Reports: G1
48330-G1 Catalytic Alpha-Functionalization of Alkyl Nitriles
Our research in the area of nitrile functionalization set out to examine two parallel lines of inquiry. First, we had preliminary results that indicated that zinc salts could be used to form transient α-metallated nitriles that would act as nucleophiles. Second, we wanted to explore the use of one of the products of this reaction, specifically α-silyl nitriles, in new carbon-carbon bond-forming reactions. Although the first part of this project suffered a setback revealed by careful control experiments, we have preliminary data that the second part of the project will succeed as described in our original proposal. In addition, this starter grant has enabled exploration of another area of chemistry that has been extremely fruitful, specifically in the area of catalyst-free functionalization of vinylogous esters.
The rapid synthesis of α-silyl nitriles will enable the easy exploration of these potentially valuable substrates. To date, these materials are made by either the stoichiometric deprotonation nitriles with amide bases or by the reduction of α-halo nitriles. In connection with our studies of the catalytic functionalization of alkynes with zinc salts, we noticed competing α-silylation of nitriles and esters. In a continuation of these studies, we found that the substrate scope was very good and high yields were universally obtained for esters (4 examples, 62-82% yield) and nitriles (4 examples, 78->99% yield) using 10 mol% of the catalyst. In analogy to our previous studies, we examined the influence of catalyst loading. In contrast to the alkyne functionalization wherein yield drops with catalyst loading and the reaction does not proceed in the absence of catalyst, nitrile silylation proceeds in the absence of catalyst with no decrease in conversion.1 Although this result is disheartening with respect to future experiments that rely on catalytic generation of zincated nitriles, this method is high yielding and avoids the use of strong bases.
The use of α-silyl nitriles in novel organocatalytic reactions appears to be a promising new avenue for the development of carbon-carbon bond-formation. We have prepared benzylcinchonium acetate for initial studies. Although related catalysts have been developed for the reactions of enolates, we believed that a nucleophilic and basic counterion would promote nitrile anion formation from α-silyl nitriles. This new catalyst can be prepared in high yield in four steps. Although no conversion is observed in a non-polar solvent, an increase in catalyst loading and a switch to DMF provided a high yield of the β-hydroxy nitrile product. We are continuing to explore this novel catalytic process and will fully optimize the catalyst structure, counterion, and solvent that are required for high catalyst turnover and stereoselectivity.
During the first year of this PRF grant, we have also been able to explore new reactivity discovered in the group. We have observed that Grignard reagents (RMgX) will displace alkoxy groups on 2-susbtituted naphthoic esters. Although this reactivity had been noticed previously, we extended it to ketones and demonstrated a preference for nucleophilic attack on the aryl ether over an unhindered ketone! Moreover, attack on a similarly substituted sulfonate ester, which is ostensibly a far superior leaving group, was not observed. This reaction offers complementary reactivity to transition-metal cross-coupling reactions and will enable the assembly of complex molecules from simple feedstocks. We will demonstrate this capability in the first enantioselective synthesis of the sesquiterpenoids myomontanone, wherein three simple fragments will be assembled two steps.
In summary, we have discovered new reactivity that enables the synthesis of useful organic frameworks from simple starting materials. Research conducted with funds from the PRF has revealed interesting new catalytic reactivity, whereas parallel research during the first half of the funding period has illuminated new direct reactions that offer reactivity that complements transition metal-catalyzed cross-couplings.
1. Emde, H.; Simchen, G. Synthesis 1977, 867-869. Emde, H.; Simchen, G. Synthesis 1977, 636-637.
