Temperature-modulated selective C(sp3)–H or C(sp2)–H arylation through palladium catalysis

Transition metal-catalysed C–H bond functionalisations have been extensively developed in organic and medicinal chemistry. Among these catalytic approaches, the selective activation of C(sp³)–H and C(sp²)–H bonds is particularly appealing for its remarkable synthetic versatility, yet it remains highly challenging. Herein, we demonstrate the first example of temperature-dependent selective C–H functionalisation of unactivated C(sp³)–H or C(sp²)–H bonds at remote positions through palladium catalysis using 7-pyridyl-pyrazolo[1,5-a]pyrimidine as a new directing group. At 120 °C, C(sp³)–H arylation was triggered by the chelation of a rare [6,5]-fused palladacycle, whereas at 140 °C, C(sp²)–H arylation proceeded instead through the formation of a 16-membered tetramer containing four 7-pyridyl-pyrazolo[1,5-a]pyrimidine–palladium chelation units. The subsequent mechanistic study revealed that both C–H activations shared a common 6-membered palladacycle intermediate, which was then directly transformed to either the [6,5]-fused palladacycle for C(sp³)–H activation at 120 °C or the tetramer for C(sp²)–H arylation at 140 °C with catalytic amounts of Pd(OAc)₂ and AcOH. Raising the temperature from 120 °C to 140 °C can also convert the [6,5]-fused palladacycle to the tetramer with the above-mentioned catalysts, hence completing the C(sp²)–H arylation ultimately.

Unprecedented 16-membered tetramer or [6,5]-fused palladacycle, mutually shadowboxing-like transformed from the shared common intermediate, accomplishes the Pd-catalysed temperature-dependent selective arylation of C(sp²)–H or C(sp³)–H.     

Mangana(iii/iv)electro-catalyzed C(sp3)–H azidation

Manganaelectro-catalyzed azidation of otherwise inert C(sp³)–H bonds was accomplished using most user-friendly sodium azide as the nitrogen-source. The operationally simple, resource-economic C–H azidation strategy was characterized by mild reaction conditions, no directing group, traceless electrons as the sole redox-reagent, Earth-abundant manganese as the catalyst, high functional-group compatibility and high chemoselectivity, setting the stage for late-stage azidation of bioactive compounds. Detailed mechanistic studies by experiment, spectrophotometry and cyclic voltammetry provided strong support for metal-catalyzed aliphatic radical formation, along with subsequent azidyl radical transfer within a manganese(iii/iv) manifold.

The merger of manganese-catalyzed C–H functionalization with electrosynthesis enabled C(sp³)–H azidation devoid of chemical oxidants or photochemical irradiation. Detailed mechanistic studies are supportive of a manganese(iii/iv) electrocatalysis.     

C(sp3)–H cyanation by a formal copper(iii) cyanide complex

High-valent metal oxo complexes are prototypical intermediates for the activation and hydroxylation of alkyl C–H bonds. Substituting the oxo ligand with other functional groups offers the opportunity for additional C–H functionalization beyond C–O bond formation. However, few species aside from metal oxo complexes have been reported to both activate and functionalize alkyl C–H bonds. We herein report the first example of an isolated copper(iii) cyanide complex (LCu^IIICN) and its C–H cyanation reactivity. We found that the redox potential (E_ox) of substrates, instead of C–H bond dissociation energy, is a key determinant of the rate of PCET, suggesting an oxidative asynchronous CPET or ETPT mechanism. Among substrates with the same BDEs, those with low redox potentials transfer H atoms up to a million-fold faster. Capitalizing on this mechanistic insight, we found that LCu^IIICN is highly selective for cyanation of amines, which is predisposed to oxidative asynchronous or stepwise transfer of H⁺/e⁻. Our study demonstrates that the asynchronous effect of PCET is an appealing tool for controlling the selectivity of C–H functionalization.

A formal copper(iii) cyanide complex and its C–H cyanation reactivity are reported. The redox potentials of substrates, instead of C–H bond dissociation energies, were found to be the key determinant of the rates of PCET.     

An iron(ii)-based metalloradical system for intramolecular amination of C(sp2)–H and C(sp3)–H bonds: synthetic applications and mechanistic studies

A catalytic system for intramolecular C(sp²)–H and C(sp³)–H amination of substituted tetrazolopyridines has been successfully developed. The amination reactions are developed using an iron-porphyrin based catalytic system. It has been demonstrated that the same iron-porphyrin based catalytic system efficiently activates both the C(sp²)–H and C(sp³)–H bonds of the tetrazole as well as azide-featuring substrates with a high level of regioselectivity. The method exhibited an excellent functional group tolerance. The method affords three different classes of high-value N-heterocyclic scaffolds. A number of important late-stage C–H aminations have been performed to access important classes of molecules. Detailed studies (experimental and computational) showed that both the C(sp²)–H and C(sp³)–H amination reactions involve a metalloradical activation mechanism, which is different from the previously reported electro-cyclization mechanism. Collectively, this study reports the discovery of a new class of metalloradical activation modes using a base metal catalyst that should find wide application in the context of medicinal chemistry, drug discovery and industrial applications.

A catalytic system for intramolecular C(sp²)–H and C(sp³)–H amination of substituted tetrazolopyridines has been successfully developed.     

N-Directed fluorination of unactivated Csp3–H bonds

Site-selective fluorination of aliphatic C–H bonds remains synthetically challenging. While directed C–H fluorination represents the most promising approach, the limited work conducted to date has enabled just a few functional groups as the arbiters of direction. Leveraging insights gained from both computations and experimentation, we enabled the use of the ubiquitous amine functional group as a handle for the directed C–H fluorination of Csp³–H bonds. By converting primary amines to adamantoyl-based fluoroamides, site-selective C–H fluorination proceeds under the influence of a simple iron catalyst in 20 minutes. Computational studies revealed a unique reaction coordinate for the catalytic process and offer an explanation for the high site selectivity.

