Iterative addition of carbon nucleophiles to N,N-dialkyl carboxamides for synthesis of α-tertiary amines

A protocol for the synthesis of α-tertiary amines was developed by iterative addition of carbon nucleophiles to N,N-dialkyl carboxamides. Nucleophilic 1,2-addition of organolithium reagents to carboxamides forms anionic tetrahedral carbinolamine (hemiaminal) intermediates, which are subsequently treated with bromotrimethylsilane (Me₃SiBr) followed by organomagnesium (Grignard) reagents, organolithium reagents or tetrabutylammonium cyanide, affording α-tertiary amines. Employment of (trimethylsilyl)methylmagnesium bromide as the 2^nd nucleophile allowed for aza-Peterson olefination of the resulting α-tertiary (trimethylsilyl)methylamines with acidic work-up, resulting in the formation of 1,1-diarylethylenes.

We herein report a concise protocol for iterative addition of carbon nucleophiles to N,N-dialkyl carboxamides for the synthesis of α-tertiary amines.     

Hydrofluoromethylation of alkenes with fluoroiodomethane and beyond

A process for the direct hydrofluoromethylation of alkenes is reported for the first time. This straighforward silyl radical-mediated reaction utilises CH₂FI as a non-ozone depleting reagent, traditionally used in electrophilic, nucleophilic and carbene-type chemistry, but not as a CH₂F radical source. By circumventing the challenges associated with the high reduction potential of CH₂FI being closer to CH₃I than CF₃I, and harnessing instead the favourable bond dissociation energy of the C–I bond, we demonstrate that feedstock electron-deficient alkenes are converted into products resulting from net hydrofluoromethylation with the intervention of (Me₃Si)₃SiH under blue LED activation. This deceptively simple yet powerful methodology was extended to a range of (halo)methyl radical precursors including ICH₂I, ICH₂Br, ICH₂Cl, and CHBr₂F, as well as CH₃I itself; this latter reagent therefore enables direct hydromethylation. This versatile chemistry was applied to ¹⁸F-, ¹³C-, and D-labelled reagents as well as complex biologically relevant alkenes, providing facile access to more than fifty products for applications in medicinal chemistry and positron emission tomography.

Herein, we report the direct hydro(halo)methylation of alkenes from a variety of (halo)methyl iodides (including F-18, C-13, D-2 isotopologues), enabling the incorporation of a plethora of C-1 fragments into complex biologically active molecules.     

Electrochemical synthesis of organosilicon compounds

Electrochemical reduction of allyl, vinyl, and aryl halides in the presence of a silylating agent (Me₃SiCl, HMe₂SiCl, or PhMe₂SiCl) afforded the corresponding organosilicon compounds offering a valuable method for introduction of a silyl group into organic molecules.     

Photomediated reductive coupling of nitroarenes with aldehydes for amide synthesis

In view of the widespread significance of amide functional groups in organic synthesis and pharmaceutical studies, an efficient and practical synthetic protocol that avoids the use of stoichiometric activating reagents or metallic reductants is highly desirable. A straight-forward pathway to access amides from abundant chemical feedstock would offer a strategic advantage in the synthesis of complex amides. We herein disclose a direct reductive amidation reaction using readily available aldehydes and nitroarenes enabled by photo-mediated hydrogen atom transfer catalysis. It avoids the use of metallic reductants and production of toxic chemical waste. While aldehydes represent a classic class of electrophilic synthons, the corresponding nucleophilic acyl radicals could be directly accessed by photo hydrogen atom transfer catalysis, enabling polarity inversion. Our method provides an orthogonal strategy to conventional amide couplings, tolerating nucleophilic substituents such as free alcohols and sensitive functional groups to amines such as carbonyl or formyl groups. The synthetic utilization of this reductive amidation is demonstrated by the late-stage modification of complex biologically active molecules and direct access of drug molecules leflunomide and lidocaine.

In view of the widespread significance of amide functional groups in organic synthesis and pharmaceutical studies, an efficient and practical synthetic protocol that avoids the use of stoichiometric activating reagents or metallic reductants is highly desirable.     

