Synthesis of secondary and tertiary amines

Graebin CS, Eifler-Lima VL, da Rosa RG (2008) One-pot synthesis of secondary and tertiary amines from R(+)-limonene by tandem hydroformylation/reductive animation (hydroamino-methylation). Catal Commun 9 1066—1070. doi 10.1016/j.catcom.2007.10.008... 

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 most commonly used method for the cleavage of hydrazones is catalytic hydrogenation in the presence of acid. An example is provided by the synthesis of secondary and tertiary amines by reduction of benzophenone hydrazones (14), derived as shown in Scheme 10. Nickel-aluminium alloy can also be used to reduce hydrazones to amines. ... 

We have already encountered alkylation of amines as a side reaction in the preparation of primary amines by the ammonolysis of halides (Sec. 22.10), and as a method of synthesis of secondary and tertiary amines (Sec. 22.13). Let us look at one further aspect of this reaction, the formation of quaternary ammonium salts. 

In 2008, Fujita, Yamaguchi and co-workers reported an efficient solvent-free synthesis of secondary and tertiary amines by [Cp IrCl2]2-catalyzed multialkylation of ammonium salts with primary or secondary alcohols [96]. The authors found that the type of ammonium salts greatly affected the selectivity of the reaction (Scheme 21a). Secondary 5- and 6-membered cyclic amines could also be prepared from ammonium tetrafluoroborate and diols by the same method. 

Owing to the high activities of the homogeneous Ru and Ir catalysts in N-alkylation reactions, many heterogeneous Ru and Ir catalysts have been developed. In 2009, Mizuno and co-workers reported an effective A-alkylation of (hetero)ary-lamines with benzylic and aliphatic alcohols catalyzed by Ru(0H)x/Al203 complex without any co-catalysts or additives (Eq. 34) [135]. The catalyst is recoverable and reusable without obvious loss of activity (1st, 89 % 2nd, 87 %). Later in the same year, the authors reported another additive-free method for synthesis of secondary and tertiary amines from alcohols and urea catalyzed by Ru(OH)x/Ti02 (Eq. 35)... 

Yamaguchi R, Kawagoe S, K-I Fujita et al (2008) Selective synthesis of secondary and tertiary amines by Cp iridium-catalyzed multialkylation of ammonium salts with alcohols. Org Lett 10(2) 181-184... 

He W, Wang L, Yu Z et al (2011) Pt-Sn/ y-Al203-catalyzed highly efficient direct synthesis of secondary and tertiary amines and imines. Chem-Eur J 17(47) 13308-13317... 

A method that achieves the same end result as that desired by alkylation of ammonia but which avoids the formation of secondary and tertiary amines as byproducts is the Gabriel synthesis Alkyl halides are converted to primary alkylamines without contam mation by secondary or tertiary amines The key reagent is the potassium salt of phthal imide prepared by the reaction... 

Among compounds other than simple alkyl halides a halo ketones and a halo esters have been employed as substrates m the Gabriel synthesis Alkyl p toluenesul fonate esters have also been used Because phthalimide can undergo only a single alkyl ation the formation of secondary and tertiary amines does not occur and the Gabriel synthesis is a valuable procedure for the laboratory preparation of primary amines... 

A diverse group of secondary and tertiary amines are readily synthesized from the reaction of primary and secondary amines with allylic carbonates in the presence of preformed iridium metalacycles, but the direct synthesis of primary amines via iridium-catalyzed allylic amination requires the use of ammonia as a nucleophile. The asymmetric allylation of ammonia had not been reported until very recently, and it is not a common reagent in other metal-catalyzed reactions. Nonetheless, Hartwig and coworkers developed the reactions of ammonia with allylic carbonates in the presence of la generated in situ [89]. Reactions conducted in the initial work led exclusively to the products from diallylation (Scheme 16). Further advances in... 

C - N bond formation is one of the most important transformations in organic synthesis. Amines are widely used as intermediates to prepare solvents, fine chemicals, agrochemicals, pharmaceuticals and catalysts for polymerization. The nucleophilic attack of alkyl halides by primary and secondary amines is useful for the preparation of tertiary amines but the reaction requires a longer reaction time and gives rise to a mixture of secondary and tertiary amines. 

Hydrogenation of nitriles under conditions favorable for the formation of secondary and tertiary amines can be applied to the synthesis of mixed secondary and tertiary amines. The iV-substituted phenethylamines were synthesized by hydrogenation of a phenylacetonitrile in the presence of an amine an example is shown in eq. 7.45,90... 

Another approach based on the introduction of amine groups onto chitosan was also proposed. Ghosn et al. investigated the introduction of secondary and tertiary amines to improve the transfection efficiency of chitosan [46]. This one-step synthesis was based on the grafting of a carboxylic acid-bearing imidazole onto chitosan by amide formation, mediated by l-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC), and was simple and reproducible and improved the solubility and the buffering capacity of the chitosan derivatives. 

