Alkylation of Amines by Alkyl Halides

Amines react with primary alkyl halides to give alkylated ammonium halides. Alkylation proceeds by the 8 2 mechanism, so it is not feasible with tertiary halides because they are too hindered. Secondary halides often give poor yields, with elimination predominating over substitution. 

Unfortunately, the initially formed salt may become deprotonated. The resulting secondary amine is nucleophilic, and it can react with another molecule of the halide. 

The disadvantage of direct alkylation lies in stopping it at the desired stage. Even if just one equivalent of the halide is added, some amine molecules will react once, some will react twice, and some will react three times (to give the tetraalkylammonium salt). Others will not react at all. A complex mixture results. 

Alkylation of amines can give good yields of the desired alkylated products in two types of reactions  

Exhaustive alkylation to the tetraalkylammonium salt. Mixtures of different alkylated products are avoided if enough alkyl halide is added to alkylate the amine as many times as possible. This exhaustive alkylation gives a tetraalkylammonium salt A mild base (often NaHCOy or dilute NaOH) is added to deprotonate the intermediate alkylated amines and to neutralize the large quantities of HX formed 

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Alkylation of Amines by Alkyl Halides 899 19-12 Acylation of Amines by Acid Chlorides 900... 

The alkylation of amines (including polyamines formed by reduction of polypeptides) was a highly popular method of derivatization in peptide chemistry before the appearance of contemporary mass-spectro-metric techniques for analysis of nonvolatile compounds (FFAB, MALDI, etc.). Direct alkylation of amines by alkyl halides (Hoffman reaction) can lead to the final nonvolatile ammonium salts and, hence, other soft reagents must be used. For example, exhaustive methylation can be provided by the mixtures CH20/NaBH4/H+ or CH20/formic add. 

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... 

Notable examples of general synthetic procedures in Volume 47 include the synthesis of aromatic aldehydes (from dichloro-methyl methyl ether), aliphatic aldehydes (from alkyl halides and trimethylamine oxide and by oxidation of alcohols using dimethyl sulfoxide, dicyclohexylcarbodiimide, and pyridinum trifluoro-acetate the latter method is particularly useful since the conditions are so mild), carbethoxycycloalkanones (from sodium hydride, diethyl carbonate, and the cycloalkanone), m-dialkylbenzenes (from the />-isomer by isomerization with hydrogen fluoride and boron trifluoride), and the deamination of amines (by conversion to the nitrosoamide and thermolysis to the ester). Other general methods are represented by the synthesis of 1 J-difluoroolefins (from sodium chlorodifluoroacetate, triphenyl phosphine, and an aldehyde or ketone), the nitration of aromatic rings (with ni-tronium tetrafluoroborate), the reductive methylation of aromatic nitro compounds (with formaldehyde and hydrogen), the synthesis of dialkyl ketones (from carboxylic acids and iron powder), and the preparation of 1-substituted cyclopropanols (from the condensation of a 1,3-dichloro-2-propanol derivative and ethyl-... 

Pentamethylpiperidine (21) is an exceptionally strong base that does not undergo quatemization hence it is employed as acid acceptor during the quatemization of amines by alkyl halides. 

The use of acyl azides in the preparation of amines by the Curtius rearrangement has been discussed previously (Section 23-12E). Alkyl azides can be reduced readily by lithium aluminum hydride to amines and, if a pure primary amine is desired, the sequence halide — azide — amine may give as good or better results than does the Gabriel synthesis (Section 23-9D). 

C) Ammonolysis of Alkyl Halides. Place 20 ml of a saturated alcoholic solution of ammonia in methanol (90 per cent) in each of two test tubes. To the first add 2 g of n-amyl bromide, and to the second 2 g of amyl bromide. Cork, shake, label, and set aside until the following laboratory period. Add to each reaction mixture 20 ml of water, and separate the upper layer of amine (and imchanged halide). Test two drops of each product for amy-lene by shaking with 2 ml of 0.1% potassium permanganate or bromine water. Record the observations. Place the sample of amine in the proper bottle provided by the instructor for future study. 

The C-4 acids (183 and 184) have also been subjected to borane reduction conditions to afford alcohol 195 in 23-50% yield or 64% yield as the C-8 epimeric mixture (195 and 196, Scheme 29) [34, 49, 64]. The C-8 alcohol epimers 195 and 196 have been treated separately as a common intermediate for a number of C-4 derivatives including esters, ethers, and amines [34, 49, 64], Alcohols 195 and 196 was subjected to DCC, DMAP, and desired acid chloride or carboxylic acid in CH2CI2 affording ester analogs in 50-92% yield [64], Esters prepared include alkyl, aryl, and fluorenylmethyloxycarbonyl (Fmoc) protected amino acid derivatives (197 and 198) [64]. Ethers were prepared with various alkyl halides and Ag20 in CH3CN at 40 °C. Alkyl, allyl, and benzyl ethers were prepared in 45-80% yield (199 and 200) [34,64]. Alcohols 195 and 196 were then activated to the triflates and displaced by a variety of amines by treatment with trifluoromethanesulfonic anhydride and desired amine in 22% - quantitative yield over two steps (201 and 202)... 

