Acid chlorides into amides

I mines.2 Bis(dichloroaluminum)phenylimide (1) is useful for conversion of ketones as well as aldehydes to imines because the by-product is a stable dialu-minoxane (equation I). In addition the reagent converts acid chlorides into amides. The reagent is particularly useful for preparation of the anil (3) of chalcone (2). 

Conversion of Acid Halides into Amides Aminolysis Acid chlorides react rapidly with ammonia and amines to give amides. As with the acid chloride plus alcohol method for preparing esters, this reaction of acid chlorides with amines is the most commonly used laboratory method for preparing amides. Both monosubstituted and disubstituted amines can be used, but not trisubstituted amines (R3N). 

The reactions proceed via a phase-transfer mechanism [23]. The amine diffuses from the aqueous phase into the organic phase and reacts with the acid chloride. The amide formed remains in the organic phase, while the salt generated from the released HCI and the auxiliary base is transferred to the aqueous phase. 

Illustrative procedures are given in Expt 5.165 which also includes typical details for the transformation of the substituted acid chloride into the corresponding amide and carboxylic acid. 

Derivatives of the 3-carboxylic acid are noteworthy. Esters,94-96 the acid chloride,94 amide,94 and the hydrazide and several of its derivatives96-98 have been prepared, and the amide has been converted into the 3-amino compound,99 sulfonamides of which have been described.100... 

The synthetic importance of reaction (a) ° comes from the fact that it reduces to one step the pathway for conversion of an acid chloride into a nitrile (instead of the classical and rather inconvenient two-step route via an acid amide). Reaction is an example of a new transformation for aliphatic amines. Previously, there were no methods available for the direct transformation of an amino into a nitro group and the stepwise procedures were too cumbersome to be of practical use. Transformation of a nitro group into a carbonyl is a well-known reaction. Its modification, shown in reaction represents a welcome opportunity to obtain a protected carbonyl group as the immediate result of such a transformation. The viability of the sequential reactions (b) plus (c) enables the employment of a > CHNH2 moiety as a synthetic equivalent to a protected carbonyl group. A one-pot sequence of imine formation and its reduction with sodium triacetoxyborohydride represents a convenient... 

Hydrazides are normally made by the reaction of acid derivatives, such as esters, acid chlorides, or amides with hydrazine. The interaction of esters and hydrazine hydrate is very straight-forward and gives good yields. If the esters are liquid, simple addition of hydrazine hydrate to the diethyl ether solution of the esters will cause the precipitation of the hydrazide. If the esters are solid or insoluble, solvents such as methanol or ethanol are required. Normally, such reactions take place very rapidly. Diesters normally form dihydrazides if an excess of hydrazine is used. However, we have been able to convert some diesters into monoester-monohydrazide derivatives (e.g., (94) and (95)) by controlling the molar ratio in a highly diluted reaction (for typical examples see Scheme 23).96... 

It is usually possible to transform a more reactive carboxylic acid derivative into a less reactive derivative (e.g. an acid chloride into an amide). 

Sulphurated borohydrides can reduce oximes to amines the intermediate hydroxylamines are isolable. Sodium borohydride reduces nitriles to amines in high yield in the presence of Raney nickel as catalyst. The titanocene-promoted fixation-reduction of molecular nitrogen has been utilized in the conversion of ketones into amides and acid chlorides into nitriles in an overall reductive deoxygenation, as exemplified in Scheme 109. 

The choice of type of derivative should be based on whether the chloride or anhydride is aliphatic or aromatic, because this factoi largely determines the reactivity. Aliphatic acid chlorides are best converted into their anilides, as in 4 above aromatic acid chloride may be similarly converted into their anilides, or they may be converted into their amides by shaking with an excess of ammonia (p, 120). (M.ps., pp. 544-545.) Aliphatic acid anhydrides should be converted into their crystalline anilides, but aromatic acid anhydrides arc best hydrolysed to the acid, which can then be converted into one of the standard derivatives (p. 349). 

Amides, anilides and p toluidides. The dry acid is first converted by excess of thionyl chloride into the acid chloride ... 

