Henry-reaction

The Henry reaction, or nitroaldo reaction, is one of the classic carbon-chain formation methods utilized in organic synthesis. It involves the condensation of nitroalkanes with aldehydes or ketones in the presence of bases (often catalytic amount) to afford the mixtures of diastereomeric 2-nitroalcohols, which in turn can be converted into other useful synthetic intermediates, such as 2-aminoalcohols, a-hydroxyketones, homologous ketones, and perhaps most importantly, nitroalkenes through various functional transformations. 

It is generally accepted that the condensation of nitroalkanes 1 with aldehydes proceeds with the nitronates 2 as the intermediates. The role of the base is to shift the tautomeric equilibrium towards the formation of nitronic acids, or ac/-nitroalkanes 3. Since 3 are much stronger acids (with a pAa range of 2 6) than 1 (with a pAa range of 9 10), they are more readily deprotonated with the base. After the deprotonation, the formed nucleophilic 

Synthetic utility of the nucleophilic addition of 7 can be exemplified by transformation using enol silanes as nucleophiles to generate 1,4-dicarbonyl compounds. Model substrate 16 reacts with 2-nitropropene in dichloromethane at -78 C in the presence of TiCU or SnCU to give the addition product 17a and/or 17b, which is hydrolyzed during work up to furnish 1,4-dicarbonyl 18 in good yield.  

Functionalized conjugated nitroalkenes, such as 2-nitro-2-propen-l-ol pivalate (NPP), deserve special considerations. They can serve as extremely versatile multiple coupling reagents by sequential coupling with various nucleophiles and electrophiles due to the unique feature of three reactive sites in one molecule.  

For instance, it is reported that a chiral copper catalyst (R,R)-L promotes asymmetric conjugate addition of dialkyl zinc to a,p-unsaturated ketone 19 to form homochiral zinc enolate 20. This intermediate is then trapped in situ with NPP as electrophile, without the need of additional palladium catalysis. Good yield, high trans/cis (95/5) ratio, and excellent enantioselectivity (99%) are obtained. Moreover, the multi-functionalized nature of 21 makes it a versatile intermediate for further elaboration. 

All the steps in the Henry reaction are completely reversible. The first step of the mechanism is the deprotonation of the nitroalkane by the base at the a-position to form the corresponding resonance stabilized anion. Next, an aldol reaction (C-alkylation of the nitroalkane) takes place with the carbonyl compound to form diastereomeric P-nitro alkoxides. Finally the P-nitro alkoxides are protonated to give the expected p-nitro alcohols. 

The first total synthesis of the 14-membered para ansa cyclopeptide alkaloid (-)-nummularine F was accomplished in the laboratory of M.M. Joullie. The A/3 nitrogen atom was introduced by using the Henry reaction between the 4-formylphenoxy group and the anion of nitromethane, followed by reduction of the nitro group to the corresponding amine. The epimeric benzyl alcohols did not pose a problem since they were dehydrated at the end of the synthetic sequence to give the C1-C2 double bond. 

The bone collagen cross-link (+)-deoxypyrrololine has potential clinical utility in the diagnosis of osteoporosis and other metabolic bone diseases. Intrigued by its novel structure and its promise to allow the early discovery of various bone diseases, the research team of M. Adamczyk developed a convergent total synthesis for this 1,3,4-trisubstituted pyrrole amino acid. The key step of the synthesis was the union of the nitroalkane and aldehyde fragments to obtain a diastereomeric mixture of the expected -nitro alcohol in good yield. This new functionality served as a handle to install the pyrrole ring. 

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. 

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. 

Formaldehyde is the most important aldehyde used in Henry reactions in relation to energetic materials synthesis. Nitroform (112) reacts with formaldehyde in the form of trioxane or formalin to yield 2,2,2-trinitroethanol (159). The Henry reaction of nitroform with aldehydes other than formaldehyde gives products which are not isolable. 

Both the Henry reaction and the reverse demethylolation are synthetically useful in the chemistry of polynitroaliphatic compounds. The Henry reaction is commonly used to mask the natural chemistry of an aliphatic nitro or terminal em-dinitro group by removing the acidic a -proton(s). In Section 1.7 we discussed the conversion of Q ,ty-dinitroalkanes to their bis-methylol derivatives before subjecting them to oxidative nitration and subsequent demethylolation with base, a procedure which results in the formation of Q ,Q , y, y-tetranitroalkanes.  

