1- Azadiene Diels-Alder cycloadditions

Scheme6.241 Azadiene Diels—Alder cycloaddition of fulvenes.

The electron-rich alkyne 14 reacts with the electron-deficient 1,2,4,5-tetrazine 15 in a thermal inverse electron-demand azadiene Diels-Alder cycloaddition reaction (see Key Chemistry). 

Hong and coworkers [18] also reported an azadiene Diels-Alder cycloaddition involving fulvenes (Scheme 7.17). Pentafulvenes 67 was reacted with A/ -sulfonyl-l-aza-l,3-butadiene 68 to give the tetrahydro-[l]pyridine system 69 efficiently. The reactions provided 69 in moderate yields at room temperature the yields could be improved by high-pressure reactions and microwave conditions. Formally, this reaction involves a regio- and diastereoselective inverse electron-demand Diels-Alder reaction. 

By using a variant of Rawal s azadiene Diels-Alder cycloaddition chemistry [103,104], it was possible to synthesize several Kornfeld ketone analogues with substitution patterns that are difficult to otherwise obtain. Thus, heating a mixture of furan 280a and Rawal s diene (281) in CH3CN at reflux for 2h resulted in the formation of a 2 1-mixture of diastereomeric amines 282 that was immediately treated with HF at room temperature to unmask the enone 283 (Scheme 13.64) [105,106]. The crude reaction mixture was then heated at reflux in toluene for 30 min to effect... 

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... 

A general hetero-Diels-Alder cycloaddition of fulvenes with azadienes to furnish tetrahydro-[l]pyrindines has been described by Hong and coworkers (Scheme 6.241 see also Scheme 6.92) [424]. A solution of the azadiene and fulvene (1.2 equivalents) precursors in chlorobenzene was heated under open-vessel microwave irradiation for 30 min at 125 °C to provide the target compounds in excellent yields and with exclusive regio- and diastereoselectivity. Performing the reactions under conventional conditions or under microwave irradiation in different solvents provided significantly reduced yields. 

Pyrazole derivatives are very reluctant to participate as dienes in Diels-Alder cycloadditions that involve the pyrazole ring, because of the loss of aromatic character during the process [79]. Microwave irradiation under solvent-free conditions, however, induces pyrazolyl 2-azadienes 96 to undergo Diels-Alder cycloadditions with ni-troalkenes 97 and 98 in 5-10 min to give good yields of pyrazolo-[3,4-b]-pyridines (Scheme 9.29) [80], Under the action of classical heating only traces of the corresponding cycloadducts were detected. 

DFT calculations have been used to study the mechanistic pathway of the intramolecular Diels-Alder cycloaddition involved in the biosynthesis of natural products paraherquamide A and VM55599. The cycloaddition involves a dihydropyrolo[l,2- ]pyrazine as the azadiene and a standard alkene as the dienophile (Scheme 1). Analysis of the results reveals that these cycloadditions take place through concerted transition structures associated with [4+2]... 

The pioneer work on this subject using simple 1-azadienes is due to Ghosez et al. (82TL3261 85JHC69) they succeeded in reacting 1-azadienes as 47r-electron components in Diels-Alder cycloadditions. Thus, l-dimethylamino-3-methyl-l-azabuta-l,3-diene (a,/3-unsaturated hydrazone) 54 did undergo [4 + 2] cycloaddition to typical electron-poor dienophiles, e.g., methyl acrylate, dimethyl fumarate, acrylonitrile, maleic anhydride, and naphthoquinone, producing pyridine derivatives 55-57 (Scheme 14). 

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-... 

Heterocyclic azadienes like di- and triazines have been used in the synthesis of pyridine rings. In general terms the reaction involves a regiospecific inverse electron demand Diels-Alder cycloaddition between the heterocycle and the enamine 280 followed by elimination of HCN (diazines) or N2 (triazines) and an amine from the primary cycloadduct 281 or 283, respectively, to give pyridines 282 and 284 (equation 61). At least in one case the latter type of intermediate has been isolated and fully characterized148. 

