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Home , Birch reduction, Carbonyl reduction

Baran Group Meeting Lisa M. Barton The 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: * ∗ = Most commonly used • Extensively developed by Arthur J. Birch and is therefore named after him Metals: *, *, *, 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: *, tert-butyl *, 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 (, 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 , 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 : 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, , alkynes) • Most common side reactions: bond cleavage, dimerization (pyridine), and substituent • Birch reduction for functionalization of nanotubes reduction (, amides, ) 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 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 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 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. Chem. Soc., Perkin Trans. I. 1975, 470 (±)-longifolene JOC 1985, 50, 915 Polyaromatic Aromatic Ketones • more reactive than simple Side Products: • site of reduction controled by distribution of e- density in anionic intermediates O •Over-reduction and • mixture products common O R HO R Pinacol Coupling major 2 HO Me 1 Li, NH ,THF, –78 ºC, 30 min; R R R side products when 3 Na, NH3, EtOH, Et2O; H2O FeCl , 45 min, –33 ºC; NH Cl use metals other than 3 4 1 1 1 1 62% R R R R Me OH K or if no H+ source/too + Li, NH , THF 30 strong of a H source 3 Li, NH ,THF, –78 ºC min, –33 ºC; NH Cl 3 (H2O/AcOH) 4 15 min; NH Cl 98% 4 O O 1) tBuOH, 1) K, tBuOH,NH3, O Me O THF, –78 ºC Me MeO K, NH3, MeO Me 2) LiBr, –78 ºC R THF, –78 ºC JOC 1983, 48, 4266 3) RI, 0 to 10 ºC 2) LiBr, MeI, J. Chem. Soc., 1951, 1945 1 mol% OsO4, –78 ºC OH 1) Ac2O, Pyridine OH 53% 1) LDA; NMMO OH 2) mCPBA OAc Alkyl Group: 59% 60% I O3, MeOH; Zn, PhSeCl + 3) 10% AcOH AcOH, then 2) H2O2 85% OH 85% OAc Br Jones' reagent O OH 1:8 OH Me O HO HO OEt 83% Me OH OH Br MeO HO OH (mix and acid) HO OH O chiro- OR neo-inositol Cl CN 26% MeO2C HO OH HO OH Tetrahedron Lett. J. Chem. Soc., Perkin OH OH JOC 1973, 38, 3887 1986, 27, 5253 Trans. I. 1985, 383 HO HO Tetrahedron Lett. 2003, 44, 3105 Baran Group Meeting Lisa M. Barton The Birch Reduction 3/10/18

Asymmetric Methods: Amides • Most methods use L- KOtBu, tBuOH, MeO OMe Me Me Same as prior O O proline derivatives as a THF, NH3, –70 ºC; R then K; Me O 4 Steps sequence O OMe chiral auxiliary for CO Me N N diastereoselective Me Me Me N 2 reductive alkylation N R R OMe 75% OMe • Procedures use K R H H H N O instead of Li to prevent O Me O I OMe (–)-longifolene H F.G. reduction 96% single diastereomer O Cl O O OMe O OMe OMe K, NH3, NH R N tBuOH; N NH K, NH , tBuOH, N Or 3 OH N THF, –78 ºC; N kinetic Br Cl OH H O H (+)-nitramine