Myers Chem 215 Birch Reduction Reviews: Additivity of Substituent Effects: Rabideau, P W.; Marcinow, Z Org React 1992, 42, 1-334 OCH3 H3C Mander, L N In Comprehensive Organic Synthesis; Trost, B M and Fleming, I., Ed.; Pergamon: Oxford, 1991, Vol 8, pp 489-521 H3C Na, NH3, MeOH OCH3 44% Hook, J M.; Mander, L N Natural Prod Rep 1986, 3, 35-85 Birch, A J J Chem Soc 1944, 430-436 Propects for Stereocontrol in the Reduction of Aromatic Compounds: Donohoe, T J.; Garg, R.; Stevenson, C A Tetrahedron: Asymmetry 1996, 7, 317-344 CO2H Na, NH3, MeOH H3C H3C CO2H NH4Cl Mechanism: 94% Electron-Donor Substituents (X): X Chapman, O L.; Fitton, P J Am Chem Soc 1963, 85, 41-47 X X X M, NH3 H H ROH – M (X = R, OR, NR2) M, NH3 Conditions: H H – • Metals: Li, K, Na, occasionally Ca or Mg M (rate-limiting step) • Co-solvents: diethyl ether, THF, glymes ortho protonation • Reductions of alkyl benzenes and aryl ethers require a stronger acid than ammonia; alcohols are typically employed X H H W ROH M, NH3 0.26 –2.99 Na 0.18 –2.59 K 0.21 –2.73 Na (excess), EtOH, NH3 W W H(R) – – 2M (Birch reduction) NH4Cl H H M M Li, EtNH2 or RX W (W = CO2H, CO2R, COR, CONR2, CN, Ar) Li Normal reduction potential at –50 °C in NH3 (V) • Reduction in low molecular weight amines (Benkeser reduction): M, NH3 W – Solubility in NH3 at –33 °C (g-atom M/mol NH3) From: Briner, K In Encyclopedia of Reagents for Organic Synthesis, Paquette, L A., Ed.; John Wiley and Sons: New York, 1995, Vol 5, pp 3003-3007 Electron-Withdrawing Substituents (W): M, NH3 Metal H • Protonation of cyclohexadienyl anions is kinetically controlled and occurs at the central carbon W • Proton sources (where appropriate): t-BuOH and EtOH are most common, also MeOH, NH4Cl, and water H • Regioselectivity of protonation steps in the Birch reduction: Zimmerman, H E.; Wang, P A J Am Chem Soc 1993, 115, 2205-2216 meta protonation ROH H H H H ROH or NH3 • Aromatic carboxylic acids and carboxylates are readily reduced with Li/NH3 in the absence of alcohol additives + (Benkeser Reduction) • Reduction in low molecular weight amines (in the absence of alcohol additives) furnishes more extensively reduced products than are obtained under Birch conditions (M, NH3, ROH) A Comparison of Methods Using Lithium/Amine and Birch Reduction Systems: Kaiser, E M Synthesis 1972, 391-415 Kent Barbay Asymmetric Birch Reduction: Reductive alkylation: • Enolates derived from 1,4-dihydrobenzoic acids are selectively alkylated at the α-carbon CO2H Reviews: Schultz, A G Acc Chem Res 1990, 23, 207-213; Schultz, A G Chem Commun 1999, 1263–1271 HO2C CH3 KNH2, NH3 RX O N CH3I 91% H O Nelson, N A.; Fassnacht, J H.; Piper, J U J Am Chem Soc 1961, 83, 206-213 See also: Birch, A J J Chem Soc 1950, 1551-1556 R OM M, NH3, THF O N RX H N t-BuOH (1 equiv) (M = Li, Na, or K) –78 °C H O O (proposed convex attack) • Loewenthal and co-workers first demonstrated single step reductive alkylation of aromatic compounds: CO2H Na, NH3 HO2C CH3 MeI 67 60 EtI 82 75 >98 PhCH2Br CH2=CH2CH2CH2Br 73 89 >96 96 ClCH2CH2CH2Br 91 (n.d.) CH2=CH2CH2Br CH3I 69% Bachi, M D.; Epstein, J W.; Herzberg-Minzly, Y.; Loewenthal, H J E J Org Chem 1969, 34, 126-135 • Reductive alkylations of aromatic esters, amides, ketones, and nitriles typically are conducted