Amines selective synthesis

Amino acids can be synthesized in racemic form by several methods, including ammonolysis of an a-bromo acid, alkylation of diethyl acetamido-malonate, and reductive amination of an cv-keto acid. Alternatively, an enantio-selective synthesis of amino acids can be carried out using a chiral hydrogenation catalyst. 

The improvements made in hydroaminomethylation technology suggest that certain variants of this reaction are sufficiently developed for the potential production of amines. The synthesis of linear tertiary and secondary amines from terminal alkenes shows promise in this regard. Belief s recent contributions towards hydroaminomethylation using ammonia to produce linear primary amines, which are of industrial significance due to their abundance, suggest a bright future for this reaction. Branched selective hydroaminomethylation remains relatively underdeveloped and needs further study. 

The methodology did not work for secondary amines, thus suggesting the formation of an isocyanate as intermediate (Scheme 27, MX2 = Pdl2, [OX] = (1/2) O2]. However, by reacting a primary amine in the presence of a secondary nucleophilic amine, a general and selective synthesis of trisubstituted ureas has been achieved, through trapping of the isocyanate intermediate by the secondary amine (Eq. 52) [274,275]. 

This reaction can furthermore be applied on chiral aminals, affording a straightforward route to optically pure frawi-2,5-pyrrolidines or chiral alkyl-substituted 1,3-oxazoUdines. This method was used for the en an tio selective synthesis of substituted piperidines . 

In 2007, Boyer and coworkers developed a complete study of the parameters that can influence the selective synthesis of p-lactam or p-aminoester during Refor-matsky reaction between ethyl bromodifluoroacetate and various imines. It clearly appeared that by modifying the nature of the amine or the reaction conditions, it was always possible to inverse the p-aminoester/p-lactam ratio (Scheme 55). 

An efficient and highly selective synthesis of bicyclic-a-keto aziridines (89) from 2-bromocyclopent-2-enone (88) and aliphatic primary amines, mediated by phase-transfer catalysts (PTCs) in water at room temperature, has been demonstrated.139... 

Nucleophilic substitution of R2. The n amines selected are dissolved in 15 mL of appropriate solvent. Each amine is in 5 M excess to the amount of amination of the gel. Each aliquot of R]-substituted gel is divided into 5-mL fractions, suspended in the previous mixture, and incubated at 85°C for 72 h. At the end of the synthesis, the gels are washed with appropriate solvent, weighed, and stored at 0-4°C in 20% v/v ethanol (Fig. 3). 

Imada, Y. Yuasa, M. Nakamura, I. Muraha-shi, S.-I. Copper(I)-catalyzed amination of pro-pargyl esters. Selective synthesis of propargyl-amines, l-alken-3-ylamines, and (Z)-allyl-amines./. Org. Chem. 1994, 59, 2282-2284. 

Tu and co-workers [56] have developed a facile and selective synthesis of A-substituted 2-aminopyridines 5 via a microwave-assisted MCR which is controlled by the basicity of the amine and the nature of the solvent. When reacted in a solvent mixture of DMF/HOAc (1 1), the desired aminopyridine 5 was formed next to 2,6-dicyanoanilines in nearly equal amounts. However, when the volume ratio was increased to 1 4, compound 5 was obtained as the main product. The elaborated... 

An effective control of the simple diastereoselectivity in boron-mediated aldol reactions of various propionate esters (162) was achieved by Abiko and coworkers (equation 45) °. They could show that under usual enolization conditions (dialkylboron triflate and amine) enol borinates are formed, which allowed the selective synthesis of 5yw-configured aldol products (Table 11). The enolization at low temperature (—78 °C) generated a (Z)-enolate selectively, which afforded mainly the syn diastereomer 164 after reaction with isobu-tyraldehyde (163), following a Zimmerman-Traxler transition-state. The anti diastereomer 164 instead was obtained only in small amounts (5-20%). 

Various procedures have been developed for the production of oximes from nitroparaffins. Direct reduction with zinc dust and acetic acid has been proposed, but the yields are poor because of the simultaneous formation of amines. A synthesis for cyclohexanone oxime has been demonstrated which involves the formation and selective hydrogenation of 1-chloro-l-nitrocyclohexane. The halogenated intermediate is prepared in quantitative yield by chlorination of the sodium salt of acz -nitrocyclo-hexane, and subsequent hydrogenation is performed in an 80% yield over palladium-on-charcoal, ... 

Olefin isomerization catalyzed by ruthenium alkylidene complexes can be applied to the deprotection of allyl ethers, allyl amines, and synthesis of cyclic enol ethers by the sequential reaction of RCM and olefin isomerization. Treatment of 70 with allyl ether affords corresponding vinyl ether, which is subsequently converted into alcohol with an aqueous HCl solution (Eq. 12.37) [44]. In contrast, the allylic chain was substituted at the Cl position, and allyl ether 94 was converted to the corresponding homoallylic 95 (Eq. 12.38). The corresponding enamines were formed by the reaction of 70 with allylamines [44, 45]. Selective deprotection of the allylamines in the presence of allyl ethers by 69 has been observed (Eq. 12.39), which is comparable with the Jt-allyl palladium deallylation methodology. This selectivity was attributed to the ability of the lone pair of the nitrogen atom to conjugate with a new double bond of the enamine intermediate. 

