Functionalization Of Complex Molecules Research Articles

1,2‐Dichloroethane‐Assisted Defluorinative Ring‐Opening Reaction of DABCO and Polyfluoroalkyl Peroxides: Synthesis of Fluorinated N‐Ethyl Piperazines

Comprehensive SummaryA catalyst‐free and additive‐free ring‐opening reaction of polyfluoroalkyl peroxides, triethylenediamine (DABCO), and 1,2‐dichloroethane (DCE) has been developed for the defluorinative synthesis of structurally diverse piperazines featuring a fluoroenone framework and a N‐chloroethyl‐substituent with high Z‐stereoselectivity. The success of this three‐component reaction is attributed to the in situ generation of an active 1‐(2‐chloroethyl)‐1,4‐diazabicyclo[2.2.2]octan‐1‐ium (DABCO·DCE) salt, which judiciously acts as a formal N‐(2‐chloroethyl)piperazine equivalent in the defluorinative coupling with less‐studied aliphatic fluorinated substances. Impressively, this reaction accomplishes multi‐activation of robust C(sp3)‐F, C(sp3)‐Cl, C(sp3)‐O, and C(sp3)‐N bonds in a one‐pot process, offering a practical platform for the late‐stage functionalization of complex molecules. Furthermore, the resulting products can not only serve as versatile building blocks for the synthesis of fluorinated heterocycles, but also undergo C—Cl bond displacement transformations with N‐, O‐, and S‐nucleophiles.

Fe‐Catalyzed α‐C(sp3)−H Amination of N‐Heterocycles

AbstractNitrogen‐heterocycles are privileged structures in both marketed drugs and natural products. On the other hand, C−H amination reactions furnish unconventional and straightforward approaches for the construction of C−N bonds. Yet, most of the known methods rely on precious metal catalysts. Herein we report a site‐selective intermolecular C(sp3)−H amination of N‐heterocycles, catalyzed by inexpensive FeCl2, which allows the functionalization of a wide range of pharmaceutically relevant cyclic amines. The C−H amination occurs site‐selectively in α‐position to the nitrogen atom, even when weaker C−H bonds are present, and furnishes Troc‐protected aminals or amidines. The method employs the N‐heterocycle as limiting reagent and is applicable to the late‐stage functionalization of complex molecules. Its synthetic potential was further illustrated through the derivatization of α‐aminated products and the application to a concise total synthesis of the reported structure for senobtusin. Mechanistic studies allowed to propose a plausible reaction mechanism involving a turnover‐limiting Fe‐nitrene generation followed by fast H atom transfer and radical rebound.

Photoredox Synthesis of Silyl Ethers via Radical Coupling of Ketones with Hydrosilanes and [1, 2]‐Brook Rearrangement

AbstractAn expedient synthesis of silyl ethers is reported via photocatalytic free radical coupling of ketones with hydrosilanes and subsequent [1, 2]‐Brook rearrangement. This strategy features the advantages of 100 % atom economy, environmental friendliness, easily available starting materials as well as late‐stage functionalization of complex molecules.

Transition-Metal-Catalyzed Silylation and Borylation of C-H Bonds for the Synthesis and Functionalization of Complex Molecules.

The functionalization of C-H bonds in organic molecules containing functional groups has been one of the holy grails of catalysis. One synthetically important approach to the diverse functionalization of C-H bonds is the catalytic silylation or borylation of C-H bonds, which enables a broad array of downstream transformations to afford diverse structures. Advances in both undirected and directed methods for the transition-metal-catalyzed silylation and borylation of C-H bonds have led to their rapid adoption in early-, mid-, and late-stage of the synthesis of complex molecules. In this Review, we review the application of the transition-metal-catalyzed silylation and borylation of C-H bonds to the synthesis of bioactive molecules, organic materials, and ligands. Overall, we aim to provide a picture of the state of art of the silylation and borylation of C-H bonds as applied to the synthesis and modification of diverse architectures that will spur further application and development of these reactions.

Photoredox/Ti Dual‐Catalyzed Dehydroxylation of Cyclobutanone Oximes for γ‐Cyanoalkyl Radical Generation: Access to Cyanoalkyl‐Substituted Oxoindolines

AbstractIn this work, we have established a photoredox/Ti dual‐catalyzed dehydroxylation of cyclobutanone oximes. The resulting γ‐cyanoalkyl radicals undergo a cascade radical addition/cyclization with N‐acrylamides to afford cyanoalkyl substituted oxoindolines under mild conditions. This reaction also exhibits broad substrate scope and good functional group tolerance. Furthermore, it is applicable to late‐stage functionalization of complex molecules and gram‐scale synthesis, which illustrates its potential value in organic synthesis.magnified image

Asymmetric Oxidative Lactonization of Enynyl Boronates

AbstractOxidation of C−B bonds is extensively used in organic synthesis, materials science, and chemically biology. However, these oxidations are usually limited to the oxidation of C(sp3)−B and C(sp2)−B bonds. The C(sp)−B bond oxidation is rarely developed. Herein we present a novel strategy for the preparation of γ‐lactones via the oxidation of enynyl boronates. This process successively involves the C(sp)−B bond oxidation, the epoxidation of C−C double bond and the lactonization. This protocol provided various γ‐lactones and unsaturated butenolides efficiently that are prevalent in numerous nature products and bioactive molecules. Most importantly, asymmetric oxidative lactonization of enynyl boronates was also achieved, providing chiral γ‐lactones in high enantioselectivities and diastereoselectivities. The versatile transformations and ubiquity of γ‐lactones shed light on the importance of this strategy in the construction and late‐stage functionalization of complex molecules.

α-Amino Radical Halogen Atom Transfer Agents for Metallaphotoredox-Catalyzed Cross-Electrophile Couplings of Distinct Organic Halides.