Spin chemistry of organometallic compounds 5. Interaction of N-bromohexamethyl disilazane with substituted silyl hydrides

Reaction of N-bromohexamethyl disilazane (Me₃Si)₂NBr with substituted triorganyl silanes R¹R²R³SiH results in asymmetric disilazanes Me₃SiNHSiR¹R²R³ and bromination product, bromotrimethyl silane Me₃SiBr. The reaction has demonstrated an unusual dependence on specific solvation. In benzene, bromination occurs immediately after mixing of the reagents, while in cyclohexane, the reaction products are formed only under UV-irradiation. Application of photoinduced CIDNP method has shown that the mechanism of bromination of triorganyl silanes is comprised of a series of consecutive radical stages involving N-centered disilazanyl (Me₃Si)₂N and Si-centered silyl R¹R²R³Si radicals.     

Me3SiSiMe2(OnBu): a disilane reagent for the synthesis of diverse silacycles via Brook- and retro-Brook-type rearrangement

Herein, a readily available disilane Me₃SiSiMe₂(OⁿBu) has been developed for the synthesis of diverse silacycles via Brook- and retro-Brook-type rearrangement. This protocol enables the incorporation of a silylene into different starting materials, including acrylamides, alkene-tethered 2-(2-iodophenyl)-1H-indoles, and 2-iodobiaryls, via the cleavage of Si–Si, Si–C, and Si–O bonds, leading to the formation of spirobenzosiloles, fused benzosiloles, and π-conjugated dibenzosiloles in moderate to good yields. Preliminary mechanistic studies indicate that this transformation is realized by successive palladium-catalyzed bis-silylation and Brook- and retro-Brook-type rearrangement of silane-tethered silanols.

A readily available disilane Me₃SiSiMe₂(OⁿBu) as a silylene source has been developed for the synthesis of diverse silacycles via Brook- and retro-Brook-type rearrangement.     

Borane-catalyzed selective dihydrosilylation of terminal alkynes: reaction development and mechanistic insight

Here, we describe simple B(C₆F₅)₃-catalyzed mono- and dihydrosilylation reactions of terminal alkynes by using a silane-tuned chemoselectivity strategy, affording vinylsilanes and unsymmetrical geminal bis(silanes). This strategy is applicable to the dihydrosilylation of both aliphatic and aryl terminal alkynes with different silane combinations. Gram-scale synthesis and conducting the reaction without the exclusion of air and moisture demonstrate the practicality of this methodology. The synthetic utility of the resulting products was further highlighted by the structural diversification of geminal bis(silanes) through transforming the secondary silane into other silyl groups. Comprehensive theoretical calculations combined with kinetical isotope labeling studies have shown that a prominent kinetic differentiation between the hydrosilylation of alkynes and vinylsilane is responsible for the chemoselective construction of unsymmetrical 1,1-bis(silanes).

A B(C₆F₅)₃/silane-based system enables the chemoselective dihydrosilylation of terminal alkynes. Using a combination of different types of hydrosilanes, a series of unsymmetrical or symmetrical 1,1-bis(silanes) could be constructed.     

1,3-Migration of a phenyl group in the conversion of (Me3Si)2(PhMe2Si)CSiMePhX into (Me3Si)2(Ph2MeSi)CSiMe2Y species

The finding that compounds of the type (Me₃Si)₂(PhMe₂Si)CSiMePhX react with electrophiles to give very predominantly rearranged products (Me₃Si)₂(Ph₂MeSi)CSiMe₂Y, which would be expected to be thermodynamically disfavoured, can be rationalized in terms of a mechanism in which the anchimerically-assisted departure of X⁻ gives the Ph-bridged cation [(Me₃Si)₂

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MePh]⁺ which is attacked by the nucleophile at the less hindered centre bearing two Me groups rather than that bearing one Me and one Ph group, with the outcome determined by kinetic rather than thermodynamic factors. Both (Me₃Si)₂(Ph₂MeSi)CSiMe₂Br and its isomer (Me₃Si)₂(PhMe₂Si)CSiMePhBr react with AgBF₄ in CH₂Cl₂ or Et₂O to give >95% of the fluoride (Me₃Si)₂(Ph₂MeSi)CSiMe₂F. Reaction of the bromide (Me₃Si)₂(PhMe₂Si)CSiMePhBr with AgO₂CCF₃ in Et₂O, and that of the hydride (Me₃Si)₂(PhMe₂Si)CSiMePhH with ICl in CCl₄, likewise give >95% of the rearranged (Me₃Si)₂(Ph₂MeSi)CSiMe₂O₂CCF₃ and (Me₃Si)₂(Ph₂MeSi)CSiMe₂Cl, respectively.     

