Nitriles Diels-Alder reactions

Fluorinated heterodienophiles and heterodienes Diels-Alder reactions in which the dienophiles have perfluoroalkyl-substituted multiple bonds between carbon and a heteroatom are quite common Reported earlier were reactions of perfluoroketones, thiones, ketimines, thioesters, nitroso compounds, and nitriles [9] Examples of a-fluoroimines [107], co-hydroperfluorothioaldehydes [108], perfluorosulfines [109, IIO], and selenocarbonyidifluoride [III] (equations 89-92) have been reported recently... 

One of the features of Diels-Alder reactions with most alkyl and aryl nitriles that has made them rather unattractive as dienophiles is the requirement of very high reaction temperatures Again, only when electron-withdrawing substituents are directly bonded to the nitnle function do [4+2] cycloaddition reactions occur at reasonably low temperatures [ 48, 231, 232] A high yield [4+2] cycloaddition was observed on reaction of 4,4-bis(trifluoromethyl) 1 thia-3-aza-l,3-butadienes with trifluoroacetonitrile at 150 °C [225]... 

The cycloadducts formed from the Diels-Alder reaction of 3-amino-5-chloro-2(17/)-pyrazinones with methyl acrylate in toluene are subject to two alternative modes of ring transformation yielding either methyl 6-cyano-l,2-dihydro-2-oxo-4-pyridinecarboxylates or the corresponding 3-amino-6-cyano-l,2,5,6-tetrahydro-2-oxo-4-pyridinecarboxylates. From the latter compounds, 3-amino-2-pyridones can be generated through subsequent loss of HCN <96 JOC(61)304>. Synthesis of 3-spirocyclopropane-4-pyridone and furo[2,3-c]pyridine derivatives can be achieved by the thermal rearrangement of nitrone and nitrile oxide cycloadducts of bicyclopropylidene <96JCX (61)1665>. 

Many other examples of synthetic equivalent groups have been developed. For example, in Chapter 6 we discussed the use of diene and dienophiles with masked functionality in the Diels-Alder reaction. It should be recognized that there is no absolute difference between what is termed a reagent and a synthetic equivalent group. For example, we think of potassium cyanide as a reagent, but the cyanide ion is a nucleophilic equivalent of a carboxy group. This reactivity is evident in the classical preparation of carboxylic acids from alkyl halides via nitrile intermediates. 

Nitro compounds have been converted into various cyclic compounds via cycloaddition reactions. In particular, nitroalkenes have proved to be useful in Diels-Alder reactions. Under thermal conditions, they behave as electron-deficient alkenes and react with dienes to yield 3-nitrocy-clohexenes. Nitroalkenes can also act as heterodienes and react with olefins in the presence of Lewis acids to yield cyclic alkyl nitronates, which undergo [3+2] cycloaddition. Nitro compounds are precursors for nitrile oxides, alkyl nitronates, and trialkylsilyl nitronates, which undergo [3+2]cycloaddition reactions. Thus, nitro compounds play important roles in the chemistry of cycloaddition reactions. In this chapter, recent developments of cycloaddition chemistry of nitro compounds and their derivatives are summarized. 

Alkyl and silyl nitronates are, in principle, /V-alkoxy and /V-silyloxynitrones, and they can react with alkenes in 1,3-dipolar cycloadditions to form /V-alkoxy- or /V-silyloxyisoxaz.olidine (see Scheme 8.25). The alkoxy and silyloxy groups can be eliminated from the adduct on heating or by acid treatment to form 2-isoxazolines. It should be noticed that isoxazolines are also obtained by the reaction of nitrile oxides with alkenes thus, nitronates can be considered as synthetic equivalents of nitrile oxides. Since the pioneering work by Torssell et al. on the development of silyl nitronates, this type of reaction has become a useful synthetic tool. Recent development for generation of cyclic nitronates by hetero Diels-Alder reactions of nitroalkenes is discussed in Section 8.3. 

