Intramolecular reactions forming heterocycles

In addition to the synthesis of industrially important azo dyes using heteroaromatic diazo components, intramolecular azo coupling reactions of heterocyclic diazonium ions also have interesting synthetic uses, because they lead to new fused-ring heterocycles, as shown by the diazotization of 2-amino-3-arylbenzimidazoles (12.7) in which, without isolation of the diazonium ion, a 1,2,4-triazine ring is formed (Kolodyazhnaya et al., 1973). Further examples of intramolecular azo couplings were reviewed by Tisler and Stanovnik (1980), and very extensively (403 references ) by Kishimoto et al. (1990). 

In 1984, we demonstrated that A-alkoxy-A-acyl nitrenium ions 15 could be generated by the reaction of A-alkoxy-A-chloroamides 14 with Lewis acids such as Ag + and Zn2+ and used these to form heterocycles by intramolecular aromatic substitution reactions (Scheme 2).90 In this manner, several novel A-acyl-3,4-dihydro-2,l-benzoxazines 16a and A-acyl-4,5-dihydro-( I //,3//)-2,1-benzoxazepines 16b were made. Subsequent work91,92 and that of Kikugawa93 96 produced numerous syntheses involving alkoxynitrenium ions including formation of natural products.97 99... 

Imine formation is an important reaction. It generates a C-N bond, and it is probably the most common way of forming heterocyclic rings containing nitrogen (see Section 11.10). Thns, cycliza-tion of 5-aminopentanal to A -piperideine is merely intramolecular imine formation. A further property of imines that is shared with carbonyl groups is their susceptibility to reduction via complex metal hydrides (see Section 7.5). This allows imines to be... 

Various intramolecular reactions are widely used to prepare this type of heterocycle. Intramolecular acylation has been used frequently (84AHC(37)i). Houben-Hoesch cyclization of I -(3-cyanoethylpyrrole (4a) gives l-oxo-2,3-dihydropyrrolizine (5a). The methyl group in (4b) selectively activates C-2 so that only the isomer (5b) is formed (66JA1305). 

A similar unravelling of the heterocyclic ring occurred in intramolecular reactions with furans,79b,159 161 leading to cyclic 1,4-diacyl-1,3-butadienes (204 equation 42)159 and (205 equation 43).79b The ideal size for the tether was five, but less efficient capture of the carbenoid was also possible with six- and seven-membered rings. With the 3-furanyl derivative (206), the acid labile structure (207) was formed, which readily rearranged to p-hydroxyphenylacetaldehyde (208 Scheme 43).161... 

The bromination of the tetracyclic compound (30) affords71 the novel compound (31) formed by capture of the Wheland intermediate by die neighbouring carboxylate ion. The intramolecular reaction of some activated pyridines witii A -acyliminium ions led to some novel heterocycles [e.g. (33) from (32) in the presence of p-toluenesulfonic acid in benzene] by cyclization para to an electron-donating substituent.72... 

Phenanthridines are obtained from 2,2 -disubstituted biphenyls in which the substituents react intramolecularly to form the heterocyclic ring. The oldest examples of syntheses of this type involve Hofmann65 and Curtius66- 67 reactions on biphenic acid, and have been explained... 

Terminal perfluoroolefins have two fluorine atoms at the double bond. The carbon atoms of the latter bear a significant positive charge, and the nucleophilic agents easily replace the fluorine atoms at the multiple bond. The reactions of binucleophilic reagents with terminal perfluoroolefins form heterocyclic systems. The first step of the reaction involves a nucleophilic attack at the carbon atom of the double bond, generating a carbanion. The latter is stabilized by elimination of the fluoride ion and formation of a new double bond. Subsequent cyclization by the intramolecular attack of the nucleophilic center at the double bond leads to the formation of a heterocyclic system. For example, when a reaction mixture of hexafluoropropylene and sodium dialkylaminodithiocarbamate in dimethylacetamide is heated with aqueous sodium tetraphenylborate, one obtains the tetraphenylborate salt of 2-dialkylamino-4-trifluoromethyl-4,5-difluoro-l,3-dithiolan-2-yl (78JFC(12)193). This compound is formed by intramolecular cyclization of the S-nucleophilic center. 

