Complex-induced Proximity Effect Research Articles

Synthesis of Unnatural α-Amino Acids from (Pyridin-2-yl) Carbamate via CIPE-Induced Carbonyl Migration.

Synthetic methods of unnatural α-amino acids have always been the focus of extensive research due to their significant bioactivities. However, convenient transition-metal-free catalyzed methods are still in demand. Herein, we report a novel strategy for the construction of an unnatural α-amino acid skeleton via intramolecular rearrangement of carbamates, which are readily available from amines and their common protecting groups. This rearrangement could afford a variety of amino ester products in up to 98% yield, even in gram-scale reaction. The reaction mechanism was studied in detail through experiments and theoretical calculations. The complex-induced proximity effect (CIPE) from the 2-pyridyl group is shown to be indispensable for this transformation.

Regioselective Functionalization of Ester-, Amide-, Carbonate-, and Carbamate-Substituted 2-Phenyl-2-oxazolines with Mixed Lithium-Magnesium Amides.

We have prepared novel highly functionalized benzene derivatives by regioselective metalation of ester-, amide-, carbamate-, and carbonate-substituted 2-phenyl-2-oxazolines with mixed lithium-magnesium amides followed by reaction with different electrophiles. While a complementary metalation site can be accessed by using different bases, steric and electronic effects promoted by the aromatic ring substituents also play an important role in reaction regioselectivity. Computational calculations of the aromatic hydrogen pKa values have helped us to rationalize the metalation preference by the complex-induced proximity effect concept.

Azetidine-Borane Complexes: Synthesis, Reactivity, and Stereoselective Functionalization.

The present study reports, for the first time, the synthesis and structural features of azetidine-borane complexes, as well as their reactivity in lithiation reactions. A temperature-dependent stereoselectivity has been disclosed in the reaction of borane with N-alkyl-2-arylazetidines, allowing for a stereoselective preparation of azetidine-borane complexes 2 and 3. A regioselective hydrogen/lithium permutation, at the benzylic position, was observed in lithiation reactions of complexes possessing a syn relationship, between the ring proton and the BH3 group. In contrast, scarce or no reactivity was noticed in complexes lacking such a stereochemical requirement. The configurational stability of the lithiated intermediates has also been investigated, in order to shed some light on the stereoselectivity of the lithiation/electrophile trapping sequence. Calculations helped in supporting experimental observations, concerning structure and reactivity of these azetidine-borane complexes. Data suggest that the BH3 group could promote the lithiation reaction likely by an electrostatic complex induced proximity effect. Interestingly, a new synthetic strategy for the synthesis of N-alkyl-2,2-disubstituted azetidines has been developed.

Regioselective Ylide Formation on Acetal-Functionalized Trialkyl Phosphonium Salts: Extending the Scope of Carbonyl Homologation

The discovery of a complex-induced proximity effect and scope of regioselective ylide formation on acetal- and ketal-functionalized trialkylphosphine-derived phosphonium salts is explored as a route to homologated unsaturated carbonyl derivatives.

ChemInform Abstract: Regioselective Lithium—Iodine Exchange‐Initiated Cleavage of 2‐Iodomethyl‐1,3‐dioxanes: A Complex‐Induced Proximity Effect.

AbstractThe fragmentation of 4‐substituted 2‐iodomethyl‐1,3‐dioxanes proceeds rapidly and regioselectively to afford enol ether alcohols by preferential cleavage of the less congested C(2)—O(1) bond.

Regioselective Lithium-Iodine Exchange-Initiated Cleavage of 2-Iodomethyl-1,3-dioxanes: A Complex-Induced Proximity Effect.

Lithium-iodine exchange-initiated fragmentation of a series of 4-substituted 2-iodomethyl-1,3-dioxanes proceeds rapidly and regioselectively to afford enol ether alcohols by preferential cleavage of the less congested C(2)-O(1) bond. The results demonstrate that a complex-induced proximity effect (CIPE) is likely responsible for the selectivity of the cleavage.

Regioselectivity Differentiation in Metalations of 3,5-Dichloro-Tertiary versus Secondary Benzamides

Metalation regioslectivity of 3,5-dichlorobenzamides is a function of the type of amide (secondary versus tertiary) used in the sequence. Metalation at the 2-position (adjacent to the carboxamide functional group) occurs when the secondary benzamide is metalated with sec-butyllithium/ TMEDA mediated through complex-induced proximity effects (CIPE) process, whereas metalation with sec-butyllithium/TMEDA occurs exclusively at the 4-position when the tertiary benzamide is used under identical reaction conditions.

Lithiation of a silyl ether: formation of an ortho-Fries hydroxyketone.

A hydroxy-directed alkylation of an N,N-diethylarylamide using CIPE-assisted α-silyl carbanions (CIPE = complex-induced proximity effect) has been developed using a simple reagent combination of LDA (lithium diisopropylamide) and chlorosilane. A study of the mechanism, and the application of the procedure to an anionic Snieckus-Fries rearrangement for a highly efficient synthesis of the potent phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002, are reported.

