Visible‐Light‐Induced ortho‐Selective Migration on Pyridyl Ring: Trifluoromethylative Pyridylation of Unactivated Alkenes

The photocatalyzed ortho‐selective migration on a pyridyl ring has been achieved for the site‐selective trifluoromethylative pyridylation of unactivated alkenes. The overall process is initiated by the selective addition of a CF₃ radical to the alkene to provide a nucleophilic alkyl radical intermediate, which enables an intramolecular endo addition exclusively to the ortho‐position of the pyridinium salt. Both secondary and tertiary alkyl radicals are well‐suited for addition to the C2‐position of pyridinium salts to ultimately provide synthetically valuable C2‐fluoroalkyl functionalized pyridines. Moreover, the method was successfully applied to the reaction with P‐centered radicals. The utility of this transformation was further demonstrated by the late‐stage functionalization of complex bioactive molecules.     

Photoredox Generation of Carbon‐Centered Radicals Enables the Construction of 1,1‐Difluoroalkene Carbonyl Mimics

Described is a facile, scalable route to access functional‐group‐rich gem ‐difluoroalkenes. Using visible‐light‐activated catalysts in conjunction with an arsenal of carbon‐radical precursors, an array of trifluoromethyl‐substituted alkenes undergoes radical defluorinative alkylation. Nonstabilized primary, secondary, and tertiary radicals can be used to install functional groups in a convergent manner, which would otherwise be challenging by two‐electron pathways. The process readily extends to other perfluoroalkyl‐substituted alkenes. In addition, we report the development of an organotrifluoroborate reagent to expedite the synthesis of the requisite trifluoromethyl‐substituted alkene starting materials.     

Decomposition of model alkoxyamines in simple and polymerizing systems. I. 2,2,6,6‐tetramethylpiperidinyl‐ N‐oxyl‐based compounds

The thermal decomposition of five alkoxyamines labeled TEMPO–R, where TEMPO was 2,2,6,6‐tetramethylpiperidinyl‐N‐oxyl and R was cumyl (Cum), 2‐tert‐butoxy‐carbonyl‐2‐propyl (PEst), phenylethyl (PhEt), 1‐tert‐butoxy‐carbonylethyl (EEst), or 1‐methoxycarbonyl‐3‐methyl‐3‐phenylbutyl (Acrylate‐Cum), was studied with ¹H NMR in the absence and presence of styrene and methyl methacrylate. The major products were alkenes and the hydroxylamine 1‐hydroxy‐2,2,6,6‐tetramethyl‐ piperidine (TEMPOH), and in monomer‐containing solutions, unimeric and polymeric alkoxyamines and alkenes were also found. Furthermore, the reactions between TEMPO and the radicals EEst and PEst were studied with chemically induced dynamic nuclear polarization. In comparison with coupling, TEMPO reacted with the radicals Cum, PEst, PhEt, and EEst and their unimeric styrene adducts by disproportionation to alkenes and TEMPOH only to a minor extent (0.6–3%) but with the radical adducts to methyl methacrylate to a considerable degree (≥20%). Parallel to the radical cleavage, TEMPO–EEst (but not the other alkoxyamines or TEMPO–Acrylate‐Cum) underwent substantial nonradical decay. The consequences for TEMPO‐mediated living radical polymerizations are discussed. © 2001 John Wiley & Sons, Inc. J Polym Sci Part A: Polym Chem 39: 3604–3621, 2001     

Pd/Light‐Accelerated Atom‐Transfer Carbonylation of Alkyl Iodides: Applications in Multicomponent Coupling Processes Leading to Functionalized Carboxylic Acid Derivatives

The atom‐transfer carbonylation reaction of various alkyl iodides thereby leading to carboxylic acid esters was effectively accelerated by the addition of transition‐metal catalysts under photoirradiation conditions. By using a combined Pd/hν reaction system, vicinal C‐functionalization of alkenes was attained in which α‐substituted iodoalkanes, alkenes, carbon monoxide, and alcohols were coupled to give functionalized esters. When alkenyl alcohols were used as acceptor alkenes, three‐component coupling reactions, which were accompanied by intramolecular esterification, proceeded to give lactones. Pd‐dimer complex [Pd₂(CNMe)₆][PF₆]₂, which is known to undergo homolysis under photoirradiation conditions, worked quite well as a catalyst in these three‐ or four‐component coupling reactions. In this metal/radical hybrid system, both Pd radicals and acyl radicals are key players and a stereochemical study confirmed the carbonylation step proceeded through a radical carbonylation mechanism.     

