Chiral Primary Amine

Reaction of 2-[A -(rra -crotyl)-A -benzylamino]-3-formyl-4/f-pyrido[l,2-n]pyrimidin-4-one (269) with chiral primary amines 270 and 271 gave mixtures of diastereoisomers of tetracyclic compounds 273 and tricyclic 275 (96T131]]). The chiral centers in 272 and 274 did not provide any stereocontrol for the formation of diastereomers 273 and 275, respectively. 

In another report, aspects for automating preparative chemistry are described [130]. A comprehensive description of the Ugi reaction is given in [132] and the vision of a micro multi-component reaction as automated parallel micro-channel synthesis is sketched. An interesting point is to convert aldehydes, chiral primary amines, carboxylic adds and isocyanates into corresponding a-amino acids and peptides (U-4CR). 

Derivatization of the optically active aldehydes to imines has been used for determination of their enantiomeric excess. Chi et al.3 have examined a series of chiral primary amines as a derivatizing agent in determination of the enantiomeric purity of the a-substituted 8-keto-aldehydes obtained from catalysed Michael additions. The imine proton signals were well resolved even if the reaction was not completed. The best results were obtained when chiral amines with —OMe or —COOMe groups were used [2], The differences in chemical shifts of diastereo-meric imine proton were ca. 0.02-0.08 ppm depending on amine. This method has been also used for identification of isomers of self-aldol condensation of hydrocinnamaldehyde. 

In determination of the absolute configuration of a-chiral primary amines, BINOL derivatives were used as chiral derivatizing agent.10 In this procedure, the chiral substrate was derivatized with R and S enantiomers of the 2,-methoxy-l,l -binaphthalene-8-carbaldehyde and the XH spectra of both diastereomers were compared. Comparison of the chemical shift differences of the diastereomers has allowed determination of the absolute configuration of the chiral substrate [5]. 

Possible racemisation of imines, derivatives of amino acids and R(—)-myrtenal, has been examined by Dufrasne et al.1 After 72 h, no significant effect on chiral purity was observed. For imines being derivatives of chiral primary amines and the a-substituted 8-keto-aldehydes, no evidence of epimerisation has been indicated by the NMR measurements.3 For a series of imines, being derivatives of amino acids or amino acid esters and (R)-BINOL reagents, Chin et al.5 have tested the possibility of epimerization under experiment conditions. It was shown that R S ratio has changed only slightly, and after 24 h, the difference was lower than 10%. 

The chlorides 73a and 73b on reacting with dimethylamine in benzene afforded the amidates 92 and 93 respectively with complete diastereoselectivity. [58] The diastero-meric amides 94-96 were prepared in a similar manner by reacting 73a with chiral primary amines (optically active or racemic) and the isolated amides were applied for quantification of enantiomeric excesses of the amines of interest (Scheme 27) [55], A similar reaction with 1,2-diaminoethane gave bisphosphoramide 98 [59],... 

Moss and coworkers provided an early example of the way in which micellization can control the stereochemical course of a reaction. Deamination of chiral primary aliphatic amines in water proceeds with net inversion and extensive racemization, and the extent of racemization depends upon the lifetime of the carbocation-like intermediate. The situation changes dramatically if the salts of the primary amine can self-micellize, because now the nucleophile, typically water, is directed in from the front-side so that there is extensive retention of configuration (Moss et al., 1973). 

Until now, few acyclic N-alkyl imines or the corresponding amines have been found to be of practical industrial importance. Most studies reported herein were carried out with model substrates, especially with the N-benzyl imine of acetophenone 5a and some analogues thereof (Fig. 34.7). One reason for this choice could be the easy preparation of a pure crystalline starting material, and another reason might be that the chiral primary amines can be obtained by hy-drogenolysis of the benzyl group. As can be seen in Table 34.4, there are several catalyst systems with fair to good ee-values and activities. 

J. J. Eddine, M. Cherqaoui, Chiral Quaternary Benzo-phenone Hydrazonium Salt Derivatives Efficient Chiral Catalysts for the Enantioselective Phase-Transfer Alkylation of Imines. Application to Synthesis of Chiral Primary Amines , Tetrahedron Asymmetry 1995, 6, 1225-1228. 

