2-Azadienes, hetero-Diels—Alder reaction

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. ... 

Catalysts such as Fe(BuEtCHC02)3 have been d eloped that are effective for the heteroatom Diels-Alder reaction. Indium trichloride (InCls) is a good catalyst for imino-Diels-Alder reactions. Hetero-Diels-Alder reactions involving carbonyls have been done in water. Ultrasound has been used to promote the Diels-Alder reactions of 1-azadienes. ... 

Methods have been described that involve microwave-assisted graphite-supported dry media for the cycloaddition of anthracene, 1-azadienes and 1,2,4,5-tetrazines with several C-C dienophiles and carbonyl compounds in hetero-Diels-Alder reactions [35], This technique leads to a shortening of reaction times, a situation that enables work to be undertaken at ambient pressure in an open reactor to avoid the formation of unwanted compounds by thermal decomposition of reagents or products. 

Similarly, Motorina described the intramolecular hetero-Diels-Alder reaction of N-alkyl-2-cyano-l-azadienes 86 (Scheme 9.26) [76] although the reaction had already been performed by heating the reactants in benzene overnight in a sealed tube at 110 °C, it was found that reaction time could be reduced to 14 min in a microwave oven at 650 W. 

Sheldrake and co-workers devised an elegant approach to interesting cage compounds based on an intramolecular hetero Diels-Alder reaction (88CC1482) (Scheme 51). The [4 + 2] cycloaddition of triazines 223 to 1,5-cyclooctadiene at M0°C resulted in the formation of 7-azatetracyclo[7.3.0.02 6.05 lo]dodec-7-ene derivatives 225 in 44-66% yield. The initial formation of 224 followed by the intramolecular cycloaddition of the electron-poor 2-azadiene moiety to the second carbon—carbon double bond of the cyclooctadiene system accounts well for the process. The dienophile unit can be placed just over the diene system favoring... 

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... 

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

Boger and Panek (85JA5754) have also accomplished a formal total synthesis of streptonigrin (63) based on two hetero Diels-Alder reactions (Scheme 8). The initial cycloaddition of the S-methylthioimidate 64 and l,2,4,5-triazine-3,6-dicarboxylate 65 provided 1,2,4-triazine 66 (82%), which was then used as an azadiene component of the second Diels-Alder reaction. The following step will be described in Section III,B,1. 

Bushby, N., Moody, C.J., Riddick, D. A., and Waldron, I.R., Double intramolecular hetero Diels-Alder reactions of a,P-unsaturated hydrazones as 1-azadienes. A new route to 2,2 -bipyridines, 7. Chem. Soc., Perkin Trans. 1, 2183, 2001. 

One sure way to make the hetero Diels-Alder reaction go well and with regio-and stereoselectivity is to make it intramolecular.14 The highly reactive diene 90 is formed by elimination with fluoride ion from 89. The cycloaddition is rapid because it restores aromaticity. The regiose-lectivity is as expected from HOMO of dienophile plus LUMO of diene but is probably controlled by the tether.15 The stereochemistry certainly is the azadiene is attached to the bottom face of the five-membered ring and is delivered to the bottom face of the dienophile to give the all-trans aza-oestrone 91. 

A representative of the hetero-Diels-Alder reaction of inverse electron demand is the cycloaddition of A-sulfonyl-l-azadienes with vinyl ethers. It is amenable to asymmetric catalysis, for example, by a nickel(II) complex of 101. ... 

Fowler and co-workers have studied the participation of 1-acyl-l-azadienes in hetero Diels-Alder reactions, finding that vacuum pyrolysis of the O-acylhydroxamic acid (298) leads to a quinolizine system (300) through an intermediate A-acyl-l-azadiene (299) (Scheme 64), a method that was later applied to the synthesis of several quinolizine alkaloids <83JA7696, 85JOC27i9>. A similar result can be achieved by flash-vacuum pyrolysis of l-acyl-2-azetines <9UOC6729>. 

Thermal isomerization of amino-substitued 2i/-azirines (e.g. 183 -> 184) results in the formation of 2-azadienes. They react with activated alkynes, e.g. with acetylenedicarboxylic ester (ADE), in a hetero-Diels-Alder reaction, giving dihydropyridines (e.g. 185), which aromatize with elimination of amine yielding pyridine-3,4-dicarboxylic esters (e.g. 186). 

Hughes et al. achieved a synthesis of amythiamicin D (121) using a biosynthesis inspired hetero Diels-Alder reaction as a key step [36]. Synthesis of the key 1-alkoxy-2-azadiene 118 was conducted by coupling of the imidate 116 and amine hydrochloride 117 and subsequent elimination of the acetate with DBU [37]. The hetero Diels-Alder reaction of the azadiene 118 and enamide 119 proceeded under microwave conditions to give the pyridine 120, which was effectively converted into the natural product 121 (Scheme 7.26). 

