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.     

Enantioselective palladium-catalyzed C(sp2)–C(sp2) σ bond activation of cyclopropenones by merging desymmetrization and (3 + 2) spiroannulation with cyclic 1,3-diketones

Catalytic asymmetric variants for functional group transformations based on carbon–carbon bond activation still remain elusive. Herein we present an unprecedented palladium-catalyzed (3 + 2) spiro-annulation merging C(sp²)–C(sp²) σ bond activation and click desymmetrization to form synthetically versatile and value-added oxaspiro products. The operationally straightforward and enantioselective palladium-catalyzed atom-economic annulation process exploits a TADDOL-derived bulky P-ligand bearing a large cavity to control enantioselective spiro-annulation that converts cyclopropenones and cyclic 1,3-diketones into chiral oxaspiro cyclopentenone–lactone scaffolds with good diastereo- and enantio-selectivity. The click-like reaction is a successful methodology with a facile construction of two vicinal carbon quaternary stereocenters and can be used to deliver additional stereocenters during late-state functionalization for the synthesis of highly functionalized or more complex molecules.

An unprecedented palladium-catalyzed (3 + 2) spiro-annulation merging C–C bond activation and desymmetrization was developed for the enantioselective construction of synthetically versatile and value-added oxaspiro products with up to 95% ee.     

Native amine-directed site-selective C(sp3)-H arylation of primary aliphatic amines with aryl iodides

Direct C(sp³)-H functionalization of N-unprotected aliphatic amines represents one of the most efficient and straightforward strategies for amine synthesis. Despite some recent progress in this field, the NH₂-directed γ-C(sp³)-H arylation of primary aliphatic amines except α-amino esters remained an unmet challenge. In this report, we established a simple and efficient method for site-selective C(sp³)-H arylation of primary aliphatic amines by aryl iodides. In the presence of only 5 mol% Pd(OAc)₂, a wide range of aliphatic amines including O-benzyl and O-silyl amino alcohols were arylated at γ- or δ-positions by aryl iodides containing a broad scope of functional groups. The synthetic application of this method had also been demonstrated by large-scale synthesis, the synthesis of a fingolimod analogue, and the conjugation with natural d-menthol and fluorescent 1,8-naphthalimide.     

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.     

Visible-light-induced 1,2-alkylarylation of alkenes with a-C(sp3)–H bonds of acetonitriles involving neophyl rearrangement under transition-metal-free conditions

An efficient visible-light-induced difunctionalization of alkenes with a-C(sp³)–H bonds of nitriles is described for the constructing of diverse 5-oxo-pentanenitriles under transition-metal-free conditions. This protocol proceeds via the functionalization of C(sp³)–H bond and radical addition/intramolecular 1,2-aryl migration processes, which features a wide scope of substituted α,α-diaryl allylic alcohols. The results of kinetic isotope experiments show that the cleavage of C(sp³)–H bond of acetonitriles is a rate-limiting step.     

Origin of enantioselectivity with heterobidentate sulfide-tertiary amine (sp) ligands in palladium-catalyzed allylic substitution

A series of new chiral heterobidentate sulfide-tertiary amine (sp³) ligands 3a-c, 6 were readily prepared from cheap and easily available (R)-cysteine and l-(+)-methionine. A Pd-catalyzed asymmetric allylic alkylation of 1,3-diphenyl-2-propenyl acetate with dimethyl malonate was used as a model reaction to examine the catalytic efficiencies of these aziridine sulfide ligands, and ligand 3b afforded the enantioselectivity of up to 91% ee. The origin of enantioselectivity for heterobidentate sulfide-tertiary amine (sp³) ligands was first rationalized based on X-ray crystallographic data, and NMR spectroscopic data for relevant intermediate palladium allylic complexes. Our results demonstrated that the sulfur atom was a better π-allyl acceptor than the nitrogen atom for heterobidentate sulfide-tertiary amine (sp³) ligands, and the steric as well electronic properties of the palladium allylic complexes were crucial for the enantioselectivity.     

Synthesis of Quaternary and Tertiary Carbon-Substituted Arenes by Lewis Base Promoted Site-Selective Coupling with Allylic Nucleophiles

A practical method for the preparation of quaternary and tertiary allyl-substituted heteroarenes by site-selective couplings of heteroaryl nitriles and allylic nucleophiles is disclosed. Transformations utilize readily accessible stable reagents, proceed in the presence of a Lewis base activator, and undergo aryl-C(sp³) quaternary and tertiary carbon formation with high γ-selectivity (up to >98 : 2 γ : α).     

