The Birch reduction - Baran Lab

1 The Birch ReductionLisa M. BartonBaran Group Meeting3/10/181) Electron-Donating SubstituentsStereochemistryReRROHRHHeRHH ROHRHHHHReRROHRHHRe2 ROHor NH3eRHHH2O or R'XR'/HRHH 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) Most common side reactions: bond cleavage, dimerization (pyridine), and substituent reduction (esters, amides, ketones) Determined by the protonation of the final monoanion reductive alkylation leads greater selectivity due to increased stericsR1R2 HHelpful Resources:BackgroundLiterature seminar, B. Hafensteiner (2005) [Group Meeting]Organic Reactions, 1992, 42, 1 [review]Nat. Prod. Rep.

2 , 1986, 3, 35 [review]Curr. Org. Chem., 2015, 19, 1491 [review]Targerts in heterocycic systems, 1999, 3, 117 [review - heterocyclic Birch ]Recl. Trav. Chim. Pays-Bas., 1995, 114, 259 [review - electrochemical Birch ]Mechanism Originally discovered by Wooster and Godfrey in 1937 in the reduction of toluene in NH3 using either Na or KJACS, 1937, 59, 596 First Publication on: J. Chem. Soc., 1944, 430 Complete list of contributions: Tetrahedron, 1988, 44, No. 10, pp. v-xviii Extensively developed by Arthur J. Birch and is therefore named after himOOHR1H When R1,2 is H no steric preference and protonation occurs equally from either face When R1,2 H Cis product predominatesHRHR When there is a substituent, a boat conformation is adopted vinyl hydrogens block bottom lobe of anion orbital and protonation comes from top faceProceduresSolvents: Ammonia*Cosolvents (used to aid in solubility): Diethyl Ether*, Tetrahydrofuran*, Glymes*Proton Sources: Ethanol*, tert-butyl alcohol*, H2 OMetals: Sodium*, Lithium*, Potassium*, Calcium, Magnesium Li most reactive but can therefore lead to overreduction, in which case Na bestConcentration: Often run under dilute conditions ( g metal per 100 mL NH3)Temperature: Most commonly ran at 78 C, due to low bp of NH3.

3 Highest at reflux ( 33 C)2) Electron-Withdrawing SubstituentsHRRHP urity of Reagents: Not necessary but recommendedOrder of Addition: Often very important and empirically determined Substrate dissolved in cosolvent with alcohol can be added to NH3 and metal solution Metal added last to solution containing all other reagents Alcohol added last to solution containing all other reagentsQuenching 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 Most commonly the fast addition of saturated NH4Cl (frothing occurs) is usedComparison with Other MethodsBenskeser reduction : reduction of arenes using Li in 1 amines, ethylenediamine, or a mix of 1 and 2 amines; more powerful than Birch conditions and can lead to reduction beyond dihydro stage and mixture of productsCatalytic Hydrogenation: procedes far past Birch reductionOrganic Reactions, 1992, 42, 1 Not Discussed in this group meeting: Birch reduction of non-aromatic compounds (ie protecting group removal, alkenes, alkynes) Birch reduction for functionalization of nanotubes = Most commonly usedThe Birch ReductionLisa M.

4 BartonBaran Group Meeting3/10/18 OROOORR'OR'ONEt2 MeONEt2 MeOMeMeMenBuLi;RBrJ. Chem. Soc., Chem. Commun., 1983, 123 OMeMeHHHM epregn-4-en-20-one(formal of pregesterone)OMeC8H17Na,NH3,tBuOHLi,NH3, tBuOHOMeC10H211) KNH2,THF, liq. NH3, 33 C; RBr2) HClOC10H21C5H11C10H21OC5H11J. Chem. Soc. Perkin Trans. 1. 1983, 7(Z) henicos-60-en-11-oneAlkylation precursorsCycloaddition precursors Limitations: Partial or complete loss of alkoxy group (usually when para or ortho to EWG)OMeLi,NH3,tBuOHOMe1)ClCN61 C, CHCl32)Na2S 9H2O80% (2 Steps)MeOO1)BrMgMe2) 250 C3) (CH2OH)2,cat. pTsOH65% (3 steps)OMeHHOO3:2 : MeNOMe( )-lucidulineJACS 1972, 94, 4779 OCO2 EtiPr1) 50 atm mol % Ir-(R)-SpiroPAP92%, >99% 95:52) PCC, 92%OCO2 EtiPrOMeI2 equiv. Cs2CO360 C65%OiPrCO2 EtOMe1) MsOH91%2) H2, Pd/C99%CO2 EtiPrOMeHNa, NH3 EtOH, THF, -78 C; then HCl80%CO2 EtiPrOH+ 6 other Mulinane Diterpenoids of same scaffoldiPrCO2 HMeOOHMeHmulinic acidACIE 2017, 56, 12708 OMeMeOMeMe1) Birch reduction (not specified)2) KOtBu, DMSOOMeMeOMeMeDMAD OMeMeOCO2 MeMeCO2 MeOHMeOOOMeMeHO2CJ.

