Allylic Sp3 Research Articles

Efficient and Direct Functionalization of Allylic sp3 C-H Bonds with Concomitant CO2 Reduction.

Solar-driven CO2 reduction integrated with C-C/C-X bond-forming organic synthesis represents a substantially untapped opportunity to simultaneously tackle carbon neutrality and create an atom-/redox-economical chemical synthesis. Herein, we demonstrate the first cooperative photoredox catalysis of efficient and tunable CO2 reduction to syngas, paired with direct alkylation/arylation of unactivated allylic sp3 C-H bonds for accessing allylic C-C products, over SiO2 -supported single Ni atoms-decorated CdS quantum dots (QDs). Our protocol not only bypasses additional oxidant/reductant and pre-functionalization of organic substrates, affording a broad of allylic C-C products with moderate to excellent yields, but also produces syngas with tunable CO/H2 ratios (1 : 2-5 : 1). Such win-win coupling catalysis highlights the high atom-, step- and redox-economy, and good durability, illuminating the tantalizing possibility of a renewable sunlight-driven chemical feedstocks manufacturing industry.

Efficient and Direct Functionalization of Allylic sp3 C−H Bonds with Concomitant CO2 Reduction

AbstractSolar‐driven CO2 reduction integrated with C−C/C−X bond‐forming organic synthesis represents a substantially untapped opportunity to simultaneously tackle carbon neutrality and create an atom‐/redox‐economical chemical synthesis. Herein, we demonstrate the first cooperative photoredox catalysis of efficient and tunable CO2 reduction to syngas, paired with direct alkylation/arylation of unactivated allylic sp3 C−H bonds for accessing allylic C−C products, over SiO2‐supported single Ni atoms‐decorated CdS quantum dots (QDs). Our protocol not only bypasses additional oxidant/reductant and pre‐functionalization of organic substrates, affording a broad of allylic C−C products with moderate to excellent yields, but also produces syngas with tunable CO/H2 ratios (1 : 2–5 : 1). Such win‐win coupling catalysis highlights the high atom‐, step‐ and redox‐economy, and good durability, illuminating the tantalizing possibility of a renewable sunlight‐driven chemical feedstocks manufacturing industry.

Site-Selective C-H Allylation of Alkanes: Facile Access to Allylic Quaternary sp3 -Carbon Centers.

The construction of allylic quaternary sp3 -carbon centers has long been a formidable challenge in transition-metal-catalyzed alkyl-allyl coupling reactions due to the severe steric hindrance. Herein, we report an effective carbene strategy that employs well-defined vinyl-N-triftosylhydrazones as a versatile allylating reagent to enable direct assembly of these medicinally desirable structural elements from low-cost alkane feedstocks. The reaction exhibited excellent site selectivity for tertiary C-H bonds, broad scope (>60 examples and >20 : 1:0 r. r.) and good efficiency, even on a gram-scale, making it a convenient alternative to the well-known Trost-Tsuji allylation reaction for the formation of alkyl-allyl bonds. Combined experimental and computational studies were employed to unravel the mechanism and origin of site- and chemoselectivity of the reaction.