Cobalt-catalyzed oxidative esterification of allylic/benzylic C(sp3)–H bonds

A protocol for the cobalt-catalyzed oxidative esterification of allylic/benzylic C(sp³)–H bonds with carboxylic acids was developed in this work. Mechanistic studies revealed that C(sp³)–H bond activation in the hydrocarbon was the turnover-limiting step and the in-situ formed [Co(III)]Ot-Bu did not engage in hydrogen atom abstraction (HAA) of a C–H bond. This protocol was successfully incorporated into a synthetic pathway to β-damascenone that avoided the use of NBS.     

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     

Silacyclization through palladium-catalyzed intermolecular silicon-based C(sp2)–C(sp3) cross-coupling

Silicon-based cross-coupling has been recognized as one of the most reliable alternatives for constructing carbon–carbon bonds. However, the employment of such reaction as an efficient ring expansion strategy for silacycle synthesis is comparatively little known. Herein, we develop the first intermolecular silacyclization strategy involving Pd-catalyzed silicon-based C(sp²)–C(sp³) cross-coupling. This method allows the modular assembly of a vast array of structurally novel and interesting sila-benzo[b]oxepines with good functional group tolerance. The key to success for this reaction is that silicon atoms have a stronger affinity for oxygen nucleophiles than carbon nucleophiles, and silacyclobutanes (SCBs) have inherent ring-strain-release Lewis acidity.

Herein, we develop the first silacyclization between 2-halophenols and SCBs, which allows the modular assembly of sila-benzo[b]oxepines with good functional group tolerance and can be applied for the late-stage modification of biologically active molecules.     

Allylic C(sp3)–H alkylation via synergistic organo- and photoredox catalyzed radical addition to imines

A new catalytic method for the direct alkylation of allylic C(sp³)–H bonds from unactivated alkenes via synergistic organo- and photoredox catalysis is described. The transformation achieves an efficient, redox-neutral synthesis of homoallylamines with broad functional group tolerance, under very mild reaction conditions. Mechanistic investigations indicate that the reaction proceeds through the N-centered radical intermediate which is generated by the allylic radical addition to the imine.

A new catalytic method for the direct alkylation of allylic C(sp³)–H bonds from unactivated alkenes via synergistic organo- and photoredox catalysis is described.     

Et3B-induced radical addition of diphenylphosphine oxide to unsaturated compounds

Et₃B-catalysed addition of diphenylphosphine oxide to unsaturated compounds, alkenes, unsaturated acids, allylic alcohols, and allylic α-O-acetyl nitriles constitutes a practical route to a variety of functionalized diphenylphosphine oxides. The very mild conditions employed, together with the short reaction times, make the procedure highly versatile and tolerant to a range of functionalities.     

Selective Carbonyl−C(sp3) Bond Cleavage To Construct Ynamides,Ynoates, and Ynones by Photoredox Catalysis

Carbon–carbon bond cleavage/functionalization is synthetically valuable, and selective carbonyl−C(sp³) bond cleavage/alkynylation presents a new perspective in constructing ynamides, ynoates, and ynones. Reported here is the first alkoxyl‐radical‐enabled carbonyl−C(sp³) bond cleavage/alkynylation reaction by photoredox catalysis. The use of novel cyclic iodine(III) reagents are essential for β‐carbonyl alkoxyl radical generation from β‐carbonyl alcohols, including alcohols with high redox potential ( >2.2 V vs. SCE in MeCN). β‐Amide, β‐ester, and β‐ketone alcohols yield ynamides, ynoates, and ynones, respectively, for the first time, with excellent regio‐ and chemoselectivity under mild reaction conditions.     

Selective Carbonyl−C(sp3) Bond Cleavage To Construct Ynamides,Ynoates, and Ynones by Photoredox Catalysis

Carbon–carbon bond cleavage/functionalization is synthetically valuable, and selective carbonyl−C(sp³) bond cleavage/alkynylation presents a new perspective in constructing ynamides, ynoates, and ynones. Reported here is the first alkoxyl‐radical‐enabled carbonyl−C(sp³) bond cleavage/alkynylation reaction by photoredox catalysis. The use of novel cyclic iodine(III) reagents are essential for β‐carbonyl alkoxyl radical generation from β‐carbonyl alcohols, including alcohols with high redox potential ( >2.2 V vs. SCE in MeCN). β‐Amide, β‐ester, and β‐ketone alcohols yield ynamides, ynoates, and ynones, respectively, for the first time, with excellent regio‐ and chemoselectivity under mild reaction conditions.     