By converting primary amines to adamantoyl-based fluoroamides, site-selective C–H fluorination proceeds under the influence of a simple iron catalyst in 20 minutes.

Due to the pervasiveness of fluorine atoms in industrially relevant small molecules, all practicing organic chemists appreciate the importance of this element. As a result of its unusual size and electronegativity, fluorine imparts unique physicochemical properties to pendant organic molecules.¹ For example, the strong C–F bond can prevent biological oxidation pathways, thereby thwarting rapid clearance and potentially improving pharmacokinetics of molecules.² Moreover, the installation of fluorine or trifluoromethyl groups, with their strong inductive effects,² can have a profound effect on the pK_a of nearby hydrogen atoms.³ These attributes, among others, have solidified the importance of fluorinated molecules in the medicinal,^1–4 material,⁵ and agrochemical⁶ industries. Yet, the same unique properties that make fluorine atoms attractive chemical modifiers also make their installation difficult. Consequently, new methods for site-selective fluorine incorporation remain highly desirable.⁷Methods to construct Csp²–F bonds traditionally make use of the Balz–Schiemann fluorodediazonization⁸ and halogen exchange (“Halex” process).⁹ Advances in transition metal-mediated fluorination have broadened access to Csp²–F-containing molecules,¹⁰ but methods to access aliphatic fluorides remain limited. Conventional methods to make Csp³–F bonds—such as nucleophilic displacement of alkyl halides¹¹ and deoxyfluorination¹²—can have limited functional group compatibility and unwanted side reactions. A more efficient route to form aliphatic C–F bonds would target the direct fluorination of Csp³–H bonds (Scheme 1).¹³Open in a separate windowScheme 1(a) Previous work on functional-group directed Csp³–H fluorination; (b) our approach to N-directed fluorination.Recent efforts with palladium catalysis employ conventional C–H-metallation strategies to target Csp³–H bonds for fluorination.¹⁴ Alternatively, radical H-atom abstraction can remove the transition metal from the C–H-cleavage step, thereby offering a promising approach for Csp³–H-bond functionalization.¹⁵ With undirected C–H fluorination,¹⁶ however, selectivity remains a challenge in molecules without strength-differentiated Csp³–H bonds.¹⁷ To overcome this, our group pioneered the directed fluorination of benzylic Csp³–H bonds through an iron-catalyzed process that involves 1,5 hydrogen-atom transfer (HAT) to cleave the desired Csp³–H bond.¹⁸ Since this work, other groups have demonstrated directed Csp³–H fluorination based on radical propagation that proceeds through an interrupted Hofmann–Löffler–Freytag (HLF)¹⁹ reaction (Scheme 1a). These examples employ various radical precursors such as enones,²⁰ ketones,²¹ hydroperoxides,²² and carboxamides²³ to direct fluorination to specific Csp³–H bonds. Since amines are ubiquitous in natural products and drugs, we sought to use amines as the building block of our directing group to achieve fluorination of unactivated Csp³–H bonds (Scheme 1b). By using amines as the starting point, one could use the approach in straightforward synthetic planning for the late-stage functionalization of remote C–H bonds.In the design phase of the project, we needed to devise a synthetically tractable N–F system that would enable 1,5-HAT and allow for fluorine transfer (Scheme 1b). To begin, we decided to examine common amine activating groups that would support 1,5-HAT while avoiding undesired radical reactions. The chosen activating group would provide the ideal steric and electronic properties to enable both N–F synthesis and N–F scission for 1,5-HAT. We first examined common acyl groups (e.g., acetyl-, benzoyl, and tosyl-based amides), but these proved unsatisfactory. For example, fluoroamide synthesis was either not achieved or low yielding, and the desired fluorine transfer proceeded with significant side reactions or returned starting material. We then turned our attention to more sterically hindered amides—which allow for higher yielding fluoroamide synthesis. For fluorine transfer, we hypothesized that the increased steric bulk could slow intermolecular H-atom transfer, thereby leading more efficient intramolecular 1,5-HAT. To that end, we were delighted that pivaloyl-based fluoroamide 1a proceeded in 64% yield to form product 2a (Scheme 2a). Interestingly, 7% of 1a underwent fluorination at the tert-butyl group of the pivaloyl—presumably through a 1,4-HAT reaction (2aa, Scheme 2a).²⁴ The problem is further exacerbated when the pivaloyl group is homologated by one methylene—providing only 7% yield of desired 2b with 32% of the fluorination taking place on the iso-pentyl group (2bb, Scheme 2a). In an attempt to “tie back” the pivaloyl group and prevent the undesired fluorination, we employed a cyclopropylmethyl-based fluoroamide but observed no improvement.Open in a separate windowScheme 2(a) The targeted 1,5-fluorination of unactivated aliphatic C–H bonds results in partial fluorination of the amine activating group; (b) DFT studies (uM06/cc-pVTZ(-f)-LACV3P**//uM06/LACVP** level of theory) identified the competing pathways responsible for alternate fluorination; (c) DFT (uM06/cc-pVTZ(-f)-LACV3P**//uM06/LACVP** level of theory) evaluation of adamantoylamides revealed higher transition state energy for 1,4-HAT due to restricted vibrational scissoring (d) adamantoyl-activated octylamine shows no fluorination of the activating group. ^{a 1}H-NMR yield using 1,3,5-trimethoxybenzene as an internal standard. ^{b 19}F-NMR yield using 4-fluorotoluene as an internal standard.At this point, 1a proved most promising for efficient fluorine transfer, as well as being the most synthetically accessible fluoroamide. The increased steric hindrance minimizes N-sulfonylation during fluorination with NFSI, a problem that plagued the synthesis of our previously targeted fluoroamides.¹⁸ Therefore, to further investigate how to improve fluorine transfer from 1a, we decided to model H-abstraction computationally.We hypothesized that the fluorinated side product 2aa was formed after 1,4-HAT. Since 1,4-HAT is rare,²⁴ we employed DFT (see ESI^† for details) to calculate the 5-membered and 6-memebered transition-states for 1,4- and 1,5-HAT, respectively. Surprisingly, we found that the barrier for 1,4 C–H abstraction in 1a was 18.7 kcal mol⁻¹, which was only 2.6 kcal mol⁻¹ higher in energy than the barrier calculated for 1,5 C–H abstraction in the same system (Scheme 2b). This suggested that both processes were competing at room temperature. We attributed the comparable barriers to the flexibility of the tert-butyl group, which undergoes vibrational scissoring to accommodate the C–H abstraction. The transition state distortion is modest and allows the molecule to maintain bond angles close to the ideal 109.5° (Scheme 2b). Based on this insight, we sought to limit the scissoring of the tert-butyl group and prevent the 1,4-HAT that leads to the undesired side product. After investigating several possible candidates, the underutilized adamantoyl group appeared promising. To evaluate the rigidity of adamantane, we calculated the barriers for 1,4- and 1,5-HAT for the adamantoyl-capped octylamine 1c (Scheme 2c). As expected, the barriers for 1,4- and 1,5-HAT differed significantly—with 1,4 C–H abstraction proceeding with a barrier of 25.1 kcal mol⁻¹ and the 1,5-HAT barely changed at 16.4 kcal mol⁻¹—an 8.7 kcal mol⁻¹ difference. Consequently, we synthesized 1c and subjected it to the reaction conditions. Excitingly, the adamantoyl-capped system produced desired product 2c in 75% yield with no fluorination of the adamantyl group (Scheme 2d).Using the newly devised adamantoyl-based fluoroamides, the reaction conditions were optimized. While a range of metal salts, ligands, and radical initiators were evaluated, Fe(OTf)₂ proved unique in catalyzing fluorine transfer with fluoroamides.¹⁸ Catalyst loading of 10 mol% allowed convenient setup and minor deviations above or below this loading had little effect on yield (see ESI^†). Increasing the temperature to 40 °C produced a slight increase in yield (entry 2, Table 1). Likewise, raising the temperature to 80 °C resulted in full conversion of the starting material in 20 minutes with 81% yield of the desired product (entry 3, Table 1). It should be noted that fluorine transfer occurs efficiently at a variety of temperatures with adjustments in reaction time (see ESI^†). Increasing the reaction concentration or changing the solvent resulted in decreased yield (entries 4 and 5, Table 1). Furthermore, the absence of Fe(OTf)₂ leads to no reaction and quantitative recovery of starting material, attesting to the stability of fluoroamides and the effectiveness of Fe(OTf)₂ (entry 6, Table 1).Optimization of pertinent reaction parameters

