Benzylamine, reactions amides

Reaction with amides. Benzamides and thiobenzamides are converted to a,a-disubstituted benzylamines. Tertiary amides form ketones on reaction with RCeCl even when the reagent is present in large excess, therefore Weinreb amides are not necessary for the ketone synthesis. Enaminones are also attacked at the carbonyl group, and in the cases of a -silylated derivatives the reaction products are 3,y-unsaturated ketones. ... 

The ureas, e.g. 28 (R = NMe2), derived from the corresponding 2-(l-arylviny )benzylamines by reaction with (dimethylamino)carbamoyl chloride (Me2NCOCl) in the presence of triethyl-amine, undergo cyclization in refluxing phosphoryl chloride to the 5-aryl-3-(dimethylamino)-l//-2-benzazepin-3-amines. e.g. 29a.84 Prepared similarly are the 3-(4-methylpiperazin-l-yl) compound 29b and the 3-methyl derivative 29c from the corresponding urea and amide, respectively. 

Madsen and co-workers have reported an important extension to the amine alkylation chemistry, in which oxidation takes place to give the amide product [13]. A ruthenium NHC complex is formed in situ by the reaction of [RuCl Ccod)] with a phosphine and an imidazolium salt in the presence of base. Rather than returning the borrowed hydrogen, the catalyst expels two equivalents of H. For example, alcohol 31 and benzylamine 27 undergo an oxidative coupling to give amide 32 in good isolated yield (Scheme 11.7). 

The acylation of benzylamine with 4-chlorobenzoyl chloride served as a model reaction to evaluate the efficacy of both of these resins. After removal of both protons and amines the corresponding amide was obtained in 77% yield contaminated with less than 1% benzylamine and acid chloride. The transformation was also performed with commercially available scavenger resins PS-NCO and/or PS-NMM to obtain comparable results, but only approximately half the mass and volume of dendronized resin was required to achieve similar scavenging efficiency. 

The proposed mechanism of the boron-catalyzed amidation is depicted in the Figure. It has been ascertained by H NMR analysis that monoacyloxyboronic add 1 is produced by heating the 2 1 mixture of 4-phenylbutyric add and [3,5-bis(trifluoromethyl)phenyl]boronic acid in toluene under reflux with removal of water. The corresponding diacyloxyboron derivative is not observed at all. When 1 equiv of benzylamine is added to a solution of 1 in toluene, the amidation proceeds even at room temperature, but the reaction stops before 50% conversion because of hydrolysis of 1. These experimental results suggest that the rate-determining step is the generation of 1. 

The ratio of the enantiomeric benzyl amide products was determined by analyzing a diluted aliquot of the quenched reaction mixture by HPLC using a chiral stationary phase column (Chiralcel OD, Daicel Chemical Co.). Since racemization is a pseudo-first-order kinetic process, these data (along with the time zero value) are sufficient for determination of the intrinsic rate of racemization kR. The half-life for racemization lRU2 can be directly calculated from the l/d ratio (or % enantiomeric excess, %ee) where t was the time of benzylamine addition (the delay time) ... 

An example of the use of DMF as CO source in the Pd-catalyzed aminocarbonylation with microwave irradiation is shown in Scheme 28. Thus, n-bromotoluene was reacted with benzylamine (4 equiv.) in the presence of Pd-dppf catalyst, imidazole, KOBu, and DMF (17equiv.) with microwave irradiation for 20min to give amide 196 in 94% yield (Scheme 28). A proposed mechanism (Scheme 28) has a close similarity to that of the aminocarbonylation of aryl bromide with formamide (see Scheme 22). However, in this process, a large excess (4 equiv.) of benzylamine was used to suppress a possible reaction involving dimethylamine generated in situ from DMF under reaction conditions. 

