In-Cage Recombination Facilitates the Enantioselective Organocatalytic [1,2]-Rearrangement of Allylic Ammonium Ylides.

The [1,2]-rearrangement of allylic ammonium ylides is traditionally observed as a competitive minor pathway alongside the thermally allowed [2,3]-sigmatropic rearrangement. Concerted [1,2]-rearrangements are formally forbidden, with these processes believed to proceed through homolytic C-N bond fission of the ylide, followed by radical-radical recombination. The challenges associated with developing a catalytic enantioselective [1,2]-rearrangement of allylic ammonium ylides therefore lie in biasing the reaction pathway to favor the [1,2]-reaction product, alongside controlling a stereoselective radical-radical recombination event.

Isothiourea-Catalyzed Enantioselective α-Alkylation of Esters via 1,6-Conjugate Addition to -Quinone Methides.

The isothiourea-catalyzed enantioselective 1,6-conjugate addition of -nitrophenyl esters to 2,6-disubstituted -quinone methides is reported. -Nitrophenoxide, generated in situ from initial -acylation of the isothiourea by the -nitrophenyl ester, is proposed to facilitate catalyst turnover in this transformation. A range of -nitrophenyl ester products can be isolated, or derivatized in situ by addition of benzylamine to give amides at up to 99% yield.

Horeau amplification in the sequential acylative kinetic resolution of (±)-1,2-diols and (±)-1,3-diols in flow.

The sequential acylative kinetic resolution (KR) of C2-symmetric (±)-1,2-syn and (±)-1,3-anti-diols using a packed bed microreactor loaded with the polystyrene-supported isothiourea, HyperBTM, is demonstrated in flow. The sequential KRs of C2-symmetric (±)-1,2-syn and (±)-1,3-anti-diols exploits Horeau amplification, with each composed of two successive KR processes, with each substrate class significantly differing in the relative rate constants for each KR process. Optimisation of the continuous flow set-up for both C2-symmetric (±)-1,2-syn and (±)-1,3-anti-diol substrate classes allowed isolation of reaction products in both high enantiopurity and yield.

NHC-catalyzed enantioselective synthesis of β-trifluoromethyl-β-hydroxyamides.

The N-heterocyclic carbene (NHC)-catalyzed formal [2 + 2] cycloaddition between α-aroyloxyaldehydes and trifluoroacetophenones, followed by ring opening with an amine or a reducing agent is described. The resulting β-trifluoromethyl-β-hydroxyamide and alcohol products are produced with reasonable diastereocontrol (typically ≈70:30 dr) and excellent enantioselectivity, and they can be isolated in moderate to good yield as a single diastereoisomer.

TMEDA in Iron-Catalyzed Hydromagnesiation: Formation of Iron(II)-Alkyl Species for Controlled Reduction to Alkene-Stabilized Iron(0).

N,N,N',N'-Tetramethylethylenediamine (TMEDA) has been one of the most prevalent and successful additives used in iron catalysis, finding application in reactions as diverse as cross-coupling, C-H activation, and borylation. However, the role that TMEDA plays in these reactions remains largely undefined. Herein, studying the iron-catalyzed hydromagnesiation of styrene derivatives using TMEDA has provided molecular-level insight into the role of TMEDA in achieving effective catalysis.

Isothiourea-Catalyzed Acylative Kinetic Resolution of Tertiary α-Hydroxy Esters.

A highly enantioselective isothiourea-catalyzed acylative kinetic resolution (KR) of acyclic tertiary alcohols has been developed. Selectivity factors of up to 200 were achieved for the KR of tertiary alcohols bearing an adjacent ester substituent, with both reaction conversion and enantioselectivity found to be sensitive to the steric and electronic environment at the stereogenic tertiary carbinol centre. For more sterically congested alcohols, the use of a recently-developed isoselenourea catalyst was optimal, with equivalent enantioselectivity but higher conversion achieved in comparison to the isothiourea HyperBTM.

Tandem sequential catalytic enantioselective synthesis of highly-functionalised tetrahydroindolizine derivatives.

