Solvent-free conditions hetero-Diels-Alder reaction

Avalos et al. has reported the microwave-assisted synthesis of tetrazine derivatives by a hetero Diels-Alder reaction of homochiral 1,2-diaza-l,3-butadienes with diethyl azodicarboxylate (Scheme 3.40)65. Under conventional conditions, reactions could be performed in benzene solution at room temperature. However, under microwave heating conditions, the reaction was significantly accelerated (by a factor of 1000) when carried out solvent free. The observed stereoselectivity was identical for the hetero Diels-Alder reaction under both microwave-heated and conventional conditions. 

The hetero-Diels-Alder reaction is amongst the most efficient processes for the synthesis of six-membered heterocyclic ring systems. Solvent-free conditions have been used to improve reactions of heterodienophiles and heterodynes with low reactivities. Cado et al. (1997) have described the hetero-Diels-Alder reaction of ethyl lH-perimidine-2-acetate as heterocyclic ketene aminal with ethyl propiolate nnder solvent-free conditions with focused microwave irradiation. The new fused perimi-dines (23) were obtained in good yields (67-98%). 

Narsaiah and Krishnaiah (2002) reported that the hetero-Diels-Alder reaction of A(-acetyl perflnoroalkyl substituted 2(1//) pyridones with DMAD on neutral alumina under solvent-free microwave irradiation conditions extended to undergo an inverse electron demand hetero-Diels-Alder reaction, resulting exclusively in E, Z isomers (3 1) of Michael-type A-adducts. 

Figure 2,18 Catalytic asymmetric hetero-Diels-Alder reaction between Danishefsky s diene and benzaldehyde under solvent free conditions.

Under solvent-free conditions with microwave irradiation. Moody et al. have improved the hetero Diels-Alder reaction of eneacylamines with l-alkoxy-2-aza-1,3-dienes [67]. A mixture of l-(2-thiazolyl)-l-acetylaminoethylene 54 and the starting 2-aza-l,3-diene 55, irradiated in a GEM Focused Synthesizer at 180 °C for 15 min produced a 64% yield of adduct 56 (Scheme 11.16). Carboxylic acid esters and thiazole rings are tolerated under these reaction conditions (Scheme 11.16). Without microwave irradiation yields were in the range 25 to 42% [67]. 

The intermolecular Diels-Alder or hetero Diels-Alder reaction has also been performed under solvent-free microwave conditions in open vessels (Section 11.3). 

The development of a catalytic enantioselective process has received much attention and, in common with the all-carbon Diels-Alder reaction, most success has been achieved using metal-based Lewis acids and, most recently, organocatalysts/ The earliest work on an enantioselective variant of this reaction was performed by Danishefsky/ The enantiomerically pure europium complex Eu(hfc)3 provided moderate enantioselectivities for the hetero-Diels-Alder reaction between derivatives of diene (8.123) and benzaldehyde (8.125), performed under solvent-free conditions. Higher ees have been obtained using the hindered BINOL ligand (8.126), as its aluminium complex. Yamamoto s CAB catalysts (see Section 8.1) such as (8.129), with the appropriate substituent on boron, have also been used to good effect. 

An efficient synthesis of pyrrlo[2,3-d]pyrimidine annulated pyrano[5,6-c]cou-marin/[6,5-c]chromone derivatives was achieved by intramolecular hetero-Diels-Alder reaction by microwave irradiation under solvent-free and solid supported conditions (Ramesh and Raghunathan, 2008). 

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