Palladium acetate, purification

Bromobenzaldehyde and triphenylphosphine were purchased from Aldrich Chemical Company, Inc. Benzeneboronic acid and palladium acetate were obtained from Lancaster Synthesis. Sodium carbonate was purchased from EM Science and deionized water was used to prepare the 2 M solution. Reagent grade 1-propanol is available from Mallinkrodt Inc. All reagents and solvents are used without purification or degassing. There was no need to dry the glassware rigorously. 

The procedure described here incorporates a number of modifications to the Suzuki coupling that result in a sound, efficient and scaleable means of synthesizing biaryls. First, the catalytic use of palladium acetate and triphenylphosphine to generate palladium(O) eliminates the need for the expensive air and light sensitive tetrakis(triphenylphosphine)palladium(0). No purification of reagents is necessary, no special apparatus is required, and rigorous exclusion of air from the reaction mixture is not necessary. Furthermore, homo-coupled products are not present in significant levels (as determined by 500 MHz 1H NMR). 

Tributyl amine, palladium acetate, triphenyl phosphine from Fluka AG and N,N-dimethylformamide and formic acid from Farmitalia Carlo Erba Chemicals were used without further purification. 

Pd2(dba)3, palladium acetate, and ( )-BINAP were purchased from Strem Chemical Company and used without further purification. (The checkers recrystallized Pd(OAc)2 from benzene prior to use. When it was used as obtained from the supplier, the reaction did not go to completion.)... 

A mixture of diisopropylethylamine (Hiinig s base, 1.74 ml, 10 mmol), palladium acetate (112 mg, 0.5 mmol, 5 mol%), tetra- -butylammonium bromide (1.61 g, 5 mmol) and 4-bromoanisole (110, 1.87 g, 10 mmol) in DMF (1.25 ml) was stirred under nitrogen at 115 "C for 96 h. After cooling to room temperature, water (50 ml) and diethyl ether (50 ml) were added. The organic phase was separated, washed with water and dried (MgS04). The solvent was evaporated in vacuo. Pure 4,4 -dimethoxy biphenyl (77, 514 mg, 48%) was obtained after purification with preperative chromatography, m.p. 172-173 "C. 

The protection of the hemiacetal hydroxyl in step C is followed by a purification of the dominant stereoisomer. The C-6 methyl group is introduced in step C by conjugate addition of dimethylcuprate. The enolate is trapped as the silyl enol ether and oxidized to the enone by palladium acetate. The enone from step D is then subjected to a Wittig reaction. As in several of the other syntheses, the hydrogenation in step E is used to establish the configuration at C-4 and C-6. 

To palladium acetate (1.8 mg, 7.8 //mol) placed in a Schlenk-type tube under a nitrogen atmosphere is added 1,1,3,3-tetramethylbutyl isocyanide (16.8 mg, 0.12 mmol) under stirring at rt. >eep red color is observed immediately, indicating the formation of active palladium(0)-isonitrile catalyst. To the mixture successively added at rt are toluene (0.1 mL), (dimethylphenylsilyl)(pinacolato)borane (102 mg, 0.39 mmol), and 3-(/er/-butyldimethylsilyloxy)-l-propyne (91 mg, 0.53 mmol). The resulting mixture is heated to reflux for 1-4 h, then cooled down to rt, and finally subjected to a short column chromatography on silica gel (diethyl ether) to remove the catalyst. Further purification by bulb-to-bulb distillation of the crude product gives the title compound in 83% 3deld. 

Dioxane, palladium (II) acetate, and triphenylphosphine were purchased from Aldrich Chemical Company, Inc. and were used without further purification. 

Palladium(ll) acetate (98%, Strem Chemicals Inc.), triphenylphosphine (99%, Fisher Scientific Co.), and sodium acetate (99%, Fluka Chemika) were used without further purification. N,N-Dimethylacetamide (DMA) was distilled from calcium hydride through a 25-cm Vigreux column directly before use. 

Palladium(II) acetate was purchased from Nippon Engelhard, and used without further purification. 2-Benzylpyridine (0.46 g, 2.72 mmol) is added to a solution of palladium(II) acetate (0.60 g, 2.67 mmol) in acetic acid (50 mL). This solution is stirred at 25 °C for 24 h affording a pale yellow precipitate. This precipitate is collected on a medium-porosity fritted glass filter and washed with water, methanol, and diethyl ether. Yield 0.80 g (89%), mp 268 °C (dec under air in a capillary tube). 

