Phthalimides halides

The independent preparation of potassium phthabmide (from a solution of phthalimide in absolute ethanol and potassium hydroxide in 75 per cent, ethanol) may be avoided in many cases by boiling phthalimide with the halide in the presence of anhydrous potassium carbonate. The N-substituted phthalimide (I) is frequently cleav with difficulty this is often facilitated by reaction with hydrazine hydrate to give an intermediate product, which is easily decomposed by hydrochloric acid to 3deld the insoluble hydrazide of phthaUc acid (II) and the primary amine (III) ... 

Phthalimide with a of 8 3 can be quantitatively converted to its potassium salt with potassium hydroxide The potassium salt of phthalimide has a negatively charged nitrogen atom which acts as a nucleophile toward primary alkyl halides m a bimolecu lar nucleophilic substitution (Sn2) process... 

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... 

Alkylation of phthalimide. The Gabriel synthesis (Section 22.8) The potassium salt of phthalimide reacts with alkyl halides to give A/-alkylphthalimide derivatives. Hydrolysis or hydrazinolysis of this derivative yields a primary alkylamine. 

Primaty amines may be prepared from alkyl halides using phthalimide. This is called the Gabriel amine synthesis. 

The reaction of potassium phthalimide 1 with an alkyl halide 2 leads to formation of a N-alkyl phthalimide 3/ which can be cleaved hydrolytically or by reaction with hydrazine (Ing-Manske variant) to yield a primary amine 5. This route owes its importance as a synthetic method to the fact that primary amines are prepared selectively, not contaminated with secondary or tertiary amines. 

Finally the aminoquinoline bearing a primary amine at the terminal carbon atom of the side chain is itself an effective antimalarial drug. Ring opening of 2-methyltetrahydrofuran by bromine gives the dibromide, 99. The primary halide is sufficiently less hindered so that reaction with potassium phthalimide affords exclusively the product of displacement of that halogen (100). Alkylation of the aminoquinoline with lOO affords the secondary amine, 101. Removal of the phthalimide group by means of hydrazine yields primaquine (102). ... 

Pi peridinobenzimidazole also serves as starting material for the antipsychotic agent halopemide (69). In the absence of a specific reference, one may speculate that the first step involves alkylation with bromochloro-ethane to give halide The chlorine may then be converted to the primary amine by any of several methods such as reaction with phthalimide anion followed by hydrazinolysis. Acylation with j -fluorobenzoyl chloride then gives the desired product. 

Another alternative for preparing a primary amine from an alkyl halide is the Gabriel amine synthesis, which uses a phthalimide alkylation. An imide (—CONHCO—) is similar to a /3-keto ester in that the acidic N-H hydrogen is flanked by two carbonyl groups. Thus, imides are deprotonated by such bases as KOH, and the resultant anions are readily alkylated in a reaction similar to the acetoacetic ester synthesis (Section 22.7). Basic hydrolysis of the N-alkylated imide then yields a primary amine product. The imide hydrolysis step is analogous to the hydrolysis of an amide (Section 21.7). 

Gabriel amine synthesis (Section 24.6) A method for preparing an amine by SN2 reaction of an alkyl halide with potassium phthalimide. followed by hydrolysis. 

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) ... 

Amides are weakly nucleophilic and react only slowly with alkyl halides. The anions of amides are substantially more reactive. The classical Gabriel procedure for synthesis of amines from phthalimide is illustrative.58... 

The enhanced acidity of the NH group in phthalimide permits formation of the anion, which is readily alkylated by alkyl halides or tosylates. The amine can then be liberated by reaction of the substituted phthalimide with hydrazine. 

The mechanism presumably involves initial oxidative addition of the alkenyl halide to the Cu(I) species and ensuing cyclization analogy for this type of process is provided by the Cu(I)-mediated reaction of phthalimide anions with alkenyl and aryl halides.40 The -isomer of 15 reacts in a different fashion to give an isothiazolidinone derivative, albeit in low yield. 

There are examples of nucleophilic displacement of halide from halo-1,2,5-thiadiazoles by ammonia, primary alkylamines, secondary alkylamines, arylamines, sulfonamides, and phthalimide <1984CHEC(6)513, 1996CHEC-II(4)355>, but the reactions often require high temperatures and excess of the nucleophile. 

A useful approach for the preparation of chiral (3-aminophospho-nic acids from the naturally occurring a-amino acids has been reported.139 The overall scheme (Equation 3.4) involves formation of the phthalimide-acid halide from the starting a-amino acid followed by a Michaelis-Arbuzov reaction with triethyl phosphite to give the acylphosphonate. Complete reduction of the carbonyl group in three steps followed by hydrolysis of the ester and amide linkages provides the target material in very high yield without racemization (>99% ee). 

Gabriel s synthesis org chem A synthesis of primary amines by the hydrolysis of n-alkylphthallmldes the latter are obtained from potassium phthalimide and alkyl halides. ga-bre-alz, sin-tha-sas ... 

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. 

Although the initial report included amine nucleophiles, the scope was limited to activated amines such as indole (which actually undergoes C-alkylation at the 3-position), phthalimide, and 7/-methylaniline. Furthermore, enantioselectivities were inferior to those observed with alcohols as nucleophiles. Lautens and Fagnou subsequently discovered a profound halide effect in these reactions. The exchange of the chloride for an iodide on the rhodium catalyst resulted in an increased enantioselectivity that is now comparable to levels achieved with alcoholic nucleophiles ... 

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. 

In summary, the direct insertion of zinc dust to organic halides is an excellent method for preparing a broad range of polyfunctional organozinc halides bearing various functional groups like an ester" , an ether, an acetate" , a ketone, cyano", halide" , N,N-bis(trimethylsilyl)amino °, primary and secondary amino, amide, phthalimide , sulfide, sulfoxide and sulfone , boronic ester , enone " or a phosphonate . An alternative method is based on transmetalation reactions. 

The reaction with ammonia or amines, which undoubtedly proceeds by the SNAr mechanism, is catalyzed by copper8" and nickel105 salts, though these are normally used only with rather unreactive halides.106 This reaction, with phase transfer catalysis, has been used to synthesize triarylamines.107 Copper ion catalysts (especially cuprous oxide or iodide) also permit the Gabriel synthesis (0-58) to be applied to aromatic substrates. Aryl bromides or iodides are refluxed with potassium phthalimide and Cu 0 or Cul in dimethylacetamide to give N-aryl phthalimides, which can be hydrolyzed to primary aryl amines.108... 

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