Aqueous Work-Up

Hate 1. This excess was used to be absolutely sure that all a-chloroether would have reacted. Traces of this compound, if still present in the reaction mixture, will hydrolyse during the aqueous work up. The acid that is liberated can cause hydrolysis of the product to H2C=CH-C(=0)CH(CH3)0C2H5. HoLp. A. Prepared by introducing 0.30 mol of dry gaseous HCl (weight increase) into 45 ml of freshly distilled ethyl vinyl ether (excess) at -30°C. 

Note 2. All operations during the aqueous work-up must be carried out without any delay the product is probably water-sensitive. 

Note 1. Aqueous work-up and extraction with diethyl ether can also be carried out but will take longer. In the proposed procedure the distilled reaction product is collected in a cooled receiver if no cooling is applied, the required pressure of 10-15 mnHg cannot be realised because of tlie presence of volatile components and water in the reaction mixture. 

Aqueous work-up of the typical Grignard reaction gives a mixed magnesium hydroxide—haUde solution or suspension which must be disposed of. The cost of disposal of the acidic aqueous waste in accordance with local wastewater treatment regulations must also be considered. 

NaBH4 is soluble in water, alcohols, pyridine, dioxane, dimethoxyethane, diglyme and triglyme. All these solvents, as well as aqueous tetrahydrofuran and aqueous dimethylformamide, have been used for reductions. The reductions go very slowly in di- and triglyme so these solvents are not suitable for preparative work. In some reductions in dry pyridine and dry dimethyl sulfoxide, reaction only takes place on aqueous work-up. This... 

LiBH4 reductions are usually done in tetrahydrofuran. They are also done in ethanol at —10°, ether, pyridine and diglyme. In dry pyridine the reduction of ketones goes very slowly and sometimes c)ttly takes place on aqueous work-up. " The best solvents for LitOC(CH3)3]3AlH are diglyme and tetrahydrofuran, " Reductions of unhindered ketones take... 

The reaction of enamines derived from cyclohexanone with dichlorocarbene to give the 1 1 adducts is now well established (137-139). The morpholine enamine (113) reacted with dichlorocarbene at —10 to —20° in tetrahydrofuran to give the stable crystalline adduct (201). Thermal decomposition followed by an aqueous work-up gave an a,)3-unsaturated ketone identified as 2-chloromethylene-cyclohexan-l-one (202) (139). 

Reaction of the morpholine or piperidine enamine of cyclopentanone, however, gives an unstable adduct which rearranges under the reaction conditions and an aqueous work-up to give the ring expanded ketone 2-chloro-2-cyclohexen-l-one (203) (138,139). 

Direct treatment of TIPS enol ethers of a variety of cyclic and acyclic ketones with the strong-base combination of n-BuLi/KO-t-Bu leads to /3-ketosilanes (2) after aqueous work-up. In contrast with the earlier method, this rearrangement appears to proceed through allylic, rather than vinylic, metallation, since enol ethers lacking an allylic a-proton are unreactive. 

The procedure described herein is an improved version of our previously reported synthesis,2 circumventing the need for an intermediate aqueous work-up, thereby providing the title compound in a one-pot procedure. 

The use of microwave irradiation for decarboxylation reactions is well appreciated [107-110]. Still, only one example of a decarboxylation performed on 2-pyridone starting materials has been reported (Fig. 10) [111]. Notably, this decarboxylation reaction is a selective and reagent-free method performed in N-methyl-2-pyrrohdin one (NMP) and microwave irradiation at 220 °C for 10 min. The products 65 were isolated in excellent yields (92-99%) by a simple aqueous work-up (Fig. 10). 

A solution of 1 equiv. 811 in CH2CI2 is added over a period of 15-20 min to a mixture of 1.5 equivalents of allyltrimetliylsilane 82 and 10 mol% HN(S02p)2 at -78 °C. The reaction is complete less than 5 min after addition, as indicated by TLC. After the usual aqueous work up the product 812 is obtained in 82% yield [19] (Scheme 6.19). 

In MeCN/Cl(CH2)2Cl in the presence of SnCU silylated co-hydroxy-acetals such as 1422 react, via cations such as 1423, with silylated 5-fluorouracil 1424 to afford, after aqueous work-up, 84% of the nucleoside analogue 1425 and MeOSiMe3 13 a [7] (Scheme 9.5). 

