Reactive heterocycles

Fig. 4. R groups having reactive heterocyclic groups attached to (8) through NH.

The applicability of the Reimer-Tiemann reaction is limited to the formylation of phenols and certain reactive heterocycles like pyrroles and indoles. Yields are usually below 50%. In contrast to other formylation procedures, the Reimer-Tiemann reaction is ort/zo-selective it is therefore related to the Kolb e-Schmitt reaction. 

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... 

A, A /-Carbonylbis[2(3//)-benzoxazolethione], obtained from mercaptobenzoxazole and dimeric phosgene as the more thermodynamically stable A-acyl product, also represents a reactive heterocyclic diamide of carbonic acid, and is therefore used in the same way for ester syntheses as A /V -carbonyldibenzimidazole.c 1321... 

Besides in the liquid phase, some polyreactions are also performed in the solid state, for example, the polymerization of acrylamide or trioxane (see Example 3-24). The so-called post condensation, for example, in the case of polyesters (see Example 4-3), also proceeds in the solid phase. Finally, ring closure reactions on polymers with reactive heterocyclic rings in the main chain (e.g., poly-imides, see Example 4-20) are also performed in the solid state. 

As highly reactive heterocycles, the thietes are well suited for the formation of metal complexes. Takahashi and Dittmer both individually and in collaboration have been involved with the interaction of thietes and iron or cobalt carbonyls. During the thermally or photochemically induced complexation process, ring opening takes place so that the resultant thioacrolein is the actual ligand in the organometallic compound (Scheme i7)/ 3-203,204... 

Several synthetic methods are available for the preparation of Fc peptide conjugates, of which the active ester method is most compatible with biological environments.41 This method works under mild conditions with an isolable FcCO-active ester, in which reactive heterocyclic isolable esters are formed. These can be isolated or reacted in situ with suitable peptides to give the desired Fc-peptide conjugate. These active esters can be used as stoichiometric Fc delivery reagents, which make them suitable for automated solid-phase synthesis of Fc-peptide conjugates. 

The reacting species is a rather weak electrophile and, therefore, only particularly reactive aromatics are suitable substrates. Consequently, the reaction is restricted for polyhydric phenols and their ethers, and reactive heterocycles. With strong acidic systems, such as AICI3 in halogenated benzene solvents, alkylben-zenes can react at more elevated temperatures (>50°C). Trichloroacetonitrile works also well with nonactivated aromatics. The 12 chloroimine, the protonated nitrile (13), or the nitrile coordinated with the Lewis acid are possible involved electrophiles. 

The list of economically attractive reactive heterocyclic intermediates also includes dichloroquinoxalines 9 and dichlorophthalazines 10. Anchor systems in both cases are bound to the chromophore via a carbonylamino group, and the reactivities correspond roughly to those of dichlorotriazinyl dyes. 

Cation 6 adds to furan, pyrrole, thiophene and some of their 2,4-dimethyl derivatives bearing a free a-position, in MeCN as solvent. Furan is the least reactive substrate giving 2-arylated product in 32% yield, whereas under the same reaction conditions the sulfur analogue provides 54% of 2-substituted-thiophene 9c (Scheme 10.37). Pyrroles are the most reactive heterocycles, and 2-arylated products 9a-b are found with 64% and 75% yields using pyrrole and 2,4-dimethyl-pyrrole, respectively. Only with 2,5-dimethylated furan and pyrrole, will arylation... 

Diaryliodonium salts, with few exceptions, are stable compounds towards heat, oxygen and humidity they are mildly light-sensitive and should be stored in the dark, without refrigeration. Generally, their reactivity is less pronounced than that of other hypervalent iodine compounds. Indeed, in several of their reactions relatively drastic conditions may be necessary, especially for the least reactive heterocyclic iodonium salts. The search for optimum conditions is often desirable even for well-established reactions, by applying new findings concerning the use of specific... 

Although nonsolvating media of low polarity are sometimes suitable for reactive heterocycles, more often polar or basic solvents such as... 

Carvalho, I., Miller, J. (1995) Synthesis of l-methyl-2-hydroxyiminomethyl-aryl-pyridinium salts with potential as acetyl-cholinesterase reactivators. Heterocycl. Commun. 1 403-10. 

CSI reacts with carboxylic acids to form nitriles via the initial adducts (75) which lose carbon dioxide to give the N-chlorosulfonylcarboxamides (76) which with DMF afford good yields of the nitriles (77) (Scheme 36). This provides a valuable procedure for the conversion of carboxylic acids into the nitriles. In addition, thiophene (78), as well as other reactive heterocycles, reacts with CSI to yield the N-chlorosulfonylcarboxamide (79) which on treatment with DMF affords the nitrile (80) (Scheme 37). 

Flash vacuum thermolysis in synthesis of new reactive heterocycles with P = Si double bonds 00EJO3253. 

Another static approach that can give us the relative reactivity of heterocycles as dienes for Diels-Alder reactions is evaluation of their aromatic stability through the ring bond order uniformity. If, for a moment, we examine reactivity of the heterocycle on the basis of FMO energy gap with cyclopropene as a dienophile, it is obvious that the most reactive heterocycle is 1,3-thiazole. It had a FMO energy gap of only 9.609 eV (Table 26). That finding is almost... 

The other method to determine reactivity for reactions with synchronous concerted cyclic transition state structures is evaluation of the transition state ring aromaticity through bond order deviation. The results of the exo cyclopropene addition to the heterocycles and to cyclopentadiene are presented in Table 33. The higher the sum of bond order deviation from average bond order (x) is, the lower aromatic character the transition state structure has. The most reactive dienophile was cyclopentadiene, followed by furan, and then heterocycles. The most reactive heterocycle with heteroatoms in 1,3-position was 1,3-oxazole as was predicted on the basis of the FMO energy changes (Table 32). The least reactive was 1,3-diazole, as one would expect on the basis of experimental observations. It is very difficult to rely on the transition state structure bond order deviation to determine the experimental feasibility of a reaction but, because SBOD for furan and 1,3-oxadiazole were very similar, one can conclude that the cycloaddition with 1,3-oxadiazole is also experimentally feasible. 

The ring bond order deviation from uniformity partially agreed with the order of reactivity computed on the basis of FMO energy gaps. The least aromatic was 1,2,5-oxadiazole, while 1,2,3-thiadiazole should be most aromatic (Table 36). The order of reactivity was oxadiazole, triazole, thiadiazole in all 1,2,3-, 1,2,5- and 1,3,4-series of the three heteroatom heterocycles. Except for 1,3,4-oxadiazole, the two other 1,3,4- five-membered heterocycles were predicted to be more reactive than their 1,2,3- isomers (Table 36). The prediction that 1,2,5-oxadiazole was the most reactive heterocycle as a diene for Diels-Alder reaction was unacceptable due to the fact that two C-N bonds should be formed in the course of the reaction, which usually requires an exceptionally high activation barrier. 

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