RX, –78 ºC O enolate O (–)-isonitramine OMe OMe M OMe Me O Cl O OMe R= Me, d.r. 260:1 O K, NH3, N R= Et, d.r. >99:1 Me tBuOH; N N (+)-sibirine O OMe O OMe • Opposite selectivity arises Br Cl R K, NH3, tBuOH, OMe OH though chelation enolate to OMe OAc OMe N THF, –78 ºC; N as well as NH OH RX, –78 ºC 3 K, NH3, OMe HO •Selectivity reversed by allowing tBuOH; O Me Me equilibration to thermodynamic OAc H JOC 1985, 50, 915 O R= Me, d.r. >99:1 enolate before addition RX Br N JACS 1996, 118 , 6210 O K, NH , H Heterocycles 1987, 25, K, NH , tBuOH, O 3 N JOC 2004437, 69, 7734 3 R MO tBuOH; OMe O N THF, –78 ºC; N single diastereomer (+)-lycorine RX, –78 ºC N MeI O OMe O OMe I O Me O H H Me Me O H I , H O O O Drawbacks: •dificulty in remove aux. R= Me, d.r. 85:15 O 2 2 N 6M HCl N 81% H Me LiOH •Need o–substituent to R= Et, d.r. ≥99:1 40% promote good selectivity JACS 1988, 110 , 7828 HO + OMe O O O OMe H O OMe 1) PDC, tBuOOH, O 3O 1) nBu3SnH, O Me 1 K, NH , tBuOH, R Celite O O R 3 R1 AIBN O 4 Steps N THF, –78 ºC; 2) H , O N N 2 2) K CO N 52% 41% 3 O 2 3 Me R X, –78 ºC [Ir(cod)py(Pcy3)]PF6 H R2 2 H 74% Opposite R Me HO2C CO2Me (–)-9,10-epi-stemoamide SPh Diastereomer: O 3 OMe 3 2 R 1 O OMe Me O • at R if R =OMe R R3 O 4 equiv. K, Me O Me O R2 R3 H • at R2 and R1 if 1 N NH , 2 equiv. H2, H O 1) NaOMe N R 3 N N N tBuOH; [Ir(cod)py(Pcy3)]PF6 use different 2) H+ O mCPBA 2 catalysts like Rh R 2 H NH4Cl H R1 O R N N H or Al O H O H N Tet. Lett. 1992, 33, 6614 H O H H O Me Me O OMe H H K, NH , tBuOH, O OMe O CO2Me H 3 Et Et N CHO Me THF, –78 ºC; Me N N O EtI, –78 ºC N OMe N Pr NHCO tBu MeO2C H 2 OMe OMe Et H H JOC 1997, 62, 1223 Me (+)-apovincamine (+)-pumiliotoxin C JACS 1987, 109, 6493 Baran Group Meeting Lisa M. Barton The Birch Reduction 3/10/18

Heterocycles Indoles •It is thought that MeOH is • Just as with carbocycles, co-solvents can be used to increase solubility (Dioxane, THF, Li, NH ; Li, NH ; acidic enough to rapidly 3 3 protonate the Et O, DME) and order of addition can impact yield and product R MeOH R NH4Cl R 2 as it forms in equilibrium with • Alcohol addition depends on substrate (i.e. moderately activated usch as e--deficient N (excess) N N Me Me Me the N-alkylindole but NH3 is and furans don't need) Reduction Reduction not acidic enough and can carbocyclic ring JOC, 1971, 36, 279 heterocyclic ring only protonate the dianion Pyrroles Unactivated or with only Electron Donating substituents: No desired products Yield Quinolines 2-substituted 1 Na, NH , R = Me, 5 eq. Li, NH3; 2 eq. Li, NH3; 3 Me N 25-30% H 1 R2 THF, R2 = R1 R1 MeOH R1 NH Cl or R2XR N + 4 N tBuOH; MeI N R JOC, 1971, 36, 279 N R1 = Me, Me O N N N J. Chem. Soc., Perkin 1 O –78 ºC R1 H R1 = 7–OMe or H Trans. 