A-Nitro-esters

One effective method for synthesis of tryptophan derivatives involves alkylation of formamido- or acetamido- malonate diesters by gramine[l,2]. Conversion to tryptophans is completed by hydrolysis and decarboxylation. These reactions were discussed in Chapter 12. An enolate of an a-nitro ester is an alternative nucleophile. The products can be converted to tryptophans by rcduction[3,4],... 

The toluene solution from the previous step was treated with an ethanol solution of NaOEt (0.1 mol in 100 ml) at O C. When about a quarter of the solution had been added a thick precipitate formed and ether (100 ml) was added to maintain a fluid slurry. The remainder of the NaOEt was added and the slurry was stirred overnight. The solid was collected and w ashed with ether. It was then mixed with ether (200 ml) and 2NHC1 (75 ml) and shaken in a separatory funnel until the solid dissolved. The ether layer was washed with 2NHHC1 (2 X 50ml) and water and dried over MgS04. The solution was decolorized with Magnesol and evaporated to give the a-nitro ester as a red oil. 

Perhaps the most reliable method for the reductive cyclization of a nitro ester to a hydroxamic acid is that which involves treatment with sodium horohydride in the presence of palladium on charcoal. Although under these conditions aromatic nitro compounds are reduced to amines, o-nitro esters such as 53, in which the ester group is suitably oriented with respect to the nitro group, give good yields of cyclic hydroxamic acids (54). Coutts and his co-... 

PclCOi-cdidlyzed subsdnidoa reacdoa, a aovel, mild reducdoa of a-nitro ester to an amino acid ester withTiCU, and an improved procedure for nracil ring formadon. 

Thus, the reaction of alkyl halides and a-halo esters with sodium nitrite provides a very useful synthetic method for nitroalkanes and a-nitro esters. However, ethyl bromoacetate is exceptional in that it fails to give ethyl nitroacetate on treatment with sodium nitrite.93 This is due to the acidic hydrogen of the ethyl nitroacetate, which undergoes a further reaction with sodium nitrite to give the oxidized products (see Section 6.1, which discusses the Nef reaction). In a similar way, the reaction of benzyl bromide with sodium nitrite at 25 °C gives benzoic acid predominantly. To get phenylnitromethane, the reaction must be carried out at low temperature (-16 °C) (Eq. 2.48).93... 

Ytterbium triflate is an extremely effective catalyst for the Michael addition of a-nitro esters to enones in water (Eq. 4.110).149... 

The carboxylation of nitroalkanes with magnesium methyl carbonate followed by esterification gives a-nitro esters in 40-58% yield.14 Magnesium methyl carbonate is prepared by the saturation of a magnesium methoxide suspension in DMF with C02. More elegantly, sodium salt of nitroalkanes can he carboxylated by means of 1 -ethoxycarbonylbenzotriazole to give a-nitro esters in 55-80% yield (Eq. 5.7).15 Nitroacetic acids and its esters can serve as useful... 

The acylation of the carbanions derived from nitroalkanes with acyl imidazoles or alkoxy-carbonylimidazoles takes place at the carbon atom to yield a-nitro ketones or a-nitro esters, respectively (Eq. 5.10).21 The lithium salts of nitroalkanes were isolated and used in THF or DMSO in the original procedure. Later, potassium salts generated in situ on treatment with r-BuOK in DMSO are reactive enough to give a-nitro ketones in good yield (Eq. 5.11).22... 

Geminal dinitro compounds 45 a-nitro sulfones 46 a-nitro esters,47 or a-nitro nitriles48 react with anions derived from nitroalkanes to give the S l products, as shown in Eqs. 5.28, 5.29, 5.30 and 5.31, respectively (Section 7.1). 

The monoanions of primary nitroalkanes, phenylnitromethane, and a-nitro esters are all preferentially C-alkylated by cinnamyl acetate and 2-butenyl acetate in 50-89% yield in the presence of Pd catalyst (Eq. 5.51).75 The a-nitro ester gives the C-alkylate in 89% yield, but 2-nitropropane gives the C-alkylate in only 29% yield. The main product is cinnamaldehyde, which is derived from 0-alkylation.75a... 

Allylic carbonates are better electrophiles than allylic acetates for the palladium-catalyzed allylic alkylation.77 Reaction of Eq. 5.54 shows the selective allylic alkylation of a-nitro ester with allylic carbonates without affecting allylic acetates.78... 

Enantioselective allylations of a-nitro ketones and a-nitro esters with allyl acetates are carried out in the presence of 2 equiv of alkali metal fluorides (KF, RbF, CsF) and 1 mol% palladium catalysts prepared in situ from Pd2(dba)3-CHC13 and chiral phosphine ligands. Moderate enantio-selectivity (ca 50% ee) is reported for allylation of cx-nitroketones (Eq. 5.60). The highest selectivity (80% ee) is observed for allylation of the reaction of tert-butyl ester (Eq. 5.61).93... 

Barton and coworkers have explored the arylation of various nucleophiles including nitroalkanes using bismuth reagents.105 Reaction of 2-nitropropane with triphenylbismuth carbonate gives 2-nitro-2-phenylpropane in 80% yield.106 Recently, this arylation has been used for the synthesis of unusual amino acids. Arylation of a-nitro esters with triphenylbismuth dichloride followed by reduction gives unique a-amino acids (Eq. 5.68).107... 

