Lithium EtOAc

Lithium-tellurium exchange generation of vinyllithium (typical procedure). Method A. To a solution of butyl vinyl telluride (0.211 g, 1 mmol) in THF (4 mL) at -78°C under N2 is added dropwise a solution of n-BuLi (1.5 M in hexane, 0.67 mL, 1 mmol). After stirring for 40 min at -78°C, benzaldehyde (0.016 g, 1 mmol) is added. The mixture is allowed to react at room temperature for 30 min, diluted with EtOAc (40 mL) and washed with brine. 

Several 1,3-diazetidinones are quite stable to reducing conditions. For example, in compound 152 the C—C bond in the side chain could be easily reduced by Pd-C (10%) in EtOAc in the presence of H2 yielding quantitatively 153 (Scheme 19). Even lithium aluminium hydride (LAH) could be used for the reduction of the COOEt group in the side chain of 153 without affecting either the ring C=0 or the N-N bond under controlled conditions to give 155 (Scheme 19). 

The Step 2 product (292.2 mmol) was dissolved in 420.0 ml dry pyridine, then treated with lithium iodide (732.2 mmol) at ambient temperature, then refluxed 2 hours. The mixture was concentrated and the residue was dissolved in 500 ml 1M HC1. It was extracted four times with 250 ml CH2Cl2/methyl alcohol, 4 1, and extracts were washed twice with 250 ml 6N HC1. The solution was then dried with MgS04 and concentrated. The residue was purified by recrystallization with EtOAc/hexane and the product isolated in 63% yield as a white solid. 

The Step 6 product (6.84 g) dissolved in 150 ml THF at 0°C was treated with lithium borohydride (960 mg) and 10 ml ethyl alcohol, then stirred 8 hours. At ambient temperature, the mixture was added to ice water and the organic solvent removed by distillation. A 10% aqueous solution of citric acid was added to the residue to adjust the pH to 3 followed by extraction with EtOAc. The mixture was worked up as described in Step 1 using hexane/EtOAc, 1 1, and the product isolated in 84% yield as a colorless viscous oil. 

The Step 4 product (3.7 mmol) dissolved in 10 ml THF was treated with lithium aluminum hydride(5.8 mmol), then refluxed 8 hours. The mixture was cooled, quenched with saturated potassium sodium tartrate solution, filtered through Celite 545, and the filtrate concentrated. The residue was dissolved in 20 ml EtOAc, washed twice with 20 ml water, dried, reconcentrated, and the product isolated as a white foam. 

A suspension of the Step 2 product (9.3 mmol) in 40 ml THF was treated with 13.9 ml 1M lithium hexamethyldisilazide, then stirred 60 minutes. It was further treated with benzylbromide (13.9 mmol) and Nal (1.0 mmol), then stirred 40 hours at 50°C, and cooled to ambient temperature. The mixture was partitioned between diethyl ether and brine and the organic phase was washed with water, then concentrated. The residue was purified by flash chromatography with silica gel using 15% EtOAc/hexane and the product isolated in 20% yield as a white solid. 

The Step 3 product (3.1 mmol) dissolved in 25 ml THF was treated with lithium borohydride (10 mmol), then stirred 48 hours at ambient temperature. The mixture was quenched with 5 ml methyl alcohol, then stirred an additional hour, and finally diluted with 300 ml EtOAc. The solution was washed with 100 ml apiece water and brine, dried, concentrated, and 0.83 g product isolated as a white solid. 

The Step 3 product (9.3 mmol) was dissolved in 54 ml THF and 15 ml water, then treated with 20 ml 0.8 M lithium hydroxide and 5.76 ml 30% aqueous H202 solution. After stirring 7 hours, the mixture was diluted with water containing sodium bisulfite (10 g) and stirred an additional 30 minutes. The two layers were then separated and the aqueous phase extracted with diethyl ether. The aqueous solution pH was then lowered to 2 with 1M HC1, then re-extracted with diethyl ether, and extracts combined. They were then dried, concentrated, the residue purified by flash chromatography using hexane/EtOAc, 5 1, and the product isolated in 95% yield as a colorless oil. 

Lithium aluminum hydride (96.24 mmol) was slurried into 130 ml THF at ambient temperature and the product from Step 4 (16.04 mmol) dissolved in 30 ml THF added over 15 minutes. Thereafter, the mixture stirred 3 hours, was quenched sequentially with 3.6 ml water, 3.6 ml 15% NaOH, 15 ml water, and the contents stirred for 2 hours. The mixture was filtered through celite and the filtrate concentrated to a yellow oil. The product was isolated by flash chromatography on silica using hexanes/EtOAc, 66 34 in 53% yield. 