Hydroxy-directed fluorination of remote unactivated C(sp3)–H bonds: a new age of diastereoselective radical fluorination

We report a photochemically induced, hydroxy-directed fluorination that addresses the prevailing challenge of high diastereoselectivity in this burgeoning field. Numerous simple and complex motifs showcase a spectrum of regio- and stereochemical outcomes based on the configuration of the hydroxy group. Notable examples include a long-sought switch in the selectivity of the refractory sclareolide core, an override of benzylic fluorination, and a rare case of 3,3′-difluorination. Furthermore, calculations illuminate a low barrier transition state for fluorination, supporting our notion that alcohols are engaged in coordinated reagent direction. A hydrogen bonding interaction between the innate hydroxy directing group and fluorine is also highlighted for several substrates with ¹⁹F–¹H HOESY experiments, calculations, and more.

We report a photochemical, hydroxy-directed fluorination that addresses the prevailing challenge of high diastereoselectivity. Numerous motifs showcase a range of regio- and stereochemical outcomes based on the configuration of the hydroxy group.

The hydroxy (OH) group is treasured and versatile in chemistry and biology.¹ Its ubiquity in nature and broad spectrum of chemical properties make it an attractive source as a potential directing group.² The exploitation of the mild Lewis basicity exhibited by alcohols has afforded several elegant pathways for selective functionalization (e.g., Sharpless epoxidation,³ homogeneous hydrogenation,⁴ cross-coupling reactions,⁵ among others⁶). Recently, we reported a photochemically promoted carbonyl-directed aliphatic fluorination, and most notably, established the key role that C–H⋯O hydrogen bonds play in the success of the reaction.⁷ Our detailed mechanistic investigations prompt us to postulate that other Lewis basic functional groups (such as –OH) can direct fluorination in highly complementary ways.⁸ In this communication, we report a hydroxy-directed aliphatic fluorination method that exhibits unique directing properties and greatly expands the domain of radical fluorination into the less established realm governing high diastereoselectivity.⁹Our first inclination that functional groups other than carbonyls may influence fluorination regiochemical outcomes was obtained while screening substrates for our published ketone-directed radical-based method (Scheme 1).^8a In this example, we surmised that oxidation of the tertiary hydroxy group on substrate 1 cannot occur and would demonstrate functional group tolerance (directing to C11, compound 2). Surprisingly, the two major regioisomers (products 3 and 4) are derivatized by Selectfluor (SF) on C12 and C16 – indicative of the freely rotating hydroxyl directing fluorination. Without an obvious explanation of how these groups could be involved in dictating regiochemistry, we continued the mechanistic study of carbonyl-directed fluorination (Scheme 2A). We established that the regioselective coordinated hydrogen atom abstraction occurs by hydrogen bonding between a strategically placed carbonyl and Selectfluor radical dication (SRD).⁷ However, we noted that the subsequent radical fluorination is not diastereoselective due to the locally planar nature of carbonyl groups. Thus, we posed the question: are there other directing groups that can provide both regio- and diastereoselectivity? Such a group would optimally be attached to a sp³ hybridized carbon; thus the “three dimensional” hydroxy carbon logically comes to mind as an attractive choice, and Scheme 1 illustrates the first positive hint.Open in a separate windowScheme 1Observed products for the fluorination of compound 1.Open in a separate windowScheme 2(A) Proposed mechanism, (B) β-caryophyllene alcohol hypochlorite derivative synthetic probe, (C) isodesmic relation of transition states showing the general importance of the hydroxy group to reactivity (ωB97xd/6-31+G*), and (D) ¹H NMR experiment with Selectfluor and various additives at different concentrations.We began our detailed study with a simple substrate that contains a tertiary hydroxyl group. Alcohol 5 was synthesized stereoselectively by the reaction of 3-methylcyclohexanone, FeCl₃, and 4-chlorophenylmagnesium bromide;¹⁰ the 4-chlorophenyl substituent allows for an uncomplicated product identification and isolation (aromatic chromophore). We sought to determine optimal reaction conditions by examination of numerous photosensitizers, bases, solvents, and light sources (7 Although we utilize cool blue LEDs (sharp cutoff ca. 400 nm), CFLs (small amount of UVB (280–315 nm) and UVA (315–400 nm)) are useable as well.¹¹ A mild base additive was also found to neutralize adventitious HF and improve yields in the substrates indicated (

