Column chromatography, quenching products

Toluene is a useful co-solvent in metal-ammonia reductions as first reported by Chapman and his colleagues. The author has found that a toluene-tetrahydrofuran-ammonia mixture (1 1 2) is a particularly useful medium for various metal-ammonia reductions. Procedure 8a (section V) describes the reduction of 17-ethyl-19-nortestosterone in such a system. Ethylene dibromide is used to quench excess lithium. Trituration of the total crude reduction product with methanol affords an 85% yield of 4,5a-dihydro-17-ethyl-19-nortestosterone, mp 207-213° (after sintering at 198°), reported mp 212-213°. For the same reduction using Procedure 5 (section V), Bowers et al obtained a 60% yield of crude product, mp, 196-199°, after column chromatography of the total reduction product. A similar reduction of 17-ethynyl-19-nortestosterone is described in Procedure 8b (section V). The steroid concentration in the toluene-tetrahydrofuran-ammonia system is 0.05 M whereas in the ether-dioxane-ammonia system it is 0.029 M. 

A suspension of Li metal (0.02 g, 2.9 mmol) in octan-l-ol (3.0 mL) was heated to 170 C and stirred until a homogeneous solution was obtained. The solution was cooled to 20 C and 3-neopentyloxyphthalonitrile (150 mg, 0.7 mmol) in THF (1 mL) was added. The mixture was stirred for 7 10 d, after which excess Zn(OAc)2 was added and the mixture stirred for another 2 3 d. The reaction was quenched with McOH/ H20 (1 1) and washed with MeOH. The crude products were purified by column chromatography (silica gel) and the title compound was obtained as a blue solid yield 28 mg (18%). 

To a solution of 1.44 g (3 mmol) of MAD in 10 mL of toluene are added 154 mg (1 mmol) of 4-rerr-butyl-cyclohexanone (3) at — 78°C. Butyimagnesium bromide (3 mmol) in btzO is added and the reaction mixture is stirred at — 78 C for 2 h. After quenching with 1 N HCI and extraction with Et20, the combined extract is dried and concentrated. The crude product is purified by column chromatography on silica gel (Et20/hex-ane) yield 142 mg (67%) d.r. 100 0 [determined by capillary GC (column PEG-HT, 0.25 mm x 25m temp. 130"C) by comparison with authentic samples]. 

To 158 mg (1 mmol) of 2-formyl-jVJV,3-trimcthylbutanamide in 5 ml, of CH2C12 are added at 0°C 2 mL of 1.0 M (dichloro)methylaluminum (2 mmol) in hexane. The reaction mixture is stirred at 25 °C for 2 h, then quenched with 1 M HC1. After extraction with CHCI,/EtOH (3 1), the combined organic layer is dried over Na,So4 and concentrated in vacuo. The crude product is purified by silica gel column chromatography yield 106 mg (62%) d.r. [(26, 35 )/(25, 3R )] 99 1 (determined by capillary GC). 

A concentrated solution of the 3-phcnylsulfinylalcohol in THF (2 mL THF per 0.5 g of sulfinylalcohol) cooled to — 78°C is added to a solution of 2.1 equiv of LDA in THK (10 mL per 3 mmol of L DA). After stirring for 1 min 1.5 equiv of the aldehyde are added to the reddish solution and one minute later, the reaction is quenched with sat. aq NH CI. The mixture is diluted with water, extracted with ElOAc or CI1CI3 and worked up. The product is purified by column chromatography. 

To a solution of thioglycoside (1.0 equiv), 1-benzenesulfinyl piperidine (1.0 equiv), TTBP (2.0 equiv), and freshly activated 3 A powdered molecular sieves in dichloromethane (25.0 ml mmol-1) was added trifluoromethanesulfonic anhydride (1.1 equiv) at —60 °C under an argon atmosphere. The reaction mixture was stirred for 5 min, after that a solution of the glycosyl acceptor (1.5 equiv) in dichloromethane (4.0 ml mmol-1) was added. The reaction mixture was stirred at — 60 °C for 2 min, after that it was slowly warmed to room temperature and quenched by the addition of saturated aqueous NaHC03. The organic layer was washed with brine, dried (MgS04), filtered and the filtrate was concentrated to dryness. Purification of the crude product by column chromatography over silica gel afforded the product. 

In 1991, Park reported123 the first synthesis of iron alkynylcarbene complexes (184), involving the nucleophilic attack of a lithium acetylide on pentacarbonyl iron, followed by electrophilic quench. With such compounds in hand, he proceeded to investigate their reactivity123,124 and found that upon addition of cyclopentadiene to the alkynylcarbene complexes 184, the products formed were 774-vinylketene complexes (185). During column chromatography, some of these products (185.a and 185.b) were transformed into the tricarbonyl(norbornadiene)iron derivatives 186. Others (185.C and 185.d, not shown) were hydrolyzed as part of the workup procedure, to afford pure samples of the norbornadiene complexes 186.C and... 