Place 125 ml. of concentrated ammonia solution (sp. gr. 0-88) in a 600 ml. beaker and surround the latter with crushed ice. Stir the ammonia solution mechanically, and introduce the n-caproyl chloride slowly by means of a suitably supported separatory funnel with bent stem. The rate of addition must be adjusted so that no white fumes are lost. The amide separates immediately. Allow to stand in the ice water for 15 minutes after all the acid chloride has been introduced. Filter oflF the amide at the pump use the flltrate to assist the transfer of any amide remaining in the beaker to the Alter (2). Spread the amide on sheets of Alter or drying paper to dry in the air. The crude n-capro-amide (30 g.) has m.p. 98-99° and is sufficiently pure for conversion into the nitrile (Section 111,112) (3). Recrystallise a small quantity of the amide by dissolving it in the minimum volume of hot water and allowing the solution to cool dry on filter paper in the air. Pure n-caproamide has m.p. 100°. 

In most other reactions the azolecarboxylic acids and their derivatives behave as expected (cf. Scheme 52) (37CB2309), although some acid chlorides can be obtained only as hydrochlorides. Thus imidazolecarboxylic acids show the normal reactions they can be converted into hydrazides, acid halides, amides and esters, and reduced by lithium aluminum hydride to alcohols (70AHC(12)103). Again, thiazole- and isothiazole-carboxylic acid derivatives show the normal range of reactions. 

Properly substituted isoxazolecarboxylic acids can be converted into esters, acid halides, amides and hydrazides, and reduced by lithium aluminum hydride to alcohols. For example, 3-methoxyisoxazole-5-carboxylic acid (212) reacted with thionyl chloride in DMF to give the acid chloride (213) (74ACS(B)636). Ethyl 3-ethyl-5-methylisoxazole-4-carboxylate (214) was reduced with LAH to give 3-ethyl-4-hydroxymethyl-5-methylisoxazole (215) (7308(53)70). 

As a consequence of these reactivity differences, it s usually possible to convert a more reactive acid derivative into a less reactive one. Acid chlorides, foi instance, can be directly converted into anhydrides, thioesters, esters, and amides, but amides can t be directly converted into esters, thioesters, anhydrides, or acid chlorides. Remembering the reactivity order is therefore a way tc keep track of a large number of reactions (Figure 21.2). Another consequence, a noted previously, is that only acyl phosphates, thioesters, esters, and amides are... 

Acid halides are among the most reactive of carboxylic acid derivatives and can be converted into many other kinds of compounds by nucleophilic acyl substitution mechanisms. The halogen can be replaced by -OH to yield an acid, by —OCOR to yield an anhydride, by -OR to yield an ester, or by -NH2 to yield an amide. In addition, the reduction of an acid halide yields a primary alcohol, and reaction with a Grignard reagent yields a tertiary alcohol. Although the reactions we ll be discussing in this section are illustrated only for acid chlorides, similar processes take place with other acid halides. 

Conversion of Esters into Amides Aminolysis Esters react with ammonia and amines to yield amides. The reaction is not often used, however, because it s usually easier to start with an acid chloride (Section 21.4). 

Oxo-4,5-dihydro-l//-l,2,4-benzotriazepine-3-carboxylates8can be transformed into the acid chlorides 10 with phosphorus pentachloride and the crude products converted into various amides and esters 11 by treatment with amines and alcohols, respectively. Selected examples are given.347... 

Furthermore, oxazoles of type 9-82 bearing a secondary amino functionality can be converted into pyrrolo[3,4-b]pyridines 9-86 by reaction with appropriate acid chlorides 9-83 in a triple domino process consisting of amide formation/hetero Diels-Alder reaction and retro-Michael cycloreversion via 9-84 and 9-85 (Scheme 9.17). The pyrrolo[3,4-fc]pyridines can be obtained in even higher yields when the whole sequence is carried out as a four-component synthesis in toluene. Here, 1.5 equiv. NH4C1 must be added for the formation of the now intermediate oxazoles [56b]. 

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