Addition Of Organometallic Reagents Research Articles

Vicinal ketoesters - key intermediates in the total synthesis of natural products.

This review summarizes examples for the application of vicinal ketoesters such as α-ketoesters, mesoxalic esters, and α,β-diketoesters as key intermediates in the total synthesis of natural products utilizing their electrophilic keto group as reactive site. Suitable key reactions are, e.g., aldol additions, carbonyl ene reactions, Mannich reactions, and additions of organometallic reagents. The vicinal arrangement of carbonyl groups allows the stabilization of reactive conformations by chelation or dipole control.

1,2-Additions on Chiral N-Sulfinylketimines: An Easy Access to Chiral α-Tertiary Amines

AbstractChiral α-tertiary amines, a motif present in α,α-disubstituted α-amino acids, in a wide range of natural products, and many drugs and drug candidates, are important targets in organic chemistry. Among the possible strategies, 1,2-addition to chiral N-sulfinyl­ketimines is one of the best routes to form chiral α-tertiary amines with a high level of stereoselectivity. In this review, we focus first on the addition of organometallic reagents or other nucleophiles as enols or ylides to chiral N-sulfinylketimines. Then secondly we cover a selection of applications of these additions in the synthesis of valuable biologically active compounds.1 Introduction2 1,2-Addition Reaction Methodologies2.1 Organolithium Reagent Additions2.2 Grignard Additions2.3 Organozinc Reagent Additions2.4 Organoindium Reagent Additions2.5 Organoboron Reagent Additions2.6 Strecker Reactions2.7 Palladium-Catalyzed Reactions2.8 Enols, Enolates, and Other Deprotonated Reagent Additions2.9 Ylide Additions2.10 Heteroatom Nucleophiles2.11 Miscellaneous Reactions3 Applications to the Synthesis of Biologically Active Molecules4 Conclusions

A Fluorenyl Activating Group Enables Addition of Simple Grignard Reagents to C=N Electrophiles

Nucleophilic addition of organometallic reagents to ketimines and hydrazones can be a challenging transformation. Here we report the use of fluorenone-derived mixed azines which promote facile addition of Grignard reagents. The fluorenylidene activating group is easily installed and removed, thereby offering practical access to highly substituted amines and hydrazines.

Ultrasound-Assisted Conjugate Addition of Organometallic Reagents to 3-Diethylphosphonocoumarin

A comparative investigation on the 1,4-conjugate addition of various nucleophiles to diethyl ester of 2-oxo-2 H -1-benzopyran-3-phosphonic acid under thermal and ultrasound promoted conditions is presented. The approach enables the usage of a simpler experimental setup and mild reaction conditions as well as excellent yield reproducibility. The trans isomers isolated showed high diastereoselectivity and the absolute structure of one of the products was confirmed by X-ray diffraction analysis.

A general method for the direct transformation of common tertiary amides into ketones and amines by addition of Grignard reagents

The direct transformation of amides into ketones by addition of organometallic reagents has attracted the attention of organic chemists for a long time. However limited methods are reliable for common amides and have found synthetic applications. Here we report a method featuring in situ activation of tertiary amides with triflic anhydride (Tf2O) followed by addition of Grignard reagents. The method displays a good generality in scope for both amides and Grignard reagents, and it can be viewed as the acylation of Grignard reagents using amides as stable and selective acylating agents. Moreover, this deaminative alkylation reaction provides a mild method for the N-Deacylation of amides to give free amines.

ChemInform Abstract: Transition Metal‐Catalyzed Direct Nucleophilic Addition of C—H Bonds to Carbon—Heteroatom Double Bonds

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Tricyclic challenges: synthetic approaches toward dodecahydrocyclopenta[a]indenes

Tetrahydrospiro[1,3-dioxolane-2,1′-pentalen]-4′-ones were stereoselectively converted to either (cis,anti,cis)- or (cis,syn)-linear dodecahydrocyclopenta[a]indene isomers employing a 1,4- or 1,2-conjugate addition of organometallic reagents and an intramolecular aldol reaction as the key steps. The relative configuration of the products was determined by X-ray crystal structure analysis and 1D NOE spectroscopy.

