Amines synthesis from halides

Show how 2-(2-bromophenyl)ethanamine could be prepared by the Gabriel amine synthesis, from A -potassiophthalimide and compound A, an alkyl halide. 

A special problem arises in the preparation of secondary amines. These compounds are highly nucleophilic, and alkylation of an amine with alkyl halides cannot be expected to stop at any specifle stage. Secondary amides, however, can be monoalkylated and lydrolyzed or be reduced to secondary amines (p. 11 If.). In the elegant synthesis of phenyl- phrine an intermediate -hydroxy isocyanate (from a hydrazide and nitrous acid) cyclizes to pve an oxazolidinone which is monomethylated. Treatment with strong acid cleaves the cyclic irethan. 

GABRIEL Amine Synthesis Synthesis ol primary amines from alkyl halides... 

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

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). 

Recently, a new method for synthesis of tertiary amines 326 from iV,iV-dialkyl O-benzoyl hydroxylamines 325 was proposed.425 The protocol is based on the copper-catalyzed reaction of hydroxylamines 325 with dialkyl- and diarylzinc reagents (Scheme 166). It is noteworthy that alkyl- and phenylzinc halides also reacted with compounds 325, however, yields were significantly lower than those for ZnR2 (18-29% vs. 69-98%). 

A simple and atom-economical synthesis of hydrogen halide salts of primary amines directly from the corresponding halides, which avoids the production of significant amounts of secondary amine side products, has been described by researchers from Bristol-Myers Squibb [227]. Microwave irradiation of a variety of alkyl halides or tosylates in a commercially available 7 m solution of ammonia in methanol at 100-130 °C for 15 min to 2.5 h followed by evaporation of the solvent provided the corre-... 

The synthesis of nitriles from halides is valuable in medicinal chemistry because nitriles are flexible building blocks readily converted into carboxylic acids, amides, amines, or a variety of heterocycles, e. g. thiazoles, oxazolidones, triazoles, and tetrazoles. The importance of the tetrazole group in medicinal chemistry is easily understood if we consider that it is the most commonly used bioisostere of the carboxyl group. 

Oxetanes are commonly obtained by intramolecular ether synthesis from a suitably functionalized alcohol. Leaving groups employed include halides, tosylates, and others. The base can range from an alkoxide to a non-nucleophilic amine. 

With respect to the synthesis from amines, C02 and alkyl halides, the synthesis of carbamates from amines, C02 and alcohols (Equation 6.10) is not only a phosgene-free, but also a halogen-free process. Moreover, water forms as the only reaction coproduct. Whilst these features make the route very attractive from the point of view of environmental sustainability, unfortunately the reaction suffers from both thermodynamic and kinetics limitations. Kinetic impediments make necessary the use of a suitable catalyst which, moreover, must be water-tolerant in order to avoid deactivation by cogenerated H20. Several strategies have been explored to overcome these restraints, based mainly on the use of alcohols in a dehydrated form (for instance, as ortho esters or ortho carbonates) [63], or on the use of dehydrating agents [64, 65]. 

Oxetanes are commonly obtained by intramolecular ether synthesis from a suitably functionalized alcohol. Leaving groups employed include halides, tosylates, and others. The base can range from an alkoxide to a non-nucleophilic amine . The classical, straightforward approach to 2-oxetanones (-lactones) is by the lacto-nization of the salts of -halocarboxylic acids and similar precursors . Thietanes and -thio-lactones are obtained analogously . 

Second-order reactions of type II are probably among the most common of all reactions studied. A few typical examples are the gas-phase formation of hydrogen iodide, II2 + I2 2HIthe reactions of free radicals with molecules, for example, H + Br2 HBr + H the famous synthesis of urea from NH4 and CNO ions the hydrolysis of organic esters in non-aqueous media and the reaction of tertiary alkyl amines with alkyl halides to produce quaternary ammonium salts, R3N + R X — R RsN+ +... 

The synthesis of cyclic carbonates, which start from COj and epoxides, is possible even with nonmetal catalysts and examples of the catalysts which have been used are ammonium salts [193 196], amines [197-199], halides... 

Synthesis from Halogen Acids.—The simplest method for the synthesis of amino acids is by the action of ammonia on the halogen acids and is exactly analogous to the formation of alkyl amines from alkyl halides. 

N.N-Dialkylgeranylamines have been prepared by the reaction of dialkyl amines with geranyl halides. The procedure described here is a modification of one we reported earlier. It is a simple, one-step synthesis of N,N-dialkylgeranylamines from myrcene and dialkylamines which are readily available bulk chemicals. The reaction proceeds stereoselectively, and yields are high. 

An alternative to the azide synthesis is the Gabriel amine synthesis, which uses a phthalimide alkylation for preparing a primary amine from an alkyl halide. Imides (-CONHCO-) are similar to ethyl acetoacetate in that... 

During (he last few years, a novel Pd(O)-catalyzed method for C-N bond formation from amines and aryl halides has emerged largely due to contributions from the Buchwald and Hartwig groups [120, 121]. In one application, an intramolecular C-N bond linkage was realized using classic palladium catalysis condition in Buchwald s synthesis of tetrahydropyrroloquinoline... 

Addition to the N=X bonds. Amine synthesis, particularly from chiral hydra-zones, using RCeCL as nucleophiles is well established. " The reagent formed from 1 1 RLi and CeClj is superior to RLi alone or RMgX. For conjugated aldimines, enantioselective 1,2-addition predominates. Allylcerium halide reagents can be pre-... 

The yield of a 1-adamantamine decreases in the presence of a more polar compound, such as cyclohexanol, which adsorbs more readily onto TiOj particles than 1-azidoadamantane. Because azides can be produced readily from alkyl halides, photoreduction of azides on SC provides an easier alternative to amine synthesis [151]. 

A) and used in organic synthesis. a-Lithio sulfides give useful carbanion reactions and sulfur ylids can be formed (secs. 8.6, 8.8.B). The difficulties in preparing primary and secondary amines by traditional methods (from halides or tosylates via reaction with imides or azides, sec. 2.7) make the hydroboration-amination sequence a mild and useful alternative for the synthesis of amines. 

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