Chap. 4. C-C Bonds with Unstabilized Carbanions Organic Chemistry of Fine Chemicals Spring 2006 Chap. 4. C-C Bonds with Unstabilized Carbanions Grignard reagents & Electrophiles Alkylation:  38 bot., 4.1 generally not useful: elimination/reduction/electron transfer however, useful reactions with epoxides:  39 top, 4.2 Addition to carbonyl compounds: depends on Y aldehydes & ketones: alcohols;  39 middle 4.3 & reactions acyl halides, anhydrides, esters:  40 top, 4.4 & examples exceptions: formation of carbonyls;  41 top CO2: carboxylic acids (-CO2H);  41, 4.5 carboxylate ions: aldehydes/ketones,  41 middle reactions amides: tertiary-aldehydes/ketones,  42 top, 4.6 & examples orthoformates: formyl group,  42 bottom, 4.7 & examples OCFC-Chap4 Chapter 4

Type of Products with Addition: [Chap. 18 & 19] OCFC-Chap4

C-C Bonds with Unstabilized Carbanions (II) Organic Chemistry of Fine Chemicals Spring 2006 C-C Bonds with Unstabilized Carbanions (II) Grignard reagents & Electrophiles (continued) Addition to C-N multiple bonds imines & nitriles: amines & ketones,  43 top Conjugated double bonds: 1,2- vs. 1,4-addition,  43 middle, 4.8 vs. 4.9; not reliable 1,2-addition: alkyl Grignards/no steric hindrance,  43 bot. 1,4-addition: aryl Grignards/steric hindrance,  43 – 44 top Chichibabin-type reactions with amine heterocycles pyridines & (iso)quinolines: -akylation,  44 middle Preparation of alkenyl and alkynyl Grignards alkenyl Grignards from alkenyl halides and Mgo: unreactive, longer reaction in THF alkynyl Grignards from alkynes and other Grignards: efficient  44 bottom, 4.10 OCFC-Chap4 Chapter 4

Other Unstabilized Carbanions (I) Organolithium reagents preparation: metal-halogen exchange:  45 top, eqns. 4.11 & 12 deprotonation with R-Li:  45 middle reactions: stronger Nu & base, small & hard cation (Li+) (1,2-)addition reactions:  45 bottom reactions Organozinc & Organocadmium reagents less reactive but more selective: limited usage Organozinc: Reformatsky reaction with -bromoesters addition to carbonyls: one-pot,  46 middle, 4.13 Organocadmium: acyl chlorides into ketones selective over ester, ketone, or alkyl halide:  46 bot. – 47 top OCFC-Chap4

Other Unstabilized Carbanions (II) Organocopper(I) reagents: soft, selective & useful Nu (mono)organocopper (R-Cu), cuprate (R2CuLi, Gilman), higher order cuprate (RmCunLim, R2CuCNM2) preparation: m R-Li/R-MgX + n CuI/CuBr/CuCN substitution of halogens:  47 bottom acyl halides: only ketone;  48 top conjugated carbonyls: exclusive 1,4-addition;  48 middle Grignard + cat. Cu(I) (Normant reagents):  48 bottom coupling reactions: heating organocopper/oxidation of cuprate mechanisms:  48, 4.15 &16 homocoupling:  49 Ullman coupling: OCFC-Chap4

Organic Chemistry of Fine Chemicals Spring 2006 Alkynyl Carbanions R-CC-M: M=Li, Na, Mg less basic (< RMgX or RLi) but good nucleophilicity preparation: R-CC-H + M-B,  49 bottom alkylation:  50 top, 4.17 & reactions addition to carbonyls:  50 middle, 4.18 Alkynylcopper(I) reagents: R-CC-Cu easy preparation: R-CC-H + CuCl (aq. NH3/DMF),  51 top more stable than R-Cu, similar reactivity to R-Cu substitution of unreactive halogens:  51 top reactions acyl chlorides: ketones;  51 middle coupling reactions: conjugated diynes;  51 middle, 4.19 oxidation of alkynylcopper: Glaser coupling,  51 bottom oxidation of alkyne with CuX: Eglinton-Galbraith  51 bottom unsymmetrical coupling: Cadiot-Chodkiewicz,  51, 4.20 &  52 OCFC-Chap4 Chapter 4

Review: C-C with Unstabilized Carbanions (I) Organic Chemistry of Fine Chemicals Spring 2006 Review: C-C with Unstabilized Carbanions (I) OCFC-Chap4 Chapter 4

Review: C-C with Unstabilized Carbanions (II) Organic Chemistry of Fine Chemicals Spring 2006 Review: C-C with Unstabilized Carbanions (II) OCFC-Chap4 Chapter 4

Synthetic Equivalents for Synthons (I) Organic Chemistry of Fine Chemicals Spring 2006 Synthetic Equivalents for Synthons (I) OCFC-Chap4 Chapter 4

Synthetic Equivalents for Synthons (II) Organic Chemistry of Fine Chemicals Spring 2006 Synthetic Equivalents for Synthons (II) OCFC-Chap4 Chapter 4

Organic Chemistry of Fine Chemicals Spring 2006 Target Compounds (I) 1-Phenylbutan-2-ol: retrosynthetic analysis: disconnection approach OCFC-Chap4 Chapter 4

Design and Synthesis Retrosynthetic Analysis Synthesis 1. recognise the functional groups in the target molecule 2. disconnect by known methods and reliable reactions 3. repeat 1 and 2 until the readily available starting materials are obtained 4. design as many alternative retrosynthetic routes as possible Synthesis 1. write down the synthetic schemes containing the detailed reaction conditions according to the analyses 2. compare the pros and cons between the syntheses designed; the number of steps, availability of reagents/starting materials, selectivity (chemo-/regio-/stereo-), economy, process, etc 3. modify the selected synthetic plan whenever unexpected problems are encountered OCFC-Chap4

Organic Chemistry of Fine Chemicals Spring 2006 Target Compounds (II) Pentadeca-4-one: OCFC-Chap4 Chapter 4

Target Compounds (III) Organic Chemistry of Fine Chemicals Spring 2006 Target Compounds (III) Methyl 3-phenylbutanoate: OCFC-Chap4 Chapter 4