Reactions Leading to the Formation of Heterocycles

Aryl tellurium halides with suitable substituents in the urt/jo-position to the tellurium atom cyclize to form heterocyclic compounds with tellurium as a ring-member. 

The other positional isomers of the thienyl tellurium bromide were similarly cyclized. With two moles of hypophosphorous acid per mole of tellurium bromide, the corresponding 5-cyclohexenes were obtained.  

Irgolic Organic Tellurium Compounds with one Te,C Bond 

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Carbon-carbon bond formation with electrogenerated nickel and palladium complexes in cyclization reactions leading to the formation of heterocycles 03EJ01605. 

Glycosyl isothiocyanates have also been allowed to react with unprotected 2-amino-2-deoxyaldoses and 1-amino-1-deoxy-2-ketoses.68 This reaction leads to the formation of heterocyclic derivatives resulting from cy-clization involving the carbonyl group of the amino sugar moiety following the mechanistic pathway already discussed for similar condensation reactions with alkyl and aryl isothiocaynates. 

The reaction of ADC compounds with carbenes and their precursors has already been discussed in Section IV,A- In general, the heterocyclic products are not the result of 1,2-addition but of 1,4-addition of the carbene to the —N=N—C=0 system.1 Thus the ADC compound reacts as a 4n unit in a cheletropic reaction leading to the formation of 1,3,4-oxadiazolines. Recent applications include the preparation of spiro-1,3,4-oxadiazolines from cyclic diazoketones and DEAZD as shown in Eq. (14),133 and the synthesis of the acyl derivatives 85 from the pyridinium salts 86.134 The acyl derivatives 85 are readily converted into a-hydroxyketones by a sequence of hydrolysis and reduction reactions. 

Dipolar cycloadditions of fullerene C6o to nitrones have been studied. Their mechanism, regiochemistry, and nature of addition have been investigated. All of the reactions lead to the formation of fullerene fused heterocycles. Theoretically, these reactions can lead to four types of additions, such as closed [6,6], open [5,6], closed [5,6], and open [6,6] additions (Scheme 2.317). Energetics and thermodynamic analyses of these reactions show that closed [5,6] and open [6,6]... 

A number of other photochemical 1,4-cycloadditions leading to the formation of heterocyclic systems have been reported, but in general these are less well investigated. The irradiation of o-quinones in the presence of sulfur dioxide affords, often in good yield, the corresponding 1,3,2-dioxathiole or cyclic sulfate 338 [see, for example, Eq. (91)]. Reaction of phenanthraquinone with triphenylphosphine can be achieved photochemically339 or thermally and the product is thought to have the cyclic structure (317). 

A recent study of proton transfer from rhenium Fisher-type carbine complexes (13) shows that the reactions lead to the formation of an aromatic product (14), following the same rules as reactions that lead to the formation of products stabilized by simple resonance. The conjugate bases of these carbine complexes represent aromatic heterocycles, i.e., substituted furan, selenophene, and thiophene derivatives, respectively. The aromatic stabilization of these heterocycles is known to follow the order furan < selenophene < thiophene (Scheme 1) [43],... 

Alternative reactions leading to the formation of large ring heterocycles will probably require ring closure at sites remote from the heteroatom. Large-membered cycloalkenes containing silicon and germanium have been prepared by this approach. 

Reactions of naphthaldehydes leading to the formation of heterocyclic derivatives 03UK498. 

The Mannich reaction is a very common process that occurs in many tandem reaction sequences. For example, the Overman Aza-Cope cascade sequence is terminated by a Mannich reaction (cf. Scheme 35). Several groups have used variants of the Mannich reaction to initiate cascades that lead to the formation of heterocyclic molecules. For example, the Lewis acid-catalyzed intermolecular vinylogous Mannich reaction (01T3221) of silyloxy furan 281 with nitrone 282 produced a diastereomeric mixture (49 3 42 6) of azabicycles 284a-d in 97% combined yield (Scheme 52) (96TA1059). These products arose from an intramolecular Michael addition of the initially formed oxonium ion 283. 

With cyanoguanidines and cyanamides compound 29 behaves as a 1,3-heterodiene forming heterocyclic compounds. These reactions lead to the formation of a [2 + 4] cycloadduct as the sole product. The [2 + 4] cycloaddition (formation of a compound of type 31) is only possible for dienophiles possessing sufficiently strong donor properties, as illustrated by reactions with various compounds containing a nitrile group (Scheme 30). 

Heterocyclic compounds have a wide range of applications and are also extensively distributed in nature. These compounds are also important intermediates in organic synthesis. Several examples involving modification of selectivity in the preparation and reactivity of heterocyclic compounds have been reported. The degradation of ethyl indole-2-carboxylate (44) with 0.2 m NaOH has been reported by Strauss [20]. This reaction leads to the formation of indole (46) if the power input enables a temperature of 255 °C to be achieved or to indol-2-carboxylic acid (45) if the temperature is limited to 200 °C (Scheme 5.14). 