Double Reformatsky Reaction: Divergent Synthesis of δ-Hydroxy-β-ketoesters

The double Reformatsky reaction, tandem addition of two molecules of zinc alkanoate to a carbonyl compound, and its synthetic application to a series of δ-hydroxy-β-ketoesters has been developed. The key to accelerate the double Reformatsky reaction is considered to be a complex-induced proximity effect of the in situ generated zinc alkoxide coordinated with the pyridyl group of the substrate or bidentate amines. A noteworthy feature of the reaction system is its high tolerance of functional groups due to the moderate nucleophilicity of organozinc reagents and the mild reaction conditions. Moreover, spectroscopic and crystallographic analyses of the zinc complex of the double Reformatsky product support the proposed mechanism of reaction site discrimination for ketones, aldehydes, nitriles, carboxylic acid anhydrides, and esters.

Isomeric and chemical consequences of the direct magnesiation of 1,3-benzoazoles using β-diketiminate-stabilized magnesium bases

Opening-up new synthetic applications of β-diketiminate stabilised magnesium complexes, this case study compares the ability of the alkyl [{Ar*NC(Me)CHC(Me)NAr*}Mg(Bu)(THF)] (1) and the amido reagent [{Ar*NC(Me)CHC(Me)NAr*}Mg(TMP)] (2) (Ar* = 2,6-i-Pr2-C6H3) to promote direct Mg–H exchange towards the series of 1,3-benzoazoles: benzoxazole (boz), benzothiazole (btz) and N-methyl benzimidazole (bImMe). Both reagents deprotonate boz at room temperature to yield [{Ar*NC(Me)CHC(Me)NAr*}Mg{O(o-C6H4)NC}(THF)] (3) via the C–O bond cleavage of a putative C2-magnesiated-benzoxazolyl intermediate. Structurally tracking the reactivity of 1 and 2 towards less acidic btz and bImMe showed that the behaviour of reagents 1 and 2 diverged dramatically. Kinetically activated TMP-reagent 2 effectively promotes the deprotonative magnesiation of btz and bImMe under mild reaction conditions, giving the alpha-metallated intermediates [{Ar*NC(Me)CHC(Me)NAr*}2Mg2{btz*}2] (4) and [{Ar*NC(Me)CHC(Me)NAr*}2Mg2{bImMe*}2] (7) (btz* = 2-benzothiazolyl; bImMe* = 2-N-methylbenzimidazolyl). Analysis of crystallographic and NMR data revealed that in 4 and 7 the metallated carbon atoms display a markedly carbenic character and that in solution these species exist at room temperature solely as the ring-closed products, without any observable equilibration to the acyclic isomers. Contrastingly, alkyl reagent 1 decreases the magnesiation rate of btz facilitating an intriguing new cascade activation process of two molecules of substrate involving a sequence of deprotonation/coordination/C–C coupling and ring-opening reactions to yield [{Ar*NC(Me)CHC(Me)NAr*}Mg{(btz*)C(H)N(o-C6H4)S}] (5). Hydrolysis of 5 followed by addition of the radical oxidant TEMPO ultimately produces the homocoupled product bis(benzothiazole) 6 in a 72% isolated yield. Thus, this establishes a novel transition-metal-free method to prepare homocoupled thiazoles. More straightforwardly, the coordination product [{Ar*NC(Me)CHC(Me)NAr*}Mg(Bu)(bImMe)] (8) was obtained when equimolar amounts of bImMe and 1 were reacted, illustrating the kinetic stubbornness of the Mg–C bond in butyl derivative 1. Complex 8 can be envisaged as a valuable guide to the constitution of a premetallation complex (in relation to the complex-induced proximity effect, CIPE).

ChemInform Abstract: Directed Remote Aromatic Metalations: Mechanisms and Driving Forces

AbstractReview: 127 refs.

Directed Remote Aromatic Metalations: Mechanisms and Driving Forces

Directed remote aromatic metalations are useful synthetic transformations allowing for rapid regioselective access to elaborate highly substituted carbocyclic aromatic and heteroaromatic systems. This review unravels the tangle of data reported on directed remote aromatic metalations. Through a careful analysis of critically selected examples, advanced rationalizations of remote metalation regioselectivities are presented. These extend beyond the complex-induced proximity effect (CIPE). Mechanisms, driving forces, and parameters influencing remote metalations are discussed. An understanding of these metalation mechanisms enables more accurate predictability of justification of regiochemical outcomes of these useful synthetic transformations.

Complex‐Induced Proximity Effect in the Regioselective Lithiation of Pyridine Derivatives

AbstractThe regioselective ring lithiation of BF3‐complexed 3‐picoline (1a), 3,4‐lutidine (1b), and 3,5‐lutidine (1c) was studied. The dilithiation of 1a, 1b, and 1c was also investigated to experimentally explore the relative preference of the sites on the substituted pyridine ring for lithiation. The role of the complex‐induced proximity effect (CIPE) for inducing lithiation in these moieties was investigated using both experimental and computational studies.

