Baran Group Meeting Lisa M. Barton The Birch Reduction 3/10/18 Helpful Resources: Stereochemistry Literature seminar, B. Hafensteiner (2005) [Group Meeting] • Determined by the protonation of the final monoanion Organic Reactions, 1992, 42, 1 [review] • reductive alkylation leads greater selectivity due to increased sterics Nat. Prod. Rep., 1986, 3, 35 [review] Curr. Org. Chem., 2015, 19, 1491 [review] • When there is a π • When R1,2 is H no steric Targerts in heterocycic systems, 1999, 3, 117 [review - HR O HR substituent, a boat heterocyclic Birch] R2 preference and protonation O R1 conformation is adopted Recl. Trav. Chim. Pays-Bas., 1995, 114 , 259 [review - R1 occurs equally from either face • vinyl hydrogens block H electrochemical Birch] H • When R1,2≠H Cis product bottom lobe of anion orbital and protonation HR predominates RH H Background comes from top face • Originally discovered by Wooster and Godfrey in 1937 in the reduction of toluene in NH3 using either Na or K JACS, 1937, 59, 596 Procedures Solvents: Ammonia* ∗ = Most commonly used • Extensively developed by Arthur J. Birch and is therefore named after him Metals: Sodium*, Lithium*, Potassium*, Calcium, Magnesium First Publication on: J. Chem. Soc., 1944, 430 Complete list of contributions: Tetrahedron, 1988, 44, No. 10, pp. v-xviii • Li most reactive but can therefore lead to overreduction, in which case Na best Cosolvents (used to aid in solubility): Diethyl Ether*, Tetrahydrofuran*, Glymes* Mechanism Proton Sources: Ethanol*, tert-butyl alcohol*, H2O 1) Electron-Donating Substituents Concentration: Often run under dilute conditions (0.1–0.5 g metal per 100 mL NH3) R R R R R Temperature: Most commonly ran at –78 ºC, due to low bp of NH3. highest at reflux (–33 ºC) H H H e ROH e ROH H H H Purity of Reagents: Not necessary but recommended H Order of Addition: Often very important and empirically determined H • Substrate dissolved in cosolvent with alcohol can be added to NH3 and metal solution • Metal added last to solution containing all other reagents 2) Electron-Withdrawing Substituents • Alcohol added last to solution containing all other reagents R Quenching Materials: either can use acidic materials (alcohols, water, NH4Cl, FeCl3),electron-transfer reagents (sodium benzoate/dienes then water), or alkyl halides in the case of reductive alkylations R R ROH e R R R'/H H O e 2 • Most commonly the fast addition of saturated NH4Cl (frothing occurs) is used or R'X Organic Reactions, 1992, 42, 1 H H R Comparison with Other Methods H H H H e ROH Benskeser Reduction: reduction of arenes using Li in 1º amines, ethylenediamine, or a mix 2 or NH3 of 1º and 2º amines; more powerful than Birch conditions and can lead to reduction beyond dihydro stage and mixture of products Catalytic Hydrogenation: procedes far past Birch reduction • In both cases reduction will occur 1,4 across the aromatic ring • Initial protonation takes place at position with highest electron density