Heterocycles, acylation substitution

Displacement of halides by secondary amines and of sulfonyl groups by alkoxides can also take place. Furoxancarboxylic acids are attacked by base to give acyclic products, but their derivatives can undergo nucleophilic acyl substitutions. Likewise nucleophilic addition reactions can be accomplished for ketofuroxans, although ring cleavage is also commonplace. The generation of new heterocyclic systems by reaction with nucleophiles is dealt with in Section 4.22.3.2.5. 

M. A. GaTbershtam, N. N. Artamonova, and N. P. Samoilova, Synthesis of 3 -acyl-substituted indoline spiropyrans, Chem. Heterocycl. Cpds., 1975, 167-172. 

Acyl chlorides obtained from aromatic, heterocyclic, or dibasic aliphatic acids allowed us to obtain acyl derivatives from NaMn(CO)5 or NaRe(CO)5-Their decarbonylation gave the respective o-aryl, o-heterocyclic, or substituted-alkyl derivatives, allowing studies as to how a substituent influenced a CO group through a benzene ring (or an alkyl chain) and a metal bonded thereto (241-244). 

Kappe, T., Aigner, R., Roschger, P., Schnell, B., Stadbauer, W. A simple and effective method for the reduction of acyl substituted heterocyclic 1,3-dicarbonyl compounds to alkyl derivatives by zinc-acetic acid-hydrochloric acid. Tetrahedron 1995, 51,12923-12928. 

Ohler, E., El-Badawi, M., and Zbiral, E., Dialkyl (l,2-epoxy-3-oxoalkyl)phosphonates as synthons for heterocyclic carbonyl compounds. Synthesis of acyl-substituted thiazoles, indolizines, imidazo[ 1,2-fii]pyridines and imidazo[l,2-fii]pyrimidines, Chem. Ber., 118, 4099, 1985. 

Nucleophilic radicals carry cation-stabilising groups on the radical carbon, allowing electron density to be transferred from the radical to an electron-deficient heterocycle they react, therefore, only with electron-poor heterocycies and will not attack electron-rich systems examples of such radicals are CH20H, alkyl", and acyl". Substitution by such a radical can be represented in the following general way ... 

Fluoroalkyl chromone derivatives can be obtained from the base catalysed reaetion between 2,2-dihydropolyfluoroalkanoates and phenols. Initial loss of HF allows Michael addition of the phenol and subsequent cyclisation of the enol ether yields the heterocycle. m-Substituted phenols give the expected mixture of 5- and 7-substituted chromones, whilst dihydroxy aromatic compounds give polycyclic materials (94JFC263). In a more conventional approach Z-3-(aryloxy)-polyfluoroalkenoic adds, derived from Michael addition of phenols to polyfluoro-2-alkynoic acids, undergo intramolecular Friedel-Crafts acylation to 2-polyfluoro-alkylchromones (94JFC25). 

An enolic OH derived from the P-diketone structural unit can act as the nucleophile in a nucleophilic acyl substitution to give a six-membered oxygen heterocycle known as a pyrone. 

Electrophilic Substitution. The rate constants and activation parameters for the formylation of selenophen by the DMF-phosgene complex in chloroform have been determined and compared with those of the other five-membered heterocycles. Acylation of 2-benzylselenophen occurs exclusively in the a-position of the selenophen ring. Formylation and acetylation of 2-(2-thienyl)selenophen went predominantly (80 and 75%, respectively) in the a-position of the selenophen ring and 20% in the a-position of the thiophen ring. 2,5-Dimethylselenophen-3-carboxylic acid could be iodinated at position 4 with iodine-iodic acid. Bromination of 2-formylselenophen in AlCh yielded the 4-isomer. Bromination of 2-methylselenophen with N-bromosuccinimide in acetic acid gave 3,5-di-bromo-2-methylselenophen. 

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). 

