Nitroalkanes synthesis

A synthesis ofstrigol using nitroalkanes Synthesis of mono-protected diketones Catalytic Methods The Stetter Reaction... 

Until recently there were few cases in which an alkali nitrite could replace silver nitrite in the synthesis of nitro compounds. Such a case was Kolbe s nitroalkane synthesis, in which an alkali salt of a 2-haloalkanoic acid was treated with a boiling aqueous solution of an alkali nitrite the 2-nitroalkanoic acid formed lost carbon dioxide under the reaction conditions and the nitroalkane distilled over in the steam. The Kolbe synthesis is, however, of practical use only for the preparation of nitromethane (38% yield from chloro-acetic acid648) and nitroethane (about 50% yield from 2-bromopropionic acid649) it is substantially valueless for higher fatty acids.649,650... 

The nitriles can also be directly reduced to di-astereomeric aldoses with PdO/BaSOa, by passing the lactone intermediate stage. Another reaction for the formation of monosaccharides is the nitroalkane synthesis. The epimeric nitro compounds, obtained by the reaction of an aldose with nitromethane as anions, are separated and converted to the corresponding aldoses by an acini-troalkane cleavage (A /-reaction) ... 

There exist a number of d -synthons, which are stabilized by the delocalization of the electron pair into orbitals of hetero atoms, although the nucleophilic centre remains at the carbon atom. From nitroalkanes anions may be formed in aqueous solutions (e.g. CHjNOj pK, = 10.2). Nitromethane and -ethane anions are particularly useful in synthesis. The cyanide anion is also a classical d -synthon (HCN pK = 9.1). 

Chemoselective C-alkylation of the highly acidic and enolic triacetic acid lactone 104 (pAl, = 4.94) and tetronic acid (pA, = 3.76) is possible by use of DBU[68]. No 0-alkylation takes place. The same compound 105 is obtained by the regioslective allylation of copper-protected methyl 3,5-dioxohexano-ate[69]. It is known that base-catalyzed alkylation of nitro compounds affords 0-alkylation products, and the smooth Pd-catalyzed C-allylation of nitroalkanes[38.39], nitroacetate[70], and phenylstilfonylnitromethane[71] is possible. Chemoselective C-allylation of nitroethane (106) or the nitroacetate 107 has been applied to the synthesis of the skeleton of the ergoline alkaloid 108[70]. 

Higher nitroalkanes are prepared from lower primary nitroalkanes by a one-pot synthesis (69). Successive condensations with aldehydes and acylating agents are followed by reduction with sodium borohydride. Overall conversions in the 75—80% range are reported. 

Hydroxylamine can be prepared by a variety of reactions involving the reduction of nitrites, nitric acid or NO, or by the acid hydrolysis of nitroalkanes. In the conventional Raschig synthesis, an aqueous solution of NH4NO2 is reduced with HS04 /S02 at 0° to give the hydroxylamido-A ,A -disulfate anion which is then hydrolysed stepwise to hydroxylammonium sulfate ... 

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. 

In 1985, in the course of their interest in nitroalkane chemistry, Barton and Zard reported the base-catalyzed reaction of nitroalkenes with a-isocyanoacetates leading to pyrrole esters having an ideal substitution pattern for the synthesis of porphyrins and bile... 

Because the anioas of nitroalkanes are stable, retro-acyladoc smoothly In the presence of a base catalyst. This type of reacdo organic synthesis." Nucleophilic attack of water or alcohol to ct-the ring cleavage v/ith the formadon of Oj-nitro acids and Oj-niti... 

Wade and coworkers have found that ct-nitro siilfones are useful reagents in organic synthesis because they are converted into nitroalkanes, nitnles, or carboxylic acids fsee Eq 5 52 ... 

Barton and co workers have explored the aryladon of various nucleophiles inclndmg nitroalkanes using bismuth reagents Reacdon of 2-nitropropane v/ith triphenylbismnth carbonate gives 2-nitro-2-phenylpropane in 80% yield Recently, this aryladon has been used for the synthesis of unusual amino acids Aryladon of ct-nitro esters v/ith triphenylbismnth dichloride followed by redncdon gives unique ct-amino acids fEq 5 68 ... 

TheNef reaction of primary nitro compounds gives iildehydes or carboxylic acids, depending on the reaction conditions. Each transformation provides an important tool in organic synthesis. Primary nitro compotmds are converted into carboxylic acids vrith concentrated mineriil acids. Because such harsh conditions iilso lead to side reactions, a milder method is required inorganic synthesis. Basic phosphate-buffered KMnO rapidly converts primary nitroalkanes into carboxylic acids in 90-99% yield fEq. 6.13. "... 

Although the base-catalyzed addition of nitroalkanes to electron-deficient olefins has been extensively used in organic synthesis fsee Michael addition Chapter 4, it is only recently that the reaction has been extended to the cyclopropanadon reaction. In 1978, it was reported that the anion of nitromethane reacts with certain highly electron-deficient olefins to produce cycloptopanesingoodyieldrEq. 7.36. More recently, this reaction has been extended to more general cyclopropanadons, as shown in Eqs. 7.37 and 7.38, in which potassittm salts of nitroalkanes are employed in DMSO as alkylidene transfer reagents." ... 

