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

For example

4.1.2 Reactions with carbonyl compounds

For example

For example

Synthesis of Alcohol by Grignard Reaction

4.1.4 Reactions with compounds containing C≡N

4.1.4 Reactions with α,β-unsaturated carbonyl compounds

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.

4.2.2 Organozinc and organocadmium reagents Organozinc reagents (Reformatsky reaction) 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 They can undergo the usuall range of reactions with electrophiles: Alkylation Reaction with carbonyl compounds

4.3.2 Alkynylcopper(I) compounds Preparation Ponits of synthetic importance: Displacement of halogens from’unreactive’ positions. Conversion of acyl halide into ketone Coupling reactions giving conjugated diynes.

4.4 Review R-R’  R-; R’+ R’-Y (Y = X (halides), OTs (sulfonates)) RCH2CH2OH  R-; +CH2CH2OH RCO2H  R-; +CO2H CO2  R-;

Synthetic equivalents Nucleophilic Synthons R- RMgX, RLi, R2Cd, RCu, R2CuLi Electrophilic R+ RCl, RBr, RI, ROSO2R1 RC+=O RCOCl, (RCO)2O, RCO2R1,RCN HC+=O HCO2R1, | OH CO2 C+H2OH HCHO RC+HOH RCHO R2C+OH R2CO +CH2CH2OH

4.5 Worked example 1-phenyl-butan-2-ol Two synthetic routes have therefor emerged: PhCH2MgBr + CH3CH2CHO and PhCH2CHO + BrMgCH2CH3

Pentadecan-4-one

3-Phenyl-butyric acid methyl ester

pent-3-yn-1-ol

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.