Mild ketone formation via Ni-catalyzed reductive coupling of unactivated alkyl halides with acid anhydrides

Ni-catalyzed ketone formation through mild reductive coupling of a diverse set of unactivated alkyl bromides and iodides with particularly aryl acid anhydrides was successfully developed using zinc as the terminal reductant. These conditions also allow direct coupling of alkyl iodides with aryl acids in the presence of Boc(2)O and MgCl(2).     

Ketone formation via mild nickel-catalyzed reductive coupling of alkyl halides with aryl acid chlorides

The present work highlights unprecedented Ni-catalyzed reductive coupling of unactivated alkyl iodides with aryl acid chlorides to efficiently generate alkyl aryl ketones under mild conditions.     

Palladium-catalyzed C-C bond formation of arylhydrazines with olefins via carbon-nitrogen bond cleavage

The unactivated carbon-nitrogen bond of various aryl hydrazines was cleaved under very mild conditions by Pd(0) with the assistance of Pd(II). The in situ generated aryl palladium complex readily takes part in the C-C bond formation with olefins. This study offered a new mode of C-Pd bond formation, which will spur the development of palladium-catalyzed cross-coupling in the future.     

Enantioselective reductive cyclization of 1,6-enynes via rhodium-catalyzed asymmetric hydrogenation: C-C bond formation precedes hydrogen activation

Asymmetric hydrogenation of 1,6-enynes using chirally modified cationic rhodium precatalysts enables enantioselective reductive cyclization to afford alkylidene-substituted carbocycles and heterocycles in a completely atom economical fashion. Good to excellent yields and exceptional levels of asymmetric induction are observed across a structurally diverse set of substrates. Mechanistic studies involving hydrogen-deuterium crossover experiments, along with the observance of nonconjugated cycloisomerization products 14c and 15c, suggest rhodium(III) metallocyclopentene formation occurs in advance of hydrogen activation. This oxidative coupling-hydrogenolytic cleavage motif should play a key role in the design of related hydrogen-mediated couplings.     

Catalytic asymmetric transformations of racemic α-borylmethyl-(E)-crotylboronate via kinetic resolution or enantioconvergent reaction pathways

We report herein catalytic asymmetric transformations of racemic α-borylmethyl-(E)-crotylboronate. The Brønsted acid-catalyzed kinetic resolution–allylboration reaction sequence of the racemic reagent gave (Z)-δ-hydroxymethyl-anti-homoallylic alcohols with high Z-selectivities and enantioselectivities upon oxidative workup. In parallel, enantioconvergent pathways were utilized to synthesize chiral nonracemic 1,5-diols and α,β-unsaturated aldehydes with excellent optical purity.

We report herein catalytic asymmetric transformations of racemic α-borylmethyl-(E)-crotylboronate.     

Ruthenium catalyzed C-C bond formation via transfer hydrogenation: branch-selective reductive coupling of allenes to paraformaldehyde and higher aldehydes

Under the conditions of ruthenium-catalyzed transfer hydrogenation employing 2-propanol as the terminal reductant, 1,1-disubstituted allenes 1a- h engage in reductive coupling to paraformaldehyde to furnish homoallylic alcohols 2a- h. Under identical transfer hydrogenation conditions, 1,1-disubstituted allenes engage in reductive coupling to aldehydes 3a- f to furnish homoallylic alcohols 4a- n. In all cases, reductive coupling occurs with branched regioselectivity to deliver homoallylic alcohols bearing all-carbon quaternary centers.     

Kinetic resolution of racemic allylic alcohols via iridium-catalyzed asymmetric hydrogenation: scope,synthetic applications and insight into the origin of selectivity

Asymmetric hydrogenation is one of the most commonly used tools in organic synthesis, whereas, kinetic resolution via asymmetric hydrogenation is less developed. Herein, we describe the first iridium catalyzed kinetic resolution of a wide range of trisubstituted secondary and tertiary allylic alcohols. Large selectivity factors were observed in most cases (s up to 211), providing the unreacted starting materials in good yield with high levels of enantiopurity (ee up to >99%). The utility of this method is highlighted in the enantioselective formal synthesis of some bioactive natural products including pumiliotoxin A, inthomycin A and B. DFT studies and a selectivity model concerning the origin of selectivity are presented.