in the presence of one equivalent of an alcohol: H O N OCH3 CH3O K, NH3 CO2t-Bu t-BuOH (1 equiv) yield (%) de (%) RX CO2t-Bu CH(CH3)2 O TFA i-PrI 94% CH3 CH3 OCH3 R N M, NH3, THF H t-BuOH (1 equiv) O (M = Li, Na, or K) OCH CH3 –78 °C OCH3 BrCH2CH2CH2Cl 85% Schultz, A G.; Macielag, M J Org Chem 1986, 51, 4983-4987 N H O CH3 OCH3 O CH3 70-88% yield, >96% de RX = MeI, EtI, PhCH2Br, Br , Cl Li, NH3, THF t-BuOH (1 equiv) O RX O M RX Hook, J M.; Mander, L N.; Woolias, M Tetrahedron Lett 1982, 23, 1095-1098 CN opposite facial selectivity >96 Br CN (CH2)3Cl OCH3 • Transition state may be complex, viz., enolate aggregation and nitrogen pyramidalization • Schultz proposes that Birch reduction results in kinetically controlled formation of a dimeric enolate aggregate wherein the metal is chelated by the aryl ether; the side chain of the chiral auxiliary is proposed to block the β-face of the enolate Schultz, A G.; Macielag, M.; Sundararaman, P.; Taveras, A G.; Welch, M J Am Chem Soc 1988, 110, 7828-7841 Kent Barbay • 1,6-Dialkyl-1,4-cyclohexadienes are accessible by asymmetric Birch alkylation: OCH3 O OCH3 O H3C H3C H2 (1 atm), CH2Cl2 N [Ir(cod)py(PCy3)]PF6 98% OTBS OCH3 O O N 53–77% 98% OTBS R CH3I OCH3 OK K (2.2 equiv), NH3, THF, t-BuOH (1 equiv) CH3 PDC, t-BuOOH N RX, –78 → 25 °C CH3 OCH3 O Celite, PhH s-BuLi, THF, –78 °C N CH3 H3C OCH3 O CH3 OCH3 O N O N N H3C OTBS MeI, –78 °C R R yield (%) de (%) H 90 > 98 Me 66 93 Et 79 90 CH2CH=CH2 76 93 CH2CH2CH=CH2 69 90 62 95 77 93 71 94 88 96 79 95 69 96 R CH2Ph CH2CH2Ph CH2OCH2CH2SiMe3 CH2CH2OTBS CH2CH2OMe Schultz, A G.; Hoglen, D K.; Holoboski, M A Tetrahedron Lett 1992, 33, 6611–6614 • Heterogenous hydrogenation with rhodium on alumina occurs anti to the bulky amide, presumably due to steric factors H3C CH3 OCH3 O H3C H2, Rh on Al2O3 CH3 N O EtOAc, 55 psi OTBS OCH3 O N O OTBS 89% Schultz, A G.; Hoglen, D K.; Holoboski, M A Tetrahedron Lett 1992, 33, 6611–6614 • Dihydroxylation of 3-cyclohexen-1-ones obtained by Schultz's asymmetric Birch alkylation occurs exclusively anti to the amido substiuent: R Ph R' OCH3 O N H3O+ R OCH3 R' OCH3 O N O OsO4, NMO HO R OCH3 OH O R' H2O, acetone N O Schultz, A G.; Green, N J J Am Chem Soc 1991, 113, 4931–4936 Transformations of asymmetric Birch alkylation products: • Amide-directed hydrogenation with Crabtree's catalyst: H3C OCH3 O N H2 (1 atm), CH2Cl2 [Ir(cod)py(PCy3)]PF6 Ph H3C OCH3 O N H 89% Ph yield (%) R R' H Me 91 H CH2Ph 86 H (CH2)3N3 88 H (CH2)3Cl 94 CH2Ph Et 73 Me Et 76 Schultz, A G.; Dai, M.; Tham, F S.; Zhang, X Tetrahedron Lett 1998, 39, 6663–6666 Schultz, A G.; Green, N J J Am Chem Soc 1991, 113, 4931–4936 Kent Barbay • Regio- and stereo-selective epoxidation has been demonstrated: H3C OMOM O O O N CH3 H3C CH3 OMOM O R1 R2 O OCH3 O H3C O H3C H N aq HCl OCH3 O N MeLi, THF CH3 → 23 °C OH O CH3 CH3 H 58% Ph 95% O H3C Schultz, A G.; Macielag, M.; Sundararaman, P.; Taveras, A G.; Welch, M J Am Chem Soc 1988, 110, 7828-7841 reflux, h Ph I 75–98% • Addition of alkyllithium reagents: • Acid catalyzed cleavage of the alkylation products requires harsh conditions: N R2 R1 O Methods of cleavage of Schultz's chiral auxiliaries: OCH3 I2, THF, H2O Schultz, A G.; Dai, M.; Khim, S.