Alkylation of an amine

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. 

TiCl4 also effectively promotes formation of imines and enamines from carbonyl compounds (Scheme 31). The combination of imine formation using TiCl4 and reduction leads to reductive alkylation of an amine moiety.113,114... 

The fifth method involves the simultaneous formation of the N1-C2 and Nj-Cg bonds, thus enabling the facile introduction of Ni-substituents by the use of primary amines as reactants. An example of this approach is the tandem acylation-alkylation of an amine with a suitable halo-ester (see Figure 1 for numbering sequence). 

The synthesis of an N-alkylarylamine by the reductive alkylation of an aromatic primary amine with a ketone is used in the preparation of antioxidants for polymers and rubber. The alkylation of an amine with a ketone is typically carried out in the liquid phase using heterogeneous catalysts such as Pd, Pt, Rh, or Ru supported on carbon (1,2). The reaction of ADPA with MIBK yields an imine, which then is hydrogenated over a Pt or sulfur promoted-Pt catalyst to yield 6-PPD. 

Merrifield resin [33-37] and other support-bound benzyl halides [38] have also been used to alkylate amines (Entries 5-10, Table 10.2). Similarly, resin-bound allyl bromides react cleanly with aliphatic or aromatic amines (Entry 16, Table 10.2). Entry 15 in Table 10.2 is a rare example of the N-alkylation of an amine under the conditions... 

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 ex-... 

B is correct. This is a simple alkylation of an amine. You should have this reaction memorized. Even if you don t, only B and D are possibilities for a base. Ethyl-methylamine is not an acid. 

The simple alkylation of an amine with an alkyl halide can occasionally be used if the product is less nucleophilic than the starting material. This may be for electronic reasons glycine 6 can be made by alkylation of ammonia with 5 as it exists mostly as the zwitterion 7 which no longer has a nucleophilic nitrogen. It may be for steric reasons the alkylation of the a-bromoketone 8, mentioned at the end of chapter 7, with the sterically hindered amine 9 gives a good yield of the even more sterically hindered amine 10 and no quaternary salt is formed. If the reaction is a cyclisation (chapter 7) it may also work well. 

The synthesis of the cation is typically performed by alkylation of an amine, phosphine or sulfide, most commonly using an alkyl halide [ ]. In most cases the reaction is carried out with chloro-, bromo- and iodoalkanes as readily available alkylating reagents, with the reaction conditions becoming more gentle changing from chloride to bromide to iodide, as can be expected for nucleophilic substitution... 

This tertiary amine (R2NR ) is a strong base but it is so hindered that it cannot be alkylated. In the alkylation of an amine it serves as a proton acceptor which cannot combine with the alkyl halide. It is useful also for the capture of acid in a dehydrohalogenation. 

Formic acid appears to be the reducing agent in the alkylation of an amine with formic acid and formaldehyde see Formaldehyde, methylation). 

Alkylation of an amine or amide usually produces a sweet tasting substance... 

Reductive Alkylation Alkylation of an amine with a ketone in the presence of hydrogen to give a secondary amine and water. 

A related though simpler compound from Bristol-Meyers Squibb 216 is their anti-psychotic agent BMS 181100. It has two p-fluorophenyl groups joined through a C4-piperazine linker containing a chiral secondary alcohol. The compound is easily made58 by alkylation of an amine with the primary chloride 217. There are two opportunities from enzymatic resolution. 

This reaction (alkylation of an amine with an alkyl halide) can occasionally be used if the product is less reactive than the starting material for electronic (e.g. 5) or steric (e.g. 6) reasons, or if it is intramolecular. This second example... 

Reductive alkylation. Alkylation of an amine simply involves treatment with an aldehyde in the presence of trimethyl orthoformate as a dehydrant and in situ reduction. An analogous method applying to a-amino esters with glyoxal results in optically active -disubstituted piperazines, and a convergent reductive amination of a ketodialdehyde to form an indolizidine skeleton in 53% yield makes possible a concise synthesis of castanospermine from a-D-glucopyranoside. ... 

Oxidative additions of alkyl halides and pseudohalides can occur by an S 2 mechanism in which the metal acts as a nucleophile (Equation 7.1). The first step of this reaction is analogous to the alkylation of an amine. The data in support of an S 2 mechanism for... 

The related Clarke-Eschweiler reaction in whidi the reductive alkylation of an amine is carried out with formaldehyde and formic acid was used to prepare 3-dimethylamino-l-phenyl-1-(2-pyridyl)ptopane (IX-2S8) from 3-phenyl-3-(2-pyridyl)propylamine (IX-257). ... 

Purpose To demonstrate the reduotive alkylation of an amine by the sequence of forming and reduoing an imine and to evaluate the selectivity of a hydride reducing agent. 

Scheme 1-1. Template Sn2 alkylation of an amine by an alkyl halide.

Sn2 examples. A. Williamson ether. synthesis, B. Alkylation of an amine, and C. Alkylation of an enolate. 

A different cytokine, IFN-j0 is approved for the treatment of multiple sclerosis in the United States, but like other cytokines, it suffers from a short blood residence, again suggesting PEGylation as a solution. An exhaustive study conducted by Pepinsky et al. [55] resulted in a PEG modification of interferon-j5-la that exploited a reductive alkylation of an amine residue... 

Lourenq o et aL [144] performed for the first time the Al-alkylation of an amine-functionalized benzene-based crystal-like PMO. The amine fimctionalization was achieved with about 87% of conversion, under microwave irradiation, using a potassium iodide-catalyzed method commonly used for the selective Al-monoalky-lation of aniline. 

Jonathan M. J. Williams of the University of Bath developed (J. Am. Chem. Soc. 2009, 131, 1766 Tetrahedron Lett. 2009, 50, 3374) a Ru-catalyzed protocol for the alkylation of an amine 11 with an alcohol 10. The reaction proceeded by oxidation of the alcohol to the aldehyde, imine formation, and reduction using the hydride generated by the initial oxidation. Jose Luis Garcia Ruano of the Universidad Autonoma de Madrid uncovered Chem. Commun. 2009, 404) a similar conversion mediated by Raney Ni. 

Memorization Task 27.1 Direct alkylation of an amine is not synthetically useful. 

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. 

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