Diverse strategies for transition metal catalyzed distal C(sp3)–H functionalizations

Transition metal catalyzed C(sp³)–H functionalization is a rapidly growing field. Despite severe challenges, distal C–H functionalizations of aliphatic molecules by overriding proximal positions have witnessed tremendous progress. While usage of stoichiometric directing groups played a crucial role, reactions with catalytic transient directing groups or methods without any directing groups are gaining more attention due to their practicality. Various innovative strategies, slowly but steadily, circumvented issues related to remote functionalizations of aliphatic molecules. A systematic compilation has been presented here to provide insights into the recent developments and future challenges in the field. The Present perspective is expected to open up a new dimension and provide an avenue for deep insights into the distal C(sp³)–H functionalizations that could be applied routinely in various pharmaceutical and agrochemical industries.

Transition metal catalyzed C(sp³)–H functionalization is a rapidly growing field.     

Site-selective coupling of remote C(sp3)–H/meta-C(sp2)–H bonds enabled by Ru/photoredox dual catalysis and mechanistic studies

Construction of C(sp²)–C(sp³) bonds via regioselective coupling of C(sp²)–H/C(sp³)–H bonds is challenging due to the low reactivity and regioselectivity of C–H bonds. Here, a novel photoinduced Ru/photocatalyst-cocatalyzed regioselective cross-dehydrogenative coupling of dual remote C–H bonds, including inert γ-C(sp³)–H bonds in amides and meta-C(sp²)–H bonds in arenes, to construct meta-alkylated arenes has been accomplished. This metallaphotoredox-enabled site-selective coupling between remote inert C(sp³)–H bonds and meta-C(sp²)–H bonds is characterized by its unique site-selectivity, redox-neutral conditions, broad substrate scope and wide use of late-stage functionalization of bioactive molecules. Moreover, this reaction represents a novel case of regioselective cross-dehydrogenative coupling of unactivated alkanes and arenes via a new catalytic process and provides a new strategy for meta-functionalized arenes under mild reaction conditions. Density functional theory (DFT) calculations and control experiments explained the site-selectivity and the detailed mechanism of this reaction.

A novel photoinduced Ru/photocatalyst-cocatalyzed regioselective cross-dehydrogenative coupling of dual remote C–H bonds, including inert γ-C(sp³)–H bonds in amides and meta-C(sp²)–H bonds in arenes, to construct meta-alkylated arenes has been accomplished.     

Iodoetherification of unactivated alkenes catalyzed by diphosphine palladium(II) complexes

A palladium-catalyzed intramolecular iodoetherification of alkenes is reported. The reaction is efficient and highly diastereoselective for disubstituted alkenes. The tether length between the alcohol and alkene can be varied to produce tetrahydrofuran and tetrahydropyran rings. Diphosphine palladium(II) salts are highly active catalysts enabling future studies on the development of an enantioselective process.     

Efficient alkyl ether synthesis via palladium-catalyzed, picolinamide-directed alkoxylation of unactivated C(sp3)-H and C(sp2)-H bonds at remote positions

We report the efficient synthesis of alkyl ethers by the functionalization of unactivated sp(3)- and sp(2)-hybridized C-H bonds. In the Pd(OAc)(2)-catalyzed, PhI(OAc)(2)-mediated reaction system, picolinamide-protected amine substrates undergo facile alkoxylation at the γ or δ positions with a range of alcohols, including t-BuOH, to give alkoxylated products. This method features a relatively broad substrate scope for amines and alcohols, inexpensive reagents, and convenient operating conditions. This method highlights the emerging value of unactivated C-H bonds, particularly the C(sp(3))-H bond of methyl groups, as functional groups in organic synthesis.     

C(sp3)–H oxygenation via alkoxypalladium(ii) species: an update for the mechanism

Pd-catalyzed C(sp³)–H oxygenation has emerged as an attractive strategy for organic synthesis. The most commonly proposed mechanism involves C(sp³)–H activation followed by oxidative addition of an oxygen electrophile to give an alkylpalladium(iv) species and further C(sp³)–O reductive elimination. In the present study of γ-C(sp³)–H acyloxylation of amine derivatives, we show a different mechanism when tert-butyl hydroperoxide (TBHP) is used as an oxidant—namely, a bimetallic oxidative addition-oxo-insertion process. This catalytic model results in an alkoxypalladium(ii) intermediate from which acyloxylation and alkoxylation products are formed. Experimental and computational studies, including isolation of the putative post-oxo-insertion alkoxypalladium(ii) intermediates, support this mechanistic model. Density functional theory reveals that the classical alkylpalladium(iv) oxidative addition pathway is higher in energy than the bimetallic oxo-insertion pathway. Further kinetic studies revealed second-order dependence on [Pd] and first-order on [TBHP], which is consistent with DFT analysis. This procedure is compatible with a wide range of acids and alcohols for γ-C(sp³)–H oxygenation. Preliminary functional group transformations of the products underscore the great potential of this protocol for structural manipulation.

