Chapter 4 Formation of carbon-carbon bonds: reaction of organometallic compounds Topics: Grignard reagents and electrophiles Other organometallic reagents and electrophiles Reactions of nucleophiles derived from alk-1-ynes Review Worked example 4.1 Grignard reagents and electrophiles 4.1.1 Alkylation 4.1.2 Reactions with carbonyl compounds 4.1.3 Reactions with imine and cyano compounds 4.1.4 Reactions with α,β-unsaturated carbonyl compounds 4.1.5 Alkenyl and alkynyl Grignard reagents 4.1.1 Alkylation XMg R `R Y R R` XMg R -+ H+ O R CH2CH2 O MgX R CH2CH3OH For example MgI I n m n m MgBr C2H5OSO2OC2 H5 C2H5 ClCH2 PhCH 2 PhMgBr Cl Cl THF PhMgBr O PhCH2CH2OH 4.1.2 Reactions with carbonyl compounds R1 R1 R1 XMg R O R O-+MgX R OH R2 R2 R2 For example HCHO MgCl CH2OH OH CH3CHO MgBr OH CH3COCH 3 MgBr R1 R1 R1 XMg R O R O-+MgX O Y Y R RMgX R1 R OH R For example 2CH3MgI PhCOCl Ph CH3 OH 2CH 3MgI (PhCO)2O CH3 O OH 2CH3MgI OC 2H 5 HCOOC2H5 MgBr OH Synthesis of Alcohol by Grignard Reaction Mg CH2O RX RMgX RCH2OH O primary RCH2CH2OH R'C ' R'' R' HCO2R' HO O O2 R'C R' C R' R R O HO R" CH OH R R' R' HO R R'CH-CH2R R ter R' tia OH CH OH ry R ry se c onda MgBr COOH CO2 4.1.4 Reactions with compounds containing C≡N O CN C MgBr N N 4.1.4 Reactions with α,β-unsaturated carbonyl compounds O -MgX+ OH O C C XMg-R R R C O-MgX + C O H R R 4.2 Other organometallic reagents and electrophiles 4.2.1 Organolithium reagents more reactive and less bulkyl 4.2.2 Organozinc and organocadmium reagents less reactive and used only for special purposes 4.2.3 Organocopper (I) reagents less reactive and more selectivity 4.2.1 Organolithium reagents Preparation RBr + 2Li RLi + LiBr RBr + R’Li RLi + R’Br (Generally R’ refers to n-BuLi) Organolithium reagents react similarly with Grignard reagents and more efficiently in certain cases. With α,β- unsaturated carbonyl compounds they show a greater preference for addition at the carbonyl carbon. PhLi PhCOO-Li+ PhCOPh CH3Li PhCH=CHCOO-Li+ PhCH=CHCOCH3 Li CHO O H3CO OCH3 H3CO OCH3 H N Ph 4.2.2 Organozinc and organocadmium reagents Organozinc reagents (Reformatsky reaction) O-+ZnBr RCH(Br)CO2R1 + Zn RCH(ZnBr)CO2R1 or RHC C OR1 R2COR3 HO CO2R1 BrZn+-O CO2R1 C C H+ C C H H R2R3 R (Work-up) R2R3 R Note: Reactions with α,β-unsaturated carbonyl compounds give preferentially the 1,2-addition products. Organocadmium reagents • Preparation 2RMgX + CdCl2 R2Cd • Used especially for the conversion of acyl chlorides into ketones R2Cd + 2R’COCl 2RCOR’ e.g. [CH3(CH2)3]2Cd + ClCH2COCl CH3(CH2)3COCH2Cl (51%) [(CH3)2CHCH2CH2]2Cd + ClCO(CH2)2CO2CH3 (CH3)2CH(CH2)2CO(CH2)2CO2CH3 (73%) 4.2.3 Organocopper (I) reagents • Preparation RMgX + CuX RCu + MgX2 RLi + CuX RCu + LiX RLi + RCu R2CuLi 2R-Li + CuX R2CuLi + LiX • Ponits of synthetic importance: – Displacement of halogens is particularly facile. – Acyl halides are the only class of carbonyl compound to react with. – When reacting with α,β-unsaturated carbonyl compounds give 1,4- addition products. – Coupling reactions occur when heated. 