Advanced organic synthesis lect 2

Advanced Organic Synthesis Chem 640 Dr Nabila Al-Jaber njaber@ksu.edu.sa 1431-1432 Latent Polarity Think about some of the reactions we've looked at for carbonyl compounds: Let, 2/11-10-2010 Let, 2/11-10-2010 10 Latent polarity in bifunctional compounds Consider a 1,3-disubstituted molecule, e.g Latent Polarities: O starting from C=O OH δ− O δ+ δ− δ+ Ph δ− Ph O starting from CΟΗ δ+ OH Let, 2/11-10-2010 OH δ− δ+ Ph δ− δ− O OH δ+ δ− O δ+ OH Ph Ph ≡ O + PhCHO Thus O O base O O PhCHO Cross Aldol Ph Acidic protne H 3O+ O OH O Na2SO Ph TM TM2 Ph - H2O Let, 2/11-10-2010 δ− R δ− δ− O O δ− δ+ δ+ δ− O δ− δ+ O R R R O e.g + R O O NaOH ∴ O R R R O Let, 2/11-10-2010 R But what about 1,4-disubstitution? δ− O O δ+ δ− δ+ δ− δ− δ+ δ− δ+ O δ− O O O synthons O O O + base Let, 2/11-10-2010 ? equivalents O O ≡ δ− δ + Br O O O base Br O O Let, 2/11-10-2010 The German word UMPOLUNG, meaning polarity reversal is used to describe the situation where the polarity in a compound is deliberately changed to facilitate a particular reaction reacts with nucleophiles δ − example: O δ + H HS SH cat BF3·OEt um p u ol ng OH SH S H - H2O S S acidic proton (pKa ~ 32) H n-Butyllithium Let, 2/11-10-2010 S reacts with electrophiles S δ − Li δ + 11 Strategy in retrosynthesis 1) Consider different possibilities 2) Try a number of disconnections and FGI's 3) Try to keep the number of steps down, and stick to known & reliable reactions 4) In real life, a synthesis has to be economically viable 5) Whenever possible, go for a convergent route rather than a linear one, as this will lead to a higher overall yield 10 Let, 2/11-10-2010 Intramolecular acylation eg the Dieckmann cyclisation; especially good for 5-membered rings: O O CO2Et CO2Et O ∴ NaO CO2 Et OEt NaOEt CO 2Et EtO2 C 21 - NaOEt Let, 2/11-10-2010 CO2Et Condensation: O O O OH OH 1-(2-methylcyclohex-1-enyl)ethanone ∴ O O O O t-BuOK - H2O nonane-2,8-dione acidic proton 22 Let, 2/11-10-2010 OH 14 Medium and Large Rings (8-11 membered and 12+) Intramolecular reaction is less favoured with bigger rings Often, high-dilution conditions and slow addition can be used to suppress intermolecular reaction and hence promote ring closure O eg MeO2C(CH2)7CO2Me NaH ester added over nine days (CH2)6 CO2Me similarly O EtO2C(CH2)14CO2Et " (CH2)13 CO2Et 23 Let, 2/11-10-2010 15 Cycloaddition reaction (Diels-Alder) Generic reaction (in retrosyntheic terms): X X electron rich eg CO2Me electron poor CO2Me concerted reaction 24 X = EWG (CHO, CO2R, CN) Let, 2/11-10-2010 Unsymmetrical Diels-Alder reactions: R R R R' R' + R' Minor product Major product R' R R R R' + R' Major product 25 Let, 2/11-10-2010 Minor product note that the 1,3-disubstituted product is the minor product in both cases CH3 CH3 CH3 CO2Me CO2Me + CO2Me 61% 26 Let, 2/11-10-2010 only 3% 16 Disconnections & Functional Group Interconversion in Aromatic Systems Some reactions used in aliphatic systems don't apply for aromatic systems (SN1 and SN2 reactions, for example, are extremely unfavourable for ArX eg O O R R ≡ PhH + RCOCl + AlCL3 Friedel-Crafts acylation i) RCOCl AlCl RCO O O H ii) 27 RCO R Let, 2/11-10-2010 R In planning synthesis of polysubstituted aromatics, the order of reactions is important to ensure that the reagents are compatible and to take advantage of the directing effect of existing substituents: Group NH2, NR2 OH, ONHAc, OR alkyl/aryl/vinyl CO2X (halogen) CO2H CN COR, CHO SO3H CX3 NO2 Directs Activation (more) activating ortho/para-* neutral meta- deactivating (more) * note that ortho/para- mixtures can be formed and may have to be separated 28 Let, 2/11-10-2010 Examples CO2Et CO2Et H2N CO2H CO2H O2N H 2N H2N benzocaine (painkiller) CO2H CO2H H2N O2N H 2N H2N benzocaine (painkiller) f rom toluene f rom toluene CO2H CO2H CO2H CO2H HNO3 KMNO4 HNO H2SO4 EtOH H2 Pd/C KMNO4 H2 Pd/C H+ H2SO4 H+ NH2 NO2 NO2 NO2 29 T.M.EtOH NO2 Let, 2/11-10-2010 NH2 T.M 17 Birch Reduction Partial reduction of aromatic systems by (usually) sodium in liquid ammonia It's an example of dissolving metal reduction Such methods used to be quite popular but most applications have been replace by modern hydride reagents Dissolving metal reduction does still have it's uses thoughand the Birch reduction is one of them, (also recall the specific reduction of alkynes totrans-alkenes) The typical conditions involve liquid ammonia (bp −33 °C) and sodium metal,in the presence of a proton source (usually an alcohol, EtOH) 30 Let, 2/11-10-2010 EWG EWG Na, NH3 (l), EtOH eg EWG = CO2H, NO2 EDG EDG " eg EDG = Me, OMe 31 Let, 2/11-10-2010 18 Fusing Rings onto aromatic systems The classical Hayworth naphthalene synthesis The fused aromatic system is formed by dehydration of a tetralin intermediate, which is prepared from an existing benzene ring and succinic anhydride O O discon + FGI 32 Let, 2/11-10-2010 O CO2H O Thus: O O O O Zn-Hg/HCl AlCl Clemmensen HO2 C intramolecular FC Pd/C O 1-subtitution ( aka α -) via enamine RBr Pd/C i) LiAlH4 ∆ R 2-subtitution ( aka β -) 33 tetralone ii) H3O+ R R i) SOCl2 ii) AlCl3 i) RMgx ∆ Dehydrogenation R HO 2C ii) H3O+ R O Let, 2/11-10-2010 19 Blocking positions in aromatic rings Functional groups that are introduced reversibly, or can be easily cleaved under mild condtions, can be used to access otherwise hard-to-make compounds Et Et Et Et SO3 Br Br2 H2SO4 Br dil H2SO4 FeBr3 1-bromo-2-ethylbenzene SO3 H SO3 H TM Br NH2 NH Br2 Br Br Br Br NaNO2/HCl Br N 2+ H3PO2 Br Br Br 1,3,5-tribromobenzene 34 Let, 2/11-10-2010 TM You have to know the terminology of stereochemistry a) Chiral, achiral compounds b) Stereogenic, nonstereogenic centers c) Enantiomers, diastereomers d) Prochiral, prostereogenic e) Enantiotopic, diastereotopic atoms and faces f) Ways of drawing stereochemistry g) For two adjacent stereocenters, we can use ) i (R) and (S ii For cyclic structures, cis and trans )iii threo and erythro (very old-fashioned )iv syn and anti (for a chain drawn in zigzag fashion )v like and unlike (only Europeans use this one 35 Let, 2/11-10-2010 [...]... Let, 2/ 11-10 -20 10 e.g Intramolecular alkylation: EtO2 C CO 2Et EtO 2C EtO2C CO2 Et CO2 Et X ∴ EtO2 C EtO2C CO 2Et NaOEt NaOEt EtO2C CO 2Et BrCH2CH2CH2CH2Br Br H 3O + COOH Cyclopentanoic acid 20 Let, 2/ 11-10 -20 10 heat CO2 E t Intramolecular acylation eg the Dieckmann cyclisation; especially good for 5-membered rings: O O CO2Et CO2Et O ∴ NaO CO2 Et OEt NaOEt CO 2Et EtO2 C 21 - NaOEt Let, 2/ 11-10 -20 10 CO2Et... substituents: Group NH2, NR2 OH, ONHAc, OR alkyl/aryl/vinyl CO2X (halogen) CO2H CN COR, CHO SO3H CX3 NO2 Directs Activation (more) activating ortho/para-* neutral meta- deactivating (more) * note that ortho/para- mixtures can be formed and may have to be separated 28 Let, 2/ 11-10 -20 10 Examples CO2Et CO2Et H2N CO2H CO2H O2N H 2N H2N benzocaine (painkiller) CO2H CO2H H2N O2N H 2N H2N benzocaine (painkiller)... (CH2)6 CO2Me similarly O EtO2C(CH2)14CO2Et " (CH2)13 CO2Et 23 Let, 2/ 11-10 -20 10 15 Cycloaddition reaction (Diels-Alder) Generic reaction (in retrosyntheic terms): X X electron rich eg CO2Me electron poor CO2Me concerted reaction 24 X = EWG (CHO, CO2R, CN) Let, 2/ 11-10 -20 10 Unsymmetrical Diels-Alder reactions: R R R R' R' + R' Minor product Major product R' R R R R' + R' Major product 25 Let, 2/ 11-10 -20 10... CO2Et H2N CO2H CO2H O2N H 2N H2N benzocaine (painkiller) CO2H CO2H H2N O2N H 2N H2N benzocaine (painkiller) f rom toluene f rom toluene CO2H CO2H CO2H CO2H HNO3 KMNO4 HNO H2SO4 3 EtOH H2 Pd/C KMNO4 H2 Pd/C H+ H2SO4 H+ NH2 NO2 NO2 NO2 29 T.M.EtOH NO2 Let, 2/ 11-10 -20 10 NH2 T.M 17 Birch Reduction Partial reduction of aromatic systems by (usually) sodium in liquid ammonia It's an example of dissolving metal... Addition, FGA) An example of this is acetoacetic ester synthesis: O O O OEt O ≡ :Thus O FGA O O CO2Et discon Bu discon CO2Et CO2Et SM, Ethylaceto acetate 17 Let, 2/ 11-10 -20 10 The s ynthe s is the re fo re is O O CO2Et O NaOEt CO2Et MeI CO 2Et Acidic proton NaOEt BuBr O O Bu − CO2 CO2H Bu TM 18 Let, 2/ 11-10 -20 10 H3O+ ∆ O CO 2Et Bu 13 Ring Closing Reactions Synthesis of carbocyclic molecules Same approach... convergent anyway) 2 disconnect at branch points 3 use symmetry where possible eg (towards the middle) O O O Ph O Ph O ∴ O O base Ph 13 MVK O Ph methyl vinyl ketone MVK Let, 2/ 11-10 -20 10 ) e g (at branc he s O O CO 2Et CO 2Et Ph Ph O O ∴ ? CO 2Et Ph CO 2Et Ph NaOEt Br O CO 2Et Ph 14 Let, 2/ 11-10 -20 10 )e g (lo o k fo r s ymme try O O O HO HO self -condensation O O O O NaOEt HO − H2O O Let, 2/ 11-10 -20 10 Alternatively,... can be easily cleaved under mild condtions, can be used to access otherwise hard-to-make compounds Et Et Et Et SO3 Br Br2 H2SO4 Br dil H2SO4 FeBr3 1-bromo -2- ethylbenzene SO3 H SO3 H TM Br NH2 NH 2 Br2 Br Br Br Br NaNO2/HCl Br N 2+ H3PO2 Br Br Br 1,3,5-tribromobenzene 34 Let, 2/ 11-10 -20 10 TM You have to know the terminology of stereochemistry a) Chiral, achiral compounds b) Stereogenic, nonstereogenic... CO2Me CO2Me + CO2Me 61% 26 Let, 2/ 11-10 -20 10 only 3% 16 Disconnections & Functional Group Interconversion in Aromatic Systems Some reactions used in aliphatic systems don't apply for aromatic systems (SN1 and SN2 reactions, for example, are extremely unfavourable for ArX eg O O R R ≡ PhH + RCOCl + AlCL3 Friedel-Crafts acylation i) RCOCl AlCl 3 RCO O O H ii) 27 RCO R Let, 2/ 11-10 -20 10 R In planning synthesis. .. EtOH) 30 Let, 2/ 11-10 -20 10 EWG EWG Na, NH3 (l), EtOH eg EWG = CO2H, NO2 EDG EDG " eg EDG = Me, OMe 31 Let, 2/ 11-10 -20 10 18 Fusing Rings onto aromatic systems The classical Hayworth naphthalene synthesis The fused aromatic system is formed by dehydration of a tetralin intermediate, which is prepared from an existing benzene ring and succinic anhydride O O discon + FGI 32 Let, 2/ 11-10 -20 10 O CO2H O Thus:... Condensation: O O O OH OH 1- (2- methylcyclohex-1-enyl)ethanone ∴ O O O O t-BuOK - H2O nonane -2, 8-dione acidic proton 22 Let, 2/ 11-10 -20 10 OH 14 Medium and Large Rings (8-11 membered and 12+ ) Intramolecular reaction is less favoured with bigger rings Often, high-dilution conditions and slow addition can be used to suppress intermolecular reaction and hence promote ring closure O eg MeO2C(CH2)7CO2Me NaH ester added