Primary nitroalkane

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. 

Trialkylisoxazoles have been prepared by the condensation of primary nitroalkanes under the influence of basic reagents (40JA2604). They can also be obtained from the reaction of a 1,3-diketone RCOCHRCOR with hydroxylamine hydrochloride <62HC(17)l, p. 54). 

Nitronates derived from primary nitroalkanes can be regarded as a synthetic equivalent of nitrile oxides since the elimination of an alcohol molecule from nitronates adds one higher oxidation level leading to nitrile oxides. This direct / -elimination of nitronates is known to be facilitated in the presence of a Lewis acid or a base catalyst [66, 72, 73]. On the other hand, cycloaddition reactions of nitronates to alkene dipolarophiles produce N-alkoxy-substituted isoxazolidines as cycloadducts. Under acid-catalyzed conditions, these isoxazolidines can be transformed into 2-isoxazolines through a ready / -elimination, and 2-isoxazolines correspond to the cycloadducts of nitrile oxide cycloadditions to alkenes [74]. 

Method G Highruiri-selecdvity is also observed in the fluoride-catalyzed reacdonof silyl nitronates v/ith aldehydes. Trialkyl silyl nitronates are prepared in good yield from primary nitroalkanes by consecndve treatment v/ith iithiiim dusopropylamide and trialkylsilyl chloride at -78 C in THF. 

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. "... 

Silylnitronates 1 are prepared14-24,25 by metalation of primary nitroalkanes with lithium diisopropylamide and treatment of the lithionitronates with either chlorotrimethylsilane or (/er/-butyldimethyl)chlorosilane. Nonaqueous workup and distillation gives the silylnitronates in >75% yield as moisture sensitive, but thermally stable, products. (e/7-Butyldimethylsilylni-tronates are more stable than the corresponding trimethylsilyl compounds. 

Secondary nitroalkanes also give silylnitronates, however, in decreased yields (30 40%)24. Due to their lower stability compared to silylnitronates derived from primary nitroalkanes. they arc prepared as tm-butyldirnethylsilyl derivatives. 

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 photochemical cyclisation of p.y-unsaturated ketoximes to 2-isoxazolines, e.g., 16—>17, has been reported <95RTC514>. 2-Isoxazolines are obtained from alkenes and primary nitroalkanes in the presence of ammonium cerium nitrate and formic acid <95MI399>. Treatment of certain 1,3-diketones with a nitrating mixture generates acyl nitrile oxides, which can be trapped in situ as dipolar cycloadducts (see Scheme 3) <96SC3401>. 

Conway, C.C., Nie, G., Huesain, N.S. and Fiala, E.S. (1991). Comparison of otddative damage to rat liver DNA and RNA by primary nitroalkanes, secondary nitroalkanes, cyclo-pentanone oxime and related compounds. Cancer Res. 51, 3143-3147. 

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... 

Generation of nitrile oxides by the Mukaiyama procedure, viz., dehydration of primary nitroalkanes with an aryl isocyanate, usually in the presence of Et3N as a base, is of high importance in nitrile oxide chemistry. Besides comprehensive monographs (4, 5), some data concerning the procedure and its use in organic synthesis can be found in References 61 and 62. 

Dehydration of primary nitroalkanes results in unstable nitrile oxides and, therefore, is limited by in situ transformation of the latter, for the preparation of various stable products, mainly those of 1,3-dipolar cycloaddition (Scheme 1.4). 

Highly efficient modifications of Mukaiyama s procedure, convenient for combinatorial syntheses, were reported recently, namely the polymer-supported synthesis of isoxazolines via nitrile oxides, starting from primary nitroalkanes, in a one-pot process (75) and by microwave activation of the process (73). 

Conjugate addition of RN02 to enones. Primary nitroalkanes and a, (3-enones when activated by alumina form conjugate addition products that are oxidized in situ by alkaline hydrogen peroxide to 1,4-diketones. A similar reaction of nitromethane with a vinyl ketone provides 1,4,7-triketones. 

Aliphatic and alicyclic ketones condense with primary nitroalkanes under the influence of A,A-dimethylethylenediamine to yield ally lie nitro compounds as mixtures of geometrical isomers, e.g. equation 125408. 

Nitroalkanes react with Jt-deficient alkenes, for example, p-nitro ketones are produced from a,P-unsaturated ketones [41], whereas allylic nitro compounds have been prepared via the Michael-type addition of nitroalkanes with electron-deficient alkynes (Table 6.19). The reaction in either dimethylsulphoxide [42] or dimethyl-formamide [43] is catalysed by potassium fluoride in the presence of benzyltriethyl-ammonium chloride the reaction with dimethyl acetylenedicarboxylate is only successful in dimethylsulphoxide [42], Primary nitroalkanes produce double Michael adducts [42,44], A-Protected a-aminoacetonitriles react with alkynes under catalysed solidiliquid conditions to produce the Michael adducts [45] which, upon treatment with aqueous copper(Il) sulphate, are converted into a,p-unsaturated ketones. 

Primary nitroalkane Secondary nitroalkane Tertiary nitroalkane... 

The tautomeric nitronic acids of secondary nitroalkanes or their nitronate salts react with nitrous acid or alkali metal nitrites to yield pseudonitroles.These pseudonitroles are often isolated as their colourless dimers (78b) but are deep blue in monomeric form (78a). Primary nitroalkanes also form pseudonitroles (80b) but these rapidly isomerise to the nitrolic acid (80a).Reactions are commonly conducted by slowly acidifying a mixture containing the nitronate salt and the metal nitrite, during which, the nitronic acid reacts with the nitrite anion. These reactions, first discovered by Meyer, have been used to prepare 2-nitroso-2-nitropropane (78a) and acetonitrolic acid (80a) from 2-nitropropane (76) and nitroethane (22) respectively. ... 