5 Chem. Soc. D, 1969, 788 OMeMeOOOOM ecurvularinOMeMeO1) Na, NH3, EtOH2) NaNH2 OMeMeO+MeOO5 ROOTHPR:1) 180 C2) H+38% (2 Steps)OMeMeOROOTHPJ. Chem. Soc. Perkin Trans. 1. 1990, 1423 OHMeOvia TiCl4 acylation when R=Si(Me)2iPrJOC 1997, 42, 2032 , -unsaturated ketones often isomerize into conjugationHOMeOMe10 StepsORMeOOMeMeR= Me, 48%R = TBDMS, 50%OMeOHOHR= Me1) Li, NH3, THF, EtOH, 78 C2)Oxalic acid or ZnBr2 or ZnCl277% (2 Steps)R= TBDMS1) Li, NH3, THF, EtOH, 78 C2)H3BO3, TBAF, 10 C78% (2 Steps)OMeOOMeMeOrg. Lett. 2006, 8, 2479 Aryl EthersOMeOMe1) K, NH3, tBuOH, THF, -78 C2) LiBr3)MeIMeOMe33%CO2 HOMeLi, NH3, THFCO2 HTetrahedron 1982, 38, 283175%JOC 1973, 38, 3887Na instead of Li, MeOH as a H+ donor, addition tBuOK prior to reduction , or quenching with FeCl3 instead of NH4Cl can limit loss of OMemycophenolic acid;H3O+The Birch ReductionLisa M.

6 BartonBaran Group Meeting3/10/18 Aromatic AcidsMOOMRRHO2CR' Presence of an alcohol proton donor can sometimes lead to over reduction to dihydrobenzoic acid and/or conjugate product If arene is para substituted will often get a mixture of cis and trans isomers largely influenced substituent sterics Use of NH4Cl in absence of alcohol can preventCO2H1) Li, NH3, tBuOH; 78 C2) MeOH, cat. H2SO43) LDA, BrCH2CO2tBu96% (3 steps)MeO2 CCO2tBu7 Steps52% overall10 mol% CuOTf15 mol%NNOOiPriPrMeMeOTBDPSHPhO2 SHOOrORMeORMe( )-platencin( )-platensimycinHO2 CHOOHHNOR:OTBDPSSO2 PhN2 OMeCO2Me1) 1,4-addition2) Friedel-Craft Acylation3) Luche reduction4) ortho directed carboxylationHOMeCO2 HMe1) Na, NH32) CH2N2 HOMeCO2 MeMe60%42% (4 Steps)Note: susceptible to re-aromatization under any basic conditionCH3C(OMe)2 NMe2xylene, refluxMeCO2 MeMeNMe2O50%MeOOMeOOOHHOHO deoxyanisatinRxn with alkyl halides(most common)RHO2 COHRxn with H2 CORHO2 CCO2R'Rxn with , -unsaturated estersOORover reductionCO2 HRCO2 HRReductionReductive AlkylationIsomerizationRHO2 CRxn with epoxideOHR'ORCO2 HLi, NH3, THF;then RClOROOORRCO2aq.

7 HCl, refluxORTetrahedron 2011, 67, 518 Org. Lett., 2001, 3, 279 JOC 1976, 41, 2649 OMeCO2 HiPrLi, NH3, THF;then Br(CH2)2 OPh;then aq. HClOiPrOPhOHOHMeHiPr( )-oplopanoneOiPrOPhBrMgDMS CuBrJOC 1978, 43, 4925Re-aromatizationAnnulationSynthesis CyclohexenonesMeOMeOMeHO2 CMeOMeOMeOOLi, NH3, THFICO2 MeOMeMeOMeOMeHO2 CMeOCO2Me84%Pb(OAc)4Cu(OAc)2pyridine88%M eOMeOMeMeOMeO2C1) KOH2) TFAA:TFA 1:1 MeOMeOMeMeO2 CMeOOH79% (2 Steps)Aust. J. Chem., 1981, 34, 2249 Electrophilic Addition ToCO2 HBirch reduction (not specified)CO2H1) Br2; recrystallization62%CO2 HBrBraq. NaHCO365%OOBrH1) NBS2) NaOAc, HMPA86%OOBrHOAcCO2 HOHOCO2H( )-chorismic acidJACS 1982, 104, 6787 Nucleophilic Addition ToCO2 HOMe1)Na, NH3, EtOH;45 minutes stirring; NH4Cl2) CH2N282%CO2 MeOMe1) eq PhMgBr, 20 C;then 15 eq HMPA, eq alkylBr2) 2M HClOCO2 MeRPhR=Br75%81%Tetrahedron Lett.