A solution of 2,8-bis(trifluoromethyl)-4-bromoquinoline (1.45 mmol) dissolved in 10 ml diethyl ether at —78°C was added to 0.64 ml 2.5 M n-butyl lithium followed by 0.15 ml benzaldehyde and the mixture stirred 1 hour. The mixture was quenched with 10 ml water, slowly warmed to ambient temperature, and extracted 3 times with 20 ml diethyl ether. The combined extracts were dried, concentrated, purified by chromatography on silica gel using heptane/EtOAc, 3 1, and the product isolated in 36% yield as a pale-yellow solid, mp = 151-152°C. H-NMR, IR, and elemental data supplied. 

Lithium bis(trimethylsilyl)amide (2.50 mmol, 1.0 M in THF) was added dropwise to a solution of l,4-dimethoxy-2-hydroxymethylnaphthalene (2.29mmol) dissolved in 10 ml THF at —78°C. This was then added dropwise to a solution of bis(2-chloroethyl)phosphoramidic dichloride (2.75 mmol) dissolved in 20 ml THF, the reaction mixture stirred at —78°C 90 minutes, warmed to —20°C, and ammonia passed through the mixture 10 minutes. Thereafter, the mixture stirred an additional 10 minutes, 30 ml 2% HCl added, and then extracted 4 times with EtOAc. The combined organic layers were washed twice with saturated brine, dried, filtered, and evaporated. The mixture was purified by chromatography using methyl alcohol/EtOAc, 2 98, and the product isolated in 50% yield as a yellow oil, Rf = 0.59. H- and P-NMR data supplied. 

The product from Stepl (0.01 mol) was dissolved in 100ml THE, 17 ml 1.6 M methyl lithium (0.03 mol) added, cooled to —20°C, and 7 ml 1 M t-butyl lithium (0.01 mol) gradually added. Dimethyl formamide (0.02 mol) was added and the mixture stirred 1 hour. After slowly warming to ambient temperature the mixture was hydrolyzed with water, poured into diethyl ether, and concentrated. The material was purified by chromatography on silica gel with petroleum ether/EtOAc, 9 1, and the product isolated. 

The product from Step 1 (0.44 mmol) was dissolved in 2 ml THE, cooled to —78°C, 1M lithium triethylborohydride (0.66 mmol in THE) added at such a rate the temperature did not exceed — 66°C, and the mixture stirred 1 hour after the addition was completed. The reaction was quenched using NaHC03 solution, extracted with EtOAc and purified as in Step 1 to give a 7 3 mixture of diasteromers at the 5 position. 

A solution of copper(II)acetylacetonate (5 mg), 4-chloro-benxaldehyde and tosyl hydrazone lithium salt (2.5 eq) were mixed and heated to 45 °C 3 hours, cooled, and 1ml EtOAc/water, 1 1, added. The epoxide was isolated as a white solid in 54% yield with a trans/cis ratio of 2.8 1, respectively. 

Indene (0.10 mole) was dissolved in 60 ml THF, 200 ml 1.0 M lithium bistrimethylsilylamide (0.20 mole) in THF added over 1 hour, and stirred for 30 minutes. Thereafter, N-t-butoxy-carbonyl-bis(2-chloroethyl)amine (0.10 mole) dissolved in 50 ml THF was added, the mixture further stirred 2 hours, and then distilled under reduced pressure. The residue was purified by chromatography on silica gel using n-hexane/EtOAc, 97 3, and the product isolated in 89% yield. H-NMR, IR, and MS data supplied. 

Ethylformyl-N-benzylpiperidine (1 eq) was added to lithium diisopropylamide (1.1 eq) dissolved in THE at —40°C, the mixture warmed to ambient temperature, and stirred 1 hour. It was re-cooled to —20°C, benzoyl chloride (1.2 eq) dissolved in THE added drop wise, and stirred 1 hour at — 20°C and 16 hours at ambient temperature. Thereafter, the mixture was poured into water, extracted with EtOAc, the organic phase washed with NH4CI, brine, dried, concentrated, and the product isolated. H-NMR data supplied. 

To trimethylsilylacetylene (20.4 mmol) dissolved in 80 ml THF at —5°C was added n-butyl lithium (20.4 mmol) followed by the dropwise addition of 3-isobutyl-9,10-dimethoxy-l,3,4,6,7,llb-hexahydro-2H-benzo[a]quinolizidin-2-one dissolved in 30ml THF. The mixture was stirred at -5 °C one hour, slowly warmed to 20 °C, stirred 2 hours, and then quenched with NH4CI solution. THF was removed, the aqueous component extracted 3 times with 100 ml EtOAc, washed with water, brine, and concentrated. The residue was dissolved in 30 ml methyl alcohol containing 5 ml 5 M KOH, heated to 65 °C 30 minutes, then cooled and quenched with NH4CI solution. The solution was concentrated, extracted 3 times with 50 ml EtOAc, washed, dried, and the product isolated in 53.7% yield as a slightly brown solid. Elemental analysis data supplied. 

