Examples heterocycles

As appropriately substituted o-disubstituted benzene derivatives are feadily available, this procedure has found widespread application in the synthesis of benzo-fused flve-membered heterocycles. Examples abound in the various chapters in these volumes and the following few examples illustrate the general trend. 

Photolysis or thermolysis of heteroatom-substituted chromium carbene complexes can lead to the formation of ketene-like intermediates (cf. Sections 2.2.3 and 2.2.5). The reaction of these intermediates with tertiary amines can yield ammonium ylides, which can undergo Stevens rearrangement [294,365,366] (see also Entry 6, Table 2.14 and Experimental Procedure 2.2.1). This reaction sequence has been used to prepare pyrrolidones and other nitrogen-containing heterocycles. Examples of such reactions are given in Figure 2.31 and Table 2.21. 

Particularly interesting is the reaction of enynes with catalytic amounts of carbene complexes (Figure 3.50). If the chain-length between olefin and alkyne enables the formation of a five-membered or larger ring, then RCM can lead to the formation of vinyl-substituted cycloalkenes [866] or heterocycles. Examples of such reactions are given in Tables 3.18-3.20. It should, though, be taken into account that this reaction can also proceed by non-carbene-mediated pathways. Also Fischer-type carbene complexes and other complexes [867] can catalyze enyne cyclizations [267]. Trost [868] proposed that palladium-catalyzed enyne cyclizations proceed via metallacyclopentenes, which upon reductive elimination yield an intermediate cyclobutene. Also a Lewis acid-catalyzed, intramolecular [2 + 2] cycloaddition of, e.g., acceptor-substituted alkynes to an alkene to yield a cyclobutene can be considered as a possible mechanism of enyne cyclization. 

Reductive cyclization of the 2-halogenophenyl group onto an adjacent phenyl substituent is a useful reaction for the preparation of condensed ring nitrogen heterocycles. Examples of the process include the formation of aromatic and conjugated 7t-systems [168, 169]. It has been applied to the synthesis of an aporphine... 

Acyclic sp2 (vinyl)-carbanions adjacent to spl-nitrogen are fairly rare, and heterocyclic examples even more so, although some are known (84T2989). Thus the acrylamide and acrylate derivatives 150, 151, and 152 can be formed by deprotonation with r-BuLi at temperatures below - 100°C, and once formed the amide 150 is stable up to room temperature [76AG(E)171 78AG(E)204 79TL4273],... 

There is a very great demand for drugs for the relief of anxiety. This was formerly met by the use of alcohol, bromides or barbiturates, which carried the risk of abuse or dangerous toxicity. The first of the modern minor tranquilizers, introduced from 1946 onwards, were drugs described as skeletal muscle relaxants. These were mainly derivatives of polyhydric alcohols, but heterocyclic examples included metaxolone (161), which is related to the aryl ethers of glycerol, chlorzoxazone (162) and chlormezanone (163). Dantrolene sodium (164) is a muscle relaxant and CNS depressant. 

During clinical studies of iproniazid (201) in the treatment of tuberculosis it was found to have a mood-elevating effect. It was later found to be an inhibitor of monoamine oxidase (MAO), the enzyme which oxidatively deaminates such neurotransmitters as noradrenaline and serotonin, and it was tried in the treatment of depression in 1957. Other MAO inhibitors were introduced later, most of them being hydrazine derivatives. Heterocyclic examples include isocarboxazid (202) and nialamide (203). They are toxic and cause dangerous hypertensive crises if food with a high tyramine content is eaten, and on this account their use is limited. 

Pyrethroids, e.g. cypermethrin (89) and fenvalerate (90), are being employed. This class of compound is the result of structural manipulation by medicinal chemists of the naturally occurring pyrethrins (91) to overcome the latters photoinstability and lack of persistence when in use as ectoparasiticides. There are no heterocyclic representatives of this important class of insecticide/acaricide in use though many heterocyclic examples have appeared in the patent literature. 

One or both of the carbocyclic aromatic rings in stilbenes or azobenzenes can be replaced by heterocycles. Examples include 2-styrylpyridine methiodide (138) and 4,4 -azopyridine (139) (53JCS1281). 

Many types of photoinitiator are known. 2-Mercaptobenzoxazoles, 2-mercaptoben-zimidazoles and 2-mercaptobenzothiazoles (56USP2773822) are heterocyclic examples of the organic sulfur class of initiator. 

Isoflavones, isoflavanones and neoflavonoids are also members of the flavonoid group. They all have the C6-C3-C6 stmcture but the B-ring is in a different position on the oxygen heterocycle. Examples are isoflavone (1.33) and the neoflavonoid dalbergin (1.34). 

Meprathu, B. V. et al., Tetrahedron Lett., 1999, 40(30), 5459 Three heterocyclic examples of this class, ArS02N=IPh were prepared, Ar being 2-pyridyl, l-oxo-2-pyridyl and l-methyl-2-imidazolyl. They decompose explosively on melting. 

Now consider condensation of ammonia with ketoester 1.18. The isolated product is not imine 1.19 but the thermodynamically more stable enamine tautomer 1.20 which has a conjugated double bond system and a strong intramolecular hydrogen-bond. Although not a heterocyclic example, 1.20 illustrates that an enamine-like linkage, as in generalised heterocycle 1.21, is also accessible by a condensation reaction. 