Asymmetric hydrogenation is one of the most commonly used tools in organic synthesis, whereas, kinetic resolution via asymmetric hydrogenation was less developed.     

Synthesis of unsaturated sulfides via cross-coupling of Grignard reagents with allylic electrophiles with simultaneous incorporation of sulfur into the metal-carbon bond

Conclusions Two-component catalysts based on Pd(acac)₂ or PdCl₂ and Ph₂P permit one to carry out the regioselective cross- coup ling of isoprenylmagnesium bromide with allyl ethers and esters, allyl halogenides, involving the simultaneous insertion of elemental sulfur into the metal-carbon bond, which results in the formation of higher order allyl sulfides, which are not easily accessible (by other means).Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 2, pp. 410–413, February, 1987.The authors thank A. A. Panasenko and R. R. Muslukhova for help in interpreting the¹³C-NMR spectra.     

Functionalisation of ethereal-based saturated heterocycles with concomitant aerobic C–H activation and C–C bond formation

With an ever-growing emphasis on sustainable synthesis, aerobic C–H activation (the use of oxygen in air to activate C–H bonds) represents a highly attractive conduit for the development of novel synthetic methodologies. Herein, we report the air mediated functionalisation of various saturated heterocycles and ethers via aerobically generated radical intermediates to form new C–C bonds using acetylenic and vinyl triflones as radical acceptors. This enables access to a variety of acetylenic and vinyl substituted saturated heterocycles that are rich in synthetic value. Mechanistic studies and control reactions support an aerobic radical-based C–H activation mechanism.

Herein we disclose a novel method for the aerobic C–H activation of ethereal-based heterocycles to generate various α-functionalised building blocks.     

Selective editing of a peptide skeleton via C–N bond formation at N-terminal aliphatic side chains

The applications of peptides and peptidomimetics have been demonstrated in the fields of therapeutics, diagnostics, and chemical biology. Strategies for the direct late-stage modification of peptides and peptidomimetics are highly desirable in modern drug discovery. Transition-metal-catalyzed C–H functionalization is emerging as a powerful strategy for late-stage peptide modification that is able to construct functional groups or increase skeletal diversity. However, the installation of directing groups is necessary to control the site selectivity. In this work, we describe a transition metal-free strategy for late-stage peptide modification. In this strategy, a linear aliphatic side chain at the peptide N-terminus is cyclized to deliver a proline skeleton via site-selective δ-C(sp³)–H functionalization under visible light. Natural and unnatural amino acids are demonstrated as suitable substrates with the transformations proceeding with excellent regio- and stereo-selectivity.

We have developed a visible light-promoted selective editing of a peptide skeleton via C–N bond formation at N-terminal aliphatic side chains. A proline skeleton was constructed in peptides under such transition metal free conditions.     

Correction: Cu-catalyzed C–C bond formation of vinylidene cyclopropanes with carbon nucleophiles

Correction for ‘Cu-catalyzed C–C bond formation of vinylidene cyclopropanes with carbon nucleophiles’ by Jichao Chen et al., Chem. Sci., 2019, 10, 10601–10606.

We regret that in the original article the structure of compound 1 in Tables 1–3 was incorrect. The correct structure is given below.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers.     

Utilizing 2‐phenylpropanal as coupling partner for C‐S bond formation via sequential thioarylation and decarbonylation process: A novel strategy for the synthesis of aryl alkyl sulfides

In this study, first direct access to aryl alkyl sulfides employing 2‐phenylpropanal as coupling partner is reported. Diaryl disulfides react with this aldehyde in the presence of morpholine and produce the corresponding sulfide products in high yields. In another part, disulfides are in situ generated in the reaction mixture from aryl halides/CuI/Cyanodithioformate and coupled with 2‐phenylpropanal to access aryl alkyl sulfides.     