1, 1973, 2754 R2 R O R2 = OiPr 20% Major Byproduct When R1=H ∗ = Optimized conditions; can also be 1 85% * R = Boc, As with pyrroles unactivated or furans with 2 used with EtI, BuI, iBuI, BnBr and AllylBr = Furans R Me iPr Bn CH2OMe CO2Me R2 N (tBuOH JOC 1996, 61, 7664 electron donating substituents cannot be excluded) reduced under Birch conditions Yield 88% 78% 45% 79% 78% 3-substituted 1 2 3 2-substituted R R R Yield 2.5 eq. Li, O O 2 2 H • Note if too large an R NH , –78 ºC; R Me iPr Bn R2 Boc N Me 70% 3 R excess of metal isused R3 Yield 75% 95% 75% 80% Na, NH3, THF; then RX dimeric and ring openned CO2H O RX O or NH4Cl CO2H side products predominate Boc N Bn 69% N –78 ºC N Tetrahedron Lett., 1 975, 9, 627 • Amides as EWG also work R1 R1 3-substituted Adoc OCy Me 72% HO autoregulator Me Li, NH ; CO2H CO2Me 10 eq. (MeOCH2CH2)2NH needed to prevent 3 1) Na, NH3, (±)-A-factor NH Cl loss of R1 group when = Adoc Adoc OCy H 74% 4 8 eq. iPrOH; Me (no added 3,4-disubstituted Tetrahedron Lett. 1998, 39, 3075 HO O NH4Cl O O proton source) O 2) CH N O 2 2 85% 3 Me R R Aust. J. Chem., 976, 29, 2553 EtO2C CO2Et R Me Et Allyl iBu O Li, NH3, EtO2C CO2Et O THF; cis:trans >20:1 >10:1 >10:1 >10:1 J. Heterocycl. Chem., 1 992, 29, 1025 then RX Yield 77% 82% 70% 79% O O O N N Theorized ring opening Boc Boc R R1 R2 do to the instability of O O N Li, NH , R1 R2 cis:trans Yield 3 EtO2C CO2Et intermediate: O R THF; iBu Me only cis 82% O O Most stable then R1X; O O N iBu Bn only cis 77% R then R2X Boc NiPr Li, NH3; J. Chem. Soc. Chem. Commun. 1999, 141 2 R H Me Et iPr allyl Bn RX, –78 ºC NiPr Pyridines Very sensitive to rxn conditions 2 3 eq. Li, NH3, R=Me or H Yield 92% 90% 98% 98% 85% 92% O Me 2 eq. EtOH; 80-93% O Note: can be done asymmetrically using same Li, NH; MeI RX or NH Cl J. Heterocycl. Chem., 1 996, 33, 1313 MeN NMe N Me 4 RN Me L-proline derived amides as previously shown 93% Me J. Chem. Soc. Chem. Commun. 1975, 480 2,5-disubstituted 3 eq. Li, NH3, R Me Et nPr tBu Bn (p-MeO)Bn 1.6 eq.MeOH Li, NH3, EtOH, 63% (2 Steps) –78 ºC; Yield 83% 85% 64% 71% 40% 40% EtOH, Et2O NaOH Et then cis: N O R O CO2H R CO2H (1:1) (1:1) (1:1) (1:1) (3:2) (3:2) N NH Cl O trans H JOC, 1975, 40, 3606 4 Me Bull. Chem. Soc. Jpn., 1 975, 48, 491 Baran Group Meeting Lisa M. Barton The Birch Reduction 3/10/18

Benzofurans Very sensitive to reaction conditions. Application to Methodology 1 2 Synthesis chiral cyclohexanes Chem. Commun. 2011, 47, 3989 R R R=H JOC, 1967, 32, 2794 Ph Ph R=H Ph Ph Li, NH , P P MeO Et Li, NH , MeO 3 MeO Na, NH3, Ir Ir 3 Or 15% EtOH 1 2 tBuOH, THF 1 2 N no proton R R R R R N R1 R2 88% or Et O Ph Ph source O 2 S N OH 50% O Or 3 3 H (20 bar) MeO R=Me R=Me MeO R R 2 R3 OH Me Li, NH3, tBuOH Li, NH3,15% EtOH Me MeO OMe trans:cis MeO OMe O O 86:14 Me Et ee trans: 94% Me ee: 89% Thiophenes Unlike furans and pyrroles, unactivated thiophenes has been reported but gives a mixtures of over-reduced and ring cleaved products MeO iPr MeO Me trans:cis trans:cis trans:cis >99:1 >99:1 NH3, Li, + + 56:44 MeOH; H O + 17% cleaved product ee >99% ee >99% S 2 S S S ee trans: 96% iPr 30% 12% 26% Me Me Me Me J. Chem. Soc., 1951, 3411 Synthesis of chiral cyclohex-2-enones JACS 2012, 134, 18209 CF3

