Benzylamine derivatives, preparation

Chiral polymer-supported thiiranes 401 were prepared by free radical copolymerization of TMA ((3)-thiiranylmethyl-methacrylate) and ethylene glycol dimethacrylate (EDMA) (Equation 60) <2006TA1944>. These chiral thiiranes were transformed into polymer-supported aminothiols by the facile ring opening of the thiirane group with benzylamine and methylamine. These derivatives, complexed with [RuCl2(p-cymene)]2, were used in assymmetric reduction of acetophenone to gave (A)-l-phenylethanol (39% ee from methylamine and 50% ee from benzylamine derivatives). 

The Bobbitt modified Pomeranz-Fritsch reaction allows the preparation of enantiopure tetrahydroisoquinolines. During the studies directed toward the total synthesis of ET 743 and its analogues, S.J. Danishefsky and co-workers utiiized this transformation for the preparation of a key tetrahydroisoquinoline intermediate. The cyclization precursor was efficiently synthesized from the enantiopure benzylamine derivative by A/-alkylation with excess diethylbromoacetal. The resulting compound was subjected to QN hydrochloric acid at 0 °C and slowly warmed to ambient temperature overnight. The desired tetrahydroisoquinoline was formed as a 4 1 mixture of diastereomers. 

Synephrine, the N-methylated analog of OA, completely blocked uptake at this concentration. The two imidazolines, naphazoline and XAMI, were somewhat effective as uptake blockers (20-30% inhibition), comparable to DCDM and DDCDM. The tricyclic antidepressant desipramine, a known amine uptake blocker in vertebrates, showed good potency in the cockroach system, as originally described by Evans (21). Finally, the N-chloroethyl benzylamine derivative, xylamine, has been described as a potent, specific and irreversible inhibitor of norepinephrine uptake in mammals (25). It was an active inhibitor of uptake in the cockroach preparation. 

An active carbonate resin 2a has also been prepared from Wang resin and used to anchor a multifunctional benzylamine derivative for a combinatorial application. Final products were cleaved using TFA-CH2CI2 (1 1)... 

V-Boc allylic amines are readily obtained by CuCN-mediated coupling of enol triflates with the a-lithiated carbamates. This method offers regio- and stereocontrol with respect to the double bond. However, it cannot be extended to the preparation of benzylamine derivatives. 

Synthesis of repaglinide involves condensation of an appropriately substituted and chi-rally pure benzylamine derivative with an appropriately substituted phenylacetic acid derivative (7) followed by saponification. The reported process for the key intermediate (7) described a five-step process with an overall yield of about 30% of theory (Scheme 23.4) We undertook development of an alternative synthetic strategy to prepare 7 and developed an efficient and commercially feasible synthesis starting from 2-hydroxy-4-methylbenzoic acid (9) in two steps. Thus, 9 was first alkylated with ethyl bromide in a polar aprotic solvent and in the presence of an inorganic base to afford ethyl 2-ethoxy-4-methylbenzoate... 

The group of Gong and coworkers explored a biomimetic 1,3-dipolar cycloaddition between a-ketoester 79 and benzylamine derivatives 80 with electron-deficient olefins 81a,b to devise a straightforward route to proline derivatives 82 in high yields and enantioselectivities [49]. The proposed biomimetic three-component 1,3-dipolar cycloaddition proceeds as illustrated in Scheme 2.22a. The azomethine ylide B is formed, via a transamination from ketimine ester A, which is in turn prepared from a-ketoesters 79 and benzyl-amine derivatives 80 then, the 1,3-dipolar cycloaddition with electron-poor olefins 81a takes place. For this purpose, the bisphosphoric acid 83 was found to be the catalyst of choice to promote such transformation (Scheme 2.22b). Replacing dimethyl maleate (previously used as deficient olefins) by methyleneindolinones, the same approach could be extended to spirooxindoles synthesis in high yields and... 

Scheme11.20 Preparation of optically active benzylamine derivatives via OAB-induced reduction of oxime ethers.

Dihydroquinazolines are stable and a large number have been prepared. They have been synthesized by reductive cyclization of acyl derivatives of o-nitrobenzylamines, and by acylation of o-amino-benzylamines followed by ring closure. The ring closure can be effected by heating with anhydrous zinc chloride ° or by distillation. ... 

Amino-3-alkyl derivatives of474 have been prepared and found to undergo facile nucleophilic 5-substitution with methanolic hydrazine (65°, 4 hr, 75% yield), hydroxide ion (20°, 3 hr, 75% yield), or pro-panolic benzylamine (100°, 5 hr, 80% yield). The first two reactions may proceed by a ring-opening and reclosure sequence. ... 

The procedure described is a modification of the general procedure of Angyal2 for the preparation of aldehydes from benzylamines by the Sommelet reaction. Isophthalaldehyde has been prepared from w-xylene by preparation of the tetrachloro derivative and hydrolysis,3 from isophthaloyl chloride by the Rosenmund reaction,4 from a,a -dibromo-m-xylene by the Sommelet reaction,5 and from isophthaloyl chloride by reduction with lithium tri-Cbutoxyaluminumhydride.6... 

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. 

B. Polymeric Urea [Benzene, diethenyl-, polymer with ethenylbenzene, [[[[(1 methylethyl)amino]carbonyt]amino]methyl] deriv.] A 10.0-g. portion of benzylamine polymer beads prepared as in Part A and 125 ml. of tetrahydrofuran (Note 6) are combined in a 300-ml., three-necked, round-bottomed flask equipped with a magnetic stirrer, a dropping funnel, and a condenser fitted with a gas-inlet tube A nitrogen atmosphere is established in the system, and the slurry is stirred while 1.35 g. (0.0159 mole) of isopropyl isocyanate [Propane, 2-isocyanato-] is added. This causes an exothermic reaction, which subsides after about 20 minutes. The mixture is then stirred at room temperature for 22 hours and at reflux for an additional 4 hours. The beads are collected by filtration, washed with 150-ml. portions of tetrahydrofuran (Note 6) and methanol, and dried under reduced pressure over calcium chloride to yield 9.09 g, of the isopropyl urea polymer. 