N02K HC NO2 2 CH2O, AcOH CH2OH O2N-C—NO2 CH2OH KOH, 99% NOjK HOCHaC + NO2 

Many of the nitronate salts of polynitroaliphatic compounds, particularly salts of gem-nitronitronates, exhibit properties similar to known primary explosives. Consequently, the storage of such salts is highly dangerous. Treatment of these nitronate salts with formaldehyde yields the corresponding methylol derivative via the Henry condensation. These methylol 

In the computational study a possibility of simultaneous binding of both reagents with hydrogen bonds with both N-H protons in different thiourea units was investigated. It was foxmd, however, that the most stable complex of this kind is significantly (by 6 kcal/mol) less stable than a complex of nitronate anion with the catalyst and free benzaldehyde, whereas the binding of free benzaldehyde is very weak. It was concluded therefore that the complex in which both reagents are boxmd to tire catalyst is not an important intermediate due to its low concentration and aldehyde 26 preferentially remains unboimd before the formation of the transition state.  

Further search of the corresponding transition states afforded TS9 and TSIO with the relative stabilities correctly predicting the experimentally 

The reasons for a significant difference in stability between TS9 and TSIO are unclear. The authors carefully checked any possible computational errors by reoptimizing these structures in numerous basis sets and with various ways of description of the dispersion effects to get almost identical difference in stabilities. 

In a computational study, a transition-state model reasonably explaining the involvement of the three functional groups of the catalyst (one guanidine and two urea groups) in the process of enantioselective a-hydroxylation was developed. In this model, the orientation of the ketoester enolate is controlled by hydrogen bonding of its two carbonyl 

---

The Barton-Zard (BZ) pyrrole synthesis is similar both to the van Leusen pyrrole synthesis that uses Michael acceptors and TosMlC (Section 6.7) and the Montforts pyrrole synthesis using a,P-unsaturated sulfones and alkyl a-isocyanoacetates." An alternative to the use of the reactive nitroalkenes 1 is their in situ generation from P-acetoxy nitroalkanes, which are readily prepared via the Henry reaction between an aldehyde and a nitroalkane followed by acetylation. Examples are shown later. 

The nitro-dldolredcdon between nitrodlkdnes and carbonyl compounds to yieldfi-nitro alcohols was discovered in 1895 by Henry. Since dien, diis reaction has been used extensively in many important syndieses. In view of its significance, diere are several reviews on die Henry reaction." These reviews cover syndiesis of fi-nitro alcohols and dieir applications in organic synthesis. The most comprehensive review is Ref 3, which summarizes the literature before 1970. More recent reviews are Refs. 4 and 5, which summarize literatures on the Henry reaction published until 1990. 

The synthedc ndlity of the Henry reaction is shovm in Scheme 3.1, where fi-nitro alcohols are converted into fi-amino alcohols, amino sugars, ketones and other important compounds. 

Thus, various kmds of bases are effective in inducing the Henry reaction The choice of base and solvent is not crucial to carry out the Henry reaction of simple nitroalkanes v/ith aldehydes, as summarized in Table 3 1 In general, sterically hindered carbonyl or nitro compounds are less reactive not to give the desired ni tro-aldol products in good yield In such cases, self-condensation of the carbonyl compound is a serious side-reaction Several mochfied procedures for the Henry reaction have been developed... 

AljO cdn be used both as a base for the Henry reaction and as a dehydrating agent Thus, nitro ilkenes are simply prepared by mixing of aldehydes and nitro ilkanes with ATO and subsequent warming at 40 C fEq 3 30 ... 

STEREOSELECTIVE HENRY REACTIONS AND APPLICATIONS TO ORGANIC SYNTHESIS... 

Seebdch and co-workers have developed complementdry protocols for stereocontrol of the Henry reaction fScheme 3.12. ... 

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... 

THE NITRO-ALDOL (HENRY) REACTION (/7)-LnLB complex... 

The Henry reactions of A, ALdibenzyl-L-phenylalaninal with nitroalkanes using 1.2 equiv of tetrabutylammonium fluoride (TBAF) as the catalyst proceed in ahighly stereoselective manner, as shown in Eqs. 3.82 and 3.83. This reaction provides rapid and stereoselective access to important molecules containing 1,3-diamino-2-hydroxypropyl segments, which are cenhal structural subunit of the HIV protease inhibitor amprenavir (in Scheme 3.21). 

The Henry reaction of ketones with nitroalkanes in the presence of etbylenediamine gives allylic nitro compounds, which give a,fi-imsanirated carbonyl compounds via the Nef reaction fEq. 6.30. ... 

An elegant example of sequence of reactions involving the Henry reaction, the Michael reaction, and elimination of HNO is demonstrated in a short synthesis of anthracyclmones. Nitromethane is used to introduce the ClO-gronp simultaneously v/irh the C9-hydroxy group fEq. 7,136. ... 