A mixture of 6-bromo-4-(tri luoromethanesulfonyloxy)-5,8-dimethoxy-quinoline (1.35 g, 3.25 mmol), trimethyl[2-[(l,l-dimethylethoxycarbonyl)-amino]phenyl]tin (1.68 g, 4.70 mmol), lithium chloride (330 mg, 7.80 mmol), copper(I) bromide (25 mg, 0.17 mmol), and tetrakis(triphenylphosphine)palla-dium (0) (180 mg, 0.16 mmol) in dioxane (60 cm ) was heated at 90 °C for 60 h. After being cooled to rt, the mixture was partitioned between EtOAc and a 5 % aqueous ethylenediamine solution to remove any copper species, completely. After the usual work up, the residue was chromatographed (1.5 1 hexanes -EtOAc) to yield the title compound as a white solid (952 mg, 64%, several other fractions contained the title compound contaminated with 6-bromo-5,8-di-methoxy-4-methylquinoline) mp 166-168 °C. 

To a solution containing THE (10 mL) and a 0.50 M stock solution of lithium naphthalenide (4.2 mL, 2.1 mmol) (prepared by stirring a mixture of equimolar quantities of lithium chips and naphthalene in THE at 25 °C for 6h) at — 70"C was added the thioacetal (1.0 mmol) dissolved in THE (3mL). After the solution had been stirred for 15 min, the electrophile was added and the solution was stirred for 5 min at — 70 °C and for 3 h at 25 °C. Hydrolysis and standard extraction procedures yielded the product which, in the case of carbonation, is pure. In all other cases the product was separated from naphthalene by silica gel chromatography (5% EtOAc/hexane). 

Phenylsulfanyl-6-trimethylsilylbicyclo[3.1.0]hexane (0.65 g, 2.5 mmol) was treated with lithium 1-dimethylaminonaphthalenide (5.7-6.0mmol) for 2h at —45 C. 2-Methylprop-2-enal (0.30mL, 0.25g, 3.0 mmol) was added, and after stirring for a short while, the reaction mixture was hydrolyzed and worked up in the usual way. Column chromatography (silica gel, 10% EtOAc/hexanes) afforded 0.51 g (91%) of the product as an oil. 

To a stirred suspension of lithium tri-/er -butoxya uminum hydride (0.33 g, 1.3 mmol) in THF (5mL) were added 2-chlorotropone (0.14 g, 1.0 mmol) and EtjN (0.13 g, 1.3 mmol), and the mixture was stirred for 20 min at rt. The resulting solution was added dropwise to a stirred suspension of 1,2-diphenylcyclo-propenylium tetrafluoroborate (0.36 g, 1.3 mmol) in THF (5 mL) and the mixture was stirred for ca. 30 min. After quenching with HjO (lOmL), the mixture was extracted with EtOAc and the extract dried (Na2S04). After evaporation of the solvent, the residue was separated by TLC (silica gel, hexane/EtOAc) to give yellow crystals yield 0.22 g (75%) mp 110-111"C (EtOH). 

EtOAc ethyl acetate LiHMDS lithium hexamethyldi-... 

To a solution of the ketone (20.4 g, 46.9 mmol) in THF (500 mL) at 0 °C was added lithium tri-tert-butoxyaluminohydride l.iAIH(O/-Bu)3l (61.0 mL of a 1.0 M solution in THF, 61.0 mmol). The resulting reaction mixture was stirred for 30 min at 0 °C and then for 30 min at 25 °C. After the reaction was complete, as established by TLC analysis, it was quenched by the addition of saturated ammonium chloride (200 mL) followed by addition of EtOAc (300 mL). The mixture was stirred at 25 °C for 2 h, followed by extraction with EtOAc (3 x 300 mL). The combined extracts were washed with brine, dried over magnesium sulfate, and concentrated to give the crude product, which was purified by flash chromatography (silica gel, 25% EtOAc in hexanes) to afford 19.4 g (95%) of the alcohol as a white sohd. 

To a solution of the isoquinolinone (1.156 g, 9.90 mmol) and fert-butyl alcohol (0.88 mL, 11.9 mmol) in THF (30 mL) at -78 °C was added liquid ammonia (about 280 mL). Lithium was added in small pieces until the blue coloration persisted, after which the solution was stirred at -78 °C for 30 min. The blue coloration was dissipated with piperlyne, 4-methoxybenzyl chloride (4.83 g, 31.00 nunol) in THF (5 mL) was introduced by syringe, and the mixture was stirred for an additional 150 min at -78 °C. Solid ammonium chloride was added and then the anunonia was allowed to evaporate. The pale yellow residue was partitioned between CH2CI2 (30 mL) and water (40 mL). The layers were separated, and the aqueous layer was extracted with CH2CI2 (2 X 30 mL). The combined organic layers were washed with 10% sodium thiosulfate solution (20 mL), dried over magnesium sulfate, and concentrated. Flash chromatography (EtOAc hexane, 2 1) on silica gave 2.21 g (75%) of the tetrahydroisoquinolinone. 

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