Synthesis of amides

A promising new method for converting esters to amides involves aluminum amides which can be prepared from trimethylaluminum and ammonia or an amine. These reagents convert esters directly to amides at room temperature. The driving 

The cyano group is at the carboxylic acid oxidation level so nitriles are potential precursors of primary amides. Partial hydrolysis is sometimes possible.A milder 

Give the products which would be expected to be formed under the specified reaction conditions. Be sure to specify all aspects of stereochemistry. 

CHAPTER 3 FUNCTIONAL GROUP INTERCONVERSION BY NUCLEOPHILIC SUBSTITUTION 

A careful investigation of the extent of isomeric products formed by reaction of several alcohols with thionyl chloride has been reported. The product compositions for several of the alcohols are given below. Show how each of the rearranged products arises and discuss the structural features which promote isomerization. 

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Nonionic template synthesis of amide-linked catenanes and rotaxanes with macroheterocyclic fragments 97AG(E)930. 

The usual methods for the synthesis of amides bearing an a-oxygen substituent will briefly be discussed below. 

Also the impact of various reaction parameters on enzymatic synthesis of amide surfactants from ethanolamine and diethanolamine has been studied, although the possibilities of acyl migration are not investigated. However, it was found that the selectivity of the reaction depended on the solubility of the product in the solvent used, and that the choice of solvent was critical to obtain an efficient process [17]. 

Scheme 6. Synthesis of amide functionalized primary phosphines...

The use of N3P3CI8 in the synthesis of amides has been described, although the fate of the phosphazene ring system was not clear ... 

Synthesis of amides from amines and acid chlorides Glass DCM 77 EOF... 

Related redox transformations allow the conversion of ynals to a,P-nnsaturated esters [33], as well as the ring expansion of formyl P-lactams [34], oxacycloalkane-2-carboxaldehydes [35], and 2-acyl-1-formyIcyclopropanes [36], Farther developments allow the synthesis of amides from a range of a-fnnctionalised compounds, but require an additive (imidazole, HO At or HOBt) for efficient amidation [37],... 

A mixed anhydride probably is formed as an intermediate which is cleaved inter-molecularily by the imidazole set free in the first step. For example, reaction with the compound in which R1 =thymyl and R2 = C6H5 yielded quantitatively O-thymylphos-phoric imidazolide and benzoylimidazole.[25 Phosphoryldiimidazoles are also used as condensing agents for the synthesis of amides and peptides, as well as for phosphorylations (see Chapters 4, 5 and 12). 

Examples are given in Table 4—1 for the synthesis of amides of AT-protected amino acids by means of imidazolides and triazolides (where Z and Boc represent the protecting groups benzyloxycarbonyl and terf-butoxycarbonyl) ... 

A modification of this method, related to the Beckmann rearrangement, entails treatment of a ketoxime with one equivalent of CDI, then four to five equivalents of a reactive halide such as allyl bromide or methyl iodide (R3X) under reflux in acetonitrile for 0.5-1.5 h. Quatemization of the imidazole ring effectively promotes the reaction by increasing the electron-withdrawing effect. The target amides then are obtained by hydrolysis. High yields, neutral conditions, and a very simple procedure make this modification of the synthesis of amides by azolides a very useful alternative. 1243... 

Other heterocyclic amines used for the synthesis of amides include, among others, 4-amino-1,2,3-trimethylpyrazolone (27%) and 6-aminoindazole (15%). 

The broad use of A -carbonyldiimidazole (CDI) for the synthesis of amide and peptide linkages became a routine method only in the early sixties. JV-Protected amino acids were treated at room temperature with an equimolar amount of CDI to give imidazolides. Anhydrous tetrahydrofuran, dimethoxyethane, dichloromethane, pyridine, dimethylfor-mamide, and diethyl phosphite were utilized as solvents. In the second step the esters of amino acids, their hydrochlorides, or sodium salts were added to yield the peptide after several minutes or hours of reaction time. 

The insertion of unsaturated molecules into metal-carbon bonds is a critically important step in many transition-metal catalyzed organic transformations. The difference in insertion propensity of carbon-carbon and carbon-nitrogen multiple bonds can be attributed to the coordination characteristics of the respective molecules. The difficulty in achieving a to it isomerization may be the reason for the paucity of imine insertions. The synthesis of amides by the insertion of imines into palladium(II)-acyl bonds is the first direct observation of the insertion of imines into bonds between transition metals and carbon (see Scheme 7). The alternating copolymerization of imines with carbon monoxide (in which the insertion of the imine into palladium-acyl bonds would be the key step in the chain growth sequence), if successful, should constitute a new procedure for the synthesis of polypeptides (see Scheme 7).348... 

