CHAPTER 21 ESTER ENOLATES SOLUTIONS TO TEXT PROBLEMS 21.1 Ethyl benzoate cannot undergo the Claisen condensation, because it has no protons on its H9251-carbon atom and so cannot form an enolate. Ethyl pentanoate and ethyl phenylacetate can undergo the Claisen condensation. 21.2 (b) The enolate formed by proton abstraction from the H9251-carbon atom of diethyl 4-methylhep- tanedioate cyclizes to form a six-membered H9252-keto ester. CH 3 CH 2 OCCH 2 CH 2 CHCH 2 CH 2 COCH 2 CH 3 CH 3 O O CH 3 CH 2 O NaOCH 2 CH 3 OCH 2 CH 3 CH 3 O O C Ethyl (5-methyl-2-oxocyclohexane)- carboxylate Diethyl 4-methylheptanedioate OCH 2 CH 3 O O C C H 2 C CHCH 3 CH 2 CH 2 CH H11002 2C 6 H 5 CH 2 COCH 2 CH 3 O Ethyl phenylacetate Ethyl 3-oxo-2,4-diphenylbutanoate C 6 H 5 CH 2 CCHCOCH 2 CH 3 O O C 6 H 5 1. NaOCH 2 CH 3 2. H 3 O H11001 2CH 3 CH 2 CH 2 CH 2 COCH 2 CH 3 O Ethyl pentanoate Ethyl 3-oxo-2-propylheptanoate CH 3 CH 2 CH 2 CH 2 CCHCOCH 2 CH 3 O O CH 2 CH 2 CH 3 1. NaOCH 2 CH 3 2. H 3 O H11001 576 Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website ESTER ENOLATES 577 (c) The two H9251 carbons of this diester are not equivalent. Cyclization by attack of the enolate at C-2 gives This H9252-keto ester cannot form a stable enolate by deprotonation. It is present in only small amounts at equilibrium. The major product is formed by way of the other enolate. This H9252-keto ester is converted to a stable enolate on deprotonation, causing the equilibrium to shift in its favor. 21.3 (b) Both carbonyl groups of diethyl oxalate are equivalent. The enolate of ethyl phenylacetate attacks one of them. (c) The enolate of ethyl phenylacetate attacks the carbonyl group of ethyl formate. 21.4 In order for a five-membered ring to be formed, C-5 must be the carbanionic site that attacks the ester carbonyl. O O H11002 H 3 C CH 3 CH 2 O Enolate of ethyl 4-oxohexanoate CH 2 CH 2 C C CH 3 CH 2 O O O H11002 CHH 3 C H11001 OCH 2 CH 3 HC O C 6 H 5 CHCOCH 2 CH 3 H11002 O Ethyl 3-oxo-2- phenylpropanoate C 6 H 5 CHCH O COCH 2 CH 3 O C 6 H 5 CHCOCH 2 CH 3 CCOCH 2 CH 3 CH 3 CH 2 O O OO H11001 C 6 H 5 CHCCOCH 2 CH 3 COCH 2 CH 3 OO O Diethyl 2-oxo-3- phenylbutanedioate H11002 CH 3 CH 2 OCCHCH 2 CH 2 CH 2 COCH 2 CH 3 NaOCH 2 CH 3 O O CH 3 Site of carbanion Enolate attacks this carbon. Ethyl (3-methyl-2- oxocyclopentane)- carboxylate O CH 3 OCH 2 CH 3 O C CH 3 CH 2 OCCHCH 2 CH 2 CH 2 COCH 2 CH 3 NaOCH 2 CH 3 O O CH 3 Site of carbanion Enolate attacks this carbon. Ethyl (1-methyl-2- oxocyclopentane)- carboxylate O O CH 3 CH 2 OC H 3 C Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website 578 ESTER ENOLATES 21.5 The desired ketone, cyclopentanone, is derived from the corresponding H9252-keto ester. This key intermediate is obtained from a Dieckmann cyclization of the starting material, diethyl hexanedioate. First treat the diester with sodium ethoxide to effect the Dieckmann cyclization. Next convert the H9252-keto ester to the desired product by saponification and decarboxylation. 21.6 (b) Write a structural formula for the desired product; then disconnect a bond to the H9251-carbon atom. Therefore H11001 CH 2 CH 2 CCH 3 O 4-Phenyl-2-butanoneBenzyl bromide CH 2 Br Ethyl acetoacetate CH 3 CCH 2 COCH 2 CH 3 O O 1. NaOCH 2 CH 3 2. HO H11002 , H 2 O 3. H H11001 4. heat CH 2 CH 2 CCH 3 O H11001 Required alkyl halide CH 2 X Derived from ethyl acetoacetate CH 2 CCH 3 O H11002 COCH 2 CH 3 O O Ethyl (2-oxocyclopentane)- carboxylate O Cyclopentanone 1. HO H11002 , H 2 O 2. H H11001 3. heat CH 3 CH 2 OCCH 2 CH 2 CH 2 CH 2 COCH 2 CH 3 O O 1. NaOCH 2 CH 3 2. H 3 O H11001 COCH 2 CH 3 O O Ethyl (2-oxocyclopentane)- carboxylate Diethyl hexanedioate CH 3 CH 2 O 2 C(CH 2 ) 4 CO 2 CH 2 CH 3 O COCH 2 CH 3 O O O O H 3 C H11001 H11002 OCH 2 CH 3 O O H11002 H 3 C CH 3 CH 2 O 2-Methyl-1,3- cyclopentanedione Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website (c) The disconnection approach to retrosynthetic analysis reveals that the preparation of 5-hexen- 2-one by the acetoacetic ester synthesis requires an allylic halide. 21.7 (b) Nonanoic acid has a CH 3 (CH 2 ) 5 CH 2 @ unit attached to the synthon. Therefore the anion of diethyl malonate is alkylated with a 1-haloheptane. (c) Disconnection of the target molecule adjacent to the H9251 carbon reveals the alkyl halide needed to react with the enolate derived from diethyl malonate. H11001 Derived from diethyl malonate CH 2 COH O H11002 Required alkyl halide CH 3 CH 2 CHCH 2 X CH 3 CH 3 CH 2 CHCH 2 O CH 2 COH CH 3 H11001 1-Bromoheptane CH 3 (CH 2 ) 5 CH 2 Br Diethyl malonate CH 2 (COOCH 2 CH 3 ) 2 Diethyl 2-heptylmalonate CH 3 (CH 2 ) 5 CH 2 CH(COOCH 2 CH 3 ) 2 Nonanoic acid CH 3 (CH 2 ) 5 CH 2 CH 2 CO 2 H NaOCH 2 CH 3 ethanol 1. HO H11002 , H 2 O 2. H H11001 3. heat H11001 Derived from diethyl malonate CH 2 COH O H11002 Required alkyl halide CH 3 (CH 2 ) 5 CH 2 XCH 3 (CH 2 ) 5 CH 2 O CH 2 COH CH 2 COH O H11001 Allyl bromide CHCH 2 BrH 2 C 5-Hexen-2-one CHCH 2 CH 2 CCH 3 O H 2 C Ethyl acetoacetate CH 3 CCH 2 COCH 2 CH 3 O O 1. NaOCH 2 CH 3 2. HO H11002 , H 2 O 3. H H11001 4. heat H11001 Required alkyl halide CHCH 2 H 2 C X Derived from ethyl acetoacetate