alkyl electrophiles
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Synthesis ◽  
2022 ◽  
Author(s):  
Takashi Nishikata ◽  
Tom Sheppard ◽  
Naoki Tsuchiya

The Suzuki-Miyaura coupling is extremely useful to construct Csp2-Csp2 carbon bonds. On the other hand, Csp2-Csp3 coupling reactions are do not work well, and tert-alkylative Suzuki-Miyaura coupling is particularly challenging due to problematic oxidative addition and beta-hydride elimination side reactions. In this short review, we will introduce recent examples of tert-alkylative Suzuki-Miyaura couplings with tert-alkyl electrophiles or -boron reagents. The review will mainly focus on catalyst and product structures and the proposed mechanisms .


2021 ◽  
Author(s):  
Song Lin ◽  
Wen Zhang ◽  
Lingxiang Lu ◽  
Wendy Zhang ◽  
Jose Mondragon ◽  
...  

Recent research in medicinal chemistry suggests a correlation between an increase in the fraction of sp3 carbons in drug candidates with their improved success rate in clinical trials. As such, the development of robust and selective methods for the construction of C(sp3)-C(sp3) bonds remains a critical problem in modern organic chemistry. Owing to the broad availability and synthetic accessibility of alkyl halides, their direct cross coupling—commonly known as cross-electrophile coupling (XEC)—provides a promising route toward this objective. However, achieving high selectivity in C(sp3)-C(sp3) XEC remains a largely unmet challenge. Herein, we employ electrochemistry to achieve the differential activation of alkyl halides by exploiting their disparate electronic and steric properties. Specifically, the selective cathodic reduction of a more substituted alkyl halide gives rise to a carbanion, which undergoes preferential coupling with a less substituted alkyl halide via bimolecular nucleophilic substitution (SN2) to forge a new C–C bond. This transition-metal free protocol enables the efficient XEC of a variety of functionalized and unactivated alkyl electrophiles and exhibits substantially improved chemoselectivity versus existing methodologies.


2021 ◽  
Author(s):  
Song Lin ◽  
Wen Zhang ◽  
Lingxiang Lu ◽  
Wendy Zhang ◽  
Jose Mondragon ◽  
...  

Recent research in medicinal chemistry suggests a correlation between an increase in the fraction of sp3 carbons in drug candidates with their improved success rate in clinical trials. As such, the development of robust and selective methods for the construction of C(sp3)-C(sp3) bonds remains a critical problem in modern organic chemistry. Owing to the broad availability and synthetic accessibility of alkyl halides, their direct cross coupling—commonly known as cross-electrophile coupling (XEC)—provides a promising route toward this objective. However, achieving high selectivity in C(sp3)-C(sp3) XEC remains a largely unmet challenge. Herein, we employ electrochemistry to achieve the differential activation of alkyl halides by exploiting their disparate electronic and steric properties. Specifically, the selective cathodic reduction of a more substituted alkyl halide gives rise to a carbanion, which undergoes preferential coupling with a less substituted alkyl halide via bimolecular nucleophilic substitution (SN2) to forge a new C–C bond. This transition-metal free protocol enables the efficient XEC of a variety of functionalized and unactivated alkyl electrophiles and exhibits substantially improved chemoselectivity versus existing methodologies.


2021 ◽  
Author(s):  
Wei Shu ◽  
Peng-Fei Yang ◽  
Jian-Xin Liang ◽  
Han-Tong Zhao ◽  
Jian-Xin Zhang ◽  
...  

Routes to efficient construction of fully aliphatic substituted tertiary chiral centers are highly challenging and desirable. Herein, a Ni-catalyzed enantioselective hydroalkylation of unactivated alkenes at room temperature is described, providing a general and practical access to tertiary stereogenic carbon centers with three alkyl substituents. This reaction involves the regio- and stereoselective hydrometalation of unactivated alkenes with Markovnikov selectivity, followed by coupling with unactivated alkyl electrophiles to access tertiary chiral centers with full alkyl substituents. The mild and robust conditions enable the use of terminal and internal unactivated alkenes as well as primary and secondary unactivated alkyl, benzyl, propargyl halides for the construction of diverse trialkyl tertiary stereogenic carbon centers with broad functional group tolerance.<br>


2021 ◽  
Author(s):  
Wei Shu ◽  
Peng-Fei Yang ◽  
Jian-Xin Liang ◽  
Han-Tong Zhao ◽  
Jian-Xin Zhang ◽  
...  

Routes to efficient construction of fully aliphatic substituted tertiary chiral centers are highly challenging and desirable. Herein, a Ni-catalyzed enantioselective hydroalkylation of unactivated alkenes at room temperature is described, providing a general and practical access to tertiary stereogenic carbon centers with three alkyl substituents. This reaction involves the regio- and stereoselective hydrometalation of unactivated alkenes with Markovnikov selectivity, followed by coupling with unactivated alkyl electrophiles to access tertiary chiral centers with full alkyl substituents. The mild and robust conditions enable the use of terminal and internal unactivated alkenes as well as primary and secondary unactivated alkyl, benzyl, propargyl halides for the construction of diverse trialkyl tertiary stereogenic carbon centers with broad functional group tolerance.<br>


2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Jia-Wang Wang ◽  
Yan Li ◽  
Wan Nie ◽  
Zhe Chang ◽  
Zi-An Yu ◽  
...  

AbstractTo increase the reliability and success rate of drug discovery, efforts have been made to increase the C(sp3) fraction and avoid flat molecules. sp3-Rich enantiopure amines are most frequently encountered as chiral auxiliaries, synthetic intermediates for pharmaceutical agents and bioactive natural products. Streamlined construction of chiral aliphatic amines has long been regarded as a paramount challenge. Mainstream approaches, including hydrogenation of enamines and imines, C–H amination, and alkylation of imines, were applied for the synthesis of chiral amines with circumscribed skeleton structures; typically, the chiral carbon centre was adjacent to an auxiliary aryl or ester group. Herein, we report a mild and general nickel-catalysed asymmetric reductive hydroalkylation to effectively convert enamides and enecarbamates into drug-like α-branched chiral amines and derivatives. This reaction involves the regio- and stereoselective hydrometallation of an enamide or enecarbamate to generate a catalytic amount of enantioenriched alkylnickel intermediate, followed by C–C bond formation via alkyl electrophiles.


2021 ◽  
Author(s):  
Radha Bam ◽  
Alexandros S. Pollatos ◽  
Austin J. Moser ◽  
Julian G. West

Terminal or subterminal olefins can be selectively formed from alkyl electrophiles via bio-inspired vitamin B12 photocatalysis.


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