Hydrogen-mediated reductive coupling of conjugated alkynes with ethyl (N-Sulfinyl)iminoacetates: synthesis of unnatural alpha-amino acids via rhodium-catalyzed C-C bond forming hydrogenation

Rhodium-catalyzed hydrogenation of 1,3-enynes 1a-8a and 1,3-diynes 9a-13a at ambient temperature and pressure in the presence of ethyl (N-tert-butanesulfinyl)iminoacetate and ethyl (N-2,4,6-triisopropylbenzenesulfinyl)iminoacetates, respectively, results in reductive coupling to afford unsaturated alpha-amino acid esters 1b-13b in good to excellent yields with exceptional levels of regio- and stereocontrol. Further hydrogenation of the diene containing alpha-amino acid esters 1b-8b using Wilkinson's catalyst at ambient temperature and pressure results in regioselective reduction to afford the beta,gamma-unsaturated alpha-amino acid esters 1c-8c in good to excellent yields. Exhaustive hydrogenation of the unsaturated side chains of the Boc- and Fmoc-protected derivatives of enyne and diyne coupling products 14b-16b occurs in excellent yield using Crabtree's catalyst at ambient temperature and pressure providing the alpha-amino acid esters 14d-16d, which possess saturated side chains. Finally, cross-metathesis of the Boc-protected reductive coupling product 14b with cis-1,4-diacetoxy-2-butene proceeds readily to afford the allylic acetate 14e. Isotopic labeling studies that involve reductive coupling of enyne 1a and diyne 9a under an atmosphere of elemental deuterium corroborate a catalytic mechanism in which oxidative coupling of the alkyne and imine residues is followed by hydrogenolytic cleavage of the resulting metallacycle. A stereochemical model accounting for the observed sense of asymmetric induction is provided. These studies represent the first use of imines as electrophilic partners in hydrogen-mediated reductive carbon-carbon bond formation.     

A 2,2′-diphosphinotolane as a versatile precursor for the synthesis of P-ylidic mesoionic carbenes via reversible C–P bond formation

A metal-templated synthetic route to cyclic (aryl)(ylidic) mesoionic carbenes (CArY-MICs) featuring an endocyclic P-ylide is presented. This approach, which requires metal templates with two cis-positioned open coordination sites, is based on the controlled cyclisation of a P,P′-diisopropyl-substituted 2,2′-diphosphinotolane (1) and leads to chelate complexes coordinated by a phosphine donor and the CArY-MIC carbon atom. The C–P bond formation involved in the former partial cyclisation of 1 proceeds under mild conditions and was shown to be applicable all over the d-block. In the presence of a third fac-positioned open coordination site, the P–C bond formation was found to be reversible, as shown for a series of molybdenum complexes. DFT modelling studies are in line with an interpretation of the target compounds as CArY-MICs.

A metal-templated synthesis of cyclic (aryl)(ylidic)mesoionic carbene complexes (CArY-MICs) is presented. In the case of molybdenum carbonyls, the crucial P–C bond formation, which occurs during CArY-MIC formation, was found to be reversible.     

1,3-Dipolar cycloaddition reactions of nitrones with vinylacetic olefins in the racemic series and synthesis of δ-lactams via isoxazolidines

A study of the cycloaddition behavior of a series of esters and nitriles α-chloro- and α-hydroxyvinyl-acetic dipolarophiles with C-aryl-N-alkylnitrones has been carried out. Regiospecific cycloadditions are observed; the reactions lead to a mixture of 5-substituted isoxazolidines either erythro or threo, wherever the nitrone is involved. We report the synthesis of some δ-lactams in which isoxazolidines are used as latent synthons.     

Practical asymmetric synthesis of beta-hydroxy-beta-trifluoromethylated ketones via the first example of the in situ generation of trifluoro-acetaldehyde and its successive asymmetric carbon-carbon bond formation reaction with chiral imines

Not only trifluoroactaldehyde ethyl hemiacetal or hydrate but also other polyfluoroalkylaldehydes acetals or hydrates react with an equimolar amount of various chiral imines, followed by hydrolysis to produce the corresponding (S)-beta-hydroxy-beta-polyfluoroalkyl ketones in good yields with good enantioselectivities; furthermore, the ee of the products can be improved by simple recrystallization.     

