Amines benzyl halides

In contrast, A, JV-diethyl-3-(methylsulfanyl)-5-phenyl-3//-azepin-2-amine (22) on treatment with methyl or benzyl halides and potassium amide in liquid ammonia undergoes alkylation solely at the masked benzylic 5-position to yield 4,4-disubstituted 4//-azepines, e.g. 23.224... 

Poly (ethylene oxide) macromonomers72 761 are made in a similar way, as the alkoxide end group is reactive enough towards benzylic halides. With methacryloyl chloride, side reactions are involved. It is better to first protonate the PEO, and then to have it react with methacryloyl chloride in the presence of some triethyl amine. One can also react co-hydroxy polyethylene oxide) with methacryloyl imidazole, or with methacrylic acid in the presence of dicyclohexyl carbodiimide (DCCf)77). 

Primary amines can be prepared from alkyl halides by the use of hexamethylenetetramine followed by cleavage of the resulting salt with ethanolic HCl. The method, called the Delepine reaction, is most successful for active halides such as allylic and benzylic halides and a-halo ketones, and for primary... 

Williams and coworkers used a [G4]-PAMAM dendrimer as a scavenger in the reactions of an arylpiperazine with slight excesses of three different electrophiles (an isocyanate, a sulfonyl chloride, and a benzyl halide) [62]. After TLC had indicated that all amine substrate had reacted the dendritic scavenger was added. Solvent removal, adding of chloroform, and filtration of the unsoluble dendrimer afforded the products in high yields (87-99%) and purities (>95%, HPLC). 

Some substituted guanidines have been obtained [457] by reaction of amines with the disulphide H2N(HN )C S S C( NH)NH2. Papers on the structure and p/fa s [458], and the synthesis [458, 459] of acylguanidines have been published. Reaction of guanidine with alkyl-, alkenyl-, and benzyl-halides, followed by distillation under basic conditions, is reported to give useful yields of amines [460]. A novel electrophilic substitution of benzene to give A -methyl-A -phenyl-guanidine amongst other products has been published [461 ]. 

Tertiary benzylic nitriles are useful synthetic intermediates, and have been used for the preparation of amidines, lactones, primary amines, pyridines, aldehydes, carboxylic acids, and esters. The general synthetic pathway to this class of compounds relies on the displacement of an activated benzylic alcohol or benzylic halide with a cyanide source followed by double alkylation under basic conditions. For instance, 2-(2-methoxyphenyl)-2-methylpropionitrile has been prepared by methylation of (2-methoxyphenyl)acetonitrile using sodium amide and iodomethane. In the course of the preparation of a drug candidate, the submitters discovered that the nucleophilic aromatic substitution of aryl fluorides with the anion of a secondary nitrile is an effective method for the preparation of these compounds. The reaction was studied using isobutyronitrile and 2-fluoroanisole. The submitters first showed that KHMDS was the superior base for the process when carried out in either THF or toluene (Table I). For example, they found that the preparation of 2-(2-methoxyphenyl)-2-methylpropionitrile could be accomplished h... 

Another way to oxidize primary alkyl halides to aldehydes is by the use of hexamethylenetetramine followed by water. However, this reaction, called the Sommelet reaction. is limited to benzylic halides. The reaction is seldom useful when the R in RCH2CI is alkyl. The first part of the reaction is conversion to the amine ArCH2NH2 (0-44), which can be isolated. Reaction of the amine with excess hexamethylenetetramine gives the aldehyde. It is this last step that is the actual Sommelet reaction, though the entire process can be conducted without isolation of intermediates. Once the amine is formed, it is converted to an imine (ArCH2N=CH2) with formaldehyde liberated from the reagent. The key step then follows transfer of hydrogen from another mole of the arylamine to the imine ... 