CH 2 CCH 3 O H11002 H 2 C CHCH 2 O CH 2 CCH 3 ESTER ENOLATES 579 Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website The necessary alkyl halide in this synthesis is 1-bromo-2-methylbutane. (d) Once again disconnection reveals the necessary halide, which is treated with diethyl malonate. Alkylation of diethyl malonate with benzyl bromide is the first step in the preparation of 3-phenylpropanoic acid. 21.8 Retrosynthetic analysis of the formation of 3-methyl-2-butanone is carried out in the same way as for other ketones. The two alkylation steps are carried out sequentially. CH 3 CCHCOCH 2 CH 3 NaOCH 2 CH 3 CH 3 Br O O CH 3 CH 3 CCH 2 COCH 2 CH 3 NaOCH 2 CH 3 CH 3 Br O O Ethyl acetoacetate Ethyl 2-methyl-3-oxobutanoate 1. HO H11002 , H 2 O 2. H H11001 CH 3 CCCOCH 2 CH 3 O O CH 3 H 3 C Ethyl 2,2-dimethyl-3-oxobutanoate CH 3 CCH(CH 3 ) 2 O 3-Methyl-2-butanone 3. heat 2CH 3 XH11001CH 3 CCH H11002 H11002 OO CH 3 CCH CH 3 CH 3 3-Methyl-2-butanone (two disconnections as shown) Derived from ethyl acetoacetate H11001 Benzyl bromide C 6 H 5 CH 2 Br Diethyl malonate CH 2 (COOCH 2 CH 3 ) 2 NaOCH 2 CH 3 ethanol Diethyl 2-benzylmalonate C 6 H 5 CH 2 CH(COOCH 2 CH 3 ) 2 1. HO H11002 , H 2 O 3-Phenylpropanoic acid C 6 H 5 CH 2 CH 2 COH O 2. H H11001 3. heat H11001 Derived from diethyl malonate CH 2 COH O H11002 Required halide C 6 H 5 CH 2 XC 6 H 5 CH 2 O CH 2 COH H11001 Diethyl malonate CH 2 (COOCH 2 CH 3 ) 2 NaOCH 2 CH 3 ethanol 1-Bromo-2-methylbutane CH 3 CH 2 CHCH 2 Br CH 3 1. HO H11002 , H 2 O 2. H H11001 3. heat Diethyl 2-(2-methylbutyl)malonate CH 3 CH 2 CHCH 2 CH(COOCH 2 CH 3 ) 2 CH 3 4-Methylhexanoic acid CH 3 CH 2 CHCH 2 CH 2 COH CH 3 O 580 ESTER ENOLATES Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website 21.9 Alkylation of ethyl acetoacetate with 1,4-dibromobutane gives a product that can cyclize to a five- membered ring. Saponification followed by decarboxylation gives cyclopentyl methyl ketone. 21.10 The last step in the synthesis of pentobarbital is the reaction of the appropriately substituted deriva- tive of diethyl malonate with urea. The dialkyl derivative of diethyl malonate is made in the usual way. It does not matter whether the ethyl group or the 1-methylbutyl group is introduced first. CH 2 (COOCH 2 CH 3 ) 2 Diethyl malonate CH 3 CH 2 CH 2 CH CH 3 CH 3 CH 2 C(COOCH 2 CH 3 ) 2 Diethyl 2-ethyl-2-(1-methylbutyl)malonate 2. NaOCH 2 CH 3 , CH 3 CH 2 Br 1. NaOCH 2 CH 3 , CH 3 CH 2 CH 2 CHCH 3 Br H11001 COCH 2 CH 3 COCH 2 CH 3 CH 3 CH 2 CH 2 CH CH 3 CH 3 CH 2 C O O Diethyl 2-ethyl-2-(1-methylbutyl)malonate H 2 NCNH 2 O Urea CH 3 CH 2 CH 2 CH CH 3 CH 2 O N N O O CH 3 Pentobarbital H H 1. HO H11002 , H 2 O 2. H H11001 3. heat CCH 3 COCH 2 CH 3 O O Ethyl 1-acetylcyclopentane- carboxylate CCH 3 H O Cyclopentyl methyl ketone H11001 NaOCH 2 CH 3 ethanol CCH 3 O COCH 2 CH 3 O BrCH 2 CH 2 CH 2 CH 2 CHCCH 3 COCH 2 CH 3 O O CH 2 CH 2 Br H 2 CC H11002 H 2 C CCH 3 O COCH 2 CH 3 O NaOCH 2 CH 3 CH 3 CCH 2 COCH 2 CH 3 O O Ethyl acetoacetate BrCH 2 CH 2 CH 2 CH 2 Br 1,4-Dibromobutane Ethyl 1-acetylcyclopentane- carboxylate ESTER ENOLATES 581 Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website 21.11 The carbonyl oxygen at C-2 of pentobarbital is replaced by sulfur in Pentothal (thiopental). The sodium salt of Pentothal is formed by removal of a proton from one of the N@H groups by sodium hydroxide. 21.12 The synthesis of phenobarbital requires diethyl 2-phenylmalonate as the starting material. Diethyl 2-phenylmalonate is prepared by a mixed Claisen condensation between ethyl phenyl- acetate and diethyl carbonate. 21.13 Like diethyl malonate, ethyl acetoacetate undergoes Michael addition to an H9251, H9252-unsaturated ketone. NaOCH 2 CH 3 CH 3 CH 2 OH H11001 CH 3 CCH 2 COCH 2 CH 3 O O O CHCOCH 2 CH 3 CH 3 O C O O H11001 NaOCH 2 CH 3 Ethyl phenylacetate C 6 H 5 CH 2 COCH 2 CH 3 O Diethyl carbonate CH 3 CH 2 OCOCH 2 CH 3 O Diethyl 2-phenylmalonate C 6 H 5 CH(COOCH 2 CH 3 ) 2 C 6 H 5 CH(COOCH 2 CH 3 ) 2 Diethyl 2-phenylmalonate Phenobarbital C 6 H 5 CH 3 CH 2 O N N O O NaOCH 2 CH 3 CH 3 CH 2 Br Diethyl 2-ethyl-2-phenylmalonate C 6 H 5 C(COOCH 2 CH 3 ) 2 CH 2 CH 3 H 2 NCNH 2 O H H Pentothal sodium CH 3 CH 2 CH 2 CH CH 3 CH 2 O N N O S CH 3 Na H11001 H11002 CH 3 CH 2 CH 2 CH CH 3 CH 2 O N N O S H11002 CH 3 Na H11001 H H Pentobarbital; prepared from urea, (H 2 N) 2 C O CH 3 CH 2 CH 2 CH CH 3 CH 2 O N N H H O O CH 3 1 3 4 6 25 Pentothal; prepared from thiourea, (H 2 N) 2 C S CH 3 CH 2 CH 2 CH CH 3 CH 2 O N N H H O S CH 3 582 ESTER ENOLATES Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website Basic ester hydrolysis followed by acidification and decarboxylation gives the diketone 3-(2- oxopropyl)cycloheptanone as the major product of the reaction sequence. 