This novel resin-bound CHD derivative was then utilized in the preparation of an amide library under microwave irradiation. Reaction of the starting resin-bound CHD with an acyl or aroyl chloride yields an enol ester, which, upon treatment with amines, leads to the corresponding amide, thus regenerating the CHD. This demonstrates the feasibility of using the CHD resin as a capture and release reagent for the synthesis of amides. The resin capture/release methodology [126] aids in the removal of impurities and facilitates product purification. 

Ester aminolysis, in general, occurs under harsh conditions that require high temperatures and extended reaction periods or the use of strong alkali metal catalysts. An efficient solid state synthesis of amides from nonenolizable esters and amines using KO Bu under the action of microwave irradiation [97] has been described. The reaction of esters with octylamine was extensively studied to identify possible micro-wave effects [98] (Eq. (45) and Tab. 3.20). 

An interesting solid-state synthesis of amides has also been reported in a MW oven that uses potassium tert-butoxidc and easily accessible reagents, nonenolizable esters and amines [83]. 

Table 13 Some of the recent applications of 1-hydroxybenzotriazole in the synthesis of amides...

The polymer-supported 5-chloromethyl-l,2,4-oxadiazole 162 undergoes easy reaction with primary amines to give the 5-aminomethyl oxadiazoles 163, which serve as excellent substrates for the synthesis of amides or sulfonamides 164 (Scheme 21 - yields not reported) <1999TL8547>. 

Humphrey CE, Easson MAM, Tierney JP, Turner N (2003) Capture and release reagent for the synthesis of amides and novel scavenger resin. J Org Lett 5 849-852... 

R. Jager, F. Vogtle, A New Synthetic Strategy towards Molecules with Mechanical Bonds Nonionic Template Synthesis of Amide-Linked Catenanes and Rotaxanes , Angew. Chem Int. Ed. Engl. 1997,36,930-944. 

S Kim, A Chang, YK Ko. Benzotriazol-l-yl diethyl phosphate. A new convenient coupling reagent for the synthesis of amides and peptides. Tetrahedron Lett 26, 1341, 1985. 

FIGURE 8.3 Synthesis of amides by aminolysis of unisolated activated esters obtained using carbodiimide by (A) ammonium hydroxide,12 (B) diaminomethane dihydrochloride neutralized with Et3N,15 and (C) the amine of crystalline salts of additives, R = H, Me, Et.13 DCC = dicyclohexylcarbodiimide HOBt = 1-hydroxybenzotriazole HONSu = A-hydroxysuccin-imide HONp = p-nitrophcnol HODhbt = 3-hydroxy-4-oxo-3,4-dihydrobenzotriazine. 

Amides contain an acid portion and an amine portion. However, unlike the formation of an ester, the reaction of a carboxylic acid with an cimine is not an efficient method for preparing an amide, because, as you see in this section, the simple reaction of an acid (carboxylic acid) with a base (amine) causes interference. Fortunately, methods similar to many of the other ester synthesis methods are useful in the synthesis of amides. 

Table 29 Synthesis of amide precursors 307b-m for the synthesis of 11 -aza-9-desmethyiartemisinin derivatives 308b-m <1995JME5038>...

When the ratio of template to acid is close to 0.5, the viscosity of the product is more than 3 times higher than the viscosity of the polymer obtained without the template. PEO participates in the change of local concentration by interaction with carbonyl groups, but not in the activation. Solution of LiCl in N-methylpyrrolidone with PlOCeHsls was found very effective system for synthesis of amides by the direct reaction of acids with amines in the presence of polymeric matrix. High molecular weight poly(aminoacids) obtained by direct polycondensation reaction, promoted by triphenyl phosphite and LiCl in the presence of poly(vinylpyrrolidone), were synthesized by Higashi et al The results for polymerization of L-leucine in the presence of poly(vinyl pyrrolidone) are presented in the Table 6.3. 

A.L.J. Beckwith, Synthesis of Amides, in J. Zabicki u. S. Patai, The Chemistry of Functional Groups, The Chemistry of Amides, S. 73, J. Wiley Sons, New York 1970. 

Similarly, glutaryl acylase was used as a biocatalyst in the synthesis of amides of glutaric acid derivatives using the acyl donor as the liquid phase in which the undissolved nucleophile was suspended [33]. In another example, immobilized lipase was used in a medium composed solely of substrate to resolve racemic ketoprofen esters via hydrolysis [36]. 

Kumari, K. A. Sreekumar, K. Polymeric Acyl Transfer Reagents Synthesis of Amides Using Polystyrene Supported Oximino Esters, Polymer 1996,37, 171. 

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