C–H Bond Activation in a Molybdenumoxo-Bismuth Compound

The reaction of [LBiNMe2], I (L = [1,8-C10H6(NSiMe3)2]2–), with [MeCp2Mo═O] results in a coordination of the Mo═O group at the Bi center, which in turn triggers C–H activation at the methylcyclopentadienyl ligand through complex-induced proximity effects. This leads to a heterobimetallic molybdenum/bismuth compound, wherein the two metal centers are linked by an oxide bridge as well as by a σ,π-binding [μ-η5:η1-CH2(C5H4)]2– ligand.

ChemInform Abstract: A Complex-Induced Proximity Effect in the Anionic Fries Rearrangement of o-Iodophenyl Benzoates: Synthesis of Dihydro-O- methylsterigmatocystin and Other Xanthones.

The success of an anionic Fries rearrangement, used to synthesise dihydro-O-methylsterigmatocystin and other xanthones, is dependent on the presence of a remote methoxyl substituent

ChemInform Abstract: Complex-Induced Proximity Effects in Enolate Formation. Highly Diastereoselective α-Methylation of Binaphthyl Esters of Arylacetic Acids.

Abstract Highly diastereoselective methylation of binaphthyl esters of arylacetic acids and its application to the syntheses of antiinflammatory drugs, ( S )- suprofen and ( S )-naproxen.

ChemInform Abstract: Amination by Lithium Alkylamide Reagents of Ketimines Derived from 2-( Trifluoromethyl)anilines and Methyl Halophenyl Ketones and Their Cyclization Products 2-(Halophenyl)quinolin-4-amines.

Abstract The title ketimines containing a fluorine atom at position 2 of the phenyl group are efficiently cyclized under mild conditions to N -[2-(dimethylamino)ethyl]-2-(2-fluorophenyl)quinolin-4-amines by the reaction with a lithium reagent derived from N , N -dimethylethylenediamine. The facile regioselective displacement of C2-F in the presence of another fluorine atom at the phenyl group by the same reagent or N -lithio- N ′-methylpiperazide at a higher temperature is explained in terms of a complex induced proximity effect (CIPE) process. The CIPE process is operative in amination of the 2-fluorophenyl ketimines by the more reactive piperazide reagent prior cyclization to quinolines. The 2-chlorophenyl derivatives are much less reactive in the CIPE assisted amination.

ChemInform Abstract: Generation of Silyl Group Stabilized Amide Homoenolates by Utilizing the Complex-Induced Proximity Effect (CIPE).

Generation of silyl group stabilized amide homoenolates from 3-trimethylsilyl- and 3-dimethylphenyl-propanamide with BusLi–TMEDA at –78 °C and their reactions with chlorosilanes, diphenyldisulfide and alkyl halides were carried out.

α- vs Ortho-Lithiation of N-Alkylarylaziridines: Probing the Role of the Nitrogen Inversion Process

The lithiation reaction of monophenyl- and diphenylaziridines has been investigated in detail in an effort to understand why the former undergo exclusively or mainly ortho-lithiation while the latter are lithiated exclusively at the alpha-position. Evidence is reported that ruled out the possibility that the alpha-lithiation, observed for the diphenylaziridines, is the result of an ortho- to alpha-translocation phenomenon, thus substantiating a direct alpha-deprotonation process. The role of the aziridine nitrogen lone-pair has been considered: dynamics at the aziridine nitrogen as well as complex-induced proximity effects seem to be responsible for the observed regioselectivity in both monophenyl and diphenylaziridines. It turns out that, by tuning the reaction conditions for the lithiation of trans-1-alkyl-2-methyl-3-phenylaziridines, it is possible to generate with high regioselectivity alpha- and/or ortho-lithiated aziridines, which can be stereoselectively functionalized by electrophilic trapping. A regioselective ortho-functionalization of diphenylaziridines is made possible by halogen- or tin-lithium exchange and by deprotonation of bis-deuterated aziridines.

Regioselectivity in the Ligand-Assisted Addition of Vinylmagnesium Bromide: An Experimental and Theoretical Study on the γ-Alkoxycyclobutenone Model

Compounds 2 (M = Mg) obtained in the mono addition of vinylmagnesium bromide to squarates are attractive structural models to determine the influence of complexation between magnesium(II) and the alkoxide group on the regioselectivity of the 1,2- versus 1,4-addition of organomagnesium by complex induced proximity effects (CIPE). The 1,4-addition is observed almost exclusively in the case of vinylmagnesium in THF solution with formation of hydroxyketones type 5, which are always side or minor products in the known reaction of alkenyllithium derivatives. A comparative study on the reactivity of alkenyllithium and magnesiun derivatives is reported. The high regioselectivitity observed in the 1,4-addition of vinylmagnesium bromide is fully understood by computational studies of compounds 2 (M = Mg) at the DFT level with the density functional B3LYP.