This hydroaminomethylation has only been applied in homogeneous one-phase systems until now. The reaction will mostly lead to secondary and tertiary amines, because the intermediate primary amines will further react with the aldehyde formed to secondary amines. The synthesis of the technically important primary amines from ammonia and alkenes via hydroaminomethylation was investigated, but only low selectivities (32 %) and TOFs (9 h ) to primary amines could be achieved, despite the high excess of ammonia. Other side products, e. g., via aldo-lization, are also observed. 

Kaiser et al. have reported a general entry for the selective synthesis of dimeric macrocycles like cyclostellettamines and for polymeric natural products [41]. It uses the Zincke reaction by which it is possible to control the number of units in a 3-alkylpyridinium polymer. As summarized in Fig. (33), the reaction of the free amine 89 with the Zincke salt 88 gives the dimer 90 (route b) which, after terminal amine deprotection and DNB functionalization at the A-pyridine centre, gives the cyclic dimer, as in the synthesis of cyclostellettamine B. Otherwise, compound 90 furnishes both the protected dimer 91 and the free linear dimer, which, refluxed together in butanol, give the linear tetramer (route c). By the same iterative sequence, the linear octamer was obtained from the tetramer, and from the latter the hexadecamer. 

The Kabachnik Fields reaction, which involves the hydrophosphonylation of phos phites with imines generated in situ from carbonyl compounds and amines, is an attractive method for the preparation of a amino phosphonates. Optically active a amino phosphonic acids and their phosphonate esters are an attractive class of compounds due to their potent biological activities as nonproteinogenic analogues of a amino acids. Therefore, considerable attention has been given to their enantio selective synthesis by hydrophosphonylation of preformed imines, using either metal based catalysts or organocatalysis [107]. 

Today, the application of hypervalent iodine reagents still dominates the reaction landscape of electrophilic N-atom transfer processes, a testament to the unique reactivity of such oxidants. Nevertheless, the past decade has witnessed a flurry of activity aimed at the invention of new reagents and protocols that enable amine and amine derivative synthesis through selective C-H bond modification. We have attempted to highlight many of these recent discoveries, with apologies in advance... 

When the reactant is ammonia or a primary amine, the product primary or secondary amine, respectively, can further react with alcohol according to Scheme 1, which reduces selectivity. Synthesis of primary amines is especially demanding because the basicity (nucleophilicity) of the product amine is substantially higher than that of ammonia. 

The initial alcohol/amine ratio can determine the product distribution. In the synthesis of primary amines a rather high ammonia/alcohol molar ratio (up to 10-25), and usually high pressure, are required to compensate for the low reactivity of ammonia and suppress the formation of secondary amines. Selectivity for primary diamines could be improved in the amination of 1,3-dihydroxy compounds when using supercritical ammonia as solvent and reactant in a continuous fixed-bed reactor [12]. The remarkable changes in selectivity in the near-critical region (100-110 bar) are attributed to the increased concentration of ammonia on the metal surface as a result of elimination of mass-transport limitations in the two-phase system, and to suppression of hydrogenolysis and water elimination reactions which lead to monofunctional by-products. An example is shown in Figure 1. 

Transalkylation of amines with alcohols is usually an undesired side-reaction which reduces amination selectivity. Several metals, e. g. Co, Fe, Ni, or Ru, are good catalysts of interchange between alcohols and amines, including tertiary amines [3]. This reaction can be used for the synthesis of asymmetric tertiary amines. Triethylamine, for example, can be transalkylated with dodecanol over a Ni-Cr alloy catalyst, at 250 °C and 15 bar, to form dodecyldimethylamine in 96 % yield. 

The ubiquitous role of amines in both nature and in a vast variety of biologically important synthetic molecules gives this functionality a place of special prominence and interest in organic chemistry. Therefore, much effort and attention has been exerted toward developing methods for the selective synthesis of primary, secondary, and tertiary amines.4 In particular, the selective synthesis of secondary amines and orthogonally protected primary amines is quite important as these are often featured as valuable synthetic intermediates.5... 

The advantages in this reaction lie in economy and simplicity however long reaction times, sealed tube conditions, and high temperatures remain major drawbacks. In addition, formation of the //-formyl derivative is frequently seen, and the selective synthesis of a primary amine from ammonia is difficult.3,4... 

This process has a high selectivity for N F bond and SF4 group in compound 67 does not undergo reduction under reaction conditions. The abihty of Al-fluoro amines selectively convert triphenyl- phospine, arsine, and stibine into the corresponding difluorides (reported in 1967 by Haszeldine group ) was utilized in an effective laboratory scale synthesis of imidoyl fluorides 81 and 83 involving the reaction of amines 30 and 31 with triphenylphosphine. ... 

Olofson, R.A., Martz, J.T., Senet J.-P. et a/. (1984) A new reagent for the selective, high-yield A-dealkylation of tertiary-amines - improved synthesis of naltrexone and nalbuphine. The Journal of Organic Chemistry, 49, 2081-2082. 

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