1. 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

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

3. 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

4. Other Unstabilized Carbanions (I)
Organolithium reagents
preparation:
metal-halogen exchange:  45 top, eqns & 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

5. 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

6. 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

7. 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

8. 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

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

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

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

12. 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

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

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