1.5- Hydride transfer/ring-closure

The rapid development of organocatalysis impels chemists to discover new synthetic methodologies. Many important transformations that could only be realized by transition metal catalysis can now be achieved via organocatalysis. In 2010, Kim and coworkers reported a novel C-H bond functionalization reaction via a tandem 1,5-hydride transfer/ring closure sequence. Based on the iminium-enamine cascade activation of catalyst 33, the fused tetrahydroquino-Unes 35 could be synthesized from substrates 34 with good stereoselectivity. This is the first example of an organocatalytic intramolecular redox reaction (Scheme 36.10) [16]. 

An efficient FeCl3-catalysed stereoselective intramolecular tandem 1,5-hydride transfer/ring-closure reaction of benzylideneindolinones to give spirooxindole 0 tetrahydroquinolines has been reported (Scheme 64)7 ... 

Scheme 36.10 Organocatalytic stereoselective hydride transfer/ring closure sequence.

The exo and the endo ring closures (the kc reactions) are in competition with the aryl radical-tributyltin hydride transfer (the ks or ku reaction). These workers162 used this competition to determine the primary hydrogen-deuterium kinetic isotope effect in the hydride transfer reaction between the aryl radical and tributyltin hydride and deuteride. 

Diols generally react with dichlorocarbene to produce a mixture of alkenes and chlorinated cyclopropanes or chloroalkanes, depending on the reaction conditions whereas, under phase-transfer catalysed conditions, the major products are the alkenes and epoxides produced by ring closure of the initial adduct (Scheme 7.20) [14]. When an excess of chloroform is used, further reaction of the alkenes with dichlorocarbene produces the cycloadducts. In addition to the formation of the alkene and epoxide, 1,2-dihydroxycyclooctane yields cyclooctanone, via a 1,2-hydride shift within the intermediate carbenium ion. 

The pyrrole ring can also be constructed starting from an 7V-vinyl-2-halobenzoic amide. The /V-(2-iodobcnzoyl)-1,4-dihydropyndine derivative shown in 3.19. underwent palladium catalysed ring closure to give a condensed isoindolone derivative. The use of formic acid as co-solvent led to the reduction of the intermediate palladium complex formed in the insertion step, instead of / -hydride elimination. The transfer of the stereochemical information from the starting material to the product was poor.25... 

Equation 16 illustrates a celebrated example where ring closure competes with vicinal hydride shift (a common form of atom transfer in cations, which does not take place in free radicals or anions). The gas phase reaction was explored by preparing the dimethylfluoronium ion, (CH3)2F" , by y-radiolysis of fluoromethane. Exothermic methylation of a sample of C-yd-phenethyl chloride (where the asterisk in equation 16 symbolizes the labeled position) in the gas mixture gives a vibrationally excited ion that loses chloromethane to form two isomeric ions, a-phenethyl cation and spirooctadienyl cation (sometimes called ethylenebenzenium). Nucleophilic attack by methanol in the reaction mixture yields PhCH(CH3)OCH3, whose isotopic label remains almost entirely at the methyl group. The recovered PhCH2CH20CH3 contains equally distributed between the two methylene positions. The spirooctadienyl ion does not isomerize to a-phenethyl cation, even though DFT calculations predict the latter to be 55 kJ/mol more stable. 

Solid-liquid phase-transfer catalysis. The final step in a recent synthesis of the -lactam (2) involved ring closure of the amide chloride (1). This was accomplished with sodium hydride in methylene chloride containing this quaternary salt (0.1 eq.). This 3-lactam synthesis is of interest since it is based on... 

In 2009, Seidel and co-workers reported a Lewis acid-catalyzed [l,5]-hydride transfer reaction for the synthesis of polycyclic tetrahydroquinolines. It was found that the gadolinium triflate could efficiently accelerate the reaction (Scheme 4.4a). Preliminary attempts to realize asymmetric catalysis revealed that when a chiral magnesium bisoxazoline was utilized as the catalyst, the desired product 6a could be obtained in 74% yield and 30% ee, which was the first example of a catalytic asymmetric [l,5]-hydride transfer reaction by a chiral Lewis acid (Scheme 4.4b). The reason for the relatively low enanti-oselectivity was attributed to the reversibility of the ring-closure step in the presence of a strong Lewis acid catalyst. 

The final cyclization can also proceed in the manner of a fitt-electrocyclic ring closure (67T-ERC) (Scheme 3). After a [l,5]-hydride transfer, the conjugated 1,3,5-hexatriene intermediate I can be produced, which imdergoes subsequent 6tt-ERC to give the cyclized product 4. Thus, the formation of unstable zwitterionic intermediate A (Schemes 1, 2) with charge separation is avoided [52-56]. 

Scheme 3 Cascade [l,5]-hydride transfer/dn-electrocyclic ring closure 2.2 Reactivity of Different Hydrogen Donors...

However, the observed remarkable selectivity for amide formation suggests that free hemiaminal intermediate in solution is not involved, since the latter would likely liberate water faster than H2. We believe that the amine reacts with the intermediate aldehyde while it is still coordinated to the metal center, leading to formation of the quaternary salt 12 (Fig. 6), which may transfer a proton to the dearomatized phosphine arm (to give intermediate 10). Subsequent (3-hydride elimination and ring closure by the amine arm would lead to the tra/is-dihydride complex 6 and product amide. Liberation of dihydrogen from 6 would complete the catalytic cycle with regeneration of catalyst 5. 

It is observed that 1,5-hydride transfer can be accelerated by iminium activation. Therefore, it is speculated that cinnamaldehyde derivatives 194 represent ideal acceptors that are susceptible to activation by secondary amine catalysts capable of forming an iminium ion (Scheme 1.85) [132], The resulting iminium ion activation is expected to increase hydride transfer to alkene. The subsequent ring-closure reaction mediated by enamine catalysis furnishes ring-fused tetrahydroquinoline derivatives in moderate yields and high levels of enantioselectivity. 

The capture of the palladium complex formed in the intramolecular insertion of A-acryloyl-2-haloanilines has also been exploited by Grigg. The addition of aryl-, and vinylboron reagents to the mixture of N-(2 methylacryloyl)-2-iodoaniline and a palladium catalyst led, after the closure of the five membered ring, to the transfer of the organic moiety to the formal terminal carbon atom of the acryloyl chain (3.16.). The role of the substituent in the 2 -position is presumably to block / -hydride elimination and so prolong the lifetime of the palladium complex formed in the insertion step.21... 

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