2444-120511

2444-120511 - 1 Reactions CHO 4 2 OHC 6 CHO 1 2 1. LDA,...

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Reactions 1 OHC CHO CO 2 Et CO 2 Et CO 2 Et CO 2 Et 1. LDA, THF, –78°C 2. H 3 O + 1.LDA, THF, –78°C 2. ethyl propanoate 3. hydrolysis 1. NaOEt , EtOH , reflux 2. aq. H + 1. LDA, THF, –78°C 2. H 3 O + 1 2 3 4 5 6 1 2 3 4 5 CHO OH 1 2 3 4 5 6 CO 2 Et O CO 2 Et O CO 2 Et O 1 2 3 4 5 CO 2 Et O OEt CO 2 Et O OEt
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Malonic Ester Enolate Anions 2 • 91 is a carbon nucleophile and it will react with both aldehydes and ketones, as well as with other esters. • If propanal is added to 91 , for example, acyl addition to the aldehyde carbonyl leads to 92 , so 91 is just another carbon nucleophile with the aldehyde. • An aqueous acid workup of 92 gives the alcohol, 93 . With malonic ester derivatives, loss of water to form 94 occurs very easily, with dilute acid or with gentle heating, b ecause the C=C unit is conjugated to two carbonyl groups, facilitating dehydration. CO 2 Et CO 2 Et H H NaH CO 2 Et CO 2 Et H Et O H CO 2 Et CO 2 Et H H O Et CO 2 Et CO 2 Et H H H O Et 94 CO 2 Et CO 2 Et H Et 90 91 92 aq. H + 93 - H 2 O
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Knoevenagel reaction 3 • Malonic acid ( 96 ) reacts with an aldehyde such as acetaldehyde, using pyridine as a base. • The enolate anion is formed by reaction with the basic amine pyridine, and it condenses with the carbonyl group of the aldehyde. • After treatment with aqueous acid, the final product isolated form this experiment was 2-butenoic acid, 98 (in 60% yield). • This specialized version of the malonic acid condensation is called the Knoevenagel reaction . O OH O OH H 3 C CHO O OH H H 3 C O OH O OH H H 3 C + pyridine reflux 96 98 1. 2. H 3 O + 97
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Decarboxylation 4 • Decarboxylation requires the presence of a carboxyl group (COOH) attached to a carbon that has another carbonyl substituent. • An internal acid-base reaction is possible that leads to cleavage of a C–C bond and loss of the neutral molecule carbon dioxide (CO 2 = O=C=O). • Malonic acid has the requisite structural features (see 96 ), and when malonic acid and related compounds are heated to 200°C, they lose carbon dioxide (CO 2 ): they decarboxylate . • 2-Methyl-1,3-propanedioic acid ( 99 ) gives propanoic acid upon heating. The initial product is an enol, 100 , the enol of a carboxylic acid. • Tautomerization of 100 leads to the carboxyl unit in propionic acid. O O H O O H O H O H O O H 99 – O=C=O 100
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Decarboxylation 5 • The Claisen condensation leads to ! -keto ester products ( 61 ), which are capable of decarboxylation after hydrolysis to the requisite COOH unit to give ! -keto acid 101 . • This molecule contains a carbonyl unit that is two carbons away from the carboxyl unit, and it undergoes decarboxylation. • Heating 101 to >200°C leads to decarboxylation with formation of enol 102 , which then tautomerizes to give 2,5-dimethyl-3-pentanone ( 103 ). Me OEt O O Me 61 Me O O O Me 101 H Me O Me Me O Me H >200°C 102 103 - CO 2 Me Me Me Me Me Me Me Me H 3 O +
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Enolate Alkylation: Ketones 6 • 2-Benzylcyclohexanone ( 104 ) is converted to the enolate anion under kinetic conditions (the solvent is dimethoxyethane, which is abbreviated DME), and subsequent reaction with iodomethane gives a 73% yield of 105 .
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2444-120511 - 1 Reactions CHO 4 2 OHC 6 CHO 1 2 1. LDA,...

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