Benzaldehyde, condensation with amino acid

Although SiCh 57 has been employed, e.g., in the presence of sodium azide to convert ketones into tetrazoles (Section 5.3), to condense cyclopentanone in high yields into 1.2.3.4.5.6-tris(trimethylene)benzene (Section 9.2), or used for the condensation of amino acids to polyamides (Chapter 14) with formation of Si02, enol-trimethylsilyl ethers 107 a of ketones such as cyclohexanone are cleanly converted by SiCh 57 in the presence of Hg(OAc)2 into the trichlorosilylenol ether 116, which adds benzaldehyde in the presence of the asymmetric catalyst 117 to give... 

Tyr and Hypro, were separated on a capillary column coated with Carbowax 1540 at 102-165°C. On a preparative scale (gram amounts) the yields ranged from 50 to 98%. The application of pivalaldehyde to the preparation of the derivatives is illustrated by Scheme 5.13 (p. 109). Benzaldehyde reputedly reacts with amino acids under moderate conditions [162]. Mere mixing of the methyl esters of amino acids with a pyridine— benzaldehyde—methanol mixture (1 1 10) is reported to be sufficient for the formation of the derivatives. N-Benzylidene methyl esters of amino acids were analysed on SP-400 at 100-280°C. Pro and Hypro did not produce condensation products, however. 

Decarboxylative condensation of N-unsubstituted tx-amino acids with benzaldehyde as an aromatic aldehyde requires somewhat harsher conditions. Benzaldehyde and oc-amino acids are heated under reflux in DMF together with N-phenylmaleimide. The azomethine ylides 108 generated can be captured as mixtures of several stereoisomeric cycloadducts (84CC180). 1-Aminocyclopentane-l-carboxylic acid undergoes a similar reaction with pyridine-3-carbaldehyde in the presence of N-phenylmaleimide to afford a spirocyclic cycloadduct, the maleimide cycloadduct of azomethine ylide 109 (84CC182). 

An exhaustive series of reports by Grigg et al. (28) outlined two basic methods for the generation of azomethine ylides proceeding via either a 1,2-prototropic shift, or by a decarboxylative approach (29). The decarboxylative route to azomethine ylides can be exemplified by the condensation of benzaldehyde with the cyclic amino acid tetrahydroisoquinoline (108) (30), in DMF at 120 °C, to generate the intermediate awfi-dipole 109, which underwent subsequent cycloaddition with N-methyl maleimide to furnish a 1 1 endo/exo mixture of adducts 110 (R = Ph), in 82% yield (Scheme 3.30). 

Cyanogen bromide reacts with amino alcohols to give 2-aminooxazolines that condense in the presence of benzaldehyde and p-toluenesulfonic acid with loss of ammonia to give aza-bis(oxazolines) 173. Aza-bis(oxazohnes) such as 173 are emerging as a new and important class of chiral ligands for asymmetric processes with the added advantage that they can be immobilized on solid supports (Scheme 8.50). 

The condensation of amino sugars with /3-keto esters in an alkaline medium results in considerable degradation of the (tetrahydroxybu-tyl)pyrrole produced, giving rise to small yields of 2-methylpyr-role,57,58 which seems to be the main chromophore in the Elson-Morgan reaction. Under these conditions, 3-amino-3-deoxyhexoses yield 2-methylpyrrole-4-carboxylic acid,59 which is, in part, responsible for the coloration produced with p-(dimethylamino)benzaldehyde. 

The preparation of the first unsaturated azlactone was reported in 1883 by Plochl/40 who condensed benzaldehyde with hippuric acid in presence of acetic anhydride. This approach was later used by Erlenmeyer/41 who extended the procedure to include other aldehydes and also established the usefulness of azlactones as intermediates in the synthesis of DHAs. The method involves the condensation of an A-acylglydne 4 with aldehydes and ketones in the presence of acetic anhydride and anhydrous sodium acetate (Scheme 2)J41 t5l Other catalysts such as copper(II) acetate/46 lead acetate/47,48 potassium carbonate/49 or potassium hydrogen carbonate 50 have also been used. The reaction proceeds via formation of an azlactone 5, which then condenses with the appropriate aldehyde or ketone to give unsaturated azlactone 6. Reaction of 6 with a nucleophile such as OH, OR, or NHR leads to the corresponding A-acyl-DHA derivatives 7. Reaction with the sodium salt of an amino acid gives a DHA containing dipeptide acid. 51 ... 