REACTIONS LEADING TO THE FORMATION OF FIVE-MEMBERED HETEROCYCLES... 

Hypervalent iodine(III) mediated/catalyzed intramolecular oxidative C-H bond functionalization of (hetero)arenes and alkenes has been widely applied in the synthesis of several biologically active heterocyclic scaffolds. This intramolecular oxidative C-H bond functionalization reaction leads to the formation of carbon-carbon and carbon-heteroatom bonds in an efficient manner. Of all bond formation reactions, C-N bond annulations have been exploited most and are of immense... 

Hypervalent iodine(III) reagents have recently been applied in the direct functionalization of heterocycles by cross-dehydrogenative coupling reactions leading to the formation of new C-N and C-C bonds. 

Certain heterocyclic compounds are also important aromatic substances in wines, such as pyrazines in Cabernet Sauvignon and Sauvignon Blanc wines (see Section 8.2.11.1.7) and both enantiomers of 3-hydroxy-4,5-dimethyl-5if-furan-2-one (sotolon), which occur in white wines, sherries and are a key component of the typical aroma of aged Port wines. The precise chemical reactions leading to the formation of bouquet substances are not yet widely known. There are two types of reactions that produce bouquet constituents oxidation, which is characterised by the presence of aldehydes and acetals (e.g. in Madeira-type wines) and reduction (such as in quality table wines after a period of bottle maturation the flavour of low-quahty wines does not improve under the same conditions, but instead maturation often leads to a loss of freshness). During wine aging, glycosides of terpenic alcohols and... 

The complex (CXVIII.l), upon heating or photolysis, is converted to the cyclopentadienone complex (CXIII.l) various other reactions lead to the formation of tetraphenylquinone or hydroquinone (38, 39). Heterocyclic compounds such as pyrones and thiapyrones are obtained upon displacement of the ring Fe(CO)3 group (128). 

Acetylenic compounds are widely used in heterocyclization reactions. Some of these reactions were considered in recent reviews and papers [441 45] and in the preceding chapters. However, the reactions of electron-deficient acetylenes leading to the formation of heterocyclic compounds are considered below. 

Heterocyclization based on simple acetylenes requires a catalyst to be present [33, 447-449]. Haloacetylenes with alkyl or aryl substituents also undergo heterocyclization but less effectively. However, activated electron-deficient haloacetylenes readily react with nucleophiles. With binucleophiles, this reaction often leads to the formation of heterocycles. Haloacetylene often reacts in a similar manner to acetyl chloride, differing from the latter by the absence of released water. However, sometimes an unusual reaction occurs, as was shown by the reaction of dialkyl l-chloroacetylene-2-phosphonates with specific binucleophiles. l-Chloro-2-dialkoxyphorylacetylenes 4.981 react readily with diethyl acetamidomalonate in acetonitrile in the presence of potassium carbonate as a base, to form oxazoline derivatives 4.991. The reaction has two steps nucleophilic substitution of the acetylenic chlorine atom followed by attack of the amide oxygen atom on the triple bond activated by... 

Another pathway occurs in the reaction of chloroacetylenephospho-nates 4.981 with 5-substituted 4-amino-3-thiolo-l,2,4-triazoles. The reaction leads to the formation of condensed bicyclic heterocycles, that is, 3-amino(or 3-methyl)-2-alkyl(aryl)-3H-thiazolo[3,2-b][1,2,4]-triazolo-7-ylium chlorides 4.992 (Scheme 4.16) [451]. Note that in this case, both acetylenic carbon atoms are involved in the formation of the heterocycle. 

Using diamines such as N,N -dimethylethylenediamine or piperazine leads to the formation of heterocycle-fused fullerene derivatives 23 and 24 (Figure 28.4). > Again, the reaction proceeds via single elctron transfer to give the C -D radical ion pair followed by successive intermolecular proton transfer, which completes the addition reaction with [60]fuUerene. 

Other well-known reactions are those offluorinated olefins with fluoride ion and negatively substituted aromatic compounds leading to the formation of per-fiuoroalkylated aromatic compounds The reaction may be considered an amonic version of a Fnedel Crafts process and can result in introduction of one or several perfluoroalkyl substituents [/ /] Aromatic substrates include substituted and unsuhstiluled perfiuorobenzenes [J3l, 212, 213, 214], fiuorinated heterocycles [131, 203, 215, 216, 217, 218, 219, 220, 221, 222, 223],perchlorinated heterocycles [224] (equation 44), and other activated aromatic compounds [225] (equation 45) The fluonnated olefins can be linear or cyclic [208] (equation 46)... 

This tendency is especially significant in compounds containing functional groups capable of addition with the formation of both five- and six-membered rings. It has been shown that for amides and hydrazides of azolecarboxylic acids, selectively, and for the acids with any arrangement of a function and triple bond, heterocyclization always leads to the closure of the six-membered ring. Similar reactions in the benzoic series mainly lead to the formation of five-membered rings. 

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