 142 by intramolecular Henry reaction) was subjected to a radical denitration by HSnBu3, after protection of the hydroxyl groups to avoid side reactions. Inositol 146 was selectively obtained in good yield, once the hydroxyl protecting groups were removed (Scheme 45).101... 

Lemaire et al. have developed a efficient fructose-1,6-bisphosphate aldolase (FBPA)-mediated synthesis of aminocyclitol analogs of valiolamine [34], This one-pot route involves the formation of two C—C bonds where four stereocenters are created. The first C—C bond formation reaction is catalyzed by the aldolase, coupling DHAP to nitrobutyraldehydes the other one is the result of a highly stereoselective intramolecular Henry reaction occurring on the intermediate nitroketone under acidic conditions during the aldolase-catalyzed reaction and phytase-catalyzed phosphate hydrolysis coupled step (Scheme 4.13). 

Reaction at the C atom of nitronate salts is known with a variety of electrophiles, such as aldehydes (Henry reaction) and epoxides (191-193). Thus the incorporation of the nitro moiety and the cyclization event can be combined into a tandem sequence. Addition of the potassium salt of dinitromethane to an a-haloaldehyde affords a nitro aldol product that can then undergo intramolecular O-alkylation to provide the cyclic nitronate (208, Eq. 2.17) (59). This process also has been expanded to a-nitroacetates and unfunctionalized nitroalkanes. Other electrophiles include functionalized a-haloaldehydes (194,195), a-epoxyaldehydes (196), a-haloenones (60), and a-halosulfonium salts (197), (Chart 2.2). In the case of unsubstituted enones, it is reported that the intermediate nitronate salt can undergo formation of a hemiacetal, which can be acetylated in moderate yield (198). 

The latter compounds are prone to an intramolecular nitroaldol (Henry) reaction, yielding nitrocyclohexanola (53) in less than 1 h. The formation of (53) can be easily observed by thin-layer chromatography (TLC), thus treatment of (53) with 4N hydrochloric acid favors the elimination of both water and a further molecule of nitrous acid, allowing the one-pot synthesis of target molecules (54) in 42-77% overall yields. It is important to note that this one-pot process formally includes five different transformations (i) Michael addition, (ii) nitrous acid elimination, (iii) intramolecular nitroaldol reaction, (iv) water elimination, and (v) elimination of a further molecule of nitrous acid. 

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. 

Soengas, R. G., Estevez, J. C., Estevez, R. J. Transformation of D-Glucose into 1D-3-Deoxy-3-hydroxymethyl-myo-inositol by Stereocontrolled Intramolecular Henry Reaction. Org. Lett. 2003, 5,4457-4459. 

In 2009, the Magnus group disclosed the synthesis of racemic codeine [50]. In their synthesis (1) an intramolecular phenol alkylation generating an A-C bicyclic ring system with a quaternary carbon, (2) a stereo-controlled, one-pot formation of a B-ring by way of the combination of Henry reaction and Michael addition of nitromethane with a cyclohexadienone-aldehyde, and (3) an introduction of the requisite functionalities in the C-ring by the epoxide-mediated selenylation followed by oxidation, were employed as the key transformations. 

Reaction of aldehydes with methyl 3-nitropropanoate in a Henry reaction, leads throngh to bntenolides. A 3(2 0-furanone can be neatly prodnced by the intramolecular displacement of bromide from a 1 -bromo-2,4-dione. ... 

The most recent entry to bicyclic P-lactam compounds through this approach, has been introduced by Barrett and his coworkers [120] by using an intramolecular Michael type reaction of a Af-silyl p-lactam to a nitroalkene induced by fluoride ion (Scheme 45). Namely, the known P-lactam 299 [32a] readily prepared from CSI addition to 1,5-hexadiene, was protected by using TBDMSCI and DIPEA to produce the p-lactam 300. Subsequent ozonolysis, gave the aldehyde 301. Henry reaction of the aldehyde 301 with (phenylthio)-nitromethane furnished, after dehydration of the resulting nitroaldol, the nitroalkene 302 which smoothly cyclized to the carbapenam 303 in the presence of... 

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