21.14 (b) The H9251-carbon atom of the ester bears a phenyl substituent and a methyl group. Only the methyl group can be attached to the H9251 carbon by nucleophilic substitution. Therefore generate the enolate of methyl phenylacetate with lithium diisopropylamide (LDA) in tetrahydrofuran (THF) and then alkylate with methyl iodide. (c) The desired product corresponds to an aldol addition product. Therefore convert cyclohexanone to its enolate and then treat with benzaldehyde. (d) This product corresponds to the addition of the enolate of tert-butyl acetate to cyclohexanone. Generate the enolate of tert-butyl acetate with lithium diisopropylamide; then add cyclohexa- none. 1. LDA, THF 2. cyclohexanone 3. H 3 O H11001 CH 2 CO 2 C(CH 3 ) 3 OH tert-Butyl (1-hydroxycyclohexyl)acetate CH 3 CO 2 C(CH 3 ) 3 tert-Butyl acetate H11001O O CH 2 COC(CH 3 ) 3 OH H11002 CH 2 COC(CH 3 ) 3 O 1. LDA, THF 2. C 6 H 5 CHO 3. H 3 O H11001 O Cyclohexanone O OH CHC 6 H 5 1-(2-Oxocyclohexyl)-1- phenylmethanol O OH CHC 6 H 5 O HCC 6 H 5 O H11002 H11001 LDA THF CH 3 I C 6 H 5 CHCO 2 CH 3 CH 3 Methyl 2-phenylpropanoate C 6 H 5 CH OCH 3 OLi C Enolate of methyl phenylacetate C 6 H 5 CH 2 CO 2 CH 3 Methyl phenylacetate CHCOCH 2 CH 3 O O 1. KOH, ethanol–water 2. H H11001 3. heat CH 2 CCH 3 O O 3-(2-Oxopropyl)- cycloheptanone (52%)CH 3 O C ESTER ENOLATES 583 Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website 21.15 To undergo a Claisen condensation, an ester must have at least two protons on the H9251 carbon: The equilibrium constant for condensation is unfavorable unless the H9252-keto ester can be deproton- ated to form a stable anion. (a) Among the esters given, ethyl pentanoate and ethyl 3-methylbutanoate undergo the Claisen condensation (b) The Claisen condensation product of ethyl 2-methylbutanoate cannot be deprotonated; the equilibrium constant for its formation is less than 1. (c) Ethyl 2,2-dimethylpropanoate has no protons on its H9251 carbon; it cannot form the ester enolate required in the first step of the Claisen condensation. 21.16 (a) The Claisen condensation of ethyl phenylacetate is given by the equation 1. NaOCH 2 CH 3 2. H H11001 C 6 H 5 CH 2 COCH 2 CH 3 O Ethyl phenylacetate C 6 H 5 CH 2 CCHCOCH 2 CH 3 OO C 6 H 5 Ethyl 3-oxo-2,4-diphenylbutanoate H11002 OCH 2 CH 3 H 3 C CH 3 CCOCH 2 CH 3 O CH 3 C H11001 no reaction Ethyl 2,2- dimethylpropanoate Ethyl 2-methylbutanoate CH 3 CH 2 CHCOCH 2 CH 3 O CH 3 No protons on H9251-carbon atom; cannot form stabilized enolate by deprotonation CH 3 CH 2 CHCCCOOCH 2 CH 3 O CH 3 CH 2 CH 3 CH 3 NaOCH 2 CH 3 K H11021 1 1. NaOCH 2 CH 3 2. H H11001 (CH 3 ) 2 CHCH 2 COCH 2 CH 3 O Ethyl 3-methylbutanoate (CH 3 ) 2 CHCH 2 CCHCOCH 2 CH 3 O O CH(CH 3 ) 2 Ethyl 2-isopropyl-5-methyl- 3-oxohexanoate 1. NaOCH 2 CH 3 2. H H11001 CH 3 CH 2 CH 2 CH 2 CCHCOCH 2 CH 3 O CH 2 CH 2 CH 3 O Ethyl 3-oxo-2-propylheptanoate CH 3 CH 2 CH 2 CH 2 COCH 2 CH 3 O Ethyl pentanoate NaOCH 2 CH 3 H110012RCH 2 COCH 2 CH 3 O 2CH 3 CH 2 OHNa H11001 H11001RCH 2 CCCOCH 2 CH 3 R O O H11002 H9251 584 ESTER ENOLATES Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website (b) Saponification and decarboxylation of this H9252-keto ester gives dibenzyl ketone. (c) This process illustrates the alkylation of a H9252-keto ester with subsequent saponification and decarboxylation. (d) The enolate ion of ethyl phenylacetate attacks the carbonyl carbon of ethyl benzoate. (e) Saponification and decarboxylation yield benzyl phenyl ketone. ( f ) This sequence is analogous to that of part (c). 21.17 (a) The Dieckmann reaction is the intramolecular version of the Claisen condensation. It employs a diester as starting material. 1. NaOCH 2 CH 3 2. H H11001 Ethyl (2-oxocyclohexane)- carboxylate COCH 2 CH 3 O O Diethyl heptanedioate CH 3 CH 2 OC(CH 2 ) 5 COCH 2 CH 3 O O C 6 H 5 CCHCOCH 2 CH 3 OO C 6 H 5 NaOCH 2 CH 3 CHCH 2 BrH 2 C C 6 H 5 CCCOOCH 2 CH 3 O C 6 H 5 CH 2 CH CH 2 1. HO H11002 , H 2 O 2. H H11001 3. heat 1,2-Diphenyl-4-penten-1-one C 6 H 5 CCHCH 2 CH O C 6 H 5 CH 2 1. HO H11002 , H 2 O 2. H H11001 3. heat OO C 6 H 5 C 6 H 5 CCHCOCH 2 CH 3 Ethyl 3-Oxo-2,3-diphenylpropanoate O C 6 H 5 CCH 2 C 6 H 5 Benzyl phenyl ketone C 6 H 5 C H11002 O O OCH 2 CH 3 C 6 H 5 CHCOCH 2 CH 3 OO C 6 H 5 C 6 H 5 CCHCOCH 2 CH 3 Ethyl 2,3-diphenyl- 3-oxopropanoate C 6 H 5 CH 2 CCHCOCH 2 CH 3 OO C 6 H 5 Ethyl 3-oxo-2,4- diphenylbutanoate NaOCH 2 CH 3 CHCH 2 BrH 2 C C 6 H 5 CH 2 CCCOOCH 2 CH 3 O C 6 H 5 CH 2 CH CH 2 1. HO H11002 , H 2 O 2. H H11001 3. heat C 6 H 5 CH 2 CCHCH 2 CH O C 6 H 5 1,3-Diphenyl-5-hexen-2-one CH 2 1. HO H11002 , H 2 O 2. H H11001 3. heat C 6 H 5 CH 2 CCH 2 C 6 H 5 O Dibenzyl ketone C 6 H 5 CH 2 CCHCOCH 2 CH 3 O O C 6 H 5 Ethyl 3-oxo-2,4- diphenylbutanoate ESTER ENOLATES 585 Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website (b) Acylation of cyclohexanone with diethyl carbonate yields the same H9252-keto ester formed in part (a). (c) The two most stable enol forms are those that involve the proton on the carbon flanked by the two carbonyl groups. (d) Deprotonation of the H9252-keto ester involves the acidic proton at the carbon flanked by the two carbonyl groups (e) The methyl group is introduced by alkylation of the H9252-keto ester. Saponification and decar- boxylation complete the synthesis. ( f ) The enolate ion of the H9252-keto ester [see part (d)] undergoes Michael addition to the carbon–carbon double bond of acrolein. This reaction has been reported in the chemical literature and proceeds in 65–75% yield. NaOCH 2 CH 3 CH 3 CH 