Myers Birch Reduction Chem 115

Reviews: Additivity of Substituent Effects: Rabideau, P. W.; Marcinow, Z. Org. React. 1992, 42, 1-334.

H3C OCH3 H3C OCH3 Mander, L. N. In Comprehensive Organic Synthesis; Trost, B. M. and Fleming, I., Ed.; Na, NH3, MeOH Pergamon: Oxford, 1991, Vol. 8, pp. 489-521. 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. 1. Na, NH , MeOH H3C CO2H 3 H3C CO2H

2. NH4Cl Mechanism: 94% Electron-Donor Substituents (X): Chapman, O. L.; Fitton, P. J. Am. Chem. Soc. 1963, 85, 41-47. X X X X H H Conditions: M, NH3 ROH M, NH3 H – H – M • Metals: Li, K, Na, occasionally Ca or Mg. (rate-limiting M step) • Co-solvents: diethyl ether, THF, glymes. (X = R, OR, NR ) 2 ortho protonation meta • Proton sources (where appropriate): t-BuOH and EtOH are most common, also MeOH, NH Cl, ROH protonation 4 and water. • Reductions of alkyl benzenes and aryl ethers require a Solubility in NH Normal reduction stronger acid than ammonia; alcohols are typically employed. X 3 H Metal at –33 °C potential at –50 °C (mol Metal/mol NH ) • Regioselectivity of protonation steps in the Birch reduction: H 3 in NH3 (V) Zimmerman, H. E.; Wang, P. A. J. Am. Chem. Soc. 1993, H Li 0.26 –2.99 115, 2205-2216. H Na 0.18 –2.59

• Protonation of cyclohexadienyl anions is kinetically controlled and occurs at the central carbon. K 0.21 –2.73

Electron-Withdrawing Substituents (W): 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.

W • Reduction in low molecular weight amines (Benkeser reduction):

ROH Na (excess), EtOH, NH M, NH3 3 W W W W H(R) (Birch reduction) M, NH3 H H NH4Cl – M – M Li, EtNH2 W or RX + H H H H (Benkeser Reduction) (W = CO2H, CO2R, ROH or M, NH3 2– 2M COR, CONR2, CN, Ar) NH3 • 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. • Aromatic carboxylic acids and carboxylates are readily reduced with Li/NH3 in the absence of alcohol additives. Synthesis 1972, 391-415.

Kent Barbay

1 Asymmetric Birch Reduction: Reductive alkylation: Reviews: Schultz, A. G. Acc. Chem. Res. 1990, 23, 207-213; Schultz, A. G. Chem. Commun. • Enolates derived from 1,4-dihydrobenzoic acids are selectively alkylated at the -carbon. ! 1999, 1263–1271.

CO2H HO2C CH3 RX 1. KNH2, NH3 O O OM R N N 2. CH3I M, NH3, THF RX H 91% N H –78 °C O t-BuOH (1 equiv) H O Nelson, N. A.; Fassnacht, J. H.; Piper, J. U. J. Am. Chem. Soc. 1961, 83, 206-213. (M = Li, Na, or K) O See also: Birch, A. J. J. Chem. Soc. 1950, 1551-1556. (proposed convex attack) • Loewenthal and co-workers first demonstrated single step reductive alkylation of RX yield (%) de (%) aromatic compounds: MeI 67 60 CO H 2 HO2C CH3 1. Na, NH3 EtI 82 >98 opposite facial CH2=CH2CH2Br 75 >96 2. CH3I selectivity PhCH2Br 73 >96 69% CH2=CH2CH2CH2Br 89 96 Bachi, M. D.; Epstein, J. W.; Herzberg-Minzly, Y.; Loewenthal, H. J. E. J. Org. Chem. 1969, ClCH2CH2CH2Br 91 (n.d.) 34, 126-135.