Arenechromiumtricarbonyl complexes of silyl(germyl)(stannyl)- and silyl(germyl)(plumbyl)methanes including the unexpected formation of arenechromiumtricarbonyldimethylsilanol, (η-C6H5)Cr(CO)3SiMe2OH

Treatment of PhMe₂SiCH₂GeMe₃ (1) with t-BuLi followed by addition of Me₃ECl, E = Sn, Pb, results in the formation of phenylsilyl(germyl)stannyl- and phenylsilyl(germyl)plumbyl-methanes, PhMe₂Si(Me₃Ge)(EMe₃)CH, E = Sn (2), Pb (3). The thermal reaction of 1, 2 and 3 with Cr(CO)₆ yields the corresponding aryl-Cr(CO)₃ analogs, {(η⁶-C₆H₅)Cr(CO)₃}Me₂Si(Me₃Ge)CH₂ (4) and {(η⁶-C₆H₅)Cr(CO)₃}Me₂Si(Me₃Ge)(EMe₃)CH, E = Sn (5), Pb (6). The thermal treatment of 2 with Cr(CO)₆ in a wet THF/di-n-butyl ether mixture results in the formation of the arenechromiumtricarbonyl silanol {(η⁶-C₆H₅)Cr(CO)₃}Me₂SiOH (7) which exhibits amphiphilic character, forming H-bonded chains in the solid state in a head-to-head arrangement of the areneCr(CO)₃ units.     

Isolation of a planar 1,2-dilithio-disilene and its conversion to a Si–B hybrid 2π-electron system and a planar tetraboryldisilene

Lithium reagents have long played important roles in synthetic chemistry. However, unsaturated organosilicon lithium reagents are few in number. Herein, we describe the first isolation of a 1,2-dilithiodisilene: [(boryl)SiLi]₂ (2) was prepared in 73% yield by the reduction of (boryl)tribromosilane (1, boryl = (HCArN)₂B, Ar = 2,6-iPr₂C₆H₃) with lithium in Et₂O. The salt elimination reaction of 2 with dihaloboranes RBX₂ afforded disilaborirenes [(boryl)Si]₂BR (3a–c), whereas the reaction with two equivalents of B-bromocatecholborane ((cat)BBr) yielded the first tetraboryldisilene [(boryl)(cat)BSi]₂ (4). X-ray diffraction analysis and density functional theory calculations indicated that the disilene 2 and tetraboryldisilene 4 feature an almost planar geometry and disilaborirenes 3a–c are aromatic with a silicon–boron hybrid 2π-electron delocalized structure. The results indicate that 1,2-dilithiodisilene 2 is a powerful synthetic reagent for the construction of novel silicon multiply bonded species with unique electronic structures and that the boryl substituents have significant electronic effects on the structure of silicon multiple bonding.

Dianionic disilyne: reduction of boryltribromosilane yielded the 1,2-dilithio-disilene 2, which is a powerful transfer reagent for the synthesis of a novel 2π aromatic system and the first tetraboryldisilene.     

General stereoretentive preparation of chiral secondary mixed alkylmagnesium reagents and their use for enantioselective electrophilic aminations

A general preparation of enantiomerically and diastereomerically enriched secondary alkylmagnesium reagents was reported as well as their use for performing highly stereoselective transition-metal free electrophilic aminations leading to α-chiral amines in up to 97% ee. Thus, the reaction of t-BuLi (2.2 equiv.) with a mixture of chiral secondary alkyl iodides and the commercially available magnesium reagent Me₃SiCH₂MgCl in a 2 : 1 mixture of pentane and diethyl ether at up to −50 °C provided optically enriched secondary mixed alkylmagnesium species of the type alkyl(Me)CHMgCH₂SiMe₃ with high retention of configuration (up to 99% ee). The resulting enantiomerically enriched dialkylmagnesium reagents were trapped with electrophiles such as non-enolizable ketones, aldehydes, acid chlorides, isocyanates, chlorophosphines and O-benzoyl hydroxylamines providing α-chiral tertiary alcohols, ketones, amides, phosphines and tertiary amines in up to 89% yield (over three reaction steps) and up to 99% ee.