2 OH O COCH 2 CH 3 O Ethyl (2-oxocyclohexane)- carboxylate H 2 C CHCH O Acrolein O O CH 2 CH 2 CH COOCH 2 CH 3 Michael adduct H11001 NaOCH 2 CH 3 CH 3 Br 1. HO H11002 , H 2 O O COCH 2 CH 3 O Ethyl (2-oxocyclohexane)- carboxylate O CH 3 COOCH 2 CH 3 Ethyl (1-methyl-2-oxocyclohexane)- carboxylate O CH 3 2-Methylcyclohexanone 2. H H11001 3. heat O COCH 2 CH 3 O H11002 O COCH 2 CH 3 O H11002 O COCH 2 CH 3 OH11002 O COCH 2 CH 3 O H O COCH 2 CH 3 O O COCH 2 CH 3 O H 1. NaOCH 2 CH 3 2. H H11001 O Diethyl carbonateCyclohexanone CH 3 CH 2 OCOCH 2 CH 3 O H11001 Ethyl (2-oxocyclohexane)- carboxylate COCH 2 CH 3 O O 586 ESTER ENOLATES Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website 21.18 (a) Ethyl acetoacetate is converted to its enolate ion with sodium ethoxide; this anion then acts as a nucleophile toward 1-bromopentane. (b) Saponification and decarboxylation of the product in part (a) yields 2-octanone. (c) The product derived from the reaction in part (a) can be alkylated again: (d) The dialkylated derivative of acetoacetic ester formed in part (c) can be converted to a ketone by saponification and decarboxylation. (e) The anion of ethyl acetoacetate acts as a nucleophile toward 1-bromo-3-chloropropane. Bromide is a better leaving group than chloride and is displaced preferentially. 1-Bromo-3- chloropropane Ethyl acetoacetate H11001 BrCH 2 CH 2 CH 2 Cl Ethyl 2-acetyl-5-chloropentanoate O CH 3 CCH 2 COCH 2 CH 3 O NaOCH 2 CH 3 CH 3 CCHCOCH 2 CH 3 CH 2 CH 2 CH 2 Cl O O Ethyl 2-acetyl-2-methylheptanoate CH 3 CCCOOCH 2 CH 3 CH 2 CH 2 CH 2 CH 2 CH 3 OCH 3 3-Methyl-2-octanone CH 3 CCHCH 3 CH 2 CH 2 CH 2 CH 2 CH 3 O 1. HO H11002 , H 2 O 2. H H11001 3. heat Ethyl 2-acetyl-2-methylheptanoate NaOCH 2 CH 3 CH 3 CCCOOCH 2 CH 3 CH 2 CH 2 CH 2 CH 2 CH 3 OCH 3 Ethyl 2-acetylheptanoate CH 3 CCHCOCH 2 CH 3 CH 2 CH 2 CH 2 CH 2 CH 3 O O H11001 CH 3 I Ethyl 2-acetylheptanoate 2-Octanone CH 3 CCH 2 CH 2 CH 2 CH 2 CH 2 CH 3 OO CH 3 CCHCOCH 2 CH 3 O (CH 2 ) 4 CH 3 1. HO H11002 , H 2 O 2. H H11001 3. heat O 1-BromopentaneEthyl acetoacetate H11001CH 3 CCH 2 COCH 2 CH 3 CH 3 CH 2 CH 2 CH 2 CH 2 Br Ethyl 2-acetylheptanoate O NaOCH 2 CH 3 CH 3 CCHCOCH 2 CH 3 CH 2 CH 2 CH 2 CH 2 CH 3 O O ESTER ENOLATES 587 Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website ( f ) Treatment of the product of part (e) with sodium ethoxide gives an enolate ion that cyclizes by intramolecular nucleophilic substitution of chloride. (g) Cyclobutyl methyl ketone is formed by saponification and decarboxylation of the product in part ( f ). (h) Ethyl acetoacetate undergoes Michael addition to phenyl vinyl ketone in the presence of base. (i) A diketone results from saponification and decarboxylation of the Michael adduct. 21.19 Diethyl malonate reacts with the reagents given in the preceding problem in a manner analogous to that of ethyl acetoacetate. (a) (b) Heptanoic acidDiethyl 1,1-hexanedicarboxylate CH 3 CH 2 CH 2 CH 2 CH 2 CH(COOCH 2 CH 3 ) 2 1. HO H11002 , H 2 O 2. H H11001 3. heat CH 3 CH 2 CH 2 CH 2 CH 2 CH 2 COH O 1-BromopentaneDiethyl malonate H11001CH 2 (COOCH 2 CH 3 ) 2 CH 3 CH 2 CH 2 CH 2 CH 2 Br Diethyl 1,1-hexanedicarboxylate (diethyl pentylmalonate) NaOCH 2 CH 3 CH 3 CH 2 CH 2 CH 2 CH 2 CH(COOCH 2 CH 3 ) 2 Ethyl 2-acetyl-5-oxo-5- phenylpentanoate CH 3 CCHCOCH 2 CH 3 CH 2 CH 2 CC 6 H 5 O O O 1-Phenyl-1,5-hexanedione CH 3 CCH 2 CH 2 CH 2 CC 6 H 5 O O 1. HO H11002 , H 2 O 2. H H11001 3. heat H11001 Phenyl vinyl ketoneEthyl acetoacetate O CH 3 CCH 2 COCH 2 CH 3 O H 2 C CHCC 6 H 5 O NaOCH 2 CH 3 ethanol Ethyl 2-acetyl-5- oxo-5-phenylpentanoate CH 3 CCHCOCH 2 CH 3 CH 2 CH 2 CC 6 H 5 O O O Ethyl 1-acetylcyclobutanecarboxylate O CH 3 C O COCH 2 CH 3 Cyclobutyl methyl ketone O CH 3 C 1. HO H11002 , H 2 O 2. H H11001 3. heat Ethyl 1-acetylcyclobutanecarboxylate Ethyl 2-acetyl-5-chloropentanoate NaOCH 2 CH 3 CH 3 CCHCOCH 2 CH 3 CH 2 CH 2 CH 2 Cl O O O CH 3 C O COCH 2 CH 3 588 ESTER ENOLATES Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website (c) (d) (e) ( f ) (g) (h) (i) 5-Oxo-5-phenylpentanoic acidDiethyl 4-oxo-4-phenylbutane- 1,1-dicarboxylate C 6 H 5 CCH 2 CH 2 CH 2 COH O O C 6 H 5 CCH 2 CH 2 CH(COOCH 2 CH 3 ) 2 O 1. HO H11002 , H 2 O 2. H H11001 3. heat Diethyl malonate CH 2 (COOCH 2 CH 3 ) 2 Phenyl vinyl ketone Diethyl 4-oxo-4-phenylbutane- 1,1-dicarboxylate H11001 NaOCH 2 CH 3 CH 3 CH 2 OH C 6 H 5 CCH CH 2 O C 6 H 5 CCH 2 CH 2 CH(COOCH 2 CH 3 ) 2 O Diethyl cyclobutane-1,1-dicarboxylate O O COCH 2 CH 3 COCH 2 CH 3 1. HO H11002 , H 2 O 2. H H11001 3. heat Cyclobutanecarboxylic acid O COH Diethyl 4-chloro-1,1-butanedicarboxylate ClCH 2 CH 2 CH 2 CH(COOCH 2 CH 3 ) 2 NaOCH 2 CH 3 Diethyl cyclobutane-1,1-dicarboxylate O O COCH 2 CH 3 COCH 2 CH 3 Diethyl malonate CH 2 (COOCH 2 CH 3 ) 2 1-Bromo-3-chloropropane BrCH 2 CH 2 CH 2 Cl Diethyl 4-chloro-1,1- butanedicarboxylate ClCH 2 CH 2 CH 2 CH(COOCH 2 CH 3 ) 2 H11001 NaOCH 2 CH 3 1. HO H11002 , H 2 O 2. H H11001 3. heat Diethyl 2,2-heptanedicarboxylate CH 3 CH 2 CH 2 CH 2 CH 2 C(COOCH 2 CH 3 ) 2 CH 3 2-Methylheptanoic acid CH 3 CH 2 CH 2 CH 2 CH 2 CHCOH O CH 3 Diethyl 2,2-heptanedicarboxylateDiethyl 1,1-hexanedicarboxylate CH 3 