Myers Birch Reduction Reviews: Chem 115 Additivity of Substituent Effects: Rabideau, P. W.; Marcinow, Z. Org. React. 1992, 42, 1-334. H3C Mander, L. N. In Comprehensive Organic Synthesis; Trost, B. M. and Fleming, I., Ed.; Pergamon: Oxford, 1991, Vol. 8, pp. 489-521. OCH3 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 1. Na, NH3, MeOH H3C H3C CO2H 2. NH4Cl Mechanism: 94% Electron-Donor Substituents (X): X Chapman, O. L.; Fitton, P. J. Am. Chem. Soc. 1963, 85, 41-47. X X M, NH3 ROH – M (X = R, OR, NR2) X H H 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 • Protonation of cyclohexadienyl anions is kinetically controlled and occurs at the central carbon. W ROH – M W (W = CO2H, CO2R, COR, CONR2, CN, Ar) M, NH3 Li 0.26 –2.99 Na 0.18 –2.59 K 0.21 –2.73 Na (excess), EtOH, NH3 W W H(R) NH4Cl H H – Normal reduction potential at –50 °C in NH3 (V) • Reduction in low molecular weight amines (Benkeser reduction): M, NH3 W M, NH3 Solubility in NH3 at –33 °C (mol Metal/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): W • Proton sources (where appropriate): t-BuOH and EtOH are most common, also MeOH, NH4Cl, and water. Metal H 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 2 – 2M H H M (Birch reduction) Li, EtNH2 or RX 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 1 Asymmetric Birch Reduction: Reductive alkylation: • Enolates derived from 1,4-dihydrobenzoic acids are selectively alkylated at the !-carbon. CO2H Reviews: Schultz, A. G. Acc. Chem. Res. 1990, 23, 207-213; Schultz, A. G. Chem. Commun. 1999, 1263–1271. HO2C CH3 1. KNH2, NH3 RX O N 2. 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. O R OM M, NH3, THF N t-BuOH (1 equiv) (M = Li, Na, or K) N RX H –78 °C H O O (proposed convex attack) • Loewenthal and co-workers first demonstrated single step reductive alkylation of aromatic compounds: CO2H 1. Na, NH3 HO2C CH3 2. 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: CO2t-Bu TFA CH(CH3)2 O 2. i-PrI 94% CH3 CH3 MeI 67 60 EtI 82 >98 CH2=CH2CH2Br 75 >96 PhCH2Br 73 >96 CH2=CH2CH2CH2Br 89 96 ClCH2CH2CH2Br 91 (n.d.) H O N OCH3 CH3O 1. K, NH3 CO2t-Bu t-BuOH (1 equiv) yield (%) de (%) RX OCH3 O R N RX M, NH3, THF O M t-BuOH (1 equiv) H O OCH3 (M = Li, Na, or K) CH3 –78 °C 70-88% yield, >96% de RX = MeI, EtI, PhCH2Br, Br , Cl 1. Li, NH3, THF t-BuOH (1 equiv) OCH3 2. BrCH CH CH Cl 2 2 2 85% Schultz, A. G.; Macielag, M. J. Org. Chem. 1986, 51, 4983-4987. N H O OCH3 CH3 O CH3 RX Hook, J. M.; Mander, L. N.; Woolias, M. Tetrahedron Lett. 1982, 23, 1095-1098. CN opposite facial selectivity 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 "-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 2 • 1,6-Dialkyl-1,4-cyclohexadienes are accessible by asymmetric Birch alkylation: OCH3 O OCH3 O 1. s-BuLi, THF, –78 °C N CH3 Celite, PhH N H2 (1 atm), CH2Cl2 N [Ir(cod)py(PCy3)]PF6 O 98% OTBS R CH3I OCH3 OK 1. K (2.2 equiv), NH3, THF, t-BuOH (1 equiv) OCH3 H3C O 98% OTBS 53–77% CH3 PDC, t-BuOOH N 2. RX, –78 ! 