SYNTHESIS OF TARGET MOLECULES BY TWO FUNCTIONAL GROUPS DISCONNECTIONS: When a target molecule (TM) contains two functional groups, the best disconnection is one that incorporates both groups and provides two synthons. Such disconnections are called two group disconnections . Definition of two groups disconnection : When we use one functional to help disconnect another group in a bifunctional target molecule, then the disconnections are known as two group disconnections. In bifunctional target molecules two group disconnections are more efficient than one group disconnections. For instance, we can consider the following target molecule. For target molecules consisting of two fragments joined by a heteroatom, we should disconnect the bond next to the heteroatom. Therefore, in the following TM, we can disconnect on either side of the ether oxygen atom to get synthons. However, the disconnection b is the best choice. Br OH a OH b O Disconnection a b Disconnection O Ph + + TM OH OH O Ph Ph OH O HO Ph Ph Cause: Disconnection a does not correspond to a reliable reaction because it might be very difficult to control chemo- selective alkylation of a primary hydroxyl group in the presence of the secondary one. In the forward synthesis by path b, nucleophilic attack on the less hindered terminal carbon atom of the epoxide, the reagent of disconnection b, can give the desired molecule selectively. O O OH H O 2 O NaH Ph O OH O Ph Ph workup SYNTHESIS OF β-HYDROXY CARBONYLS AND α,β-UNSATURATED CARBONYLS : BY ALDOL REACTION: The aldol reaction of aldehydes and ketones is one of the most important methods for the synthesis of β-hydroxy carbonyls and α,β-unsaturated carbonyls. For example, With Acetaldehyde: O OH O + O aq. NaOH H3O 2 H3C H H3C H H3C H (Aldol) (Crotonaldehyde) With Acetone: O OH O + CH O aq. NaOH H C H3O 3 2 3 H C CH CH H C CH 3 3 H3C 3 3 3 (Diacetone alcohol) (4-Methyl-pent-3-en-2-one) Mechanism : Base catalyzed aldol reaction : O O O O R CH3 O O O OH aq. NaOH H2O R CH2 R CH 2 R CH2 R CH3 R CH3 H R R - (enolate anion) OH (X) Acid catalyzed aldol reaction : OH O OH H+ OH R CH3 OH OH + O OH -H R CH 3 R CH2 R CH R CH R CH 2 R 3 3 H (enol) R Mechanism of the dehydration of β-hydroxy carbonyl product : Acid catalyzed dehydration: + OH O H3O OH2 O (-H2O) O H2O O E1 H OH2 Base catalyzed dehydration: OH O OH OH O OH O - OH O E1cb H OH Mixed aldol reactions: CHO CHO CHO CHO OH + R R + + + R CHO R' CHO R' R' R' R R R' OH OH OH OH (Self-condensation products) (Crossed condensation products) On the other hand, if only one of the two aldehydes has an α-hydrogen, then two aldol products are formed. OH Ph H C CHO 3 CH3CHO + PhCHO + CHO OH OH α-hydrogen no α-hydrogen When one of the reactant involved in mixed aldol reaction is aromatic aldehyde such as benzaldehyde, furfural etc, the reaction is known as Claisen-Schmidt condensation . In this case aromatic aldehyde cannot act as a nucleophilic component due to the absence of α-protons for enolization. O O OH Ph Ph Ph Ph i) + Ph CH EtOH, heat 3 Ph H OH O O Ph Ph Ph O Ph OH ii) + O O EtOH, heat Ph O Ph Ph Ph O O OH iii) + Ph CH3 Ph H EtOH, heat O Intramolecular aldol reactions : H C CH3 O NaOEt/ EtOH O 3 OH H+ (-H2O) O O Nucleophile O O Electrophilic O H C OH O O 3 OH NaOEt/ EtOH NaOEt/ EtOH O O O O 1,4-dicarbonyl compound O Strained and not formed (Formed) O O O H KOH/MeOH H not heat O O CHO more reactive aldehyde group Synthesis of O2N CHO Retrosynthesis: OH OH Retro-Aldol O2N CHO O2N CHO + O2N CHO FGI O2N CHO CH3CHO Synthesis: O2N CHO OH O N CHO 1. KHSO4 2 O2N CHO O LDA/THF O dehydration o H - 78 C H 2. Aq. NH4Cl (work up) Work backward and identify the starting materials of the following products by aldol condensation and also point out which syntheses are particularly feasible. Me CO Et O O OH 2 i) ii) iii) Ph Ph Me Answer: Retrosynthesis: Me i) Me CO2Et O + CH3CO2Et Me Me Synthesis of the given molecule with these substrates will not be successful. Because when the carbanion derived from ethyl acetate mixed with acetone, proton transfer occurs more rapidly than the condensation occurs and forms the carbanion