-K.; Pettus, L.; Thakkar, K Tetrahedron Lett 1998, 39, 4203–4206 Schultz, A G.; Harrington, R E.; Tham, F S Tetrahedron Lett 1992, 33, 6097–6100 O O 89–100% >13 : diastereoselectivity H3C O OCH3 O N MeOH, 25 °C OCH3 CH3 R2 R1 N aq HCl N N acetone 68% CH3 • Iodolactonization: Asymmetric synthesis of amino-substituted cyclohexenes: Schultz, A G.; Green, N J J Am Chem Soc 1991, 113, 4931–4936 O H R1 N O R N H O N H THF, t-BuOH (2 equiv) O R NH H 100 °C NH4Cl 62–82% R1 • Lactonization can be effectively employed for amide cleavage: H3C OCH3 O BF3•OEt2 N H2O H O SiMe3 H3C O H O R1 H 82% Schultz, A G.; Green, N J J Am Chem Soc 1991, 113, 4931–4936 H3C OCH3 O N O H3C m-CPBA O O 82% OTBS H3C O OCH3 N O OTBS R2 O H RX O CH NaOMe, MeOH; H+ 100% O CH3 Schultz, A G.; Hoglen, D K.; Holoboski, M A Tetrahedron Lett 1992, 33, 6611–6614 O N N H H OK N H R = Me, Et, Bn Schultz, A G.; McCloskey, P J.; Court, J J J Am Chem Soc 1987, 109, 6493–6502 CH3 N K (4.4 equiv), NH3 H N H O 18 N aq H2SO4 KO R2 O • Olefinic substrates undergo protiolactonization under the conditions of acidic hydrolysis: R1 R2 O R H H O RX yield (%) N H N O H de (%) H H MeI 54 70 H H EtI 68 82 H H NH4Cl 73 not reported H Me MeI 53 > 88 Me H NH4Cl 84 one diastereomer Me H MeI 78 52 Me H EtI 87 78 Me H CH2=CHCH2Br 68 > 95 : Me H BnBr 78 > 95 : Schultz, A G.; McCloskey, P J.; Court, J J J Am Chem Soc 1987, 109, 6493–6502 Kent Barbay Chiral substrates: Asymmetric Birch Reduction of heterocycles: O Ph CH3 O N CH3 Boc O CH3 Li, NH3, THF, –78 °C (CH3OCH2CH2)2NH Isoprene RX 91-96% NaOH (Boc)2O R Me N CO H Boc R OR' N Boc O Li, NH3, THF t-BuOH (1 equiv) –78 °C CH3 RX Et 79 71 78 86 i-Bu 70 90 CH2Ph 67 90 R O CH3 N CH3 >90% de R = CH3 R = CH2CH=CH2 R = CH2Ph (R' = (–)-8-phenylmenthol) yield(%) ee(%) R TFA N CH3 72% 66% 68% Schultz, A G.; Kirinich, S J.; Rahm, R Tetrahedron Lett 1995, 36, 4551-4554 H H Li, NH3, THF CH3O HO2C • Addition of the chelating amine (CH3OCH2CH2)2NH was found to increase yields; the anion derived from this amine is less basic and less nucleophilic than LiNH2, supressing byproduct formation CO2H CH3I 51% CH3O HO2C CH3CO2H House, H O.; Strickland, R C.; Zaiko, E J J Org Chem 1976, 41, 2401-2408 Donohoe, T J.; Guyo, P M.; Helliwell, M Tetrahedron Lett 1999, 40, 435-438 CH3 OCH3 OM Na, NH3 –78 °C O N O Dissolving metal reductions of conjugated alkenes: CH3 OCH3 CH3 O H3CO OCH3 O • Styrenes, conjugated dienes, and enones are more readily reduced under dissolving metal conditions than are aromatics; reduction occurs at low temperature without alcohol additives RX N –78 °C 62-88% OCH3 N R O OCH3 RX O O H3C (proposed TS geometry) H CH3 N HCl 100 °C CO2H O R R yield(%) ee(%) Me Et 86 >94 74 >94 i-Bu 68 >94 H3CO O O H3C K, NH3 THF, –70 °C H H 62% H H3CO Ananchenko, S N.; Limanov, V Y.; Leonov, V N.; Rzheznikov, V N.; Torgov, I V Tetrahedron 1962, 18, 1355-1367 • Trans-fused products are favored, carbon proposed pyramidalized in the transition state Donohoe, T J.; Helliwell, M.; Stevenson, C A.Tetrahedron Lett 1998, 39, 3071-3074 Kent Barbay Transformations of Birch Reduction products: Stereochemical and/or regiochemical control by intramolecular protonation: H3C CH3 • Synthesis of α,β or β,γ-unsaturated cyclohexanones H3C CH3 CH2OH H H H CH3 THF, –78 °C TBSO H 93% H3C CH3 TBSO H H3C CH3 H CH2OH Li, NH3 CH3 H3C