25 °C CH3 OCH3 H3C O OCH3 H3C O CH3 N O N N OCH3 H3C O OTBS 2. MeI, –78 °C R R yield (%) de (%) H 90 > 98 Me 66 93 Et 79 90 CH2CH=CH2 76 93 CH2CH2CH=CH2 69 90 CH2Ph 62 95 CH2CH2Ph 77 93 CH2OCH2CH2SiMe3 71 94 CH2CH2OTBS 88 96 CH2CH2OMe 79 95 R 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. Ph 89% H2 (1 atm), CH2Cl2 OCH3 N H OCH3 R' O N H3O+ R OCH3 H3C O 89% O OTBS • Dihydroxylation of 3-cyclohexen-1-ones obtained by Schultz's asymmetric Birch alkylation occurs exclusively anti to the amido substituent: • Amide-directed hydrogenation with Crabtree's catalyst: [Ir(cod)py(PCy3)]PF6 N Schultz, A. G.; Hoglen, D. K.; Holoboski, M. A. Tetrahedron Lett. 1992, 33, 6611–6614. Transformations of asymmetric Birch alkylation products: N EtOAc, 55 psi OTBS R OCH3 N OCH3 H3C O H2, Rh on Al2O3 CH3 O Schultz, A. G.; Green, N. J. J. Am. Chem. Soc. 1991, 113, 4931–4936. H3C O OCH3 H3C O CH3 Ph Schultz, A. G.; Green, N. J. J. Am. Chem. Soc. 1991, 113, 4931–4936. OCH3 R' O N O OsO4, NMO H2O, acetone HO R HO OCH3 R' O N O 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. Kent Barbay 3 • Regio- and stereo-selective epoxidation has been demonstrated: OMOM O O H3 C O N OMOM H3C O CH3 CH3 R1 O OCH3 R2 O CH3 H3C • Acid catalyzed cleavage of the alkylation products requires harsh conditions: OCH3 O H3C O H 6 N aq. HCl O O CH3 0 ! 23 °C CH3 H 58% OH CH3 Schultz, A. G.; Macielag, M.; Sundararaman, P.; Taveras, A. G.; Welch, M. J. Am. Chem. Soc. 1988, 110, 7828-7841. reflux, 7 h Ph 95% H3C MeLi, THF N Ph I • Addition of alkyllithium reagents: Methods of cleavage of Schultz's chiral auxiliaries: N R2 R1 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. OCH3 75–98% O 89–100% >13 : 1 diastereoselectivity H3C O O I2, THF, H2O N MeOH, 25 °C OCH3 O OCH3 R2 O R1 6 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. R H O R1 N O N H N H O R NH H 100 °C 2 NH4Cl R1 • Lactonization can be effectively employed for amide cleavage: OCH3 1. BF3•OEt2 N 2. H2O O SiMe3 H O R1 H 82% CH3 OCH3 N O H3C m-CPBA O O 82% OTBS H3C O OCH3 N O OTBS R2 O H H3C O Schultz, A. G.; Green, N. J. J. Am. Chem. Soc. 1991, 113, 4931–4936. H3C O H NaOMe, MeOH; H+ 100% O CH3 O CH3 Schultz, A. G.; Hoglen, D. K.; Holoboski, M. A. Tetrahedron Lett. 1992, 33, 6611–6614. O R1 N N H N H OK RX R = Me, Et, Bn Schultz, A. G.; McCloskey, P. J.; Court, J. J. J. Am. Chem. Soc. 1987, 109, 6493–6502. H N THF, t-BuOH (2 equiv) O 62–82% H3C O R1 K (4.4 equiv), NH3 H N H O 18 N aq. H2SO4 R2 KO R2 O • Olefinic substrates undergo protiolactonization under the conditions of acidic hydrolysis: 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 : 5 Me H BnBr 78 > 95 : 5 Schultz, A. G.; McCloskey, P. J.; Court, J. J. J. Am. Chem. Soc. 1987, 109, 6493–6502. Kent Barbay 4 Chiral substrates: Asymmetric Birch Reduction of heterocycles: O Ph CH3 O N CH3 Boc O CH3 1. Li, NH3, THF, –78 °C (CH3OCH2CH2)2NH 2. Isoprene 3. RX 91-96% 2. NaOH 3. (Boc)2O R OR' N Boc O 1. Li, NH3, THF t-BuOH (1 equiv) –78 °C Me 79 78 N CO2H Boc Et 71 86 i-Bu 70 90 CH2Ph 67 90 O N CH3 CH3 >90% de R = CH3 72% R = CH2CH=CH2 66% R = CH2Ph 68% (R' = (–)-8-phenylmenthol) R R CH3 2. RX yield(%) ee(%) R 1. TFA N CH3 Schultz, A. G.; Kirinich, S. J.; Rahm, R. Tetrahedron Lett. 1995, 36, 4551-4554. H H 1. 