A quinazolodione provides the nucleus for yet another eompound that inhibits aldose reductase. The sequence for the preparation of this agent starts with the isatoate acid (90-1) from 4-chloroantharanilic acid. Heating the compound with the substituted benzylamine (90-2) results in the formation of the ring-opened amide (90-3) with a loss of carbon dioxide. The ring is then reclosed, this time by reaction with carbonyl diimidazole, to afford the quinolodione (90-4). The anion from the reaction of this last intermediate with sodium hydride is then alkylated with ethyl bromoacetate. Saponification of the ester completes the preparation of zenarestat (90-5) [100]. 

The combinatorial reactions chosen for the novel amines were amide bond formation and sulfonamide formation. The novel carboxylic acids were derivatized to simple amides. For the amine reactions, we chose two simple carboxylic acids (propionic acid and benzoic acid) and two simple sulfonyl chlorides (methyl-sulfonyl chloride and benzenesulfonyl chloride) as the capping groups. Propyl amine and benzylamine were chosen as the capping groups to react with the novel carboxylic acids. Because only one reactant will be variable, these combinatorial libraries were essentially 1 x N libraries, where the one reactant was a simple reactant and the N component is the novel amines or acids. 

Formation of an amide is also indicated in the reaction of PCTFE with Cr(CO)6 and the primary amine, benzylamine. The infrared absorption spectrum shows an N-H stretch centered at 3400 cm, aromatic C-H stretches at 3063 and 3030 cm1, aliphatic C-H stretches at 2933 and 2876 cm1, a broad amide I/amide II band ranging from 1680-1580 cm1, and a C-N stretch at 1454 cm1. The C-Cl stretch at 970 cm1 also shows a significant decrease in... 

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). 

Aldehydes are still used to prepare diuretics (82USP4338435) and antihypertensives (87USP4634689), e.g., when 106 is heated with 6-bromohexanal, thiadiazine 107 (X = Br) results. Substituted sulfonamide 106 can apparently be made from the corresponding disulfonyl chloride by sequential amidation with methylamine and then benzylamine. The presence of the bromine moiety in 107 allows 107 [X = PO-(OH)CH2COOH] to be made by reaction with diethyl carboethoxy-methylphosphonite [(EtO)2PCH2COOEt] and subsequent saponification of the phosphinate and acetate groups. Hence, condensation in trifluo-... 

The 2-benzazepin-3-ones 259 have been made in moderate yields by sequential intramolecular acid-catalyzed addition followed by thiol elimination from the precursor phenylsulfanylacrylamides 258 (Scheme 33). The acrylamides 258 were prepared from reaction of the benzylamines 255 with the PNB-ester 256 to give the amides 257, and then N-methylation with Mel in the presence of potassium hydroxide and tetraethylammonium bromide, as a phase-transfer catalyst. Other noncyclized products were also observed depending on the structure of the A-aryl methyl group in 258 and on the nature of the solvent <2002H(57)1063>. 

Reactions between a representative range of alkyl- and aryl-amines and of aliphatic and aromatic acids showed that the direct formation of amides from primary amines and carboxylic acids without catalyst occurs under relatively low-temperature conditions (Scheme 1). The best result obtained was a 60% yield of N-bcnzyl-4-phenylbutan-amide from benzylamine and 4-phenylbutanoic acid. For all these reactions, an anhydride intermediate was proposed. Boric and boronic acid-based catalysts improved the reaction, especially for the less reactive aromatic acids, and initial results indicated that bifunctional catalysts showed even greater potential. Again, anhydride intermediates were proposed, in these cases mixed anhydrides of carboxylic acids and arylboronic acids, e.g. (I).1... 

Another interesting convertible isocyanide, 2-(t-butyldimethylsilyloxymethyl)-phenyl isocyanide 21 was used by Linderman and co-workers [10] in a reaction with formic acid, benzylamine, and benzaldehyde to afford the Ugi adduct 22, which, upon acid treatment followed by basification, underwent O-desilylation and amide/ester exchange to afford the ester 23 (Scheme 2.8). A remarkable feature of 21 is the high diastereoselectivity observed when it is employed in combination with chiral aminosugar derivatives in Ugi-4CR [10]. 

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