8 , 1982, 23, 328772%95% eeThe Birch ReductionLisa M. BartonBaran Group Meeting3/10/18 Aromatic EstersOORRRCO2RR Limitations include competitive carbonyl reduction 1-2 equiv. H2O or tBuOH added before Na in NH3 can prevent (doesn't work for methyl esters or those with 4-alkyl substituents) tBuOH with Li/K in NH3 work with methyl esters and some 4-alkyl substituted Unlike aromatic acids, for reductive alkylation esters are usually more soluble, resistant to isomerization, rearomatization and decarboxylationOMeCO2 MeMeMeOMeOMeIKOtBu, tBuOH, THF, NH3, 70 C; then K;MeOCO2Me98%N-bromoacetamide, MeOH, 95%RCO2 MeBrOMeMeONNreflux;silica, 85%MeMeMe( )-longifolene1)2) Acetone, pTsOH3 MeMeOMeOMeOCO2 MeCHO3 MeMe2) xylene, reflux40%CO2 MeOMeMeJOC 1985, 50, 915 NNH2 PhPh1)Aromatic KetonesORR1R1R2 ORHORR1R1R1 MeHOMeOH Over- reduction and Pinacol Coupling major side products when use metals other than K or if no H+ source/too strong of a H+ source (H2O/AcOH)MeORMeO1) K, tBuOH,NH3, THF, 78 CAlkyl Group:I59%85%83% (mix ester and acid)26%BrBrOEtOClCNJOC 1973, 38, 38872) LiBr, 78 C3) RI, 0 to 10 COOMe1) tBuOH, K, NH3, THF, 78 C2) LiBr, MeI, 78 C 53%OMeOMeMeO2CO3, MeOH; Zn, AcOH, then Jones' reagentMeOMeOMeOJ.

9 Chem. Soc., Perkin Trans. I. 1985, 383 Tetrahedron Lett. 1986, 27, 52531) LDA; PhSeCl2) H2O2 Arylsilanes Most commoly used to control regiochemistry of reduction as give allylic silanes Many times C Si bond cleaved directly using standard conditionsSiMe3 RSide Products:RRSiMe3 RSiMe3Li, NH3, EtOHRP roduct(major)SiMe3 Yield76%SiMe3 MeSiMe3 MeSiMe3 MeMeSiMe3 MeMeSiMe3 MeSiMe3Me60%70%70%SiMe3 SiMe3 SiMe396%J. Chem. Soc., Perkin Trans. I. 1975, 470 Polyaromatic more reactive than simple benzenes site of reduction controled by distribution of e- density in anionic intermediates mixture products commonNa, NH3, EtOH, Et2O; H2O62%Li, NH3, THF 30 min, 33 C; NH4Cl98%Li, NH3,THF, 78 C 15 min; NH4 ClLi, NH3,THF, 78 C, 30 min; FeCl3, 45 min, 33 C; NH4 ClJOC 1983, 48, 4266J. Chem. Soc., 1951, 19451 mol% OsO4, NMMO60%OHOH+OHOH1:81) Ac2O, Pyridine2) mCPBA3) 10% AcOH85%OAcOAcOHOHOHOHOHOHHOHOHOHOOHOHOHO HHOHOHOHOneo-inositolORchiro-inositolTet rahedron Lett.

10 2003, 44, 3105 The Birch ReductionLisa M. BartonBaran Group Meeting3/10/18 Asymmetric Methods: AmidesJACS 1988, 110, 7828 NOOMeRNHNOOHRONOHR Most methods use L-proline derivatives as a chiral auxiliary for diastereoselective reductive alkylation Procedures use K instead of Li to prevent reductionNOOMeONOHOMeNOOMeOMeRONOHRR= Me, 85:15R= Et, 99:1R= Me, 260:1R= Et, >99:1 Opposite selectivity arises though chelation enolate to OMe as well as NH3 Selectivity reversed by allowing equilibration to thermodynamic enolate before addition RXNOOMeMeNOOMeMeRR= Me, >99:1K, NH3, tBuOH, THF, 78 C;RX, 78 CK, NH3, tBuOH, THF, 78 C;RX, 78 CONOMeOMMekineticenolateK, NH3, tBuOH, THF, 78 C;RX, 78 CONMOHD rawbacks: dificulty in remove aux. Need o substituent to promote good selectivityMeMeMe( )-longifoleneJOC 1985, 50, 915 MeMeOMeOMeIKOtBu, tBuOH, THF, NH3, 70 C; then K;96%ONOH single diastereomerMeMeOMeMeO75%RCO2 MeOMeSame as prior sequenceNHOHNHOHMeNOH( )-isonitramine(+)-nitramine(+)-sibirineN OOMeOMeNOOMeOMeK, NH3, tBuOH;ClBrK, NH3, tBuOH;NOOMeOMeOAcBrOAcsingle diastereomerHeterocycles 1987, 25, 437 NOOOHHOHH(+)-lycorineJACS 1996, 118, 6210 ONOHK, NH3, tBuOH;ClBrONOHClOrNOOMeR2R14 StepsK, NH3, tBuOH, THF, 78 C;R3X, 78 CNOOMeR2R1R3 Opposite Diastereomer: at R3 if R2=OMe at R2 and R1 if use different catalysts like Rh or Al1) PDC, tBuOOH, Celite2) H2, [Ir(cod)py(Pcy3)]PF6 NOOMeR2R1R3OR2 OOR1R3 ONOMe1) NaOMe2) H+mCPBAOR1OR2CO2 MeR3 Tet.