(Invited) Catalytic Allylation of Aldehydes Using Feedstock Alkenes

The efficient production of fine chemicals from simple and readily available bulk materials such as simple alkenes is an important research area in synthetic organic chemistry. Lower alkenes are produced by one of the most common chemical processes (i.e. hydrocarbon cracking) on over 500 million metric tons scale. Development of catalytic methods which enable the direct use of these abundant organic molecules as carbon sources is highly demanded for practical and selective chemical reactions. However, despite several previous examples, the use of feedstock alkenes in synthetically useful transformations remains a challenging task.Catalytic aldehyde allylation plays an important role in synthetic organic chemistry. Traditionally, nucleophilic allylmetal species as stoichiometric starting materials have contributed to the development of this catalytic process. Despite usefulness of this approach, however, there is room for improvement in the overall efficiency, redox/atom/step economy, and environmental sustainability. The catalytic generation of nucleophilic allylmetal species in situ from simple and feedstock alkenes via allylic sp3 C-H bond activation would be a straightforward approach. We envisioned that radical sp3 C-H bond activation followed by oxidative interception of the resulting carbon-centered radical by a metal complex is a promising strategy for the catalytic generation of organometallic species from inert substrates. We supposed the ternary hybrid catalysis comprising a photoredox catalyst, a hydrogen-atom-transfer (HAT) catalyst, and a metal catalyst would realize catalytic allylation of aldehydes with simple alkenes.We planned to use a combination of an acridinium photoredox catalyst (Mes-Acr+) and a thiophosphoric imide (TPI) HAT catalyst to activate an allylic C-H bond of the alkenes through the HAT process. Under visible light irradiation, single-electron oxidation of TPI by a photo-excited acridinium catalyst (*Mes-Acr+) generates a sulfur-centered radical (RS•). The RS• radical abstracts the allylic C-H bond of alkenes, affording allyl radicals. Based on the mechanism of Nozaki-Hiyama allylation, we expected that a chromium(II) complex catalyst oxidatively intercepted allyl radicals, giving allylchromium(III) species. This species reacts with aldehydes via a Zimmerman-Traxler transition state to produce chromium alkoxides in an anti-selective fashion. Protonolysis by the proton generated in the HAT catalysis should afford the target homoallylic alcohols and chromium(III) species. Single-electron reduction by the photoredox catalyst (Mes-Acr•) would close the catalytic cycle with regenerating a chromium(II) complex catalyst and the oxidized form of the photoredox catalyst (Mes-Acr+).Based on this mechanism, we studied the substrate scope with a combination of 5 mol% CrCl2, 10 mol% TPI catalyst (HAT) and 5 mol% acridinium photoredox catalyst (PC). First, the scope of alkenes was investigated. In all cases, the branched constitutional isomer was produced exclusively (>20/1). The reactions of C4 feedstocks, 1-butene and 2-butenes which are annually produced on a 105 metric ton scale, with benzaldehyde afforded the product in 94% and 100% yield, respectively, with high diastereoselectivity (14-16/1). This crotylation reaction using butenes as a starting material will significantly streamline polyketide synthesis. 3-Methyl-1-butene selectively afforded the product containing a quaternary carbon. Branched C6 alkenes were also competent substrates. Other alkenes, including cyclic, halide-containing, and ether-containing, all afforded the product in high yield. The aldehyde scope was then investigated by fixing the alkene substrate to 2-butene. A series of aromatic aldehydes bearing halogens, electron-withdrawing groups, and a boronate ester afforded the corresponding products with high diastereoselectivity. A methyl substituent at the ortho-, meta-, and para positions of the aromatic ring did not affect the results. The reactions of aliphatic aldehydes, including those containing potentially sensitive functional groups (e.g. amine, alkyl halide, sulfide and benzyl oxy moiety), also proceeded efficiently. Next, we investigated the application to highly functionalized substrates. Propranolol derivative bearing free hydroxy group were competent substrate. A dipeptide and a nucleic acid derivative containing coordinating polar functional groups such as amides and an adenine heterocycle did not affect the reaction progress. Therefore, the allylation of aldehydes mediated by the ternary hybrid catalysis realized high functional group compatibility and chemoselectivity using easily available feedstock alkenes.In conclusion, we developed a ternary hybrid catalysis, enabling catalytic allylation of aldehydes using simple alkenes, under visible light irradiation at room temperature. This hybrid catalysis is applicable to various types of unactivated alkenes including feedstock lower alkenes. Due to the high chemoselectivity and mild conditions, the reaction was applicable to highly functionalized bioactive molecules. The asymmetric variant enabled facile access to enantiomerically and diastereomerically enriched homoallylic alcohols by introducing a chiral ligand to the chromium catalyst. Further studies to expand the scope are ongoing. Figure 1

Sp3 carbon-fluorine bond activation in 2,2-difluorohomoallylic alcohols via nucleophilic 5-endo-trig cyclisation: synthesis of 3-fluorinated furan derivatives.

Nucleophilic 5-endo-trig cyclisation was achieved in 2,2-difluorohomoallylic alcohols. Upon treatment with potassium hydride, 2,2-difluorohomoallylic alcohols underwent an intramolecular SN2'-type reaction to afford 3-fluoro-2,5-dihydrofurans in high yields. In addition, the oxidation of these dihydrofurans formed 4-fluorofuran-2(5H)-ones. Thus, ring-fluorinated furan derivatives were efficiently obtained via allylic sp3 carbon-fluorine bond cleavage.

Iron-catalyzed esterification of allylic sp 3 C–H bonds with carboxylic acids: Facile access to allylic esters

Abstract The first general and efficient iron-catalyzed esterification of allylic sp3 C–H bonds with carboxylic acids using ionic iron(III) complexes (1–4) as a catalyst and DTBP (DTBP = di-tert-butyl peroxide) as an oxidant is achieved. A variety of allylic esters were synthesized in good to excellent yields using the ionic iron(III) complex 2 as a catalyst in a 5 mol% loading. This reaction is characterized by its high efficiency, broad substrate scope with excellent steric hindrance tolerance and good functional group compatibility.

Catalytic Multisite-Selective Acetoxylation Reactions at sp2 vs sp3 C-H Bonds in Cyclic Olefins.

The first Pd-catalyzed multisite-selective acetoxylation reactions are disclosed at an unactivated alkene sp2 C-H bond versus secondary allylic sp3 C-H bond in cyclic olefins via the modulation of directing groups. The different directing groups overcome the key challenge in differentiating C-H bonds and provide a new controlling approach for site-specific C-H activation. A wide variety of substrates are readily acetoxylated under operationally simple conditions. Mechanistic studies suggest that different Pd (IV) intermediates were involved in the multisite-selective acetoxylation reactions.

ChemInform Abstract: Catalysis Dual Catalysis at the Flick of a Switch

AbstractReview: 14 refs.

Catalysis: dual catalysis at the flick of a switch.