We report a general method for the preparation of enantiomerically enriched secondary alkylmagnesium reagents, which undergo highly stereoselective transition-metal free electrophilic aminations, leading to α-chiral amines in up to 97% ee.     

Practical synthesis of 3-aryl anthranils via an electrophilic aromatic substitution strategy

We report a practical route for the synthesis of valuable 3-aryl anthranils from readily available anthranils and simple arenes by using the classical electrophilic aromatic substitution (EAS) strategy. This transformation goes through an electrophilic substitution and rearomatisation sequence by employing Tf₂O as an effective activator. A wide range of arenes were compatible in this transformation, delivering various structurally diversified 3-aryl anthranils in good yields and high regioselectivity. In addition, a variety of readily available feedstocks such as olefins, alkenyl triflates, silyl enolethers, carbonyl compounds, thiophenols and thiols could also participate in the reaction to achieve the C3 alkenylation, alkylation and thioetherification of anthranils. Of note, the synthesized 3-aryl anthranils proved to be a highly robust platform to access a series of biologically active compounds, drug derivatives and organic optoelectronic materials.

A practical route for the synthesis of valuable 3-aryl anthranils from readily available anthranils and simple arenes has been achieved through an electrophilic substitution and rearomatization sequence by employing Tf₂O as an effective activator.     

Unraveling the reactivity of a cationic iminoborane: avenues to unusual boron cations

A cationic terminal iminoborane [Mes*N B ← IPr₂Me₂][AlBr₄] (3⁺[AlBr₄]⁻) (Mes* = 2,4,6-tri-tert-butylphenyl and IPr₂Me₂ = 1,3-diisopropyl-4,5-dimethylimidazol-2-ylidene) has been synthesized and characterized. The employment of an aryl group and N-heterocyclic carbene (NHC) ligand enables 3⁺[AlBr₄]⁻ to exhibit both B-centered Lewis acidity and BN multiple bond reactivities, thus allowing for the construction of tri-coordinate boron cations 5⁺–12⁺. More importantly, initial reactions involving coordination, addition, and [2 + 3] cycloadditions have been observed for the cationic iminoborane, demonstrating the potential to build numerous organoboron species via several synthetic routes.

An NHC-stabilized aryliminoboryl cation exhibits both boron-centered Lewis acidity and multiple bond reactivity and could be utilized as an effective synthon for unusual cationic boron species.     

Asymmetric addition of Grignard reagents to ketones: culmination of the ligand-mediated methodology allows modular construction of chiral tertiary alcohols

A new class of biaryl chiral ligands derived from 1,2-diaminocyclohexane (1,2-DACH) has been designed to enable the asymmetric addition of aliphatic and, for the first time, aromatic Grignard reagents to ketones for the preparation of highly enantioenriched tertiary alcohols (up to 95% ee). The newly developed ligands L12 and L12′ together with the previously reported L0 and L0′ define a set of complementary chiral promoters, which provides access to the modular construction of a broad range of structurally diverse non-racemic tertiary alcohols, bearing challenging quaternary stereocenters. The present advancements bring to completion our asymmetric Grignard methodology by expanding the scope to aromatic organomagnesium reagents, while facilitating its implementation in organic synthesis thanks to improved synthetic routes for the straightforward access to the chiral ligands. The synthetic utility of the method has been demonstrated by the development of a novel and highly enantioselective formal synthesis of the antihistamine API clemastine via intermediate (R)-3a. Exploiting the power of the 3-disconnection approach offered by the Grignard synthesis, (R)-3a is obtained in 94% ee with ligand (R,R)-L12. The work described herein marks the finalization of our ongoing effort towards the establishment of an effective and broadly applicable methodology for the asymmetric Grignard synthesis of chiral tertiary alcohols.

Easily applied enantioselective addition of aliphatic and aromatic Grignard reagents to ketones provides modular and universal access to challenging chiral tertiary alcohols, enabling the straightforward preparation of natural products and APIs.     

