Intramolecular Henry

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... 

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). 

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 2013, Enders and co-workers reported a kinetically controlled asymmetric organocatalytic Michael addition/intramolecular Henry domino reaction, providing a facile access to enantioenriched cis-nitroindanol products 164 in excellent yields (61->99%) with up to 97% ee and 17 1 dr (Scheme 6.77). ... 

Scheme 16.8 FSA -catalyzed aldol addition of DHA and HA to nitroaldehydes with an ensuing intramolecular Henry reaction to produce the nitrocyditols 29. (a) FSA 29S...

The 2,4,6-triphenyl pyrylium ion reacts (a) with nitromethane in the presence of a base to give 2,4,6-triphenyl-nitrobenzene (43) via intermediate 42 and its intramolecular Henry reaction and (b) with P-ylides to give 1,3,5-triphenyl benzene derivatives 45 via intermediate 44 and its intramolecular Wittig olefination ... 

A protonated O-TMS-diphenylproUnol 103/BzOH catalytic system was used by Ni et al. in an asymmetric domino Michael/Henry reaction in an aqueous medium. Chiral Michael adducts 107 generated in situ from pentane-1,5-dial (106) and (i-nitrostyrene derivatives spontaneously underwent an intramolecular Henry reaction under the proposed conditions to afford 3-substituted 2-nitro-4-formylcyclohexanols 108 containing four stereocenters in moderate to high yields and with almost complete enantioselectivity (Scheme 22.31) [116]. The catalyst could be recycled at least four times, with only a slight reduction in yields and diastereoselectivity. 

Enamine-Intramolecular Addition Cascades Hayashi et al. envisioned that an enamine generated from one carbonyl of pentane-1,5-dial with catalyst 34 reacted with a nitroalkene in a Michael addition, followed by an intramolecular Henry reaction with the other aldehyde, would provide substituted nitrocyclohexan-ecarbaldehyde 104 (Scheme 1.37) [54],... 

What s more, the addition of nilroalkanes to ot,P-unsaturated aldehydes followed by an intramolecular Henry reaction which led to the formation of highly substituted cyclo-hexanols with control over five contiguous stereocenters was illustrated (Scheme 1.79) [124], This novel domino reaction catalyzed by diarylprolinol sily 1 ether 128 proceeded in moderate to good yields with high diastereo- and enantioselectivity. 

L. El Blidi, D. Crestia, E. Gallienne, C. Demuynck, J. Bolte, M. Lemaire, A straightforward synthesis of an aminoq ditol based on an enzymatic aldol reaction and a highly stereoselective intramolecular Henry reaction. Tetrahedron Asymmetry 15 (2004) 2951-2954. 

Aminocyclitol (e.g., 63) synthesis from nitroaldehydes (e.g., 62). Aldol addition of DHAP to nitroaldehyde 62 cataiyzed by DHAP-dependent aldolases followed by an ensuing spontaneous intramolecular Henry reaction, (a) DHAP-dependent aldolase and (b) Dephosphorylation by acid phosphatase and subsequent catalytic reduction of the nitro group. 

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