OMe O NH2 OMe MeO H2N O NH3, Li, + + N N MeOH; H O + 10% cleaved product NH HN S 2 S S S 1) Birch Reduction 27% 7% 32% 2) N N QA Or QDA + cleaved product N NH3, Li, + + R2 (conditions not specified) R2 * R2 (Yields not reported) Or Cl MeMeOH; H2O Me Me Me 1 1 1 S S S S R R Me CO2H R 2-substituted Me CO2H O O O O PhCH3 PhF Li, NH3, Li, NH3, (slight ring MeOH; R2 MeOH; R2 opening only -25ºC -15ºC OR1 OH NH4Cl NH4Cl observed OMe O HS CO Me S S 2 R1=H 1 when R2=H) * * * * O R =Li salt O iPr Me Me Me Li, NH3, Et2O; J. Chem. Soc., 1951, 3411 (CO2H)2 Me CO2Me Me 74% Na, NH3, R1 nPr nPr Cy nPr nC7H15 QA= 75%, QA= 84%, QA= 60%, QA= 58%, R1 Et O, EtOH; R3 ee: -87% ee: -83% ee: -78% ee: -80% Me Me 2 2 2 R2 H H H nBu Me R R S R1 QDA= 83%, QDA= 79%, QDA= 67%, QDA= 75%, Me Me S NH4Cl; O 3 allyl Bn ee: 90% ee: 89% ee: 85% ee: 88% R3X O R Bn Bn Me O Chem. Lett., 1981, 1341 Yield 82% 68% 80% 76% 44% QDA No comment on cis:trans selectivity Synthesis of Spiral Lactams Eur. J. Org. Chem. 2017, 6, 1074 method 3-substituted - almost no examples 69% O O O CN NH 2 Steps CO H Li, NH , ee: 86% 2.5 eq. Na, 2 3 CO H H OH OH OH 3:2 mix product to starting –78 ºC; 2 O NH3,iPrOH; material; low yielding Me + + ClCH2CN H2, PtO2 H3O Tetrahedron Lett., 1985, 26, 1791 Me S S S Me R1 R1 R1 Me O CHO Benzothiophenes and Dibenzothiophenes - very few examples NH NH NH NH 140ºC Et O O O O Na, NH Me 3 Na, NH3 H 46% H (3 Steps) S 78% 70% Me Me SH S Me Me SH Me Targets in heterocyc. sys., 1999, 3, 117 98% 96% 97% Me 96% (–)-isoacanthodoral Baran Group Meeting Lisa M. Barton The Birch Reduction 3/10/18

Synthesis ortho-alkylated vinylarenes ACS Catal. 2018, 8, 1213 γ-Arylation of β,γ-Unsaturated Ketones ACIE 2008, 47, 177 O 1 CO2H R1 CO H R OH O O 2 5 mol% Pd(TFA)2 Li, NH3, 2% Pd(OAc)2 Li, NH ; R1X 4 eq.TEMPO 2 2 3 + R2 R EtOH,THF; 4% dppe R + + ArBr Or (specific conditions EtCO2H H 1.5 equiv. Cs2CO3, 1 NH not reported) 80 ºC 2 100 ºC 2 R R2 R R 1 R1 R1 Ar R O O 3 when Ar = Me O Me O R=H, 34% Me iPr O O R ortho-NH O O 2 P OEt R=Me, 44% Ph R 33% Me H OEt R=Ph, 83% H H 82% R=OMe, 77% 62% NH Me Me Me nPr NH 80% 61% R=NMe2, 74% NH NH CO2Me Me Me O Me Me Me O Synthesis of chiral allylsilanes for Hosomi–Sakurai allylation Chem. Eur. J. 2018, 24, 1681 F Me - Ph + BArF MeO C Me Ph 81% 60% 2 69% MeO 66% Ir Li, NH , SiMe3 3 SiMe3 N SiMe Synthesis of annulated arenes Org. Lett. 2007, 9, 2677 O O 1 1 OMe 1 3 R tBuOH or R N R 2)Bu3SnH, 2 2 MeO Li, NH , 1) CrO , AIBN, 85 ºC R EtOH, THF; R R2 3 3 H tBuOH; AcOH, Ac O 2) Saegusa [O] NH4Cl 2 2 TiCl4, Et Me Br Br Br 2) NaI I RCHO, CO tBu OH tBuO C Me 3,4 2 CO2tBu 2 Me Me Me -78ºC CO2tBu 