From the foregoing it can be seen that the nitro group can be activated for C-C bond formation in various ways. Classically the nitro group facilitates the Henry reaction, Michael addition, and Diels-Alder reaction. Komblum and Russell have introduced a new substitution reaction, which proceeds via a one electron-transfer process The Spj l reactions have... 

Sequential radical cyclizations are also featured in an efficient and clever synthesis of the cedrane framework 83 (see Scheme 15).30 Compound 81, the product of a regioselective Diels-Alder reaction between isoprene (79) and nitroethylene (80), participates in a nitroaldol reaction (Henry reaction) with 5-methyl-4-hexenal in the presence of a basic resin to give 82. Because the nitro group in... 

The chemical yield of the classical Henry reaction is not always good and depends on steric factors thus, highest yields are obtained when nitromethane is used. Performing the reaction under high pressure (9 kbar, 30 °C) with tetrabutylammonium fluoride catalysis19 enlarges the scope of the reaction dramatically. Thus, addition of nitropropane to 2-methylcyclohexanone, which is not reactive under the classical conditions, was achieved in 40 % yield. Improved yields... 

The basc-eatalyzcd addition of nilroalkancs to carbonyl compounds is a reversible reaction and proceeds under thermodynamic control. Thus low (R, R )/(R, S ) selectivities arc observed in the classical Henry reaction which leads to the silylated x-nitro alcohols 2. 

In the presence of a catalytic amount of tetrabutylammonium fluoride, either freshly dried over molecular sieves22 or as the trihydrate16, silylnitronates 2 derived from primary nitroalkanes react readily at — 78 C or below, via their in situ generated nitronates. with aromatic and aliphatic aldehydes to give the silyl-protected (/J, S )-nitroaldol adducts 3 in excellent yield4,22-24-26,27. Silylnitronates, derived from secondary nitroalkanes. afford the adducts in 30 40% overall yield24. In contrast to the classical Henry reaction (vide supra), the addition of silylnitronates to aldehydes is irreversible. Ketones are unreaetive under such conditions. 

Moderate stereoselectivity (80 20) was observed in the potassium fluoride catalyzed Henry reaction of nitromethane with isopropylidenc-D-glyceraldehyde (10). The major product could be separated from the mixture by fractional crystallization9. 

Henry reactions of readily accessible 1-deoxy-l-nitroaldoses (e.g., 1) with a variety of aldehydes proceed with a high degree of stereoselection. The crude products are hydrolyzed with loss of the nitro group to generate higher ketoses8. 

Henry reaction of the (V-acetyl-D-glucosamine derived nitrosugar 1 with 2,3-O-cyclohexylidene-D-glyceraldehyde (2) furnishes a single product 3 in 85-90% yield7. 

The barium hydroxide catalyzed Henry reaction of 6-deoxy-3-0-methyl-6-nilro-L-ta/r -pyra-nosc (17), generated from l,2-0-isopropylidcnc-3-0-mcthyl-o -D-r/7to-pcntodialdo-1.4-furanose (16), furnishes 5-deoxy-2-GMnethyl-5-nitro-wi o-inositol (18) in 92% yield and 90% purity1 2 3 4 5 6. 

Recently, enantioselective organo-catalytic procedures for the aza-Henry reaction have been disclosed. The presence of either an acidic or a basic function appears to be a requisite of the catalyst. In fact, the condensation of ni-tromethane with M-phosphinoyl arylimines 72 is catalyzed by the chiral urea 85 derived from (R,R)-l,2-diaminocyclohexane and gives the product (R)-74 with good yield and moderate enantioselectivity (Scheme 15) [50]. The N-phosphinoyl substituent is determinant, as the addition of nitromethane to the N-phenyl benzaldimine failed and the reaction of the N-tosyl ben-zaldimine gave the expected adduct with quantitative yield but almost no... 

Scheme 15 Organo-catalytic enantioselective aza-Henry reactions...

An enantioselective aza-Henry reaction catalysed by the same bifimctional organocatalyst was recently reported by the same group (Scheme 47) [163]. 

The aza-Henry reaction is the nucleophilic addition of nitroalkanes to imines to give nitroamine derivatives. This reaction was also studied with metal-based catalysts [164]. 

The nitroaldol reaction or Henry reaction is a powerful and highly versatile carbon-carbon bond-forming reaction, allowing a plethora of key molecular frameworks, such as p-hydroxynitroalkanes, 1,2-amino alcohols or a-hydroxy carboxylic acids to be synthesised in a straightforward manner. Therefore, the development of practical catalytic asymmetric versions of this reaction is still largely desirable. The first catalytic asymmetric nitroaldol reaction was reported in 1992, " but despite its long history, relatively few chiral ligands have... 

---