Azadiene, electron-rich

With this foundation, Boger communicated the use of 1,2,4-triazines as a dependable, azadiene equivalent for Diels-Alder approaches to substituted pyridines. Electron rich olefin 19, prepared from the corresponding ketone, was allowed to... 

The Boger pyrrole synthesis based on a heterocyclic azadiene Diels-Alder strategy (1,2,4,5-tetrazine to 2,2-diazine to pyrrole) was employed by the author for the total synthesis of ningalin B . Thus a Diels-Alder reaction of the electron-rich acetylene 52 with the electron deficient 1,2,4,5-tetrazine 53 proceeded to give the desired diazine 54 which underwent subsequent ring contraction to afford the core pyrrole structure 55. 

This procedure describes the preparation of an electron-deficient heterocyclic azadiene suitable for use in inverse electron demand (LUMOd gpg controlled) Diels-Alder reactions with electron-rich dienophiles. 

Dihydro-l,2,4-tetrazine 49 reacts with trimethylaluminium to produce mono 5 a and diketones 50b depending upon the reaction conditions. Borohydride reduction of 50a gives alcohol 50c. Aromatization of 50a-c by exposure to nitrous gases affords tetrazines 51a-c which have proved to be very good electron-defficient heteroatomic azadienes for inverse electron demand Diels-Alder chemistry. Numerous examples are described with symmetric and nonsymmetric electron rich dienophiies <98JOC10063>. 

The oxime derived from 2-furfural has been used for the first time as an electron-rich 1-azadiene by Kusurkar and Bhosale (91TL3199) (Scheme 16). Thus, 2-furfuraldoxime 60 undergoes at 120°C [4 + 2] cycloaddition to acrylonitrile, acrylic acid esters, and maleic anhydride to give stereoiso-meric cycloadducts 61 and 62. The isomeric fused pyridines obtained were not separated, but dehydrogenated to the corresponding furo[2,3-c]pyridine N-oxide derivatives. 

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. 

N-Vinyl heterocumulenes represent a new, highly reactive 2-azadiene species, which react, in general, with electron-rich alkenes and alkynes. Accordingly, we think it is of interest to complement the utility of electron-poor 2-azadienes in [4 + 2] cycloadditions by showing some examples involving A-vinyl isocyanates, -isothiocyanates, -carbodiimides, and -ketenimines. 

Azadienes of this sort were studied simultaneously by Mariano et al., who reacted mixtures of (1 ,3 ) and (1E, 3Z)-l-phenyl-2-aza-l,3-pentadiene 275 with several electron-rich alkenes, e.g., enamines and enol ethers (85JOC5678) (Scheme 61). They found the (l ,3 )-stereoisomer to be reactive in this process affording stereoselectively endo 276 or exo 277 piperidine cycloadducts in 5-39% yield, after reductive work-up with sodium borohydride. The stereochemistry of the resulting adducts is in agreement with an endo transition state in the case of dienophiles lacking a cis alkyl substituent at the /8-carbon (n-butyl vinyl ether, benzyl vinyl ether, and 1-morpholino cyclopentene), whereas an exo transition state was involved when dihydropyrane or c/s-propenyl benzyl ether were used. Finally, the authors reported that cyclohexene and dimethyl acetylenedi-carboxylate failed to react with these unactivated 2-azadienes. 

VI. Enamines as Electron-Rich Synthons in Reactions with Electron-Deficient Azadienes... 

Ab initio and density functional theoretical studies of the 4 + 2-cycloaddition of 2-azabutadiene with formaldehyde predict a concerted reaction that agrees well with experimental evidence.184 The azadiene A-plienyl-l-aza-2-cyanobuta-l,3-diene reacts with electron-rich, electron-poor, and neutral dipolarophiles under mild thermal conditions.185 5,6-Diliydro-4//-1,2-oxazines have been shown to be usefiil as synthon equivalents of 2-cyano-l-azabuta-1,3-dienes.186 The intramolecular Diels-Alder reaction of 1-aza-l,3-butadienes (106) can be activated by a 2-cyano substituent (Scheme 37).187 Stereoselectivity in the hetero-Diels-Alder reactions of heterobutadienes, nitrosoalkenes, and heterodienophiles has been extensively reviewed.188 The azadiene l-(f-butyldimethylsilyloxy)-l-azabuta-1,3 -diene (107) reacts with halobenzo-quinones, naphthoquinones, and A-phcnylmalcimidc to yield low to good yields of various pyridine heterocycles (108) (Scheme 38).189 The 4 + 2-cycloaddition of homophthalic anhydride with A-(cinnamylidcnc)tritylaminc produces the 3,4-adduct whereas with A -(cinnamylidcnc)bcnzylidinc the 1,2-adduct is produced.190... 