OH H3C OH H H Li, NH3 H H EtOH MeO 90% aq HCl H H H H O CH3 CH2OH H3CO H H THF, –40 °C H O CH3 CH2OH 100% β O CH3 H CH2OH H3C O H CH3 H CH2OH H Na, NH3, THF, –40 °C OTBS t-BuOH, –33 °C H3C • Ozonolysis of Birch reduction products: OH Lin, Z.; Chen, J.; Valenta, Z Tetrahedron Lett 1997, 38, 3863-3866 H3CO –78 °C, hr (t1/2 ca 10 h) R = H or R = OMe R H Li, NH3, THF t-BuOH H HO H Rapid R = OH O H H3CO O O3, CH2Cl2, MeOH, OH Li, NH3, i-PrOH CH3 OTIPS Li, NH3, THF t-BuOH O 96% H3CO • Initial intramolecular protonation at the β-position is proposed H H3C OTBS 92% Fuchs, P L.; Donaldson, R E J Org Chem 1977, 42, 2032-2034 71% R TBAF Li, NH3, THF H3C O H3CO H • Reduction of aryl silyl ethers and synthesis of β,γ-unsaturated cyclohexanones: whereas: α OH Nelson, N A.; Wilds, A L J Am Chem Soc 1953, 75, 5366-5369 H3CO H3C O H O H3C O Na, NH3, H 83% aq oxalic acid Corey, E J.; Lee, J J Am Chem Soc 1993, 115, 8873-8874 β H O H3C α H 77% MeO • It is proposed that the stereochemical outcome is the result of intramolecular protonation of the radical anion H3C O H3C OH H3CO CH3 OTIPS py, –78 °C; Me2S 56% (two steps) OH CH3 OTIPS Evans, D A.; Gauchet-Prunet, J A.; Carreira, E M.; Charette, A B J Org Chem 1991, 56, 741-750 Cotsaris, E.; Paddon-Row, M N J Chem Soc., Chem Commun 1982, 1206-1208 Kent Barbay Birch Reduction – Application in Synthesis: • Reductive alkylation of aromatics without electron-withdrawing groups is unsuccessful (±)-Gibberellic Acid: • Directed metalation of Birch products is possible: CH3 CH3 CH3 Birch O O NEt2 NEt2 CH3O OCH3 CO2CH3 O Amupitan, J.; Sutherland, J K J Chem Soc., Chem Commun 1978, 852-853 Bishop, P M.; Pearson, J R.; Sutherland, J K J Chem Soc., Chem Commun 1983, 123-124 H CH3O H 88% OMOM O CH3O CH3O2C O CO2CH3 CO2H H Cl OCH3 OCH3 O O OCH3 CN O 0.1 mole % 80–90 °C H3C O OCH3 K, NH , t-BuOH, O –78 °C; O 80% (two steps) But: Ph3P O O ArCOCl, Et3N O ≥ 99% ee 58% H H Eaborn, C.; Jackson, R A.; Pearce, R J Chem Soc., Perkin Trans I 1975, 470-474 OH O O SiMe3 AIBN, Bu3SnH N O Li, NH3 SiMe3 HCl, MeOH I2, THF, H2O O BnOH, THF, n-BuLi Br O N3 CH3 EtOH, –70 °C DEAD, PPh3, (PhO)2P(O)N3 O I I Rabideau, P W.; Karrick, G L Tetrahedron Lett 1987, 28, 2481-2484 • In the absence of competing factors, allylic silanes are generally produced from Birch reduction of aryl silanes; this is attributed to stabilization of negative charge at the α-carbon by silicon OCH3 O N TBAF CH3 COOH BrCH2CH2OAc OCH3 –78 → 25 °C; KOH, MeOH 96%, single diastereomer OCH3 CH3 SiMe3 OH N • Silyl substituents can be used to modify the regiochemistry of Birch reduction: SiMe3 OH H (±)-Gibberellic Acid Birch, A J.; Dastur, K P Tetrahedron Lett 1972, 41,4195-4196 M, NH3 HO (+)-Lycorine: • Isomerization is proposed to occur through a charge transfer complex CH3 CO OMOM O Hook, J M.; Mander, L N.; Urech, R J Org Chem 1984, 49, 3250-3260 75% CH3 CH3I, –33 °C 84% H O CH3O CH3O2C CH3 CO2H CN t-BuOK, THF; K, NH3, –78 °C; O • Diels-Alder cycloaddition by isomerization of 1,3-dienes in situ: Cl OCH3 CO H CO2CH3 I H3CO RBr H+ PPA Li, NH3, THF,–33 °C; HO2C n-BuLi, HMPA –70 °C Reduction CH3O CH3O O HO CO2Bn H O N O (single diastereomer) H O N O (+)-Lycorine Schultz, A G.; Holoboski, M A.; Smyth, M S J Am Chem Soc 1996, 118, 6210-6219 Kent Barbay