14C synthesis strategies, Chem 315/316 / Beauchamp 1 Functional Group Reactions O O Alkanes: Make O from R Br OH R Br R H R R R H haloalkanes S H haloalkanes aldehydes aldehydes alkenes alkynes O H2SO4 1. LiAlH4 & ketones & ketones H2O 1. Mg (LiAlD4) Wolff-Kishner Clemmenson H2 /Pd H2 /Pd 2. workup 2. workup NH2NH2 /ROH/ Zn / HCl aromatic sulfonic acids y:\files\classes\316\special handouts\316_FG_syn.doc 14C synthesis strategies, Chem 315/316 / Beauchamp 2 O Esters O O O O O O Make R OH ROH R OH R R' from R O R OH R Cl ketones R' H2SO4 (-H2O) RBr RBr alkene R O ROH mCPBA Fischer ester syn Baeyer-Villigar S 2 S 1 N N acyl substitution acyl substitution H2SO4 rxn O Aldehydes O OH N R R O C Make R R O R Cl R R from R nitriles esters acid chlorides 1o alcohols alkenes alkynes 1. HCON(CH ) /POCl R H 1. R AlH 3 2 3 CrO 1. R2AlH 1. R2AlH 2 2. workup 3 1. O , -78oC 1. R BH pyridine 3 2 (DIBAH) (DIBAH) (DIBAH) 2. H O , HO Vilsmeier Rxn (PCC) 2. CH3SCH3 2 2 2. workup 2. workup 2. workup Ketones R O O O OH N R O O O C Make R' R R NR R 2 R' Cl R R' R OH from R R' 3o amides 2o alcohols R' alkynes nitriles acid chlorides ketals acids R R' CrO3 alkenes deprotect 1. 2 eqs. R'Li H2SO4/H2O 1. R'MgBr 1. R'MgBr 1. R2Cu Li 2. workup pyridine o 1. O , -78 C +2 2. workup 2. workup 2. workup + (PCC) 3 Hg cat. H O /H O (2 ways) (2 ways) (2 ways) 3 2 2. CH3SCH3 (2 ways) O O O 1o, 2o, 3o amides N C O Make from R' Cl R' O R R R acid chlorides anhydrides nitriles R N o from from (1 amides) NH , 1o, 2o amides o o R = C, H R 3 NH3, 1 , 2 amides HCl / H2O O Reactions of Acid Chlorides O R' O O O O R N R O O O R" aromatic R' R H R R R O R' 1o,2o,3o amides R' ketones R Cl R O anhydrides esters R S aldehydes ketones H thioesters R R AlCl O Cu 3 O N Al H SH R Li R' H R' R Friedel-Crafts R' cuprates R' OH R=CorH R DIBAH Acylation y:\files\classes\316\special handouts\316_FG_syn.doc 14C synthesis strategies, Chem 315/316 / Beauchamp 3 Reactions of Alkenes OH OH Br Br OH OH Br Br Br + HBr / ROOR H3O / H2O 1. Hg(OAc)2/H2O 1. BH3 2. NaBH or (poss. rearrangement) 4 2. H2O2 / HO HBr Br2 Br2 / H2O (no rearrangement) (anit-Markovnikov) 1. BH3 OH 2. Br2 / CH3O (anit-Markovnikov) NaOH OH (mild) O O OH O OH O HO O OH OH CH 2 CH3 C O + OsO or KMnO H / Pd o o H H O / H O 4 4 2 1. O3 , -78 C 1. O , -78 C o OH 2 2 mCPBA syn diol 3 1. O3 , -78 C or 2. CH3SCH3 2. NaBH4 2. H O , HO 2 2 anti diol H2O / HO Alkynes H R Br Br R electrophiles H H R R X O Make R R R alkynes haloalkanes from alkene alkynes R R dihaloalkane 1. NaNR 1. Br 2 O 2 1. NaNR 1. NaNR2 2. NaNR 2 excess/zipper aldehydes excess/zipper excess/zipper excess/zipper 2. electrophile & ketones R 2. workup 2. workup 3. workup 3. workup epoxides Reactions of Alkynes OH O O Br OH H 1. R BH + 2 H3O / H2O 2. H O HO +2 2 2 / 1. NaNR2 1. NaNR Hg cat. (anit-Markovnikov) HBr 2 1. NaNR2 2. 2. O 2. Br O H 3. workup 3. workup Reactions of Alkynes O start O over H Pd, H2 1. excess NaNR 1. R BH Na / NH / ROH Pd, H 2 2 quinoline 3 2 2. workup 2. H O HO H O+ / H O E alkenes 2 2 / 3 2 (Lindlar's Cat.) (zipper reaction) (anit-Markovnikov) Hg+2 cat. Z alkenes O R R R H O aldehydes & ketones Make from alkene alkene H3C H3C R epoxides S CH n-butyl lithium 1. Br2 /H2O 2 S CH3 mCPBA 2. mild NaOH H3C sulfur ylid H3C I anhydrides acid chlorides & acids O O O O Make from R O R' R Cl R' OH (2 ways) Organometallics (Li, Mg, Cu) 2 eqs. Make R X Make R X R Cu R Make from from R Li R Li from haloalkanes R (MgBr) haloalkanes Li CuBr Li Mg y:\files\classes\316\special handouts\316_FG_syn.doc 14C synthesis strategies, Chem 