Absolute Rate Constants for the Addition of the 2‐(Methoxycarbonyl)propan‐2‐yl and the 3,3,3‐Trifluoracetonyl Radicals to Alkenes in Solution

Absolute rate constants and some of their Arrhenius parameters were obtained by time‐resolved electron spin resonance (ESR) spectroscopy for the addition of the 2‐(alkoxycarbonyl)propan‐2‐yl and 3,3,3‐trifluoroacetonyl (=3,3,3‐trifluoro‐2‐oxopropyl) radicals to a variety of mono‐ and 1,1‐disubstituted alkenes. Their analysis shows that the addition of 2‐(alkoxycarbonyl)propan‐2‐yl is mainly governed by the exothermicity of the reaction with slight modifications by nucleophilic and electrophilic effects giving rise to an overall ambiphilic behavior. In contrast, large electrophilic polar effects dominate the addition of the 3,3,3‐trifluoroacetonyl (=3,3,3‐trifluoro‐2‐oxopropan‐2‐yl) radical, as it is expected from its large electron affinity. For both radicals, the activation energies are well‐predicted by analytic equations for the enthalpic and polar terms. A comparison of the rate data of 2‐(alkoxycarbonyl)propan‐2‐yl with the homo‐ and copolymerization rate constants of the propagating radical of methyl methacrylate shows that the additions of these structurally related low‐ and high‐molecular‐weight radicals to alkenes are governed by very similar effects.     

New Radical Borylation Pathways for Organoboron Synthesis Enabled by Photoredox Catalysis

Radical borylation using N‐heterocyclic carbene (NHC)‐BH₃ complexes as boryl radical precursors has emerged as an important synthetic tool for organoboron assembly. However, the majority of reported methods are limited to reaction modes involving carbo‐ and/or hydroboration of specific alkenes and alkynes. Moreover, the generation of NHC‐boryl radicals relies principally on hydrogen atom abstraction with the aid of radical initiators. A distinct radical generation method is reported, as well as the reaction pathways of NHC‐boryl radicals enabled by photoredox catalysis. NHC‐boryl radicals are generated via a single‐electron oxidation and subsequently undergo cross‐coupling with the in‐situ‐generated radical anions to yield gem‐difluoroallylboronates. A photoredox‐catalyzed radical arylboration reaction of alkenes was achieved using cyanoarenes as arylating components from which elaborated organoborons were accessed. Mechanistic studies verified the oxidative formation of NHC‐boryl radicals through a single‐electron‐transfer pathway.     

Electrochemical Intramolecular Aminooxygenation of Unactivated Alkenes

An electrochemical approach to the intramolecular aminooxygenation of unactivated alkenes has been developed. This process is based on the addition of nitrogen‐centered radicals, generated through electrochemical oxidation, to alkenes followed by trapping of the cyclized radical intermediate with 2,2,6,6‐tetramethylpiperidine‐N‐oxyl radical (TEMPO). Difunctionalization of a variety of alkenes with easily available carbamates/amides and TEMPO affords aminooxygenation products in high yields and with excellent trans selectivity for cyclic systems (d.r. up to>20:1). The approach provides a much‐needed complementary route to existing cis‐selective methods.     

A Bulky Thiyl‐Radical Catalyst for the [3+2] Cyclization of N‐Tosyl Vinylaziridines and Alkenes

Thiyl‐radical‐catalyzed cyclization reactions of N‐tosyl vinylaziridines and alkenes were developed as a new synthetic method for the generation of substituted pyrrolidines. The key to making this process accessible to a broad range of substrates is the use of a sterically demanding thiyl radical, which prevents the undesired degradation of the catalyst.     

Solvent‐Free Photooxidation of Alkanes by Dioxygen with 2,3‐Dichloro‐5,6‐dicyano‐p‐benzoquinone via Photoinduced Electron Transfer

Photooxidation of alkanes by dioxygen occurred under visible light irradiation of 2,3‐dichloro‐5,6‐dicyano‐p‐benzoquinone (DDQ) which acts as a super photooxidant. Solvent‐free hydroxylation of cyclohexane and alkanes is initiated by electron transfer from alkanes to the singlet and triplet excited states of DDQ to afford the corresponding radical cations and DDQ^??, as revealed by femtosecond laser‐induced transient absorption measurements. Alkane radical cations readily deprotonate to produce alkyl radicals, which react with dioxygen to afford alkylperoxyl radicals. Alkylperoxyl radicals abstract hydrogen atoms from alkanes to yield alkyl hydroperoxides, accompanied by regeneration of alkyl radicals to constitute the radical chain reactions, so called autoxidation. The radical chain is terminated in the bimolecular reactions of alkylperoxyl radicals to yield the corresponding alcohols and ketones. DDQ^??, produced by the photoinduced electron transfer from alkanes to the excited state of DDQ, disproportionates with protons to yield DDQH₂.     