Dichloro-3-nitropyridine was reacted with N-ethoxycarbonylpiperazine to give 6-chloro-2-(4-ethoxycarbonyl-l-piperazinyl)-3-nitropyridine. The product, without purification, was heated with ethanolic ammonia in a sealed tube at 120°-125°C to give 6-amino-2-(4-ethoxycarbonyl-l-piperazinyl)-3-nitropyridine (mp 132°-134°C), which was treated with acetic anhydride in acetic acid to give 6-acetylamino-2-(4-ethoxycarbonyl-l-piperazinyl)-3-nitropyridine (mp 168°-169°C). This compound was catalytically hydrogenated in the presence of 5% palladium-carbon in acetic acid to yield 3-amino-6-acetylamino-2-(4-ethoxycarbonyl-l-piperazinyl)pyridine. The obtained 3-amino derivative, without further purification, was dissolved in a mixture of ethanol and 42% tetrafluoroboric acid, and to this solution was added a solution of isoamyl nitrite in ethanol at below 0°C with stirring 20 minutes later, ether was added to the solution. The resulting precipitate was collected by filtration and washed with a mixture of methanol and ether and then with chloroform to yield 6-acetylamino-2-(4-ethoxycarbonyl-l-piperazinyl)-3-pyridine diazonium tetrafluoroborate mp 117°-117.5°C (dec.). 

Deprotection of the chiral auxiliary groups is performed using ammonium formate, acetic acid, and palladium hydroxide in refluxing ethanol (eq 2). This sequence gives, after purification by distillation, the free optically pure (/J,/J)-diamine 3. ... 

In fact, one important parameter is the water content of the medium, which causes the undesirable production of acetaldehyde by its reaction with ethylene in the presence of palladium chloride, or by the hydrolysis of the vinyl acetate formed. This operating variable can be adjusted to make the acetate production plant self-sufficient in terms of acetic acid. In this case, die acetaldehyde co-produced is oxidized to the arid in a separate section. It is the water content of the acetic arid employed, controlled by the degree of purification of the by-product arid which is recycled, which ultimately serves to determine the vinyl acetate to acetaldehyde ratio. Longer reridence time in the reactor or higher temperature also favors the formation of acetaldehyde. 

Preparation of the jcy/o-configurated deoxyimino sugars 805 and 807 from 802 or 806 illustrates the value of tartaric acid in enantiospecific syntheses of valuable target molecules. Ozonolysis of 802 followed by reduction with sodium borohydride in methanol provides 803. Subsequent borane-dimethylsulfide—THF complex reduction, OTBS deprotection with 60% aqueous acetic acid, and purification with Amberite IRA400(OH) resin provides, after acidification, 804 in 75% yield. Catalytic debenzylation in the presence of palladium hydroxide occurs quantitatively to afford (27, 3/ ,4R)-2-(2-hydroxyethyl)-3,4-dihydroxypyrrolidine hydrochloride (805) in an overall yield of 53% (Scheme 176). 

This is generally the easiest and quickest method of tritium labelling. The unlabelled organic substance is heated with, for example, tritium-labelled water or acetic acid and a catalyst such as palladium or platinum. After removal of the excess solvent, labile tritium is removed by repeated equilibration with water or other appropriate solvents and the product purified by suitable methods. This results in labelling which is general but not, as a rale, uniform, and the precise determination of the labelhng is usuahy so laborious that it is not often attempted. The method is not apphcable to compoimds which are unstable under the conditions used, and it is not often possible to obtain a theoretical equilibrium concentration without excessive breakdown of the starting material. Purification... 

Typical of the methods available for the preparation of 7t-allylpalladium complexes is the preparation of the crystalline compound 70 by heating prenyl acetate 71 in acetic acid with PdCl2 in the presence of copper(II) chloride, followed by chromatographic purification. Alkylation of 70 with the anion derived from the Ci5-sulphone 72 is then carried out in DMF in the presence of at least four equivalents of triphenylphosphine (two per Pd) and gives the crystalline C2o-sulphone 73 from which vitamin A may be obtained by ethoxide-catalysed elimination of phenylsulphinic acid [40] (Scheme 16). Despite the moderate yield (52%) in the alkylation step and the use of stoichiometric amounts of palladium, this synthesis of vitamin A (7) avoids the lengthy functionalization process that is often necessary with more conventional methods of carbon-carbon bond formation. 

However, Eastman Chemical has developed a selective palladium catalyst that gives acetaldehyde with selectivity of up to 86% at 46% conversion. Byproducts formed include ethanol, acetone and ethyl acetate, all of which can be sold after purification. 

For example, reaction of methoxyallene with an allyHc alcohol under palladium catalysis yielded unsymmetrical mixed acetal 22a in 74% yield (Scheme 5(a)). Treatment of 22a with 10 mol% of Grubbs second generation catalyst 3, followed by add promoted aromatization yielded fiiran 12a in 79% isolated yield for the one-pot protocol. However, the nonpolar furan products were usually contaminated with (nonpolar) phosphine residues from the catalyst, which made the purification step problematic. Therefore, it was generally advantageous to purify the dihydrofuran intermediate prior to the aromatization step. In a similar manner to furans, allyftc sulfonamide 21a was converted to the N,0-acetal 23a in 63% yield under palladium catalysis. Then RCM followed by aromatization proceeded smoothly to provide the desired N-protected pyrrole 13a in 61% yield over two steps (Scheme 5(b)). This procedure can also be applied... 

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