Alkoxypalladium(ii) species lead to γ-C(sp³)–H acyloxylation and alkoxylation products using tert-butyl hydroperoxide as the oxidant.     

Copper(ii) ketimides in sp3 C–H amination

Commercially available benzophenone imine (HN CPh₂) reacts with β-diketiminato copper(ii) tert-butoxide complexes [Cu^II]–O^tBu to form isolable copper(ii) ketimides [Cu^II]–N CPh₂. Structural characterization of the three coordinate copper(ii) ketimide [Me₃NN]Cu–N CPh₂ reveals a short Cu-N_ketimide distance (1.700(2) Å) with a nearly linear Cu–N–C linkage (178.9(2)°). Copper(ii) ketimides [Cu^II]–N CPh₂ readily capture alkyl radicals R˙ (PhCH(˙)Me and Cy˙) to form the corresponding R–N CPh₂ products in a process that competes with N–N coupling of copper(ii) ketimides [Cu^II]–N CPh₂ to form the azine Ph₂C N–N CPh₂. Copper(ii) ketimides [Cu^II]–N CAr₂ serve as intermediates in catalytic sp³ C–H amination of substrates R–H with ketimines HN CAr₂ and ^tBuOO^tBu as oxidant to form N-alkyl ketimines R–N CAr₂. This protocol enables the use of unactivated sp³ C–H bonds to give R–N CAr₂ products easily converted to primary amines R–NH₂via simple acidic deprotection.

Commercially available benzophenone imine (HN CPh₂) reacts with β-diketiminato copper(ii) tert-butoxide complexes [Cu^II]–O^tBu to form isolable copper(ii) ketimides [Cu^II]–N CPh₂ that serve as intermediates in catalytic sp³ C−H amination via radical relay.     

Transition metal-catalyzed arylation of unactivated C(sp3)-H bonds

Transition-metal-catalyzed C-H bond arylation has recently emerged as a powerful tool for the functionalization of organic molecules that may complement or even replace traditional catalytic cross-couplings. While many efforts have focused on the arylation of arenes and heteroarenes in the past two decades, less studies have been devoted to the arylation of nonacidic C-H bonds of alkyl groups. This tutorial review highlights recent work in this active area.     

Merging C(sp3)–H activation with DNA-encoding

DNA-encoded library (DEL) technology has the potential to dramatically expedite hit identification in drug discovery owing to its ability to perform protein affinity selection with millions or billions of molecules in a few experiments. To expand the molecular diversity of DEL, it is critical to develop different types of DNA-encoded transformations that produce billions of molecules with distinct molecular scaffolds. Sequential functionalization of multiple C–H bonds provides a unique avenue for creating diversity and complexity from simple starting materials. However, the use of water as solvent, the presence of DNA, and the extremely low concentration of DNA-encoded coupling partners (0.001 M) have hampered the development of DNA-encoded C(sp³)–H activation reactions. Herein, we report the realization of palladium-catalyzed C(sp³)–H arylation of aliphatic carboxylic acids, amides and ketones with DNA-encoded aryl iodides in water. Notably, the present method enables the use of alternative sets of monofunctional building blocks, providing a linchpin to facilitate further setup for DELs. Furthermore, the C–H arylation chemistry enabled the on-DNA synthesis of structurally-diverse scaffolds containing enriched C(sp³) character, chiral centers, cyclopropane, cyclobutane, and heterocycles.

DNA-compatible C(sp³)–H activation reactions of aliphatic carboxylic acids, amides, and ketones were developed for efficient access to DEL synthesis.     

Modular allylation of C(sp3)–H bonds by combining decatungstate photocatalysis and HWE olefination in flow

The late-stage introduction of allyl groups provides an opportunity to synthetic organic chemists for subsequent diversification, furnishing a rapid access to new chemical space. Here, we report the development of a modular synthetic sequence for the allylation of strong aliphatic C(sp³)–H bonds. Our sequence features the merger of two distinct steps to accomplish this goal, including a photocatalytic Hydrogen Atom Transfer and an ensuing Horner–Wadsworth–Emmons (HWE) reaction. This practical protocol enables the modular and scalable allylation of valuable building blocks and has been applied to structurally complex molecules.

We report a flow platform for the modular allylation of strong aliphatic C(sp³)–H bonds based on the merger of photocatalytic HAT and a HWE reaction. This approach enables both early- and late-stage diversification of various hydroalkanes.