This method is mainly restricted to the synthesis of amino acids with aromatic side-chains since the required unsaturated azlactones [e.g. (30)] are most readily prepared using aromatic aldehydes. Typically, benzaldehyde condenses under the influence of base with the reactive methylene group in the azlactone (29) which is formed by the dehydration of benzoylglycine (28) when the latter is heated with acetic anhydride in the presence of sodium acetate (cf. Expt 8.21). The azlactone ring is readily cleaved hydrolytically and compounds of the type (30) yield substituted acylaminoacrylic acids [e.g. (31)] on boiling with water. Reduction and further hydrolysis yields the amino acid [e.g. phenylalanine,... 

N-Methyl-N-(2-pyridyl)amino)ethoxy]benzaldehyde was converted into highly crystalline 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl] thiazolidine-2,4-dione by Knoevenegal condensation with 2,4-thiazolidinedione. 800 g of 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy] benzyl]thiazolidine-2,4-dione and 280 g maleic acid were dissolved in 1.3 L of acetone in 5 L three necked round bottom flask. The reaction mixture was heated to 50-55°C and the solution was filtered and slowly cooled to obtain 986 g of 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione maleate, (yield 95% M.P. 120-122°C). 

Tri-3-amino-tri-p-tolylarsine, formed from the nitro-oxide by reduction wth tin and hydrochloric acid, crystallises in prisms, M.pt. 198° C. It yields a hydrochloride, crystallising in fine, colourless needles, and a crystalline acid stdphate. The triacetyl derivative melts at 228° C., and a ibenzyl derivative (CH3.C8H3.NH.CH2.CgH5)3A,s is formed by heating the amino-arsine with benzyl chloride (3 mols.), but has only been isolated in the form of its hydrochloride. The amino-arsine also condenses with benzaldehyde and with diazobenzene cliloride. 

A new strategy for the synthesis of heterocyclic a-amino acids utilizing the Hantzsch dihydropyridine synthesis was developed in the laboratory of A. Dondoni." ° The enantiopure oxazolidinyl keto ester was condensed with benzaldehyde and fert-butyl amino crotonate in the presence of molecular sieves in 2-methyl-2-propanol to give a 85% yield of diastereomeric 1,4-dihydropyridines. The acetonide protecting group was removed and the resulting amino alcohol was oxidized to the target 2-pyridyl a-alanine derivative. 

The enzyme has also been used in the production of several natural amino acids such as L-serine from glycine and formaldehyde and L-tryptophan from glycine, formaldehyde, and indole [77-79], In addition, SHMT has also been used for the production of a precursor, 20, to the artificial sweetener aspartame (21) through a non-phenylalanine-requiring route (Scheme 14) [80-83]. Glycine methyl ester (22) is condensed with benzaldehyde under kinetically controlled conditions to form L-enY/ ra-p-phenylserine (23). This is then coupled enzymatically using thermolysin with Z-aspartic acid (24) to form A -carbobcnzyloxy-L-a-aspartyl-L-eryt/zro-p-phenylserine (20). and affords aspartame upon catalytic hydrogenation. 

Reactions using highly acidic active methylene compounds (pAa = 9-13) comprise nearly all the early examples of imine condensation reactions, some of which date back to the turn of the century. Reviews by Layer and Harada have summarized many of these reactions and include examples using diethyl malonate, ethyl cyanoacetate, ethyl malonamide, acetoacetic acid, benzoylacetic esters and nitroalkanes. Conditions of these reactions vary they have been performed both in protic and aptotic solvents, neat, and with and without catalysts. Elevated temperatures are generally required. Reactions with malonates have useful applications for the synthesis of 3-amino acids. For example, hydrobenzamide (87), a trimeric form of the benzaldehyde-ammonia Schiff base, and malonic acid condense with concomitant decarboxylation to produce p-phenylalanine (88) in high yield (equation 14). This is one of the few examples of a Mannich reaction in which a primary Mannich base is produced in a direct manner but is apparently limited to aromatic imines. 

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