Halides, alkyl, reaction with ammonia

Under the conditions of the Birch reduction, IV-Boc amides such as 60 can be reductively alkylated in high yields, presumably via a dianion intermediate which is protonated by ammonia at C-5 leaving an enolate anion at C-2 <96JOC7664>. Quenching the reaction with alkyl halides or ammonium chloride then affords the 3-pyrrolines 61. 

Some examples of industrially important uses are the following reactions With alkyl halides or alcohols amines or imines can be manufactured. For example, inethanol forms mono- through trimethylamine dichloromethane yields ethylene imine in the presence of calcium oxide. Amines can also be produced by reacting ammonia with alkyl halides in multistage processes [1425]. 

Lithium acetylide stabilized as its ethylenediamine complex is a very effective reagent in reactions with alkyl halides . DMSO is found to be the best polar solvent for its use (80-90% yields) but DMF is also satisfactory. These solvents have the advantage that the use of the inconvenient liquid ammonia is avoided. The reaction with iodo- and bromoalkanes requires lower temperatures (8 °C) than with chloroalkanes (25-35 °C). No internal alkynes or 1,2-dienes are formed . The lithium acetylide complex has also been used in the preparation of fluoroalkynes in DMSO (e.g. equation 129) . ... 

The reduction of benzoic acids affords the dienolate (77) which may be alkylated in situ by a variety of electrophiles to afford 1-substituted derivatives. Clearly, the addition of alcohol must be avoided or limited to small quantities. It may also be necessary to remove the ammonia before adding the electrophile. The vast majority of applications have been based on reactions with alkyl halides to form (78), but additions of (77) to formaldehyde, epoxides and a,p-unsaturated esters to form the range of adducts (79) to (81) have also been reported (Scheme 14). 

Dimethyl-4,8-dioxaspiro[2.5]oct-l-ene is a synthetically useful precursor for cyclopropenones because of its stability and ready availability. The sodium derivative 1 of the cyclopropenone acetal in liquid ammonia reacted with alkyl halides giving alkyl-substituted cyclopropenone acetals 3. The lithiated cyclopropenone acetal 4 was generated by treating the cyclopropenone acetal with one equivalent of butyllithium in tetrahydrofuran. Reaction of the lithium carbanion 4 with alkyl halides proceeded cleanly in the presence of two equivalents of hexamethylphosphoric triamide (Table 1, entries 1-4). The lithium compound underwent nucleophilic addition to carbonyl compounds smoothly at — 70 C giving hydroxymethyl derivatives 5 (Table 1, entries 5-10). 

Metalation of phenylhydrazine with sodium in liquid ammonia and then reaction with alkyl halides occur readily and give good yields of 1-alkyl-1-phenylhydrazines.529 1,2-Dialkylhydrazines cannot be obtained at all by direct alkylation of hydrazine, but they are quite smoothly prepared by alkylation of 1,2-diacylhydrazines and subsequent hydrolysis.530-533 Alkylation of monoacylhydrazines has been discussed by Hinman and Flores.534... 

Because ammonia and amines are good nucleophiles, they readily undergo Sn2 reactions with alkyl halides. (X denotes a halogen.)... 

Although we had good results in some subsequent reactions with alkyl halides, the metallation of imines by alkali amides has a limited applicability. We assume, on the basis of our results, that the pK values of the imines are close to that of ammonia. Thus, the reaction with alkali amides in this solvent will give rise to certain... 

Treatment of 1,3-diketones, such as CH3COCH2COCH3, with two equivalents of sodamide or potassium amide in liquid ammonia followed by reaction with alkyl halides gives the homologues in good yields [5,6] e.g. ... 

The molecule of ammonia has an electron lone pair on the nitrogen atom and is a strong nucleophile. In the reaction with alkyl halides it yields amines. The reaction mechanism includes removing hydrogen halide as the leaving group. 

Ammonia reacts with alkyl halides to give amines via a two-step process. The first step is a nucleophilic substitution reaction (8 2). 

Amines are prepared by the reaction of an alkyl halide with ammonia or another amine. Polyalkylation of an amine during reaction with alkyl halides is a serious problem 1, 2,12,14, 34, 46, 48, 49, 50, 51, 52, 64. 

Because a T amine is a better nucleophile than a 1° amine, and a 1° amine is a better nucleophile than ammonia, the products of Rxns lA, IB and 1C on the previous page will compete with the starting material for reaction with alkyl halide (e.g., methyl bromide). ITie result is a mixture of all possible products, including the quaternary (4°) ammonium salt shown below. For this reason direct alkylation of an amine is not a synthetically useful option for making primary, secondary or tertiary amines. 

Although this reaction is useful for preparing a ammo acids (Table 22 3 fifth entry) it IS not a general method for the synthesis of amines Its major limitation is that the expected primary amine product is itself a nucleophile and competes with ammonia for the alkyl halide... 

The reaction of amines with alkyl halides was seen earlier (Section 22 7) as a complicat ing factor in the preparation of amines by alkylation of ammonia... 