Modern drug discovery programs capitalize increasingly on the application of late-stage functionalization methodologies to accelerate the lead optimization phase.^1,2 Such strategies allow for the rapid and cost-efficient^3,4 diversification of the parent molecule by exploiting native functionalities (e.g., C–H bonds), thus effectively avoiding the need to redesign its entire synthetic route to access new leads.^5–7 More specifically, the late-stage decoration of organic molecules with multipurpose functional groups would provide new points of entry for subsequent diversification.⁸ Such a strategy could be particularly convenient when it is realized via a chemo- and regioselective functionalization of C–H bonds in the absence of any proximal directing or activating groups.⁷ However, while C(sp²)–H activation has been extensively investigated, the direct functionalization of C(sp³)–H bonds remains challenging and is often narrow in scope.⁹ Recently, photocatalytic Hydrogen Atom Transfer (HAT) has been exploited to enable the late-stage functionalization of C(sp³)–H bonds, showing remarkable levels of regioselectivity even in complex molecules (Scheme 1A).¹⁰ In HAT photocatalysis, a catalyst converts light energy into chemical energy for the homolytic cleavage of strong aliphatic C–H bonds.Open in a separate windowScheme 1Allylation of C(sp³)–H bonds. (A) Photocatalytic HAT enables late-stage functionalization of structurally complex molecules. (B) Reported approaches for the photocatalyzed radical allylation of organic molecules. (C) A telescoped approach for the modular allylation of C(sp³)–H bonds (this work).Especially, the decatungstate anion ([W₁₀O₃₂]⁴⁻) has shown remarkable selectivity for specific C(sp³)–H bonds, governed by an intricate balance between steric and electronic interactions.^9,11,12We envisioned that the regioselective introduction of an allyl moiety onto hydrocarbon frameworks would be particularly useful as it provides a convenient branching point for further late-stage synthetic exploitation.¹³ To install such moieties, radical allylation has manifested itself as a valuable strategy. One approach relies on the use of transition metal complexes to activate a substrate containing an allylic leaving group to afford a π-allyl complex, which is then suited to trap a C-centered radical (Scheme 1B).¹⁴ This strategy can engage a diverse set of allyl coupling partners but typically requires purposely designed radical precursors, which prevents the direct allylation of unactivated C(sp³)–H bonds.Another tactic exploits radicofugal groups X (e.g., X = halide, SO₂R, SnR₃, etc) in the allylic position to afford the desired product via a radical addition–fragmentation process (Scheme 1B).^15–28 However, while synthetically useful, this transformation is not suitable for the synthesis of densely functionalized allylic functionalities.Seeking to address these challenges, we sought to develop a robust and versatile synthetic platform for the allylation of strong aliphatic C(sp³)–H bonds. Hereto, a modular synthetic sequence is preferred in which the allylic moiety is assembled in a stepwise fashion, enabling the rapid generation of structurally diverse analogues. Specifically, our sequence features the merger of two distinct synthetic steps to accomplish this goal (Scheme 1C). First, we planned to activate C(sp³)–H bonds via decatungstate-catalyzed Hydrogen Atom Transfer^29,30 and subsequently trap the resulting C-centered radical with a vinyl phosphonate.^31,32 The ensuing radical addition product serves as a suitable linchpin for the second step, in which a classical Horner–Wadsworth–Emmons (HWE) olefination^33,34 is able to deliver the targeted allylated compounds. In order to streamline these two steps, we reasoned that a telescoped flow protocol where the reactions are performed in tandem without the need for tedious purification of intermediates would be indispensable not only to accelerate access to these valuable building blocks but also to ensure facile scalability.^35–37 Herein, we report the successful realization of a flow platform enabling the allylation of a wide range of unactivated hydrocarbons.Our investigations commenced with the decatungstate-enabled hydroalkylation of ethyl 2-(diethoxyphosphoryl)acrylate (2) using cyclohexane as the H-donor (see ESI, Table S1^†). Following a careful optimization of different reaction parameters, we found that the photocatalytic radical addition performed optimal in continuous-flow using a commercially available Vapourtec UV-150 photochemical reactor (PFA (perfluoroalkoxy) capillary, ID: 0.75 mm; V = 3.06 mL, flow rate = 0.612 mL min⁻¹, t_r = 5 min) equipped with a 60 W UV-A LED light source (λ = 365 nm), which matches the measured absorption spectrum of decatungstate. A 65% NMR yield (64% after isolation) was obtained for the targeted hydroalkylated compound when a CH₃CN solution of the acrylate (0.1 M), cyclohexane (20 equivalents) and tetrabutylammonium decatungstate (TBADT, (Bu₄N)₄[W₁₀O₃₂]) as the photocatalyst (1 mol%)^38–46 was irradiated for 5 minutes (see ESI, Table S1, Entry 9^†). Other HAT photocatalysts, such as Eosin Y,⁴⁷ anthraquinone,⁴⁸ 5,7,12,14-pentacenetetrone²⁸ and 9-fluorenone⁴⁹ were also evaluated, but failed to deliver the targeted product. Interestingly, benzophenone^50,51 showed a comparable activity to the decatungstate anion, although only when used at high catalyst loading (20 mol%, 68% NMR yield). Due to the lower extinction coefficient of benzophenone compared to TBADT (<200 vs. 13 500 M⁻¹ cm⁻¹),^52,53 and its known tendency to dimerize to form benzopinacol upon UV-A irradiation, we selected TBADT as the best photocatalyst for the targeted hydroalkylation reaction. Notably, this transformation is quite general and a diverse set of alkylphosphonates (3) could be readily isolated and characterized (see ESI, Section 7). A mechanistic study confirmed the radical nature of the process (see ESI, Section 5), where HAT is likely to occur during the rate-determining step (KIE = 1.9).Next, the obtained alkylphosphonates were subjected to the successive HWE olefination (Scheme 2). A telescoped flow approach was developed in which the two individual steps were connected in a single streamlined flow process without intermediate purification. We selected 1,3-benzodioxole (1a), a common moiety in many medicinally-relevant molecules, as the H-donor and exposed it to the photocatalytic reaction conditions. Upon exiting the photochemical reactor, the reaction mixture containing the alkylphosphonate is merged with a stream containing paraformaldehyde (3 equiv.) and lithium tert-butoxide (1.1 equiv.) in tetrahydrofuran. The combined reaction mixture is subsequently introduced into a second capillary microreactor (PFA, ID: 0.75 mm; V = 7.1 mL; t_r = 5 min; T = 40 °C) and, after only 5 minutes of residence time, the targeted C(sp³)–H allylated product 4 could be obtained in 80% overall NMR yield (70% after isolation). Interestingly, the reaction performed decently also with 1 equivalent of 1a (65% NMR yield). Notably, the tactical combination of these two steps in flow results in a very efficient and operationally simple protocol, delivering these coveted scaffolds in only 10 minutes overall reaction time. As another benefit, the flow process could be readily scaled to produce 10 mmol of the desired compound 4 (1.52 g, 65% isolated yield, Scheme 2) without the need for tedious reoptimization of the reaction conditions, which is typically associated with batch-type scale up procedures.Open in a separate windowScheme 2Scope of the modular allylation of strong aliphatic C–H bonds with (deuterated) paraformaldehyde. Yields are given over two steps. For further experimental details see the SI. ^a For (CH₂O)_n: 0.23 M aldehyde and 0.084 M LiOtBu