Intermolecular coupling synthesis

Electroreduction of y- and 5-cyano ketones in isoPrOH with a Sn cathode gave a-hydroxyketones with good diastereo-selectivities as cyclization products. The reaction has been used as a key step for the synthesis of, for example, guaiazulene, triquinanes, and dihydrojasmone. Similarly, the corresponding intermolecular couplings were realized [315]. 

In a similar way, a novel route for synthesis of cr,/ -unsaturated amide 242 is explored via intermolecular coupling of four components, that is, alkyne, hydrosilane, amine, and GO (Equation (41)). All of these components are assembled in the ordered manner with the assistance of an Rh complex. Pyrrolidine as a nucleophile gives the best results. None of the alcohols can participate in a similar transformation. 

On anodic oxidation of 3,6-diisobutylpiperazine-2,5-dione in acetonitrile, a compound was obtained, which was suggested to be 1,6-diisopropyl-3,8-dimethyl-5//, 10//-diimidazo[ 1,5-n 1, 5 -d]pyrazine-5,10-dione (44), formed by 1,3-cycloaddition of a primary oxidation product to the solvent.96 Another heterocyclic synthesis by intermolecular coupling of 2,4,5-tri-tert-butylphenol with acetonitrile has been reported.97... 

The bridging of sulfonamide groups with diiodo compounds can also be applied to the intermolecular coupling of rotaxanes. When rotaxane 80e was treated with 95 under standard conditions, 76% of the wheel-bis[2]rotaxane 102 and 8% of the iodine-substituted rotaxane 101 were isolated (Figure 40) [46]. 101 is an excellent substrate for the synthesis of higher and unsymmetric rotaxane assemblies. 

This method is particularly effective with cyclic substrates, and the combined effects of intramolecular and intermolecular asymmetric induction give up to 76 1 (kf/ks) differentiation between enantiomers of a cyclic allylic alcohol. This kinetic resolution provides a practical method to resolve 4-hydroxy-2-cyclopentenone, a readily available but sensitive compound. Hydrogenation of the racemic compound at 4 atm H2 proceeds with kf/ks =11, and, at 68% conversion, gives the slow-reacting R enantiomer in 98% ee. The alcoholic product is readily convertible to its crystalline, enantiomerically pure fert-butyldimethylsilyl ether, an important building block in the three-component coupling synthesis of prostaglandins (67). 

Yet another synthesis of corrphycene 64, by means of copper-catalyzed intermolecular coupling of the easily accessible l,2-bis-(l-iodo-dipyrrin-9-yl)-ethanes 68, resulting in the formation of 69 (Scheme 32) and subsequent demetallation to corrphycenes 64 (R =Me), has been reported (1996MC69). 

Scheme 32 Synthesis of corrphycene through copper-catalyzed intermolecular coupling.

Although the Heck reaction may be efficiently employed for synthesis, it has its limits that should not go unmentioned the Heck reaction can not—at least not intermolecularly—couple alkenyl triflates (-bromides, -iodides) or aryl triflates (-bromides, -iodides) with metal-free aromatic compounds in the same way as it is possible with the same substrates and metal-free alkenes. The reason is step 4 of the mechanism in Figure 16.35 (part II). If an aromatic compound instead of an alkene was the coupling partner the aromaticity with this carbopallada-tion of a C=C double bond would have to be sacrificed in step 4. Typically, Heck reactions can only be run at a temperature of 100 °C even if they proceed without any such energetic effort. This is why this additional energetically demanding loss of aromaticity is not feasible. 

Bringmann and co-workers have shown that modest control of atrop-selectivity can be achieved upon oxidative intermolecular coupling (dimerization) of the chiral phenol 205 [77]. In the synthesis of magistophorenes A and B (206a/b), the chiral precursor 205 afforded both isomers with a slight preference for the B series when exposed to di-tert-butyl peroxide (DTBP) (Scheme 51). 

Intermolecular coupling between ketones and 0-methyl oximes, hydrazones, and nitrones occurs during reduction at a tin cathode in isopropanol [59]. The reaction with O-methyloxinies is a convenient synthesis of 2-aminoalcohols XVI. It is not clear in these reactions which of the functions, C=N or CO, is reduced first to generate the species active toward the coupling reaction. 

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