ESTER EN。 LATES 581 21.9 Alkylation of ethyl acetoacetate with 1, 4-dibromobutane gives a product that can cyclize to a five CH3,, CH3 BrCHlCH,CH,CH,Br BrCH, CH, CH, CH,CHCCH3 Ethyl acetoacetate 1.4-Dibromobutane COCHCH NaOCH CH, CCH CCH COCH,CH H2C、 COCH, CH3 Ethyl 1-acetylcyclopentane- Saponification followed by decarboxylation gives cyclopentyl methyl ketone. CCH 1. HO.H,O CCH COCH 3. heat Ethyl l-acetylcyclopentane- carboxylate Cycloketonlemethyl 21.10 The last step in the synthesis of pentobarbital is the reaction of the appropriately substituted deriva- tive of diethyl malonate with urea. CHCH2CH2CH、OcHH CHCH,CH,CH H,NCNH2 CHCH, COCH,CH CH- CH Diethyl 2-ethyl-2-(1-methylbutyl)malonate U Pentobarbital 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 1. NaoCH CH3, CH, CH,CH, CHCH CH3CH2CH2CH、 CH2(COOCH_ CH3)2 2.NaOCHCHCHCHBT C(COOCH, CH3)2 Diethyl malonate Diethyl 2-ethyl-2-(1-methylbutyl)malonate 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 fivemembered 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 derivative 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. CH2(COOCH2CH3)2 Diethyl malonate CH3CH2CH2CH CH3 CH3CH2 C(COOCH2CH3)2 Diethyl 2-ethyl-2-(1-methylbutyl)malonate 2. NaOCH2CH3, CH3CH2Br 1. NaOCH2CH3, CH3CH2CH2CHCH3 Br COCH2CH3 COCH2CH3 CH3CH2CH2CH CH3 CH3CH2 C O O Diethyl 2-ethyl-2-(1-methylbutyl)malonate H2NCNH2 O Urea CH3CH2CH2CH CH3CH2 O N N O O CH3 Pentobarbital H H 1. HO, H2O 2. H 3. heat CCH3 COCH2CH3 O O Ethyl 1-acetylcyclopentanecarboxylate CCH3 H O Cyclopentyl methyl ketone NaOCH2CH3 ethanol CCH3 O COCH2CH3 O BrCH2CH2CH2CH2CHCCH3 COCH2CH3 O O CH2 CH2 Br H2C C H2C CCH3 O COCH2CH3 O NaOCH2CH3 CH3CCH2COCH2CH3 O O Ethyl acetoacetate BrCH2CH2CH2CH2Br 1,4-Dibromobutane Ethyl 1-acetylcyclopentanecarboxylate ESTER ENOLATES 581 Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
582 ESTER EN。 LATES 21.11 The carbonyl oxygen at C-2 of pentobarbital is replaced by sulfur in Pentothal( thiopental) CH3o CH3 CH..CH CH2CHCH2CH、 CH3 CH2 6 CHCH Pentobarbital; prepared from urea, (HNC=O The sodium salt of Pentothal is formed by removal of a proton from one of the N-H groups by odium hydroxide O H3 CH, CHCHCH CH, CHCH、>NNa CH-C CH3 CH2 Pentothal sodium 21.12 The synthesis of phenobarbital requires diethyl 2-phenylmalonate as the starting material NaTCH.C HN C6HS CH(COOCH_ CH3)2 CHCHBr CHSC(COOCH2 CH3)2 H3 CH2 CH- CH3 Diethyl Phenobarbital -ethyl-2-phenylmalonate ethyl 2-phenylmalonate is prepared by a mixed Claisen condensation between ethyl phenyl- acetate and diethyl carbonate. C6H-CH, COCH, CH3+ CH3 CH,OCOCH, CH C6H_CH(COOCH,CH3) Diethyl carbonate Diethyl 2-phenylmalonate 21.13 Like diethyl malonate, ethyl acetoacetate undergoes Michael addition to an a, B-unsaturated ke NaoCH, CH, CHa CCH,COCH,CH3 CH,CH,OH CHCOCHCH 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 phenylacetate and diethyl carbonate. 21.13 Like diethyl malonate, ethyl acetoacetate undergoes Michael addition to an , -unsaturated ketone. NaOCH2CH3 CH3CH2OH CH3CCH2COCH2CH3 O O O CHCOCH2CH3 O CH3 C O O NaOCH2CH3 Ethyl phenylacetate C6H5CH2COCH2CH3 O Diethyl carbonate CH3CH2OCOCH2CH3 O Diethyl 2-phenylmalonate C6H5CH(COOCH2CH3)2 C6H5CH(COOCH2CH3)2 Diethyl 2-phenylmalonate Phenobarbital C6H5 CH3CH2 O N N O O NaOCH2CH3 CH3CH2Br Diethyl 2-ethyl-2-phenylmalonate C6H5C(COOCH2CH3)2 CH2CH3 H2NCNH2 O H H Pentothal sodium CH3CH2CH2CH CH3CH2 O N N O S CH3 Na CH3CH2CH2CH CH3CH2 O N N O S CH3 Na H H Pentobarbital; prepared from urea, (H2N)2C O CH3CH2CH2CH CH3CH2 O N N H H O O CH3 1 3 4 6 5 2 Pentothal; prepared from thiourea, (H2N)2C S CH3CH2CH2CH CH3CH2 O N N H H O S CH3 582 ESTER ENOLATES Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
