Heterocyclics closure

A/ -HeterocycHc derivatives can be formed in some cases by a ring closure to give the heterocycle. Sulfadiazine, sulfamethazine, sulfamerazine, and sulfathiazole have been prepared in this fashion, but also by the usual procedure from the sulfonyl chloride and heterocycHc amine. The synthesis of sulfamethazine from sulfaguanidine is an example of the ring closure method. 

The course of the acid catalyzed dehydration of 1,4-diketones to furans, known as the Paal-Knorr method (1884CB2756), entails the formal addition of the enol of one carbonyl group to the other carbonyl. Examples which illustrate some of the routes used to make the necessary 1,4-diketones are shown in Scheme 13. Few examples are known of the preparation of the other heterocycles by this general approach using isolated intermediates, although some of the ring closures discussed in Section 3.03.3.1.1 are mechanistically equivalent. One example of the preparation of a hydroxypyrrole is included in Scheme 13 <59AC(R)2075). 

The synthetic application of reactions based upon the intramolecular addition of a carbanion or its enamine equivalent to a carbonyl or nitrile group has been explored extensively. One class of such reactions, namely the Dieckman, has already been discussed in Section 3.03.2.2, since ring closure can often occur so as to form either the C(2)—C(3) or C(3)—C(4) bond of the heterocyclic ring. Some illustrative examples of the application of this type of ring closure are presented in Scheme 46. 

The role of the 1,1-bielectrophile in ring closures of this type is to provide a one-carbon unit (or heteroatbm) to close the cycle. Thus, the synthesis of the four-atom precursor with two nucleophilic centers 1,4 to each other is an appreciable challenge, especially to obtain a heterocycle at the desired oxidation level. The examples below illustrate the way this approach to synthesis may be gainfully utilized. 

Numerous examples of the ring closure of a binucleophilic system with a 1,1 -bielectrophile leading to five-membered heterocycles with three or more heteroatoms have been described, the popularity of this route no doubt reflecting the comparative ease with which the penultimate product may be obtained. 

Oxidative procedures have been utilized for the synthesis of both monocyclic five-membered heterocycles and their ring-fused analogs, although the ease of synthesis of the precursors for the latter ring closures results in wider application of this procedure. A variety of oxidizing agents have been used and the conversion of the benzylidene hydrazidines (221) into the 4-arylamino-l,2,4-triazole (222) was effected with mercury(II) oxide (77BCJ953). 

Polyfluorinated a-diketones react with 1,2-diainino compounds, such as ortlio-phenylenediamine, to give 2,3-substituted quinoxalmes [103] Furthermore, the carboxyl function of trifluoropyruvates offers an additional electrophilic center. Cyclic products are obtained with binucleophiles [13, 104] With aliphatic or aromatic 1,2-diamines, six-memhered heterocycles are formed Anilines and phenols undergo C-alkylation with trifluoropyruvates in the ortho position followed by ring closure to form y-lactams and y-lactones [11, 13, 52, 53, 54] (equation 23). 

Once formed, 7 and 8 undergo a Michael reaction that gives rise to ketoenamine 9. Ring closure, to form 10, and loss of water then afforded 1,4-dihydropyridine 11. The presence of 9 and 10 could not be detected thus ring closure and dehydration were deduced to proceed faster than the Michael addition. This has the result of making the Michael addition the rate-determining step in this sequence. Conversely, if the reaction is run in the presence of a small amount of diethylamine, compounds related to 10 could be isolated. Diol 20 has been isolated in an unique case (R = CFb). Attempts to dehydrate this compound under a variety of conditions were unsuccessful. Stereoelectronic effects related to the dehydration may be the cause. In related heterocyclic ring formations, it has been determined that dehydration (20 —> 10) is about 10 times slower than diol formation (19 —> 20). Therefore, one would expect 20 to... 

Amides, prepared by condensation of tryptamine or substituted tryptamines with a large number of aliphatic, homocyclic, aromatic,and heterocyclic acids, have been used in the reaction. In few cases only did ring closure fail. ... 

Successive nucleophilic addition/ring closure (NARC) in stereocontrolled synthesis of heterocycles 97MI38. 

Synthesis of heterocycles by ring closure of orr/io-substituted r-anilines 96AHC(65)1. 

JA742). However, the heterocyclization of 4-phenylethynylpyrazole-3- and 4-phenylethynylpyrazole-5-carboxylic acid in alcohol or acetonitrile solutions in the presence of AgNOs caused, once again, the closure of the six-membered lactones. 

Intramolecular addition of the amide group to the triple bond in pyrazoles is more difficult, and results in closure of the 5-lactam rather than the y-lactam ring. The reaction time of the 4-phenylethynylpyrazole-3-carboxylic acid amide under the same conditions is extended to 42 h (Scheme 129) (Table XXVII). The cyclization of l-methyl-4-phenylethynyl-l//-pyrazole-3-carboxylic acid amide, in which the acetylene substituent is located in the 7r-electron-rich position of the heterocycle, is the only one complete after 107 h (Scheme 130) (90IZV2089). 

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. 

An important application of the Friedel-Crafts acylation is the intramolecular reaction, leading to ring closure. This variant is especially useful for the closure of six-membered rings, but five-membered ring products and larger rings, as well as heterocycles, are also accessible ... 

---