Benzylamines, synthesis

Benzylamine may be obtained by the Gabriel synthesis, which depends upon the use of potassium phthalimide. The latter upon heating with benzyl... 

Chapter IV. a-Chloromethylnaphthalene (IV,23) benzylamine (Gabriel synthesis) (IV,39) i r.N -dialkylanilines (from amines and trialkyl orthophosphates) (IV,42) a-naphthaldehyde (Sommelet reaction) (IV,120) a-phenyl-cinnamic acid (Perkin reaction using triethylamine) (IV,124) p-nitrostyrene (IV,129) p-bromonaphthalene and p naphthoic acid (from 2 naphthylamine-1 -sulphonic acid) (IV,62 and IV,164) diphenic acid (from phenanthrene) (IV,165). 

The Gabriel synthesis is based on work carried out by Siegmund Gabriel at the Uni versity of Berlin in the 1880s A detailed discussion of each step in the Gabriel synthesis of benzylamine can be found in the October 1975 Journal of Chemical Education (pp 670-671)... 

A variation involves the reaction of benzylamines with glyoxal hemiacetal (168). Cyclization of the intermediate (35) with sulfuric acid produces the same isoquinoline as that obtained from the Schiff base derived from an aromatic aldehyde and aminoacetal. This method has proved especially useful for the synthesis of 1-substituted isoquinolines. 

Benzylamine, o-chloro-N-(cyanomethyl)-N-methyl-isoindole synthesis from, 4, 323 Benzylisoquinoline alkaloids synthesis, 1, 446 Benzynes... 

Modification of the Erlenmeyer reaction has been developed using imines of the carbonyl compounds, obtained with aniline," benzylamine or n-butylamine. Ivanova has also shown that an A-methylketimine is an effective reagent in the Erlenmeyer azlactone synthesis. Quantitative yield of 19 is generated by treatment of 3 equivalents of 2-phenyl-5(4ff)-oxazolone (2) (freshly prepared in benzene) with 1 equivalent of iV-methyl-diphenylmethanimine (18) in benzene. Products resulting from aminolysis (20), alkali-catalyzed hydrolysis (21), and alcoholysis (22) were also described. 

Addition of amines to a,/J-unsaturated sulfones has been used in synthesis of key intermediates of biotin. In this reaction, benzylamine serves first as a base in the reaction with 60 to afford thiophene 1,1-dioxide (61) and also as a nucleophile to introduce two amino groups (equation 57)49. 

The synthesis of highly substituted rigid tricyclic nitrogen heterocycles via a tandem four-component condensation (the Ugi reaction)/intramolecular Diels-Alder reaction was investigated in both solution and solid phase [24]. The Ugi reaction in MeOH (Scheme 4.2) involves the condensation of furylaldehydes 17, benzylamine 18, benzyl isocyanide 19 and maleic or fumaric acid derivatives 20, and provides the triene 21 which immediately undergoes an intramolecular Diels-Alder reaction, affording the cycloadduct 22 in a diastereoisomeric mixture with high yield. 

The Strecker reaction has been performed on the aldehyde 182 prepared from L-cysteine [86] (Scheme 28). The imine was formed in situ by treatment with benzylamine, then TMS cyanide was added to afford prevalently in almost quantitative yield the syn-diamine 183, which is the precursor of (-l-)-biotin 184. The syn selectivity was largely affected by the solvent, toluene being the solvent of choice. Since the aldehyde 182 is chemically and configurationally unstable, a preferred protocol for the synthesis of 183 involved the prehminary formation of the water-soluble bisulfite adduct 185 and the subsequent treatment with sodium cyanide. Although in this case the syn selectivity was lower, both diastereomers could be transformed to (-l-)-biotin. 

Besides direct reduction, a one-pot reductive amination of aldehydes and ketones with a-picoline-borane in methanol, in water, and in neat conditions gives the corresponding amine products (Scheme 8.2).40 The synthesis of primary amines can be performed via the reductive amination of the corresponding carbonyl compounds with aqueous ammonia with soluble Rh-catalyst (Eq. 8.17).41 Up to an 86% yield and a 97% selectivity for benzylamines were obtained for the reaction of various benzaldehydes. The use of a bimetallic catalyst based on Rh/Ir is preferable for aliphatic aldehydes. 

The intramolecular photoelimination of HC1 from JV-chloroacetyl derivatives of suitable amines is a useful and versatile approach to the synthesis of azaheterocycles. The iV-chloroacetyl derivative 357 has been converted in this way to 7-oxodesethylcatharanthine (358) in 55% yield.300 Investigations in this area have been particularly concerned with the A-chloroacetyl derivatives of benzylamines and phenethylamines the N-chloroacetyl-benzylamine 359 on irradiation affords the two 3-oxo-l,2,3,4-tetrahydroiso-quinolines 360 and 361.301 Competing photocyclizations have been observed in the case of l-[3-(chloroacetylamino)propyl]-3-methylindole (362) which is converted into three photoproducts, 363, 364, and 365.302... 

The increasingly common theme of developing new pyrrole syntheses that involve cyclopropane fragmentations appeared in a type Ilae pyrrole synthesis <06OL835>. Treatment of doubly activated cyclopropane 43 with benzylamine in the presence of magnesium sulfate led to complex pyrrole 44 via a nucleophilic cleavage of the cyclopropane ring, intramolecular condensation, and isomerization of the exocyclic JC-bond. 

