Chem 353 Final 2004 : Synthesis

Part 9: SYNTHESIS

The schemes below give possible syntheses of the targets. There are of course other variations. The first part for each compound gives a "retro-synthesis", the "plan" and then the required forward synthesis with reagents is given. Red arrows try to show carbon-carbon bond forming reactions, blue arrows are functional group manipulations. The blue text rationalise the retrosynthetic analysis and information about important reactions are given in green.

Quick and simple suggestions for analysis / solutions for now.....images take a while to draw.....
men at work!

1. Cyclohexane derivative with defined stereochemistry.... Diels-Alder (actually very similar to number 2)

via Diels-Alder

2. Cyclohexane derivative with defined stereochemistry.... Diels-Alder.

Diels-Alder

3. An ether with aromatic rings. The ether could come from a Williamson ether synthesis of the primary -OH and primary -Br

dibenzyl ether

4. Alpha aryl cyclohexanone (enolate will not work since Ar-Br don't do SN1 or SN2), therefore get ketone via oxidation of secondary alcohol

a-arylketone

5. Beta-hydroxy carbonyl = enolate chemistry.... here a Claisen of an ester - reduction of ketone to -OH needed as well

The propanoate ester (CH3CH2-CO2Et) can be made from the acid and an alcohol : CH3CH3-CO2H + EtOH + H+ / heat
Claisen.... CH3CH2-CO2Et plus NaOEt gives the beta-keto ester : CH3CH2C(=O)CH(CH3)COOEt
Reduce the ketone with NaBH4 to leave ester unreacted to give the product, CH3CH2CH(OH)CH(CH3)COOEt

6. A para-nitro ether..... ether suggests using a Williamson ether synthesis. So use the alkyl bromide and the p-nitrophenol - the phenol can be made via diazonium chemistry

Benzene to nitrobenzene to aminobenzene to diazobenzene to phenol....C6H6 -- HNO3/H2SO4 -> C6H5NO2 -- Sn / HCl then NaHCO3 --> C6H5NH2 -- NaNO2 / HCl --> C6H5N2+ -- H2O / H2SO4 / heat --> C6H5OH
Phenol to p-nitrophenol C6H5OH -- HNO3/H2SO4 -> HOC6H4NO2
p-nitrophenol to p-propoxynitrobenzene : HOC6H4NO2 + CH3CH2CH2Br + K2CO3 (base) --> CH3CH2CH2OC6H4NO2

7. A 1,3,5-trisubstituted aromatic.... 2 acid groups.

Benzoic acid.... C6H5Br + Mg / THF -> C6H5MgBr then add CO2 (work up with H3O+) give C6H5CO2H (benzoic acid)
Nitrate using HNO3/H2SO4 to give m-nitrobenzoic acid
Reduce and the diazotise using Sn/HCl then Na2CO3, then NaNO2/ HCl
Use CuCN to get the nitrile, then hydrolyse the nitrile with H3O+ / heat to give the meta-dicarboxylic acid.
Now use FeBr3 / Br2 to get the bromine m to the 2 acid groups.

8. Tertiary alcohol, 2 aryl groups the same suggests Grignard chemistry of an ester... ester from carboxylic acid + alcohol

Benzoic acid.... C6H5Br + Mg / THF -> C6H5MgBr then add CO2 (work up with H3O+) give C6H5CO2H (benzoic acid)
Benzoate ester....C6H5CO2H + EtOH / H+ / heat ---> C6H5CO2Et
p-bromotoluene....C6H6 + CH3Cl + AlCl3 --> C6H5CH3 --- Br2 / FeBr3 --> p-CH3C6H4Br
Grignard ....p-CH3C6H4Br + Mg / THF -> CH3C6H4MgBr
Add 2 eq. Grignard to ester : 2 CH3C6H4MgBr + C6H5CO2Et --(work up with H3O+)--> target

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