Amides examples

Direct thiation is used predominantly for the synthesis of annelated thiazoles, most often from heterocyclic acyl-amides. Examples are highlighted in CHEC-II(1996) <1996CHEC-II(7)49> no further examples have been reported in this period. 

By treatment of an amide with sodium hypobromite or sodium hypochlorite solution (or with halogen admixed with aqueous alkali), a primary amine having one less carbon atom is produced. Good yields are obtained when the reaction is applied to most aliphatic and aromatic amides. Examples are provided by the preparation of anthranilic acid and 3-aminopyridine (Expt 6.53). 

Hydrozirconation of imines.1 Reaction of Schiff bases containing an a-hydrogen with 1 followed by acylation provides a route to enamides and/or imides and amides. Examples ... 

The transition metal catalyzed synthesis of arylamines by the reaction of aryl halides or tri-flates with primary or secondary amines has become a valuable synthetic tool for many applications. This process forms monoalkyl or dialkyl anilines, mixed diarylamines or mixed triarylamines, as well as N-arylimines, carbamates, hydrazones, amides, and tosylamides. The mechanism of the process involves several new organometallic reactions. For example, the C-N bond is formed by reductive elimination of amine, and the metal amido complexes that undergo reductive elimination are formed in the catalytic cycle in some cases by N-H activation. Side products are formed by / -hydrogen elimination from amides, examples of which have recently been observed directly. An overview that covers the development of synthetic methods to form arylamines by this palladium-catalyzed chemistry is presented. In addition to the synthetic information, a description of the pertinent mechanistic data on the overall catalytic cycle, on each elementary reaction that comprises the catalytic cycle, and on competing side reactions is presented. The review covers manuscripts that appeared in press before June 1, 2001. This chapter is based on a review covering the literature up to September 1, 1999. However, roughly one-hundred papers on this topic have appeared since that time, requiring an updated review. 

Alkanolamides are the reaction products of mono- or dialkanolamines with fatty acids or their esters to form the respective secondary or tertiary amides, examples of which are depicted in Scheme 1.8. " Monoalkanolamides can be prepared by the reaction of monoalkanolamines with triglycerides such as coconut or palm kernel oil as well as from fatty acids or their methyl esters. The reaction of MEA with triglyceride at temperatures of 140-160°C liberates glycerin as a by-product, and because of the stability of the secondary amide formed, the reaction can be driven to a very low ester content with only a slightly super-stoichiometric amount of MEA. 

Many organosilanes have been employed over the years as crosslinkers speed of reaction, the nature of the byproducts, and cost have been major factors in the selection of systems for commercialization. Crosslinker silanes that have been employed are those that afford as byproducts alcohols,carboxylic acids, amines, ketoximes, aldoximes, and amides.Examples of some of these organosilanes are shown below ... 

By analogy, ammonium salts should behave as acids in liquid ammonia, since they produce the cation NH4 (the solvo-cation ), and soluble inorganic amides (for example KNHj, ionic) should act as bases. This idea is borne out by experiment ammonium salts in liquid ammonia react with certain metals and hydrogen is given off. The neutralisation of an ionic amide solution by a solution of an ammonium salt in liquid ammonia can be carried out and followed by an indicator or by the change in the potential of an electrode, just like the reaction of sodium hydroxide with hydrochloric acid in water. The only notable difference is that the salt formed in liquid ammonia is usually insoluble and therefore precipitates. 

Reactions with electropositive metals. Ammonia gas reacts with strongly electropositive metals to form the amide, for example... 

As an example, experimental kinetic data on the hydrolysis of amides under basic conditions as well as under acid catalysis were correlated with quantitative data on charge distribution and the resonance effect [13]. Thus, the values on the free energy of activation, AG , for the acid catalyzed hydrolysis of amides could be modeled quite well by Eq. (5)... 

In Eq. (16 i denotes an atom up to lour non-rotatable bonds away from the proton and is the total number of those atoms. A bond is deRned as non-rotatable if it belongs to a ring, to a. T-system, or to an amide functional group q- is the partial atomic charge of the atom i, and is the 3D distance between the proton j and the atom i. Figure 10.2-5 shows an example of a proton RDF descriptor. 