A solution (0.2 M, 1 equiv.) of the co-acetylenic ketone 2093 in THF, Zn powder (20 equiv.), MesSiCl 14 (6 equiv), and 2,6-lutidine (2—4 equiv.) are heated under reflux under an atmosphere of argon or nitrogen for 12-18 h to give, via intermediate 2094, after aqueous work-up with NaHC03 and subsequent chromatography, 77% of the cyclized product 2095 [25] (Scheme 13.32). 

Conversion of the amino alcohol 53 to Efavirenz (1) was readily accomplished by reaction with phosgene or phosgene equivalents. The most convenient and economically sound method is to react 53 with phosgene in the absence of base in THF-heptane at 0-25 °C. After aqueous work-up, Efavirenz was crystallized from THF-heptane in excellent yield (93-95%) and purity (>99.5%, >99.5% ee). 

Cul, 12mol% of 2,2 -dipyridyl, in lOvol of xylene diglyme (9 1) at 140°C with azeotropic removal of the water as it was formed. The azeotropic removal of water helped alleviate the problem of solids coating the reaction vessel walls, which led to stalling of the reaction. The reaction was complete in less than lOh, typically with 96% assay yield and 92% isolated yield for 49 after aqueous work-up and subsequent crystallization [14b-d]. It was noteworthy that this catalytic system composed of the copper(I) salt with bipyridyl ligand was recently reported to be applicable to a wide range of Ullmann-type ether formations [14d]. 

Initially, two plausible mechanisms were considered, as depicted in Scheme 5.16. The first was a hydroboration route (a), where the B-H bond was added across the olefin from the same face of S-0 and upon aqueous work-up, the resulting C-B bond was replaced with a C-H bond. The tis B-H addition to the olefin led to the cis-stereochemistry of the two adjacent aryl substituents. The reduction of the sulfoxide oxygen occurs in the next step. The alternative mechanism was the borane reduction route (h), which was similar to 1,4-addition of hydride,... 

Herein, the stereogenic center in 2-12 controls the stereochemistry in the way that the Michael addition occurs from the less-hindered a-face of the enolate to the si-side of the crotonate 2-13 according to transition structure 2-16. The second Michael addition occurs from the same face, again under chelation control, followed by an axial protonahon of the formed enolate to give the cis-compound 2-14a. It should be noted that after the usual aqueous work-up procedure an inseparable... 

One very fascinating domino reaction is the fivefold anionic/pericydic sequence developed by Heathcockand coworkers for the total synthesis of alkaloids of the Daphniphyllum family [351], of which one example was presented in the Introduction. Another example is the synthesis of secodaphniphylline (2-692) [352]. As depicted in Scheme 2.154, a twofold condensation of methylamine with the dialdehyde 2-686 led to the formation of the dihydropyridinium ion 2-687 which underwent an intramolecular hetero- Diels-Alder reaction to give the unsaturated iminium ion 2-688. This cydized, providing carbocation 2-689. Subsequent 1,5-hydride shift afforded the iminium ion 2-690 which, upon aqueous work-up, is hydrolyzed to give the final product 2-691 in a remarkable yield of about 75 %. In a similar way, dihydrosqualene dialdehyde was transformed into the corresponding polycyclic compound [353]. 

A rather new concept in the context of domino radical cydizations has been developed by Gansauer and coworkers utilizing titanocene-complexes for the radical opening of unsaturated epoxides. The titanocene-catalyzed reactions [61] of 3-145 primarily led to radical 3-146, which underwent a subsequent intermolecular addition to a present a,(3-unsaturated carbonyl compound to form bicyclic carbocy-cles of type 3-148 via the intermediate 3-147 after aqueous work-up (Scheme 3.38) [62]. From a kinetic point of view, the reaction is remarkable since the intermolecular addition of simple radicals to a,(3-unsaturated carbonyl compounds is not an easy task, as highlighted above. 

Azatriquinadiene (2,3-dihydroazatriquinacene) 39 has been efficiently synthesized from enamine 389. Enamine 389 on treatment with bromine followed by aqueous work-up afforded the tetrabromohemiaminal 390. Dehydrohalogenation of 390 with potassium hexamethyldisilazide (KHMDS) and compound 391 on reduction with lithium aluminium hydride yielded the target molecule azatriquinadiene 39 in good overall yield (Scheme 85) <2000JOC7253>. 

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