of acetone. The carbanion of acetone reacts with ethyl acetate to give Claisen condensation product after final work up with dilute acid. O NaOEt O + CH CO Et CH3CO2Et CH2CO2Et 3 2 O O + H3O O O NaOEt O O CH 3 CH3 CH3 So the given molecule can be synthesized by aldol reaction. But other methods such as Reformasky reaction,Wittig reaction or Knoevenagal reaction may be used for this purpose. ii) Retrosynthesis: O O + 2 PhCHO Ph Ph Synthesis of the given molecule by mixed aldol condensation using one molecule of acetone and two molecules of benzaldehyde is feasible. This is because only acetone has α-protons and benzaldehyde does not have any α-protons and therefore, the carbanion of acetone reacts with highly reactive benzaldehyde to give the desired product. The self- condensation of acetone is not feasible because of its unfavourable equilibrium constant. O O O NaOEt NaOEt PhCHO Ph Ph Ph PhCHO iii) Retrosynthesis: O OH O O + H Synthesis: O 1. H O OH O LDA/THF O o - 78 C 2. Aq. NH4Cl (work up) Synthesis of O Ph CO2H Retrosynthesis: OH O Retro-Aldol OH O O FGI + Ph CO H Ph CO2H Ph CO2H 2 O O Synthesis: Ph H CO2Et O 1. 1. Dil. KOH O Ph H OH O O EtO O Ph CO H + 2 CO Et Ph CO2Et 2. H3O /heat CO2Et 2 2. Aq. NH4Cl (work up) Synthesis of CHO from Retrosynthesis: CHO CHO Reconnection CHO Synthesis: CHO CHO NaIO4 Aq. NaOH OsO4 OH CHO CH O NMO OH CHO CHO CHO CHO OH H2O - OH E cb O 1 OH OH How will you bring about the following transformation? O Answer: O O O + 1. O3 NaOEt/EtOH H 2. Me2S; CH2Cl2 Aldol deaction Dehydration O OH Synthesis of O O Ph Ph OH Retrosynthesis: O O O Path b O O Ph Path a O Ph b + + Ph Ph OH a Ph Ph OH OH O O O NO Ph 2 Ph Ph Ph O O Path a is the best choice, because: The starting materials of path a are cyclohexanone and benzyl, which are simple starting materials and readily available. But 2-benzoylcyclohexanone, one of the starting materials of path b, is complicated and it has to be synthesized from cyclohexanone and ethyl benzoate by Claisen condensation. Again, since 2-benzoylcyclohexanone is an unsymmetrical 1,3-diketone, nucleophilic addition of enolate of nitroalkane may occur at both carbonyl to provide mixture of products. Synthesis: O Ph O Ph O 1. O O LDA/THF O Ph -78 oC 2. H O 2 Ph OH workup BY REFORMATSKY REACTION: The reaction of α-halo ester with an aldehyde or ketone having α-hydrogen or without having α-hydrogen to form β- hydroxy ester in the presence of zinc metal is referred to as the Reformatsky reaction . Zn OZnBr + OH O Ether-Benzene Dil. H + CO Et CO2Et Br CO2Et 2 Reflux β-Hydroxy ester Mechanism : EtO O O Zn O Zn O ZnBr O Br Br Zn Br EtO EtO EtO Zn O THF Br O OEt Dimer of zinc enolate O O Br O Br O Zn OEt Zn O OH + Dil. H O O O O Zn EtO O EtO Br EtO β-Hydroxy ester O When a nitrile is allowed to react with the zinc enolatederived from ethyl bromoacetate the corresponding β-keto ester is obtained. This is known as Blaise reaction . O 1. Zn(0), THF, reflux CN CO2Et + Br CO2Et 2. Aq. HCl, Suggest suitable method for the synthesis of the following compounds using the given reaction. CO Et 2 Using Reformatsky reaction Answer: Zn O OZnBr + OH Ether-Benzene dil H CO Et CO2Et + Br CO Et 2 2 Reflux Ac2O, heat CO2Et Transformation of O CH2CO2Et Answer: CO2Et CO Et O 2 HO CO2Et KHSO BrCH2CO2Et 4 Pd/ heat Heat Zn, THF-Benzene heat Then dil HCl How would synthesize the following molecule using Reformatsky reaction? OMe O CO Et O 2 3. 4. 2. HO CO2Et 1. CO2Et HO MeO OMe Ph CO2Et BY KNOVENAGEL REACTION Condensation of aldehydes or ketones with a compound having active methylene group in the presence of a weak base to form an α,β -unsaturated compound is known as Knoevenagel condensation. Weak bases like amines or buffer systems containing an amine and a weak acid catalyze these reactions. O CN cat. pyrrolidine CO2Et + CO2Et CN Mechanism : CN CN + + N CO Et N CO2Et 2 H H H O H O N O N HO N N + + N H -H + H + + + H -H+ (Iminium ion) CN CN N EtO C + 2 N CN EtO2C N + N + N H H H H H CO2Et EtO2C CN CN EtO C N + 2 + N N H H H H Regenerated catalyst Describe the synthesis of the following compound with proper retrosynthetic analysis.