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Nitro aldol additions with

Combining, in tandem, the nitro-aldol reaction with the Michael addition using thiophenol is a good method for the preparation of P-nitro sulfides as shown in Eqs. 4.2 and 4.3. This reaction is applied to a total synthesis of tuberine. Tuberine is a simple enamide isolated from Streptomyces amakusaensis and has some structural resemblance to erbastatin, an enamide which has received much attention in recent years as an inhibitor of tyrosine-specific kinases. The reaction of p-anisaldehyde and nitromethane in the presence of thiophenol yields the requisite P-nitro sulfide, which is converted into tuberine via reduction, formylation, oxidation, and thermal elimination of... [Pg.79]

Ono and Kamimura have found a very simple method for the stereo-control of the Michael addition of thiols, selenols, or alcohols. The Michael addition of thiolate anions to nitroalkenes followed by protonation at -78 °C gives anti-(J-nitro sulfides (Eq. 4.8).11 This procedure can be extended to the preparation of a/jti-(3-nitro selenides (Eq. 4.9)12 and a/jti-(3-nitro ethers (Eq. 4.10).13 The addition products of benzyl alcohol are converted into P-amino alcohols with the retention of the configuration, which is a useful method for anri-P-amino alcohols. This is an alternative method of stereoselective nitro-aldol reactions (Section 3.3). The anti selectivity of these reactions is explained on the basis of stereoselective protonation to nitronate anion intermediates. The high stereoselectivity requires heteroatom substituents on the P-position of the nitro group. The computational calculation exhibits that the heteroatom covers one site of the plane of the nitronate anion.14... [Pg.73]

Heterobimetallic asymmetric complexes contain both Bronsted basic and Lewis acidic functionalities. These complexes have been developed by Shibasaki and coworkers and have proved to be highly efficient catalysts for many types of asymmetric reactions, including catalytic asymmetric nitro-aldol reaction (see Section 3.3) and Michael reaction. They have reported that the multifunctional catalyst (f )-LPB [LaK3tris(f )-binaphthoxide] controls the Michael addition of nitromethane to chalcones with >95% ee (Eq. 4.140).205... [Pg.119]

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). [Pg.159]

Ono and coworkers have extended the radical elimination of v/c-dinitro compounds to P-nitro sulfones151 and P-nitro sulfides.138,152 As P-nitro sulfides are readily prepared by the Michael addition of thiols to nitroalkenes, radical elimination of P-nitrosulfides provides a useful method for olefin synthesis. For example, cyclohexanone is converted into allyl alcohol by the reaction shown in Eq. 7.110. Treatment of cyclohexanone with a mixture of nitromethane, PhSH, 35%-HCHO, TMG (0.1 equiv) in acetonitrile gives ahydroxymethylated-P-nitro sulfide in 68% yield, which is converted into the corresponding allyl alcohol in 86% yield by the reaction with Bu3SnH.138 Nitro-aldol and the Michael addition reactions take place sequentially to give the required P-nitro sulfides in one pot. [Pg.216]

On treatment of glutaraldehyde with 2-hydroxy-3-nitropropionic acid, only 2-nitrocyclohexane-l,3-diol could be isolated in 10% yield, indicating that, under the conditions used, a retro-aldol degradation takes place with liberation of nitromethane. However, when using methyl 2-methoxy-3-nitropropionate, which cannot undergo a retro-nitro-methane addition", products (101) and (102) are obtained in yields of 7 and 13% respectively... [Pg.207]

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). [Pg.135]

Similar changes take place in the acidification of the enol salt of a carbonyl compound, the principal difference being the much longer life of the acf-nitro compound compared to that of an enol of a simple ketone (see Section 17-IB), Primary and secondary nitro compounds undergo aldol additions and Michael additions with suitable carbonyl compounds and basic catalysts ... [Pg.1196]

Most peptidyl a,a-difluoroalkyl ketones are actually extended chains based on statone, rather than simple difluoromethyl ketones. The statone derivatives are based on pepstatin, which is an extremely potent peptide inhibitor of aspartic proteases. The difluoro derivatives of statone take advantage of both the electronegativity of fluorine and the potential for additional interactions between the protease and structures on the leaving group side of the inhibitor. 15 This dual nature is part of what makes a,a-difluoroalkyl ketones effective inhibitors of aspartyl proteases as well as serine proteases. There are three main methods of synthesizing peptidyl a,a-difluoroalkyl ketones (1) the Reformatsky reaction with peptide aldehydes (Section 15.1.4.2.1), (2) a modified Dakin-West reaction (Section 15.1.4.2.2), and (3) a Henry nitro-aldol condensation (Section 15.1.4.2.3). [Pg.231]

Pyrrole synthesis. A new route to pyrroles1,2 is based on a base-catalyzed Michael addition of an alkyl isocyanoacetate to a nitroalkene to give an intermediate that cyclizes to a pyrrole. The nitroalkene is generally obtained from a P-acetoxy nitroalkane (1), prepared by a nitro aldol reaction of an aldehyde with a nitroalkane. The synthesis of ethyl 3,4-diethylpyrrole-2-carboxylate (2) is typical. [Pg.164]