As illustrated by the examples in Table 3.9, resin-bound 4-alkoxybenzylamides often require higher concentrations of TFA and longer reaction times than carboxylic acids esterified to Wang resin. For this reason, the more acid-sensitive di- or (trialkoxy-benzyl)amines [208] are generally preferred as backbone amide linkers. The required resin-bound, secondary benzylamines can readily be prepared by reductive amination of resin-bound benzaldehydes (Section 10.1.4 and Figure 3.17 [209]) or by A-alkyla-tion of primary amines with resin-bound benzyl halides or sulfonates (Section 10.1.1.1). Sufficiently acidic amides can also be A-alkylated by resin-bound benzyl alcohols under Mitsunobu conditions (see, e.g., [210] attachment to Sasrin of Fmoc cycloserine, an O-alkyl hydroxamic acid). 

Aliphatic primary and secondary amines can be linked to insoluble supports as ben-zylamines by reductive alkylation with support-bound benzaldehydes or by N-alkyla-tion with support-bound benzyl halides or sulfonates (Figure 3.25 see also Section 10.1). Benzhydrylamines and tritylamines are usually prepared by N-alkylation with the corresponding halides. 

The only drawback of strategies for the synthesis of tertiary amines that are based on the quaternization of polystyrene-bound /V-nucleophiles is that quaternizations on polystyrene only proceed sluggishly and generally require the use of highly reactive alkylating agents (methyl, allyl, or benzyl halides or sulfonates see Section 10.2). 

Illustrative examples of cleavage reactions of /V-arylbenzylaminc derivatives are listed in Table 3.25. Aromatic amines can be immobilized as /V-bcnzylanilincs by reductive amination of resin-bound aldehydes or by nucleophilic substitution of resin-bound benzyl halides (Chapter 10). The attachment of the amino group of 5-aminoin-doles to 2-chlorotrityl chloride resin has been reported [486]. Anilines have also been linked to resin-bound dihydropyran as aminals [487]. 

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 one-pot PTC reaction procedure for the overall conversion of an alkyl halide into a primary amine via an azide is particularly illustrative.204 Thus the reduction of the azide is effected by the addition of sodium borohydride to a reaction mixture arising from the PTC displacement reaction of an alkyl halide with sodium azide (the preparation of 1-octylamine, Expt 5.193). The reaction appears to be applicable to primary and secondary alkyl halides, alkyl methane-sulphonates and benzylic halides. 

This process leads to products identical to those obtained through nucleophilic amination of a-silyl benzyl halides (See Section III.A.3), but this method of synthesis is less satisfactory as far as convenience and yields are concerned (See Section III.B.4). 

The synthesis of N-alkylated dihydropteridinones 34 started with a displacement reaction of 4,6-dichloro-5-nitropyrimidine with a fluorous amino-ester (Scheme 23) [53]. The compounds formed 35 were then reacted with secondary amines to yield 36. The reduction of the nitro group of 36 was conducted by hydrogenation using Pd on charcoal as a catalyst. The cyclization reactions of 37 were promoted by microwave irradiation. The N-alkylation reaction of the cyclized products 38 with benzyl halides gave monobenzylated... 

In general, the excited radicals shown have been found to possess enhanced donor/acceptor properties, especially in interactions with such quenchers as oxygen, dienes, amines, and halides. To date, the most well-characterized intermolecular processes are charge (electron) transfer reactions between excited diphenyl-methyl radicals and electron donors and acceptors. Thus, excited 132 reacts with methyl benzoates and benzyl bromides (Schemes 23 and 24) with rates that increase with the increasing electron withdrawing ability of substituents on the... 

Alkylation of amines and amides with benzylic halides is an early and useful method for the protection of amines and amides. Primary amines can alkylate twice to give the W,N-dibenzyl derivative, but severe steric congestion prevents quatemisation [Scheme 8.199].410... 

The interaction of alkyl halides, preferably iodides or bromides, with hexamine in chloroform or alcohol solution forms quaternary ammonium salts which on heating with hydrochloric acid are readily converted to primary amines. The procedure has been employed successfully in the reaction of primary, but not secondary or tertiary, aliphatic halides, certain benzyl halides, halo ketones, halo acids, and halo esters. The yields range from 40% to 85%. 

Benzylic halides have also been reduced to hydrocarbons by hydrogenolysis over Raney nickel (equation 31). Benzylic amines have been cleaved by hydrogenolysis over Raney nickel (equation 32) or by treatment of a methiodide salt with basic Raney nickel (equation 33). ... 

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