Organocatalytic

The synthesis of functionahzed tetrahydrocarbazoles can be promoted by microwave irradiation [84], The organocatalytic four-component reaction of a solution of 2-substituted indole, aromatic aldehyde (2 equiv) and Mel-drum s acid in benzene in the presence of DL-proline proceeds when heated under Dean-Stark conditions for 5 min in a single-mode microwave reactor to give the tetrahydrocarbazole product as a mixture of diastereoisomers (Scheme 24). 

Similar organocatalytic species to those successfully used for the Strecker reaction were used for the asymmetric Mannich reaction. Catalyst structure/ enantioselectivity profiles for the asymmetric Strecker and Mannich reactions were compared by the Jacobsen group [160]. The efficient thiourea... 

Major advances in the application of NHCs in organocatalysis have been achieved, and this arena has become a focus of considerable research. The use of chiral NHCs has allowed access to highly enantioselective organocatalytic transformations and the breadth and depth of reactivity that can be accessed is ever expanding. 

For recent reviews of the ability of NHCs to catalyse organocatalytic processes see Enders D, Niemeier O, Henseler A (2007) Chem Rev 107 5606-5655 Marion N, Diez-Gonzalez S, Nolan, SP (2007) Angew Chem Int Ed 46 2988-3000... 

Ramachary, D.B. Barbas, C.R III (2004) Towards Organo-Click Chemistry Development of Organocatalytic Multicomponent Reactions Through Combinations of Aldol, Wittig, Knoevenagel, Michael, Diels-Alder and Huisgen Cycloaddition Reactions. Chemistry A European Journal, 10, 5323-5331. 

Tejedor, D., Gonzalez-Cruz, D., Santos-Exposito, A., Marrero-Tellado, J.J., de Armas, R, Garcid-TeUado, F. (2005) Multicomponent Domino Processes Based on the Organocatalytic Generation of Conjugated Acetylides Efficient Synthetic Manifolds for Diversity-Oriented Molecular Construction. Chemistry A European Journal, 11, 3502-3510. 

An impressive organocatalytic asymmetric two-component domino Michael/ aldol reaction has been recently published by Jorgensen and coworkers (Scheme 2.23) [38]. 

Scheme 2.63. Organocatalytic synthesis of 2-271 by a domino O-nitroso-aldol/Michael reaction.

Recently, a first example of an organocatalytic asymmetric domino Knoevenagel/ Diels-Alder reaction was reported by Barbas and coworkers (Scheme 2.182) [409]. Spiro[5,5]undecane-l,5,9-triones of type 2-818/2-819 were obtained from comma-daily available 4-substituted-3-butene-2-ones 2-813, aldehydes 2-814, and Mel-drum s acid (2-801) in the presence of 20 mol% of the amino acid 2-815 with 80-95% ee and diastereoselectivity of dr> 12 1. 

Organocatalytic annulation of phthalazinium iodide 51 in the presence of (2A,5A)-2,5-dibenzylpyrrolidine furnished optically active (l,9,llM)-tetrahydro-l//-pyrido[2,l-tf]phthalazine 52 with high diastereo- and enantioselectivities (Equation 8) <2005AGE6058>. 

A series of functionalized tetrahydrothiophenes has been prepared by acid induced organocatalytic reactions involving a,p-unsaturated aldehydes and 2-mercapto-l-phenylethanone 24. This procedure led to good yields of products displaying useful enantiomeric excess, as illustrated by construction of the target 25 in the presence of the catalyst 26 <06JA14986>. 

L2909>. An organocatalytic addition of 2-trimethylsilyloxyfuran to aldehydes using 10 mol% of l,3-bis(3-(trifluoromethyl)phenyl)urea provided adducts with modest threo selectivity <06TL8507>. A syn-selective, enantioselective, organocatalytic vinylogous Mukaiyama-Michael addition of 2-trimethylsilyloxyfuran to (E)-3-... 

An enantioselective organocatalytic 1,3-DC reaction, based on the activation of a,fi-unsaturated aldehydes through the reversible formation of iminium ions with chiral imidazolidinones 100, was described. Good levels of asymmetric induction and diastereocontrol were achieved (up to 94% ee and 94 6 dr) <00JA9874>. 

Organocatalytic processes provide the capacity to catalyze known transformations with chemo-, regio-, diastereo-, or enantioselectivities that are orthogonal or complementary to known metal-catalyzed systems. 

A literature survey of articles that focus on the use of organocatalytic concepts indicate that this area began exponential growth in 2000, and that interest in this field has continued to rapidly expand on a yearly basis ever since (Figure 11.1) As a further example of this phenomenon, the total number of organocatalysis articles for year 2004 has been overtaken in the first 6 months of 2005. 

Figure 11.1. Diagram indicating the number of articles per year focusing on the use of organocatalytic concepts.

The catalytic asymmetric epoxidation of a,p-unsaturated aldehydes has also been an important challenge in iminium catalysis and for chemical synthesis in general. More recently, Jprgensen and coworkers have developed an asymmetric organocatalytic approach to ot, (3-epoxy aldehydes using pyrrolidine catalyst 20 and H2O2 as the stoichiometric oxidant. The reaction appears to be extremely general and will likely receive wide attention from the chemical synthesis community (Scheme 11.6b). 

Diels-Alder Reactions The organocatalytic Diels-Alder reaction of a,P-unsaturated carbonyl compounds can be performed either via iminium (see Section 11.3) or enamine catalysis. The first highly selective enamine-promoted cycloaddition reaction was reported by Jprgensen and coworkers, who developed an amine-catalyzed inverse-electron-demand hetero-Diels-Alder (HDA) reaction (Scheme ll.lOa). ... 

For a recent review on the organocatalytic synthesis of carbohydrates, see Limbach, M. Chem. Biodiv. 2005, 2, 825-836. 

Up to now, only a few organocatalytic reactions of the above types have been investigated with post-Hartree-Fock methods. Potential reasons are computational costs, spatial and conformational flexibility (ab initio methods do not necessarily find... 

Scheme 7 Two alternative reaction routes for the organocatalytic Michael-addition of acetylacetone to nitrostyrene...

As a third example for an organocatalytic reaction, based on multiple hydrogen bonding and mechanistically investigated by DFT, we selected olefin epoxidation with hydrogen peroxide in fluorinated alcohol solvents, such as 1,1,1,3,3,3-hex-afluoro-2-propanol (HFIP) (Scheme 8). Here we encounter a new type of catalytic hydrogen bond the cooperative hydrogen bond. 

For the related organocatalytic ring-opening of oxazinones, see Berkessel A, Cleemann F, Mukherjee S (2005) Angew Chem Int Ed 44 7466-7469... 

Scheme 35 Enamines and iminium ions in organocatalytic domino reactions...

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