Treatment of 206 with cesium fluoride in DMF clearly promoted an intramolecular nitro-aldol reaction furnishing, after acetylation, nitrocyclitol 207 as an a, 3-anomeric mixture. Exposure of 207 to liquid ammonia in THF resulted in formation of kinetically favoured a-acetamido derivative 208, probably from a Michael-type addition of ammonia to a nitroolefin intermediate. Reductive elimination of nitro-group in 208 and subsequent deprotection gave validamine 202, in a global 6% yield from glucuronolactone 205. [Pg.481]

The Henry reaction or the nitroaldol is a classical reaction where the a-anion of an alkyinitro compound reacts with an aldehyde or ketone to form a p-nitroalcohol adduct. Over the decades, the Henry reaction has been used to synthesize natural products and pharmaceutical intermediates. In addition, asyimnetric catalysis has allowed this venerable reaction to contribute to a plethora of stereoselective aldol condensations. Reviews (a) Ballini, R. Bosica, G. Fiorini, D. Palmieri, A. Front. Nat. Prod. Chem. 2005, 1, 37-41. (b) Ono, N. In The Nitro Group in Organic Synthesis Wiley-VCH Weinheim, 2001 Chapter 3 The Nitro-Aldol (Henry) Reaction, pp. 30-69. (c) Luzzio, F. A. Tetrahedron 2001, 57, 915-945. [Pg.148]

Michael condensations, together with the Diels-Alder cycloaddition and the aldol reactions, are the most powerful and useful bond-fonning reactions in synthetic organic chemistry. Like the nitro-aldol (Henry) additions, nitroalkanes are particularly appropriate reagents in Michael reactions they act as a-hydrogen donors. Nitroalkanes react easily with typical Michael acceptors such as a,p-unsaturated aldehydes or ketones under base or Lewis acid catalysis. ... [Pg.262]

With 41 in hand, a two-step nitro reduction and protection, followed by partial reduction of the lactam and resulting cyclization furnished aminal 42. Further treatment with cyanogen azide generated Wcyanoamidine 43. Hydrolysis and amide protection followed by alkylation with allyl iodide yielded olefin 44 as a single diastereomer. Conversion of 44 to aldehyde 45 was the followed reaction of the mesylate with azide, a cross-aldol reaction with acetone, lactam reprotection with Boc, and trimethylphosphine-mediated reductive rearrangement to provide spiro-y-lactam 46. Methyllithium addition to lactam 46 and similar chemistry as reported by Qin et al. gave communesin F (17) (Scheme 6). [Pg.438]

In 2008 Brimble and coworkers examined the effect of a-substitution in proline-based catalysts for the asymmetric aldol addition of acetone to aromatic aldehydes. In the benchmark aldol reaction between acetone and p-nitro-benzaldehyde they observed a remarkable improvement of stereoselectivity using (5 )-a-methyl-tetrazole 9, albeit with longer reaction times caused by the a-geminal disubstitution. Surprisingly 7a afforded a completely racemic product (Scheme 11.7). Using 9 the scope of this reaction was extended efficiently to several other aromatic aldehydes with excellent enantioselectivities (enantiomeric excess — 70-91%). [Pg.267]

Recently, a detailed study on the use of unprotected hydroxy-prolines in several asymmetric organocatalytic transformations was reported by Al-Momani. In the benchmark aldol addition between acetone and p-nitro-benzaldehyde, ds-3-hydroxy-proline (ds-12) afforded the best enantio-selectivity, with excellent activity (Scheme 11.13A). On the other hand, in the analogous Mannich addition, cis-12 afforded the worst enantioselectivities, albeit maintaining good catalytic activities (Scheme 11.13B). [Pg.271]

Prior investigations on enantioselective aldol additions by Wennemers and coworkers in 2007 demonstrated the crucial relevance of the secondary amine at the N-terminus, the carboxylic acid in the side chain and a well-defined p-turn conformation of H-Pro-Pro-Asp-NH2-type proteins for the high catalytic activity and selectivity Thus, the employment of tripeptides comprising this motive was expanded to the 1,4-addition of aldehydes to nitro-olefins and nitroethylene (Scheme 13.12a) ° Peptide 15a comprising D-proline at the N-terminus showed the best catalytical performance for the addition of a series of aliphatic and aromatic aldehydes to aliphatic and aromatic nitro-olefins with good to excellent yields and excellent enantioselec-tivity The proposed transition states for both 15a and the above-mentioned parent peptide predicts the formation of the enantiomeric products. [Pg.320]

