Aqueous acidic work

The initial medicinal chemistry route to the azabicyclo[3.3.0]octane-3-carboxylic acid produced the azabicyclo system in a diastereoselective but racemic manner, and required a classical resolution to achieve enantioenriched material (Teetz et al., 1984a, b 1988). Reaction of (R)-methyl 2-acetamido-3-chloropropanoate (43) and 1-cyclopentenylpyrrolidine (44) in DMF followed by an aqueous acidic work-up provided racemic keto ester 45 in 84% yield (Scheme 10.11). Cyclization of 45 in refluxing aqueous hydrochloric acid provided the bicyclic imine, which was immediately reduced under acidic hydrogenation conditions. The desired cis-endo product 46 was obtained upon recrystaUization. The acid was protected as the benzyl ester using thionyl chloride and benzyl alcohol, providing subunit 47 as the racemate. Resolution of 47 was accomplished by crystallization with benzyloxy-carbonyl-L-phenylalanine or L-dibenzoyl-tartaric acid. 

Enantioselective Hydrosilylation of C=N Double Bonds in Ketoximes and Ketimines. Homogeneous enantioselective hydrosilylation of prochiral alkyl aryl ketoximes has been carried out by using a Rh-(R,R)-NORPHOS catalyst. Thus, hydrosilylation of r-butyl phenyl ketoxime in the presence of [Rh(COD)Cl]2-(R,R)-NORPHOS followed by aqueous acidic work-up afforded the corresponding amine (eq 3) [16.5% ee, (5)], which became inverted to 15.0% ee (R) when this reaction was performed in the presence of added ammonium hexafluo-rophosphate (RhiNHaPF = 1.1, CH2CI2 solvent). ... 

In this cyclic transition state, one Grignard molecule donates its alkyl group to the carbonyl carbon, while the other Grignard molecule activates this carbon by acting as a Lewis acid in complexing to the carbonyl oxygen. The resultant magnesium alkoxide is hydrolysed in the aqueous acidic work-up to yield the alcohol. 

Working forward now, here tire reasonable answers. All reactions use (Cll.>Cll2)20 as. solvent and are followed by aqueous acid work-up. 

Assume aqueous acid work-up for both this and the next problem. 

Notice that the aqueous acid work-up. necessary in the Grignard synthesis to protonate the initially formed alkoxide and convert it into the target tertiary alcohol, is also sufficient to hydrolyze the tertiary ether protecting group, releasing the primary alcohol at the end of the three-carbon chain. 

A Grignard reagent must be formed from the alkyl bromide and this must add to the ketone. Aqueous acidic work up (not mentioned in the problem as is often the case) must give a tertiary alcohol and that is biperidin. 

Azulene reacts with ethylene oxide in the presence of aluminium chloride to give, after aqueous acid work-up, 2-Cl-azulcnyl]ethanol [109]. Oxetan similarly gives 3-fl-azulenyl3propanol [109], With tetracyanoethylene oxide the major product is azulene-l-carbonyl cyanide, whose formation apparently involves cleavage of the carbon--carbon bond of the epoxide ring [110]. 

Scheme 13.8 Reaction of in situ generated [Cp2Zr(=NNPh2)] with an alkyne giving a metaiiacycie which was converted to an indoie derivative upon aqueous acidic work-up [16].

For each reaction presented in Problem 43, write out the complete, step-by-step mechanism using curved-arrow notation. Include the aqueous acid work-up. 

Ketone + Grignard reagent "After aqueous acid work-up. R2CO R MgX, (CH,CH,),0 > R RjCOH Tertiary alcohol... 

In this scheme, the aqueous acid work-up does double duty It protonates the aUcoxide that results from alkynyllithium addition, and it hydrolyzes the acetal to a ketone. 

Lithium aluminum hydride is capable of reducing carboxyhc acids all the way to the corresponding primary alcohols, which are obtained upon aqueous acidic work-up. 

Give the expected results of the reaction of each of the following molecules (or combinations of molecules) with excess NaOCH2CH3 in CH3CH2OH, followed by aqueous acidic work-up. 

The entire synthesis is shown below. Benzene is first treated with chlorine in the presence of a Lewis acid to give chlorobenzene, which is then treated with sulfuric acid and nitric acid, to give the key intermediate. The chlorine atom is then replaced with an OH group upon treatment with hydroxide, followed by aqueous acid work-up. Reduction of the nitro group affords the desired product. 

Under these basic conditions, the product (orf/jo-nitrophenol) is deprotonated upon its formation (because the resulting resonance stabilized anion is more stable than hyiioxide). In order to return the proton and regenerate ortho-nitrophenol, we must introduce a proton source into the reaction flask after the reaction is complete (aqueous acidic work-up). The problem statement did not mention an acidic workup, so the product is the following salt (the conjugate base of orf/jo-nitrophenol) ... 

Now let s draw the forward scheme. Dehydration of the amide with thionyl chloride produces a nitrile. Subsequent reaction with ethyl magnesium bromide, followed by aqueous acidic work-up, yields 3-pentanone, which can be converted to the desired enamine via an acid-catalyzed reaction with dimethylamine, as shown. 

This chapter covers many reactions. Some of them require aqueous work-up, some require aqueous acidic work-up, while others require no work-up at all. Students often confuse the appropriate work-up conditions by associating the work-up conditions with the reagents, rather than the reaction occurring. For example, consider the following reaction ... 

Since the two partners are different, we use a crossed Claisen condensation. LDA is used as the base in the first step, and the final step of the process is aqueous acidic work-up, as shown ... 

Now let s draw the forward scheme. The starting diol is converted to a diacid upon treatment with chromic acid. This diacid is then converted to a diester upon treatment with ethanol and an acid catalyst (with removal of water). The resulting diester wiU imdergo a Dieckmann cychzation upon treatment with sodium ethoxide, followed by aqueous acid work-up. Alkylation, followed by hydrolysis and decarboxylation, gives the product, as shown. 

The forward scheme is shown here. The starting ketone is first treated with a secondary amine in acidic conditions (with removal of water) to give an enamine. This enamine is then used as a Michael donor in a Michael reaction with an a,P-unsaturated ketone. Aqueous acidic work-up gives the desired product. 

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