By the action of concentrate aqueous ammonia solution upon esters. This process is spoken of as ammonolysls of the ester, by analogy with hydrolysis applied to a similar reaction with water. If the amide is soluble in water, e.g., acetamide, it may be isolated by distillation, for example ... 

Sparingly soluble amides crystallise out from the reaction mixture upon standing, for example ... 

The reaction is applicable to the preparation of amines from amides of aliphatic aromatic, aryl-aliphatic and heterocyclic acids. A further example is given in Section IV,170 in connexion with the preparation of anthranilic acid from phthal-imide. It may be mentioned that for aliphatic monoamides containing more than eight carbon atoms aqueous alkaline hypohalite gives poor yields of the amines. Good results are obtained by treatment of the amide (C > 8) in methanol with sodium methoxide and bromine, followed by hydrolysis of the resulting N-alkyl methyl carbamate ... 

By treatment of this oxime with phosphorus pentachloride or thionyl fhloride in ether solution, smooth conversion into benzanilide, m.p. 163°, results. The change of any oxime into a substituted amide under the conditions mentioned is usually termed the Beckmann rearrangement. The above example may be represented ... 

The melting points of some typical substituted aromatic amides are collected in Table IV,192. Other examples will be found in the appropriate columns of Tables IV,100A and B Primary and Secondary Aromatic Amines) and of Table IV,175 (Aromatic Carboxylic Acids). 

It will be observed that the reaction involves two equivalents of the amine and produces, in addition to the substituted amide, an equivalent quantity of the amine hydrochloride. Acetic anhydride, on the other hand, converts the amine quantitatively into the acyl derivative, for example ... 

The conversion of acetylenes into acetyl ides, M-C=C-R (M = Li, Na, K, MgBr), by means of alkyllithium or Grignard reagents in organic solvents or by alkali metal amides in liquid ammonia is well documented (for practical examples see ref. 1, for review articles consult inter alia refs. 2-5). 

The formation of the above anions ("enolate type) depend on equilibria between the carbon compounds, the base, and the solvent. To ensure a substantial concentration of the anionic synthons in solution the pA" of both the conjugated acid of the base and of the solvent must be higher than the pAT -value of the carbon compound. Alkali hydroxides in water (p/T, 16), alkoxides in the corresponding alcohols (pAT, 20), sodium amide in liquid ammonia (pATj 35), dimsyl sodium in dimethyl sulfoxide (pAT, = 35), sodium hydride, lithium amides, or lithium alkyls in ether or hydrocarbon solvents (pAT, > 40) are common combinations used in synthesis. Sometimes the bases (e.g. methoxides, amides, lithium alkyls) react as nucleophiles, in other words they do not abstract a proton, but their anion undergoes addition and substitution reactions with the carbon compound. If such is the case, sterically hindered bases are employed. A few examples are given below (H.O. House, 1972 I. Kuwajima, 1976). 

Regioselectivity becomes important, if unsymmetric difunctional nitrogen components are used. In such cases two different reactions of the nitrogen nucleophile with the open-chain educt may be possible, one of which must be faster than the other. Hydrazone formation, for example, occurs more readily than hydrazinoLysis of an ester. In the second example, on the other hand, the amide is formed very rapidly from the acyl chloride, and only one cyclization product is observed. 

The purity of the peptide finally obtained depends critically on the yield of each cycle. It must be extraordinarily good to produce even moderately pure products (K. Ltibke, 1975). If the average yield of amide formadon in the synthesis of an undecapeptide (n = 10) is. for example, 98< to, the product will contain already about 20% of different impurities which may be difficult to remove. 

The "zip-reaction (U. Kramer, 1978, 1979) leads to giant macrocycles. Potassium 3- ami-nopropyl)amide = KAPA ( superbase ) in 1,3-diaminopropane is used to deprotonate amines. The amide anions are highly nucleophilic and may, for example, be used to transam-idate carboxylic amides. If N- 39-atnino-4,8,12,16,20,24,28,32,36-nonaazanonatriacontyl)do-decanolactam is treated with KAPA, the amino groups may be deprotonated and react with the macrocyclic lactam. The most probable reaction is the intramolecular formation of the six-membered ring intermediate indicated below. This intermediate opens spontaneously to produce the azalactam with seventeen atoms in the cycle. This reaction is repeated nine times in the presence of excess KAPA, and the 53-membered macrocycle is formed in reasonable yield. 