Synthesis and biological evaluation of 4-hydroxy-4-(4-methoxyphenyl)-substituted proline and pyrrolidin-2-ylacetic acid derivatives as GABA uptake inhibitors

A series of enantiomerically pure 4-hydroxy-4-(4-methoxyphenyl)-substituted proline and pyrrolidin-2-ylacetic acid derivatives have been synthesized starting from the respective N-protected 4-hydroxy derivatives via oxidation to the corresponding 4-oxo compounds, subsequent addition of organometallic reagents, final hydrolysis and deprotection. The major diastereoisomers obtained by the addition of the Grignard reagents were found to have opposite stereoconfigurations depending on whether cerium trichloride was present or absent as an additive. The final compounds were evaluated for their capability to inhibit the GABA transport proteins GAT1 and GAT3. 4-Hydroxyproline derivatives substituted with a tris(4-methoxyphenyl)methyloxyethyl residue at the nitrogen and a 4-methoxyphenyl group in 4-position showed, with the exception of the (2R,4R)-diastereomer, an improved inhibition at GAT3 compared to the derivatives missing the 4-methoxyphenyl group in 4-position. This may imply that an appropriate lipophilic group at the C-4 position of the proline moiety is beneficial for potent inhibition at GAT3.

Asymmetric Synthesis of 1-Substituted 1,2,3,4-Tetrahydropyrrolo[1,2-a]pyr­azines

The reactions of 1-(2-haloethyl)pyrrole-2-carbaldehydes with (1S)-1-phenylglycinol or (1S)-valinol gave the corresponding fused tricyclic oxazolidines as single diastereomers from which 1,2-disubstituted 1,2,3,4-tetrahydropyrrole[1,2-a]pyrazines were obtained by addition of organometallic reagents. The diastereoselectivity was dependent on the nature of both the chiral auxiliary and the organometallic reagent. The best diastereoselectivity (dr ≤ 98:2) was obtained by using Grignard reagents with the oxazolidine derived from (1S)-phenylglycinol. (+)-1-Methyl- and (+)-1-ethyl-1,2,3,4-tetrahydropyrrole[1,2-a]pyrazines were obtained by reductive removal of the N2-substituent.

ChemInform Abstract: Enantioselective Addition of Organometallic Reagents to Carbonyl Compounds: Chirality Transfer, Multiplication and Amplification

Nucleophilic addition of organometallic reagents to carbonyl substrates constitutes one of the most fundamental operations in organic synthesis. Modification of the organometallic compounds by chiral, nonracemic auxiliaries offers a general opportunity to create optically active alcohols, and the catalytic version in particular provides maximum synthetic efficiency. The use of organozinc chemistry, unlike conventional organolithium or -magnesium chemistry, has realized an ideal catalytic enantioselective alkylation of aldehydes leading to a diverse array of secondary alcohols of high optical purity. A combination of dialkylzinc compounds and certain sterically constrained β-dialkylamino alcohols, such as (–)-3-exo-dimethylaminoiso- borneol [(–)-DAIB], as chiral inducers affords the best result (up to 99% ee). The alkyl transfer reaction occurs via a dinuclear Zn complex containing a chiral amino alkoxide, an aldehyde ligand, and three alkyl groups. The chiral multiplication method exhibits enormous chiral amplification: a high level of enantioselection (up to 98%) is attainable by use of DAIB in 14% ee. This unusual nonlinear effect is a result of a marked difference in chemical properties of the diastereomeric (homochiral and heterochiral) dinuclear complexes formed from the dialkylzinc and the DAIB auxiliary. This phenomenon may be the beginning of a new generation of enantioselective organic reactions.

ChemInform Abstract: Stereoselective Michael Addition of Organometallic Reagents to α, β-Unsaturated Ester Containing Oxazolidine Ring.

Asymmetric conjugate addition of various organometallic reagents to chiral α,β-unsaturated ester derived from L-glutamic acid proceeded cleanly with almost complete diastereoface selection to furnish R-configurated adducts.

ChemInform Abstract: Asymmetric Conjugate Addition of Organometallic Reagents to Chiral . alpha.,β-Unsaturated Esters.

ChemInform Abstract: Asymmetric Conjugate Addition of Organometallic Reagents to Chiral . alpha.,β-Unsaturated Esters.

ChemInform Abstract: Asymmetric Syntheses of 3-Substituted-cyclohexanone Derivatives by Stereoselective Conjugate Addition to Chiral 2-Substituted-2- cyclohexen-1-ones.

