Benzylamine, basicity

Benzoylation, abnormal products 99 in analysis 99 Benzylamine, basicity 178 Biosynthesis—see individual compounds... 

Finally, with compounds of type 7, which have one chlorine atom and two ZR substituents, the reactions are, as expected, more frequently acid catalyzed than with compounds of type 6 e.g., the reaction with aniline in acetone is distinctly acid catalyzed. Again, reactions stiU occur, e.g., with benzylamine in tetrahydrofuran, in which autocatalysis is absent, possibly because of a combination of the marked basicity of the reagent and the low solubility of the acidic product. 

Thus, condensation of isoniazide with acetone at the basic nitrogen gives the corresponding Shiff base (8). Catalytic reduction affords the antidepressant, iproniazid (9). Addition of the same basic nitrogen to methyl acrylate by Michael condensation leads to the 3-amino ester (10). This is converted to the amide, nialamide (11), on heating with benzylamine. 

Poly(arylene ether ketone)s can also be modified by introducing the functional groups using similar approaches to polysulfones. For example, poly(arylene ether ketone)s were sulfonated.189 In addition, o-dibenzoylbenzene moieties in the poly(arylene ether)s can be transformed to heterocycles by cyclization with small molecules. These polymers can react with hydrazine monohydrate in the presence of a mild acid in chlorobenzene or with benzylamine in a basic medium.190 Another example of the use of the o-benzyl cyclization strategy is the intramolecular ring closure of poly(arylene ketone)s containing 2,2/-dibenzoylbiphenyl units to form poly(arylene ether phenanthrenes).191... 

For R = benzylamine (B) and R — cyclohexylamine (C) the amounts of BB and CC and of the BC cross product formed as the relative concentration of the reactants varies is shown in Figure 3. Clearly whilst for an approximately 50 50 reactant mixture the amount of CC formed has dropped to practically zero that of the cross product (BC) is still hi. The interpretation suggests that the less baisic atmine is more readily intercalated auid essentially remains urprotonated whilst the more basic amine, althou present in much smaller concentration, removes nearly all of the available protons. Hence the major reaction is between protonated B and non-protonated C, yielding BC (23,23). 

Another methodology for the construction of the terminal ring is given in Scheme 13. Thus, the reaction of 115 with chloroacetyl chloride in boiling toluene under basic conditions provided the diketone 116, the subsequent cyclocondensation of 116 with benzylamine furnished the cyclic trione 117 <1996JHC1737>. 

Synthesis of a C(8)-C(18) segment of the larger fragment of lb using the same basic strategy is depicted in Scheme 25. Here, hydroxy ketone 176 was subjected to syn-selective (dr of crude product=90 10) reductive amination [42] with sodium cyanoborohydride and benzylamine followed by tetrahydro-oxazine formation using aqueous formaldehyde. The resulting heterocycle 182 was then converted to unsaturated ester 184 by successive desilylation, oxidation, and entirely (Z)-selective Horner-Wadsworth-Emmons olefination. Re-... 

A kinetic smdy has been reported of substituent effects on the reactions of 2-phenoxy- and 2-(4-nitrophenoxy)-3-nitro-5-X-thiophenes with benzylamine and with A-methylbenzylamine in benzene as solvent. The intramolecularly hydrogen-bonded intermediate (14) is postulated. Reactions of the 5-unsubstimted thiophenes (X = H) are not base-catalysed, indicating that nucleophilic attack is rate limiting, and the more basic secondary amine shows higher reactivity than the primary... 

A structurally unusual 3-blocker that uses a second molecule of itself as the substituent on nitrogen is included here in spite of the ubiquity of this class of compounds. Exhaustive hydrogenation of the chromone (13-1) leads to a reduction of both the double bond and the carbonyl group, as in the case of (11-2). The car-boxyhc acid is then reduced to an aldehyde (13-2) by means of diisobutylaluminum hydride. Reaction of that intermediate with the ylide from trimethylsulfonium iodide gives the oxirane (13-3) via the addition-displacement process discussed earlier (see Chapters 3 and 8). Treatment of an excess of that epoxide with benzylamine leads to the addition of two equivalents of that compound with each basic nitrogen (13-4). The product is then debenzylated by catalytic reduction over palladium to afford nebivolol (13-5) [16]. The presence of four chiral centers in the product predicts the existence of 16 chiral pairs. 