Heterocyclic Amines. Heterocyclic amines can be alkylated with alkyl halides or with alcohols in the presence of hydrogen plus a nickel catalyst. The Wallach reaction for the alkylation of amines by the action of aldehydes or ketones and formic acid has been studied for piperidine. Reactions between toluene and cyclohexanone with piperidine and formic acid yielded 1-benzyl- and 1-cyclohexylpiperidine, respectively. An optimum amount of formic acid is desired since large amounts are harmful and wasteful. 

The difference in the rate at which the reaction takes place in the two cases is marked. In the case of the acyl chloride reaction takes place when the two substances are brought together at room temperature. It will be recalled, on the other hand, that in the preparation of amines by this reaction the alkyl halide is heated with ammonia at a high temperature to bring about the reaction. The introduction of a negative radical into ammonia is thus much more readily accomplished than the introduction of a positive radical. 

Preparation of aromatic amines by the reaction of aryl halides with aliphatic and aromatic amines has been regarded as a difficult reaction. Recently a facile synthetic method for aromatic amines by amination of aryl halides has been discovered, and rapid progress has occurred in the Pd-catalyzed reaction of amines with aryl halides [1]. One simple example which shows the usefulness of the new method is cited here. The commercially important arylpiperazines 1 have been synthesized by intramoleular N-alkylation of aniline derivatives with N,N-di-(2-chloroethyl)amine (2), which is highly carcinogenic. Now the amines 3 can be prepared efficiently by coupling aryl iodides, bromides or chlorides with N-substituted piperidines. This example provides a big contribution to synthetic chemistry by the new Pd-catalyzed efficient preparative method for arylamines, which are usefial in medicinal and material chemistry. 

Nearly a century ago, Menschulkin (1) showed that the rate of quater-narization of amines by alkyl halides,... 

An attractive route to secondary amines has always been the monoalkylation of primary amines. However, over-alkylation has been an inevitable problem with this approach, and new methodologies that avoid this complication are always welcome. One such method is the transition-metal catalysed N -alkyla-tion of amines by alcohols (Scheme 12). An alternative procedure utilizes aminosilanes (Scheme 13), which react readily with primary halides in the presence of sodium methoxide to afford, selectively, the corresponding secondary amines. 

In general, the preparation of amines by nucleophilic displacement is restricted to inexpensive alkyl halides and to easily separated amines. Separation by distillation using efficient fractionating columns makes possible the industrial preparation of some simple amines by substitution reactions. 

The preparation of pure primary amines by the interaction of alkyl halides and ammonia is very difficult, because the primary amine which is formed reacts with unchanged alkyl halide to give the secondary amine the latter... 

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... 

A number of 2eohtic materials have been claimed to cataly2e this reaction and reaction temperatures are on the order of 200—350°C with pressures as high as 18000 kPa (2600 psi) reported. This is a low conversion process and recycle of the unconverted starting materials is necessary to provide an economical process. Amination of ethylene to produce ethylamines cataly2ed by ammonium iodide is reported, but not beheved to be practiced commercially (15,16). Alkyl Halide Amination (Method 7). The oldest technology for pioducing amines is the reaction of ammonia with an alkyl hahde. This... 

The amines are a group of compounds with the general formula R-NHj, and all the common amines are hazardous. As a class the amines pose more than one hazard, being flammable, toxic, and, in some cases, corrosive. The amines are an analogous series of compounds and follow the naming pattern of the alkyl halides and the alcohols that is, the simplest amine is methyl amine, with the molecular formula of CH NHj. Methyl amine is a colorless gas with an ammonia-like odor and an ignition temperature of 806°F. It is a tissue irritant and toxic, and it is used as an intermediate in the manufacture of many chemicals. Ethyl amine is next in the series, followed by propyl amine, isopropyl amine, butyl amine and its isomers, and so on. 

Various sources of fluoride ion have been investigated, of which highly nucleophilic tetraalkylammonium fluorides ate the most effective Thuf, fluoro alkyl halides and N (fluoroalkyl)amines are efficiently synthesized by treatment of the corresponding trifluoromethanesulfonic esters with tetrabutylammonium fluoride trihydrate in aprotic solvents [5fl] (equation 34) The displacement reactions proceed quantitatively at room temperature within seconds, but tail with hydrogen fluoride-pyridine and give reasonable yields only with hydrogen fluo ride-alkylamine reagents... 

The formation of bicyclic imines (263,264) from piperidine enamines and y-bromopropyl amines may appear at first sight to be a simple extension of the reactions of enamines with alkyl halides. However, evidence has been found that the products are formed by an initial enamine exchange, followed by an intramolecular enamine alkylation. Thus y-bromodiethylamino-propane does not react with piperidinocyclohexene under conditions suitable for the corresponding primary amine. Furthermore, the enamine of cyclopentanone, but not that of cyclohexanone, requires a secondary rather than primary y-bromopropylamine, presumably because of the less favorable imine to enamine conversion in this instance. 

Amines can be prepared by means of Sn2 reactions involving alkyl halides and nitrogen nucleophiles. 

In 1974, Hegedus and coworkers reported the pa]ladium(II)-promoted addition of secondary amines to a-olefins by analogy to the Wacker oxidation of terminal olefins and the platinum(II) promoted variant described earlier. This transformation provided an early example of (formally) alkene hydroamination and a remarkably direct route to tertiary amines without the usual problems associated with the use of alkyl halide electrophiles. 

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