Heterocyclic ring, construction

Although widely applied in functional group modification in a variety of heterocyclic systems, phosphorus ylides have only been employed sparingly in heterocyclic ring construction with two or more heteroatoms in the nucleus. Their potential is shown in the applications illustrated below. 

If ammonium thiocyanate is used, the ammonium ion can itself provide a nitrogen atom for heterocyclic ring construction. Such nitrogen and sulfur transfer is the basis of an elegant synthesis of isothiazoles (15) from 3-chloropropenals (16).18... 

DAIB-induced conversions of the anthranilamides 195 and salicylamides 196 to the benzimidazolones 197 and benzoxazolones 198, respectively, and similar rearrangements of two representative pyridinecarboxamides, are recent examples of direct heterocyclic ring-construction by the iodine(III)-Hofmann pathway (Scheme 57) (01S541). These reactions may be contrasted with BTIB-oxidations of the 2-aminonicotinamides 67 and amidopyridones 69 in aqueous DMF (Section II.A.2) which lead, without rearrangement, to N-N and N-O bond formation (97SC2217). 

Vapor phase pyrolysis of 2-dimethylaminoazirine (168), on the other hand, proceeds in a similar manner at 340 °C to give substituted azadiene (169) in high yield (7SJA4409). Azadiene (169) has been employed in the construction of heterocyclic rings such as pyridines via a [4-1-2] cycloaddition-elimination sequence. 

The 1,3-dipolar molecules are isoelectronic with the allyl anion and have four electrons in a n system encompassing the 1,3-dipole. Some typical 1,3-dipolar species are shown in Scheme 11.4. It should be noted that all have one or more resonance structures showing the characteristic 1,3-dipole. The dipolarophiles are typically alkenes or alkynes, but all that is essential is a tc bond. The reactivity of dipolarophiles depends both on the substituents present on the n bond and on the nature of the 1,3-dipole involved in the reaction. Because of the wide range of structures that can serve either as a 1,3-dipole or as a dipolarophile, the 1,3-dipolar cycloaddition is a very useful reaction for the construction of five-membered heterocyclic rings. 

This ring system can be constructed by building one of the two heterocyclic rings on the other preformed ring the construction of the thiazeto ring on a quinoline moiety or generating a pyridine ring on a... 

One of the standard methods for construction of the basic heterocyclic ring was elaborated not long after the turn of the century. Thus, condensation of ethyl lactate with guanidine leads to the imine of the desired ring system (47), possibly by a reaction scheme such as that outlined below. Hydrolysis affords the oxazolidinedione (48). Methylation in the presence of base gives 49. 

The intramolecular Hiyama reaction is excellently suited for the construction of carbocyclic and heterocyclic ring systems of different size. In most examples, problems of induced diastereoselectivity are involved (Sections 1.3.3.3.9.2.2. and D.2.3.). In the total synthesis of the antitumor germacranolide ( )-costunolide from ( ,.E)-farnesol, the correctly substituted ( , )-cyclodecadiene moiety was constructed by an intramolecular Hiyama reaction22. 

All synthetic references are printed in boldface in Tables 1-3. The synthetic methods reported have been classified below into several general approaches according to a one-pot construction of one, two, and three fused heterocyclic ring systems. 

To get a complex set of substituents by direct derivatization of benzotriazole is not feasible. In such situations, it is better to have all the substituents in place first and later construct the heterocyclic ring. High reactivity of anilines and their well-developed chemistry makes them good stating materials. In an example shown in Scheme 215, acetanilide 1288 is nitrated to afford nitro derivative 1289 in 73% yield. Catalytic reduction of the nitro group provides methyl 4-acetylamino-3-amino-5-chloro-2-methoxybenzoate 1290 in 96% yield. Nitrosation of compound 1290 in diluted sulfuric acid leads to intermediate 1291, which without separation is heated to be converted to 7-chloro-4-methoxy-l//-benzotriazole-5-carboxylic acid 1292, isolated in 64% yield <2002CPB941>. 

An analysis of the principal methods for construction of compounds with 1,2,5-oxadiazole heterocyclic units was published in CHEC(1984) and CHEC-II(1996) < 1984CHEC(6)393, 1996CHEC-II(4)229>. In this chapter only reactions that lead to the formation of 1,2,5-oxadiazole cyclic fragments are considered. The functionalization or replacement of substituents of heterocyclic ring as well as oxidation or deoxidation of nitrogen atoms are described in Section 5.05.4. 

N-Methyl-2-phenyl-A2-tetraJiydropyridine and similar compounds have previously been prepared by the hydrolysis and decarboxylation of a-benzoyl-N-methyl-2-piperidone3 and by the addition of phenyl Grignard reagents to N-methyl-2-piperidone followed by dehydration.4 Both of these methods require that a heterocyclic ring already be present in the system. In contrast, this procedure offers a new flexible route to the construction of five- or six-membered heterocyclic rings which may easily be incorporated into a larger polycyclic product. Several examples of this process that can be cited to demonstrate this utility are... 

A different mode of fragmentation of the lactone ring in 35 occurred to give butyrolactone 38 when anhydrous lithium alkoxides were used in place of metal hydroxides under aqueous conditions (Scheme 10). It is noteworthy that 36, 37 and 38 (R = H) are all formed without racemization. Although we are only in the early stages of development of the chemistry of iodolactones 35, it is already clear that there is considerable potential for utilization of the butenolides derived from 35 as scaffolds for construction of carbocyclic and heterocyclic ring... 

The first synthesis of racemic DHP A was done by constructing the heterocyclic ring onto amine 1100 (65JMC502). This was done by a reaction with 5-amino-4,6-dichloropyrimidines, followed by construction of the imidazole... 

It has been known since 1939 that the 1,2-dihydropyridine ring system is capable of behaving as a four-electron component in the Diels-Alder reaction (39LA(538)195). This reaction produces the isoquinuclidine ring system and has proven to be the method of choice for the synthesis of this heterocyclic ring system. For example, a classic synthesis of ibogamine (248) used the Diels-Alder reaction of 1,2-dihydropyridine (246) to construct the isoquinuclidine portion of this alkaloid (Scheme 45) (66JA3099). 

Synthesis by construction of the second heterocyclic ring onto an existing heterocycle 10.01.9.1.1 Benzoderivatives... 

Synthesis by Construction of the Second Heterocyclic Ring onto an Existing... 

Pyrido[2,3- pyrimidine bicyclic systems represent interesting fused heterocyclic compounds having pharmacological and biological properties. Their syntheses are well documented in the literature. The pyridine or pyrimidine rings have been used as precursors for constructing the second heterocyclic ring. 

The only report concerning the construction of the heterocyclic ring of diazafluorenes was described in CHEC-11(1996) <1996CHEC-II(7)921> using a variant of the Hantzsch pyridine synthesis. Somewhat surprisingly, no further reports using this method have been found. 

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