CH 2 CH 2 CH 2 CH 2 CH(COOCH 2 CH 3 ) 2 NaOCH 2 CH 3 CH 3 I CH 3 CH 2 CH 2 CH 2 CH 2 C(COOCH 2 CH 3 ) 2 CH 3 ESTER ENOLATES 589 Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website 21.20 (a) Both carbonyl groups of diethyl malonate are equivalent, and so enolization can occur in either direction. (b) Ethyl acetoacetate can give three constitutionally isomeric enols: (c) Bromine reacts with diethyl malonate and ethyl acetoacetate by way of the corresponding enols: Br 2 Ethyl acetoacetate CH 3 CCH 2 COCH 2 CH 3 O O Ethyl H9251-bromoacetoacetate CH 3 CCHCOCH 2 CH 3 Br O O H OCH 2 CH 3 CH O C O C H 3 C OCH 2 CH 3 H CHCH 3 CH 2 O O C O C CH 2 (COOCH 2 CH 3 ) 2 Diethyl malonate Br 2 Diethyl bromomalonate CH 3 CH 2 OCCHCOCH 2 CH 3 Br O O Least stable enol; double bond not conjugated with carbonyl group OCH 2 CH 3 H CH 2 H 2 C O C O C CH 3 CCH 2 COCH 2 CH 3 O O Ethyl acetoacetate Enol stable but lacking ester resonance OCH 2 CH 3 CH O C O C H H 3 C Most stable enol; double bond conjugated with carbonyl group; ester carbonyl stabilized by resonance H OCH 2 CH 3 CH O C O C H 3 C Diethyl malonate OCH 2 CH 3 H CHCH 3 CH 2 O O C O C OCH 2 CH 3 CH 2 CH 3 CH 2 O O CC O C OCH 2 CH 3 CHCH 3 CH 2 O O C O H 590 ESTER ENOLATES Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website 21.21 (a) Recall that Grignard reagents are destroyed by reaction with proton donors. Ethyl acetoacetate is a stronger acid than water; it transfers a proton to a Grignard reagent. (b) Adding D 2 O and DCl to the reaction mixture leads to D H11001 transfer to the H9251-carbon atom of ethyl acetoacetate. 21.22 (a) Ethyl octanoate undergoes a Claisen condensation to form a H9252-keto ester on being treated with sodium ethoxide. (b) Saponification and decarboxylation of the H9252-keto ester yields a ketone. (c) On treatment with base, ethyl acetoacetate is converted to its enolate, which reacts as a nucle- ophile toward 1-bromobutane. (d) Alkylation of ethyl acetoacetate, followed by saponification and decarboxylation, gives a ketone. The two steps constitute the acetoacetic ester synthesis. 2-Heptanone CH 3 CCH 2 CH 2 CH 2 CH 2 CH 3 O 1. NaOH, H 2 O 2. H H11001 3. heat Ethyl 2-acetylhexanoate CH 3 CCHCOCH 2 CH 3 CH 2 CH 2 CH 2 CH 3 O O Ethyl acetoacetate CH 3 CCH 2 COCH 2 CH 3 O O 1-Bromobutane CH 3 CH 2 CH 2 CH 2 BrH11001 NaOCH 2 CH 3 ethanol Ethyl 2-acetylhexanoate CH 3 CCHCOCH 2 CH 3 CH 2 CH 2 CH 2 CH 3 O O 2. H H11001 3. heat 1. NaOH, H 2 O 8-Pentadecanone CH 3 (CH 2 ) 5 CH 2 CCH 2 (CH 2 ) 5 CH 3 O Ethyl 2-hexyl-3-oxodecanoate CH 3 (CH 2 ) 5 CH 2 CCHCOCH 2 CH 3 O O (CH 2 ) 5 CH 3 Ethyl octanoate CH 3 (CH 2 ) 5 CH 2 COCH 2 CH 3 O 2. H H11001 1. NaOCH 2 CH 3 Ethyl 2-hexyl-3-oxodecanoate CH 3 (CH 2 ) 5 CH 2 CCHCOCH 2 CH 3 O O (CH 2 ) 5 CH 3 H11001 Deuterium oxide D 2 O Iodomagnesium salt of ethyl acetoacetate CH 3 CCHCOCH 2 CH 3 O O MgI Ethyl H9251-deuterioacetoacetate O CH 3 CCHCOCH 2 CH 3 O D DCl Methylmagnesium iodide Ethyl acetoacetate H11001 CH 3 MgI Methane H11001CH 4 Iodomagnesium salt of ethyl acetoacetate CH 3 CCH 2 COCH 2 CH 3 O O CH 3 CCHCOCH 2 CH 3 O O MgI ESTER ENOLATES 591 Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website (e) An alkylated derivative of ethyl acetoacetate is capable of being alkylated a second time. ( f ) The dialkylated derivative of acetoacetic ester formed in part (e) is converted to a ketone by saponification and decarboxylation. (g) The enolate of acetophenone attacks the carbonyl group of diethyl carbonate. (h) Diethyl oxalate acts as an acylating agent toward the enolate of acetone. (i) The first stage of the malonic ester synthesis is the alkylation of diethyl malonate with an alkyl halide. ( j) Alkylation of diethyl malonate is followed by saponification and decarboxylation to give a carboxylic acid. (k) The anion of diethyl malonate undergoes Michael addition to 6-methyl-2-cyclohexenone. CH 2 (COOCH 2 CH 3 ) 2 NaOCH 2 CH 3 ethanol H11001 O H 3 C O H 3 C CH(COOCH 2 CH 3 ) 2 Diethyl malonate 6-Methyl-2- cyclohexenone Diethyl 2-(4-methyl-3-oxocyclohexyl)malonate (isolated yield, 50%) CH 3 CH 2 CHCH 2 CH(COOCH 2 CH 3 ) 2 Diethyl 3-methylpentane-1,1-dicarboxylate 4-Methylhexanoic acid (57% yield from 1-bromo-2-methylbutane) CH 3 CH 3 CH 2 CHCH 2 CH 2 COH CH 3 1. NaOH, H 2 O 2. H H11001 3. heat O C CH 2 (COOCH 2 CH 3 ) 2 CH 3 CH 2 CHCH 2 CH(COOCH 2 CH 3 ) 2 BrCH 2 CHCH 2 CH 3 H11001 NaOCH 2 CH 3 ethanol Diethyl malonate 1-Bromo-2-methylbutane Diethyl 3-methylpentane-1,1-dicarboxylate CH 3 CH 3 Ethyl 2,4-dioxopentanoate CH 3 CCH 2 CCOCH 2 CH 3 O OO Diethyl oxalate CH 3 CH 2 OCCOCH 2 CH 3 OO Acetone CH 3 CCH 3 O H11001 1. NaOCH 2 CH 3 2. H H11001 3-Oxo-3-phenylpropanoate C 6 H 5 CCH 2 COCH 2 CH 3 O O Diethyl carbonate CH 3 CH 2 OCOCH 2 CH 3 O Acetophenone C 6 H 5 CCH 3 O H11001 1. NaOCH 2 CH 3 2. H H11001 3-Butyl-2-heptanone CH 3 CCH(CH 2 CH 2 CH 2 CH 3 ) 2 O Ethyl 2-acetyl-2-butylhexanoate CH 3 CC(CH 2 CH 2 CH 2 CH 3 ) 2 COOCH 2 CH 3 O 1. NaOH 2. H H11001 3. heat 1-Iodobutane CH 3 CH 2 CH 2 CH 2 IH11001 NaOCH 2 CH 3 ethanol Ethyl 2-acetylhexanoate CH 3 CCHCOCH 2 CH 3 CH 2 CH 2 CH 2 CH 3 O O Ethyl 2-acetyl-2-butylhexanoate CH 3 CC(CH 2 CH 2 CH 2 CH 3 ) 2 COOCH 2 CH 3 O 592 ESTER ENOLATES Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website (l) Acid hydrolysis converts the diester in part (k) to a malonic acid derivative, which then undergoes decarboxylation. (m) Lithium diisopropylamide (LDA) is used to convert esters quantitatively to their enolate ions. In this reaction the enolate of tert-butyl acetate adds to benzaldehyde. 