315/316 / Beauchamp 4 Mg and Li Organometallics Reactions OH OH OH OH O O OH R Li R R" R R' R R R R' R' R' R OH R R' R (MgBr) O O O O O N O similar C C R chemistry O R' H H R' H R' R" R' O 1. make R-Metal 1. make R-Metal 1. make R-Metal 1. make R-Metal 1. make R-Metal 1. make R-Metal 1. make R-Metal 2. electrophile 2. electrophile 2. electrophile 2. electrophile 2. electrophile 2. electrophile 2. electrophile 3. workup 3. workup 3. workup 3. workup 3. workup 3. workup 3. workup Mg and Li Organometallics Reactions OH O OH OH R Li R R R" R' R R R' R' R R R' O (MgBr) O similar O O R' R" chemistry R' NR R' Cl 2 R' 1. make R-Metal 1. make R-Metal 1. make R-Metal 1. make R-Metal o 2. electrophile 2. electrophile 2. electrophile 2. 3 amides 3. workup 3. workup 3. workup 3. workup Cuprate Reactions Li Li Li R Cu R R Cu R O R Cu R R O Make Make Make O from from O R R' R' X from R R' (2 ways) haloalkanes (2 ways) R' Cl conjugate addition Dithiane Synthesis of Aldehydes and Ketones S R S S S S O O R Make R Make from R' Li from S S S S S R R' R H 1. n-BuLi HgBr HgBr2 Aldehydes 2 Br n-BuLi Ketones H2O 2. R'Br H2O R OH S Dithiane Synthesis S S S OH O Make S Li S S HO from S O OH 1. 2 eqs. n-BuLi 1. HgBr OH 2. H C=O 2 2 n-BuLi H O 3. workup 2. workup 2 Wittig Reactions Ph R Ph O Ph Ph Make P Ph Ph R' from P makes very C specific alkenes HC n-butyl lithium P R Br R H H2C Br Ph Ph (usually Z) R (very strong base) R carbonyl Ph (2 ways) compound ylid (Wittig salt) Enolate Chemistry electrophiles O O O R X E haloalkanes o 1. LDA,-78 C aldehydes or 2. electrophile (E) O (aldol rxns) 3. workup O O & ketones epoxides (Claisen rxns) R R E O O y:\files\classes\316\special handouts\316_FG_syn.doc 14C synthesis strategies, Chem 315/316 / Beauchamp 5 Acetoacetic Ester Synthesis + O H3O /H2O/ O 1. RO Na O O O or 2. electrophile (E) R HO /H O/ R 3. workup O 2 O O E (-CO2) E O R X substituted acetones electrophiles haloalkanes epoxides aldehydes & ketones y:\files\classes\316\special handouts\316_FG_syn.doc 14C synthesis strategies, Chem 315/316 / Beauchamp 6 O O Electrophilic Aromatic Substitution Reactions (aromatic ring is a nucleophile) 1. CO 2 NaOH, second substituent 2. WK OH RX OR Reaction 1 1 o/p dibromo Br2 Br 2 o/p bromo / alkyl FeBr3 1. H2CO 3 o/p bromo / keto 2. WK OH HBr Br ortho/para director 4 o/p bromo / nitro Organometallic O 5 o/p bromo / sulfonic acid reactions 1. C R R H Reaction 2 1 o/p alkyl / bromo (MgBr) NaCN R 2. WK OH RCl 2 o/p alkyl / alkyl AlCl Br 3 Mg O 3 o/p alkyl / keto CN 1. alkyl benzenes 4 o/p alkyl / nitro C RR ortho/para director R R O 5 o/p alkyl / sulfonic acid the aromatic ring 2. WK is a nuclephile, OH O 1 meta keto / bromo Reaction 3 the electron donation O Cl R poor reaction R 2 comes from an sp2 AlCl3 1. C 1. amine (1.LAH, 2. WK) 3 poor reaction orbital not the R OR' 2. amide (HCl, H O) 4 meta keto / nitro electrons 2. WK 2 aromatic ketones R 3. acid (H SO , H O) meta director 5 meta keto / sulfonic acid reacts 2 4 2 4. ketone (1.RMgBr, 2. WK) twice OH Reaction 4 1 meta nitro / bromo 5. aldehyde (1.DIBAH, 2. WK) HNO3 NO O 2 2 1. H2SO4 poor reaction HBr OH OH Ph 3 poor reaction 2. WK CrO 4 meta dinitro 3 O meta director (PCC) Ph 5 meta nitro / sulfonic acid 1. O CrO3 H Reaction 5 meta director 1 meta sulfonic acid / bromo OH R H2O H SO SO3H 2 poor reaction 2. WK O 2 4 (Jones) Ph 3 poor reaction R OH benzene sulfonic acids and this reaction 4 meta sulfonic acid / nitro 1. CuBr R CrO can be reversed with the addition of water. meta disulfonic acid 2. RX 3 5 (PCC) O the aromatic ring Cl CuCl 1.