Diels-Alder reactions of azadienes

Synthetic aspects of diels-alder cycloadditions with heterodienophiles

The discovery of important roles of C-nitroso compounds in various biological metabolic processes has generated a renewed interest in the general chemical properties of nitrosoalkanes (R–N=O; R =alkyl) and nitrosoarenes (ArNO; Ar =aryl), two important subsets of this general class of compounds. For example, the identification of the nitrosobenzene adduct of hemoglobin as a product of nitrobenzene poisoning1,2 and the realization that some amine-containing drugs may be metabolized to nitroso derivatives3–6 led to an increased desire to study the fundamental biochemical properties of this fascinating class of C-nitroso compounds. To this end, many studies have been reported on the fundamental chemistry of C-nitroso compounds under conditions that either stabilize the C-nitroso functionality or enhance their reactivity toward isomerization or reactivity with substrates.

A major difficulty in C-nitroso chemistry, however, is that the high reactivity of these compounds necessarily imposes constraints upon the methods employed for their preparation, particularly with regard to the yield of the desired product. For example, the ease of oxidation of the desired nitroso compound (if oxidation of a suitable precursor is the chosen synthetic route) to its nitro derivative can significantly reduce the yield of the nitroso product. Similarly, the ease of isomerization of R2C(H)NO compounds to the corresponding oximes R2C=NOH can restrict the choice of solvent for the preparation of primary and secondary nitrosoalkanes. A further consideration to be borne in mind is the possibility of reaction of the C-nitroso compound with the starting material and/or preparative reagents. There is, however, a considerable variety of synthetic routes available for the high-yield preparations of C-nitroso compounds (monomers or dimers; Figure 1), some of which have been in regular use for well over 100 years.




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Figure 1



Some earlier reviews of this area have been published. Book chapters by Sandler and Karo (in 1986)7 and by Williams (in 1988)8 present the most detail to date on the experimental techniques for preparations of C-nitroso compounds. Other useful earlier reviews are those by Touster,9 Boyer,10 Metzger and Meier,11 Seidenfaden,12 and Katritzky et al.13

Given the renewed interest in the study of the biological and environmental consequences of C-nitroso compound formation, it is not surprising that many new and/or improved procedures for the preparations of these compounds have been developed over the last two decades. In this review, we present a comprehensive review of the synthetic procedures for the preparation of C-nitroso compounds and place these procedures in proper historical context. We also include a small number of routes to the production of C-nitroso compounds that may have preparative possibilities or which require improved workup methods. We indicate, when known, whether the method of preparation is applicable to all types of C-nitroso compounds or only to separate classes such as nitrosoarenes, nitrosoalkanes, nitrosohomocycles, or nitrosoheterocycles. Nitrosoalkenes are considered in a separate section. The coordination chemistry of C-nitroso compounds with metals has been reviewed recently.6,14

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Preparations of C-Nitroso Compounds

Chemistry of Six-Membered Cyclic Oxime Ethers. Application in the Synthesis of Bioactive Compounds

Diels–Alder reactions of heterodienophiles have been known for decades, but only recently has this methodology become widely accepted by the synthetic community. There is enormous diversity in the structural types of compounds which can act as heterodienophiles, and a wide array of heterocyclic adducts can be prepared via these [4 + 2] cycloadditions. It seems clear that hetero Diels–Alder reactions span a range of mechanism from concerted to stepwise ionic processes. In many instances, mechanistic information is totally lacking. The discussion below therefore classifies heterodienophiles by structural rather than mechanistic class. Only the major types of synthetically useful heterodienophiles have been included. Moreover, the significant regio- and stereo-chemical features of the reactions have been exemplified as much as possible using recently reported cases. Other more comprehensive and more specialized reviews1 should be consulted for older material and more obscure hetero Diels–Alder cycloadditions.

Heterodienophile Additions to Dienes

Some α- and β-halonitrosoalkenes 1 have been synthesized and characterized. The halogen atoms of the oxime precursors 2 can be substituted by alkoxy groups. Two kinds of cycloaddition reaction of 1 have been observed: (i) reaction of the NO group with dienes gives 3, 6-dihydrooxazine derivatives 6 which isomerise to epoxyepimines 7 in most cases of β-substituted nitrosoalkenes; (ii) if 4, 5-dihydrooxazines 22 are obtained, the cycloaddition of the nitrosoalkenes as 4π-component is presumed.

Heinz-Günther Viehe

Papers

Nitrosoalkenes: Synthesis and Reactivity

Nitrosoalkenes: synthesis and reactivity