ESTER EN。 LATES 583 Basic ester hydrolysis followed by acidification and decarboxylation gives the diketone 3-(2 oxopropyl)cycloheptanone as the major product of the reaction sequence 1. KOH ethanok-water CHCOCHCH CHCCH 3. heat CH3 cycloheptanone (52%o) 21. 14 (b) The a-carbon atom of the ester bears a phenyl substituent and a methyl group. Only the methyl group can be attached to the a carbon by nucleophilic substitution. Therefore generate the enolate of methyl phenylacetate with lithium diisopropylamide (lda)in tetrahydrofuran THF) and then alkylate with methyl iodide CH__ CO, CH,- THE C6HSCH=C → CH CHCO2CH3 OCH Methyl phenylacetate Methyl (c) The desired product corresponds to an aldol addition product CHC6H5 HCCSH Therefore convert cyclohexanone to its enolate and then treat with benzaldehyde CHCH L LDA THF 3.H2O Cyclohexanone 1-(2-Oxocyclohexyl)I (d) This product corresponds to the addition of the enolate of tert-butyl acetate to cyclohexanone OH 0 +: CH, COC(CH3)3 CH,COC(CH3)3 Generate the enolate of tert-butyl acetate with lithium diisopropylamide; then add cyclohexa 1. LDA, THF OH CH3CO2C(CH3)3 2. cyclohexanone 3.H2O CH, CO,C(CH3) tert-Butyl acetate (1-hydroxycyclohexyl)acetate 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 -carbon atom of the ester bears a phenyl substituent and a methyl group. Only the methyl group can be attached to the 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 cyclohexanone. 1. LDA, THF 2. cyclohexanone 3. H3O CH2CO2C(CH3)3 OH tert-Butyl (1-hydroxycyclohexyl)acetate CH3CO2C(CH3)3 tert-Butyl acetate O O CH2COC(CH3)3 OH CH2COC(CH3)3 O 1. LDA, THF 2. C6H5CHO 3. H3O O Cyclohexanone O OH CHC6H5 1-(2-Oxocyclohexyl)-1- phenylmethanol O OH CHC6H5 O HCC6H5 O LDA THF CH3I C6H5CHCO2CH3 CH3 Methyl 2-phenylpropanoate C6H5CH OCH3 OLi C Enolate of methyl phenylacetate C6H5CH2CO2CH3 Methyl phenylacetate CHCOCH2CH3 O O 1. KOH, ethanol–water 2. H 3. heat CH2CCH3 O O 3-(2-Oxopropyl)- CH cycloheptanone (52%) O 3 C ESTER ENOLATES 583 Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
584 ESTER EN。 LATES 21.15 To undergo a Claisen condensation, an ester must have at least two protons on the a carbon 2RCH, COCH, CH3 NaOCH, CH3 RCH,CCCOCH2 CH3 Na 2CH CH2OH The equilibrium constant for condensation is unfavorable unless the B-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 L Natch. ch CHaCH,,CH,COCH, CH CHa,CH,CH, CCHCOCH,CH Ethyl 3-ox0-2-propylheptanoate 1. NaOCH,CH, (CH3)2CHCH2 COCH CH3 2Ht (CH,) CHCH, CCHCOCH, CH3 CH(CH3h2 Ethyl 3-methylbutanoate Ethyl 2-isopropyl-5-methyl- 3-oxohexanoate (b) The Claisen condensation product of ethyl 2-methylbutanoate cannot be deprotonated; the uilibrium constant for its formation is less than 1 CHCH..CH CH CH, CHCCCOOCH,CH3 CH3 CH,CH Ethyl 2-methylbutanoate No protons on a-carbon atom form stabilized enolate by depr (c) Ethyl 2, 2-dimethylpropanoate has no protons on its a carbon; it cannot form the ester enolate required in the first step of the Claisen condensation H, C CH CCOCH,CH3 OCH,CH no reaction H3 Ethyl 2, 2- dimethylpropanoate 21.16(a) The Claisen condensation of ethyl phenylacetate is