Other SC- and BSC-PEG derivatives were prepared using the same general protocol. The active carbonate contents of the products were determined according to Kalir et al. (77) by reacting aliquots of the polymers with an excess of benzylamine and back titration of the latter with perchloric acid in dioxane using thymol blue as an indicator. The results of these determinations are summarized in Table I. 

In a more recent study, Westman and Lundin have described solid-phase syntheses of aminopropenones and aminopropenoates en route to heterocycles [32], Two different three-step methods for the preparation of these heterocycles were developed. The first method involved the formation of the respective ester from N-pro-tected glycine derivatives and Merrifield resin (Scheme 7.12 a), while the second method involved the use of aqueous methylamine solution for functionalization of the solid support (Scheme 7.12 b). The desired heterocycles were obtained by treatment of the generated polymer-bound benzylamine with the requisite acetophenones under similar conditions to those shown in Scheme 7.12 a, utilizing 5 equivalents of N,N-dimethylformamide diethyl acetal (DMFDEA) as reagent. The final... 

The derivative 90 was obtained by condensation of the purpurin-18-A-hexylimide-17-propionic acid with aminolactose heptaacetate in the presence of benzotriazol-l-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP) followed by the deacetylation procedure. The lactose-photosensitiser conjugate linked by an ethylene moiety was also prepared by following a similar approach. The purpurin-18-methyl ester 81 was converted into /V-(3-iodobenzyl)/ /evo-purpurin-18-7V-hexylimide-17-propionic ester by hydrogenation over Pd/C followed by reaction with 3-iodo-benzylamine. Afterwards, the propargyllactose heptaacetate reacted with A-(3-iodobenzyl)rMeio-purpurin-18-A-hexylimide-l 7-propionic ester in the presence of tris(dibenzylidieneacetone)dipalladium(0) (Pd2-dba3) which, after deacetylation conditions, afforded the derivative 89 (Fig. 9).68... 

Several 2-amino-2-deoxy-D-gulononitrile derivatives (68) have been obtained by treating D-xylose with hydrogen cyanide and an amine. Among the amines that were used in preparing these derivatives were aniline,107-109 9-aminofluorene,110 p-methylphenylamine,109 and benzylamine.109 In all cases, as expected, both the D- and L-gly-cero configurations at C-2 are formed. When a solution of 68 (R = Ph)... 

Derivatives of the 2,5-diazabicyclo[2.2.1]heptaine ring system (bridged piperazines) have been prepared from 4-hydroxyprolines. In a multistep transformation from tra j-4-hydroxy-L-proline (the last step was cyclization with benzylamine) a mixture of diastereoisomers 71 was obtained and separated [92H(34)241]. In a similar manner, the methyl and oxo analogs were obtained [67AJC1493 92H(34)679]. The commercially available N-... 

These amino alcohols can be prepared by disubstitution of the benzylamine with a suitable halogenated or sulfonated derivative of the alcohol, followed by debenzylation (hydrogenolysis) using H2. 

Substitution of hydrogen with phenyl, as in trifluoro-substituted acetophenone derivative 14h, enhances the rate of Lhe isomerization reaction. In fact, small amounts of 15h have been formed in the preparation of 14h, presumably catalyzed by benzylamine.14 Use of the stronger base l,8-diazabicyclo[5.4.0]undec-7-ene (DBU) accelerates the isomerization and is a very effective catalyst for the tautomerization reaction in the ketimine series.13... 

The 1,3-proton shift reaction has also been applied to the synthesis of a-(perfluoroalkyl)-a-amino acids, specifically 3.3,3-trifluoroalanine.2 -26 Attempts to prepare the A-benzylimine of ethyl 3,3.3-trifluoro-2-oxopropanoate by direct condensation with benzylamine were very difficult due to the exceptionally high stability of the intermediate a-amino alcohol, which fails to dehydrate. By contrast, 1-phenylethanamine reacted with ethyl 3,3,3-trifluoro-2-oxo-propanoate to form ketimine 33 in 83 % yield.26 The 1,3-proton shift reaction of 33 is much faster than those of ketimines derived from perfluoroalkyl ketones or perfluoroaldehydes (see Table 5). Complete conversion in triethylamine required 6 hours at room temperature and afforded the isomeric Shiff base 34 in 92 % yield. Mild hydrolysis of Shifif base 34 gives a-amino ester 35, which in turn hydrolyzes to 3,3,3-trjfluoroalanine hydrochloride (36). 

While sluggish under thermal conditions,274-275 the asymmetric conjugate addition of amines to alkyl crotonates is achieved at room temperature under high pressure (15 kbar).276 Thus, benzylamine can be added to the crotonate derived from 8-p-naphthyl menthol, with virtually complete diastereoselectivity. A related intramolecular 1,4-addition of an amine to a chiral enoate was used in a total synthesis of the alkaloid (-)-tylophorine.277 Additions of amines to chiral iron complexes of type (116) proceed with excellent selectivity and allow the preparation of homochiral p-lactams.l27128,l3() l32 In contrast, the addition of amine nucleophiles to chiral vinylic sulfoxides278-2811 and to chiral vinylsulfoximines281 proceeds with comparably low selectivities. 

---