1,3-Dipole, Heterocyclic

This particularly valuable technique for studying molecules which possess permanent dipole moments in the vapour phase has been reviewed on many occasions. For its application to heterocyclic compounds the excellent account by Sheridan <74PMH(6)53) should be consulted. 

An appreciable amount of information concerning the conformational preferences of substituted heterocycles has accrued, largely through dipole moment and NMR studies. However, the earliest appreciation of this topic apparently arose out of the extension of studies of restricted rotation in biphenyls to heterocyclic analogues. 

Azomethine ylides are also frequently obtained by ring opening of aziridines, and the analogous carbonyl ylides from oxiranes. These aspects are dealt with in Section 3.03.5.1. A variety of five-membered heterocycles can also function as masked 1,3-dipoles and this aspect is considered in Section 3.03.5.2. 

Table 2 illustrates 1,3-dipoles with a double bond and with internal octet stabilization, commonly referred to as the propargyl-allenyl anion type. These are all reactive dipoles and a large number of five-membered heterocycles can be constructed from these readily available dipoles, especially when the dipolarophile is varied to include heterocumulenes, etc. 

Formation of ring-fused systems by reactions of this type can be achieved in two ways in one the heterocycle to which ring annulation is to occur acts as the dipolarophile the alternative mode utilizes incorporation of the 1,3-dipole into the heterocyclic ring for reaction with the dipolarophile. Both approaches have been investigated intensively. 

As the sp nitrogen atom in many heterocycles can be alkylated and aminated, the construction of an azomethine ylide or azomethine imine dipole is readily attainable as shown in Scheme 13. These ylides are very reactive and undergo cycloaddition with a... 

Use of mesoionic ring systems for the synthesis of five-membered heterocycles with two or more heteroatoms is relatively restricted because of the few readily accessible systems containing two heteroatoms in the 1,3-dipole. They are particularly suited for the unambiguous synthesis of pyrazoles as the azomethine imine is contained as a masked 1,3-dipole in the sydnone system. An attractive feature of their use is that the precursor to the mesoionic system may be used in the presence of the cyclodehydration agent and the dipolarophile, avoiding the necessity for isolating the mesoionic system. 

Dipoles can also be built into heterocyclic systems, and though of limited use, they may also be utilized for the synthesis of [5,6] ring-fused systems. Reaction of 2 3H)-benzothiazolethione with (chlorocarbonyl)phenylketene in warm anhydrous benzene gave the heteroaromatic betaine (416). On heating with DMAD in boiling toluene the tricyclic pyridinone (418) was obtained, presumably by elimination of COS from the intermediate cycloadduct (417) (80JOC2474). 

The concept of a 1,5-dipolar cyclization gives rise to a general method for the synthesis of an appreciable number of heterocyclic systems. 1,5-Dipoles are derived from 1,3-dipoles by conjugation with different double bond systems, and it is possible to derive 98 theoretically possible 1,5-dipolar systems. The general expression for a 1,5-dipole and some possible combinations of double bond systems are shown in Scheme 14. 

Heterocyclics of all sizes, as long as they are unsaturated, can serve as dipolarophiles and add to external 1,3-dipoles. Examples involving small rings are not numerous. Thiirene oxides add 1,3-dipoles, such as di azomethane, with subsequent loss of the sulfur moiety (Section 5.06.3.8). As one would expect, unsaturated large heterocyclics readily provide the two-atom component for 1,3-dipolar cycloadditions. Examples are found in the monograph chapters, such as those on azepines and thiepines (Sections 5.16.3.8.1 and 5.17.2.4.4). 

Four-membered heterocycles can be formed by the addition of isocyanides to 1,3-dipoles (80AG(E)45) and by the reaction of carbon monoxide with -haloamines, with the aid of palladium catalysis (Scheme 10) (79CC699). 

