2-Azadienes, hetero-Diels—Alder

For examples of Diels-Alder reactions involving 2-azadienes, see (a) Boger, D.L. Weinreb, S.M. In Hetero Diels-Alder Methodology in Organic Synthesis, Academic Press San Diego, 1987, p. 255 (b) Boger, D. L. Tetrahedron 1983, 39, 2869. 

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... 

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. ... 

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. 

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... 

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. 

A few examples of hetero-Diels-Alder adducts have been reported [75-81]. A thio-chroman-fused fuUerene adduct was synthesized by the reaction of o-thioquinone with CgQ in o-dichlorobenzene at 180 °C [77]. The obtained cyclic sulfide 84 (Figure 4.4) can be oxidized to the corresponding sulfoxide and sulfone with m-chloroperoxybenzoic acid. Reaction of azadienes with Cgg leads to hetero Diels-Alder adducts such as, for example, 85 (Figure 4.4) [79]. The tetrahydropyrido[60]-fullerene 85 is formed in refluxing o-dichlorobenzene. 

The reaction of diphenylketene with an azadiene was reported to produce piperidinones <99SL1379>. An intramolecular hetero-Diels-Alder of the activated azadiene 65 was carried out either by heating or with catalysis <99TL7211,99TL7215>. 

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>. 

Amythiamicin D was the first in the family to be synthesized. The 2,3,6-trisubstituted pyridine core was synthesized from serine-derived l-alkoxy-2-azadienes and thiazoyl enamide dienophiles ultilizing a biosynthesis-inspired hetero-Diels-Alder route under MW irradiation. After successive incorporation of glycine and bis-thiazole fragments, amythismicin D was obtained by macrocyclization <2005JA15644, 2004CC946>. 

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. 

Diels-Alder reactions of heterocyclic azadienes scope and applications , Boger, D. L., Chem. Rev., 1986, 86,781 Hetero Diels-Alder mediodology in organic syndiesis , Ch. 10, Boger, D. L. and Weinreb, S. M., Academic Press, 1987 1-Azadienes in cycloaddition and multicomponent reactions towards N-heterocycles , Groenendaal, B., Ruijter, E. and Orru, V. A., Chem. Commun., 2008, 5474. 

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). 

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