Silylhydrazine und dimere N,N′‐Dilithium‐N,N′‐bis(silyl)hydrazide – Synthesen,Reaktionen, Isomerisierungen

Silylhydrazines and Dimeric N,N′‐Dilithium‐N,N′‐bis(silyl)hydrazides – Syntheses, Reactions, Isomerisations Di‐tert.‐butylchlorosilane reacts with dilithiated hydrazine in a molar ratio to give the N,N′‐bis(silyl)hydrazine, [(Me₃C)₂SiHNH]₂, ( 5 ). Isomeric tris(silyl)hydrazines, N‐difluorophenylsilyl‐N′,N′‐bis(dimethylphenylsilyl)hydrazine ( 7 ) and N‐difluorophenylsilyl‐N,N′‐bis(dimethylphenylsilyl)hydrazine ( 8 ) are formed in the reaction of N‐lithium‐N′‐N′‐bis(dimethylphenylsilyl)hydrazide and F₃SiPh. Isomeric bis(silyl)hydrazines, (Me₃C)₂SiFNHNHSiMe₂Ph ( 9 ) and (Me₃C)₂‐ SiF(PhMe₂Si)N–NH₂ ( 10 ) are the result of the reaction of di‐tert.‐butylfluorosilylhydrazine and ClSiMe₂Ph in the presence of Et₃N. Quantum chemical calculations for model compounds demonstrate the dyotropic course of the rearrangement. The monolithium derivative of 5 forms a N‐lithium‐N′,N′‐bis(silyl)hydrazide ( 11 ). The dilithium salts of 5 ( 13 ) and of the bis(tert.‐butyldiphenylsilyl)hydrazine ( 12 ) crystallize as dimers with formation of a central Li₄N₄ unit. The formation of 12 from 11 occurs via a N′ → N‐silyl group migration. Results of crystal structure analyses are reported.     

Biphasic electrochemical peptide synthesis

The large amount of waste derived from coupling reagents is a serious drawback of peptide synthesis from a green chemistry viewpoint. To overcome this issue, we report an electrochemical peptide synthesis in a biphasic system. Anodic oxidation of triphenylphosphine (Ph₃P) generates a phosphine radical cation, which serves as the coupling reagent to activate carboxylic acids, and produces triphenylphosphine oxide (Ph₃P O) as a stoichiometric byproduct. In combination with a soluble tag-assisted liquid-phase peptide synthesis, the selective recovery of desired peptides and Ph₃P O was achieved. Given that methods to reduce Ph₃P O to Ph₃P have been reported, Ph₃P O could be a recyclable byproduct unlike byproducts from typical coupling reagents. Moreover, a commercial peptide active pharmaceutical ingredient (API), leuprorelin, was successfully synthesized without the use of traditional coupling reagents.

The large amount of waste derived from coupling reagents is a serious drawback of peptide synthesis from a green chemistry viewpoint.     

Thermolysis of [tris(trimethylsilyl)methyl](diphenyl)fluorosilane. Isomerization of a sila-olefin intermediate

The compound (Me₃Si)₃CSiPh₂F loses Me₃SiF under reflux or on passage through a tube at 450°C to give three products, A, B, and C, in approximately 20/20/60 ratio. Products A and B, which are solids, were shown by X-ray crystallographic analysis to be the diastereoisomeric forms of 1-dimethylsila-2-trimethylsilyl-3-[(methyl)(phenyl)sila]indane. From its mass and ¹H NMR spectra, C (a liquid) was tentatively identified as 1,3-bis(dimethylsila)-2-[(dimethyl)(phenyl)silyl]indane. All three products are isomers of the sila-olefin (Me₃Si)₂CSiPh₂, and it is suggested that the latter is first formed by loss of Me₃SiF from (MeSi)₃CSiPh₂F, and the equilibrium (Me₃Si)₂CSiPh₂ ? (Me₃Si)(Ph₂MeSi)CSiMe₂ ? (Me₃Si)(PhMe₂Si)CSiMePh ? (Me₂PhSi)₂CSiMe₂ is then rapidly established; internal cyclizations involving addition of aryl CH bonds across SiC bonds then occur to give the observed products. Consistent with this is the observation that a mixture of silicon alkoxides, thought to be (Me₃Si)₂CHSiPh₂OMe and its isomers (which would be formed by addition of methanol across the SiC bonds of the four sila-olefins) is produced when methanol is passed through the hot tube with the (Me₃Si)₃CSiPh₂F.Full structural details are given for compounds A and B. Some features of interest are: (a) the conformation of the 5-membered ring is different in the two diastereoisomers; (b) the exocyclic SiCSiMe₃ bond angles, of ca. 120° are unusually large; and (c) there is a little distortion of the fused benzene ring, which is attributed to the effect of silicon substituents on the hybridization of carbon atoms to which they are attached.     

