Synthesis of Amides from Alcohols and Amines

Amide formation plays a very important role in chemical synthesis [1, 46]. Preparation of amides under neutral conditions and without generation of waste is a challenging goal [46-48]. Applying our pyridine-based ruthenium pincer complexes as catalysts, amides were synthesized directly from amines and alcohols or esters polyamides were obtained from diols and diamines, as delineated in this section. 

Direct catalytic conversion of alcohols and amines into amides and dihydrogen is a desirable method for the synthesis of amides. Using this environmentally benign reaction [14], an assortment of simple alcohols and amines were converted 

Secondary amines do not react under these conditions. Thus, heating dibenzylamine with 1-hexanol under the experimental conditions resulted in a quantitative yield of hexyl hexanoate (entry 6, Table 1.8). The scope of this method was extended to the bis-acylation processes with diamines. Upon refluxing a slight excess of a primary alcohol and catalyst 1 with diamines (500 equivalent relative to 1) in toluene under argon, bis-amides were produced in high yields (Table 1.9). The high selectivity of the dehydrogenative amidation reaction to primary amine functionalities enabled the direct bis-acylation of diethylenetriamine with 1-hexanol to provide the bis-amide in 88% yield without the need to protect the secondary amine functionality [14]. 

The discovery of the catalytic amide formation with liberation of dihydrogen provides the most atom-economical method to make amides directly from amines and alcohols as such, it elicited much research interest in this direction and diverse catalytic systems were reported, although generally in significantly lower catalyst turnovers [51]. 

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The first example of the ruthenium-catalyzed synthesis of amides from alcohols and amines was reported by Murahashi et al. in 1991 [82aj. The contrast results were obtained from the RuH2(PPh3)4-catalyzed reaction of 5-aminopentanol. Thus, piperidine was obtained in 79% yield, while similar treatment in the presence of a hydrogen acceptor of l-phenyl-l-buten-3-one gave piperidone in 65% yield (Eq. (7.36)). Recently, Williams reported the intermolecular amidation reaction of benzyl alcohols with amines in the presence of [Ru(p-cymene)Cl2]2 and 3-methyl-2-butanone [82bj. 

Gunanathan C, Ben-David Y, Milstein D (2007) Direct synthesis of amides from alcohols and amines with liberation of H2. Science 317 790... 

Cho D, Ko KC, Lee JY (2013) Catalytic mechanism for the ruthenium-complex-catalyzed synthesis of amides from alcohols and amines a DFT study. Organometallics 32 4571... 

Direct Synthesis of Amides from Alcohols and Amines.60... 

Fig. 5 Possible catalytic cycle for the direct synthesis of amides from alcohols and amines, catalyzed by the PNN ruthenium pincer complex 5...

In 2007, Milstein reported an approach for the transition metal catalysed intermolecular formation of amides from alcohols and amines in the absence of a hydrogen acceptor (Scheme 12.19). In contrast with conventional amide synthesis from activated carboxylic acid derivatives which produces chemical waste, this environmentally benign approach produces hydrogen gas as the only byproduct. The catalyst used for this reaction is a dearomatised Ru(PNN)pincer complex which serves as a bifunctional catalyst. The ligands, as well as the metal centre, play a role in bond making or bond breaking steps of the catalytic cycle. 

A-Alkylation of amides and amines and dehydrative -alkylation of secondary alcohols and a-alkylation of methyl ketones " have been carried out by an activation of alcohols by aerobic oxidation to aldehydes, with copper(II) acetate as the only catalyst. A relay race process rather than the conventional borrowing hydrogen-type mechanisms has been proposed for the aerobic C-alkylation reactions, based on results of mechanistic studies. A Winterfeldt oxidation of substituted 1,2,3,4-tetrahydro-y-carboline derivatives provides a convenient and efiflcient method for the synthesis of the corresponding dihydropyrrolo[3,2-fc]quinolone derivatives in moderate to excellent yields. The generality and substrate scope of this aerobic oxidation have been explored and a possible reaction mechanism has been proposed. Direct oxidative synthesis of amides from acetylenes and secondary amines by using oxygen as an oxidant has been developed in which l,8-diazabicyclo[5.4.0]undec-7-ene was used as the key additive and copper(I) bromide as the catalyst. It has been postulated that initially formed copper(I) acetylide plays an important role in the oxidative process. Furthermore, it has been postulated that an ct-aminovinylcopper(I) complex, the anti-Markovnikov hydroamination product of copper acetylide, is involved in the reported reaction system. Copper(I) bromide... 

Table 1.8 Synthesis of amides directly from alcohols and amines. ...

Synthesis of amides from the coupling reactions of esters and amines is a potentially attractive method however, stoichiometric amounts of promoters or metal mediators are normally required [52], Complex 8 also catalyzes the amide synthesis from esters and amines and the reaction is general and efficient, and proceeds under neutral conditions, thus providing an environmentally benign method [15]. As demonstrated in the alcohol acylation process (Section 1.3.3, Table 1.6), when symmetrical esters are used, acylation of amines occurs by both acyl and alkoxo parts of the esters and they are incorporated in the products, and the only byproduct generated from this reaction is H2. 

