Chemoselectivity, domino reactions

The domino reaction is initiated by the chemoselective attack of the carbanion 2-458 on the terminal ring carbon atom of epoxyhomoallyl tosylate 2-459 to give the alkoxides 2-460 after a 1,4-carbon-oxygen shift of the silyl group. The final step to give the cyclopentane derivates 2-461 is a nucleophilic substitution. In some cases, using the TBS group and primary tosylates, oxetanes are formed as byproducts. 

More recently, Bachi and coworkers extended and adapted the TOCO reaction to the synthesis of 2,3-dioxabicyclo[3.3.1]nonane derivatives hke 228 (Scheme 52) ° ° . As detailed in Scheme 53a, the bridged bicyclic hydroperoxide-endoperoxides hke 229 are obtained, from (S )-limonene (227), in a 4-component one-operation free-radical domino reaction in which 5 new bonds are sequentially formed. Particular experimental conditions are required in order to reduce the formation of by-products 230 and (PhS)2, and to favor the critical 6-exo-ring closure of peroxy-radical 231 to carbon-centered radical 232206 chemoselective reduction of bridged bicyclic hydroperoxide-endoperoxides... 

Stepwise Versus Domino Reactions—the Problem of Chemoselectivity.. . 52... 

Ma and coworkers recently utilized a double arylation strategy for an efficient synthesis of benzofuran-3-carboxylates 69 (Scheme 9.24) [125]. In the first step of this domino reaction, the Cu( I)-catalyzed chemoselective C-arylation of (3-ketoesters 67 vtith ortho-bromoiodobenzenes 66 provided the key o-bromoaryl-substituted eno-lates 68. These reactive intermediates vide supra) readily underwent the second Cu (I)-catalyzed intramolecular O-arylation, furnishing the desired benzofurans 69. The reaction tolerates a variety of substituents on both coupling partners 66 and 67, allowing for the preparation of tri- and tetra-substituted frameworks in good yields. 

For other example of catalyst free multicomponent synthesis of pyrroles, see X. Wang, X.-P. Xu, S.-Y. Wang, W. Zhou, S.-J. Ji, Org. Lett. 2013, 15, 4246- 249. Highly efficient chemoselective synthesis of polysubstituted pyrroles via isocyanide-based multicomponent domino reaction. 

The successful completion of this domino reaction encouraged us to check some further hydroformylation-allylboration-hydroformylation sequences. For instance, the homoallylic alcohol 58 was converted to the ynol ether 59. To convert the latter to the alkenyl boronate (55%) 60 a zirconium catalyst (30) had to be chosen for the hydroboration. With rhodium catalysts chemoselectivity between the alkyne and the alkene moieties was... 

Finally, multicomponent reactions (MCRs) are a subclass of domino reactions and can be defined as processes in which three or more starting materials react to form a product, where basically all or most of the atoms contribute to the newly formed product [10]. A recent example reported by our group (Scheme 1.4c) involves the reaction between p-ketoamides, acrolein, and aminophenols, allowing the preparation of an enantioenriched diazabicyclo[2.2.2]octanone (2,6-DABCO) scaffold [11]. The chemoselective reaction sequence installs five new bonds and three stereocenters, with excellent yields and high levels of stereocontrol. 

In order to study any chemoselectivity influences of microwave irradiation on the domino Knoevenagel/hetero-Diels-Alder process (the so-called Tietze reaction), Raghunathan and coworkers [31a] investigated the transformation of 4-hydroxy coumarins (10-85) with benzaldehydes 10-86 in EtOH to afford pyrano[2,3-c]cou-marin 10-87 and pyrano[2,3-b]chromone derivatives 10-88. Normal heating of 10-85a and 10-86a at reflux for 4h gave a 68 32 mixture of 10-87a and 10-88 in 57% yield, whereas under microwave irradiation a 97 7 mixture in 82% yield was obtained. Similar results were found using the benzo-annulated substrates 10-85b and 10-86b. 

MacMillan s catalysts 56a and 61 allowed also the combination of the domino 1,4-hydride addition followed by intramolecular Michael addition [44]. The reaction is chemoselective, as the hydride addition takes place first on the iminium-activated enal. The enamine-product of the reaction is trapped in a rapid intramolecular reaction by the enone, as depicted in Scheme 2.54. The intramolecular trapping is efficient, as no formation of the saturated aldehyde can be observed. The best results were obtained with MacMillan s imidazolidinium salt 61 and Hantzsch ester 62 as hydride source. As was the case in the cyclization reaction, the reaction affords the thermodynamic trans product in high selectivity. This transformation sequence is particularly important in demonstrating that the same catalyst may trigger different reactions via different mechanistic pathways, in the same reaction mixture. 

---