21.23 (a) Both ester functions in this molecule are H9252 to a ketone carbonyl. Hydrolysis is followed by decarboxylation. (b) Examine each carbon that is H9251 to an ester function to see if it can lead to a five-, six-, or seven- membered cyclic H9252-keto ester by a Dieckmann cyclization. H11002 COOCH 2 CH 3 COOCH 2 CH 3 COOCH 2 CH 3 Cyclization gives a five-membered ring; H9252-keto ester deprotonated under reaction conditions; this is the observed product (C 12 H 18 O 5 ). O H 3 C COOCH 2 CH 3 COOCH 2 CH 3 H11002 COOCH 2 CH 3 COOCH 2 CH 3 COOCH 2 CH 3 Cyclization not likely; resulting ring is four-membered and highly strained. H11002 COOCH 2 CH 3 COOCH 2 CH 3 COOCH 2 CH 3 O H 3 C COOCH 2 CH 3 CH 3 CH 2 OOC Cyclization to a five-membered ring possible, but H9252-keto ester cannot be deprotonated to give a stable anion. H 2 O, H 2 SO 4 heat O CH 3 CH 2 COOCH 2 CH 3 COOCH 2 CH 3 O CH 3 CH 2 Diethyl 3-ethylcyclopentanone-2,5-dicarboxylate 3-Ethylcyclopentanone (C 7 H 12 O) CH 3 COC(CH 3 ) 3 C 6 H 5 CHCH 2 COC(CH 3 ) 3 OH O O LDA 1. C 6 H 5 CH 2. H H11001 OC(CH 3 ) 3 OLi H 2 C C O tert-Butyl acetate Lithium enolate of tert-butyl acetate tert-Butyl 3-hydroxy-3- phenylpropanoate O H 3 C CH 2 COOH (4-Methyl-3-oxocyclohexyl)acetic acid (isolated yield, 80%) O H 3 C CH(COOCH 2 CH 3 ) 2 Diethyl 2-(4-methyl-3-oxocyclohexyl)malonate H 2 O, HCl heat ESTER ENOLATES 593 Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website (c) Both ester function undergo hydrolysis in acid, but decarboxylation occurs only at the carboxyl group that is H9252 to the ketone carbonyl. (d) A Dieckmann cyclization occurs, giving a five-membered ring fused to the original three- membered ring. (e) Saponification and decarboxylation convert the H9252-keto ester to a ketone. 21.24 The heart of the preparation of capsaicin is a malonic ester synthesis. The first step is bromination of the primary alcohol by phosphorous tribromide. The resulting primary alkyl bromide is used to alkylate the sodium salt of diethyl malonate. A substituted malonic acid derivative is obtained following basic hydrolysis of the ester groups. Malonic acid derivatives undergo decarboxylation on heating. heat 160–180H11034C COH O C 10 H 18 O 2 COH O O COH OH PBr 3 1. NaCH(CO 2 CH 2 CH 3 ) 2 2. KOH, H 2 O, heat 3. H H11001 Br C 8 H 15 Br COH O O COH C 11 H 18 O 4 1. HO H11002 , H 2 O 2. H H11001 3. heat O H H Bicyclo[3.1.0]hexan-3-one (C 6 H 8 O, 43%) COOCH 2 CH 3 O H H Ethyl bicyclo[3.1.0]hexan-3- one-2-carboxylate 1. NaOCH 2 CH 3 2. H H11001 CH 2 COOCH 2 CH 3 CH 2 COOCH 2 CH 3 H H Diethyl cis-1,2- cyclopropanediacetate COOCH 2 CH 3 H H O Ethyl bicyclo[3.1.0]- hexan-3-one-2-carboxylate (C 9 H 12 O 3 , 79%) Diethyl 2-methylcyclopentanone- 3,5-dicarboxylate O COOCH 2 CH 3 COOCH 2 CH 3 H 3 C O CO 2 H CO 2 HH 3 C 2-Methylcyclopentanone-3- carboxylic acid (C 7 H 10 O 3 ) O CO 2 HH 3 C H 3 O H11001 heat 594 ESTER ENOLATES Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website Formation of the amide completes the synthesis of capsaicin. 21.25 (a) First write out the structure of 4-phenyl-2-butanone and identify the synthon that is derived from ethyl acetoacetate. Therefore carry out the acetoacetic ester synthesis using a benzyl halide as the alkylating agent. (b) Identify the synthon in 3-phenylpropanoic acid that is derived from malonic ester by discon- necting the molecule at its H9251-carbon atom. Here, as in part (a), a benzyl halide is the required alkylating agent. CH 2 (COOCH 2 CH 3 ) 2 NaOCH 2 CH 3 ethanol Benzyl bromideDiethyl malonate Diethyl benzylmalonate 3-Phenylpropanoic acid 1. HO H11002 , H 2 O 2. H H11001 3. heat C 6 H 5 CH 2 Br C 6 H 5 CH 2 CH(COOCH 2 CH 3 ) 2 C 6 H 5 CH 2 CH 2 COOHH11001 C 6 H 5 CH 2 CH 2 COH O C 6 H 5 CH 2 X CH 2 COH O H11001 H11002 CH 3 CCH 2 COCH 2 CH 3 C 6 H 5 CH 2 Br NaOCH 2 CH 3 ethanol CH 3 CCHCOCH 2 CH 3 OOO O CH 2 C 6 H 5 Ethyl acetoacetate Benzyl bromide CH 3 CCH 2 CH 2 C 6 H 5 O 4-Phenyl-2-butanone 1. HO H11002 , H 2 O 2. H H11001 3. heat H11001 Ethyl 2-benzyl-3- oxobutanoate C 6 H 5 CH 2 OH C 6 H 5 CH 2 Br HBr or PBr 3 Benzyl alcohol Benzyl bromide C 6 H 5 CH 2 C 6 H 5 CH 2 XCH 2 CCH 3 O CH 2 CCH 3 O H11001 H11002 SOCl 2 COH O CCl O CNHCH 2 OCH 3 OH O HO CH 2 NH 2 CH 3 O Capsaicin (C 18 H 27 NO 3 ) ESTER ENOLATES 595 Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website (c) In this synthesis the desired 1,3-diol function can be derived by reduction of a malonic ester derivative. First propene must be converted to an allyl halide for use as an alkylating agent. (d) The desired primary alcohol may be prepared by reduction of the corresponding carboxylic acid, which in turn is available from the malonic ester synthesis using allyl chloride, includ- ing