High-Pressure Multicomponent Domino Cycloaddition Reactions

High-Pressure Multicomponent Domino Cycloaddition Reactions 

Over the past 5 years we have studied high-pressure multicomponent domino cycloaddition reactions in the liquid phase and on solid supports. Multicomponent domino cycloaddition reactions can generate mono-, di- and tricyclic systems in an efficient manner depending on the reaction components used. Application of high pressure is sometimes essential for the progress of every individual step of a 

High Pressure-Promoted One-Pot Three-Component [4 -i- 2]/[3 2] Cycloadditions  

Four subtypes of this domino reaction are possible, in which each cycloaddition step can be intra- or intermolecular [12-14]. The domino intermolecular [4 -F 2]/ intramolecular [3 + 2] cycloaddition has been studied extensively, mainly by Denmark and coworkers [12]. The domino intermolecular [4 + 2]/intermolecular [3 + 2] cycloaddition, which has been studied less extensively [13], mostly leads to a lower degree of stereoselectivity than the domino inter/intra cycloadditions. From a combinational point of view however, domino inter [4 + 2 /inter [3 + 2] cycloadditions are more attractive as a high degree of structural diversity can be obtained from simple building blocks. 

In general the inverse electron-demand Diels-Alder reaction is carried out using stoichiometric amounts of Lewis acid catalysts (SnCU, TiCU, TiCl2(OR)2, MAD (methylaluminium bis(2,6-di-fert-butyl-4-methylphenoxide) and MAPh (methyl-aluminium bis(2,6-diphenylphenoxide) [15]) at low temperatures (-90 to 0 °C). Before the [3 + 2] cycloaddition with an electron-poor alkene can take place, the first-formed nitronate has to be separated from the Lewis acid catalyst by an aqueous work-up and chromatography [13, 16]. Probably complexation of the Lewis acid catalyst to the nitronate dipole inactivates the dipole and hinders the 1,3-dipolar cycloadditions from taking place [17]. 

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High-Pressure Multicomponent Domino Cycloaddition Reactions... 

High-Pressure Multicomponent Domino Cycloaddition Reactions 291 O, + o UU Me 15kbar... 

Often one of the steps in this domino reaction is a cycloaddition. A recent review by Dax et al. [Id] gives an overview of the state of the art of multicomponent reactions in solid phase synthesis. High pressure can play an important role in extending the scope of these reactions. 

Despite the wealth of opportunities for high-pressure applications in solid phase cycloaddition reactions and multicomponent domino reactions, only very few processes have been studied up until now. We hope that the results presented in this chapter will stimulate application of high pressure in combinational chemistry. 

Finally, Chataigner and Piettre [100] also developed a multicomponent domino [4+2]/[3+2] cycloaddition under high pressure of 3-nitroindole 177, ethoxyethene 178, and acrylates 141 (Scheme 12.72). The starting material was consumed in 24 h at room temperature, and the formed cycloadduct 179 was isolated in 83% yield and a diastereomeric ratio of 55 45. This domino reaction can be extended to the use of 3-nitropyrroles instead of nitroindoles at 1.6 GPa and 50 °C to afford diastereomeric nitrosoacetals. 

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