Tertiary amine amide formation

Scheme 55, Eq. 55a) [119]. A plausible mechanism is depicted in Scheme 55 and involves radical addition of the 2-tetrahydrofuryl radical to the aldehyde followed by a rapid reaction of the alkoxyl radical with Et3B. Triethylborane has a crucial role since by reacting with the alkoxyl radical it favors the formation of the condensation product relative to the -fragmentation process (back reaction). A similar reaction with tertiary amines, amides and urea is also possible (Eq. 55b) [120]. 

The preparation of amines by the methods described m this section involves the prior synthesis and isolation of some reducible material that has a carbon-nitrogen bond an azide a nitrile a nitro substituted arene or an amide The following section describes a method that combines the two steps of carbon-nitrogen bond formation and reduction into a single operation Like the reduction of amides it offers the possibility of prepar mg primary secondary or tertiary amines by proper choice of starting materials... 

In classical organic chemistry, nltrosamlnes were considered only as the reaction products of secondary amines with an acidified solution of a nitrite salt or ester. Today, it is recognized that nitrosamines can be produced from primary, secondary, and tertiary amines, and nltrosamides from secondary amides. Douglass et al. (34) have published a good review of nitrosamine formation. For the purposes of this presentation, it will suffice to say that amine and amide precursors for nitrosation reactions to form N-nitroso compounds are indeed ubiquitous in our food supply, environment, and par-... 

Angelici and Brink (40) have found that in the reactions of amine with trans-M(CO),(PPhMe2)2+ (M = Mn or Re), the rate of carbamoyl formation follows the order, n-butylamine > cyclohexyl-amine >, isopropylamine > sec-butylamine >> tert-butylamine, implying a strong steric effect in carbamoyl formation. A similar order has been observed in the rate of reaction of organic esters with amines to form amides (41). The data in Table III indicate that a steric effect may be operative in the Ru (CO) /NR3-catalyzed WGSR, since with tertiary amines the rate follows the order, NMeQ > MeNC.H > NEt > NBu0, which does not reflect the basicity of these amines. 

Do not use brominated nitropropanes/dioxanes for applications at pH above 8 or temperature above 60°C because of decomposition, or with secondary or tertiary amines or amides because of formation of health hazards [17]. 

There has been a study of the mechanism of the activation of carboxylic acids to peptide formation by chloro-s -triazines in combination with tertiary amines. The first step, exemplified in Scheme 2 by the reaction of 2-chloro-4,6-disubstituted-l,3,5-triazines (18) with A -methylmorpholine, is formation of a quaternary triazinylammonium salt (20). Here there is NMR evidence for the formation at —50°C of the intermediate (19), showing that the substitution involves the two-step SnAt mechanism rather than a synchronous pathway. The subsequent reaction of (20) with a carboxylic acid yields the 2-acyloxy derivative (21), which carries an excellent leaving group for the amide-forming step. ... 

The scope of nitrolysis is huge, with examples of nitramine formation from the cleavage of tertiary amines, methylenediamines, carbamates, ureas, formamides, acetamides and other amides. The deflnition of nitrolysis must be extended to the nitrative cleavage of other nitrogen bonds because sulfonamides and nitrosamines are also important substrates for these reactions. The nitrative cleavage of silylamines and silylamides is also a form of nitrolysis (Section 5.7). 

Amines may also behave as nucleophiles (Lewis bases). Primary amines are stronger nucleophiles than secondary amines, which, in turn, are stronger nucleophiles than tertiary amines. As nucleophiles, amines attack acid chlorides to form amides. Later in this chapter you see that they re important in the formation of sulfonamides. 

Two equivalents of the tertiary amine base are required, and a significant improvement in the diastereoselectivity was observed with TMEDA over DIPEA. Purification and further enrichment of the desired RRR isomer to >98% ee was achieved by crystallization. Oxidative removal of the chiral auxiliary followed by carbodiimide mediated amide formation provides (3-keto carboxamide 14 in good yield. Activation of the benzylic hydroxyl via PPha/DEAD, acylation, or phosphorylation, effects 2-azetidinone ring-closure with inversion of stereochemistry at the C4 position. Unfortunately, final purification could not be effected by crystallization and the side products and or residual reagents could only be removed by careful chromatography on silica. 

In addition to the mentioned side products, formation of the piperidyl amide of the linear precursors has been observed as deriving from the piperidine-mediated cleavage of the Fmoc/OFm groups used for intermediate protection of the functionalities involved in the cyclization. In these cases, a brief washing with 0.4% (v/v) concentrated aqueous HC1 in DMFt375l or with tertiary amines, e.g. DIPEA/369 prior to cyclization is recommended in order to displace the piperidine. Moreover, both these extra washings were found to shorten the cyclization time to 2 hours with BOP and 0.5 hours with HATU. 

Acylation of A-hydroxy-2-phenylbutyramidine (112-1) with 3-chloropropionyl chloride in the absence of an added base proceeds as might be expected to give the product (112-2) from acylation on the more basic nitrogen. Heating this compound leads to the formation of the oxadiazole (112-3) almost certainly via the enol tautomer of the amide. Displacement of the terminal chlorine with diethylamine leads to the tertiary amine and thus proxazole (112-4) [123], a compound that is said to exhibit antispasmodic activity. 

In a detailed study on phosphonate diester and phosphonamidate synthesis, Hirschmann, Smith, and co-workers reported that pyrophosphonate anhydrides may be produced as side products during conversion of phosphonate monoesters into phosphonochloridates. 72 They recommended adding the phosphonate monoester to a solution of the chlorinating agent (thionyl chloride or oxalyl chloride) to minimize formation of the less reactive anhydrides. They also found that addition of tertiary amines (e.g., TEA) to the phosphonochloridates, prior to addition of the alcohol or amine component, results in formation of a phospho-nyltrialkylammonium salt that is more reactive than the corresponding phosphonochloridate and leads to better yields of the phosphonate esters and amides. 

Several reports have described the formation of alkyl formates or form-amides from C02, hydrogen, and an alcohol or amine. The earlier catalytic preparations have been reviewed (108). A recent paper describes the production of alkyl formates catalyzed by several transition metal complexes and tertiary amines under 25 atm each of C02 and H2 at 140°C, (78) (159). 

Formation of a tertiary amine requires a tertiary amide. 

Our experience with tributylamine shows that its cathodic potential limit may be as low as 0 V Li/Li+. The cathodic limiting reaction may be the reduction of the cation (for alkaline metals and TAA salts). We have evidence that tributylamine reacts with lithium to form amides (RjNLi, 0 < x < 2, ldeposition potentials of the alkaline metals are reached, trialkylamine solvents will react with the deposits. The anodic limit of most of the trialkylamines, as well as of secondary amines, is in the 3.5-4 V range versus Li/Li+. The reaction is probably the formation of tetraalkyl ammonium cations, protons, and nitrogen. Hence, the electrochemical limit of amines may range between 2-4 V (higher for the tertiary amines). 

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