Direct Henry reactions

Ooi has recently reported application of chiral P-spiro tetraaminophosphonium salt 37 as a catalyst for the highly enantio- and diasterioselective direct Henry reaction of a variety of aliphatic and aromatic aldehydes with nitroalkanes (Scheme 5.51) [92]. Addihon of the strong base KO Bu generates in situ the corresponding catalyhcally active triaminoiminophosphorane base A. Ensuing formation of a doubly hydrogen-bonded ion pair B positions the nitronate for stereoselective addition to the aldehyde. This catalyst system bears many similarities to guanidine base catalysis. 

Uraguchi D, Nakamura S, Ooi T. Catalytic asymmetric direct Henry reaction of ynals short syntheses of (2S,3/f)-(- -)-xes-toaminol C and (—)-codonopsinines. Angew. Chem Int. Ed. 2010 49 7562-7565. 

The diastereoselectivity is observed in the Henry reaction using optical active niti o compounds or a-heteroatom substituted aldehydes. Lor example, the reaction of O-benzyl-D-lactal-dehyde with methyl 3-niti opropionate in the presence of neubal alumina leads to a mixture of three niti o-aldol products from which D-ribo isomer is isolated by direct crystallization. D-Ribo... 

Polynitroaliphatic alcohols are invaluable intermediates for the synthesis of energetic materials (see Section 1.11). The most important route to /i-nitroalcohols is via the Henry reaction where a mixture of the aldehyde and nitroalkane is treated with a catalytic amount of base, or the nitronate salt of the nitroalkane is used directly, in which case, on reaction completion, the reaction mixture is acidified with a weak acid. Reactions are reversible and in the presence of base the salt of the nitroalkane and the free aldehyde are reformed. This reverse reaction is known as demethylolation if formaldehyde is formed. 

Vongvilai P, Larsson R, Ramstrom O (2008) Direct asymmetric dynamic kinetic resolution by combined lipase catalysis and nitroaldol (Henry) reaction. Adv Synth Catal 350 448 152... 

An electrosynthetic approach to 2-nitroalcohols via activation of nitromethane by electrogenerated superoxide anion has been reported by Evans et al. [166-168]. Recently, the electrochemically induced Henry reaction has been performed via direct cathodic reduction of nitromethane (Scheme 16.28) [169, 170]. 

Scheme 16.28 Henry reaction performed via direct cathodic reduction of nitromethane (Reprinted from Ref. [170] with kind permission of John Wiley and Sons)...

X = OH) act as very efficient bases for the Heck reaction and catalyze efficiently the Henry reaction with excellent yields and selectivities. The catalyst can be used both in batch and under flow conditions and can be directly reused several times with only a minor decrease in activity. The spent polymer can be easily regenerated simply by its treatment with a basic solution [363],... 

The asymmetric Henry reaction is important because products are convertible to many other valuable bifunctional or polyfunctional compounds. Organocatalysts for the reaction containing a guanidine unit are represented by the C2-symmetric 76, which directs the addition of nitroalkanes to a-keto esters asymmetrically. 

It is also noteworthy that Ricci and co-workers have disclosed phase nitro-Mannich (or aza-Henry) reaction using Al-Carbamoyl imines generated in situ from a-amido Sulfones using phase-transfer catalysts [78]. Ricci s direct use of a-amido sulfones as acceptors has also inspired developments in aminocatalysis as described vide infra. Here the 7/-benzyl quininium chloride catalyst has a dual function by generating the corresponding Al-carbamoyl imines in situ and next activate the nucleophile for the highly stereoselective addition (Scheme 4.17). 

Nitroalkene Synthesis. Henry reaction of (phenylthio)nitro-methane with aldehydes fohowed by dehydration has been used to prepare (. -l-nitro-l-phenylthioalkenes. potassium 7eri-butoxide-catalyzed addition and dehydration via mesylation (eq 1), or direct condensation catalyzed by piperidinium acetate (eq 2), are the methods of choice. Henry reaction can be also carried out by reaction of the nitroalkene dianion with aldehydes. ... 

Nitrohydroxylated pyrrolidine and piperidine ring systems 1824 have been conveniently obtained by a one-pot procedure involving sequential Michael-Henry reaction between nitroethene and a nitrogen nucleophile 1823 suitably predisposed for the oxidative generation (Swem reaction) of an aldehyde group, which is directly trapped in the subsequent nitroaldolization step [1384]. 