C(sp3)–C(sp3) coupling of non-activated alkyl-iodides with electron-deficient alkenes via visible-light/silane-mediated alkyl-radical formation

Here, we present a remarkably mild and general initiation protocol for alkyl-radical generation from non-activated alkyl-iodides. An interaction between a silane and an alkyl iodide is excited by irradiation with visible light to trigger carbon–iodide bond homolysis and form the alkyl radical. We show how this method can be developed into an operationally simple and general Giese addition reaction that can tolerate a range of sensitive functionalities not normally explored in established approaches to this strategically important transformation. The new method requires no photocatalyst or other additives and uses only commerical tris(trimethylsilyl)silane and visible light to effectively combine a broad range of alkyl halides with activated alkenes to form C(sp³)–C(sp³) bonds embedded within complex frameworks.

Here, we present a remarkably mild and general initiation protocol for alkyl-radical generation from non-activated alkyl-iodides.

The efficient and straightforward construction of C(sp³)–C(sp³) bonds is a crucial process in organic synthesis. Over the past 80 years, the polar conjugate addition reaction has become a powerful method to forge a variety of C(sp³)–C(sp³) bonds.¹ Alongside two-electron nucleophiles, alkyl-radicals – neutral yet nucleophilic species – have emerged as alternatives to organometallic reagents for additions to electron deficient alkenes.² Since the 1960s, a variety of methods have been reported for the formation of alkyl-radicals; early examples include the decomposition of in situ generated organomercurial hydrides, the fragmentation of xanthate or Barton esters, or the UV-mediated homolysis of alkyl halides, amongst many others.³ Although these strategies tolerate a broad range of functionalities, the initiation processes can be complicated by the need for aggressive reaction conditions and frequently require toxic reagents such as tributyltin hydride, with notable exceptions.^4,5The emergence of photoredox catalysis has obviated many of the potential drawbacks to the generation and use of alkyl-radicals. The exploitation of the multifaceted reactivity of visible light excited transition metal or organic-photocatalysts, whose properties can be tuned through modification of the ligand, metal and/or scaffold, facilitates optimization of the single electron transfer event towards alkyl-radical generation from a wide range of functionalized alkyl groups.⁶ In addition, the reactivity of electron donor–acceptor (EDA) complexes has also provided a straightforward means to form alkyl-radicals from a variety of precursors.⁷ As such, a plethora of methods have been developed for the generation of C(sp³)-centred radicals from a variety of commercially available native functionalities, which dramatically expand the scope of alkyl-radical chemistry^†. In this context, the single electron reduction of non-activated alkyl halides provides a useful means to generate alkyl radicals.⁸ As an example, Leonori and co-workers recently developed a method wherein halogen atom abstraction pathways were leveraged using radical species forged through photocatalyst-mediated oxidation event leading to a general alkyl-radical generation.⁹ Related to the current study, Jørgensen and co-workers published a visible-light mediated reduction of alkyl halides under very mild conditions. Accordingly, there remains a need for further innovation towards orthogonal, general and benign methods of alkyl-radical generation that tolerate a broad range of functionalities, thereby enabling the construction of a greater variety of C(sp³)–C(sp³) bonds.¹⁰Recently, we reported a general reaction to form tertiary alkylamines via the addition of alkyl-radicals (generated from non-activated alkyl-iodides) to in situ-generated all-alkyl iminium ions.^11a This carbonyl alkylative amination (CAA) reaction was promoted by the action of blue LEDs and tris(trimethylsilyl)silane ((Me₃Si)₃Si–H). No photoredox catalyst is required. We believe that the alkyl-radical formation step, devoid of traditional initiating reagents, proceeds through the visible-light excitation of a transient ternary EDA complex, which stimulates homolysis of the carbon–iodide bond that would be otherwise stable under such irradiation conditions (Fig. 1B). The presence of an enamine was important to the initiation pathway, as revealed by an absorption band in the UV/vis spectrum of its mixture with an alkyl-iodide and (Me₃Si)₃Si–H.^11a Gouverneur and co-workers have also reported an elegant example of visible-light mediated addition of more functionalized alkyl halides, such as iodofluoromethane, to electron deficient alkenes.¹² They proposed that light mediated homolytic cleavage of iodofluoromethane was responsible for radical initiation prior to a classical chain process.Open in a separate windowFig. 