4.3 Reactions of nucleophiles derived from alk-1-ynes 4.3.1 Sodium, lithium and magnesium derivatives RC CNa Na+-NH2 RC CH RLi, ether R'MgX RC CLi RC CMgX They can undergo the usuall range of reactions with electrophiles: • Alkylation • Reaction with carbonyl compounds 4.3.2 Alkynylcopper(I) compounds • Preparation RC CH + CuCl RC CCu + 2HCl • Ponits of synthetic importance: – Displacement of halogens from’unreactive’ positions. – Conversion of acyl halide into ketone – Coupling reactions giving conjugated diynes. Me Synthetic equivalents 4.4 Review Et OH EtMgX + PhCOMe Ph synthons: Et or Et- Me Me OH + OH Ph Ph R-R’ R-; R’+ R’-Y (Y = X (halides), OTs (sulfonates)) RCH2CH2OH R-; +CH CH OH 2 2 O RCO2H R-; +CO H 2 CO2 R C +C C O R-; C O H H C C O Synthetic equivalents Nucleophilic - R RMgX, RLi, R2Cd, RCu, R2CuLi Synthons R+ RCl, RBr, RI, ROSO2R1 RC+=O RCOCl, (RCO)2O, RCO2R1,RCN HC+=O HCO2R1, HC+=O Electrophilic | CO2 OH Synthons C+H2OH HCHO RC+HOH RCHO R2C+OH R2CO +CH CH OH 2 2 O 4.5 Worked example 1-phenyl-butan-2-ol Synthetic equivalent PhCH2+ + CHCH2CH3 PhCH2+ PhCH2Br OH PhCH2- PhCH2MgX OH + + PhCH2- + CHCH2CH3 CHCH2CH3 CH3CH2CHO OH OH PhCH2CH+ - + CH2CH3 - EtMgX CH2CH3 OH + EtBr CH2CH3 OH PhCH2CH- + +CH2CH3 PhCH2CH+ PhCH2CHO OH OH Two synthetic routes have therefor emerged: PhCH2MgBr + CH3CH2CHO and PhCH2CHO + BrMgCH2CH3 Pentadecan-4-one O O O + - O - + O O + - O - + 3-Phenyl-butyric acid methyl ester O O O O O - + O O O O CuLi + Cl O O O MgBr O OH CO2 CH3OH H+ Br Br O O O CH3- O O O methyl cinnmate O O O Ph- O O O methyl crotonate pent-3-yn-1-ol OH Summary Grignard reagents, RMgX, are strongly nucleopholic, I.e. they act as synthetic equivalents of the synthon R-. They are alkylated by halogenoalkanes, they undergo addition to the carbonyl group of aldehydes and ketones, they react with acyl halides, anhydrides and esters giving first ketones and thence tertiary alcohols, with carbon dioxide giving carboxylic acids, and with tertiary amides, orthoesters and nitriles giving , after hydrolysis, carbonyl compounds (aldehydes or ketones). Summary With α,β-unsaturated carbonyl compounds, nucleophilic addition to the carbonyl group and conjugate addition (at the β-carbon) are both observed, the former usually predominating. Grignard reagents are also strong bases and are protonated even by weak acids such as water, alcohols and alk-1- ynes. Organolithium reagents react similarly but are even stronger nucleophiles and stronger bases. With α,β-unsaturated carbonyl compounds they show a greater preference for addition at the carbonyl carbon. Organozinc and organocadmium reagents are less reactive nucleophiles than Grignard reagents but are used nowadays only for certain specific purposed. Organocopper(I) reagents (Rcu or R2CuLi), although also synthetic equivalents of the synthon R-, show a different pattern of reactivity: they readily undergo alkylation, acylation and conjugate addition but do not undergo addition to carbonyl groups. Deprotonation of alk-1-ynes (using a strong base such as sodamide or a Grignard reagent) furnishes useful nucleophiles which undergo the expected reactions, e.g. alkylation and reaction with carbonyl compounds. Alkynyl-copper(I) reagents react smilarly to alkyl- and aryl-copper reagents but they also undergo oxidative coupling to give conjugated diynes. Some rules for the disconnection of target molecules, tabulated lists of synthetic equivalents for various synthons and one worked example are includeded at the end of the chapter.
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