An isothiourea-catalysed enantioselective synthesis of novel tetrahydroindolizine derivatives is reported through a one-pot tandem sequential process. The application of 2-(pyrrol-1-yl)acetic acid in combination with either a trifluoromethyl enone or an α-keto-β,γ-unsaturated ester in an enantioselective Michael addition-lactonisation process, followed by ring-opening and cyclisation, led to a range of 24 tetrahydroindolizine derivatives containing three stereocentres in up to >95 : 5 dr and >99 : 1 er.

Unanticipated Silyl Transfer in Enantioselective α,β-Unsaturated Acyl Ammonium Catalysis Using Silyl Nitronates.

The use of silyl nitronates is reported for the isothiourea-catalyzed synthesis of γ-nitro-substituted silyl esters containing up to two contiguous stereocenters in good yields with excellent enantioselectivities (up to 93% yield and 99:1 er). The serendipitously discovered formation of silyl ester products in this reaction demonstrates a novel platform for catalyst turnover in α,β-unsaturated acyl ammonium catalysis.

Catalytic enantioselective synthesis of perfluoroalkyl-substituted β-lactones a concerted asynchronous [2 + 2] cycloaddition: a synthetic and computational study.

The enantioselective preparation of a range of perfluoroalkyl-substituted β-lactones through an isothiourea (HyperBTM) catalysed reaction using symmetric anhydrides as ammonium enolate precursors and perfluoroalkylketones (R = CF, CF, CF) is reported. Following optimisation, high diastereo- and enantioselectivity was observed for β-lactone formation using CF- and CF-substituted ketones at room temperature (26 examples, up to >95 : 5 dr and >99 : 1 er), whilst -78 °C was necessary for optimal dr and er with CF-substituted ketones (11 examples, up to >95 : 5 dr and >99 : 1 er). Derivatisation of the β-lactones through ring-opening, as well as a two-step conversion to give perfluoroalkyl-substituted oxetanes, is demonstrated without loss of stereochemical integrity.

Mechanism of the Bis(imino)pyridine-Iron-Catalyzed Hydromagnesiation of Styrene Derivatives.

Iron-catalyzed hydromagnesiation of styrene derivatives offers a rapid and efficient method to generate benzylic Grignard reagents, which can be applied in a range of transformations to provide products of formal hydrofunctionalization. While iron-catalyzed methodologies exist for the hydromagnesiation of terminal alkenes, internal alkynes, and styrene derivatives, the underlying mechanisms of catalysis remain largely undefined. To address this issue and determine the divergent reactivity from established cross-coupling and hydrofunctionalization reactions, a detailed study of the bis(imino)pyridine iron-catalyzed hydromagnesiation of styrene derivatives is reported.

Isothiourea-Catalysed Regioselective Acylative Kinetic Resolution of Axially Chiral Biaryl Diols.

An operationally simple isothiourea-catalysed acylative kinetic resolution of unprotected 1,1'-biaryl-2,2'-diol derivatives has been developed to allow access to axially chiral compounds in highly enantioenriched form (s values up to 190). Investigation of the reaction scope and limitations provided three key observations: i) the diol motif of the substrate was essential for good conversion and high s values; ii) the use of an α,α-disubstituted mixed anhydride (2,2-diphenylacetic pivalic anhydride) was critical to minimize diacylation and give high selectivity; iii) the presence of substituents in the 3,3'-positions of the diol hindered effective acylation. This final observation was exploited for the highly regioselective acylative kinetic resolution of unsymmetrical biaryl diol substrates bearing a single 3-substituent.

Chiral Au - and Au -Isothiourea Complexes: Synthesis, Characterization and Application.

During an investigation into the potential union of Lewis basic isothiourea organocatalysis and gold catalysis, the formation of gold-isothiourea complexes was observed. These novel gold complexes were formed in high yield and were found to be air- and moisture stable. A series of neutral and cationic chiral gold(I) and gold(III) complexes bearing enantiopure isothiourea ligands was therefore synthesized and fully characterized.

Multiple roles of aryloxide leaving groups in enantioselective annulations employing α,β-unsaturated acyl ammonium catalysis.