andprotonation of the dianion will usually occur at the site that will give the most stable monoanion (exceptions exist) Not Discussed in this group meeting: • Birch reduction of non-aromatic compounds (ie protecting group removal, alkenes, alkynes) • Most common side reactions: bond cleavage, dimerization (pyridine), and substituent • Birch reduction for functionalization of nanotubes reduction (esters, amides, ketones) Baran Group Meeting Lisa M. Barton The Birch Reduction 3/10/18 Aryl Ethers OMe OR O O OR O I OMe OH O via TiCl4 O 1) 50 atm H2 O O R' R' acylation 0.04 mol % Me when Ir-(R)-SpiroPAP CO Et CO Et R=Si(Me) iPr 2 2 2 92%, >99% ee 2 equiv. Cs2CO3 CO2Et JOC 1997, 42, 2032 d.r. 95:5 60 ºC 1) MsOH • Limitations: Partial or complete loss of alkoxy group (usually when para or ortho to EWG) iPr 2) PCC, 92% iPr 65% iPr 91% O Me 2) H2, Pd/C 1) K, NH3, O CO2H CO2H 99% tBuOH, THF, Me Li, NH , Me 3 O OMe -78ºC Me THF + 6 other Mulinane Na, NH 2) LiBr Diterpenoids of H 3 H 75% H O EtOH, THF, 3)MeI same scaffold O -78ºC; 33% OMe OMe H Me then HCl JOC 1973, 38, 3887 Tetrahedron 1982, 38, 2831 80% iPr CO2Et iPr CO2Et Na instead of Li, MeOH as a H+ donor, addition tBuOK prior to reduction, or quenching with iPr CO2H FeCl3 instead of NH4Cl can limit loss of OMe mulinic acid ACIE 2017, 56, 12708 •β,γ-unsaturated ketones often isomerize into conjugation Cycloaddition precursors R= TBDMS 1) Li, NH , THF, Me Cl H 3 OMe OMe O Me EtOH, –78 ºC Li, 1) 1) NH , BrMg Me 10 Steps Me 3 CN O 2)H3BO3, TBAF, O tBuOH 2) 250 ºC 10 ºC 61 ºC, CHCl3 MeO Me O Me 2)Na S•9H O O 3) (CH2OH)2, O H HO R= Me, O 78% (2 Steps) O 2 2 3:2 α:β Me 80% (2 Steps) cat. pTsOH 48% OR Me JACS 1972, 94, 4779 65% (3 steps) O R= Me Me Me O R = TBDMS, Me 50% 1) Li, NH3, THF, OMe EtOH,–78 ºC OMe OH Me Me Org. Lett. 2006, 8, 2479 2)Oxalic acid or 1) Birch reduction DMAD Me O (not specified) N ZnBr or ZnCl Δ 2 2 OH 2) KOtBu, DMSO Me 77% (2 Steps) MeO MeO Me Alkylation precursors Me Me Me Me Me O Me OH OMe O (±)-luciduline Me Me O Na, nBuLi; Me CO Me 2 OMe O NH3, RBr HO2C + Me H O tBuOH H3O O O MeO MeO CO Me NEt NEt H H 2 2 2 mycophenolic acid Me Me O MeO J. Chem. Soc. D, 1969, 788 J. Chem. Soc., Chem. Commun., 1983, 123 pregn-4-en-20-one curvularin (formal of pregesterone) O O Me ; OMe OMe O R 1) 180 ºC OMe O 1) KNH ,THF, 2) H+ OMe Li, OMe 2 O O 1) Na, NH3, liq. NH , 38% (2 Steps) NH , 3 C H EtOH R 3 –33 ºC; RBr 5 11 + C10H21 2) NaNH tBuOH MeO 2 MeO R: 2) HCl C H O O MeO OTHP C H C H C H 5 11 8 17 10 21 10 21 (Z)–henicos-60-en-11-one Me J. Chem. Soc. Perkin Trans. 1. 1990, 1423 5 J. Chem. Soc. Perkin Trans. 1. 