Defluorinative C(sp3)−P Bond Construction for the Synthesis of Phosphorylation gem‐Difluoroalkenes under Catalyst‐ and Oxidant‐Free Conditions

Defluorinative C(sp³)?P bond formation of α‐trifluoromethyl alkenes with phosphine oxides or phosphonates have been achieved under catalyst‐ and oxidant‐free conditions, giving phosphorylation gem‐difluoroalkenes as products. α‐Trifluoromethyl alkenes bearing various of aryl substituents such as halogen, cyano, ester and heterocyclic groups are available in this transformation. The results of control experiments demonstrated that the mechanism of dehydrogenative/defluorinative cross‐coupling reactions was not a radical route, but might be an S_N2′ process involving phosphine oxide anion.     

Reaction between Azidyl Radicals and Alkynes: A Straightforward Approach to NH‐1,2,3‐Triazoles

Reaction between nitrogen‐centered radicals and unsaturated C?C bonds is an effective synthetic strategy for the construction of nitrogen‐containing molecules. Although the reactions between nitrogen‐centered radicals and alkenes have been studied extensively, their counterpart reactions with alkynes are extremely rare. Herein, the first example of reactions between azidyl radicals and alkynes is described. This reaction initiated an efficient cascade reaction involving inter‐/intramolecular radical homolytic addition toward a C?C triple bond and a hydrogen‐atom transfer step to offer a straightforward approach to NH‐1,2,3‐triazoles under mild reaction conditions. Both the internal and terminal alkynes work well for this transformation and some heterocyclic substituents on alkynes are compatible. This mechanistically distinct strategy overcomes the inherent limitations associated with azide anion chemistry and represents a rare example of reactions between a nitrogen‐centered radicals and alkynes.     

Quantitative Treatment of the Kinetics of Free‐Radical‐Mediated Damage. Protection by Free‐Radical Scavengers

Equations are derived to quantitatively describe the effect of a free‐radical scavenger upon the rate of a radical‐mediated process that senses the steady‐state free‐radical concentration. The dependence of the ratio R°/R (where R° is the rate of the process in the absence of additive) upon the additive concentration depends upon the type of reaction that determines the free‐radical lifetime. Normal Stern‐Volmer‐like behavior is expected only when the lifetime of the radical in the absence of free‐radical scavengers is determined by the concentration of the substance employed as the reporter of the free‐radical concentration. These predictions are tested in a system comprised of 2,2′‐azobis[2‐methylpropanimidamide dihydrochloride) as the free‐radical source, c‐phycocyanin as the reporter molecule, and Trolox (=3,4‐dihydro‐6‐hydroxy‐2,5,7,8‐tetramethyl‐2H‐1‐benzopyran‐2‐carboxylic acid) tryptophan and 4‐methoxyphenol as peroxyl‐radical scavengers. The data obtained with Trolox show that it behaves as a nearly ideal free‐radical scavenger. On the other hand, the data obtained with tryptophan and 4‐methoxyphenol as scavengers show, when plotted according to the Stern‐Volmer equation, a strong downward curvature. These results are explained in terms of c‐phycocyanin bleaching by scavenger‐derived free radicals.     

Copper‐Catalyzed Radical/Radical CH/PH Cross‐Coupling: α‐Phosphorylation of Aryl Ketone O‐Acetyloximes

The selective radical/radical cross‐coupling of two different organic radicals is a great challenge due to the inherent activity of radicals. In this paper, a copper‐catalyzed radical/radical C? H/P? H cross‐coupling has been developed. It provides a radical/radical cross‐coupling in a selective manner. This work offers a simple way toward β‐ketophosphonates by oxidative coupling of aryl ketone o‐acetyloximes with phosphine oxides using CuCl as catalyst and PCy₃ as ligand in dioxane under N₂ atmosphere at 130 °C for 5 h, and yields ranging from 47 % to 86 %. The preliminary mechanistic studies by electron paramagnetic resonance (EPR) showed that, 1) the reduction of ketone o‐acetyloximes generates iminium radicals, which could isomerize to α‐sp³‐carbon radical species; 2) phosphorus radicals were generated from the oxidation of phosphine oxides. Various aryl ketone o‐acetyloximes and phosphine oxides were suitable for this transformation.     

Copper‐Catalyzed Alkylarylation of Unactivated Alkenes: Synthesis of 3‐Alkyl Indolines from N‐Allyl Anilines and Alkanes

A rare example of C(sp³)?H functionalization of simple alkanes with unactivated alkenes is presented. In the presence of a copper salt and di‐tert‐butyl peroxide (DTBP), N‐allyl anilines underwent exo‐selective alkylation/cyclization cascade with unactivated alkenic bonds as radical acceptors and simple alkanes as radical precursors, providing a direct access to 3‐alkyl indolines. The present protocol features simple operation, broad substrate scope and great exo selectivity.     