An isothiourea-catalysed Michael addition-annulation process using β-fluoroalkyl-substituted α,β-unsaturated aryl esters and a range of 2-acylbenzazoles is reported for the enantioselective synthesis of dihydropyranone and dihydropyridinone products bearing polyfluorinated stereocenters (29 examples, up to 98% yield, >99 : 1 er). The choice of aryl group of the aryl ester proved essential in determining reaction enantioselectivity and dihydropyranone : dihydropyridinone product selectivity. The aryloxide leaving group is shown to play a number of essential additional roles, operating (i) as a Brønsted base, circumventing the need for an auxiliary base; and (ii) as a Lewis base to catalyse the isomerisation of dihydropyranone products into thermodynamically-favoured dihydropyridinones.

A C=O⋅⋅⋅Isothiouronium Interaction Dictates Enantiodiscrimination in Acylative Kinetic Resolutions of Tertiary Heterocyclic Alcohols.

A combination of experimental and computational studies have identified a C=O⋅⋅⋅isothiouronium interaction as key to efficient enantiodiscrimination in the kinetic resolution of tertiary heterocyclic alcohols bearing up to three potential recognition motifs at the stereogenic tertiary carbinol center. This discrimination was exploited in the isothiourea-catalyzed acylative kinetic resolution of tertiary heterocyclic alcohols (38 examples, s factors up to >200). The reaction proceeds at low catalyst loadings (generally 1 mol %) with either isobutyric or acetic anhydride as the acylating agent under mild conditions.

Aryloxide-Facilitated Catalyst Turnover in Enantioselective α,β-Unsaturated Acyl Ammonium Catalysis.

A new general concept for α,β-unsaturated acyl ammonium catalysis is reported that uses p-nitrophenoxide release from an α,β-unsaturated p-nitrophenyl ester substrate to facilitate catalyst turnover. This method was used for the enantioselective isothiourea-catalyzed Michael addition of nitroalkanes to α,β-unsaturated p-nitrophenyl esters in generally good yield and with excellent enantioselectivity (27 examples, up to 79 % yield, 99:1 er). Mechanistic studies identified rapid and reversible catalyst acylation by the α,β-unsaturated p-nitrophenyl ester, and a recently reported variable-time normalization kinetic analysis method was used to delineate the complex reaction kinetics.

Broad scope hydrofunctionalization of styrene derivatives using iron-catalyzed hydromagnesiation.

The highly regioselective iron-catalyzed formal hydrofunctionalization of styrene derivatives with a diverse range of electrophiles has been developed using a single, operationally simple hydromagnesiation procedure and only commercially available, bench-stable reagents. Using just 0.5 mol % FeCl2·4H2O and N,N,N',N'-tetramethylethylenediamine, hydromagnesiation and electrophilic trapping have been used to form new carbon-carbon bonds (13 examples) and carbon-heteroatom bonds (5 examples) including the products of formal cross-coupling reactions, hydroboration, hydroamination, hydrosilylation, and hydrofluorination.

Chemo-, regio-, and stereoselective iron-catalysed hydroboration of alkenes and alkynes.

The highly chemo-, regio-, and stereoselective synthesis of alkyl- and vinyl boronic esters with good functional group tolerance has been developed using in situ activation of a bench-stable iron(II) pre-catalyst and pinacolborane (16 examples, 45-95% yield, TOF up to 30,000 mol h(-1)). The first iron-catalysed alkene hydrogermylation is also reported.

Iron-catalyzed, highly regioselective synthesis of α-aryl carboxylic acids from styrene derivatives and CO2.

The iron-catalyzed hydrocarboxylation of aryl alkenes has been developed using a highly active bench-stable iron(II) precatalyst to give α-aryl carboxylic acids in excellent yields and with near-perfect regioselectivity. Using just 1 mol % FeCl(2), bis(imino)pyridine 6 (1 mol %), CO(2) (atmospheric pressure), and a hydride source (EtMgBr, 1.2 equiv), a range of sterically and electronically differentiated aryl alkenes were transformed to the corresponding α-aryl carboxylic acids (up to 96% isolated yield).

Iron-catalysed, hydride-mediated reductive cross-coupling of vinyl halides and Grignard reagents.

An iron-catalysed, hydride-mediated reductive cross-coupling reaction has been developed for the preparation of alkanes. Using a bench-stable iron(II) pre-catalyst, reductive cross-coupling of vinyl iodides, bromides and chlorides with aryl- and alkyl Grignard reagents successfully gave the products of formal sp(3)-sp(3) cross-coupling reactions.