Diels-Alder reactions, 4, 842 flash vapour phase pyrolysis, 4, 846 reactions with 6-dimethylaminofuKenov, 4, 844 reactions with JV,n-diphenylnitrone, 4, 841 reactions with mesitonitrile oxide, 4, 841 structure, 4, 715, 725 synthesis, 4, 725, 767-769, 930 theoretical methods, 4, 3 tricarbonyl iron complexes, 4, 847 dipole moments, 4, 716 n-directing effect, 4, 44 2,5-disubstituted synthesis, 4, 116-117 from l,3-dithiolylium-4-olates, 6, 826 electrocyclization, 4, 748-750 electron bombardment, 4, 739 electronic deformation, 4, 722-723 electronic structure, 4, 715 electrophilic substitution, 4, 43, 44, 717-719, 751 directing effects, 4, 752-753 fluorescence spectra, 4, 735-736 fluorinated derivatives, 4, 679 H NMR, 4, 731 Friedel-Crafts acylation, 4, 777 with fused six-membered heterocyclic rings, 4, 973-1036 fused small rings structure, 4, 720-721 gas phase UV spectrum, 4, 734 H NMR, 4, 7, 728-731, 939 solvent effects, 4, 730 substituent constants, 4, 731 halo... 

The reaction of tnfluoromethyl-substituted A -acyl umnes toward nucleophiles in many aspects parallels that of the parent polyfluoro ketones Heteronucleophiles and carbon nucleophiles, such as enarmnes [37, 38], enol ethers [38, 39, 40], hydrogen cyanide [34], tnmethylsilylcarbomlnle [2,47], alkynes [42], electron-nch heterocycles [43], 1,3-dicarbonyl compounds [44], organolithium compounds [45, 46, 47, 48], and Gngnard compounds [49,50], readily undergo hydroxyalkylation with hexafluoroace-tone and amidoalkylation with acyl imines denved from hexafluoroacetone... 

The majority of analgesics can be classified as either central or peripheral on the basis of their mode of action. Structural characteristics usually follow the same divisions the former show some relation to the opioids while the latter can be recognized as NSAlD s. The triamino pyridine 17 is an analgesic which does not seem to belong stmcturally to either class. Reaction of substituted pyridine 13 (obtainable from 12 by nitration ) with benzylamine 14 leads to the product from replacement of the methoxyl group (15). The reaction probably proceeds by the addition elimination sequence characteristic of heterocyclic nucleophilic displacements. Reduction of the nitro group with Raney nickel gives triamine 16. Acylation of the product with ethyl chlorofor-mate produces flupirtine (17) [4]. 

Trimethylsilylketene and acyl isocyanates generate 4-trimethylsiloxy-l,3-oxazin-6-ones 12 in situ, which smoothly react with the enamines of cycloalkanones to give bicyclic 2-pyridones 13 <96TL(37)4977>. The heterocycles 12 also undergo the Diels-Alder reaction with dimethyl acetylenedicarboxylate or methyl propiolate to furnish substituted 2-pyridones <96TL(37)4973>. 

The aerobic reduction of aryl and alkyl carboxylates to the corresponding aldehydes. The reaction involves formation of an acyl-AMP intermediate by reaction of the carboxylic acid with ATP NADPH then reduces this to the aldehyde (Li and Rosazza 1998 He et al. 2004). The oxidoreductase from Nocardia sp. is able to accept a range of substituted benzoic acids, naphthoic acids, and a few heterocyclic carboxylic acids (Li and Rosazza 1997). 

In general, heterocyclic nitro compounds undergo cine substitution reactions more readily than nitrobenzenes. For example, the reaction of 5-acyl- or 5-alkoxycarbonyl-2-nitrofurans with the anion of nitroalkanes gives cine substitution products in excellent yields (Eq. 5.66).104... 

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). 

Nucleophilic substitution of a halogeno-heterocycle is the key step in the synthesis of imidazo-, oxazolo-, thiazolo-, and benzothiazolopyridopyrimidines 255 and 256 <2000T5185> and 257. Intramolecular iV-acylation is the final cyclization step leading to the thiazolino compound 258 (Scheme 63) <1995AF306>. 

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