A combination of two catalysts — one of which is light-activated — has been used to promote new chemical reactivity, opening up fresh opportunities for the synthesis of structurally complex organic molecules. See Letter p.74 James Cuthbertson and David MacMillan describe the development of a new and general strategy for the direct arylation of allylic sp3 C–H bonds, potentially providing a strategy for the construction of complex organic molecules via the coupling of simple and otherwise inert building blocks, without introducing extraneous functional groups. The process, combing photoredox and thiol-based organic catalysis, requires only under mild conditions; and can accommodate a wide range of alkene and electron-deficient arene coupling partners.

Allylic and benzylic sp3 C-H oxidation in water.

A copper-catalyzed method for the oxidation of allylic and benzylic sp(3) C-H by aqueous tert-butyl hydroperoxide (T-Hydro) in water using a recyclable fluorous ligand has been developed. The reaction procedure is tolerant to additional functional groups and the fluorous ligand could be reused with little loss of catalytic activity.

Allylic sp3 C-H borylation of alkenes via allyl-Pd intermediates: an efficient route to allylboronates.

Palladium catalyzed allylic C-H functionalization was performed using exocyclic alkene substrates. Multi-component synthesis of stereodefined homoallylic alcohols could be performed using a reaction sequence involving allylic C-H borylation and allylation of aldehydes.

DDQ-mediated direct oxidative coupling of amides with benzylic and allylic sp3 C–H bonds under metal-free conditions

A simple and efficient method for the direct oxidative coupling of amides with benzylic and allylic sp3 C–H bonds using DDQ as an oxidant is described. A range of amides including benzamide, benzyl carbamate, and substituted sulfonamides reacted efficiently with various benzylic and allylic substrates under metal free conditions to afford amidation products in good to excellent yields.

ChemInform Abstract: Challenge and Progress. Palladium‐Catalyzed sp3 C—H Activation

AbstractReview: 114 refs.

Challenge and progress: palladium-catalyzed sp3 C–H activation

Palladium-catalysis has been broadly applied to sp2 C–H activation. Recently, palladium-catalyzed sp3 C–H activation has also been considered as an important strategy to construct synthetically useful C–C/C–X bonds. Allylic sp3 C–H bonds can be successfully activated by Pd(II) species to produce η3-coordinated palladium species for further transformations, while activation of general sp3 C–H bonds mainly proceeds through directed pathways with the assistance of proper directing groups or initiated by oxidative addition. Various catalytic mechanisms were extensively investigated through either Pd(II)/Pd(0), Pd(II)/Pd(IV) or Pd(0)/Pd(II) catalytic cycles. The challenges faced in this area have also been addressed in this perspective article.

ChemInform Abstract: Pyrrole Synthesis via Allylic sp3 C—H Activation of Enamines Followed by Intermolecular Coupling with Unactivated Alkynes.

AbstractA novel method is applied to prepare tri‐ and tetrasubstituted pyrrole derivatives in high yields.

An unexpected palladium migration from vinylic sp2 carbon to allylic sp3 carbon

A unique transformation to realize the allylic amination from vinylic bromides was described and an unexpected C-Pd migration was observed from sp2 carbon to adjacent allylic sp3 carbon initiated from vinyl bromide. Various 3-aryl-2-bromopropenes and secondary amines were surveyed and the allyl amination products were obtained in moderate isolated yields. The primary amine was not fit for this transformation. Mechanistic studies indicate that this migration went through β-hydride elimination and reverse C=C bond insertion.

Pyrrole Synthesis via Allylic sp3 C−H Activation of Enamines Followed by Intermolecular Coupling with Unactivated Alkynes

A conceptually novel pyrrole synthesis is reported, efficiently merging enamines and (unactivated) alkynes under oxidative conditions. In an intermolecular Rh catalyzed process, the challenging allylic sp(3) C-H activation of the enamine substrates is followed by the cyclization with the alkyne (R(3) = CO(2)R). Alternatively, in some cases (R(3) = CN), the enamine can be utilized for a vinylic sp(2) C-H activation. A total of 17 examples with yields above 60% is presented, together with the results of an initial mechanistic investigation.

A Concise, Metal‐Free Approach to the Synthesis of Oxime Ethers from Cross‐Dehydrogenative‐Coupling of sp3 C–H Bonds with Oximes

AbstractA concise oxime ether synthesis by a metal‐free dehydrogenative cross‐coupling reaction between allylic sp3 C–H bonds and oximes promoted by 2,3‐dichloro‐5,6‐dicyanoquinone (DDQ) is reported. The corresponding oxime ethers are obtained in good yields.

Catalytic Allylic Alkylation via the Cross-Dehydrogenative-Coupling Reaction between Allylic sp3C−H and Methylenic sp3C−H Bonds

A catalytic allylic alkylation was developed via the cross-dehydrogenative-coupling reaction of allylic sp3 C-H and methylenic sp3 C-H catalyzed by copper bromide and cobalt chloride in the presence of an oxidizing reagent, t-BuOOH. This methodology provides a direct way to use allylic sp3 C-H bonds for forming C-C bonds.

New transformations of unsaturated hydrocarbon ligands coordinated with mono- and dinuclear palladium units

Abstract