Sodium silylsilanolate as a precursor of silylcopper species

Silylcoppers function as convenient and effective sources of silicon functional groups. Commonly used precursors for those species have been limited to certain symmetric disilanes and silylboranes. This fact renders the development of silylcopper precursors desirable so that more diverse silyl groups could be efficiently delivered. Here we extend the utility of sodium silylsilanolates as competent precursors of silylcoppers. A silanolate unit operates as an auxiliary to transfer a variety of silyl groups to the copper centre, which was demonstrated in the copper-catalysed hydrosilylation of internal alkynes, α,β-unsaturated ketones, and allenes. Our mechanistic studies through DFT calculation suggested that a copper silylsilanolate undergoes intramolecular oxidative addition of the Si–Si bond to the copper centre to generate a silylcopper, in contrast to the typical formal σ-bond metathesis mechanism for conventional disilanes or silylboranes and copper alkoxides. Accordingly, sodium silylsilanolate has been established as an expeditious precursor of a variety of silylcopper species.

Sodium silylsilanolates are demonstrated as useful silylating reagents for copper-catalysed hydrosilylation of unsaturated bonds via the formation of reactive silylcopper species that can deliver a series of silyl groups.     

Über die Si---N-bindung : XLIV. Die umsetzung von benzophenon mit bis- und tris(trimethylsilyl)amin

The thermal LiHal elimination of

- and

functional compounds provides a simple synthetic route to four-membered SiC and SiN rings. In attempts to inhibit dimerisation sterically, bulky silylmethyl and silylamino substituents were introduced (I–III). (Me₃Si)₃CSiF₂R reacts with LiNHR′, 1,3- migration of a silyl group from carbon to the nitrogen (I, R′= 2,4,6-Me₃C₆H₂) taking place. Substitution occurs for R′ = SiMe₂CMe₂, (II, III) only.Dichloro-bis(trimethylsilyl)methane reacts with halogenosilanes and lithium in THF to give bis(trimethylsilyl)-halogenosilaethanes (Me₃Si)₂CHSi(Hal)RR′; R= Me, R′ = N(SiMe₃)₂, IV, Hal = F; V, Hal = Cl. However a reductive THF cleavage accompanied by a silyl group migration to the oxygen occurs and 1-halogenosilyl-1- trimethylsilyl-5-trimethylsiloxi-pent-1-ene,(Me₃Si)(RR′SiHal)CCH(CH₂)₃OSiMe₃, Are The main products (VII–X) of these reactions. Disubstitution occurs with F₃Si-i-Pr (VI). (Me₃Si)₃CSiFNHSiMe₂CMe₃ (II) reacts with C₄H₉Li in a molar ratio $\text{1}\text{2}$ to give an 1-aza-2,3-disilacyclobutane (XI), involving substitution, LiF elimination, and nucleophilic migration of a methanide ion of the unsaturated precusor.(Me₃Si)₂CHSiFMeN (2,4,6-Me₃C₆H₂)SiMe₃ cyclizes under comparable conditions in the reaction with MeLi via a methylene group of the mesityl group (XII).     

Synthesis and characterisation of the ternary intermetalloid clusters {M@[As8(ZnMes)4]}3− (M = Nb,Ta) from binary [M@As8]3− precursors

The development of rational synthetic routes to inorganic arsenide compounds is an important goal because these materials are finding applications in many areas of materials science. In this paper, we show that the binary crown clusters [M@As₈]³⁻ (M = Nb, Ta) can be used as synthetic precursors which, when combined with ZnMes₂, generate ternary intermetalloid clusters with 12-vertex cages, {M@[As₈(ZnMes)₄]}³⁻ (M = Nb, Ta). Structural studies are complemented by mass spectrometry and an analysis of the electronic structure using DFT. The synthesis of these clusters presents new opportunities for the construction of As-based nanomaterials.

Two ternary intermetalloid clusters were constructed through binary intermetalloid clusters with a low valent group 12 metal salt. These clusters represent the first example of the structural transformation for intermetalloid clusters.