The Michael addition of nih oalkanes to alkenes substituted with two elecbon-withdrawing groups at the a- and 3-positions provides a new method for the preparation of functionalized alkenes. Although reactions are not new, Ballini and coworkers have used this sbategy in the synthesis of polyfunctionalized unsaturated carbonyl derivatives by Michael addition of nih oalkanes to enediones as shown in Eqs. 7.124-7.126. Success of this type of reaction depends on the base and solvent. They have found that DBU in acetonihile is the method of choice for this puipose. This base-solvent system has been used widely in Michael additions of nitroalkanes to elechon-deficient alkenes (see Section 4.3, which discusses the Michael addition). ... 

Very simple synthesis of ct-siibsdnited Y-methyl-y-lactones is also possible by olefinadon using nitroalkanes followed by reduedon, as shown in Eq. 7.128. ... 

The condensation of nitro compounds and imines, the so-called aza-Henry or nitro-Mannich reaction, has recently emerged as a powerful tool for the enantioselective synthesis of 1,2-diamines through the intermediate /3-amino nitro compounds. The method is based on the addition of a nitronate ion (a-nitro carbanion), generated from nitroalkanes, to an imine. The addition of a nitronate ion to an imine is thermodynamically disfavored, so that the presence of a protic species or a Lewis acid is required, to activate the imine and/or to quench the adduct. The acidic medium is compatible with the existence of the nitronate anion, as acetic acid and nitromethane have comparable acidities. Moreover, the products are often unstable, either for the reversibility of the addition or for the possible /3-elimination of the nitro group, and the crude products are generally reduced, avoiding purification to give the desired 1,2-diamines. Hence, the nitronate ion is an equivalent of an a-amino carbanion. 

As previously described, in basic conditions the proUne-derived a-sulfonyl amide 141 generates the imine function, which afterwards undergoes addition by a nucleophile, e.g., a nitronate ion see the diastereoselective synthesis of the diamino nitroalkane derivative 172, which is the precursor of the piperazine-2-carboxyUc acid 173, through a Nef reaction [45]. Similarly, the addition of the Uthium enolate of ethyl acetateto the a-sulfonyl amide 174 gave the diamino ester derivative 175, wich was then converted to (-)-l-aminopyrrolizidine 176 (Scheme 27). 

Jorgensen et al. [84] studied how solvent effects could influence the course of Diels-Alder reactions catalyzed by copper(II)-bisoxazoline. They assumed that the use of polar solvents (generally nitroalkanes) improved the activity and selectivity of the cationic copper-Lewis acid used in the hetero Diels-Alder reaction of alkylglyoxylates with dienes (Scheme 31, reaction 1). The explanation, close to that given by Evans regarding the crucial role of the counterion, is a stabilization of the dissociated ion, leading to a more defined complex conformation. They also used this reaction for the synthesis of a precursor for highly valuable sesquiterpene lactones with an enantiomeric excess superior to 99%. 

In practice, the condensation of nitroalkane (60) and aldehyde (59) gives nitro lactone (57) directly. Synthesis ... 

The earliest reported Fxs were the result of the reaction of nitrous acid with naturally occurring alkenes being the identified intermediate a a-nitrooxime that suffers dehydration with cyclization. Apart from these conditions, the most recent Fxs synthesis descriptions have involved reactions between alkenes and dinitrogen trioxide (Fig. 3), nitroalkanes and aluminum trichlo-... 

The reaction of alkyl halides with metal nitrites is one of the most important methods for the preparation of nitroalkanes. As a metal nitrite, silver nitrite (Victor-Meyer reaction), potassium nitrite, or sodium nitrite (Kornblum reaction) have been frequently used. The products are usually a mixture of nitroalkanes and alkyl nitrites, which are readily separated by distillation (Eq. 2.47). The synthesis of nitro compounds by this process is well documented in the reviews, and some typical cases are listed in Table 2.3.92a Primary and secondary alkyl iodides and bromides as well as sulfonate esters give the corresponding nitro compounds in 50-70% yields on treatment with NaN02 in DMF or DMSO. Some of them are described precisely in vol 4 of Organic Synthesis. For example, 1,4-dinitrobutane is prepared in 41 -46% yield by the reaction of 1,4-diiodobutane with silver nitrite in diethyl ether.92b 1-Nitrooctane is prepared by the reaction with silver nitrite in 75-80% yield. The reaction of silver nitrite with secondary halides gives yields of nitroalkanes of about 15%, whereas with tertiary halides the yields are 0-5%.92c Ethyl a-nitrobutyrate is prepared by the reaction of ethyl a-bromobutyrate in 68-75% yield with sodium nitrite in DMF.92d Sodium nitrite is considerably more soluble in DMSO than in DMF as a consequence, with DMSO, much more concentrated solutions can be employed and this makes shorter reaction times possible.926... 

Table 2.3 Synthesis of nitroalkanes from alkyl halides...

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