S)-2-amino-3-methyl-l-phenylbutane [(S)-4], the carboxyl group becoming an isopropyl group27. The use of a-amino acids and other reagents can afford either enantiomer of a variety of chiral primary amines. 

Additional NMR information may be useful in difficult enantiomer analyses of alcohols, thiols, and primary and secondary amines. Reaction 32 illustrates the process for a chiral primary amine, RNIF, undergoing N-substitution with chiral reagent 185. Besides the 31P NMR spectra of the diasteroisomers 186, also 1H, 13C and 19F spectra may be taken. Addition of sulfur or selenium to the NMR tube will afford diasteroisomers 187, for which the corresponding spectra can also be taken397. 

Procedure for KR of an a-chiral primary amine using catalyst 17 KR of( )- 1-phenylethyl-amine [99]... 

BASF successfully developed a process, which is operated on a rnulti-thousand-ton scale, for the resolution of chiral primary amines by lipase-catalyzed acylation... 

Synthesis of the sulfonamides is accomplished with the camphorsulfonic acid chloride in a 1 1 ratio with the chiral primary amine in pyridine (2 h, 60 °C). 

A useful method for the establishment of the absolute configurations of chiral primary amines involves formation of their salicylidene derivatives and application the salicylidcnamino chirality rule 172. Other procedures for primary amines are based on, either the CD of their V-(2,4-diniirophenylsulf enyl)- V-(4-methylphenylsulfonyl) derivatives as described in Section 4.3.4.I.5.251, or on the exciton chirality method313. 

A method for the determination of the absolute configuration of chiral primary amines of type 1 has been developed on this basis251. The amines 1 are converted via sulfonamides 2 into... 

Many studies of the electronic spectra of bidentate N,0 Schiff bases derived from chiral primary amines have been reported68 in order to establish the absolute configuration of the amine. Three absorption bands, designated69 I, II and III at about 315, 255 and 215 nm, respectively, are present... 

The highly enantioselective direct conjugate addition of ketones to nitroalkenes has been promoted by a chiral primary amine-thiourea catalyst (7).31 The observed anti diastereoselectivity has suggested participation of a (Z)-enamine intermediate, given (g) the complementary diastereoselectivity obtained in analogous reactions involving (E)-enamines generated from secondary amine catalysts. 

The Gabriel synthesis is a classical but useful preparative method for primary amines. Reaction of an alkyl bromide (24) with potassium phthalimide (25) gives the corresponding A -alkylphthalinude (26), which upon treatment with hydrazine followed by KOH affords the primary amine (27). When a chiral alkyl halide is used in the Gabriel synthesis, a chiral primary amine is obtained. However, preparation of optically active alkyl halides is not easy. If optical resolution of 26 which has a chiral alkyl group can be done, a new preparative method for optically active amines can be established by a combination of the resolution with the Gabriel synthetic method. Some examples of the combination method are described. 

Chiral primary amines.1 Alkylation of the lithium anion of the N-benzyloxazo-lidinone 1 (derived from valinol) proceeds with high 1,3-stereoselectivity to provide 2 in 75-96% de, which can be improved by crystallization or chromatography. The products can be degraded to (R)-primary amines (5) by hydrolysis (3) and oxidation to an imine (4), which is then hydrolyzed to an amine. Slight racemization is observed in these last steps. 

Chiral amines (both primary and secondary amines) and amino acids have been used as catalysts for aldol reactions, Mannich-type reactions, and other reactions that proceed through enamine intermediates. An enamine-based catalytic cycle is shown in Scheme 2.1. The catalytic cycle includes formation of an iminium intermediate between a donor carbonyl compound and the amine-containing catalyst, the formation of an enamine intermediate from the iminium, C-C bond forma-... 

Amino Alcohols and Mono-Protected 1,2-Diols 302 a-Chiral Primary Amines 306 Type I Acylative ASD of Achiral/meso-Diols 307 Type I Asymmetric Acyl Addition to 7r-Nucleophiles ... 

Although they are extremely useful analytically, the protein based stationary phases 3-6,371 have found little application in preparative HPLC because they suffer from low loading capacity, due primarily to the low number of active sites. The natural macrocylic molecules Cyclodextrin 3 8,3 91 and antibiotics such as Vancomycin 3 10] have shown some promise. Synthetic chiral crown ethers 311 are particularly useful for the separation of chiral primary amines. 

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