1983, 7 OTHP Baran Group Meeting Lisa M. Barton The Birch Reduction 3/10/18 Aromatic Acids Synthesis Cyclohexenones O O O CO2H CO2H OR OR O OR MO OM over Li, NH , THF; CO aq. HCl, R Reduction Isomerization 3 2 reduction CO2H then RCl reflux R R R O R R R' JOC 1976, 41, 2649 HO2C R' HO2C OH HO2C HO2C O OMe Li, NH3, THF; O Me OH CO2R' OH H Reductive then BrMg OPh R R R R CO2H Alkylation Br(CH2)2OPh; DMS•CuBr then aq. HCl Rxn with OPh Rxn with Rxn with Rxn with alkyl halides -unsaturated H CO α,β epoxide iPr H (most common) 2 esters iPr iPr iPr O •Presence of an alcohol proton donor can sometimes lead to over reduction to JOC 1978, 43, 4925 (±)-oplopanone dihydrobenzoic acid and/or conjugate product Re-aromatization •Use of NH4Cl in absence of alcohol can prevent •If arene is para substituted will often get a mixture of cis and trans isomers largely OMe O OMe I OMe influenced substituent sterics HO2C HO2C Li, NH3, Annulation THF O CO2Me MeO OTBDPS Me OMe CO Me Me 1) Li, NH3, Me 2 CO H tBuOH; –78 ºC 10 mol% OMe 84% OMe 2 CuOTf OMe 2) MeOH, cat. MeO2C CO2tBu 7 Steps 15 mol% MeO H2SO4 52% overall Me Me OMe Pb(OAc)4 3) LDA, O O O Cu(OAc)2 BrCH CO tBu MeO2C OMe 2 2 N2 N N 1) KOH pyridine 96% (3 steps) SO2Ph HO C 2) TFAA:TFA 1:1 88% 2 iPr iPr MeO Me Me OTBDPS 79% (2 Steps) Me R O R O MeO C OH OMe HO OH 2 Me Or 72% Aust. J. Chem., 1981, 34, 2249 OMe HN O 95% ee O Electrophilic Addition To R: H Br H PhO S H CO H (–)-platensimycin (–)-platencin 2 CO2H Birch CO2H 2 1) Br ; Br aq. NaHCO Tetrahedron 2011, 67, 518 reduction 2 3 O (not specified) recrystallization 65% 1) 1,4-addition 62% Me Me O 2) Friedel-Craft Acylation CO H Br 2 1) NBS 3) Luche reduction 1) Na, NH3 Br H Me 4) ortho directed 2) CH2N2 2) NaOAc, CO2Me (±)-chorismic acid HMPA carboxylation Me 60% Me OAc 42% (4 Steps) JACS 1982, 104, 6787 O 86% HO CO H HO O CO2H O 2 CO2Me O OH O Note: susceptible Me O Me to re-aromatization Nucleophilic Addition To NMe2 under any basic CO2H CO2Me 1) 1.5 eq R CO2Me CH C(OMe) NMe 1)Na, NH3, EtOH; 3 2 2 condition R= Me xylene, reflux 45 minutes stirring; PhMgBr, –20 ºC; Ph Br 75% then 15 eq HMPA, OH Me NH4Cl HO 50% HO O 2) CH2N2 2.6 eq alkylBr O CO2Me OMe OMe deoxyanisatin O 82% 2) 2M HCl Org. Lett., 2001, 3, 279 Tetrahedron Lett., 1982, 23, 3287 81% Baran Group Meeting Lisa M. Barton The Birch Reduction 3/10/18 Aromatic Esters • Limitations include competitive carbonyl reduction Arylsilanes • Most commoly used to •1-2 equiv. H O or tBuOH added before Na in NH can O OR 2 3 SiMe control regiochemistry of 3 SiMe3 SiMe3 R CO2R prevent (doesn't work for methyl esters or those with 4- reduction as give allylic silanes alkyl substituents) Li, NH3, R • Many times C–Si bond R EtOH R R • tBuOH with Li/K in NH3 work with methyl esters and cleaved directly using R R some 4-alkyl substituted standard conditions • Unlike aromatic acids, for reductive alkylation esters are usually more soluble, resistant to isomerization, rearomatization and decarboxylation Me SiMe Me SiMe 3 SiMe3 3 KOtBu, tBuOH, MeO SiMe SiMe3 CO Me N-bromoacetamide, 3 OMe THF, NH3, –70 ºC; 2 MeO OMe then K; 3 OMe MeOH, 95% CO2Me R Me CO2Me Br Me SiMe Me Me R 3 OMe Me Me OMe Me Me 1) N SiMe3 I OMe NH2 SiMe SiMe3 98% 1) Product 3 Me Me Me N N (major) Me O Me SiMe3 reflux; Me Ph Ph CO2Me silica, 85% O 2) xylene, reflux 3 2) Acetone, 40% CHO pTsOH Yield 76% 60% 70% 70% 96% Me Me Me CO2Me J.