Portnoy and coworkers immobilized chiral hydroxyproline derivatives on polystyrene support functionalized with polyether dendrons (Scheme 15.45).These catalysts promoted the aldol addition of acetone to aromatic aldehydes with excellent enantioselec-tivities, significantly superior to those achieved in the same reaction with analogous catalyst lacking the dendritic interface. The same group prepared polymer-supported chiral bifunctional aminocarbamate and aminourea catalysts for nitro-Michael reaction (Scheme 15.46). However, in this case the dendritic catalysts were inferior to their simpler dendron-lacking analogues. [Pg.477]

Kitazume and coworkers used microreactors with microchaimels 100 pm wide and 40 pm deep for the synthesis of a series of organofluorine compounds [19,20]. The silylation of4,4,4-trifluorobutan-2-one and the Mukaiyama-type aldol reaction of the resulting enol silyl ether with acetals gave good yields of the desired products [20]. They also described nitro-aldol reactions of 2,2-difluoro-l-ethoxyethanol and Michael additions of nitroalkanes to ethyl 4,4,4-trifluorocrotonate and ethyl 4,4-difluorocrotonate [19,20]. Reactions were carried out at room temperature, and... [Pg.107]

TBDMSCl-Assisted Reactions. Nitro aldol (Henry) reactions have been reported to be promoted by TBDMSCl. To a THF solution of tetra-n-butylammonium fluoride is added sequentially equimolar amounts of the nitro compound, aldehyde, and EtsN, followed by an excess of TBDMSCl (eq 11). Substitution of TMSCl for TBDMSCl reduces the yield of nitro aldol product. The authors speculate that TBDMSCl is responsible for activation of the aldehyde while n-Bu4NF activates the nitro compound. In a related method, primary and secondary nitro alkanes were treated with LDA in THF followed by addition of TBDMSCl to give the corresponding silyl nitronates. The silyl nitronates reacted with a variety of aliphatic and aromatic aldehydes which gave vicinal nitro TBDMS aldol products. ... [Pg.112]

The second most important synthetic application of silyl nitronates in C-C bond-forming reactions is their fluoride-mediated addition to aldehydes. Silyl nitronates from secondary nitroalkanes lead to free nitro aldols such as (4), while those from primary nitro alkanes give silylated products. In contrast to the classical Henry reaction, the silyl variant is highly diastereose-lective with aldehydes, furnishing e yfAro-0-silylated nitro aldols (e.g. 5). It is important that the reaction temperature does not rise above 0 °C, otherwise threo/erythro equilibration takes place. The same erythro-nitio aldol derivatives are available by diastere-oselective protonation of silyloxy nitronates (eq 3) (usually the dr is >20 1), while the nonsilylated fAreo-epimers (R = H, dr = 7 3-20 1) are formed by kinetic protonation of lithioxy lithio nitronates in THF/DMPU (eq 4). Other recent modifications of the nitroaldol addition using titanium nitronates or ClSiRs in situ are less selective. It should also be mentioned that there are recent reports about the enantioselective addition of nitromethane to aldehydes in the presence of rare earth binaphthol complexes. [Pg.654]

The Henry reaction is a base-catalyzed C-C bond-forming reaction between nitroalkanes and aldehydes or ketones. It is similar to the aldol addition, and is also referred to as the nitroaldol reaction. Since its discovery in 1895 [1] the Henry reaction has become one of the most useful reactions for the formation of C-C bonds, and most particularly for the synthesis of P-nitroalcohol derivatives [2]. The general features of this reaction are (i) the potential offered by the nitro and hydroxyl groups on the products for transformation into other compound families such as P-amino alcohols, P-amino acids, or nitroalkenes (ii) only a catalytic amount of base is required (iii) up to two contiguous stereogenic centers may be created in a single step concomitantly to the C-C bond formation. Several recent reviews with a focus on the asymmetric Henry reaction and its applications have appeared [3j. [Pg.841]

The enantioselective Henry reaction with ketones is challenging, owing to the attenuated reactivity of the ketone carbonyl group compared to the aldehyde carbonyl moiety and the high tendency of tertiary nitro-aldol adducts to undergo a retro-addition reaction under basic conditions [15], Stereoselective construction of... [Pg.846]

The addition reaction of enolates and enols with carbonyl compounds is of broad scope and of great synthetic importance. Essentially all of the stabilized carbanions mentioned in Section 1.1 are capable of adding to carbonyl groups, in what is known as the generalized aldol reaction. Enolates of aldehydes, ketones, esters, and amides, the carbanions of nitriles and nitro compounds, as well as phosphoms- and sulfur-stabilized carbanions and ylides undergo this reaction. In the next section we emphasize the fundamental regiochemical and stereochemical aspects of the reactions of ketones and aldehydes. [Pg.65]

Nitration of furfuryl alcohol (2-furylmethanol) in acetic anhydride yields the nitro-nitrate 57 which possesses both a reactive methylene group able to undergo aldol reactions, etc., and also a nitrate ion leaving group for nucleophilic substitutions.137 Detailed studies of the nitration disclose various products resulting from the addition of one or even two acetic acid residues to the furan nucleus in competition with the nitrations.138,139... [Pg.193]


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