Synthesis of amines

Calculate the percentages of neutral and protonated forms present in a solution of 0.0010 M pyrimidine at pH = 7.3. The pK of pyrimidinium ion is 1.3. 

We ve already seen in Sections 20.7 and 21.7 how amines can be prepared by reduction of nitriles and amides with LiAlH4. The two-step sequence of Sn2 displacement with CN followed by reduction thus converts an alkyl halide into a primary alkylamine having one more carbon atom. Amide reduction converts carboxylic acids and their derivatives into amines with the same number of carbon atoms. 

Propose structures for either a nitrile or an amide that might be a precursor of each of the following amines  

Ammonia and other amines are good nucleophiles in Sn2 reactions. As a result, the simplest method of alkylamine synthesis is by 5 2 alkylation of ammonia or an alkylamine with an alkyl halide. If ammonia is used, a primary amine results if a primary amine is used, a secondary amine results and so on. Even tertiary amines react rapidly with alkyl halides to yield quaternary ammonium salts, R4N+ X-. 

Unfortunately, these reactions don t stop cleanly after a single alkylation has occurred. Because ammonia and primary amines have similar reactivity, the initially formed monoalkylated substance often imdergoes further reaction to yield a mixture of products. Even secondary and tertiary amines imdergo further alkylation, although to a lesser extent. For example, treatment of 1-bromooctane with a twofold excess of ammonia leads to a mixture containing only 45% of octylamine. A nearly equal amount of dioctylamine is produced by double alkylation, along with smaller amounts of trioctylamine and tetraoctylammoniiun bromide. 

Solving the two simultaneous equations gives RNH3 J = 0.0010 M and IRNH2J = 5 X 10 VI. In other words, at a physiological pH of 7.3, essentially 100% of the methylamine in a 0.0010 M solution exists in its protonated form as methylammonium ion. The same is true of other amine bases, so we write cellular amines in their protonated form and amino acids in their ammonium car-boxylate form to reflect their structures at physiological pH. 

Thomson NOW Click Organic Interactive to use a web-based palette to predict products from a variety of reactions that yield amines. 

Problem 24.7 Calculate the percentages of neutral and protonated forms present in a solution of 

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Although this reaction is useful for preparing a ammo acids (Table 22 3 fifth entry) it IS not a general method for the synthesis of amines Its major limitation is that the expected primary amine product is itself a nucleophile and competes with ammonia for the alkyl halide... 

In this representation the FeCl2 which takes part in the first step of the reaction is not a tme catalyst, but is continuously formed from HQ. and iron. This is a highly exothermic process with a heat of reaction of 546 kj /mol (130 kcal/mol) for the combined charging and reaction steps (50). Despite the complexity of the Bnchamp process, yields of 90—98% are often obtained. One of the major advantages of the Bnchamp process over catalytic hydrogenation is that it can be mn at atmospheric pressure. This eliminates the need for expensive high pressure equipment and makes it practical for use in small batch operations. The Bnchamp process can also be used in the laboratory for the synthesis of amines when catalytic hydrogenation caimot be used (51). 

Using a procedure similar to the synthesis of amine boranes, a series of amine cyanoboranes where the amine = (CH3)3N, (CH3)2NH, (CH3)NH2, C3H3N, or (CgH3)NH2 have been prepared as shown in equation 4 (11). 

Recent efforts in the development of efficient routes to highly substituted yS-ami-no acids based on asymmetric Mannich reactions with enantiopure sulfmyl imine are worthy of mention. Following the pioneering work of Davis on p-tolu-enesulfmyl imines [116], Ellman and coworkers have recently developed a new and efficient approach to enantiomerically pure N-tert-butanesulfmyl imines and have reported their use as versatile intermediates for the asymmetric synthesis of amines [91]. Addition of titanium enolates to tert-butane sulfmyl aldimines and ketimines 31 proceeds in high yields and diastereoselectivities, thus providing general access to yS -amino acids 32 (Scheme 2.5)... 

Amides are weakly nucleophilic and react only slowly with alkyl halides. The anions of amides are substantially more reactive. The classical Gabriel procedure for synthesis of amines from phthalimide is illustrative.58... 

Reduction of amides by LiAlH4 is an important method for the synthesis of amines. 