Dipolar addition is closely related to the Diels-Alder reaction, but allows the formation of five-membered adducts, including cyclopentane derivatives. Like Diels-Alder reactions, 1,3-dipolar cycloaddition involves [4+2] concerted reaction of a 1,3-dipolar species (the An component and a dipolar In component). Very often, condensation of chiral acrylates with nitrile oxides or nitrones gives only modest diastereoselectivity.82 1,3-Dipolar cycloaddition between nitrones and alkenes is most useful and convenient for the preparation of iso-xazolidine derivatives, which can then be readily converted to 1,3-amino alcohol equivalents under mild conditions.83 The low selectivity of the 1,3-dipolar reaction can be overcome to some extent by introducing a chiral auxiliary to the substrate. As shown in Scheme 5-51, the reaction of 169 with acryloyl chloride connects the chiral sultam to the acrylic acid substrate, and subsequent cycloaddition yields product 170 with a diastereoselectivity of 90 10.84... 

Acyl nitroso compounds react with 1, 3-dienes as N-O heterodienophiles to produce cycloadducts, which have found use in the total synthesis of a number of nitrogen-containing natural products [21]. The cycloadducts of acyl nitroso compounds and 9,10-dimethylanthracene (4, Scheme 7.3) undergo thermal decomposition through retro-Diels-Alder reactions to produce acyl nitroso compounds under non-oxidative conditions and at relatively mild temperatures (40-100°C) [11-14]. Decomposition of these compounds provides a particularly clean method for the formation of acyl nitroso compounds. Photolysis or thermolysis of 3, 5-diphenyl-l, 2, 4-oxadiazole-4-oxide (5) generates the aromatic acyl nitroso compound (6) and ben-zonitrile (Scheme 7.3) [22, 23]. Other reactions that generate acyl nitroso compounds include the treatment of 5 with a nitrile oxide [24], the addition of N-methyl morpholine N-oxide to nitrile oxides and the decomposition of N, O-diacylated or alkylated N-hydroxyarylsulfonamides [25-29]. 

Another method to prepare allenyl ketones uses flash vacuum pyrolysis of the heterocycles 121 (Scheme 7.19) [163], This elimination of carbon monoxide is at least formally a cheletropic reaction. Highly reactive allenes such as esters and nitriles of type 124 or unsubstituted butadienal can be generated if retro-Diels-Alder reaction of 123 or similar precursors, respectively, is performed by flash vacuum pyrolysis [164]. 

Diazo transfer to 1 followed by irradiation in the presence of bis-(trimethylsilyl)amide led to ring contraction with concomitant carbonyl extrusion, to give 7. Dehydration to the nitrile followed selenation then set the stage for a highly diastereoselective ytterbium-catalyzed Diels-Alder reaction, to give, after reduction and protection, the pentacyclic intermediate 2. 

This and other similar cycloadditions, however, when unactivated hydrocarbons without heteroatom substituents participate in Diels-Alder reaction, are rarely efficient, requiring forcing conditions (high temperature, high pressure, prolonged reaction time) and giving the addition product in low yield. Diels-Alder reactions work well if electron-poor dienophiles (a, p-un saturated carbonyl compounds, esters, nitriles, nitro compounds, etc.) react with electron-rich dienes. For example, compared to the reaction in Eq. (6.86), 1,3-butadiene reacts with acrolein at 100°C to give formy 1-3-cyclohexene in 100% yield. 

Several types of 1,2-oxazines undergo thermal pericyclic reactions in which the N—O bond is cleaved. Thus (506, R = Me, Ph) undergo a thermal retro Diels-Alder reaction on heating to give the corresponding nitrile and o-benzoquinone methide, which can be intercepted by alkenes (Scheme 56) (90JA5341, 94TL7273). 

The expected adduct (430) from the Diels-Alder reaction of the oxazole (429) with diphenylcyclopropenone could not be isolated (Scheme 145) (70JCS(C)552). Instead the pyran-4-one (431) is obtained, resulting from elimination of acetonitrile. This process is essentially irreversible because the pyranone lacks diene properties and nitriles are poor dienophiles. 

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