solution in tetrahydrofuran; flow rate = 0.802 mL min⁻¹; t_R = 5 min. For (CD₂O)_n: 0.11 M aldehyde and 0.084 M LiOtBu solution in tetrahydrofuran; flow rate = 0.802 mL min⁻¹; t_R = 8 min. ^b TBADT was used 5 mol%.This telescoped strategy could be subsequently applied to a wide variety of hydrogen atom donors 1 (Scheme 2). Activated substrates, such as hydrocarbon scaffolds with α-to-O C(sp³)–H bonds (5–7), were regioselectively allylated in yields ranging from 49–66% over two steps. Similarly, substrates containing α-to-S (8 and 9) and α-to-N (10–13) C(sp³)–H bonds were functionalized without difficulty (52–70% overall yield). Allylic functional groups could also be appended to activated benzylic positions (14, 32% overall yield).Finally, even strong, non-activated aliphatic C–H bonds could be readily allylated using our approach (15–19, 44–53% overall yield).To further demonstrate the potential of this operationally facile approach to introduce allylic functional groups, we wondered whether paraformaldehyde-d₂ could be used in the HWE step. Such a straightforward, regioselective introduction of deuterium atoms in organic molecules would be of tremendous importance for mechanistic,^54,55 spectroscopic and tracer studies.⁵⁶ Using our two-step flow protocol, the analogous deutero-allylated compound 4-d₂ was isolated in 68% yield, perfectly matching the result obtained for the non-deuterated version 4. Similarly, N-Boc piperidinone and N-methyl-2-pyrrolidone were competent substrates for this protocol affording the deuterated products 20 and 21 in 44% and 52% yield, respectively. Finally, in an effort to demonstrate the applicability of this method to the late-stage functionalization of medicinally relevant molecules, we subjected biologically active molecules to our two-step flow protocol: the terpenoid ambroxide (22, 40% yield) and the nootropic drug aniracetam (23, 21% yield) could be decorated with a deuterated allylic moiety.In a similar vein, we turned our attention to introduce aromatic and aliphatic aldehydes in the second step, yielding trisubstituted allylic moieties, which are particularly challenging to synthesize via traditional photocatalyzed radical allylation approaches (Scheme 1B). By exploiting our modular protocol, a virtually limitless array of substituents can be systematically introduced (Scheme 3). In most cases, prolonged reaction times were required to obtain full conversion. In particular, electron-deficient aldehydes were convenient substrates for a fully telescoped manifold, where the flow exiting the photoreactor was directly merged with a stream containing the aldehyde and the base (see e.g., 26–30, 35–40). The HWE step required 30 minutes residence time and the temperature was kept at 40 °C. We found that a range of pyridine-derived nicotinaldehydes and heteroaromatic aldehydes (35–41) were ideal substrates for this approach as well. As for electron-neutral and -rich carbonyl compounds, the HWE step required considerably longer reaction times and thus a fed-batch approach was found to be more practical (e.g., 25, 31). Here, the reaction stream exiting the photoreactor was directly dosed into a stirring solution of aldehyde and base. It is important to stress that a fully telescoped approach was still possible in these cases, however higher reaction temperature (60 °C) and a back-pressure regulator (BPR, 2.8 bar) were needed to obtain full conversion within 1 hour (e.g., 24, 33, 45). Another general observation that could be made is that the presence of ortho-substituents resulted in higher E : Z ratios (e.g., 28–31, 33 and 40).Open in a separate windowScheme 3Scope of the modular allylation of strong aliphatic C–H bonds with aromatic and aliphatic aldehydes. Yields are given over two steps. For the experimental details of the fed-batch procedure see GP4 in the ESI,^† while for fully telescoped approach see GP5. ^a Reactions were carried out on a 0.5 mmol scale and yields refer to isolated products, E : Z ratios were measured by ¹H-NMR. ^b Reaction performed according to GP5, but the HWE step required 60 °C, a BPR (2.8 bar) and 1 hour residence time. ^c Reaction time: 16 h. ^d Reaction performed via general procedure GP6 in the ESI.^†Next, we turned to investigate different classes of hydrogen donors, such as hydrocarbons (43, 43%), (thio)ethers (44–45, 47–68%), protected amines (46, 51%) and amides (47, 55%): all proved to be competent reaction partners. In all cases, the reaction performed well, delivering densely functionalized alkenes in good yields and stereoselectivity.It is important to note that it would be extremely challenging to access either of these motifs with the current radical allylation methodologies (Scheme 1B). Unfortunately, all attempts to engage ketones in the HWE step did not afford the desired fully-substituted olefins.Interestingly, our protocol was also amenable to aliphatic aldehydes containing enolizable positions (48–52, 57–71% yield). The use of protected piperidine-4-carboxaldehydes allowed to obtain the corresponding allylated products 51 and 52 in excellent yields (60–68%) and with good diastereomeric ratios. In addition, medicinal agents and natural products containing carbonyls, such as acetyl-protected helicin, citronellal and indomethacin aldehyde derivatives, were also reactive delivering the targeted olefins in synthetically useful yields (53–55, 20–63%). This proves the potential of this strategy to rapidly diversify double bonds.Next, the importance of the ester moiety as electron-withdrawing group (EWG) in the substrates to enable the targeted transformations was evaluated (Scheme 4A). Thus, we synthesized different vinyl phosphonates (2′–2′′′) and found that all of them performed well (40–68% ¹H-NMR yield) in the photocatalytic radical hydroalkylation. We then tested our streamlined process with benzaldehyde (GP4) to study the effect of the EWG on the diastereomeric ratio in the final allylated compound. The cyano group-bearing substrate furnished the targeted compound 56 with an excellent diasteroselectivity; however, a poor mass balance was observed (22% yield despite full conversion of 3′). In contrast, products 57 and 58 (EWG : COR) were not formed, with a complete recovery of 3′′ and 3′′′. Interestingly, we found that compound 2′′′′ could serve as a suitable radical trap as well (Scheme 4B). Using 1a as coupling partner, the targeted hydroalkylation product was obtained in excellent yield (3′′′′, 90% by ¹H-NMR). A solvent switch and a stronger base (nBuLi, n-butyl lithium) were however required to induce the subsequent HWE step yielding styrenes 59–61 in good yields after isolation (see GP7 in the ESI^†).^57,58Open in a separate windowScheme 4(A) Effect of the EWG on the diasteroselectivity in the final allylated product; (B) synthesis of densely functionalized styrenes by exploiting phenyl-substituted vinyl phosphonate 2′′′′; (C) examples of further diversification of compound 4, including olefin reduction, ester reduction, Giese-type radical addition and Mizoroki–Heck coupling. ^a Full conversion of 3′ was observed. ^b Full recovery of the alkyl phosphonates.The regioselective and late-stage installation of allylic groups opens up innumerable possibilities for further diversification.¹³ As an illustration of this synthetic potential, we explored diverse conditions for the conversion of 4 into functionalized derivatives (Scheme 4C). The olefin and the ester functionalities could be orthogonally reduced by exploiting different reduction conditions, yielding compounds 62 (70%) and 63 (62%), respectively.^59,60 Moreover, compound 4 was an ideal substrate for another Giese-type radical addition using decatungstate-photocatalyzed HAT (64, 62%). Finally, product 65 could be obtained via a classical Mizoroki–Heck-type coupling (60%).⁶¹     