Cyclopropanation of Cjq with diethyl bromomalonate in toluene with NaH as auxiliary base proceeds smoothly at room temperature (Scheme 3.5). By-products are unreacted Cjq and higher adducts. The formahon of higher adducts is discussed in detail in Chapter 10. The monoadduct can be isolated easily from the reach on mixture by column chromatography. Saponificahon of such di(efhoxycarbonyl)-methylene adducts of Cgg is achieved by treatment with NaH in toluene at elevated temperatures and subsequent quenching with methanol (Scheme 3.6) [32], This method provides easy access to defined water-soluble fullerenes and can also be applied to higher adducts. These malonic acid derivatives of are very soluble in polar solvents, for example acetone, THF or basic water, but insoluble in aqueous acids. 

A reactor containing an ice-cooled solution of the step 2 product (19.76 mmol) dissolved in 150 ml THF was treated dropwise with -butyl lithium (2.5M in hexanes 19.76 mmol) and after 2 hours treated with pinacol boronate (21.72 mmol). The ice bath was then removed and the mixture stirred overnight at ambient temperature. The reaction was quenched with aqueous NH4CI and the mixture extracted three times with 70 ml of ethyl acetate. Combined extracts were then washed with brine, dried over MgSC>4, and concentrated. The residue was purified by column chromatography on silica eluting with petroleum ether/ethyl acetate, 9 1, respectively, and 9.52 g of product isolated as a blue oil. 

The reaction mixture is cooled to 0°C, one ol the septa is removed, and excess hydride is quenched by the cautious addition of 10-mL portions of 3 N aqueous hydrochloric acid solution (350 mL total) over 5 min (Note 18). The biphasic mixture is stirred at 23°C for 30 min, then poured into a 1-L separatory funnel. The aqueous layer is separated and extracted with three 150-mL portions of ether. The combined organic fractions are washed with 50 mL of 3 N aqueous hydrochloric acid solution followed by 50 mL of brine. The organic layer is dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure (Note 19). The residue is purified by flash column chromatography (230-400 mesh silica gel, 250 g, 43% ether-petroleum ether as eluent) to afford 4.35 g (90%) of analytically pure (R)-p-methylbenzenepropanol as a colorless oil (Note 20). The ee of this product is determined to be >95% (Note 21). 

In addition to quenching excess hydride, the acidification and subsequent extraction steps remove pseudoephedrine and any tertiary amine reaction by-product the latter is otherwise difficult to remove by column chromatography. 

The methyl ester 106 (380 mg, 0.91 mmol) and anhyd LiCl (376 mg, 8.89 mmol) were dissolved in dry DMF (10 mL). The mixture was heated at 90 °C for 4d, cooled to rt, then quenched with dil HC1 and extracted several times with EtOAc. The organic layer was washed with brine, dried (Na2S04), and concentrated under reduced pressure. The crude product was purified by flash column chromatography (EtOAc/hexane 2 8) to recover starting material 106 (75 mg, 20%) elution with EtOAc/AcOH/hexane (25 5 70) gave carboxylic acid 101B as a white solid yield 77% mp 107-108 °C (Et20/hexane) [a]D20 -143.70 (c 1.66, CHClj). 

A solution of the aldehyde (1 mmol), the diene (1.5 mmol) and bis(trimethylsilyl) sulfide (2 mmol) in acetonitrile (0.5 ml) was treated at room temperature with a solution of CoC12.6H20 (0.2 mmol) in acetonitrile (2.5 ml). Progress of the reaction was monitored by GC/MS analysis. The reaction mixture was quenched with saturated ammonium chloride, extracted with ether and dried over sodium sulfate, and the solvent removed under vacuum. The crude reaction product was then purified by column chromatography or TLC on silica gel. For R1 = Ph a 94% yield was secured. 

The reaction of 2,4-dinitrofluorobenzene (DNFB) (Sanger s reagent [10]) with amino acids is another useful technique which is often employed for the analysis of N-terminal amino acids by TLC and column chromatography after derivatization. The reaction involved in product formation is shown in Fig.4.6. The separated derivatives are determined by measuring the quenching of fluorescence on TLC plates or by UV analysis after column chromatography. The generalized absorption curves of dinitrophenyl (DNP)-amino acids in acidic and alkaline solutions are shown in Fig. 4.7. 

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