Hydrogen gas can be replaced by ammonium formate for the reduction of nitro compounds to amines. The ammonium formate method is efficient, and the rapid workup procedure by simple filtration makes it widely used for converting the N02 to the NH2.96 For example, a-nitro esters are reduced to cx-amino esters in excellent yields on treatment with HC02NH4 and Pd/C in methanol.96... 

In 1970, a new reaction, the displacement of a nitro group from a-nitro esters, a-nitro nitriles, a-nitro ketones, and a,a-dinitro compounds by nitroalkane salts, was described.3 These displacements, which are exemplified by the reaction presented in Eq. 7.1, take place at room temperature and give excellent yields of pure products. The reaction proceeds via a radical chain mechanism involving one electron-transfer processes as shown in Scheme 7.1 the details of the mechanism are described in a review.1... 

The reaction was carried out with /3-keto esters, /3-diketones, malonate, a-formyl ketones, a-cyano and a-nitro esters, cyanoacetamide, and phen-ylsulfonylacetate. (PPh3)2PdCl2 was used with sodium phenoxide. Also, Pd(OAc)2 and PPh3 are good catalysts. When bidentate ligand was used, the 1 1 rather than 1 2 addition reaction took place (56). For example, bis(diphenylphosphino) 1,2-ethane (39) produced a mixture of the following 1,4- (59) and 1,2- (60) addition products ... 

Iron and acetic or dilute hydrochloric acid can be safely used for the reduction of nitro group to an amino group in nitro esters. The problem arises when a nitro ester is to be reduced to a nitro alcohol. Nitro groups are not inert toward the best reagents for the reduction of esters to alcohols, complex hydrides. However the rate of reduction of a nitro group by lithium... 

Active methylene or methine compounds, to which two EWGs such as carbonyl, alkoxycarbonyl. formyl, cyano. nitro, and sulfonyl groups are attached, react with butadiene smoothly and their acidic hydrogens are displaced with the 2,7-octadienyl group to give mono- and disubstituted compounds[59], 3-Substituted 1,7-octadienes are obtained as minor products. The reaction is carried out with a /3-keto ester, /3-diketone, malonate, a-formyl ketones, a-cyano and a-nitro esters, cyanoacetamide, and phenylsulfonylacetate. Di(octadienyl)malonate (61) obtained by this reaction is converted into an... 

Chiral crown ether phosphine-palladium complexes have been used to catalyse the alkylation of carbanions derived from a-nitro ketones and a-nitro esters,63 and proline rubidium salts have been used to catalyse asymmetric Michael addition of nitroalkanes to prochiral acceptors 64 80% enantioselectivity can be achieved in each case. 

Substituted isoxazoline A -oxides 52 were synthesised by condensation of a-nitro-esters 51 and aldehydes catalysed by zinc complexes of amino acids. In DMSO the selectivity of the reaction was high and products 52 were obtained as single trans diastereomers in 77-88% yields <02TL5287>. 

Rare earth metal-catalyzed Michael additions of a-nitro esters or y9-keto esters with af-nn-saturated carbonyl compounds were investigated by Feringa and co-workers [7]. According to these authors, the use of Yb(OTf)3 enables addition products 5 to be isolated in higher yields and greater purities than those obtained in organic solvents (Scheme 1). 

The same method can he used to convert a-nitro esters into a-methylene esters, except that the hydroxymethylation step is catalyzed with sodium hydroxide rather than triphen-ylphosphine. 

Feringa et al. developed aqueous Michael reactions catalyzed by Yb(OTf)3 (Eq. 1) [4]. fi-keto esters and a-nitro esters could be used as Michael donors for the reaction. a,y3-Unsaturated ketones and a,/5-unsaturated aldehydes without /S-substituents were good Michael acceptors for the reaction but the reaction did not proceed with ethyl acrylate or acrylonitrile. The reported yields were excellent, though the reaction required prolonged reaction time (3-5 days). 

The reagent is useful also for the nitration of active-methylene compounds in the form of the sodio derivatives this is the basis for a general synthesis of a-nitro esters. ... 

Stereoselective a-fluorination of a-nitro esters 107 was performed using Selectfluor as a fluorinating agent and cinchona alkaloid catalyst 109 by Togni and coworkers (Scheme 6.32) [60]. Under the basic condition (NaH inTHFat —40 °C) were obtained the a-fluorinated products 99 in high yield (up to 91%) with relatively low enantios-electivities (up to 31%). 

However, during the addition of -keto esters onto enals, ytterbium triflate proved to be an efficient catalyst [171] as in the Michael additions of a-nitro esters [172]. Several water-soluble phosphines gave the corresponding phos-phonium salts in good yields when added to a,j9-unsaturated acids [173] or activated alkynes [174]. With alkynes, vinyl phosphine oxides or alkenes were formed depending on the pH of the aqueous solution. Significantly, the reaction of nitroalkanes with buten-2-one is considerably accelerated when going from... 

Let us assume that the nitro ester (I.I) is to be converted into a novel tricyclic compound (1.2). No useful references are to be found in Chapter 72 (carboxylic acid or its derivative and nitro) because the nitro group has to be reduced before this kind of cyclization can occur. Chapter 48, which includes cyclization of amino esters, is more promising and Section II. I (p. 228) offers at least one example of the direct conversion of a nitro ester into a pyridin-2-one ring the conditions given [821] are also likely to be applicable to the synthesis of triazine (1.2). 

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