Valence tautomerism refers to the interconversion of isomers without any accompanying rearrangement including proton transfer. Heterocyclic examples are essentially electrocyclic reactions (Scheme 15). If one of the isomers is colored and the position of the equilibrium can be changed by heat or light, the heterocycles can have useful thermochromic or photochromic applications. 

Valence tautomerism refers to the interconversion of isomers without any accompanying rearrangement including proton transfer. Heterocyclic examples of valence tautomerism are essentially electrocyclic reactions. 

The two-carbon ring expansion which involves the [2 + 2] cycloaddition of enamines of cyclic ketones with electron-deficient acetylenes followed by thermal rearrangement of the resulting fused cyclobutenes (see Section II.E) has been successfully used in the synthesis of medium-size heterocycles. Examples include the preparation of compounds 407246, 408247 and 409248. 

Carbodiimides also play a role as building blocks of numerous N-heterocycles. Examples are the cycloaddition reactions of carbodiimides. In the formation of [2-1-2] cycloadducts N-methyl-N -t-butylcarbodiimide is used as a marker to determine the mode of addition of isocyanates or isothiocyanates to carbodiimides. In these reactions addition across the C=N or the C=0 bond of the isocyanate or across the C=N or the C==S bond of the isothiocyanate can occur. Addition to the N-methyl-N -t-butylcarbodiimide always proceeds across the N-methyl double bond. Also, theretroreaction of the [2-1-2] cycloaddition reaction of carbodiimides can afford a different set of heterocumulenes. ... 

Nitrogen Heterocycles.- Reactions of iminophosphoranes have been used to prepare a wide range of heterocycles. Examples of compounds prepared by intramolecular aza-Wittig reactions include 3,4-dihydroquinazolines (191) and quinazolines (192), quinazoline derivatives (e.g. 193),pyrrolo( 1,2-a)quinoxalines (194), indolo[3,2-clquinolines (195), and indolo[l,2-c]quinazolines (196),"8 imidazolinones (197),"9 quinazolinones (198),"9, 120 pyrido[2,3-d]pyrimidine derivatives (199), 21 and 4,5-dihydropyrazolo(3,4-d]pyrimidine derivatives (200). 22 Tributyl(cyclohepta-1,3,5-trienylimino)phosphorane (201), prepared by thermal isomerization of the 2,4,6-derivative, reacts with a,p-unsaturated ketones to give 9H-cyclohepta[b]pyridine derivatives (202). 23 a synthesis of (2,4)pyridinophanes (204) by the reaction of N-vinyliminophosphoranes (203) with a,P-unsaturated ketones has been reported. 24... 

The metaiation of heterocycles is possible without the aid of a directing group. This type of reaction is most common in the ir-excessive heterocycles, and is most important for thiophenes. For nitrogen heterocycles, examples of unactivated lithiation of ir-excessive azoles have been reported, and are summarized below. ir-Deficient heterocycles such as pyridine are resistant to unactivated lithiation, although pyridine can be metalated with low regioselectivity using butylsodium. Pyridines also form weak complexes with fluoro ketones the complex of 4-r-butylpyridine and hexafluoroacetone can be lithiated and added to benzaldehyde in 60% yield. ... 

The thermal rearrangement of 3-azido-3//-indoles to a mixture of quin-azolines and quinoxalines is a heterocyclic example of this reaction (Eq. 128).456... 

Fe(III) salts catalyse the coupling of Grignard reagents with alkenyl and aryl halides. The mechanism is not fully understood, but probably resembles the standard palladium sequence, through either an Fe(0)-Fe(II) or an Fe(I)-Fe(III) cycle. A particular feature is that chlorides are superior, in terms of yield, to bromides and iodides as substrates. Triflates also give very high yields and couple selectively in the presence of chlorides. Heterocyclic examples include 6-chloropurines, 4-chloropyrimidines, 6-chloro-l,3-dimethyluracil and 2-chloropyridines," and the dichloropyridine example below." ... 

A variation on the standard reaction avoids isolation of the diazonium salt by its generation, under anhydrous conditions, at its decomposition temperature. The only heterocyclic example so far described is the preparation of 3-fluoroquinoline, but the method could no doubt be applied to other systems. 

Under strictly anhydrous conditions, the iminophosphorane intermediate that is formed as a result of the Staudinger reaction can react with aldehydes and ketones in an intermolecular fashion (as in the synthesis of imine 36 described above) or intramolecularly with a variety of carbonyl containing functional groups to afford a host of products. Nitrogen containing ring systems such as cyclic imines (44) represent just one of the many products one can prepare and the reaction is particularly well suited for the facile synthesis of five, six, and seven-membered rings. In addition to aldehydes and ketones, carboxylic acids, esters, thio-esters, and amides can also react in an intramolecular fashion to trap an iminophosphorane to afford a variety of heterocycles. Examples from the current literature are described in Section 2.5.5. 

Cesium fluoride induced desilylation of immonium salts provides reactive azomethine yields, which are capable of 1,3-dipolar addition to many a, 8-unsaturated compounds to form heterocycles. Examples utilizing... 

H. C. Brown and coworkers proposed a rule for the chemical behavior of 5- and 6-membered ring compounds having an endo- or exocyclic double bond. According to this proposal, reactions will proceed in such a manner as to favor the formation or retention of the exo double bond in the 5-ring and to avoid the formation or retention of the exo double bond in the 6-ring systems. Although this rule is in accord with experimental results on a large number of compounds, some exceptions have been observed. " The validity of this stability rule was verified mainly with carbocyclic compounds, but some heterocyclic examples have also been reported. 

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