1(A) Selected visible-light mediated methods for the generation of alkyl-radicals; (B) previous work – a method for tertiary amine formation exploiting a visible-light activation of a ternary EDA complex to promote alkyl-radical formation. (C) Previous work from Gouverneur & Gaunt labs on radical fluoromethylation. (D) This work – alkyl-radical formation promoted solely by visible light and tris-trimethylsilyl silane demonstrated through a remarkably practical and straightforward Giese reaction.Gouverneur et al. also showed methyl iodide was only efficient as a radical source under these conditions when an organic photocatalyst was present and the reaction of other simple non-activated alkyl iodides was only demonstrated in the presence of iodofluoromethane, which was presumably responsible for the initiation pathway (vide supra). Our prior work in this area also identified iodofluoromethane as a visible-light activated source of fluoromethyl radical and its addition to iminium ions and electron deficient alkenes (Fig. 1C).^11b Taken together, these works reveal that the use of visible light and (Me₃Si)₃Si–H to initiate radical formation from non-activated alkyl halides has not been achieved in an unbiased transformation without the requirement of an initiation process via of the reaction components or a photocatalyst. Accordingly, we questioned whether a pathway mediated by visible-light and (Me₃Si)₃Si–H alone might facilitate alternative modes of radical initiation from non-activated alkyl halides, and therefore enable the general coupling of unbiased alkyl fragments with a wider range of acceptors under practical, straightforward reaction conditions.Herein, we report the successful realization of this idea through the development of a remarkably straightforward visible-light mediated method for alkyl-radical generation from non-activated alkyl iodides using only non-toxic tris(trimethylsilyl)silane as a reagent (Fig. 1D). While we are not certain of the precise pathway for the radical initiation, it seems likely that excitation of a species resulting from the interaction of tris(trimethylsilyl)silane and the alkyl iodide, leading to carbon–iodide bond homolysis. The utility of this activation mode is demonstrated through a broad and chemoselective Giese addition to electron deficient alkenes and is notable by its tolerance to a range of synthetically valuable functionalities in both alkyl iodide and alkene components. In comparison to other methods for Giese-addition,^2,3,8,9,12 the conditions are mild and do not require expensive catalysts or cocktails of additives.Our studies were stimulated from an observation arising from the development of the visible light mediated carbonyl alkylative amination (shown in Fig. 1B). High yields of the tertiary amine product, arising from the union of alkyl-radical, aldehyde and secondary amine were maintained when using a 455 nm long-pass filter, which discounted UV-mediated carbon–iodide bond homolysis as the initiation pathway for alkyl-radical formation.^11a To explore the formation of an alkyl-radical independently from the enamine component, the reaction conditions were simplified to comprise a representative alkyl halide and (Me₃Si)₃Si–H, which allowed us to first assess any impact solvent might have on the radical forming process. As shown in 13 However, 47% of 5 was still obtained after visible-light irradiation of a reaction mixture from which air had been rigorously excluded (entry 10), suggesting an alternative initiation pathway excluding oxygen could also operate.¹⁴ A reaction at 80 °C in the absence of light showed no conversion to 5. This data shows the nature of the solvent is not relevant for the initiation step and suggests a straightforward radical initiation process that results from visible-light excitation of an intermediate arising from an interaction between the alkyl halide and (Me₃Si)₃Si–H.Effect of different parameters on radical initiation^a

One-pot conversion of alkyl aldehydes into substituted propanoic acids via Knoevenagel condensation with Meldrum’s acid

Reaction of a range of alkyl aldehydes and Meldrum’s acid in triethylammonium formate (TEAF) at 100 °C generates substituted propanoic acids in a single step.     

A palladium-catalyzed C–H functionalization route to ketones via the oxidative coupling of arenes with carbon monoxide

We describe the development of a new palladium-catalyzed method to generate ketones via the oxidative coupling of two arenes and CO. This transformation is catalyzed by simple palladium salts, and is postulated to proceed via the conversion of arenes into high energy aroyl triflate electrophiles. Exploiting the latter can also allow the synthesis of unsymmetrical ketones from two different arenes.

A palladium catalyzed route to prepare aryl ketones from their two fundamental building blocks, two arenes and carbon monoxide, is described.