saponification and decarboxylation of the diester [prepared in part (c)]. The correct sequence of reactions is (e) The desired product is an alcohol. It can be prepared by reduction of a ketone, which in turn can be prepared by the acetoacetic ester synthesis. Therefore 1. HO H11002 , H 2 O CH 2 O CH 3 CCH 2 CH 2 CH NaBH 4 CH 3 OH CH 2 OH CH 3 CHCH 2 CH 2 CH 5-Hexen-2-ol H11001 CH 2 CH 2 CH CH 3 CCHCOCH 2 CH 3 O O NaOCH 2 CH 3 ethanol CHCH 2 ClH 2 C Allyl chloride CH 3 CCH 2 COCH 2 CH 3 O O Ethyl acetoacetate 2. H H11001 3. heat CHCH 2 CH 2 CHCH 3 OH H 2 C O CHCH 2 CH 2 CCH 3 H 2 C H11001CHCH 2 XH 2 C O CH 2 CCH 3 H11002 CHCH 2 CH(COOCH 2 CH 3 ) 2 H 2 C Diethyl 2-allylmalonate [prepared as in part (c)] CHCH 2 CH 2 COOHH 2 C 4-Pentenoic acid CHCH 2 CH 2 CH 2 OHH 2 C 4-Penten-1-ol 1. HO H11002 , H 2 O 2. H H11001 3. heat 1. LiAlH 4 2. H 2 O CHCH 2 CH 2 CH 2 OHH 2 C CHCH 2 CH 2 CO 2 HH 2 C CHCH 2 CH(CO 2 CH 2 CH 3 ) 2 H 2 C 4-Penten-1-ol NaOCH 2 CH 3 ethanol CHCH 2 ClH 2 C Allyl chloride H11001CH 2 (COOCH 2 CH 3 ) 2 Diethyl malonate CHCH 2 CH(COOCH 2 CH 3 ) 2 H 2 C Diethyl 2-allylmalonate CHCH 2 CH(CH 2 OH) 2 H 2 C 2-Allyl-1,3-propanediol 1. LiAlH 4 2. H 2 O Cl 2 heat CHCH 3 H 2 C Propene CHCH 2 ClH 2 C Allyl chloride CHCH 2 CH(CH 2 OH) 2 H 2 C CHCH 2 XH 2 C H11001 CH(COOCH 2 CH 3 ) 2 H11002 596 ESTER ENOLATES Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website ( f ) Cyclopropanecarboxylic acid may be prepared by a malonic ester synthesis, as retrosynthetic analysis shows. The desired reaction sequence is (g) Treatment of the diester formed in part ( f ) with ammonia gives a diamide. (h) We need to extend the carbon chain of the starting material by four carbons. One way to accomplish this is by way of a malonic ester synthesis at each end of the chain. 21.26 The problem states that diphenadione is prepared from 1,1-diphenylacetone and dimethyl 1,2- benzenedicarboxylate. Therefore, disconnect the molecule in a way that reveals the two reactants. and CH 3 CCH(C 6 H 5 ) 2 O CX CX O O CCH(C 6 H 5 ) 2 O O O Diphenadione H11001 NaOCH 2 CH 3 2CH 2 (COOCH 2 CH 3 ) 2 Diethyl malonate Br(CH 2 ) 8 Br 1,8-Dibromooctane (CH 3 CH 2 OOC) 2 CH(CH 2 ) 8 CH(COOCH 2 CH 3 ) 2 1. HO H11002 , H 2 O 2. H H11001 3. heat HOCCH 2 (CH 2 ) 8 CH 2 COH O O Dodecanedioic acid 1. LiAlH 4 2. H 2 O Octanedioic acid HOC(CH 2 ) 6 COH O O HOCH 2 (CH 2 ) 6 CH 2 OH 1,8-Dibromooctane BrCH 2 (CH 2 ) 6 CH 2 Br HBr or PBr 3 NH 3 COCH 2 CH 3 COCH 2 CH 3 O O Diethyl cyclopropane- 1,1-dicarboxylate [prepared as in part ( f )] CNH 2 CNH 2 O O Cyclopropane- 1,1-dicarboxamide H11001 COOCH 2 CH 3 COOCH 2 CH 3 NaOCH 2 CH 3 ethanol 1. HO H11002 , H 2 O 2. H H11001 3. heat CH 2 (COOCH 2 CH 3 ) 2 Diethyl malonate BrCH 2 CH 2 Br 1,2-Dibromoethane COH O Cyclopropane- carboxylic acid CH 2 (CO 2 CH 2 CH 3 ) 2 H11001 CH 2 X CH 2 X CO 2 H CO 2 CH 2 CH 3 CO 2 CH 2 CH 3 ESTER ENOLATES 597 Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website Thus all that is required is to treat dimethyl 1,2-benzenedicarboxylate and 1,1-diphenylacetone with base. Two successive acylations of a ketone enolate occur; the first is intermolecular, the second intramolecular. 21.27 Esters react with amines to give amides. Each nitrogen of 1,2-diphenylhydrazine reacts with a separate ester function of diethyl 2-butylmalonate. 21.28 Styrene oxide will be attacked by the anion of diethyl malonate at its less hindered ring position. The product is 4-phenylbutanolide. It has been prepared in 72% yield by this procedure. 1. HO H11002 , H 2 O 2. H H11001 3. heat C 6 H 5 COOCH 2 CH 3 O O C 6 H 5 O O O C 6 H 5 CH(COOCH 2 CH 3 ) 2 H11002 C 6 H 5 CH CH 2 COCH 2 CH 3 O CH C O OCH 2 CH 3 O H11002 H11001 COCH 2 CH 3 CH 3 CH 2 CH 2 CH 2 CH COCH 2 CH 3 O O Diethyl 2-butylmalonate C 6 H 5 C 6 H 5 N H H N 1,2-Diphenylhydrazine CH 3 CH 2 CH 2 CH 2 C 6 H 5 C 6 H 5 O O N N Phenylbutazone (C 19 H 20 N 2 O 2 ) H11001 CH 3 CCH(C 6 H 5 ) 2 O COCH 3 COCH 3 O O NaOCH 3 ethanol CCH(C 6 H 5 ) 2 O O O Diphenadione CCH 2 CCH(C 6 H 5 ) 2 COCH 3 O O O H9252-Diketone; not isolated1,1-DiphenylacetoneDimethyl 1,2-benzene- dicarboxylate 1. NaOCH 3 2. H H11001 598 ESTER ENOLATES Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website 21.29 The first task is to convert acetic acid to ethyl chloroacetate. Chlorination must precede esterification, because the Hell–Volhard–Zelinsky reaction requires a carboxylic acid, not an ester, as the starting material. The remaining step is a nucleophilic substitu- tion reaction. 21.30 From the hint given in the problem, it can be seen that synthesis of 2-methyl-2-propyl-1,3-propane- diol is required. This diol is obtained by a sequence involving dialkylation of diethyl malonate. Begin the synthesis by dialkylation of diethyl malonate. Convert the ester functions to primary alcohols by reduction. Conversion of the primary alcohol groups to carbamate esters completes the synthesis. 