Heterocycle transformations

We devote a new chapter (31) to some important topics flnorinated heterocycles, isotopically labelled heterocycles, the nse of bioprocesses in heterocyclic transformations, green chemistry and the somewhat related topic of ionic liquids, and some the applications of heterocyclic compounds in every-day life. 

Heterocycle transformation. 6//-l,2-Oxazines are converted to aziridines by way of N-O bond cleavage, C=N bond reduction, and cyclization. 

Cycloaddition Reactions Involving Heterocyclic Compounds as Synthons in the Preparation of Valuable Organic Compounds. An Effective Combination of a Computational Study and Synthetic Applications of Heterocycle Transformations... 

From l-aminoazulenes. Usual methods of heterocyclization transform, for instance, 1,2-diaminoazulene 71 (Scheme 19) by the action of formic acid, nitrite, diacetyl or 5-nitrosotropolone to imidazole 72, triazoles 73 and 271 (see Scheme 66), pyrazine 74 (and defunctionalized compound 75), and pyrazinotroponoxime 76, respectively (73BCJ3161, 85TL335). 

Much of the nitrogen chemistry and heterocyclic transformations in the synthetic schemes illustrated in this short chapter derive from a proper understanding of heterocyclic chemistry—all owe an enormous debt of gratitude to the systematic and innovative research and publications of Alan Katritzky. It is certain that much work yet to come will depend on the innovations and firm foundations of the Katritzky legacy. 

Isoxazole-oxazole photoisomerization was studied by irradiation of matrix-isolated 3,5-dimethylisoxazole (18) at 222 nm. 2-Acetyl-3-methyl-2H-azirine (20) was obtained, likely through an acetyl vinyl nitrene intermediate 19 as primary photoproduct, while upon longer time UV irradiation, two additional photoproducts were identified as acetyl nitrile ylide 21 and 2,5-dimethyloxazole (22) (13JOC10657). Analogously, 3,5-diphenylisoxazole and 2-benzoyl-3-phenyl-2f/-azirine behaved as precursors to triplet vinyl nitrene (of type 19) through laser flash photolysis (13JOC11349). Reductive heterocycle—heterocycle transformations of (2-nitrophenyl)isoxazole precursors, such as 23 and 26, afforded 4-amino quinolines of type 24, quinolin-4(lfJ)-ones 25, and 3-acylindoles 27. Che-moselective heterocyclizations were observed from 3,4-,4,5-, and 3,4-bis(2-nitrophenyl)isoxazoles (13OL2062). 

Methods for the synthesis of trifluoromethyl-substituted furans and benzofurans can be divided into several groups direct trifluoromethylation of heterocycle, transformation of functional groups of hetarene into trifluoromethyl substituent, Diels-Alder/retro-Diels-Alder sequence, and various methods for the furan ring formation from precursors bearing trifluoromethyl moiety. 

As a class of compounds, nitriles have broad commercial utility that includes their use as solvents, feedstocks, pharmaceuticals, catalysts, and pesticides. The versatile reactivity of organonitnles arises both from the reactivity of the C=N bond, and from the abiHty of the cyano substituent to activate adjacent bonds, especially C—H bonds. Nitriles can be used to prepare amines, amides, amidines, carboxyHc acids and esters, aldehydes, ketones, large-ring cycHc ketones, imines, heterocycles, orthoesters, and other compounds. Some of the more common transformations involve hydrolysis or alcoholysis to produce amides, acids and esters, and hydrogenation to produce amines, which are intermediates for the production of polyurethanes and polyamides. An extensive review on hydrogenation of nitriles has been recendy pubHshed (10). 

A more recent development in quinone chemistry has been the tandem reaction sequence. In seeking elegant syntheses of complex molecules, careful orchestration of transformations has become essential. The use of the Thiele-Winter reaction in tandem with arylation gives good yields of pharmacologically interesting heterocycles, such as (62), from 2,5-dihydroxy-l,4-ben2oquinone [615-94-1] and pyridines, where R = H or CH (60). 

Recently, many transformations of various heterocycles into pyridazines have been reported. From the synthetic point of view it appears that furan derivatives are the most valuable. 

Transformations from Other Heterocyclic Ring Systems... 

Examination of the pyrazino[2,3-rf]pyrimidine structure of pteridines reveals two principal pathways for the synthesis of this ring system, namely fusion of a pyrazine ring to a pyrimidine derivative, and annelation of a pyrimidine ring to a suitably substituted pyrazine derivative (equation 76). Since pyrimidines are more easily accessible the former pathway is of major importance. Less important methods include degradations of more complex substances and ring transformations of structurally related bicyclic nitrogen heterocycles. 

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). 

TRANSFORMATION OF EXISTING HETEROCYCLES 3.03.S. 1 Three-membered Heterocycles... 

There are several useful syntheses which effectively commence with the cycloaddition of oxygen, a nitroso compound, an azo compound or a sulfinylamine to a 1,3-diene leading to the corresponding 1,2-dioxins, 1,2-oxazines, pyridazines or 1,2-thiazines. Examples of the transformation of these adducts into five-membered heterocycles are shown in Scheme 114 together with leading references. 

The richness and complexity of the present section is considerable. Almost any heterocycle conveniently substituted can be transformed into another chosen ring system, and this is shown in the two excellent volumes of van der Plas ( Ring Transformations of Heterocycles ) (B-73MI4Q4Q2). The arrangement of the aforementioned book (from the starting heterocycle point of view) does not suit this section and for the purposes of this chapter an alternative classification has been selected. When no explicit references are given, the material has been taken from (B-73MI4Q4Q2). 

Ring transformations of heterocycles leading to isoxazoles have been briefly reviewed (79AHC(25)147). The heterocycles undergoing such transformations may be divided into three classes. 

Other heterocycles which provide the CCC component in related ring transformations are benzodiazepine-3-carbonitrile (80CPB567), benzotriazepines (74T2765), azaxanthones (75JOC1734), acyloxiranes (61AP769) and oxetanones (65CPB248). 

Other heterocycles which rearrange to isoxazoles are pyridazine 1,2-dioxides (77CC856) and pyridinium salts (80CPB2083), although these transformations are of little synthetic importance. 

The most useful reactions combine carbanion nucleophiles with activated aziridines. For example, the ring expansion which occurs on treatment of aziridines (219) with malonate salts typifies the heterocyclic synthesis possible. The conversion is quite general since many analogous transformations have been observed in which different carbanion stabilizing substituents were employed (73S546). 

Ring transformations heterocyclic compounds reviews, 1, 70 Ring-chain tautomerism polyheteroatom six-membered rings, 3, 1056 Ripariochromene A synthesis, 3, 751, 755 Robinson-Gabriel synthesis oxazoles, 6, 216... 

These consider ring syntheses from non-heterocyclic compounds first, followed by transformation of other heterocyclics. Syntheses in which no new heterocyclic ring is formed are dealt with primarily in the appropriate reactivity section, but with cross-referencing when necessary. Ring syntheses from acyclic precursors are dealt with as logically as possible according to the number and nature of the new ring bonds formed in the process. 

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