Electrophilic nitrations of aliphatic nitriles, carboxylic acids,carboxylic esters, ° and /3-diketones have been reported. The nitration of 2-alkyl-substituted indane-l,3-diones with nitric acid, followed by alkaline hydrolysis, is a standard laboratory route to primary nitroalkanes. ... 

Oxidative dimerization gives reasonable yields of vtc-dinitroalkanes for some substrates 2,3-dimethyl-2,3-dinitrobutane (48, 53 %) and 3,4-dimethyl-3,4-dinitrohexane (37 %) are obtained from 2-nitropropane (76) and 2-nitrobutane respectively.However, oxidative dimerization fails to convert 1,1-dinitroethane and trinitromethane into 2,2,3,3-tetranitrobutane and hexanitroethane respectively. Additionally, oxidative dimerisation is not a feasible route for the synthesis of v/c-dinitroalkanes from primary nitroalkanes. Although oxidative dimerization is limited in scope, and yields are often poor, the starting materials are usually inexpensive. 

Dinitromethane has two acidic protons and reacts with Michael acceptors to form bis-adducts. " Secondary nitroalkanes can only react with one equivalent of Michael acceptor. In the absence of steric effects primary nitroalkanes usually react with two equivalents of Michael acceptor to form bis-adducts. Depending on the reaction stoichiometry, 1,4-dinitrobutane can be reacted with methyl acrylate to form either the bis-adduct (129) or the tetra-adduct (130) in good yield. " ... 

Synthetic routes to a-nitroalkenes have been discussed in previous sections. General routes include (1) treating /3-nitroacetates with alkali metal acetates, carbonates or bicarbonates, (2) elimination of water from /3-nitroalcohols via heating with phthalic anhydride or in the presence of a base," ° and (3) degradation of the Mannich products derived from a primary nitroalkane, formaldehyde, and a secondary amine. ... 

Some 1,3-dinitroalkanes (145) have been synthesized from the reaction of nitroalkanes with a-nitroalkenes (144) generated in situ from the decomposition of Mannich bases (143) derived from primary nitroalkanes. Reported yields for these reactions are low and the formation of by-products limits the feasibility of the method. 

Reaction of 3-diazotriazoles with several primary and secondary mono-nitroalkanes, dinitro, and trinitroalkanes led to the azo derivatives 235 [69AJC2251 72KGS713]. In the case of primary nitroalkanes, the coupling products mainly exist in the hydrazo form 236. The coupUng reaction of a-halodicarbonyl compounds with 3-diazotriazole led to the corresponding halohydrazides 237 (80JHC209). 

The chemistry of nitro compounds forms the basis of a number of well-known processes, such as the Henry or the Nef reactions . Transformations such as the latter permit the interconversion between nitro and other functional groups and are therefore of prime importance. The most commonly employed methods for the reduction of primary nitroalkanes to oximes involve the use of BusSnH, Se/NaBH4, CS2 or SnCla (often in combination with thiophenol) . 

The second class of benzo-fused heterocycles accessible from benzofuroxans are benzimidazole oxides. In this case only one carbon from the co-reactant is incorporated in the product. With primary nitroalkanes 2-substituted l-hydroxybenzimidazole-3-oxides (46) are formed via displacement of nitrite, and / -sulfones behave similarly. The nitrile group of a-cyanoacetamides is likewise eliminated to alford 2-amide derivatives (46 R = CONRjX and the corresponding esters are formed in addition to the expected quinoxaline dioxides from acetoacetate esters. Under similar conditions secondary nitroalkyl compounds afford 2,2-disubstituted 2//-benzimidazole-1,3-dioxides (47). Benzimidazoles can also result from reaction of benzofuroxans with phosphorus ylides <86T3631>, nitrones (85H(23)1625>, and diazo compounds <75TL3577>. 

A more common method for the preparation of silyl nitronates is the use of trimethylsilyl chloride (TMSCl) in the presence of a base. With triethylamine, silyl nitronates are prepared from primary nitroalkanes in moderate yields however, it is necessary to conduct the silylation in acetonitrile for good yields with secondary nitroalkanes (18,101). In several cases, this silylation has been done in the presence of the dipolarophile for both inter- and intramolecular processes, or the nitronate has been used in subsequent reactions without purification (18,22). Employment of l,8-diazabicyclo(5.4.0)undec-7-ene (DBU) as the base allows this procedure to be general for most nitroalkanes (19). 

There are also several variations on this procedure. The use of trimethylsilyl triflate (TMSOTQ provides the silyl nitronate of methyl nitroacetate in good yield. However, for primary nitroalkanes, a second silylation occurs at the a-position of the nitronate (Eq. 2.5) (102). The use of TMSCl in the presence of lithium sulfide provides good yields of silyl nitronates from secondary nitroalkanes (103,104). Unfortunately, the number of examples is limited and this procedure is not applicable to primary nitroalkanes. 

The most widely used method for the dehydration of primary nitroalkanes involves their treatment with phenyl isocyanate and triethylamine, introduced in 1960 by Hoshino and Mukaiyama (7). A probable mechanism for the formation of the nitrile oxide is shown in Scheme 6.4. This method is known to be very effective for the preparation of aliphatic or aromatic nitrile oxides. In some cases, the separation of the byproduct A,A -diphenylurea from the reaction mixture may be troublesome. In order to circumvent this problem, 1,4-phenylene diisocyanate was introduced (82,83). The polymeric urea that is formed as a byproduct is largely insoluble in the reaction mixture and can easily be removed. 

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