Quaternary Centers by Nickel-Catalyzed Cross-Coupling of Tertiary Carboxylic Acids and (Hetero)Aryl Zinc Reagents.
ABSTRACT: This work bridges a gap in the cross-coupling of aliphatic redox-active esters with aryl zinc reagents. Previously limited to primary, secondary, and specialized tertiary centers, a new protocol has been devised to enable the coupling of general tertiary systems using nickel catalysis. The scope of this operationally simple method is broad, and it can be used to simplify the synthesis of medicinally relevant motifs bearing quaternary centers.
Project description:Despite remarkable recent advances in transition-metal-catalyzed C(sp3)-C cross-coupling reactions, there remain challenging bond formations. One class of such reactions include the formation of tertiary-C(sp3)-C bonds, presumably due to unfavorable steric interactions and competing isomerizations of tertiary alkyl metal intermediates. Reported herein is a Ni-catalyzed migratory 3,3-difluoroallylation of unactivated alkyl bromides at remote tertiary centers. This approach enables the facile construction of otherwise difficult to prepare all-carbon quaternary centers. Key to the success of this transformation is an unusual remote functionalization via chain walking to the most sterically hindered tertiary C(sp3) center of the substrate. Preliminary mechanistic and radical trapping studies with primary alkyl bromides suggest a unique mode of tertiary C-radical generation through chain-walking followed by Ni-C bond homolysis. This strategy is complementary to the existing coupling protocols with tert-alkyl organometallic or -alkyl halide reagents, and it enables the expedient formation of quaternary centers from easily available starting materials.
Project description:The Pd-catalyzed cross-coupling of racemic tertiary allylic carbonates and allylboronates is described. This reaction generates all-carbon quaternary centers in a highly regioselective and enantioselective fashion. The outcome of these reactions is consistent with a process that proceeds by way of 3,3'-reductive elimination of bis(?(1)-allyl)palladium intermediates. Strategies for distinguishing the product alkenes and application to the synthesis of (+)-?-cuparenone are also described.
Project description:Enantiopure aziridin-2-yl methanols 3-7 are used as highly effective sensors for enantiodiscrimination of ?-racemic carboxylic acids containing tertiary or quaternary stereogenic centers. A linear correlation between theoretical and observed % ee values for CSA-3 and enantiomerically enriched samples of mandelic acid has been observed, indicating the possible application of these compounds in the ee determination. The free NH and OH groups in 3-7 ensure good recognition.
Project description:Selective creation of quaternary carbon centers has been a long-standing challenge in synthetic chemistry. We report here the chromium-catalyzed, para-selective formation of arylated quaternary carbon centers by alkylative reactions of benzamide derivatives with tertiary alkylmagnesium bromides at room temperature. The reaction, which was enabled by a low-cost chromium(III) salt combined with trimethylsilyl bromide, introduces a sterically bulky tertiary alkyl scaffold on the para-position of benzamide derivatives in a highly selective fashion without either isomerization of the tertiary alkyl group or formation of ortho-alkylated byproducts. Forming low-valent Cr species in situ by reaction of CrCl3 with t-BuMgBr accompanied by evolution of hydrogen can be considered, which serves as reactive species to promote the reaction. The para-alkylation likely occurs via a radical-type nucleophilic substitution of imino-coordination benzimidate intermediate.
Project description:The design and gram-scale synthesis of a cyclohexa-1,4-diene-based surrogate of isobutene gas is reported. Using the highly electron-deficient Lewis acid B(C6 F5 )3 , application of this surrogate in the hydromethallylation of electron-rich styrene derivatives provided sterically congested quaternary carbon centers. The reaction proceeds by C(sp3 )-C(sp3 ) bond formation at a tertiary carbenium ion that is generated by alkene protonation. The possibility of two concurrent mechanisms is proposed on the basis of mechanistic experiments using a deuterated surrogate.
Project description:Ruthenium-catalyzed tert-prenylation of isatin 1 occurs efficiently in the absence of N-protecting groups under the conditions of C-C bond-forming transfer hydrogenation employing 1,1-dimethylallene as the prenyl donor. The prenylated adduct, 3-hydroxy-3-tert-prenyl-oxindole 2, is converted to the tertiary neopentyl chloride 3, which participates in nucleophilic substitution by way of an aza-o-xylylene intermediate to furnish adducts 4a-4i. Through tertiary neopentyl substitution, two contiguous all-carbon quaternary centers are established.
Project description:An efficient and mild method for acyl-C<sub>sp3</sub> bond formation based on the direct conversion of carboxylic acids has been established. This protocol is enabled by the synergistic, Ir-photoredox/nickel catalytic cross-coupling of in situ activated carboxylic acids and alkyltrifluoroborates. This versatile method is amenable to the cross-coupling of structurally diverse carboxylic acids with various potassium alkyltrifluoroborates, affording the corresponding ketones with high yields. In this operationally simple cross-coupling protocol, aliphatic ketones are obtained in one step from bench stable, readily available carboxylic acids.
Project description:Ruthenium-catalyzed transfer hydrogenation of 2-substituted dienes 1a-i in the presence of paraformaldehyde results in reductive coupling at the 2-position to furnish the hydroxymethylation products 3a-i, which embody all-carbon quaternary centers. Reductive coupling of diene 1g to paraformaldehyde under standard conditions, but employing deuterio-paraformaldehyde, 2-propanol-d(8), or both, corroborated a catalytic mechanism involving rapid, reversible diene hydrometalation with incomplete regioselectivity in advance of C-C coupling. The present method provides an alternative to the hydroformylation of conjugated dienes, for which efficient, regioselective catalytic systems remain undeveloped.
Project description:Unsymmetrical dialkyl ketones can be directly prepared by the nickel-catalyzed reductive coupling of carboxylic acid chlorides or (2-pyridyl)thioesters with alkyl iodides or benzylic chlorides. A wide variety of functional groups are tolerated by this process, including common nitrogen protecting groups and C-B bonds. Even hindered ketones flanked by tertiary and secondary centers can be formed. The mechanism is proposed to involve the reaction of a (L)Ni(alkyl)(2) intermediate with the carboxylic acid derivative.
Project description:Catalytic enantioselective allylic substitution (EAS) reactions, which involve the use of alkyl- or aryl-substituted vinylaluminum reagents and afford 1,4-dienes containing a quaternary carbon stereogenic center at their C-3 site, are disclosed. The C-C bond-forming transformations are promoted by 0.5-2.5 mol % of sulfonate bearing chiral bidentate N-heterocyclic carbene (NHC) complexes, furnishing the desired products efficiently (66-97% yield of isolated products) and in high site (>98% S(N)2')- and enantioselectivity [up to 99:1 enantiomer ratio (er)]. To the best of our knowledge, the present report puts forward the first cases of allylic substitution reactions that result in the generation of all-carbon quaternary stereogenic centers through the addition of a vinyl unit. The aryl- and vinyl-substituted vinylaluminum reagents, which cannot be prepared in high efficiency through direct reaction with diisobutylaluminum hydride, are accessed through a recently introduced Ni-catalyzed reaction of the corresponding terminal alkynes with the same inexpensive metal-hydride agent. Sequential Ni-catalyzed hydrometalations and Cu-catalyzed C-C bond-forming reactions allow for efficient and selective synthesis of a range of enantiomerically enriched EAS products, which cannot be accessed by previously disclosed strategies (due to inefficient vinylmetal synthesis or low reactivity and/or selectivity with Si-substituted derivatives). The utility of the protocols developed is demonstrated through a concise enantioselective synthesis of natural product bakuchiol.