Benzyl-2-phenylthiazolidin-4-one (41). A solution of benzylamine (0.2 ml, 0.2 mmol) in toluene (0.2 ml) was treated with a benzaldehyde (1.2 ml, 0.30 mmol) solution in toluene (1.2 ml), followed by the addition of a mecaptoacetic acid (49, 1.2 ml, 0.6 mmol) solution in toluene (1.2 ml) and molecular sieves (3 A). The reaction mixture was heated to 80° for 1.5 h. Then 2-aminoethanethiol resin (48, 0.3 g, 1.0 mmol) was added and the mixture was allowed to cool to RT overnight. The mixture was then treated with basic alumina (0.5 g) and shaken for 1 h. Additional toluene (5 ml) was added. Upon filtration and evaporation of the solvent, the product (47) was thus obtained. 

In recent work within our laboratories, we have evaluated a number of unbonded silicas by CEC specifically for the separation of a range of pharmaceutically relevant basic analytes and mixtures. We purposefully chose strong basic analytes that comprised a wide range of lipophilicities, molecular weights and log P values to robustly test the separation systems. The basic analyte test mixture contained two AstraZeneca R D compounds, benzylamine, nortriptyline, diphenhydramine and procainamide. 

Fig. 3.2. CEC separation of the basic test mixture using (A) Hypersil silica, (B) Hypersil BDS silica and (C) HyPURITY silica capillaries (100 pm i.d., 25 cm effective length, 33.5 cm total). Conditions 6 2 2 v/v/v ACN-H2O-5O mM TRIS, pH 7.8, 20 kV, 20°C, 5 kV/3 s injections, 210 nm. Injection mixtures in (A) and (C) were equivolume compositions of each base at 1 mg/ml and in (B), equivolume compositions of each base at 0.1 mg/ml. The EOF marked by biphenyl under these conditions and was similar on all phases at approximately 4 minutes. Peak identities I = AZ compound A, II = Benzylamine, III = Nortriptyline, IV = Diphenhydramine, V = AZ compound B and VI = Procainamide. Adaptation of [20]. Reproduced with the permission of Chromatographia.

Fig. 3.3. Separation of neutral, acidic and basic components in their ionised form with Hypersil unbonded BDS silica. Peak identities 1= Benzylamine, 11= Caffeine and 111= p-hydroxy benzoic acid. The arrow denotes the EOF. Conditions= 6 2 2 v/v/v ACN H2O 50 mM MES, pH 6.1, 20 kV, 20°C, 214 nm, 8 bar for 15 sec. inj. Adaptation of [20]. Reproduced with the permission of Chromatographia.

A purpose designed CEC stationary phase that gives excellent EOF character yet allows rapid simultaneous acidic, basic and neutral separations under isocratic conditions without tailing is yet to be discovered. Nevertheless, the Hypersil BDS unbonded silica used in this work was taken forward to explore such complex mixture separations as it combines features of both pure and traditional media. As a phase, it possesses a reasonable EOF (as it is based on traditional silica) with a lower number of activated silanol groups on the silica surface (due to the pre-treatment procedure used to remove surface metal contamination). Figure 3.3 shows the separation of benzylamine, caffeine and p-hydroxybenzoic acid in a single chromatographic analysis. 

Cyclization of A-aryl-iV-(2-hydroxybenzyl)-3-phenylpropynamide 528a-d in basic medium (LiCl and K2G03) under the influence of a catalytic amount of Pd(OAc)2 afforded the 5-(4-aryl)-2-phenyl-5,6-dihydrobenzo[A][l,5]ox-azocin-4-ones 412a-d (32-62%) (Scheme 107) <2003H(60)1793>. Treatment of 2-(2-bromobenzyloxy)-5-chloro-benzylamine 529 with BINAP and r-BuONa in presence of Pd(dba)2 provided the dibenzoxazocine 480 51% yield (Scheme 107) <2005W0084296>. 

Whereas ammonia is an unsuitable nucleophile towards 7r-allylpalladium complexes, primary amines often participate well. Benzylamine and 4,4 -dimethoxybenzhydrylamine are especially useful, since subsequent removal of the benzylic substituents permits their use as ammonia equivalents. Such a deblocking procedure was used in a short synthesis of the enzyme inhibitor gabaculine from amino ester 1118. An allyl carbonate can be successfully employed as a substrate for palladium(0)-catalyzed animation to give 1219,20, but experimental difficulties have been experienced with a structurally similar carbonate9. As shown by the formation of 1016 and by the partial production of 13 prior to basic hydrolysis16, additional attack on an ester function may occur. Amino alcohols 13, formed with complete regioselectivity due to steric reasons, have been efficiently converted into isoquinuclidines16. 

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