A valuable application of sodium cyanoborohydride is in the synthesis of amines by reductive amination. What combination of carbonyl and amine components would give the following amines by this method ... 

Organocerium reagents also show excellent reactivity toward nitriles and imines,205 and organocerium compounds were found to be the preferred organometallic reagent for addition to hydrazones in an enantioselective synthesis of amines.206... 

Figure 9.2 Potential starting materials for synthesis of amine 2.

Aslant M, Schultz EA, Sun T, Meade T, Dravid VP (2007) Synthesis of amine-stabilized aqueous colloidal iron oxide nanoparticles. Cryst Growth Design 7(3) 471 175... 

The synthesis of amines by the in-situ reductive amination of ketones is termed the Leuckart-Wallach reaction. Recently, an asymmetric transfer hydrogenation version of this reaction has been realized [85]. Whilst many catalysts tested give significant amounts of the alcohol, a few produced almost quantitative levels of the chiral amine, in high enantiomeric excess. 

Nucleophilic displacement, for the synthesis of Amines, thiols, halides, azides, acetates [204, 205]... 

Aqueous organometalHc catalysis allows the use of NH3-solutions in water for the direct synthesis of amines from olefins in a combined hydroformylation/reductive amination procedure (Scheme 4.19). The hydroformylation step was catalyzed by the proven Rh/TPPTS or Rh/BINAS (44) catalysts, while the iridium complexes formed from the same phosphine ligands and [ IrCl(COD) 2] were found suitable for the hydrogenation of the intermediate imines. With sufficiently high NH3/olefin ratios (8/1) high selectivity towards the formation of primary amines (up to 90 %) could be achieved, while in an excess of olefin the corresponding... 

The development of versatile and efficient methods for the synthesis of amines has long been an active area of research, mainly because a wide variety of amines play important roles in many fields of organic chemistry. The N-alkylation of amines with alcohols represents an attractive method for synthesizing various amines because it does not generate any wasteful byproducts (H2O is the only stoichiometric coproduct). Although several catalytic systems for this process have been studied using transition-metal catalysts [53-57], most of these require a high reaction temperature (>150°C). 

Another class of enzymes that can be used for the enantioselective synthesis of amines and amino acids is the aminotransferases or transaminases (TAs) [29]. As shown in Scheme 6.15, they can be employed in a kinetic resolution or an asymmetric synthesis mode. 

The Gabriel synthesis of amines uses potassium phthalimide (prepared from the reaction of phthalimide with potassium hydroxide). The structure and preparation of potassium phthalimide is shown in Figure 13-13. The extensive conjugation (resonance) makes the ion very stable. An example of the Gabriel synthesis is in Figure 13-14. (The N2H4 reactant is hydrazine.) The Gabriel synthesis employs an 8, 2 mechanism, so it works best on primary alkyl halides and less well on secondary alkyl halides. It doesn t work on tertiary alkyl halides or aryl halides. 

The synthesis of amines from oximes is exemplified by the reduction of oxime 332 to 333 (99W032453) and of bicyclic oximes (derived from ketones 3 and 23a), for instance, of oxime 387 (Scheme 87) to amine 388 that is acylated to yield potential pharmaceutical agent 390 (92BML1147). Nucleophilic substitution of chloropyridine 384 generates morpholino derivative 385 (76IJB400). 

This methodology is also an important and potentially valuable method for C—N bond formation using the amination of carbon nucleophiles with electrophilic nitrogen transfer reagents (Scheme 1) Amination of ordinary carbanions and a-carbanion derived from carbonyl compounds and nitriles provides an important method for the synthesis of amines and a-amino carbonyl compounds and nitriles", respectively. For this purpose, a number of electrophilic amination reagents, which are synthetic equivalents of the R2N+ synthon, have been developed and the synthetic potential of electrophilic amination of carbon nucleophiles has been studied in detail . ... 

Due to the synthetic and biological importance of amines and a-aminoketones, acids and esters, the introduction of amino functionality into carbon nucleophiles provides a convenient and practical route for their synthesis "In addition, a number of electrophilic amination methodologies have been developed for the asymmetric synthesis of amines and a-aminocarbonyl compounds " ". 

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