given by the equation 00 NaOCH.CH C6H CH,COCH, CH CBHSCH, CCHCOCH,CH Ethyl phenylacetate Ethyl 3-oXo-2, 4-diphenylbutanoat 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 carbon: The equilibrium constant for condensation is unfavorable unless the -keto ester can be deprotonated 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 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. NaOCH2CH3 2. H C6H5CH2COCH2CH3 O Ethyl phenylacetate C6H5CH2CCHCOCH2CH3 O O C6H5 Ethyl 3-oxo-2,4-diphenylbutanoate OCH2CH3 H3C CH3CCOCH2CH3 O CH3 C no reaction Ethyl 2,2- dimethylpropanoate Ethyl 2-methylbutanoate CH3CH2CHCOCH2CH3 O CH3 No protons on -carbon atom; cannot form stabilized enolate by deprotonation CH3CH2CHCCCOOCH2CH3 O CH3 CH2CH3 CH3 NaOCH2CH3 K 1 1. NaOCH2CH3 2. H (CH3)2CHCH2COCH2CH3 O Ethyl 3-methylbutanoate (CH3)2CHCH2CCHCOCH2CH3 O O CH(CH3)2 Ethyl 2-isopropyl-5-methyl- 3-oxohexanoate 1. NaOCH2CH3 2. H CH3CH2CH2CH2CCHCOCH2CH3 O CH2CH2CH3 O Ethyl 3-oxo-2-propylheptanoate CH3CH2CH2CH2COCH2CH3 O Ethyl pentanoate 2RCH2COCH2CH3 NaOCH2CH3 O Na 2CH3CH2OH RCH2CCCOCH2CH3 R O O 584 ESTER ENOLATES Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
ESTER EN。 LATES 585 (b) Saponification and decarboxylation of this B-keto ester gives dibenzyl ketone. 00 1. HO.H C..CCHCOCHCH CsH-CH, CCH,CSH C6H5 Ethyl 3-0Xo-2,4- Dibenzyl ketone (c) This process illustrates the alkylation of a B-keto ester with subsequent ication and decarboxylation OCHCH=CH C6HsCH, CCHCOCH,CH CHCH, Br CH-CH,CCCOOCH, CH- CH CH,CCHCH,CH=CH CsHs (d) The enolate ion of ethyl phenylacetate attacks the carbonyl carbon of ethyl benzoate. CHC OCH,CH C6HSCCHCOCH,CH C6HSCHCOCH,CH O Ethyl 2, 3-diphenyl 3-oxopropanoate (e) Saponification and decarboxylation yield benzyl phenyl ketone 1. HO, H,O CH_CCHCOCU (32.H C6H CCH,C6H5 CsH Ethyl Benzyl phenyl ketone 3-0xo-2, 3-diphenylpropanoate (f This sequence is analogous to that of part(c) OCHCHECH NaOCH, CH, CaH_CCHCOCH2 CH, H,C=CHCH,Br CaH, CCCOOCH2CH, 2HT C6HSCCHCH,CH=CH, CBHs CAHs 3. heat CAHs 1. 2-Diphenyl-4-penten-1-o 21.17(a) The Dieckmann reaction is the intramolecular version of the Claisen condensation. It employs a diester as starting material COCH.CH CH,CH_OC(CH),COCH_CH, L/CH,CHS Diethyl heptanedioat Ethyl (2-oxocyclohexane)- Back Forward Main Menu TOC Study Guide Toc Student OLC MHHE Website
(b) Saponification and decarboxylation of this -keto ester gives dibenzyl ketone. (c) This process illustrates the alkylation of a -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. NaOCH2CH3 2. H Ethyl (2-oxocyclohexane)- carboxylate COCH2CH3 O O Diethyl heptanedioate CH3CH2OC(CH2)5COCH2CH3 O O C6H5CCHCOCH2CH3 O O C6H5 NaOCH2CH3 H CHCH2Br 2C C6H5CCCOOCH2CH3 O C6H5 CH2CH CH2 1. HO, H2O 2. H 3. heat 1,2-Diphenyl-4-penten-1-one C6H5CCHCH2CH O C6H5 CH2 1. HO, H2O 2. H 3. heat O O C6H5 C6H5CCHCOCH2CH3 Ethyl 3-Oxo-2,3-diphenylpropanoate O C6H5CCH2C6H5 Benzyl phenyl ketone C6H5C O O OCH2CH3 C6H5CHCOCH2CH3 O O C6H5 C6H5CCHCOCH2CH3 Ethyl 2,3-diphenyl- 3-oxopropanoate C6H5CH2CCHCOCH2CH3 O O C6H5 Ethyl 3-oxo-2,4- diphenylbutanoate NaOCH2CH3 H CHCH2Br 2C C6H5CH2CCCOOCH2CH3 O C6H5 CH2CH CH2 1. HO, H2O 2. H 3. heat C6H5CH2CCHCH2CH O C6H5 1,3-Diphenyl-5-hexen-2-one CH2 1. HO, H2O 2. H 3. heat C6H5CH2CCH2C6H5 O Dibenzyl ketone C6H5CH2CCHCOCH2CH3 O O C6H5 Ethyl 3-oxo-2,4- diphenylbutanoate ESTER ENOLATES 585 Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website