Heterocycles, acylation amination

Ring-closing metathesis is well suited for the preparation of five- or six-membered heterocycles, and has also been successfully used to prepare tetrahydropyridines on insoluble supports (Entries 1 and 2, Table 15.23). Because metathesis catalysts (ruthenium or molybdenum carbene complexes) are electrophilic, reactions should be conducted with acylated amines to avoid poisoning of the catalyst. 

The [3 + 2] annulation reaction can be extended to the synthesis of heterocycles. Thus, the reaction of crotylsilanes with in situ-generated imines produces, diastereoselectively, [3 + 2] adducts 208 at low temperature or homoallylic iV-acyl amines 209 at elevated temperature (equation 171)311,312. 

The nitrogen of aHphatic and aromatic amines is alkylated rapidly by alkyl sulfates yielding the usual mixtures. Most tertiary amines and nitrogen heterocycles are converted to quaternary ammonium salts, unless the nitrogen is of very low basicity, eg, ia tn phenylamine. The position of dimethyl sulfate-produced methylation of several heterocycles with more than one heteroatom has been examined (22). Acyl cyanamides can be methylated (23). Metal cyanates are converted to methyl isocyanate or ethyl isocyanate ia high yields by heating the mixtures (24,25). 

Aminofurans substituted with electron-withdrawing groups e.g. NO2) are known and 3-amino-2-methylfuran is a relatively stable amine which can be acylated and diazotized. 2-Amino-3-acetylfurans are converted into 3-cyano-2-methylpyrroles on treatment with aqueous ammonia. This transformation is a further illustration of the relative instability of the amino derivatives of five-membered ring heterocycles compared with anilines (Scheme 67) (781003821). 

Ruonnated carboxylic anhydrides and acyl halides as common acylating reagents to convert amines to amides and to acy late suitable heterocyclic nitiogen atoms have already been described in the first edition [10] Like in the acylation at oxygen, much synthetic activity was concentrated m the past few years on the denvatization of biomolecules by fluoroacylation reactions, that is, tnfluoroacetylation of amino sugars,... 

A surpnsing feature of the reactions of hexafluoroacetone, trifluoropyruvates, and their acyl imines is the C-hydroxyalkylation or C-amidoalkylaOon of activated aromatic hydrocarbons or heterocycles even in the presence of unprotected ammo or hydroxyl functions directly attached to the aromatic core Normally, aromatic amines first react reversibly to give N-alkylated products that rearrange thermally to yield C-alkylated products. With aromatic heterocycles, the reaction usually takes place at the site of the maximum n electron density [55] (equaUon 5). 

Esters of diphenylacetic acids with derivatives of ethanol-amine show mainly the antispasmodic component of the atropine complex of biologic activities. As such they find use in treatment of the resolution of various spastic conditions such as, for example, gastrointestinal spasms. The prototype in this series, adiphenine (47), is obtained by treatment of diphenyl acetyl chloride with diethylaminoethanol. A somewhat more complex basic side chain is accessible by an interesting rearrangement. Reductive amination of furfural (42) results in reduction of the heterocyclic ring as well and formation of the aminomethyltetrahydro-furan (43). Treatment of this ether with hydrogen bromide in acetic acid leads to the hydroxypiperidine (45), possibly by the intermediacy of a carbonium ion such as 44. Acylation of the alcohol with diphenylacetyl chloride gives piperidolate (46). ... 

Acylation of thiosemicarbazide with propionyl chloride, interestingly, does not stop at the acylated product (124). Instead, this intermediate cyclizes to the thiadiazole, 125, under the reaction conditions. Hydrolysis then affords the heterocyclic amine, 126. Acylation by 88 followed by removal qf the acetyl group affords sulfaethidole (116) variation of thle acid chloride used in the preparation of the heterocycle leads to 117 and 118. 

A heterocyclic ring may be used in place of one of the benzene rings without loss of biologic activity. The first step in the synthesis of such an agent starts by Friedel-Crafts-like acylation rather than displacement. Thus, reaction of sulfenyl chloride, 222, with 2-aminothiazole (223) in the presence of acetic anhydride affords the sulfide, 224. The amine is then protected as the amide (225). Oxidation with hydrogen peroxide leads to the corresponding sulfone (226) hydrolysis followed by reduction of the nitro group then affords thiazosulfone (227). ... 

Hoesch reaction. In most cases, a Lewis acid is necessary zinc chloride is the most common. The reaction is generally useful only with phenols, phenolic ethers, and some reactive heterocyclic compounds (e.g., pyrrole), but it can be extended to aromatic amines by the use of BCls. Acylation in the case of amines is regioselectively ortho. Monohydric phenols, however, generally do not give ketones " but are attacked at the oxygen to produce imino esters. Many nitriles... 

In recent years, the importance of aliphatic nitro compounds has greatly increased, due to the discovery of new selective transformations. These topics are discussed in the following chapters Stereoselective Henry reaction (chapter 3.3), Asymmetric Micheal additions (chapter 4.4), use of nitroalkenes as heterodienes in tandem [4+2]/[3+2] cycloadditions (chapter 8) and radical denitration (chapter 7.2). These reactions discovered in recent years constitute important tools in organic synthesis. They are discussed in more detail than the conventional reactions such as the Nef reaction, reduction to amines, synthesis of nitro sugars, alkylation and acylation (chapter 5). Concerning aromatic nitro chemistry, the preparation of substituted aromatic compounds via the SNAr reaction and nucleophilic aromatic substitution of hydrogen (VNS) are discussed (chapter 9). Preparation of heterocycles such as indoles, are covered (chapter 10). 

Methods for the A-acylation of similar heterocycles, such as simple thiazolidinethiones, have been reported since 1977, namely acyl chlorides in miscellaneous conditions,586 or carboxylic acids under DCC-activation.60,61 However the easiest and most effective method involves acyl chlorides or carboxylic anhydrides in the presence of an amine.47 Applying that procedure on carbohydrate scaffolds Rollin and co-workers62 reported the synthesis of diverse /V-acylated OZTs. The reactions were performed with good yields and the /V-selective acylation was ascertained by NMR— namely the thiocarbonyl 13C chemical shift (Scheme 41). Thanks to the dual nature of the carbanion drifting in the reaction,596 60 no competitive formation of the thioester, as mentioned by Plusquellec el al. in the case of benzothiazole, was observed. 

Table 3.19 lists examples of the preparation of nitrogen-containing heterocycles by RCM. As mentioned in Section 3.2.5.3, free amines can partly deactivate metathesis catalysts. With the highly reactive molybdenum catalyst 1 it is, however, possible to cyclize dienes containing a basic amino group. If the less reactive catalysts 2 or 3 are to be used, protonation or acylation of the amine can be used to reduce their nucleophilicity. This will generally lead to higher yields with smaller amounts of catalyst. 

The synthetic approaches described thus far for 191 resemble quite closely those reported for similar heterocycles. The system has been prepared for the first time by Tamura and co-workers (79CPB2521). 2-Aminothiadiazole can be aminated with O-mesitylsulfonylhydroxylamine, giving an N-3-aminated product that on treatment with acylating agents (benzoyl chloride, acetic acid anhydride, 200°C) yields the desired compounds (192, R = Me, Ph). Yields are low (15-26%). 

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