Chiral 2-substituted-2-cyclohexen-1-one 2a is prepared. Conjugate additions of organometallic reagents to 2a occur with good to excellent diastereoselectivities. Enone 2b, which contains an additional potentially coordinating oxygen atom on the side chain of the chiral auxiliary, gave about the same stereoselectivity as 2a. The chiral auxiliary (S)-(+)-2-(methoxymethyl)pyrrolidine can be removed from the product of conjugate addition by treatment with hydroxylamine hydrochloride and sodium acetate in 95% ethanol at 60°C to give an oxime of a 3-substituted cyclohexanone

ChemInform Abstract: Electrophilic and Nucleophilic Reactivities of the Azomethine Carbon of SAMP-Hydrazones: Stereoselective Synthesis of γ-Amino Ketone Derivatives.

A novel methodology for the asymmetric synthesis of secondary N-Boc-protected γ-amino ketones is described. After the highly diastereoselective nucleophilic 1,4-addition of formaldehyde SAMP-hydrazone 1 to prochiral conjugated enones 2, the carbonyl group of the resulting 4-oxo aldehyde SAMP-hydrazones 4 was protected as ethylene ketals 5. The stereoselective (de 58−88%) addition of organometallic reagents to the CN double bond of the latter was then performed, and the unstable intermediate hydrazines obtained were either trapped as Moc-protected hydrazines 8 in good yields (65−87%) or reduced by Raney nickel-catalyzed hydrogenolysis of the N−N bond to afford the corresponding amines, which were isolated as their corresponding N-Boc derivatives 11. Noteworthy, the azomethine carbon of SAMP-hydrazones, not being essentially modified during the process, sequentially serves as a nucleophilic and an electrophilic center, acting as a nexus between the conjugated enone (electrophile) and the organometallic reag...

ChemInform Abstract: Design and Synthesis of Enantiopure 1-[1(S)-(2-Pyridyl)alkyl]-2(R)-isopropylaziridines, New Ligands for Asymmetric Catalysis.

Abstract Enantiopure 1-(2-pyridyl)alkyl aziridines were designed as bidentate ligands for asymmetric catalysis. Their synthesis involved the addition of organometallic reagents to the imine prepared from 2-pyridinealdehyde and an enantiopure β-aminoalcohol, followed by cyclisation of the β-aminoalcohol moiety to the aziridine ring. Two such ligands (N–N)* were prepared from ( S )-valinol and converted to the complexes (η 3 -allyl)(N–N)*Pd + SbF 6 − , one of which was characterised by X-ray crystallography. Modest enantioselectivities were achieved in a representative Pd-catalysed allylic substitution reaction.

ChemInform Abstract: Enantioselective Conjugate Addition of Organometallic Reagents to Cycloalkenones by the Aid of Chiral Lactam-Phosphine Ligand.

ChemInform Abstract: Enantioselective Conjugate Addition of Organometallic Reagents to Cycloalkenones by the Aid of Chiral Lactam-Phosphine Ligand.

ChemInform Abstract: Chiral Oxime Ethers in Asymmetric Synthesis. Part 4. Asymmetric Synthesis of N-Protected Amines and β-Amino Acids by the Addition of Organometallic Reagents to ROPHy/SOPHy-Derived Aldoximes.

Addition of organolithium or Grignard reagents to (R)- or (S)-O-(1-phenylbutyl)aldehyde oximes 1 in the presence of boron trifluoride–diethyl ether results in the formation of hydroxylamines 2 in good to excellent diastereoselectivity. Subsequent cleavage of the N–O bond with zinc–acetic acid–ultrasound, and carbamate formation, gives N-protected amines 3 in good enantiomeric purity (77–100% ee). When allylmagnesium bromide was used as the organometallic reagent, the resulting hydroxylamines were converted into β-amino acid derivatives 4 and γ-amino alcohols 5.

ChemInform Abstract: Synthesis of 5-Substituted α,β-Butenolides by Iron-Promoted Intramolecular Cyclocarbonylation: Addition of Organometallic Reagents to Iron-Substituted Enals.

ChemInform Abstract: Synthesis of 5-Substituted α,β-Butenolides by Iron-Promoted Intramolecular Cyclocarbonylation: Addition of Organometallic Reagents to Iron-Substituted Enals.

(R)-4-menthenone in reactions of 1,4-conjugate and 1,3-dipolar addition

(R)-4-Menthenone compared with common cyclic enones exhibits considerably lower reactivity in 1,4-conjugate addition of organometallic reagents, is inert in Michael reactions and pyrazoline formation evidently due both to the distorted polarization in the enone system and to steric hindrances from the α-isopropyl group in the cyclohexene ring.

Adventures in Sulfur—Nitrogen Chemistry

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