1-Azadienes, cycloaddition reactions

The first microwave-assisted hetero-Diels-Alder cycloaddition reaction was described by Diaz-Ortiz and co-workers in 1998 between 2-azadiene 198 and the same electron-poor dienophiles as for the preparation of pyrazolo[3,4-b]pyridines 200 (Scheme 72) [127]. These dienes reacted with... 

It has been shown that cross-coupling reactions constitute a very mild method to introduce different alkyl and aryl groups to the most active C-3 position of the pyrazinone ring [26]. The broadly functionahzed 2-azadiene system of the title compounds was studied in cycloaddition reactions with various electron-reach and electron-poor dienophiles to provide highly substituted heterocycles [24]. 

The 2-azadiene system of the pyrazinone scaffold undergoes inter- and intramolecular cycloaddition reactions with a variety of (functionalized) alkenes forming bicyclic adducts, leading to the stereoselective generation of a variety of natural product analogues as well as peptidomimetics [58]. These bicyclic compounds could serve as key intermediates in the synthesis... 

For 4-nitrophenyl 2-azadiene 617, vigorous reaction conditions are necessary (110°C, sealed tube, 25h) and give bicyclic product 619. The formation of this compound could be explained by [4+2] cycloaddition reaction leading to 618 followed by dehydrogenation (Scheme 99) <1994T12375, 2003H(61)493>. 

Moody and coworkers have employed a biomimetic hetero-Diels-Alder-aroma-tization sequence for the construction of the 2,3-dithiazolepyridine core unit in amythiamicin D and related thiopeptide antibiotics (Scheme 6.243 a) [426]. The key cycloaddition reaction between the azadiene and enamine components was carried out by microwave irradiation at 120 °C for 12 h and gave the required 2,3,6-tris(thi-azolyl)pyridine intermediate in a moderate 33% yield. Coupling of the remaining building blocks then completed the first total synthesis of the thiopeptide antibiotic... 

TABLE 7.28 2-PYRIDONES FROM CYCLOADDITION REACTIONS OF SATURATED 5(4//)-OXAZOLONES WITH I-AZADIENES, 199... 

The other dihydropyridines containing electron-deficient 7r-systems should also be capable of undergoing cycloaddition reactions. However, the instability of these compounds and lack of general methods for their preparation have precluded their study. In principle both the 2,3- and 3,4-dihydropyridines could behave as heterodienes in the Diels-Alder reaction. Although these reactions are known for the 2-azadienes, lack of information in the literature on 1-azadienes suggests that they will be reluctant to participate in cycloadditions double bonds present in the 2,5-dihydropyridine are isolated and would only be expected to behave as two-electron partners in cycloaddition reactions. 

The ability of related acylhydrazones 94 (Scheme 24), derived from a,/3-unsaturated aldehydes, to participate in intramolecular Diels-Alder cycloaddition reactions has been proven to occur by Gilchrist and coworkers (91TL125). They reported that azadiene 94 (n = 1) cyclized to 95, whereas compound 94 (n = 0) did not undergo intramolecular cycload-... 

In sharp contrast to the development of the [4 + 2] cycloaddition reactions of electron-rich 2-azadienes, reports dealing with the chemistry of electron-poor 2-azadienes remained unknown until a few years ago. In fact, the first cycloaddition of an electron-withdrawing substituted 2-azadiene was observed in 1986 by Wulff and Bohnke [86AG(E)90] while they were preparing dehydroaminoacid derivatives (Scheme 48). They isolated AL(arylmethylene)dehydroalanine methyl esters 208 by dehydration of the Schiff base of the serine methyl ester 207 and found that it dimerized through a [4 + 2] cycloaddition to give tetrahydropyridine derivative 209 in 56% yield as a sole diasteroisomer. 

Studies focused on the ability of ALvinyl carbodiimides to undergo cycloaddition reactions have been carried out in recent years (Scheme 56). Thus, 2-azadiene derivatives 245 reacted with tetracyanoethylene to yield dihydropyridines 246 (86CL135), whereas treatment of 245 with... 

Phthalazines undergo [2 + 4] cycloaddition with enamines to give naphthalene derivatives. Pyrimidines also react as azadienes in reactions with enamines, e.g. (398 — 399). 

In a [4+2] cycloaddition reaction that proceeds via a Michael addition, an azadiene has been shown to react with Fischer carbenes yielding the 1,4-dihydropyridine after removal of the metal (Scheme 82) <1997TL3981>. Reactions of 1-azadienes with allenic esters yield the 1,4-dihydropyridine in excellent yield (Scheme 83) <20010L2133>. 

The cycloaddition reaction on the azadiene substrate is usually followed by elimination of nitrogen, hydrogen cyanide, water, amines, or other simple compounds and, as a result of this retrograde process, a new carbo- or heterocyclic system is formed (Scheme 67). The method provides a very convenient route to the synthesis of many not easily accessible compounds. In... 

Cycloaddition reactions with participation of azadienes are important in pyridine synthesis . Although a dihydropyridine is an intermediate, spontaneous conversion into a pyridine occurs when a suitable leaving group is present, e.g., 301 302 (Scheme 152) (the process can be accelerated by sonication) <1994T10047>. 

Nitro-3-phenylisoxazole-5-carboxylates (290) act as heterocyclic 1-azadiene components in [4 + 2] cycloaddition reaction with some enamines affording bicyclo derivatives 295 probably via a stepwise ionic cycloaddition involving the Michael adducts 292 as primary intermediates. Further intramolecular attack by the isoxazole nitrogen on the immonium carbon followed by elimination of the amine and aromatization of dihydropyridine 293 afforded 294, which was transformed into pyridine 295 by simple reduction164 (equation 63). 

The pyridine ring system has also been obtained via the [4 + 2] cycloaddition reaction between enamines and acyclic azadienes like a,/ -unsaturated carbodiimides165,166. In this way, compounds like 297 (obtained from the vinyliminotriphenylphosphorane 296... 

An example of a [2+2] cycloaddition reaction across two carbodiimide groups generated in a pyrazole system is shown Section 3.2.3. However, unsaturated carbodiimides often react as azadienes in [2+4] cycloaddition reactions (for example in the preceding reaction). 

Other intramolecular cyclization reactions involving arylcarbodiimides with an ortho vinyl group to form 2-aminoquinolines and pyrido[2,3-b]indoles are listed in Table 3.1. The latter reactions involve a [2-1-4] cycloaddition in which the carbodiimide intermediate acts as an azadiene and the bond of the ortho vinyl group acts as the dienophile. Calculated transition states for electrocyclization and cycloaddition reactions show that the mode of reaction depends on substituents, stereoelectronic, eutropic and steric factors." ... 

A select set of useful [4 + 2] cycloaddition reactions of simple 2-aza-1,3-butadienes have been detailed (Table 11), " and in most instances the 2-azadienes employed are substituted with strong electron-donating substituents responsible for enhancing its Diels-Alder reactivity toward electron-deficient dienophiles. The ease with which the l,3-bis(t-butyldimethylsilyloxy)-2-aza-1,3-butadienes may be prepared from imides, and the demonstrated facility with which they participate in HOMOdiene-controlled [4 + 2] cycloaddition reactions, may prove exceptionally useful their use constitutes the most general approach to implementing the 477 participation of 2-aza-1,3-butadienes (Scheme 12). With the recent introduction of a convenient preparation of 3-trimethylsilyloxy-2-aza-1,3-butadienes, their comparable synthetic utility may be anticipated. ... 

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