Acidic conditions Gabriel synthesis

The hydrazinolysis is usually conducted in refluxing ethanol, and is a fast process in many cases. Functional groups, that would be affected under hydrolytic conditions, may be stable under hydrazinolysis conditions. The primary amine is often obtained in high yield. The Gabriel synthesis is for example recommended for the synthesis of isotopically labeled amines and amino acids. a-Amino acids 9 can be prepared by the Gabriel route, if a halomalonic ester—e.g. diethyl bromomalonate 7—is employed as the starting material instead of the alkyl halide ... 

Since the 2-nitrobenzenesulfonamide group is stable under acidic [HCI (10 eq), MeOH, 60°C, 4 hr] as well as basic [NaOH (10 eq), MeOH, 60°C, 4 hr] conditions, it can be used extensively for protection of primary and secondary amines. Because of the mild conditions and easy procedure, the submitters believe that the use of 2-nitrobenzenesulfonamides serves as a method of choice for the preparation of a wide variety of secondary amines comparable to the Gabriel synthesis for primary amines. 

Under acidic conditions the equilibrium for the hydrolysis of an amide is driven toward the products by the protonation of the ammonia or amine that is formed. Under basic conditions the equilibrium is driven toward the products by the formation of the carboxylate anion, which is at the bottom of the reactivity scale. The pH of the final solution may need to be adjusted, depending on which product is to be isolated. If the carboxylic acid is desired, the final solution must be acidic, whereas isolation of the amine requires that the solution be basic. Several examples are shown in the following equations. Also, note that the last step of the Gabriel amine synthesis, the hydrolysis of the phthalimide (see Section 10.6 and Figure 10.5 on page 365), is an amide... 

The limitations of this approach can be seen in the reaction of a saturated solution of ammonia in 90% ethanol with ethyl bromide in a 16 1 molar ratio, under which conditions the yield of primary amine was 34.2% (at a 1 1 ratio the yield was 11.3%). Alkyl amines can be one type of substrate that does give reasonable yields of primary amine (provided a large excess of NH3 is used) are a-halo acids, which are converted to amino acids. A-Chloromethyl lactams also react with amines to give good yields to the A-aminomethyl lactam. Primary amines can be prepared from alkyl halides by 10-43, followed by reduction of the azide (19-32), or by the Gabriel synthesis (10-41). 

Methyl r-butyl iminodicarboxylate (91) and di-r-butyl iminodicarboxylate (93) have been used in a modified Gabriel synthesis. Thus, the potassium salt of (91) reacted with alkyl halides to give the corresponding A/-alkylated products (92) in 59-95% yields (in DMF or DMSO, 20-60 C) except for alkylating reagents susceptible to base-catalyzed side reactions. Under basic conditions, (92) gave N-t-butoxycarbonylamines, whereas, with trifluoroacetic acid, iV-methoxycarbonylamines were obtained (Scheme 40). ... 

The reaction conditions are mild, and the method is suitable for preparation of amines containing nitrile, ester, and amide groups these groups, under the conditions of the Gabriel synthesis, are hydrolyzed to carboxylic acid groups. 

Gabriel Synthesis of Amines. )V-Benzyltriflamide was originally introduced as a new nitrogen source for the Gabriel synthesis of amines. Based on its pKa of 6.8 in 67% DMF-water and a gas phase acidity of AGacid = 318.8, due to the powerful electron-withdrawing effect of the triflate function, it was reasoned that a weak base should be sufficient to induce the necessary A deprotonation. Typical conditions (eq 1) for W alkylation... 

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