21.31 The compound given in the problem contains three functionalities that can undergo acid-catalyzed hydrolysis: an acetal and two equivalent ester groups. Hydrolysis yields 3-oxo-1,1-cyclobutane- dicarboxylic acid and 2 moles each of methanol and 2-propanol. The hydrolysis product is a malonic C CH 2 OH CH 2 OH CH 3 CH 2 CH 2 H 3 C 2-Methyl-2-propyl-1,3-propanediol 1. COCl 2 2. NH 3 , H 2 O Meprobamate C CH 2 OCNH 2 CH 2 OCNH 2 CH 3 CH 2 CH 2 H 3 C O O C COOCH 2 CH 3 COOCH 2 CH 3 CH 3 CH 2 CH 2 H 3 C Diethyl 2-methyl-2-propylmalonate C CH 2 OH CH 2 OH CH 3 CH 2 CH 2 H 3 C 2-Methyl-2-propyl-1,3-propanediol 1. LiAlH 4 2. H 2 O NaOCH 2 CH 3 1. CH 3 CH 2 CH 2 Br, 2. CH 3 Br, NaOCH 2 CH 3 C COOCH 2 CH 3 COOCH 2 CH 3 CH 3 CH 2 CH 2 H 3 C Diethyl 2-methyl-2-propylmalonate CH 2 (COOCH 2 CH 3 ) 2 Diethyl malonate CH 3 CH 2 CH 2 CH 2 OCNH 2 O O CH 2 OCNH 2 H 3 C C CH 3 CH 2 CH 2 CO 2 CH 2 CH 3 CO 2 CH 2 CH 3 H 3 C C CH 3 CH 2 CH 2 CH 2 OH CH 2 OHH 3 C C NaCN ClCH 2 COCH 2 CH 3 O Ethyl chloroacetate Ethyl cyanoacetate CCH 2 COCH 2 CH 3 N O Cl 2 P CH 3 CH 2 OH H H11001 CH 3 COH O Acetic acid ClCH 2 COH O Chloroacetic acid ClCH 2 COCH 2 CH 3 O Ethyl chloroacetate ESTER ENOLATES 599 Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website acid derivative that decarboxylates on heating. The final product of the reaction is 3-oxocyclobu- tanecarboxylic acid (C 5 H 6 O 3 ). SELF-TEST PART A A-1. Give the structure of the reactant, reagent, or product omitted from each of the following: 1. NaOCH 2 CH 3 2. C 6 H 5 CH 2 Br ?CH 3 CCH 2 COCH 2 CH 3 OO (e) NaOCH 2 CH 3 ethanol ?H11001(CH 3 CH 2 OOC) 2 CH 2 H 2 C CHCOCH 2 CH 3 O (d) Cl COCH 2 CH 3 COCH 2 CH 3 ? (two isomeric products; C 5 H 7 ClO 2 ) O O 1. HO H11002 , H 2 O 2. H 3 O H11001 3. heat (c) 1. NaOCH 2 CH 3 2. H 3 O H11001 ?H11001HCOCH 2 CH 3 (b) O O C 6 H 5 CHCOCH 2 CH 3 C HO 1. NaOCH 2 CH 3 2. H 3 O H11001 ?CH 3 CH 2 CH 2 COCH 2 CH 3 (a) O HCl, H 2 O heat heat H11001H110012CH 3 OH Methanol OH 2CH 3 CHCH 3 2-Propanol COH COH O O O 3-Oxo-1,1-cyclobutanedicarboxylic acid H11001COH O O 3-Oxocyclobutanecarboxylic acid CO 2 Carbon dioxide COCH(CH 3 ) 2 COCH(CH 3 ) 2 CH 3 O CH 3 O O O Diisopropyl 3,3-dimethoxycyclobutane- 1,1-dicarboxylate 600 ESTER ENOLATES Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website A-2. Provide the correct structures of compounds A through E in the following reaction sequences: (a) (b) A-3. Give a series of steps that will enable preparation of each of the following compounds from the starting material(s) given and any other necessary reagents: (a) (b) A-4. Write a stepwise mechanism for the reaction of ethyl propanoate with sodium ethoxide in ethanol. A-5. Ethyl 2-methylpropanoate does not undergo a Claisen condensation, whereas ethyl 3-methylbutanoate does. Provide a mechanistic explanation for this observation. PART B B-1. Which of the following compounds is the strongest acid? (a) HCO 2 CH 2 CH 3 (b)CH 3 CH 2 O 2 CCH 2 CO 2 CH 2 CH 3 (c)CH 3 CH 2 O 2 CCH 2 CH 2 CO 2 CH 2 CH 3 (d)CH 3 CO 2 CH 2 CH 3 B-2. Which of the following will yield a ketone and carbon dioxide following saponification, acidification, and heating? (a)(c) (b)(d) CH 3 CH 2 CHCCH 3 O COCH 2 CH 3 O CH 3 CH 2 CHCOCH 2 CH 3 O COCH 2 CH 3 O CH 3 CH 2 CHCCH 3 O CCH 2 CH 3 O CH 3 CH 2 CHCH 2 CCH 3 O O COCH 2 CH 3 and diethyl carbonatefrom C 6 H 5 CCH 3 O C 6 H 5 CCH 2 CH 2 CH 2 CCH 3 OO CH 3 CCH 2 CH 2 COH from ethyl acetoacetate OO 1. NaOCH 2 CH 3 2. H 3 O H11001 DEH11001 CO 2 1. HO H11002 , H 2 O 2. H 3 O H11001 3. heat CH 3 CH 2 CH 2 COCH 2 CH 3 O COCH 2 CH 3 O O 1. NaOCH 2 CH 3 2. H 3 O H11001 1. NaOCH 2 CH 3 2. CH 3 CH 2 I ABC 1. HO H11002 , H 2 O 2. H 3 O H11001 3. heat CO 2 H11001 ? CO 2 H CH 3 CCHCH 2 CO 2 H O heat (g) Product of part (e)C 6 H 5 CH 2 CH 2 CCH 3 O ? ( f ) ESTER ENOLATES 601 Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website B-3. Which of the following keto esters is not likely to have been prepared by a Claisen condensation? (a)(c) (b)(d) B-4. Dieckmann cyclization of will yield (a)(c) (b)(d) B-5. What is the final product of this sequence? (a)(c) (b)(d) CH CH CH 2 O O O O CH 2 COCH 2 CH 3 CH 2 COCH 2 CH 3 O O NaOCH 2 CH 3 CH 3 CH 2 OH 1. HO H11002 , H 2 O 2. H H11001 3. heat O COCH 2 CH 3 O O COCH 2 CH 3 O O COCH 2 CH 3 COCH 2 CH 3 O O COCH 2 CH 3 CH 3 CH 2 OC(CH 2 ) 5 COCH 2 CH 3 O O CH(CH 3 ) 2 (CH 3 ) 2 CHCH 2 CCHCOCH 2 CH 3 O O C 6 H 5 CCHCOCH 2 CH 3 O O CH 3 (CH 3 ) 2 CHCC(CH 3 ) 2 O COCH 2 CH 3 O CH 3 CH 2 CCHCOCH 2 CH 3 O O CH 3 602 ESTER ENOLATES Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website B-6. What is the final product of the following sequence of reactions? (a)(c) (b) (d) B-7. Which of the following would be a suitable candidate for preparation by a mixed Claisen condensation? (a)(c) (b d) B-8. What is the major product of the following reaction? (a)(c)(e) (b)(d) HCCHCOCH 3 CH 3 O O HCOCHCOCH 3 CH 3 O O CH 3 OCHCOCH 3 CH 3 O HOCH 2 CHCOCH 3 CH 3 O CH 3 OCCHCOCH 3 CH 3 O O CH 3 CH 2 COCH 3 HCOCH 3 ? 1. NaOCH 3 2. H H11001 H11001 O O C 6 H 5 C O CH 3 CH 3 O COCH 2 CH 3 CC 6 H 5 CCH 2 COCH 2 CH 3 O O C 6 H 5 CH 2 CCH 2 COCH 2 CH 3 O O CH 3 CH 2 CCH 2 COCH 2 CH 3 O O O OH O O OH O O O OH O O OCH 2 CH 3 NaOCH 2 CH 3 ethanol ?H11001CH 2 (CO 2 CH 2 CH 3 ) 2 (CH 3 ) 2 C CHCCH 3 O 1. KOH 2. H H11001 3. heat ESTER ENOLATES 603 Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website