CBr4‐Mediated Cross‐Dehydrogenative Coupling Reaction of Amines

A novel CBr₄‐mediated dehydrogenative Povarov/aromatization tandem reaction of glycine derivatives with alkenes, leading to complex quinoline derivatives, and a CBr₄‐mediated dehydrogenative C?H functionalization of N‐aryl tetrahydroisoquinolines with nucleophiles to form C?C and C?P bonds are reported. The reactions were performed under very simple and mild reaction conditions; only CBr₄ was used as a promoter. A plausible mechanism involving a radical process is proposed.     

Free‐Radical Termination Kinetics Studied Using a Novel SP‐PLP‐ESR Technique

Summary: A novel method for measuring termination rate coefficients, k_t, in free‐radical polymerization is presented. A single laser pulse is used to instantaneously produce photoinitiator‐derived radicals. During subsequent polymerization, radical concentration is monitored by time‐resolved electron spin resonance (ESR) spectroscopy. The size of the free radicals, which exhibits a narrow distribution increases linearly with time t, which allows the chain‐length dependence of k_t to be deduced. The method will be illustrated using dodecyl methacrylate polymerization as an example.

Two straight lines provide a very satisfactory representation of the chain‐length dependence of k_t over the entire chain‐length region (c_R = radical concentration).     

Absolute Rate Constants for the Addition of the 1‐(tert‐Butoxy)carbonylethyl Radical to Alkenes in Solution

Absolute rate constants and some of their Arrhenius parameters are reported for the addition of the 1‐[(tert‐butoxy)carbonyl]ethyl radical (MeC . HCO₂Me₃) to several mono‐ or 1,1‐disubstituted alkenes in acetonitrile as obtained by time‐resolved electron spin resonance spectroscopy. At 295 K, the rate constants range from 470 M ⁻¹ s⁻¹ (but‐1‐ene) to 2.4⋅10⁵ M ⁻¹ s⁻¹ (1,1‐diphenylethene), the experimental activation energies range from 26.8 kJ/mol (but‐1‐ene) to 14.7 kJ/mol (styrene), and the frequency factors obey on the average log (A/M ⁻¹ s⁻¹)=7.9±0.5. The rate constants of the secondary 1‐[(tert‐butoxy)carbonyl]ethyl radical are close to the geometric mean of those of the related primary [(tert‐butoxy)carbonyl]methyl and the tertiary 2‐(methoxycarbonyl)propan‐2‐yl radicals. The activation energies for addition of these three carboxy‐substituted alkyl radicals are mainly governed by the addition enthalpy but are also substantially lowered by ambiphilic polar effects. The results support a previously derived predictive analysis, and relations to rate constants of acrylate polymerizations are discussed.     

Antiferromagnetic Interactions in 1D Heisenberg Linear Chains of 7‐(4‐Fluorophenyl) and 7‐Phenyl‐Substituted 1,3‐Diphenyl‐1,4‐dihydro‐ 1,2,4‐benzotriazin‐4‐yl Radicals

7‐(4‐Fluorophenyl) and 7‐phenyl‐substituted 1,3‐diphenyl‐1,4‐dihydro‐1,2,4‐benzotriazin‐4‐yl radicals were characterized by X‐ray diffraction analysis and variable‐temperature magnetic susceptibility studies. The radicals pack in 1D π stacks of equally spaced slipped radicals with interplanar distances of 3.59 and 3.67 Å and longitudinal angles of 40.97 and 43.47°, respectively. Magnetic‐susceptibility studies showed that both radicals exhibit antiferromagnetic interactions. Fitting the magnetic data revealed that the behavior is consistent with 1D regular linear antiferromagnetic chain with J=?12.9 cm^?1, zJ′=?0.4 cm^?1, g=2.0069 and J=?11.8 cm^?1, zJ′=?6.5 cm^?1, g=2.0071, respectively. Magnetic‐exchange interactions in benzotriazinyl radicals are sensitive to the degree of slippage, and inter‐radical separation and subtle changes in structure alter the fine balance between ferro‐ and antiferromagnetic interactions.     

Copper‐Catalyzed 1,2‐Methoxy Methoxycarbonylation of Alkenes with Methyl Formate

Reported here is a copper‐catalyzed 1,2‐methoxy methoxycarbonylation of alkenes by an unprecedented use of methyl formate as a source of both the methoxy and the methoxycarbonyl groups. This reaction transforms styrene and its derivatives into value‐added β‐methoxy alkanoates and cinnamates, as well as medicinally important five‐membered heterocycles, such as functionalized tetrahydrofurans, γ‐lactones, and pyrrolidines. A ternary β‐diketiminato‐Cu^I‐styrene complex, fully characterized by NMR spectroscopy and X‐ray crystallographic analysis, is capable of catalyzing the same transformation. These findings suggest that pre‐coordination of electron‐rich alkenes to copper might play an important role in accelerating the addition of nucleophilic radicals to electron‐rich alkenes, and could have general implications in the design of novel radical‐based transformations.