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, suppressing byproduct formation. CO2H 2. CH3I 51% CH3O HO2C CH3 CO2H 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 62-88% H3CO OCH3 N N O Dissolving metal reductions of conjugated alkenes: CH3 CH3 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 –78 °C O OCH3 N R O OCH3 RX H3C (proposed TS geometry) O O H CH3 6 N HCl 100 °C CO2H O R R yield(%) ee(%) Me 86 >94 Et 74 >94 i-Bu 68 >94 H3CO H3C K, NH3 THF, –70 °C O O 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 pyramidalization is proposed in the transition state. Donohoe, T. J.; Helliwell, M.; Stevenson, C. A.Tetrahedron Lett. 1998, 39, 3071-3074. Kent Barbay 5 Transformations of Birch Reduction products: Stereochemical and/or regiochemical control by intramolecular protonation: H3C CH3 • Synthesis of !," or ",#-unsaturated cyclohexanones H3C CH3 H3C H CH2OH H CH3 H3C Li, NH3 H TBSO H3C CH3 H CH2OH H H CH3 THF, –78 °C TBSO 93% H3C CH3 H3C OH H3C OH H H Li, NH3 H EtOH 90% MeO H H 77% MeO Corey, E. J.; Lee, J. J. Am. Chem. Soc. 1993, 115, 8873-8874. H H " H O CH3 CH2OH H3CO H THF, –40 °C H CO 3 H H O CH3 CH2OH " O CH3 H CH2OH H3C O H CH3 H CH2OH H Na, NH3, THF, –40 °C OTBS t-BuOH, –33 °C H3C H3CO OH Lin, Z.; Chen, J.; Valenta, Z. Tetrahedron Lett. 1997, 38, 3863-3866. H (t1/2 ca. 10 h) R = H or R = OMe H Li, NH3, THF t-BuOH O H3CO H HO H Rapid R = OH O H H3CO O –78 °C, 4 hr O3, CH2Cl2, MeOH, OH Li, NH3, i-PrOH CH3 OTIPS R H3C 96% • Ozonolysis of Birch reduction products: • Initial intramolecular protonation at the "-position is proposed. Li, NH3, THF t-BuOH 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 ",#-unsaturated cyclohexanones: 100% ! H Nelson, N. A.; Wilds, A. L. J. Am. Chem. Soc. 1953, 75, 5366-5369. whereas: H3C O H O O H3C O Na, NH3, H 83% aq oxalic acid H3C OH ! H aq HCl • 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, 741750. Cotsaris, E.; Paddon-Row, M. N. J. Chem. Soc., Chem. Commun. 1982, 1206-1208. Kent Barbay 6 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 O O OCH3 CN O 0.1 mole % 80–90 °C BrCH2CH2OAc –78 " 25 °C; KOH, MeOH OCH3 O 80% (two steps) But: 1. Ph3P O O 2. ArCOCl, Et3N 58% Eaborn, C.; Jackson, R. A.; Pearce, R. J. Chem. Soc., Perkin Trans. I 1975, 470-474. I O 1. BnOH, THF, n-BuLi 2. AIBN, Bu3SnH N O OH O H O SiMe3 Br O ≥ 99% ee CH3 EtOH, –70 °C 2. HCl, MeOH 3. I2, THF, H2O 96%, single diastereomer O N3 1. DEAD, PPh3, (PhO)2P(O)N3 OCH3 O Li, NH3 SiMe3 COOH N I Rabideau, P. W.; Karrick, G. L. Tetrahedron Lett. 1987, 28, 2481-2484. CH3 OH H OCH3 O –78 °C; TBAF • 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 !-carbon by silicon. OH N CH3 SiMe3 H3C O OCH3 K, NH , t-BuOH, 3 O • Silyl substituents can be used to modify the regiochemistry of Birch reduction: SiMe3 HO (±)-Gibberellic Acid Birch, A. J.; Dastur, K. P. Tetrahedron Lett. 1972, 41,4195-4196. M, NH3 CO OMOM O (+)-Lycorine: • Isomerization is proposed to occur through a charge-transfer complex. CH3 84% H Hook, J. M.; Mander, L. N.; Urech, R. J. Org. Chem. 1984, 49, 3250-3260. 75% CH3 CH3I, –33 °C O O CH3O CH3O2C CH3 CO2H CN OCH3 CO2H H Cl t-BuOK, THF; K, NH3, –78 °C; OMOM O CH3O CH3O2C O • Diels-Alder cycloaddition by isomerization of 1,3-dienes in situ: OCH3 H 88% CO2CH3 Cl OCH3 CO H CO2CH3 2 I H3CO 2. RBr 3. H+ PPA Li, NH3, THF,–33 °C; HO2C 1. n-BuLi, HMPA –70 °C Reduction CH3O CH3O H O HO CO2Bn N O (single diastereomer) H O H O N O (+)-Lycorine Schultz, A. G.; Holoboski, M. A.; Smyth, M. S. J. Am. Chem. Soc. 1996, 118, 6210-6219. Kent Barbay 7