• Reductive alkylations of aromatic esters, amides, ketones, and nitriles typically are conducted H OCH O 3 O in the presence of one equivalent of an alcohol: N R N N M, NH3, THF RX O OCH O CH 3 1. K, NH CH3O 3 –78 °C H 3 CO2t-Bu O H t-BuOH (1 equiv) M O CO2t-Bu t-BuOH (1 equiv) TFA (M = Li, Na, or K) O OCH CH(CH ) CH3 OCH3 CH 3 3 2 CH3 3 2. i-PrI CH3 94% RX 70-88% yield, >96% de Hook, J. M.; Mander, L. N.; Woolias, M. Tetrahedron Lett. 1982, 23, 1095-1098. RX = MeI, EtI, PhCH2Br, Br,Cl Br

CN 1. Li, NH3, THF CN t-BuOH (1 equiv) (CH2)3Cl • Transition state may be complex, viz., enolate aggregation and nitrogen pyramidalization. OCH3 2. BrCH CH CH Cl 2 2 2 OCH3 85% • 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 Schultz, A. G.; Macielag, M. J. Org. Chem. 1986, 51, 4983-4987. 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: O OCH3 O OCH3 H3C H3C CH PDC, t-BuOOH CH H (1 atm), CH Cl 3 N 3 N 2 2 2 O OCH3 O OCH3 Celite, PhH 1. s-BuLi, THF, –78 °C O [Ir(cod)py(PCy3)]PF6 N N 98% 2. RX, –78 ! 25 °C OTBS OTBS 98% CH3 53–77% R O OCH3 H3C CH3I CH OCH3 3 OK OCH3 O N H3C 1. K (2.2 equiv), NH3, THF, t-BuOH (1 equiv) N N O

2. MeI, –78 °C OTBS R 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, R yield (%) de (%) presumably due to steric factors. H 90 > 98 O OCH3 OCH H3C H C O 3 Me 66 93 3 CH3 CH N H2, Rh on Al2O3 3 Et 79 90 N

CH2CH=CH2 76 93 O EtOAc, 55 psi O CH CH CH=CH 69 90 2 2 2 OTBS 89% OTBS CH Ph 62 95 2 Schultz, A. G.; Hoglen, D. K.; Holoboski, M. A. Tetrahedron Lett. 1992, 33, 6611–6614. CH CH Ph 77 93 2 2 • Dihydroxylation of 3-cyclohexen-1-ones obtained by Schultz's asymmetric Birch alkylation occurs CH2OCH2CH2SiMe3 71 94 exclusively anti to the amido substituent:

CH2CH2OTBS 88 96 OCH3 OCH3 OCH3 79 95 O O HO O CH2CH2OMe R' R' HO R' R + R N H3O N OsO4, NMO R N H O, acetone OCH3 O 2 O Schultz, A. G.; Green, N. J. J. Am. Chem. Soc. 1991, 113, 4931–4936. R R' yield (%) Transformations of asymmetric Birch alkylation products: H Me 91 • Amide-directed hydrogenation with Crabtree's catalyst: H CH2Ph 86 O OCH3 O OCH3 H3C H3C H (CH2)3N3 88 H (1 atm), CH Cl N 2 2 2 N H (CH2)3Cl 94 CH Ph Et 73 [Ir(cod)py(PCy3)]PF6 2 H Ph Ph Me Et 76 89% 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

3 • Regio- and stereo-selective epoxidation has been demonstrated: • Iodolactonization:

O OCH3 O OCH3 O O OMOM O OMOM R2 R2 H C O CH3 H C O 3 3 R1 6 N aq. HCl R1 I , THF, H O O N N 2 2 N CH3 N R R2 MeOH, 25 °C 75–98% 1 acetone OCH3 O I O CH3 CH3 68% O 89–100%

>13 : 1 diastereoselectivity 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. • Addition of alkyllithium reagents:

Methods of cleavage of Schultz's chiral auxiliaries: OCH O 3 O • Acid catalyzed cleavage of the alkylation products requires harsh conditions: H3C H3C MeLi, THF N CH3 O OCH3 O 0 ! 23 °C H C H C CH3 CH3 3 3 H H N 6 N aq. HCl OH 58% reflux, 7 h Schultz, A. G.; Macielag, M.; Sundararaman, P.; Taveras, A. G.; Welch, M. J. Am. Chem. Soc. 1988, 110, 7828-7841. Ph 95% Ph Asymmetric synthesis of amino-substituted cyclohexenes: Schultz, A. G.; Green, N. J. J. Am. Chem. Soc. 1991, 113, 4931–4936. R2 O R2 KO • Olefinic substrates undergo protiolactonization under the conditions of acidic hydrolysis: R1 N R1 N K (4.4 equiv), NH3 O O H R N THF, t-BuOH (2 equiv) N H N O O H OK 18 N aq. H2SO4 H H H R N 100 °C NH2 H NH Cl O 4 RX H R = Me, Et, Bn 62–82% R2 O R O Schultz, A. G.; McCloskey, P. J.; Court, J. J. J. Am. Chem. Soc. 1987, 109, 6493–6502. H 2 R R1 N R N • Lactonization can be effectively employed for amide cleavage: 1 H H OCH3 N O O H N H3C H3C O H O 1. BF •OEt H H N 3 2 O R1 RX yield (%) de (%) 2. H2O H H H H MeI 54 70 SiMe 82% O 3 H H EtI 68 82 H H NH Cl 73 not reported Schultz, A. G.; Green, N. J. J. Am. Chem. Soc. 1991, 113, 4931–4936. 4 H Me MeI 53 > 88 O O OCH3 Me H NH4Cl 84 one diastereomer H3C H C H C O OCH3 CH 3 3 O 3 m-CPBA O CH Me H MeI 78 52 N N NaOMe, MeOH; 3 O Me H EtI 87 78 O + O 82% H Me H CH =CHCH Br 68 > 95 : 5 O 2 2 OTBS 100% OTBS CH3 Me H BnBr 78 > 95 : 5 Schultz, A. G.; Hoglen, D. K.; Holoboski, M. A. Tetrahedron Lett. 1992, 33, 6611–6614. Schultz, A. G.; McCloskey, P. J.; Court, J. J. J. Am. Chem. Soc. 1987, 109, 6493–6502. Kent Barbay

4 Asymmetric Birch Reduction of heterocycles: Chiral substrates:

O 1. Li, NH3, THF O t-BuOH (1 equiv) R CH3 CH3 Ph CH3 1. Li, NH3, THF, –78 °C N –78 °C N (CH OCH CH ) NH O 3 2 2 2 R CH3 OR' CH3 2. RX CH3 N CH3 N O 2. Isoprene >90% de Boc 3. RX Boc O R = CH3 72% 91-96% (R' = (–)-8-phenylmenthol) R = CH2CH=CH2 66% R = CH2Ph 68% R yield(%) ee(%) Schultz, A. G.; Kirinich, S. J.; Rahm, R. Tetrahedron Lett. 1995, 36, 4551-4554. 1. TFA R Me 79 78 N Et 71 86 2. NaOH CO2H H H i-Bu 70 90 3. (Boc)2O Boc 1. Li, NH3, THF CH2Ph 67 90 CH3O 2. CH3I CH3O HO2C CO2H 51% HO2C CH3 CO2H

• 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. 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.

Dissolving metal reductions of conjugated alkenes: CH 3 OCH OCH3 3 • Styrenes, conjugated dienes, and enones are more readily reduced under dissolving metal CH Na, NH OM CH3 3 3 OCH3 conditions than are aromatics; reduction occurs at low temperature without alcohol additives. –78 °C O RX N N N –78 °C O O R O 62-88% H3CO O OCH OCH3 3 RX O O O O H3C H3C (proposed TS geometry) K, NH3 THF, –70 °C H

H 62% H H R yield(%) ee(%) H3CO H3CO CH3 6 N HCl Me 86 >94 CO2H 100 °C Et 74 >94 Ananchenko, S. N.; Limanov, V. Y.; Leonov, V. N.; Rzheznikov, V. N.; Torgov, I. V. O R i-Bu 68 >94 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 Stereochemical and/or regiochemical control by intramolecular protonation: Transformations of Birch Reduction products:

• Synthesis of !," or ",#-unsaturated cyclohexanones H3C CH3 H3C CH3 OH OH H3C H3C H C OH H 3 H C H H H H 3 CH2OH H3C CH OH Li, NH aq HCl Li, NH 2 3 3 H H H H H H H H CH3 H H CH3 EtOH THF, –78 °C MeO MeO 77% TBSO TBSO 90% O H C CH 93% H C CH 3 3 3 3 aq oxalic acid 83% • It is proposed that the stereochemical outcome is the result of intramolecular protonation OH H3C of the radical anion. Corey, E. J.; Lee, J. J. Am. Chem. Soc. 1993, 115, 8873-8874. H H H O O H C O H3C 3 O O H Nelson, N. A.; Wilds, A. L. J. Am. Chem. Soc. 1953, 75, 5366-5369. CH3 ! " CH3 Na, NH3, CH OH CH2OH 2 H H H • Reduction of aryl silyl ethers and synthesis of ",#-unsaturated cyclohexanones: THF, –40 °C H CO H3CO 3 100% Li, NH , THF TBAF whereas: 3 O H C O O H3C H3C OTBS t-BuOH, –33 °C H3C OTBS 3 H3C 96% O O H CH3 92% ! " CH3 Na, NH3, H H Fuchs, P. L.; Donaldson, R. E. J. Org. Chem. 1977, 42, 2032-2034. H CH2OH CH2OH THF, –40 °C H CO H CO 3 3 • Ozonolysis of Birch reduction products: 71% • Initial intramolecular protonation at the "-position is proposed. OH Li, NH3, i-PrOH OH O3, CH2Cl2, MeOH, Lin, Z.; Chen, J.; Valenta, Z. Tetrahedron Lett. 1997, 38, 3863-3866. CH CH H CO 3 3 3 –78 °C, 4 hr H3CO py, –78 °C; Me2S OTIPS OTIPS 56% (two steps) R R H Li, NH3, THF H Li, NH3, THF H HO O O OH t-BuOH t-BuOH H H CH3 H3CO Rapid (t1/2 ca. 10 h) OTIPS

R = H or R = OMe R = OH 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

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: CH3O CH3 CH3O Li, NH3, THF,–33 °C; PPA

HO2C OCH3 CH3O OCH3 CH CH3 1. n-BuLi, HMPA CO2H 3 CO2CH3 Birch –70 °C I H3CO Reduction 2. RBr CO2CH3 O O 3. H+ NEt2 NEt2 O 88% H H t-BuOK, THF; K, NH , –78 °C; OMOM 3 Amupitan, J.; Sutherland, J. K. J. Chem. Soc., Chem. Commun. 1978, 852-853. CH O CH O O 3 O Bishop, P. M.; Pearson, J. R.; Sutherland, J. K. J. Chem. Soc., Chem. Commun. 1983, 123-124. 3 CH3I, –33 °C CH3O2C CO2H CO2CH3 O 84% H • Diels-Alder cycloaddition by isomerization of 1,3-dienes in situ: O H OMOM CO Cl Cl CH O OH 3 O HO OCH CN CH O C CH 3 OCH3 3 2 3 CO2H H OCH3 O H3C COOH O O O CN (±)-Gibberellic Acid 0.1 mole % Hook, J. M.; Mander, L. N.; Urech, R. J. Org. Chem. 1984, 49, 3250-3260. 80–90 °C 75% (+)-Lycorine: • Isomerization is proposed to occur through a charge-transfer complex. Birch, A. J.; Dastur, K. P. Tetrahedron Lett. 1972, 41,4195-4196. OH OCH3 OCH3 O K, NH3, t-BuOH, O 1. DEAD, PPh3, –78 °C; (PhO)2P(O)N3 • Silyl substituents can be used to modify the regiochemistry of Birch reduction: N N BrCH2CH2OAc 2. HCl, MeOH OCH CH3 CH3 CH3 3 –78 " 25 °C; OCH3 3. I2, THF, H2O KOH, MeOH M, NH3 TBAF 96%, single diastereomer

O I O I SiMe3 SiMe3 80% (two steps) O 1. Ph3P Br O 1. BnOH, THF, n-BuLi Rabideau, P. W.; Karrick, G. L. Tetrahedron Lett. 1987, 28, 2481-2484. O

2. ArCOCl, Et3N 2. AIBN, Bu SnH • In the absence of competing factors, allylic silanes are generally produced from Birch reduction O O N 3 of aryl silanes; this is attributed to stabilization of negative charge at the !-carbon by silicon. N3 ≥ 99% ee O But: CH OH CH3 3 O HO Li, NH3 H CO2Bn H O EtOH, –70 °C O H H N N SiMe3 58% SiMe3 O O O Eaborn, C.; Jackson, R. A.; Pearce, R. J. Chem. Soc., Perkin Trans. I 1975, 470-474. O (single diastereomer) (+)-Lycorine

Schultz, A. G.; Holoboski, M. A.; Smyth, M. S. J. Am. Chem. Soc. 1996, 118, 6210-6219. Kent Barbay

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