Gabriel synthesis amines

Where there are two carbonyl groups to stabilize the amide anion, as in the l,2-benzenedicarboximide (phthalimide) anion (Section 18-IOC), the acidity increases markedly and imides can be converted to their conjugate bases with concentrated aqueous hydroxide ion. We have seen how imide salts can be used for the synthesis of primary amines (Gabriel synthesis, Section 23-9D and Table 23-6). 

The modified procedure involves refluxing the N-substituted phthaUmide in alcohol with an equivalent quantity of hydrazine hydrate, followed by removal of the alcohol and heating the residue with hydrochloric acid on a steam bath the phthalyl hydtazide produced is filtered off, leaving the amine hydrochloride in solution. The Gabriel synthesis has been employed in the preparation of a wide variety of amino compounds, including aliphatic amines and amino acids it provides an unequivocal synthesis of a pure primary amine. 

Chapter IV. a-Chloromethylnaphthalene (IV,23) benzylamine (Gabriel synthesis) (IV,39) i r.N -dialkylanilines (from amines and trialkyl orthophosphates) (IV,42) a-naphthaldehyde (Sommelet reaction) (IV,120) a-phenyl-cinnamic acid (Perkin reaction using triethylamine) (IV,124) p-nitrostyrene (IV,129) p-bromonaphthalene and p naphthoic acid (from 2 naphthylamine-1 -sulphonic acid) (IV,62 and IV,164) diphenic acid (from phenanthrene) (IV,165). 

A method that achieves the same end result as that desired by alkylation of ammonia but which avoids the formation of secondary and tertiary amines as byproducts is the Gabriel synthesis Alkyl halides are converted to primary alkylamines without contam mation by secondary or tertiary amines The key reagent is the potassium salt of phthal imide prepared by the reaction... 

Among compounds other than simple alkyl halides a halo ketones and a halo esters have been employed as substrates m the Gabriel synthesis Alkyl p toluenesul fonate esters have also been used Because phthalimide can undergo only a single alkyl ation the formation of secondary and tertiary amines does not occur and the Gabriel synthesis is a valuable procedure for the laboratory preparation of primary amines... 

Isobutylamine and 2 phenylethylamine can be prepared by the Gabriel synthesis ten butyl amine N methylbenzylamine and aniline cannot... 

Reaction of alkyl halides 1 with hexamethylenetetramine 2 (trivial name urotropine) followed by a hydrolysis step, leads to formation of primary amines 3 free of higher substituted amines. This method is called the Delepine reaction, a comparable method is the 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 ... 

The Gabriel synthesis represents another indirect but highly valuable approach to amines. Trost has demonstrated a method for the asymmetric ring-opening of butadiene monoepoxide by use of one equivalent of phthalimide, 7t-allylpalladium chloride dimer, and the chiral bisphosphine 22 (Scheme 7.37). The dynamic kinetic asymmetric transformation proceeded through a putative achiral intermedi-... 

The Gabriel synthesis for converting halides to primary amines is based on this reaction. The halide is treated with potassium phthalimide and the product hydrolyzed (10-11) ... 

An alternative to the Gabriel synthesis, in which alkyl halides can be converted to primary amines in good yields, involves treatment of the halide with the strong base guanidine followed by alkaline hydrolysis. There are several alternative... 

The reaction with ammonia or amines, which undoubtedly proceeds by the SnAt mechanism, is catalyzed by copper and nickel salts, though these are normally used only with rather unreactive halides. This reaction, with phase-transfer catalysis, has been used to synthesize triarylamines. Copper ion catalysts (especially cuprous oxide or iodide) also permit the Gabriel synthesis (10-61) to be... 

The simplicity of the two-phase modification of the Gabriel synthesis of primary amines, via the N-alkylation of potassium phthalimide, makes the procedure considerably more convenient than the traditional method, which normally requires the use of anhydrous dipolar aprolic solvents. The reaction can be conducted under solid liquid conditions using potassium hydroxide in toluene [25], or with preformed potassium phthalimide [26, 27] (cf ref. 28). As is normal for acylation reactions, relatively mild conditions are required for the preparation of the A-ethoxycarbonyl derivative [29], whereas a reaction temperature of 100°C is generally used for N-alkylation (Table 5.16). The reaction time for the soliddiquid two-phase system can be reduced dramatically with retention of the high yields, when the reaction mixture is subjected to microwave irradiation [30]. 

Cf. Gabriel synthesis, where the product is also amine and Sommelet reaction, where the product is aldehyde. The Delepine works well for active halides such as benzyl, allyl halides, and a-halo-ketones. 

Gabriel synthesis is used for the preparation of primary amines. Phthalimide on treatment with ethanolic potassium hydroxide forms potassium salt of phthalimide which on heating with allqrl halide followed by alkaline hydrolysis produces the corresponding primary amine. Aromatic primary amines cannot be prepared by this method because aryl halides do not undergo nucleophilic substitution with the anion formed by phthalimide. 

The sulphonyl chloride 23 is proposed as a protecting group for the Gabriel synthesis of secondary amines from primary amines. At the deprotecting stage, carbon-sulphur bond cleavage is achieved using zinc and acid as the electron source [109]. 

The Gabriel synthesis of amines uses potassium phthalimide (prepared from the reaction of phthalimide with potassium hydroxide). The structure and preparation of potassium phthalimide is shown in Figure 13-13. The extensive conjugation (resonance) makes the ion very stable. An example of the Gabriel synthesis is in Figure 13-14. (The N2H4 reactant is hydrazine.) The Gabriel synthesis employs an 8, 2 mechanism, so it works best on primary alkyl halides and less well on secondary alkyl halides. It doesn t work on tertiary alkyl halides or aryl halides. 

Gabriel Synthesis The reaction of an alkyl halide with potassium phthalimide to form, after hydrolysis, a primary amine. 

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. 

It was originally thought that one should be able to remove the succinic acid group by treatment of 7 with hydrazine in the same way one is able to produce a primary amine by treating a phthalimide with hydrazine in the classical Gabriel synthesis (12). This was not the case, though, since 7 did not react with hydrazine. However, it was found that treatment of 7 with dilute sodium hydroxide readily hydrolyzed the succinimide to produce the amino alcohol, 1, in 90% yield and having a 98 - 99% ee. 

Problem 18.8 Prepare ethylamine by (a) Gabriel synthesis, (6) alkyl halide amination, (c) nitrile reduction, (d) reductive amination, (e) Hofmann degradation. ... 

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