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). 

The Diels-Alder reaction of 2-azadienes also benefits from the presence of an electron-donating substituent, to enhance the reactivity with electron-deficient dienophiles. Cycloaddition with alkynyl dienophiles and aromatization leads to substituted pyridines (3.54). Silyloxy-substituted 2-azadienes such as 68 are effective dienes and have been used to prepare substituted 2-pyridones and piperidones after methanolysis (3.55). Asymmetric hetero Diels-Alder reactions with the chiral Lewis acid catalyst 66 provide access to the piperidone products with very high enantioselectivity. ... 

The nickel-iminophosphine-catalysed 4- -2-cycloaddition of enones with allenes formed highly substituted dihydropyrans. The enantioselective amine-catalysed 4-I-2-cycloaddition of allenoates with oxo-dienes produced polysubstituted dihydropyrans in high yields and with high enantioselectivities. Novel enam-ine/metal Lewis acid bifunctional catalysis has been used in the asymmetric inverse-electron-demand hetero-Diels—Alder reactions of cyclic ketones with Q ,j9-unsaturated a-ketoesters. The 4- -2-cycloaddition of acylketenes (80) with 2-unsubstituted and 2-monosubstituted 3-aryl-2//-azirines (81) produced 1 1 (82) or 2 1 (83) adducts, being derivatives of 5-oxa-l-azabicyclo[4.1.0]hept-3-ene or 5,7-dioxa-l-azabicyclo[4.4.1]undeca-3,8-diene. The formation of the monoadducts proceeds via a stepwise non-pericyclic mechanism (Scheme 25). A-heterocyclic carbene-catalysed 4- -2-cycloaddition of ketenes with 1-azadienes yielded optically active 3,4-dihydropyrimidin-2-ones (93% ee) ... 

Metal bis(oxazoline) catalysts are also highly efficient at promoting asymmetric Diels-Alder reactions. Ishira developed a highly selective copper bis(oxazoline) catalyst for use in standard intermolecular Diels-Alder reactions. Arrayas and Carretero used a nickel bis(oxazoline) catalyst in inverse electron demand hetero Diels-Alder reactions of 1-azadienes for the production of functionalized piperidines. bis(oxazoline) catalysts in reactions pyrazolidinone dienophiles and determined that copper and palladium catalysts were most efficient. Sibi applied a copper bis(oxazoline) catalyst in a kinetic resolution experiment in which one enantiomer of dienophile 46 reacts selectively with cyclopentadiene to yield cycloadduct 48 and 98% ee... 

Using a relatively simple chiral secondary amine catalyst (56), Chen prepared a series of highly functionalized enantiomerically pure piperidines via inverse electron demand hetero Diels-Alder reactions. For example, amine catalyst 56 reacts with unsaturated aldehyde 55 to fiimish a dienamine that functions as the electron-rich dienophile for combination with electron-poor 1 -azadiene 54 and provides piperidine 57 in high yield and enantiomeric... 

Bode demonstrated the effectiveness of A -heterocyclic carbenes as catalysts for inverse electron demand hetero Diels-Alder reactions involving both azadienes and oxodienes. In the oxodiene case, reaction of enones with a-chloroaldehydes affords substituted dihydropyranones. In one example, addition of catalyst 60 to chloroaldehyde 58 followed by elimination of HCl yields the electron-rich dienophile that readily combines with oxodiene 59 to selectively fiimish cycloadduct 61. ... 

The group of Ghosez has reported a very fast, convergent route to piperidine derivatives, which they applied to the preparation of the spiro compound 147. The sequence of reactions involves the in situ generation of 2-azadiene 150 and its subsequent hetero Diels-Alder reaction with the exocyclic unsaturated lactone 146 (Scheme 3.44). This process provides a very concise access to a structurally... 

Cuellar MA, Alegria LK, Prieto YA, Cortes MJ, Tapia RA, Preite MD (2002) Hetero-Diels-Alder reaction of halogenated quinones with a polygodial-derived azadiene. Tetrahedron Lett 43 (12) 2127-2131. doi 10.1016/S0040-4039(02)00246-0... 

In the absence of a suitable nucleophile, the homoenolate-derived acyl azolium intermediate can undergo deprotonation to generate a nucleophilic azolium enolate. Bode and coworkers showed such enolates to be competent dienophiles in hetero-Diels-Alder reactions with N-sulfonyl azadiene partners, providing dihy-dropyridinone products in very high diastereo- and enantioselectivity [106]. This work was quickly followed up by an analogous hetero-Diels-Alder reaction with oxodienes 130 (Scheme 18.25) [107]. In this case, the enolate intermediates (132)... 

---