Ruthenium catalysts for hydroesterification are also known, but these catalysts typically operate by the addition of formates, rather than by the use of the combination of CO and alcohol. Nevertheless, some leading citations to this literature are provided here. In some cases, milder conditions have been developed with pyridylmethyl formates (Equation 17.36). These substrates were designed so that the pyridyl group would bind to the catalyst. -The synthesis of amides from olefins, CO, and amines is much less developed, and the most active catalyst for this process and for the addition of for-mamides to olefins is simply Ru3(C0)jj. Ruthenium-catalyzed hydroesterification with pyridylmethylformates has been used to prepare the lactone fragment of an HIV inte-grase inhibitor shown in Scheme 17.17. 

Nordstrpm LU, Vogt H, Madsen R (2008) Amide synthesis from alcohols and amines by the extrusion of dihydrogen. J Am Chem Soc 130 17672... 

Similar procedures (Table 12.1) for the synthesis of amides from amines and alcohols using homogeneous Ru, Rh, and Ir eatalysts have heen developed by the groups of Madsen (entries 1, 6, and Crabtree (entry... 

Amines and ammonia are good nucleophiles and are rather hard to displace, once a tetrahedral intermediate has been formed. The synthesis of amides from acid chlorides and amines has been widely applied (Figure 15.27). Notice in the second example that it is the nitrogen rather than the oxygen of the amino alcohol that acts as the nucleophile, and in the third example that the acid chloride is more reactive toward substitution than the aliphatic bromide. 

A number of selective transformations (Fig. 10) have been described which include the selective allylation on alcohols in the presence of amides [47], the Lewis acid catalyzed cleavage of benzyl alcohol esters with secondary amines to afford tertiary amides [48], the synthesis of ketones from Weinreb-type amides [49], and the synthesis of tertiary amines by a Michael addition/alkylation/Hoffman elimination sequence [50],... 

This ether is prepared by the Williamson ether synthesis from alcohols and phenols using a-bromomethylstyrene. It is cleaved by treating the ether in THF with f-BuLi at —78°C for 30 min (75-97% yield). The phenallyl ether can be cleaved in the presence of an allyl ether. Phenallyl amines and amides are cleaved similarly. Cleavage occurs by an addition of the alkyllithium to the olefin followed by elimination. 

SCHEME 10.21 One-pot synthesis of amides 67 from alcohols, amines, and cyanide. 

Acetamides have been prepared in moderate to good yield from alcohols by reaction with acetonitrile and sulphuryl chloride. It has been found that the hydrolysis of nitriles to amides can be effected in excellent yield using potassium hydroxide in t-butanol if the amide produced is relatively insoluble in water. Experimental details for the large scale anodic oxidation of iV-formyl derivatives of amines to a-methoxyalkylamides have been recorded, and an interesting synthesis of trichloroacetamides from allylic alcohols via a thermal [Att + 2a] rearrangement has been described (Scheme 50). ... 

This amidation process, poorly exploited till 2007 [100], regained popularity after Milstein s report on a highly efficient and atom-economical procedure that did not require a sacrificial hydrogen acceptor, the oxidations of the alcohol and the hemiaminal proceeding with formation of hydrogen gas as the only by-product [101]. The catalytic system, based on the PNN-pincer rathenium derivative 28, was successfully applied to the highly selective synthesis of a variety of secondary amides from 1 1 mixmres of primary alcohols and amines (Scheme 21). However, when amines with only a moderate nucleophilic character were employed as substrates, small amounts of esters were also formed as by-products. 

Chen C, Zhang Y, Hongs H (2011) V-heterocyclic carbene based ruthenium-catalyzed direct amide synthesis from alcohols and secondary amines involvement of esters. J Org Chem... 

An alternative synthesis of amide ions is the treatment of amines with alkali metals. Alkali metals dissolve in amines (albeit relatively slowly) with the evolution of hydrogen and the formation of amine salts (much as they dissolve in water and alcohol, furnishing H2 and metal hydroxides or alkoxides. Section 9-1). For example, sodium amide can be made in liquid ammonia from sodium metal in the presence of catalytic amounts of Fe, which facilitates electron transfer to the amine. In the absence of such a catalyst, sodium simply dissolves in ammonia (labeled Na, liquid NH3 ) to form a strongly reducing solution (Section 13-6). 

Chirality derived from the readily accessible a-amino acids has been incorporated into the side chains of aza and diaza macrocyclic polyethers. A number of procedures suitable for peptide synthesis have proved (178) to be unsuitable for acylating the relatively unreactive secondary amine groups of aza crown ethers. Eventually, it was discovered that mixed anhydrides of diphenylphos-phinic acid and alkoxycarbonyl-L-alanine derivatives do yield amides, which can be reduced to the corresponding amines, e.g., l-172. By contrast, the corresponding bisamides of diaza-15-crown-S derivatives could not be reduced and so an alternative approach, involving the use of chiral A-chloroacetamido alcohols derived from a-amino acids, has been employed (178) in the synthesis of chiral receptors, such as ll-173 to ll-175, based on this constitution. 

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