Syntheses Limited to Primary Amines

Primary amines are the most common class of amines, and they are also used as starting materials for synthesis of secondary and tertiary amines. Many methods have been developed for making primary amines, ranging from simple alkylation of ammonia to sophisticated multistep syntheses. We will consider some of the more common syntheses. 

The Sn2 reaction of amines with alkyl halides is complicated by a tendency for over-alkylation to form a mixture of monoalkylated and polyalkylated products (Section 19-12). Simple primary amines can be synthesized, however, by adding a halide or tosylate (must be a good Sn2 substrate) to a large excess of ammonia. Because there is a large excess of ammonia present, the probability that a molecule of the halide will alkylate ammonia is much larger than the probability that it will overalkylate the amine product. 

I Show how you would use direct alkylation of ammonia to synthesize 1-heptanamine. 

In 1887, Siegmund Gabriel (at the University of Berlin) developed the Gabriel amine synthesis for making primary amines without danger of overalkylation. He used the phthalimide anion as a protected form of ammonia that cannot alkylate more than once. Phthalimide has one acidic N—H proton (pXg 8.3) that is abstracted by potassium hydroxide to give the phthalimide anion. 

The phthalimide anion is a strong nucleophile, displacing a halide or tosylate ion from a good Sis)2 substrate. Heating the A -alkyl phthalimide with hydrazine displaces the primary amine, giving the very stable hydrazide of phthalimide. 

---

Scheldt and co-workers have synthesized similar products using this reaction manifold [112], While results are limited to primary and secondary alcohols, the authors provided a single example of the use of an amine nucleophile. The reaction of cinnamaldehyde 187 and P-amino alkylidene malonate 188 provide amide product 189, albeit in moderate yield Eq. 18. 

Other fairly recent commercial products, poly(vinyl amine) and poly(vinyl amine vinyl alcohol), have addressed the need for primary amines and their selective reactivity. Prior efforts to synthesize poly(vinyl amine) have been limited because of the difficulty hydrolyzing the intermediate polymers. The current product is prepared from /V-ethenylformamide (20) formed from the reaction of acetaldehyde and formamide. The vinyl amide is polymerized with a free-radical initiator, then hydrolyzed (eq. 7). 

Reductive alkylation is an efficient method to synthesize secondary amines from primary amines. The aim of this study is to optimize sulfur-promoted platinum catalysts for the reductive alkylation of p-aminodiphenylamine (ADPA) with methyl isobutyl ketone (MIBK) to improve the productivity of N-(l,3-dimethylbutyl)-N-phenyl-p-phenylenediamine (6-PPD). In this study, we focus on Pt loading, the amount of sulfur, and the pH as the variables. The reaction was conducted in the liquid phase under kinetically limited conditions in a continuously stirred tank reactor at a constant hydrogen pressure. Use of the two-factorial design minimized the number of experiments needed to arrive at the optimal solution. The activity and selectivity of the reaction was followed using the hydrogen-uptake and chromatographic analysis of products. The most optimal catalyst was identified to be l%Pt-0.1%S/C prepared at a pH of 6. 

Several additional amine syntheses are effectively limited to making primary amines. The reduction of azides and nitro compounds and the Gabriel synthesis leave the carbon chain unchanged. Formation and reduction of a nitrile adds one carbon atom. Show how these amine syntheses can be used for the following conversions. 

Myriad polydentate aza-macrocycles have been reported 41. The extent of the subject forces limitation of this discussion to only macrocycles containing a pyridine or dipyridine subunit. Most of these coronands have been synthesized by a SchifF base condensation of an aldehyde or ketone with a hfc-primary amine in the presence of a metal ion. The metal ion acts as a template, resulting in dramatic increases in yield of the desired cyclic product over linear polymerization products42 46. Lindoy and Busch45 have described this effect in two ways, kinetic and thermodynamic. If the metal ion controls the steric course of a series of stepwise reactions, the template effect is considered to be kinetic. If the metal ion influences an equilibrium in an organic reaction sequence by coordination with one of the reactants, the template effect is termed thermodynamic. It is the kinetic effect that is believed to be operative in most metal ion-assisted (in situ) syntheses of... 

A few reports have appeared of syntheses of 1,2-benzothiazines lacking a ketone group in the thiazine ring. Bicking and Sprague52 treated l-(2-chloroethyl)benzene-2,4-disulfonylchloride derivatives (68) with a variety of primary amines to afford 7-sulfamoyl-3,4-dihydro-2//-l,2-benzo-thiazine 1,1-dioxides (69) in poor to fair overall yield. The requisite starting materials (68) were readily prepared by exhaustive chlorosulfonation of phenethyl halides (67) (Eq. 15), but the scope was limited by the concomitant introduction of a sulfamoyl substituent into the benzene ring of the 1,2-benzothiazine 1,1-dioxide (69). 

Tetrasubstituted imidazoles 32 can also be synthesized by a three-component condensation [55]. These reactions are usually limited and cannot be performed under neutral conditions [70]. With use of MW irradiation, however, the reaction becomes possible. The procedure requires benzonitrUe derivatives, benzU, and primary amines on the surface of silica gel to obtain the tetrasubstituted imidazoles 32 in moderate to good yields (58-92%, Scheme 17.23). 

Thiazolidones are another class of heterocycles that attract much attention because of their wide ranging biological activity [106], They are usually synthesized by three-component condensation of a primary amine, an aldehyde, and mercapto-acetic acid with removal, by azeotropic distillation, of the water formed [107]. The reaction is believed to proceed via imine formation then attack of sulfur on the imine carbon. Finally, an intramolecular cyclization with concomitant elimination of water occurs, generating the desired product. The general applicability of the reaction is limited, however, because it requires prolonged heating with continuous removal of water. To circumvent these difficulties and to speed up the synthesis, Miller et al. developed a microwave-accelerated three-component reaction for the synthesis of 4-thiazolidinones 63 [108]. In this one-pot procedure, a primary amine, an aldehyde, and mercaptoacetic acid were condensed in ethanol under MW conditions for 30 min at 120 °C (Scheme 17.44). The desired 4-thiazolidinones 63 were obtained in 55-91% yield. 

---