Nitroalkanes, Henry reaction

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. 

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... 

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. ... 

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. 

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 nitro-aldol reaction between nitroalkanes and carbonyl compounds to yield [3-nitro alcohols was discovered in 1895 by Henry.1 Since then, this reaction has been used extensively in many important syntheses. In view of its significance, there are several reviews on the Henry reaction.2-5 These reviews cover synthesis of (3-nitro alcohols and their 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 3-nitro alcohols are generally obtained in good yield by the reaction of aldehydes with nitroalkanes in the presence of a catalytic amount of base. When aryl aldehydes are used, the (3-nitro alcohols formed may undergo elimination of water to give aryl nitroalkenes. Such side reactions are not always disadvantageous, for nitroalkenes are sometimes the ultimate target for the Henry reaction. The choice of reaction conditions is important to stop the reaction at the stage of 3-nitro alcohols in aromatic cases. 

Proazaphosphatrane, P(RNCH2CH2)3N, is an efficient catalyst for the Henry reaction, and various ketones give nitro-aldols by the reaction with nitromethane and other nitroalkanes (Eq. 3.20).21... 

A1203 can be used both as a base for the Henry reaction and as a dehydrating agent. Thus, nitroalkenes are simply prepared by mixing of aldehydes and nitroalkanes with A1203 and subsequent warming at 40 °C (Eq. 3.30).53... 

Nitromethylation of aldehydes has been carried out in a one pot procedure consisting of the Henry reaction, acetylation, and reduction with sodium borohydride, which provides a good method for the preparation of l-nitroalkanes.16b 79 It has been improved by several modifications. The initial condensation reaction is accelerated by use of KF and 18-crown-6 in isopropanol. Acetylation is effected with acetic anhydride at 25 °C and 4-dimethylaminopyridine (DMAP) as a catalyst. These mild conditions are compatible with various functional groups which are often... 

The Michael addition of nitroalkanes to election-deficient alkenes provides a powerful synthetic tool in which it is perceived that the nitro group can be transformed into various functionalities. Various kinds of bases have been used for this transformation in homogeneous solutions, or, alternatively, some heterogeneous catalysts have been employed. In general, bases used in the Henry reaction are also effective for these additions (Scheme 4.18).133... 

The conversion of primary or secondary nitro compounds into aldehydes or ketones is normally accomplished by use of the Nef reaction, which is one of the most important transformations of nitro compounds. Various methods have been introduced forthis transformation (1) treatment of nitronates with acid, (2) oxidation of nitronates, and (3) reduction of nitroalkenes. Although a comprehensive review is available,3 important procedures and improved methods published after this review are presented in this chapter. The Nef reaction after the nitro-aldol (Henry reaction), Michael addition, or Diels-Alder reaction using nitroalkanes or nitroalkenes has been used extensively in organic synthesis of various substrates, including complicated natural products. Some of them are presented in this chapter other examples are presented in the chapters discussing the Henry reaction (Chapter 3), Michael addition (Chapter 4), and Diels-Alder reaction (Chapter 8). 

The Henry reaction of nitroalkanes followed by denitration is a good method for the preparation of alcohols. This methodology has been applied in carbohydrate chemistry. For... 

The condensation reaction of neat carbonyl compounds with nitroalkanes to afford nitroalkenes, Henry reaction, also proceeds rapidly via this MW approach in the presence of only catalytic amounts of ammonium acetate, thus avoiding the use of a large excess of polluting nitrohydrocarbons normally employed (Scheme 6.22) [72],... 

The nucleophilic addition of nitroalkane to carbonyl groups is known as the Henry reaction. The products of the Henry reaction are 2-nitroalkanols,115 which are useful intermediates for nitroalkenes, 2-amino alcohols, and 2-nitro-ketones. However, this does not always give high yields because of the possible O-alkylation in preference to C-alkylation during the Henry reaction. 

The base-catalyzed reaction of nitroalkanes and sugar-based aldehydes (the Henry reaction) is one of the most common procedures for the lengthening of the carbon skeleton of a carbohydrate.16 The mild reaction conditions required for the formation of C C bonds by this method are usually compatible with most of the protective groups and masked functionalities involved in multistep synthesis from sugars.17... 

The nucleophilic addition of a nitroalkane to a carbonyl group, referred to as the nitroaldol or Henry reaction, is a very powerful C-C bondforming reaction of great tradition and with numerous applications in synthetic organic chemistry [36-39], Moreover, the diversity of further... 

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. 

Henry reactions have been extensively exploited for the synthesis of nitrate ester explosives. The condensation of nitroalkanes with aldehydes, followed by esterification of the hydroxy groups with nitric acid, leads to a number of nitrate ester explosives (see Chapter 3). The two examples given above (166 and 167) are synthesized from the C-nitration of the polyols obtained from the condensation of formaldehyde with nitromethane and nitroethane respectively. 

The nitroaldol (Henry) reaction constitutes a powerful C-C bond-forming process in organic chemistry, providing efficient access to valuable functionalized organic compounds such as 1,2-amino-alcohols, a-hydroxy-carboxylic acids and 3-hydroxy-nitroalkanes [215, 216]. 

The Michael reaction of malonates to nitroolefins and the aza-Henry reaction of nitroalkanes to Al-phosphinoylimines are catalyzed by thiourea derivative 5a to provide the respective products in good and moderate enantioselectivities. Thiourea... 

Nitroaldol (Henry) reactions of nitroalkanes and a carbonyl were investigated by Hiemstra [76], Based on their earlier studies with Cinchona alkaloid derived catalysts, they were able to achieve moderate enantioselectivities between aromatic aldehydes and nitromethane. Until then, organocatalyzed nitroaldol reactions displayed poor selectivities. Based on prior reports by Sods [77], an activated thionrea tethered to a Cinchona alkaloid at the quinoline position seemed like a good catalyst candidate. Hiemstra incorporated that same moiety to their catalyst. Snbsequently, catalyst 121 was used in the nitroaldol reaction of aromatic aldehydes to generate P-amino alcohols in high yield and high enantioselectivities (Scheme 27). 

The aza-Henry reaction of imines to nitroalkanes promoted by modified Cinchona alkaloids has been investigated by several groups. Optically active p-nitroamine products are versatile functional building blocks. In 2005 and 2006, several reports regarding use of chiral thioureas emerged, using nitroalkanes in the aza-Henry reaction to various imines. 

Takemoto and co-workers communicated that bifunctional organocatalyst 166 would promote aza-Henry reactions of phosphinoyl imines with nitroalkanes (Scheme 52) [104]. The catalytic additions provided high selectivities and yields... 

Recently, Takemoto and co-workers reported the use of bifunctional ihiourea catalyst 166 for the aza-Henry reaction of nitroalkanes to A -Boc imines [107, 108], Using a... 

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. 

Scheme 6.75 Proposed mechanism of the enantio- and diastereoselective aza-Henry reaction between N-Boc-protected aldimines and nitroalkanes in the presence of biflinctional catalyst 12 and catalyzed epimerization of the syn-adduct at increased temperature.

A few years later, Hass reported an alternative synthesis of racemic amphetamine, which exemplifies the use of a nitroalkane as the source of the nitrogen atom (Scheme 17.4) (Hass et al., 1950). In this route, calcium-hydroxide-promoted Henry reaction of nitroethane and benzaldehyde (12) afforded an 86% yield of the nitro alkene 13. Simultaneous hydrogenation... 

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). 

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