ACS catalyst: palladium catalyzed asymmetric hydroalkynylation of cyclopropene

At present, the non enantioselective addition of non activated 1,2-disubstituted double bonds to organometallic compounds (carbon metallization) is still very challenging Since lautens, Fox and Nakamura reported the related work, the direct functionalization of the achiral unsaturated ternary carbon ring has attracted extensive attention, and the enantioselective addition of SP 3 and SP 2 hybrid alkyls and heteroatom asymmetric addition (scheme 1a) catalyzed by copper, rhodium and lanthanide have been reported However, it is still difficult to introduce alkynyl group into the direct functionalization of the non chiral unsaturated ternary carbon ring Recently, Hou Zhaomin reported the gadolinium catalyzed asymmetric hydroalkynylation of cyclopropene (scheme 1b) Chiral alkynyl cyclopropane is an important structural fragment of many natural products, and can be used to construct more complex skeletons Recently, a palladium catalyzed asymmetric hydroalkynylation of cyclopropene has been developed by Ilan Marek research group of Israel Institute of technology The results were published in ACS catalyst (DOI: 10.1021 / acscalal 9b04960) (picture source: ACS catalyst.) firstly, the author explored the PD catalyzed non enantioselective and enantioselective hydroalkylation (Table 1) with cyclopropene 1a and phenylacetylene as model substrates Through the screening of catalyst, chiral ligand and reaction solvent, the author found that PD (ACAC) 2 was the best catalyst, r-dm-binap was the best ligand, et 2O was the best reaction solvent, and the substrate could obtain alkynylcyclopropane 2a with excellent enantioselectivity (er98:2, Dr 20:1) (picture source: ACS catalyst.) next, the effect of the properties of ternary ring substituents on the reaction selectivity (scheme 2) was investigated Cyclopropene with electron withdrawing or electron donating groups can obtain the corresponding hydroalkylation products with good yield and non enantioselectivity When cyclopropene contains benzyl substituents, alkyne cyclopropane 2e and 2e ʹ can be separated with good enantiomer ratio In addition, when C3 contains the same substituents, the expected products can be obtained with high enantioselectivity (picture source: ACS catalyst.) then, the author prepared dimethylcyclopropene for palladium catalyzed asymmetric Alkynylation, and separated the expected product 2g (DR 88:12) in medium yield Then, the author investigated the nucleophilic alkynyl group (scheme 3) Different substituted aromatic ethynes show excellent selectivity, and the enantioselectivity of nonameric and enantiomeric is not significantly affected by the presence of alkyl substituents in the intermediate or para position of aromatic rings In addition, the conversion can also tolerate electron deficient p-bromophenylacetylene, and O -, M - and p-fluorophenylacetylene can also obtain fluoroalkynyl cyclopropane with good enantioselectivity In addition, the alkynyl group can also tolerate various functional groups, such as esters, ferrocene, pyridine and acetal This method can also be extended to the asymmetric addition of 1-phenyl-1,3-butanediyne and shows excellent enantioselectivity It should be noted that TMS substituted alkynes generate racemic products, while alkyl substituted alkynes do not produce expected products (picture source: ACS catalyst.) based on the above results, the author attempts to extend this method to the catalytic asymmetric addition of conjugated alkynes and synthesize a series of alkynes (scheme 4) under standard conditions The results showed that the corresponding products could be obtained with medium yield and excellent enantioselectivity (DR 20:1, er ≥ 99:1) In addition, the enantioselectivity and non enantioselectivity will not be changed when aromatic ring substrates are substituted (picture source: ACS catalyst.) conclusion: Ilan Marek research group has developed a Pd (ACAC) 2 / (R) - dm-binap catalyzed asymmetric hydroalkylation of achromatic cyclopropene with different terminal alkynes, diynes and alkynes This method has excellent enantioselectivity and provides a simple, mild and atom economical method for the synthesis of alkynyl cyclopropane enriched with enantiomers.