Teng and Fowler62 showed that N-acyl-2-cyano-l-azadienes react with electron-rich (e.g. CH2=CHOEt) and electron-poor dienophiles (e.g. methyl acrylate) under relatively mild conditions. Stirring the reaction below at room temperature for 22 h gave a 61% yield for the intramolecular cyclization ... 

The azadiene FOs are close in energy, so they must both be considered in every reaction, even those with electron-rich dienophiles. Hexene and the ether can be modeled as propene and vinyl methyl ether, respectively the calculations then give the following (the figures are the values of FO interaction in the corresponding incipient bond) ... 

Diels-Alder reactions 1,2,4-triazines. The electron-deficient azadiene system present in 1 can undergo Diels-Alder reactions with electron-rich dienophiles to give an adduct that loses nitrogen to provide 1,2-diazines. Reactions with imidates (>C=NH) substituted with an active leaving group such as SCH, proceed at moderate temperatures to afford 1,2,4-triazines in high yield (equation I). 

A limited number of examples of this class of reactions exist. One heteroaromatic compound which has been used as an azadiene in inverse electron demand reactions with electron-rich imines is tetrazine... 

The protic acid and Lewis acid-catalyzed [4 + 2] cycloaddition reactions of electron-rich alkenes with imines derived from anilines and aryl aldehydes constitute an extensively explored class of 2-azadienes capable of providing the products of a formaJ Diels-Alder reaction (equation 9).i5.27.i77 a useful extension of these studies and in efforts to increase the rate of the Att participation of simple 2-aza-1,3-buta-dienes in [4 + 2] cycloaddition reactions, Mariano and coworkers have examined the Lewis acid-catalyzed intermolecular reactions of (l ,3 )-l-phenyl-2-aza-l,3-pentadiene with electron-rich dienophiles, including enol ethers. Reductive work-up of the cycloaddition reactions provided the pro-... 

The preparation or in situ generation of azabutadienes bearing a formal positive charge, i.e. an im-monium cation, provides a substantial enhancement of the electron-deficient character of the azadiene and in many instances such systems have proven to be effective 4rr components in Ehels-Alder reactions with electron-rich or neutral dienophiles. The most widely recognized class of cationic azadienes shown... 

The acid-catalyzed or Lewis acid-catalyzed (TiCU, BF3-OEt2 -78 C) in situ generation of A -alkyl-aiylimmonium ions in the presence of electron-rich or neutral alkenes has been shown to provide [4 + 2] cycloadducts (IV-methyltetrahydroquinolines) in excellent yields (Scheme 27). More recent efforts have demonstrated that immonium ions derived from the cmidensation of aryl amines and aldehydes in the presence of cyclopentadiene participate as effective 4 ir components of [4 + 2] cycloadditions and complement their demonstrated 2 ir participation in related [4 + 2 ] cycloaddition reactions (Scheme 27). Additional examples of the participation of cationic azadienes in [4 + 2] cycloaddition reactions... 

Heteroaromatic systems that possess an electron-deficient azadiene are ideally suited for participation in inverse electron-demand Diels-Alder reactions. Additional substitution of the heterocyclic azadiene system with electron-withdrawing groups accents the electron-deficient nature of the heterodiene and permits the use of electron-rich, strained or even simple olefins as dienophiles. 

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). 

An inverse electron demand aza D A reaction of electron rich alkenes with N aryl imines as 2 azadiene (Povarov reaction) provides tetrahydroquinolines. Reactions catalyzed by chiral phosphoric acids yielded different absolute ste reochemical outcomes when ethyl vinyl efher and enecarbamate are employed as electron rich alkenes, although chiral phosphoric acids have the same axial chirality in both cases (see Scheme 3.26). 

The protic acid and Lewis acid-catalyzed [4 + 2] cycloaddition reactions of electron-rich alkenes with imines derived from anilines and aryl ddehydes constitute an extensively explored class of 2-azadienes capable of providing the products of a formal Diels-Alder reaction (equation 9). .27.i77 useful exten-... 

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