Tetrahydropyridines => azadienes

Azadienes undergo Diels-Alder reactions to form pyridine, dihydro- and tetrahydropyridine derivatives. N-Vinyl lactim ethers undergo Diels-Alder reactions with a limited set of dienophiles. " Thioketones react with dienes to give Diels-Alder cycloadducts. The carbonyl group of lactams have also been shown to be a dienophile. Certain heterocyclic aromatic rings (among them furans) can also behave as dienes in the Diels-Alder reaction. Some hetero dienes that give the reaction are -C=C-C=0, 0=C-C=0, and N=C-C=N. ... 

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. 

An intramolecular hetero-Diels-Alder reaction of activated azadienes gives rise to the fused tetrahydropyridines by heating or catalysis (Equation 139) <1999TL7211, 1999TL7215>. 

In the presence of 10 mol % Sc(OTf)3, A-benzylideneaniline reacts with 2-trans-l-methoxy-3-trimethylsiloxy-l, 3-butadiene (Danishefsky s diene) [23] to afford the corresponding aza Diels-Alder adduct, a tetrahydropyridine derivative, quantitatively (Eq. 7) [24]. In the reaction of A -benzylideneaniline with cyclopentadiene under the same conditions, on the other hand, the reaction course ehanged and a tetrahydroqui-noline derivative was obtained (Eq. 8). In this reaction, the imine aeted as an azadiene toward one of the double bonds of cyclopentadiene as a dienophile [25]. In the reaction with 2,3-dimethylbutadiene a mixture of tetrahydropyridine and tetrahydroqui-noline derivatives was obtained. A vinyl sulfide, a vinyl ether, and a silyl enol ether worked well as dienophiles to afford the tetrahydroquinoline derivatives in high yields [26,27]. 

In the presence of 10 mol% of ytterbium triflate (Yb(OTf)3> a representative lanthanide triflate), N-benzylideneaniline (10a) was treated with 2-trimethylsi-loxy-4-methoxy-1,3-butadiene (Danishefsky s diene, 11) [59] in acetonitrile at room temperature. The imino Diels-Alder reaction proceeded smoothly to afford the corresponding tetrahydropyridine derivative in a 93% yield (Table 19). The adduct was obtained quantitatively when Sc(OTf)3 was used as a catalyst. Imines 10b and 10c also reacted smoothly with 11 to give the corresponding adducts in high yields. The reaction of 10a with cyclopentadiene was performed under the same reaction conditions. It was found that the reaction course changed in this case and that a tetrahydroquinoline derivative was obtained in a 69% yield. In this reaction, the imine worked as an azadiene toward one of the double bonds of cyclopentadiene as a dienophile [43,60]. In the reactions of 2,3-dimethylbutadiene, mixtures of tetrahydropyridine and tetrahydroquinoline derivatives were obtained. 

Diels-Alder reaction of I-azadienes. Tetrahydropyridine derivatives are readily synthesized in high yields. 

For instance, a, p-unsaturated A-phenylaldimines react as 1-azadienes with maleic acid affording tetrahydropyridines 182. 

Six-membered heterocycles The Diels-Alder reaction of azadienes with TCNE yielded tetrahydropyridines. Dicyanopyridines 402 have been obtained by cyclization of tetracyanoethylated ketones with hydrochloric (X = Cl) or hydrobromic (X = Br) acid. Yields are between 61 and 84%". ... 

A very selective hetero Diels-Alder reaction of azadiene (32) with maleic anhydride gave tetrahydropyridine (33) in greater than 98% d.e. under mild conditions (Scheme 13) <94T(A)557). 

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. 

Azadiene 1, bearing an electron-withdrawing substituent (C02Me), is expected to be electron-deficient and, therefore, more likely to react with electron-rich dieno-philes in an inverse electron demand Diels-Alder reaction. However, for a diene, 1 shows a very unusual reactivity, since it participates in cycloadditions with both electron-rich and electron-deficient dienophiles. As an example, reaction of azadiene 1 with diethyl flimarate yields pyridine 2 whereas in the presence of A-cyclo-penten-l-ylpyrrolidine, tetrahydropyridine 3 is obtained (Scheme 18.1). 

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