Among the few examples of simple 1-azadiene Diels-Alder reactions is a dihydropyridine synthesis using the stable azadiene 39 (prepared from cinnamaldehyde and aniline) with the dienophile 38 prepared from the isoxazole 35 by elimination. This is a reverse-electron-demand cycloaddition, the HOMO of the dienophile 38 combining with the LUMO of the azadiene 39 to give the cycloadduct 40 and hence the dihydropyridine 41 with complete regioselectivity and in very high yield.3... 

A pyrimidine acting as an azadiene in a Diels-Alder cycloaddition... 

In many instances, the entropic assistance provided in the intramolecular Diels-Alder reaction is sufficient to promote azadiene participation in Diels-Alder reactions.12 The incorporation of the azadiene system, or dienophile, into a reactive or sensitive system, e.g., heterocumulene or strained olefin, allows a number of specialized azadiene Diels-Alder reactions. Many such examples may represent stepwise, polar [4 + 2] cycloaddition reactions. 

In addition to the [4 + 2] cycloadditions of oxazoles (Section 1) and substituted 1,2,4,5-tetrazines (Section 14), the Diels-Alder cycloadditions of substituted 1,2,4-triazines constitute one of the most thoroughly investigated heteroaromatic azadiene systems capable of 4tt diene participation.3,89 In contrast to the oxazole or sym-tetrazine series, two potential and observed modes of cycloaddition are open to 1,2,4-triazines cycloaddition across C-3/C-6 or C-5/N-2 of the 1,2,4-triazine nucleus, and the former is subject to 1,2,4-triazine substituent control of the observed regioselectivity.90 The complementary addition of electron-withdrawing substituents to the 1,2,4-triazine nucleus generally increases its rate of participation in inverse electron demand Diels-Alder reactions, influences the mode of [4 + 2] cycloaddition (C-3/C-6 versus C-5/N-2 cycloaddition), and controls the observed regioselectivity. In addition, the reactivity of the electron-rich dienophile as well as the reaction conditions, polar versus nonpolar solvent, have a pronounced effect on the observed course of the [4 -I- 2] cycloadditions.89... 

Alternatively, the complementary addition of strong electron-donating substituents to the azadiene system increases the nucleophilic character of the azadiene system and permits the use of conventional electron-deficient dienophiles in Diels-Alder reactions. In such instances, the azadiene systems are participating in normal (HOMOd,ene controlled) Diels-Alder reactions. The appropriate introduction of electron-donating substituents to the azadiene system raises the HOMOazadiene, reduces the magnitude of the HOMOazadiene-LUMOdienophiie energy separation, and accounts for the accelerated participation of nucleophilic azadienes in normal Diels-Alder cycloadditions. 

The first use of an oxazole as an azadiene in a Diels-Alder cycloaddition was reported by Kondrat eva in 1957. In these seminal studies a variety of alkyl-substituted oxazoles 1 (Ri, R2, R3 = H, alkyl) reacted with maleic anhydride in either benzene or ether to provide the cinchomeronic anhydrides 2, rather than the expected bicyclic ethers analogous to the Diels-Alder adducts of furans (Fig. 3.1). 

A variety of azadienes have been shown to participate in inverse electron demand Diels-Alder cycloadditions [10,11]. A few examples of such reactions with indoles as the dienophiles have been recently reported. 

The pyrazolo[3,4-fe]pyridines 257, 258, and 259 were constructed by Diels-Alder cycloaddition of the 2-azadienes, alkylidene derivatives of 5-aminopyrazole 254 or 255, with nitroalkenes 256 as electron-poor dienophiles under MWI and solvent-free... 

Synthesis of Pyridine Derivatives. Tetrahydropyridine derivatives are readily formed by Diels-Alder cycloadditions of a 1-azadiene with activated alkenes. A review makes clear the many uses of this type of heterodiene in Diels-Alder and other heterocycle-forming processes. An example of tetrahydropyridine synthesis is shown in Scheme 5.4. 

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