As a further application of the reaction, the conversion of an endocyclic double bond to an c.xo-methylene is possible[382]. The epoxidation of an cWo-alkene followed by diethylaluminum amide-mediated isomerization affords the allylic alcohol 583 with an exo double bond[383]. The hydroxy group is eliminated selectively by Pd-catalyzed hydrogenolysis after converting it into allylic formate, yielding the c.ro-methylene compound 584. The conversion of carvone (585) into l,3-disiloxy-4-methylenecyclohexane (586) is an example[382]. 

Another variation of the Madelung synthesis involves use of an O-alkyl or O-silyl imidate as the C2 electrophile. The mechanistic advantage of this modification stems from avoiding competing N-deprotonation, which presumably reduces the electrophilicity of the amide group under the classical conditions. Examples of this approach to date appear to have been limited to reactants with a EW substituent at the o-alkyl group[15,16]. 

Another category Ic indole synthesis involves cyclization of a-anilino aldehydes or ketones under the influence of protonic or Lewis acids. This corresponds to retro.synthetic path d in Scheme 4.1. Considerable work on such reactions was done in the early 1960s by Julia and co-workers. The most successful examples involved alkylation of anilines with y-haloacetoacetic esters or amides. For example, heating IV-substituted anilines with ethyl 4-bromoacetoacetate followed by cyclization w ith ZnClj gave indole-3-acetate esterfi]. Additional examples are given in Table 4.3. 

One of the virtues of the Fischer indole synthesis is that it can frequently be used to prepare indoles having functionalized substituents. This versatility extends beyond the range of very stable substituents such as alkoxy and halogens and includes esters, amides and hydroxy substituents. Table 7.3 gives some examples. These include cases of introduction of 3-acetic acid, 3-acetamide, 3-(2-aminoethyl)- and 3-(2-hydroxyethyl)- side-chains, all of which are of special importance in the preparation of biologically active indole derivatives. Entry 11 is an efficient synthesis of the non-steroidal anti-inflammatory drug indomethacin. A noteworthy feature of the reaction is the... 

Oxidative dimerization of various 2-benzyloxy-2-thiazoline-5-ones (222) catalyzed by iodine and triethylamine is another example of the nucleophilic reactivity of the C-4 atom (469) (Scheme 112). Treatment of 212 with pyrrolidinocyclohexene yields the amide (223) (Scheme 113). The mechanism given for the formation of 223 is proposed by analogy with the reactivitx of oxazolones with enamines (4701. 4-Substituted 2-phenylthiazol-5(4Hi-ones react with A -morphoiino-l-cyclohexene in a similar manner (562j. Recently. Barret and Walker have studied the Michael addition products... 

Thiazolecarboxylic acid hydrazides are prepared by the same general methods used to prepare amides, that is, by treating acids, esters, amides, anhydrides, or acid halides with hydrazine or substitued hydrazines. For example, see Scheme 21 (92). The dihydrazides are obtained in the same way (88). With diethyl 2-chloro-4,5-thiazoledicarboxylate this reaction gives the mono hydr azide monoester of 2-hydrazine-4,5-... 

Water can also be a Brpnsted acid donating a proton to a base Sodium amide (NaNH2) for example is a source of the strongly basic amide ion which reacts with water to give ammonia... 

Example A common misconception is that the conjugate base of a weak acid is strong This is sometimes but not always true It is true for example for ammo nia which is a very weak acid (pK 36) Its conjugate base amide ion (H2N ) is a much stronger base than HO It is not true however for acetic acid both acetic acid and its conjugate base acetate ion are weak The conjugate base of a weak acid will be strong only when the acid is a weaker acid than water... 

Double dehydrohalogenation of gemmal dihalides (Section 9 7) An E2 elimination reaction of a gemmal dihalide yields an alkenyl halide If a strong enough base IS used sodium amide for example a second elimination step follows the first and the alkenyl halide IS converted to an alkyne... 

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