Chains,helices, sheets and unusual 3D nets: Diverse structures of the flexible,ditopic ligand 1,2-bis(3-(4-pyridyl)pyrazolyl)ethane

The flexible ditopic ligand 1,2-bis(3-(4-pyridyl)pyrazol-1-yl)ethane (L^4Et) displays remarkable versatility in the complexes that it forms with transition metals with products ranging from 1D chains to interpenetrating 3D networks. The L^4Et ligand itself crystallises in the space group P2₁, adopting a helical twist, although it is found in a variety of other conformations in its complexes. Coordination polymers containing the L^4Et ligand vary from almost straight, parallel 1D chains of [Ag₂(L^4Et)₂(ClO₄)₂(DMF)]·DMF (1), through interdigitating helical complexes containing tetrahedral Zn(II), [Zn(NCS)₂(L^4Et)]·DMF·H₂O (2) to 2D sheets of [Cu(L^4Et)₂(H₂O)₂](PF₆)₂·xH₂O (3) and the three-fold interpenetrating 3D network of [Co(L^4Et)₂(NCS)₂] (4). The 3D network adopts an unusual 3D 4-connected dmp (6⁵.8) topology. Dimensionality can be limited by the use of chelating co-ligands, demonstrated by the formation of the dinuclear complex [{Cu(py-2,6-CO₂)(H₂O)}₂(L^4Et)] (5).     

Synthesis of aza-aromatic hydroxylamine-O-sulfonates and their application to tandem nucleophilic addition-electrophilic 5-endo-trig cyclization

Hydroxylamine-O-sulfonic acid (HOSA) was used as an efficient nucleophilic amination reagent for 2-chloropyrimidines, 2-chloroquinolines, and 1-chloroisoquinoline. The newly obtained heteroaromatic hydroxylamine-O-sulfonates subjected to the reaction with acyl isothiocyanates underwent tandem nucleophilic addition-electrophilic 5-endo-trig cyclization. The mechanism of the cyclization was investigated with use of the long-range corrected hybrid density functional ωB97X-D/6-31+G^∗ and SM8 (DMF) solvation model. The structures of the heteroaromatic hydroxylamine-O-sulfonates and N-(5-methoxy-2H-[1,2,4]thiadiazolo[2,3-a]pyrimidin-2-ylidene)benzamide were confirmed by single crystal X-ray analysis. N-(2H-[1,2,4]thiadiazolo[3,2-a]isoquinolin-2-ylidene)benzamide exhibited a pronounced in vitro cytostatic activity against human tumor cell lines SISO, LCLC, A-427, DAN-G, and RT-4 (IC₅₀ in the range 1.47-2.97 μM).     

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.     

Photocatalytic C(sp3) radical generation via C–H,C–C,and C–X bond cleavage

C(sp³) radicals (R˙) are of broad research interest and synthetic utility. This review collects some of the most recent advancements in photocatalytic R˙ generation and highlights representative examples in this field. Based on the key bond cleavages that generate R˙, these contributions are divided into C–H, C–C, and C–X bond cleavages. A general mechanistic scenario and key R˙-forming steps are presented and discussed in each section.

C(sp³) radicals (R˙) are of broad research interest and synthetic utility.     

Direct oxidative C(sp3)─H/C(sp2)─H coupling reaction using recyclable Sr-doped LaCoO3 perovskite catalyst

A strontium-doped lanthanum cobaltite perovskite, La_0.6Sr_0.4CoO₃, was prepared and utilized as a recyclable heterogeneous catalyst for the direct oxidative C(sp³)─H/C(sp²)─H coupling reaction between cyclic ethers and alkenes or coumarins to achieve corresponding α-functionalized ethers. The α-functionalization of cyclic thioethers or amides with alkenes or coumarins was also achieved via this protocol. The La_0.6Sr_0.4CoO₃ catalyst exhibited better performance than a variety of homogeneous and heterogeneous catalysts. Utilizing a recyclable catalyst would offer a greener option for the direct oxidative C(sp³)─H/C(sp²)─H coupling reaction. To our best knowledge, the C(sp³)─H/C(sp²)─H coupling between olefins and ethers to generate α-functionalized ethers using a heterogeneous catalyst has not been previously reported, and the α-functionalization of cyclic thioethers or amides with alkenes or coumarins is new.     

Direct C(sp2)C(sp3) Cross‐Coupling of Diaryl Zinc Reagents with Benzylic,Primary, Secondary,and Tertiary Alkyl Halides

The direct C(sp²)? C(sp³) cross‐coupling of diaryl zinc reagents with benzylic, primary, secondary, and tertiary alkyl halides proceeded in the absence of coordinating ethereal solvents at ambient temperature without the addition of a catalyst. The C(sp²)? C(sp³) cross‐coupling showed excellent functional‐group tolerance, and products were isolated in high yields, generally without the requirement for purification by chromatography. This process represents an expedient, operationally simple method for the construction of new C(sp²)? C(sp³) bonds.