Amines with acyl chlorides

Amides are readily prepared by acylation of ammonia and amines with acyl chlorides acid anhydrides or esters... 

Reaction of amines with acyl chlorides (Section... 

Section 20.14 Amides are noimally prepared by the reaction of amines with acyl chlorides, anhydrides, or esters. 

Reaction of amines with acyl chlorides (Section 20.4) Amines are converted to amides on reaction with acyl chlorides. Other acylating agents, such as carboxylic acid anhydrides and esters, may also be used but are less reactive. 

On the other hand, Kim and Le reported that the use of PS-BEMP was very convenient for the A -acylation of several weakly nucleophihc heterocychc amines with acyl chloride (Scheme 6.1) [25]. In this example, treatment with polymer-based trisamine after completion of the reaction with PS-BEMP was convenient for removing excess acyl chloride. Thus, the corresponding A -acylated compounds could be obtained in good yields and high purities by simple filtration. The utility of PS-BEMP as an acid scavenger has also been established in other types of transformations to make free amines from their salts [26]. 

Synthesis of Amides Tables 19.1, 19.2, and 19.4 included nucleophilic acyl substitutions that are useful for preparing amides by the reaction of amines with acyl chlorides, anhydrides, and esters, respectively. These are the most common methods for the laboratory synthesis of amides. 

Because acylation of amines with acyl chlorides and anhydrides yields an acid as one of the products (HCl from acyl chlorides, a carboxylic acid from an anhydride), the efficient synthesis of amides requires some attention to stoichiometry. 

Two molar equivalents of amine are required m the reaction with acyl chlorides and acid anhydrides one molecule of amine acts as a nucleophile the second as a Brpnsted base... 

With more strongly basic tertiary amines such as triethylamine, another mechanism can come into play. It has been found that wften methanol deuterated on oxygen reacts with acyl chlorides in the presence of triethylamine, some deuterium is found a to the carbonyl group in the ester... 

Incorporation of extensive branching in the side chain similarly does not decrease pharmacologic activity. Reductive alkylation of aminoalcohol, 42, with isobutyraldehyde affords the amine, 43. Acylation of the amine with benzoyl chloride probably goes initially to the amide (44). The acid catalysis used in the reaction leads to an N to 0 acyl migration to afford iso-bucaine (45). ... 

It must further be mentioned that the acylation of alcohols, phenols, and amines with acid chlorides (and also anhydrides) is now frequently carried out in pyridine solution instead of according to the older Schotten-Baumann method (action of acid chloride in aqueous-alkaline suspension). The hydrogen chloride is fixed by the pyridine. 

Additional work was carried out by the GE group on optimization of the reaction yield and to eliminate unwanted linear oligomers [14], Three side reactions which interfere with synthesis of cyclics were identified reaction of the amine with acid chloride to form an acyl ammonium salt, followed by decomposition to an amide (Equation (3.2)) reaction with CH2CI2 to form a salt (Equation (3.3)) hydrolysis of the acid chloride, forming carboxylate via catalysis... 

The use of ethylene adduct lb is particularly important when the species added to activate catalyst la is incompatible with one of the reaction components. Iridium-catalyzed monoallylation of ammonia requires high concentrations of ammonia, but these conditions are not compatible with the additive [Ir(COD)Cl]2 because this complex reacts with ammonia [102]. Thus, a reaction between ammonia and ethyl ciimamyl carbonate catalyzed by ethylene adduct lb produces the monoallylation product in higher yield than the same reaction catalyzed by la and [Ir(COD)Cl]2 (Scheme 27). Ammonia reacts with a range of allylic carbonates in the presence of lb to form branched primary allylic amines in good yield and high enantioselectivity (Scheme 28). Quenching these reactions with acyl chlorides or anhydrides leads to a one-pot synthesis of branched allylic amides that are not yet directly accessible by metal-catalyzed allylation of amides. 

Quantitative stoichiometric gas-solid or solid-solid (these at 0 °C) acylations of amines with acid chlorides are varied (Scheme 32). However, for a clean reaction the liberated hydrochloric acid has to be neutralized by an additional gaseous or solid base that may also be a second mole of the amine. The reactions are performed in an evacuated flask or in a ball-mill, respectively. There are only minimal losses of the amides or sulfonamides upon removal of the stoichiometric coproduct with water [91]. The solid-solid reactions can be turned into sustainable 100% yield processes with optimal atom efficiency by milling stoichiometric 1 1 1 mixtures of acid chloride, aniline derivative, and K2CO3... 

A -Unsubstituted 1,2,4-diazaphospholes (4) undergo A -alkylation by reaction with alkyl vinyl ether, sulfur ylides, and diazo compounds <95HAC403>. They react with acyl chlorides in a 2 1 molar ratio to give a mixture of the A -acylated diazaphosphole and the diazaphosphole hydrochloride. Preparative A -acyclation is achieved in presence of a tertiary amine. Sulfonyl chlorides and phosphorus trichloride also give A -substitution reactions (Scheme 2) <87TH 422-01 >. 

Acylations of anions formed by deprotonation of azinones are not described in previous editions <1984CHEG(2)1, 1996CHEC-II(6)1>. 4,5-Dichloropyridazin-3(2//)-one is smoothly acylated at N-2 with acyl chlorides in the presence of triethylamine in dichloromethane at room temperature, —10 or —22°C <2002S733>. The resulting compounds have been used as mild acylating reagents for amines (see Section 8.01.8.4). 

J.H. Cooley u. E.J. Evain, Synthesis 1989, 1-7 Amine Dealkylations with Acyl Chlorides". 

An additional modification in the above synthetic scheme is possible by introducing the aromatic diamine in the form of its trimethylsilyl derivative [72]. Monotrimethylsilyl-substituted amines are readily prepared from the free amine with hexamethyldisilazane or trimethylsilyl chloride in the presence of a tertiary amine [73, 74] whereas bis(trimethylsilyl)-substituted amines require more aggressive reagents, such as butyllithium in conjunction with trimethylsilyl chloride [75]. As illustrated in Scheme 19, monotrimethylsilyl-substituted amines react with acyl chlorides to form the corresponding amides and liberate trimethylsilyl chloride. Monotrimethylsilyl-substituted amines are reported to display increased reactivity with acyl chlorides [76], This is of great synthetic importance since the increased reactivity allows for reaction with low basicity amines. Bis(trimethylsilyl)-substituted amines, on the other hand, react with acyl chlorides to form the corresponding JV-trimethylsilyl amides, see Scheme 20. The JV-trimethylsilyl amides are much more soluble in common organic solvents. However, they are hydrolytically unstable and readily convert back to the free amides. 

Amino groups react very easily with aldehydes or ketones, and with aldehydes in the presence of amines, they can be acylated by the usual acylating agents, and they react with amidacetals, Vilsmeier reagents and nitroso compounds (Scheme 12). As mentioned earlier, alkylation leads mainly to AT(2)-alkylated products. The hydrazino group reacts in the same way as the amino group with aldehydes or ketones, with acyl chlorides or carboxylic anhydrides, with sulfonyl chlorides, ortho esters, carbon disulfide and with nitrous acid. The last three reactions have mainly been used for the synthesis of condensed 1,2,4-triazines. 

We have seen that amines react with acyl chlorides to give amides. A very similar reaction occurs with sulfonyl chlorides to give sulfonamides. An... 

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