Owing to the importance of optically active amino acid derivatives and the lack of successful systems for catalytic asymmetric CDC reactions of glycine derivatives with p-keto esters, Wang and co orkers embarked on the study of enantioselective CDC reactions of secondary and tertiary amines for the synthesis of optically active a-alkyl a-amino acids. In the presence of a catalytic amount of Cu(OTf)2 and BOX ligand L2 as the chiral catalyst, in combination with DDQ as the stoichiometric oxidant, the reactions of glycine esters 47 with a-substituted p-keto esters 48 underwent smoothly to afford the desired products 49 in satisfactory yields, moderate dr and excellent ee (Scheme 2.17). 

In 2008, the Beller group extended the method to the iV-alkylation of aryl amines with secondary amines and tertiary amines (Eq. 74) [215]. In the same year, they further applied the method to the A -alkylation of tert-alkylamines with aliphatic amines [216]. In 2011, the Beller group also reported the synthesis of primary amines by the reaction of secondary and tertiary amines with ammonia catalyzed by Shov catalyst (Eq. 75) [217]. 

Murahashi S-I, Kondo K, Hakata T (1982) Ruthenium catalyzed synthesis of secondary or tertiary amines from amines and alcohols. Tetrahedron Lett 23(2) 229-232... 

The azide synthesis is a better method for preparing primary amines than alkylation of ammonia because it avoids the formation of secondary and tertiary amines. This method involves treating an alkyl halide with sodium azide followed by reduction (Mechanism 23.1). 

The Gabriel synthesis is another method for preparing primary amines while avoiding formation of secondary and tertiary amines. The key reagent is potassium phthahmide, which is prepared by treating phthalimide with potassium hydroxide. 

As previously discussed, the palladium-catalyzed aminocarbonylation of aryl halides in the presence of carbon monoxide gas and amines constitutes a versatile methodology for the selective and direct synthesis of secondary and tertiary benza-mide derivatives. Unfortunately, the synthesis of primary amides is recognized as considerably more difficult, attributed, in part, to the lower nucleophilicity of ammonia in combination with the less convenient handling of gaseous ammonia. As with DMF, the solvent formamide has been shown to be an excellent source of carbon monoxide that also serves as an effective ammonia synthon [41]. Scheme 4.28 illustrates the reported results in which, again, KOt-Bu and imidazole were used as essential activating agents. 

The majority of U(V1) coordination chemistry has been explored with the trans-ddo s.o uranyl cation, UO " 2- The simplest complexes are ammonia adducts, of importance because of the ease of their synthesis and their versatihty as starting materials for other complexes. In addition to ammonia, many of the ligand types mentioned ia the iatroduction have been complexed with U(V1) and usually have coordination numbers of either 6 or 8. As a result of these coordination environments a majority of the complexes have an octahedral or hexagonal bipyramidal coordination environment. Examples iuclude U02X2L (X = hahde, OR, NO3, RCO2, L = NH3, primary, secondary, and tertiary amines, py n = 2-4), U02(N03)2L (L = en, diamiaobenzene n = 1, 2). The use of thiocyanates has lead to the isolation of typically 6 or 8 coordinate neutral and anionic species, ie, [U02(NCS)J j)/H20 (x = 2-5). 

Amines are important industrial chemicals which are involved in everyday life [3, 4]. Apart from the usual classification into primary, secondary, and tertiary amines, the distinction is often made between lighf amines (less than six-carbon substituents) and fatty amines. light amines are intermediates for the synthesis of drugs, herbicides, cosmetics, etc. [3]. They also find use as vulcanization accelerators and extraction agents. Fatty amines are involved in the synthesis of corrosion inhibitors and cationic surfactants, which are used in ore flotation processes and are good fabric softeners and antistatic agents [4—6],... 

Secondary and tertiary amines can be obtained if the hydroformylation of olefins is conducted in the presence of primary and secondary amines under elevated hydrogen partial pressures. Here the rhodium catalyst is involved in both steps, the hydroformylation of an olefin as well as the hydrogenation of the imine or enamine resulting from a condensation of the oxo-aldehyde with the amine (Scheme 14). This combination of hydroformylation and reductive amination is also known as hydroaminomethylation and has been applied to the synthesis of various substrates of pharmaceutical interest [55-57] as well as to the synthesis of macrocycles [60-63] and dendrimers [64,65]. 

The present method is experimentally simple, requires no special apparatus, and is generally applicable to the synthesis of a variety of primary, secondary, and tertiary amines as illustrated in Table I. 

The benzotriazole moiety of iV-(a-aminoalkyl)benzotriazoles is readily replaced by hydride upon reduction with sodium borohydride, or with a carbanion by reaction with Grignard or lithium reagents. These are two most important reactions of benzotriazole derivatives from which versatile routes have been developed for the synthesis of primary, secondary, and tertiary amines. 

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