The synthesis of the previously undescribed 4,6,7,8-tetrahydropyrrolo[2,3-d]azepine ring system has been reported, based on pyrroles or azepinedione derivatives. For example, reaction of the azepinedione shown below with benzylamine in the presence of p-toluenesulfonic acid gave the fused derivative 26 <0OM104>. 

As second example for the scale-up of solid-phase reactions directly on solid support, we chose an arylsulfonamido-substituted hydroxamic acid derivative stemming from the matrix metalloproteinase inhibitor library (MMP) of our research colleagues (Breitenstein et al. 2001). In this case, there was already a solution-phase synthesis available for comparison (see Scheme 4). The synthesis starts with the inline formation of a benzaldehyde 18 with the glycine methyl ester, which is then reduced to the benzylamine 20 using sodium borohydride in methanol/ THF (2 1). The sulfonamide formation is carried out in dioxane/H20 (2 1) with triethylamine as the base and after neutralisation and evaporation the product 21 can be crystallised from tert. butylmethyl ether. After deprotection with LiOH, the acid is activated by treatment with oxalyl chloride and finally converted into the hyroxamic acid 23 in 33.7% yield overall. 

Similarly, ketimines (benzylimines of aromatic ketones) undergo the rhodium-catalyzed ortho-alkenylation with alkynes to give or/ o-alkenylated aromatic ketones after hydrolysis.61 This method is applied to an efficient one-pot synthesis of isoquinoline derivatives by using aromatic ketones, benzylamine, and alkynes under Rh catalysis (Equation (55)). 

A new pyrrole ring synthesis developed by Arcadi involves the addition of ammonia or benzylamine to 4-pentynones, the latter of which are conveniently prepared via a palladium oxidative coupling sequence as shown below for the synthesis of 40 [39,40]. 

Difficulties were encountered (125) in repeating the previously described synthesis of nojirimycin. Thus, when the lactone 51a was treated with benzylamine under a number of conditions, the only product isolated was, as... 

Thomson, C.G., Carlson, E., Chicchi, G.G., Kulagowski, J.J., Kurtz, M.M., Swain, C.J., Tsao, K.C. and Wheeldon, A. (2006) Synthesis and structure-activity relationships of 8-azabicyclo[3.2.1]octane benzylamine NKj antagonists. Bioorganic el Medicinal Chemistry Letters, 16,811-814. 

The variety of educts and products of the higher MCRs is illustrated here. Product 72 (Scheme 1.18) is formed from the five functional groups of lysine, benzaldehyde, and tert-butylisocyanide. The synthesis of 73 is achieved with hydrazine, furanaldehyde, malonic acid, and the isocyano methylester of acetic acid, compound 74 results from the reaction of benzylamine, 5-methyl-2-furanaldehyde, maleic acid mono-ethylester, and benzylisocyanide. ° Zhu et al. prepared a variety of related products, such as, 75, from (9-amino-methyl cinnamate, heptanal, and a-isocyano a-benzyl acetamides. 

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-... 

The synthesis and purification of C12BMG by the reaction of N-methyl-benzylamine with sodium chloroacetate followed by the quaternization of the resulting tertiary ammonioacetate with 1-bromododecane is described elsewhere (12). Purification of aqueous solutions of the surfactant for surface tension measurements and determination of the surface tension of the solutions by the Wilhelmy method using a sandblasted platinum blade were by techniques previously described (13). The concentration of C12BMG in aqueous solution was determined by measuring its absorbance at 263 nm (e = 350.5). 

Fujita and Yamaguchi et a. reported a new method for the N-heterocyclization of primary amines with diols catalyzed by the l/NaHC03 system, and its application to the asymmetric synthesis of (S)-2-phenylpiperidine [61], The representative results of the reaction of primary amines with diols are summarized in Table 5.11. As shown in entry 1, the reaction of benzylamine with 1,4-butanediol at 110°C for... 

In view of the ability of nitromethane to undergo a cyclizing bis-aminoalkylation when reacted with dialdehydes in the presence of amines 80,61) its application to other nitromethylene compounds seems an obvious extension. This reaction has already been verified when glutar-aldehyde is allowed to react with nitromethane and benzylamine in a 1 2 4 molar ratio in water, lr-methyl-l-nitro-2c,6c-bis-benzylamino-cyclohexane (110) is obtained in 56% yield 2) xhe same product is isolated in even higher yield (83%) on treatment of the nitroethane-glutaraldehyde cyclization product (6) with benzylamine However, further work is required to evaluate the preparative utility of this reaction principle for the synthesis of C-methyl branched triaminosugars. 

The Michael adducts of nitrogen nucleophiles are among the most important ones for organic synthesis (their synthetic applications will be discussed in the corresponding Sections). The addition of primary amines onto 1 and 2 in methanol was normally complete after a few minutes at - 10°C and gave moderate to good yields of the monoadducts 89 (for example, 67 % for n-butylamine and benzylamine adducts 89a-Me and 89b-fBu [261 ) But later it was found that performing these additions in THF leads to better and well reproducible yields of the adducts 89 (Scheme 25) [11b, 53,561. 

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