In the forward direction, diene 5 was prepared by alkylation of metallated 1,3-dithiane 9 with allylic bromide 8. In this reaction, 9 plays the role of an acyl anion equivalent . We will talk about equivalencies in more detail in Chapter 6, but at this point it is worth noticing that the dithiane will eventually emerge as the C15 protected ketone. Dienophile 4 was prepared by an aldol-dehydration reaction between nitromethane and aldehyde 10, a reaction known as the Henry reaction. The Diels-Alder reaction between 4 and... 

Thomas Albright is currently Professor Emeritus at the Department of Chemistry, University of Houston. He has been awarded the Camille and Henry Dreyfus Teacher Scholar and Alfred P. Sloan Research fellowships. He is the author and coauthor of 118 publications. He has been elected to serve on the Editorial Advisory Board of Organometallics and the US National Representative to lUPAC. His current research is directed toward reaction dynamics in organometallic chemistry. He received his PhD degree at the University of Delaware and did postdoctoral research with Roald Hoffmann at Cornell. 

An impressive array of new catalysts for enantioselective homologation have been reported. Carlos F. Barbas 111 of Scripps/La Jolla has found (Angew. Chem. Int. Ed. 2007, 46, 5572) that the commercial amino acid 3 mediated the addition of dibydroxyacetone 2 to an aldehyde such as 1 to give the triol 4 with high enantio- and diastereocontrol. Takashi Ooi ofNagoya University has devised (J. Am. Chem. Soc. 2007,129, 12392) the catalyst 6 for the anti addition (Henry reaction) of nitro alkanes such as 5 to aldehydes. Takayoshi Arai of Chiba University has developed (Organic Lett. 2007, 9, 3595) a complementary catalyst (not shown) that mediated syn addition. Jonathan A. EUman of the University of California, Berkeley has uncovered (J. Am. Chem. Soc. 2007,129,15110) the catalyst 10 for the aza-Henry reaction. Yian Shi of Colorado State University has found (J. Am. Chem. Soc. 2007,129,11688) hgands for Pd that direct the absolute sense of the addition of 13 to dienes such as 12. 

In 2007, Ooi and coworkers introduced chiral tetraaminophosphonium salts as a new class of Bronsted acids [166]. Similar to the guanidine/guanidinium case, these tetraaminophosphonium salts act as Bronsted bases in their neutral/ deprotonated (triaminoiminophosphorane) form, while they can also be used as mono-functional Bronsted acids in their protonated, phosphonium form. Phos-phonium salt 67, when neutralized in situ with KO Bu, was shown to be a highly effective catalyst in the enantioselective Henry reaction of nitroalkanes with various aromatic and aliphatic aldehydes (Scheme 10.65). The same strategy was further applied to the catalytic asymmetric Henry reaction of ynals [167] and hydrophosphonylation of ynones (Scheme 10.66) [168]. Brfunctional catalysis using this scaffold were also obtained using the carboxylate salts of tetraaminophosphoniums in the direct Mannich reaction of sulfonyl imines with azlactones (Scheme 10.67) [169]. 

As mentioned above, the intrinsic non-directional nature of electrostatic interactions between substrates and monofunctional BB catalysts makes the development of highly selective processes in a predictable manner difficult. As an illustration, the few chiral guanidine organocatalysts that have been described that are capable of promohng the aza-Henry reaction between N-Boc aryl imines and nitromethane lead to the corresponding P-nitroamines in generally low enanhomeric excesses (20-70% ee) [43]. 

MichaeU-Henry Reaction Liu et al. and Xie et al. independently found that tertiary amine-thioureas could stereoselectively promote the addition of diethyl a-aminomalonate-derived azomethine ylides to nitroolefms, affording Michael adducts other than dipolar cycloaddition adducts as the major products. Using monofunctional chiral thioureas 140d instead of tertiary amine-thiourea catalysts, Liu et al. successfully developed a three-component [3-1-2] dipolar cycloaddition of benzaldehydes 3, diethyl a-aminomalonates 45a, and nitrostyrenes 165, resulting directly in the enantioenriched pyrrolidines 208 as the only products (Scheme 2.56) [81a] while Xie et al. efficiently converted the Michael adducts 210 to pyrrolidines 208 in high yield and maintained ee by the use of 30 equiv of 2,2,2-trifluoroethanol as the additive (Scheme 2.56) [81b]. 

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