Gabriel synthesis, reaction intermediates

The most successful approach to producing an aminomethyl derivative was the Gabriel synthesis. A phthalimide substituent can be introduced by Sn2 displacement of the chloride on 17 with potassium phthalimide under homogeneous conditions in DMF. The reaction is quantitative in all D.F. ranges and the phthalimldo-methyl intermediates, 18, are quite soluble in organic solvents. 

The enantioselective complexation technique can also be applied as one step in the reaction sequence, providing chiral substrates for the next step. We will now discuss the example of Gabriel synthesis between potassium phthalimide 41 and alkyl bromide 42, which leads to optically active amines (Scheme 1) [51], Instead of the complicated preparation of chiral alkyl bromides (halides), imides (43), which are reaction intermediates, have been resolved. Upon treatment with hydrazine and KOH, these gave optically active amines. The chiral host (S,S)-(-)-6 or the chiral biaryl host (,S>(-j-40 was used for the effective resolution of the intermediates 43. Racemic mixtures 43a-d were resolved by complex formation with the host (S,S)-(-)-6 in a mixture of diethyl ether and light petroleum. 

Identify the lettered intermediates in the following reaction scheme. This is an alternative method to synthesize amino acids, based on the Gabriel synthesis of 1 ° amines (Section 25.7A). 

The first step of the Gabriel synthesis, the alkylation of potassium phthalimide with alkyl halides, proceeds via an Sn2 reaction. The second step, the hydrazinolysis of the A/-alkylphthalimide, proceeds by a nucleophilic addition of hydrazine across one of the carbonyl groups of the phthalimide. Subsequently, the following steps occur ringopening then proton-transfer followed by an intramolecular SnAc reaction, another proton-transfer and finally, the breakdown of the tetrahedral intermediate to give the desired primary amine and the side product phthalyl hydrazide. 

Commercial hexythiazox is a racemic mixture of the two trans enantiomers Scheme 26.2.2 shows the main synthetic pathways [11, 17, 19]. Starting from 4-chloro propiophenone the key intermediate erythro amino alcohol may be obtained by stereoselective catalytic reduction of the corresponding hydroxy imi-noketone or by sodium borohydride reduction of the aminoketones obtained via Gabriel synthesis. Different routes lead from this aminoalcohol to the trans-thiazolidinone system the basis of all routes is activation of the hydroxy group, e.g., in form of the sulfonate and a ring forming reaction with carbon disulfide or carbonyl sulfide. The final acylation of the NH group with cyclohexyl isocyanate leads to hexythiazox. 

The intermediate in the Gabriel-Posner synthesis of quinazolin-2(lH)-one (fusion of o-aminobenzaldehyde with excess of urea), was found to be o-ureidobenzylidene urea (19), which then cyclized on heating, or in the presence of acid, with elimination of urea. The intermediate reacted with aniline, iV-methylaniline, and N,V-dimethylaniline to form 4-p-aminophenyl, 4-p-methylaminophenyl, and 4-p-dimethylaminophenyl quinazolin-2(lH)-ones in an unusual manner. Several quinazolin-2(li/)-ones were prepared by converting o-acylanilines into o-ureidophenyl ketones followed by cycli-zation in acetic acid medium for long periods at 55°C. A novel modification of this cyclization involved a Curtius or Hofmann reaction on 2 -benzoyl-oxanilic acid chlorides (20 = Cl) or amides (20 = NH2), respectively. 

Several examples of this widely practiced name reaction have been applied in drug discovery abound. For example in a study describing the design and synthesis of inhibitors of hepatitis C virus (HCV) NS5B polymerase, thiazole intermediate was constructed via the Gabriel reaction, ... 

Gabriele et al. reported a sequential homobimetallic palladium-catalyzed cascade reaction for the synthesis of benzofuran derivatives 207 [80] (Scheme 6.57). Sequential homobimetallic catalysis is different in catalytic cycles promoted by the same metal but in different oxidation states. After oxidative addition and oxopalladation, 5-exo-dig cyclization occurs, followed by carbonylation, affording the intermediate 206. The allylic alcohol is reduced by H—Pd—I through formation of a ji-aUyl complex and the elimination of water. Finally, the product observed is afforded... 

---