Kinetic resolution of sulfur-stereogenic sulfoximines by Pd(ii)–MPAA catalyzed C–H arylation and olefination

A direct Pd(ii)-catalyzed kinetic resolution of heteroaryl-enabled sulfoximines through an ortho-C–H alkenylation/arylation of arenes has been developed. The coordination of the sulfoximine pyridyl-motif and the chiral amino acid MPAA ligand to the Pd(ii)-catalyst controls the enantio-discriminating C(aryl)–H activation. This method provides access to a wide range of enantiomerically enriched unreacted aryl-pyridyl-sulfoximine precursors and C(aryl)–H alkenylation/arylation products in good yields with high enantioselectivity (up to >99% ee), and selectivity factor up to >200. The coordination preference of the directing group, ligand effect, geometry constraints, and the transient six-membered concerted-metalation–deprotonation species dictate the stereoselectivity; DFT studies validate this hypothesis.

A Pd/MPAA catalysed KR of heteroaryl substituted sulfoximines through C–H alkenylation and arylation (up to >99% ee) is developed. In-depth DFT studies uncover the salient features.     

Highly regioselective carbonylation of unactivated C(sp3)-H bonds by ruthenium carbonyl

The regioselective carbonylation of unactivated C(sp(3))-H bonds of aliphatic amides was achieved using Ru(3)(CO)(12) as a catalyst. The presence of a 2-pyridinylmethylamine moiety in the amide is crucial for a successful reaction. The reaction shows a preference for C-H bonds of methyl groups as opposed to methylene C-H bonds and tolerates a variety of functional groups. The stoichiometric reaction of an amide with Ru(3)(CO)(12) gave a dinuclear ruthenium complex in which the 2-pyridinylmethylamino moiety was coordinated to the ruthenium center in an N,N manner.     

Mild electrophilic trifluoromethylation of secondary and primary aryl- and alkylphosphines using hypervalent iodine(iii)-CF(3) reagents

A direct, mild and efficient trifluoromethylation of primary and secondary phosphines is achieved with easily accessible, cheap hypervalent iodine compounds acting as electrophilic CF(3)-transfer reagents.     

Visible light driven deuteration of formyl C–H and hydridic C(sp3)–H bonds in feedstock chemicals and pharmaceutical molecules

Deuterium labelled compounds are of significant importance in chemical mechanism investigations, mass spectrometric studies, diagnoses of drug metabolisms, and pharmaceutical discovery. Herein, we report an efficient hydrogen deuterium exchange reaction using deuterium oxide (D₂O) as the deuterium source, enabled by merging a tetra-n-butylammonium decatungstate (TBADT) hydrogen atom transfer photocatalyst and a thiol catalyst under light irradiation at 390 nm. This deuteration protocol is effective with formyl C–H bonds and a wide range of hydridic C(sp³)–H bonds (e.g. α-oxy, α-thioxy, α-amino, benzylic, and unactivated tertiary C(sp³)–H bonds). It has been successfully applied to the high incorporation of deuterium in 38 feedstock chemicals, 15 pharmaceutical compounds, and 6 drug precursors. Sequential deuteration between formyl C–H bonds of aldehydes and other activated hydridic C(sp³)–H bonds can be achieved in a selective manner.

A selective hydrogen deuterium exchange reaction with formyl C–H bonds and a wide range of hydridic C(sp³)–H bonds has been achieved by merging tetra-n-butylammonium decatungstate photocatalyst and a thiol catalyst under 390 nm light irradiation.     

Substrate-controlled C–H or C–C alkynylation of cyclopropanes: generation of aryl radical cations by direct light activation of hypervalent iodine reagents

We report the first oxidative C–H alkynylation of arylcyclopropanes. Irradiation of ethynylbenziodoxolone (EBX) reagents with visible light at 440 nm promoted the reaction. By the choice of the aryl group on the cyclopropane, it was possible to completely switch the outcome of the reaction from the alkynylation of the C–H bond to the oxyalkynylation of the C–C bond, which proceeded without the need for a catalyst, in contrast to previous works. The oxyalkynylation could also be extended to aminocyclopropanes as well as styrenes. Computations indicated that the C–H activation became a favoured nearly barrierless process in the presence of two ortho methyl groups on the benzene ring.

C–C or C–H alkynylation of aryl cyclopropanes was realized by direct activation of EBX reagents with visible light. With ortho methyl groups on the benzene, C–H functionalization became favoured.