3,4 3,4 Cy iBu Ph Ph 0,1 Me Me 1 2 OH OH OH OH 32% 69% 42% R R BiCl3•H2O 65% OH OH OH OH R3 d.r. single d.r. 24:1 d.r. single d.r. 31:1 Or diastereomer diastereomer OH 0,1 Me R 1) NaBH Ph 4 Enantioselective Birch-Cope Sequence for Quaternary Stereocenters JOC 2007, 72, 930 0,1 2) BiCl3•H2O R3 R3 Or O 1) Li, NH3, tBuOH, R1 6M HCl 1) RMgCl 2 THF, –78 ºC R4 R2 R4 R2 Δ R R1 R1 2) BiCl •H O 2)R3 R 0,1 3 2 OMe O O R4 OMe O 2 Me R =(S)-2-(methoxymethyl)pyrrolidine 4 O R O 3 O O R MeO 2 2 Me R R1 R 2 2 Ph R R O MeO O O O 51% (3 Steps) 32% (3 Steps) 53% (3 Steps) d.r. = >99:1 d.r. = 35:1 d.r. = >99:1 (when K instead of R2 Li and AllylCl) O

O R2 61% (3 Steps) Me 41% (3 Steps) d.r. = 50:1 MeO d.r. = 110:1 O O Baran Group Meeting Lisa M. Barton The Birch Reduction 3/10/18

Electrochemical Birch Reduction Electrochemical Birch reductions •First reported by Birch himself: CO H CO H 2 Pt, 2 72% Other reported procedures: NH NH3, LiOAc, NH 2 H O, tBuOH 2 C.E. 45% • Pt, LiCl, MeNH2 2 JACS 1963, 85, 2858; • Pt, Graphite or C; LiCl, ethylenediamine: Me O Me OH major product cyclohexene J. Electrochem. Soc., 1963, 110, 425 Pt, LiCl, 93% •Al, LiCl, EtOH:HMPA 67:33, undivided: MeNH2 C.E. 44% major product cyclohexane Bull. Chem. Soc. Jpn., 1982, 55, 347 Nature, 1946, 158, 60 MeO MeO •Hg, (Bu3EtN)OH, H2O, 60ºC, J. Electrochem. Soc., 1981, 128, 322 NH2 Al, NH2 •Hg, (TBA)BF , THF/H O, rt HMPA, LiCl, 44-48% 4 2 C.E. 41-46% JOC., 1985, 50, 556 EtOH Divided Undivided O Me OH R= H 49% 49% Sn, Pt, LiCl, Pt, LiCl, Me 44% 64% iPrOH, 70% MeNH , MeNH , Et 63% 73% Et NOTs R 2 R 2 R 4 undivided cell divided cell iPr 75% 82% tBu 81% 85% OMe Al, OMe HMPA, LiCl, 34-37% EtOH C.E. 33-35% Mechanism • methylamide serves as proton HO HO OMe Al, OMe e + Solvent e source forming LiNHMe cath S HMPA, LiCl, 46% • in undivided cell methylamine EtOH e + HCl can quench LiNHMe; in S divided two are seperated so Red. Trav. Chim. Pays-Bas. 1995, 114 , 259 LiNHMe isn't neutralized and Pt, LiCl, H SiMe SiMe isomerizes to conjugated 1,3- 3 MeNH , 3 H diene which can be further 2 + MeNH2 + MeNHLi R –5 ºC or –50 ºC R reduced undivided H H JACS 1963, 85, 2858; H + eS H SiMe3 SiMe3 JACS 1964, 86, 5272; SiMe SiMe J. Electrochem. Soc., 1966, 113, 1060 3 SiMe3 SiMe3 3 H 4% H + regioisomer and + 75% H overreduced H + MeNH2 + MeNHLi H 80% 53% 17% Me H + 5% regioisomer •substrates Me Si SiMe SiMe3 93% 3 3 cis:trans: resulting in •The observed differences in product distribution (cyclohexadiene vs. cyclohexene vs + 6% 78:20 at –5 ºC vinylic TMS cyclohexane) has been attributed to proton availability overreduced Me3Si 85:15 at –50 ºC groups can be Control by lowering current density, temperature and EtOH concentration 68% overreduced JACS 1969, 91, 4194 Note that unlike under standard Birch conditions no loss of Si reported J. Chem. Soc., Perkin Trans. 1 1974, 2055