Alkylamines are, in principle, capable of being prepared by nucleophilic substitution reactions of alkyl halides with ammonia. 

Ammonia and other amines are good nucleophiles in SN2 reactions. As a result, the simplest method of alkylamine synthesis is by Sn2 alkylation of ammonia or an alkylamine with an alky) halide. If ammonia is used, a primary amine results if a primary amine is used, a secondary amine results and so on. Even tertiary amines react rapidly with alkyl halides to yield quaternary ammonium salts, R4N+ X-... 

Ammonia has always been the starting material for the synthesis of aliphatic amines. Thus, processes have been developed for the condensation of NH3 with alkyl halides (Hoffman reaction) or with alcohols in the presence of various catalysts. The latter reachon, first discovered by Sabatier in 1909 [8, 9] is nowadays the main method of industrial production of light amines (e.g. methylamines 600 000 t/yr) [5]. 

As esters the alkyl halides are hydrolysed by alkalis to alcohols and salts of halogen acids. They are converted by nascent hydrogen into hydrocarbons, by ammonia into amines, by alkoxides into ethers, by alkali hydrogen sulphides into mercaptans, by potassium cyanide into nitriles, and by sodium acetate into acetic esters. (Formulate these reactions.) The alkyl halides are practically insoluble in water but are, on the other hand, miscible with organic solvents. As a consequence of the great affinity of iodine for silver, the alkyl iodides are almost instantaneously decomposed by aqueous-alcoholic silver nitrate solution, and so yield silver iodide and alcohol. The important method of Ziesel for the quantitative determination of alkyl groups combined in the form of ethers, depends on this property (cf. p. 80). 

The general reactions of the compounds are much as expected. They react with strong reducing agents to give ammonia and amines, with complete destruction of the complexes.143-14 The halides are labile and can be substituted.144 The compounds react with acids to form alkylhydrazido complexes,148 and with alkyl halides to form dialkylhydrazido(2 —) complexes, in reactions which are typical SN2 reactions,149 though electrophilic attack (viz. by Me+) is also a possibility.150... 

Ammonia and amines can function as nucleophiles in SN2 displacement reactions of alkyl halides (Section 8-7E). Such processes provide syntheses of alkanamines only with those halides that are reactive in SN2 but not E2 reactions. For example,... 

The reaction of the salt 308 with alkyl halides in base gave the corresponding 2-alkylthiothieno[3,4-d]pyrimidin-4(3//)-ones 369. Heating the latter with ammonia or amines afforded 2-amino(or substituted amino)thieno[3,4-d]pyrimidin-4(3//)-ones 370 (90EUP404356). When 2-methylthiothieno[3,4-d]pyrimidin-4(3//)-one 360 was heated with o-tolu-idine at 200°C, displacement of the 2-methylthio group afforded compound 372 (91MIP1). 

The reaction of the sodium derivative of methylpyrazine with alkyl halides in liquid ammonia gives good yields (44-81%) of mono-alkylated products phenylation has been achieved by reaction with benzyne (generated from bromobenzene and sodamide in liquid ammonia) and gives 53% benzylpyrazine.178 The alkylation of the sodio derivative of 2-methoxy-3-methylpyrazine with methyl iodide, and of the product with ethyl bromide, gives 2-methoxy-3-sec-butylpyrazine (25) a constituent of galbanum oil.31... 

The reaction of tetramethylpyrazine with alkyl halides using either sodamide in liquid ammonia or phenyllithium in ether as condensing agent gives mixtures of alkyltrimethylpyrazines and 2,5-dialkyl-3,6-dimethylpyrazines. A number of carbinols were also prepared from... 

The Sn2 reaction of amines with alkyl halides is complicated by a tendency for overalkylation to form a mixture of monoalkylated and polyalkylated products (Section 19-11). Simple primary amines can be synthesized, however, by adding a halide or tosylate (must be a good SN2 substrate) to a large excess of ammonia. Because there is a large excess of ammonia present, the probability that a molecule of the halide will alkylate ammonia is much larger than the probability that it will over-alkylate the amine product. 

One common present day preparation of dialkyl mono-and ditellurides involves the reaction of alkyl halides with alkali metal tellurides that have been prepared in situ. The reactions are commonly carried out in aqueous or nonaqueous solutions. Solutions of sodimn in liquid ammonia also provide a useful media for the reduction of tellurium. ... 

It was found that 7,8- and 7,9-dicarbollide dianions, formed on abstraction of a bridging endo proton from the corresponding dicarba-nzrfo-undecaborate monoanion with sodium metal solution or sodium amide in liquid ammonia or butyl lithium in THF, very easily interact with alkyl halides to yield B-alkyl-7,8- and -7,9-dicarba-nz[Pg.205]

Lithium acetylide is best prepared from acetylene and LiNH in liquid ammonia. Lithium acetylides are more soluble in liquid ammonia than sodium acetylides and therefore give higher yields (50-80%) on reaction with higher halides. trans-2-Alken-4-ynols have been generally obtained on alkylation of sodium acetylides with... 

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