α‐Amino radicals from simple tertiary amines were employed as halogen atom transfer (XAT) agents in metallaphotoredox catalysis for cross‐electrophile couplings of organic bromides with organic iodides. This XAT strategy proved to be efficient for the generation of carbon radicals from a range of partners (alkyl, aryl, alkenyl, and alkynyl iodides). The reactivities of these radical intermediates were captured by nickel catalysis with organobromides including aryl, heteroaryl, alkenyl, and alkyl bromides, enabling six diverse C−C bond formations. Classic named reactions including Negishi, Suzuki, Heck, and Sonogashira reactions were readily achieved in a net‐reductive fashion under mild conditions. More importantly, the cross coupling was viable with either organic bromide or iodide as limiting reactant based on the availability of substrates, which is beneficial to the late‐stage functionalization of complex molecules. The scalability of this method in batch and flow was investigated, further demonstrating its applicability.

Recent Developments in Enantioselective Organocatalytic Cascade Reactions for the Construction of Halogenated Ring Systems

AbstractChiral halogenated substances have many applications in pharmaceuticals, agrochemicals, and materials, such as polymers, liquid crystals and as intermediates in synthesis. The presence of a halogen atom in a molecule can have a large effect in its properties; for instance, halogens are used in drugs to improve lipophilicity, membrane permeability and absorption, and even the blood‐brain barrier permeability. As highlighted in this review, there are nowadays a range of highly selective, versatile halogenating reagents, electrophilic, nucleophilic or radical in nature, which operate under mild conditions, allowing late‐stage functionalization of complex molecules in cascade reactions. Recent developments in organocatalyst design revealed novel Cinchona alkaloids derivatives, chiral phosphoric acids, amines, phosphines and several bifunctional catalysts, mostly thiourea‐ or squaramide‐based, which introduced chirality, with high levels of enantio‐ and diastereoselection, in the formation of one or multiple chiral centers in a single synthetic operation, as shown. In this review we survey the literature published in this field from 2014 to 2020.

Site Selective Chlorination of C(sp3)−H Bonds Suitable for Late‐Stage Functionalization

AbstractC(sp3)−Cl bonds are present in numerous biologically active small molecules, and an ideal route for their preparation is by the chlorination of a C(sp3)−H bond. However, most current methods for the chlorination of C(sp3)−H bonds are insufficiently site selective and tolerant of functional groups to be applicable to the late‐stage functionalization of complex molecules. We report a method for the highly selective chlorination of tertiary and benzylic C(sp3)−H bonds to produce the corresponding chlorides, generally in high yields. The reaction occurs with a mixture of an azidoiodinane, which generates a selective H‐atom abstractor under mild conditions, and a readily‐accessible and inexpensive copper(II) chloride complex, which efficiently transfers a chlorine atom. The reaction's exceptional functional group tolerance is demonstrated by the chlorination of >30 diversely functionalized substrates and the late‐stage chlorination of a dozen derivatives of natural products and active pharmaceutical ingredients.

Site Selective Chlorination of C(sp3 )-H Bonds Suitable for Late-Stage Functionalization.

C(sp3 )-Cl bonds are present in numerous biologically active small molecules, and an ideal route for their preparation is by the chlorination of a C(sp3 )-H bond. However, most current methods for the chlorination of C(sp3 )-H bonds are insufficiently site selective and tolerant of functional groups to be applicable to the late-stage functionalization of complex molecules. We report a method for the highly selective chlorination of tertiary and benzylic C(sp3 )-H bonds to produce the corresponding chlorides, generally in high yields. The reaction occurs with a mixture of an azidoiodinane, which generates a selective H-atom abstractor under mild conditions, and a readily-accessible and inexpensive copper(II) chloride complex, which efficiently transfers a chlorine atom. The reaction's exceptional functional group tolerance is demonstrated by the chlorination of >30 diversely functionalized substrates and the late-stage chlorination of a dozen derivatives of natural products and active pharmaceutical ingredients.

Selective Electrochemical Hydrolysis of Hydrosilanes to Silanols via Anodically Generated Silyl Cations

AbstractThe first electrochemical hydrolysis of hydrosilanes to silanols under mild and neutral reaction conditions is reported. The practical protocol employs commercially available and cheap NHPI as a hydrogen‐atom transfer (HAT) mediator and operates at room temperature with high selectivity, leading to various valuable silanols in moderate to good yields. Notably, this electrochemical method exhibits a broad substrate scope and high functional‐group compatibility, and it is applicable to late‐stage functionalization of complex molecules. Preliminary mechanistic studies suggest that the reaction appears to proceed through a nucleophilic substitution reaction of an electrogenerated silyl cation with H2O.

Photoredox‐Mediated Minisci Alkylation of N‐Heteroarenes using Carboxylic Acids and Hypervalent Iodine

AbstractA new protocol of photoredox‐mediated Minisci alkylation of N‐heteroarenes with aliphatic carboxylic acids has been developed. Using Ru(bpy)3Cl2 as photocatalyst and acetoxybenziodoxole (BI–OAc) as oxidant, a variety of primary, secondary and tertiary alkyl groups can be efficiently incorporated into various electron‐deficient N‐heteroarenes. This protocol demonstrated excellent substrate scope and good functional group tolerance and can be applied to late‐stage functionalization of complex molecules.

ChemInform Abstract: Synthesis and Late‐Stage Functionalization of Complex Molecules Through C—H Fluorination and Nucleophilic Aromatic Substitution.

AbstractThe selectivity of the first step, the fluorination, is examined on medicinally relevant heteroaromatic substrates with several electronically deferring mono or 3,5‐disubstituted pyridines (such as (XIV)).