Transformations into Other Heterocyclic Systems

A related transformation is the reaction of carbanion 283 with methyl ether 21a to afford, after hydrolysis, 4-pyrone 284 [84JCS(P1) 1035]. 

The previously mentioned reaction of 1 with salicylaldehyde to yield pyrones 171 through 173 (86JHC1511 87T2381) can be included in this section, the overall transformation being of the type C2/O—C—C—C/ C3. This sort of process is not uncommon, and similar cases have been described in the patent literature (87EGP252188, 87EGP252604). 

Treatment of dehydroacetic acid (2) with ammonia or primary amines affords 2,6-dimethyI-4-pyridones 291 [I885CB452 7IT258I 78JCS(P1)1373 88ACS(B)373]. This reaction, of the C3—C/N/C6 type, has been extensively studied, and intermediates 289 and 290 (R = Me) have been isolated and identified (63CJCI435, 63JOCI886). 

Interesting versions of this reaction occur with hydrazine and with N-amino heterocycles. Thus, reactions of 2 with N-amino-I,2,4-triazole, hydrazine, and 2V-aminopyridinium salts produce compounds 292 and 293 [77JCS(PI)I428] and 294 [77JCS(PI)327]. Similar examples have been reported [85JCS(PI)I209]. 

A different version of the C3—C/N/C6 transformation is exemplified by the conversion of 295 into 296 (72JOCI145 83MI4 88MI3), which occurs without decarboxylation. 

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Ortho-cyclization products can usually be isolated, while meta- and para-bridged cycloadducts are unstable and are often transformed into other heterocyclic systems. Their presence as intermediates can, however, often be rationalized by spectroscopic methods or 15N-labeling studies. 

It has been known for a considerable time that furan derivatives can be converted into a large number of different compounds. Only the reactions which have been carried out recently will be described in detail. The conversion of furan derivatives into other heterocyclic systems is usually expected when the labile oxygen system is transformed into a more stable heterocycle. 

Conversion of other heterocyclic systems into pyridazines has also been used, for example the reaction of 3-aminopyrone 9 with hydrazine, followed by oxidative aromatisation <06T9718> and the more unusual utilisation of a 1,2,4-triazole 10 as the source of the N-N unit <06T8966>. In this latter transformation, the intermediate quaternary salt 11 was isolable. An even more unusual example was the reaction of the diazetidine 12 with enolates <06S2885>. 

There are two important general types of reaction by which six-membered heterocycles containing two or more heteroatoms can be transformed into other six-membered heterocyclic systems, namely reactions which involve an ANRORC mechanism, and reactions which proceed by a Diels-Alder/retro-Diels-Alder type of mechanism. Transformation of 1,3-oxazinones and -thiazinones into pyrimidones (equations 193 and 194) has been extensively used, especially in the conversion of isatoic anhydride into quinazolinones (e.g. equation 195). 2,4-Diaryl-l,2,3,5-oxathiadiazines, which are readily accessible by reaction of sulfur trioxide with aryl isocyanates, are useful precursors to pyrimidines and 1,3,5-triazines (equation 196). 

The Raillard group at Affymax developed a multigram synthesis of a 2,5-diketopiperazine and other heterocyclic systems by employing a high-load Merri-field resin transformed into polymer-supported valine, which was used as the amino component in an Ugi-4CR to gave the target diketopiperazine 137 after cleavage of 136 from the resin [77] (Scheme 2.49). 

The generation from furoxans of other heterocyclic systems, some of which show useful biological activity (see Section 4.22.5), has been the subject of intensive investigation. The following subsections summarize the conversion of benzofuroxans into quinoxaline and benzimidazole oxides, the rearrangement of 4-substituted benzofuroxans, and the transformation of monocyclic furoxans into isoxazoles and isoxazolines, furazans, and pyrazolines. More detailed discussion is to be found in recent comprehensive reviews (75S415, 76H(4)767, 81AHC(29)251>. 

Monocyclic furoxans can be transformed into a variety of other heterocyclic systems, including isoxazolines, isoxazoles, pyrazolines and furazans. Much of the early literature dealing with these reactions has required substantial revision an up-to-date assessment is provided in a recent review <8lAHC(29)25i>, and there follows hereafter only a summary of the better-substantiated transformations. 

It is important to recall that the reactivity pattern of phosphoies is very different from that of the related S, N, and O ring systems due to their limited aromatic character. For example, electrophilic substitution takes place only with a handful of phosphoies that have been specifically tailored via increasing the bulkiness of the P substituent (see Section 3.15.10.4, Scheme 83). In fact, electrophiles react at the phosphoms atom affording a panel of neutral and cationic CN 4 derivatives (Scheme 8). Phosphoies are also versatile synthons for the preparation of other heterocyclic systems via Diels-Alder reactions. The cycloaddition can involve the dienic moiety of the phosphole ring or can occur following a 1,5-shift of the P-substituent (Scheme 8). Finally, phosphoies can be transformed into phospholide ions, which are powerful nucleophiles that have found a variety of applications (Scheme 8). All these facets of phosphole reactivity are presented in this section. It should also be noted that CN 3 phosphoies exhibit a rich coordination chemistry toward transition metals (see Section 3.15.12.2). 

The publications that appeared up to 1975 on the transformations of oxiranes into other heterocyclic compounds are reviewed in detail in the monograph by van der Plas and the relevant chapters of other reviews. Accordingly, we merely supplement the earlier data with more recently reported results and, at the same time, present some of the varied transformations of the oxiranes. The possibility of stereoselective synthesis of heterocyclic systems was broadened considerably by 1,3-dipolar cycloaddition reactions. Heterocycles are formed if the ylide intermediates produced from oxiranes in photolytically or thermally induced reactions are made to react intramolecularly or with external dipolarophiles. Reactions of these types will be treated in Sections IV.8 and IV.9. 

The transformation of the 1,2-dithiole ring into other heterocycles is described in other sections, e.g., formation of the 1,3-dithiole system by addition of alkenes in Section I1I,J by addition of alkynes in Section 1II,G and formation of the l,6,6a24-trithiapentalene in Section HI,I. 

Pyridazines have been prepared from a variety of other heterocyclic systems and in most cases these transformations were specific. The 3(S), 4(5) 36, a constituent of the antibiotic antitumor luzopeptin A, was prepared in a multistep synthesis from malonaldehyde dimethyl acetal in 32% overall yield. In the last step a highly regiospecific nucleophilic ring opening of the glycidic acid (oxirane derivative) took place (89JOC3260). In another example, c75,frani-l,3-cycloundecadiene was transformed in five steps in low yield into 59. In the last step the epoxide 58 was treated with excess of LDA (89TL4649). 

The transformation of oxiranes into other oxygen-containing heterocyclic systems (e.g., cyclic ethers, dioxolanes, orthoesters, lactones, and cyclic carbonates), via a variety of heterolytic, homolytic, enzymatic, and single-electron transfer processes, has been reviewed <2004RJ01227>. 

Methylthio)benzthiazole for example gives two products when irradiated in the presence of rraui-stilbene. This reaction was investigated by G. Kaupp and seems to proceed via two different biradical intermediates. Whereas one biradical leads to an azetane simply by radical recombination, the other rearranges to a seven-membered heterocycle. Thermolysis of the latter cycloadduct leads to an 1-azabutadiene which can be subsequently transformed into its geometrical isomer. This isomerization is reversible at another wavelength and thus constitute a simple photochromic system (see also Chapter 8). 

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