Intramolecular reaction with nucleophilic groups can also lead to heterocycles. For example, good yields of 3-acylbenzofurans result from cyclization caused by intramolecular substitution of the tertiary amino group by a phenol formed by cleavage of a phenol ether by boron tribromide251 (equation 182). 0-Hydroxy benzyl alcohols were used to obtain 4//-chromenes by their reaction with 4-morpholino-3-buten-2-one in acetic acid-acetic anhydride187. 

Also, the one pot reaction of heterocyclic bis-iminophosphoranes with one or two equivalents of aryl isocyanates leads to selective formation of fused heterocycles. For example, from the pyrazole derivative 17 either [l,3]-diazepines 18 or tricyclic ring systems 19 are formed. The latter reaction involves an intramolecular [2-1-2] cycloaddition of both carbodiimide substituents. ... 

Although also a special case of a MPV reduction (Section 1.3.3.3) some unusual reactions of practical import will be considered here because of the heterocyclic characteristics. Donation in an intramolecular reaction of a hydride from a tertiary aniline derivative to generate an iminium ion initiates the reaction. An example is given in Scheme 7. Tertiary aniline derivative (99) rearranges thermally apparently via intermediate (100) to pyrrolo[ 1,2-a]quinoline (101). ° The highly electron-deficient double bond is clearly the hydride acceptor in this case exclusively the most substituted iminium salt is formed. Subsequent ring closure provides the end product (101). Formation of the more substituted iminium ion is not always the case. ° ° ... 

The ene reaction forms a heterocyclic ring if the two components are tethered by a nitrogen atom. Simple examples described by Oppolzer and Snieckus show that there is some kinetic preference for the "endo product. After 24 hours at 150 °C, the syn product 126 is the only one from the intramolecular ene reaction22 125. 

The work reported here relates to (i) intermolecular reactions, and (ii) intramolecular reactions, where the two reacting -electron systems constitute part of one heterocyclic molecule. In the first type of reaction two o-bonds are formed [Eqs. (1) and (2)], whereas in the second type either... 

Tanaka et al. established the chemistry of using the bromoallene moiety as the equivalent of allyl dications.This dication can react with an intermolecular nucleophile (MeOH) and an intramolecular nucleophile to form heterocyclic alkenes (Scheme 26) [19]. The PdCl2-catalyzed reaction of 2,3-allenoic acids 58 with allylic halides in DMA at 50 °C afforded 4-allylic-substituted 2(5Tf)-fura-nones 59 in moderate to excellent yields (Scheme 27) [20]. 

The various approaches to forming heterocyclic ring systems by intramolecular cyclizations were discussed in Chapter 4 and by cycloaddition reactions in Chapter 5. In Chapters 6 and 7, numerous reactions of heterocyclics were described. We will now reexamine some of this material from a different standpoint, taking a particular heterocyclic family and considering some of the methods that are useful for the construction of the family. In addition, some information on the synthesis of important heterocycles not yet considered will be presented. As was discussed in Chapter 8, great numbers of new heterocyclic compounds have been, and continue to be, synthesized in the research laboratories of the pharmaceutical industry in their search for new materials of value in medicine, and the many accomplishments from this work provide a multitude of examples that can be used to illustrate the practical application of heterocycMc chemistry. However, the presentation must be limited to a small number of examples for more in-depth discussions of important syntheses, two works by... 

Many examples of intramolecular ring-closing reactions have been presented in Chapter 4 and elsewhere, which makes it clear that this is an important concept for heterocyclic synthesis. However, certain types of proposed intramolecular reactions fail. These observations led J. E. Baldwin to develop a set of empirical mles that allow prediction of which structural types will be favored or disfavored for cyclization. For an intramolecular cyclization to occur, the functional group at one end of a chain must be able to reach the site where a new bond is to be formed, so that efficient orbital interaction can take place. The ease of the interaction is reflected in the activation energy for the formation of the transition state thus, cyclization is under kinetic control. Baldwin s rules are based on the following stmctural features ... 

The initial studies on Pd-catalyzed C—O bond formation were conducted as intramolecular reactions to form oxygen heterocycles (Eq. 1). It is known that copper complexes will catalyze these transformations, and copper acetylide is particularly valuable for these... 

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