Oxirane (1) and methyloxirane (3) are miscible with water, ethyloxirane is very soluble in water, while compounds such as cyclopentene oxide and higher oxiranes are essentially insoluble (B-73MI50501) (for a discussion of the solubilities of heterocycles, see (63PMH(l)l77)). Other physical properties of heterocycles, such as dipole moments and electrochemical properties, are discussed in various chapters of pmh. The optical activity of chiral oxiranes has been investigated by ab initio molecular orbital methods (8UA1023). 

Furazano[3,4-/]quinoxaline, 7,8-diphenyl-synthesis, 6, 412 Furazanothiophene synthesis, 6, 417 Furazans, 6, 393-426 biological activity, 6, 425 bond angles, 6, 396 bond lengths, 6, 396 coordination compounds, 6, 403 diamagnetic susceptibilities, 6, 395 dipole moments, 6, 395, 400 heats of combustion, 6, 400 heterocyclic ring reactions, 6, 400-403 IR spectra, 6, 398 isoxazoles from, 6, 81 mass spectra, 6, 399 microwave spectroscopy, 6, 395, 396 MO calculations, 6, 395 monosubstituted... 

Diels-Alder reactions, 4, 842 flash vapour phase pyrolysis, 4, 846 reactions with 6-dimethylaminofuKenov, 4, 844 reactions with JV,n-diphenylnitrone, 4, 841 reactions with mesitonitrile oxide, 4, 841 structure, 4, 715, 725 synthesis, 4, 725, 767-769, 930 theoretical methods, 4, 3 tricarbonyl iron complexes, 4, 847 dipole moments, 4, 716 n-directing effect, 4, 44 2,5-disubstituted synthesis, 4, 116-117 from l,3-dithiolylium-4-olates, 6, 826 electrocyclization, 4, 748-750 electron bombardment, 4, 739 electronic deformation, 4, 722-723 electronic structure, 4, 715 electrophilic substitution, 4, 43, 44, 717-719, 751 directing effects, 4, 752-753 fluorescence spectra, 4, 735-736 fluorinated derivatives, 4, 679 H NMR, 4, 731 Friedel-Crafts acylation, 4, 777 with fused six-membered heterocyclic rings, 4, 973-1036 fused small rings structure, 4, 720-721 gas phase UV spectrum, 4, 734 H NMR, 4, 7, 728-731, 939 solvent effects, 4, 730 substituent constants, 4, 731 halo... 

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. 

Reactions offluorinated dipoles. In recent years, much effort has been devoted to the preparation of tnfluoromethyl-substituted 1,3-dipoles with the goal of using them to introduce trifluoromethyl groups into five-membered nng heterocycles Fluorinated diazoalkanes were the first such 1,3-dipoles to be prepared and used in synthesis A number of reports of cycloadditions of mono- and bis(tnfluo-romethyl)diazomethane appeared prior to 1972 [9] Other types of fluonne-substi-tuted 1,3-dipoles were virtually unknown until only recently However, largely because of the efforts of Tanaka s group, a broad knowledge of the chemistry of tnfluoromethyl-substituted nitrile oxides, nitnle imines, nitnle ylides, and nitrones has been accumulated recently... 

Dipole moments and molar Kerr constants of phenotellurazines were measured (85ZOB846). The results suggest a significant shift of electron density from the benzene rings toward the heterocycle. 

Thus, 4-amino- and 4-alkoxybut-3-en-2-ones react with 1,3-dipoles involving only the carbon-carbon double bond, the negative part of the 1,3-dipole adding to position 4 of the butenone. The heterocyclizations are accompanied by elimination of the 4-hetero group. 

There are specific associations of various types of dipoles with the four major classes of heterocyclic mesomeric betaines, which have implications in providing a rational foundation for correlating the chemical reactions of these compounds (85T2239). Eight dipole types, systematically generated by union of the heterocations H2C = with carbanions and... 

The importance of the 1,3-dipolar cycloaddition reaction for the synthesis of five-membered heterocycles arises from the many possible dipole/dipolarophile combinations. Five-membered heterocycles are often found as structural subunits of natural products. Furthermore an intramolecular variant makes possible the formation of more complex structures from relatively simple starting materials. For example the tricyclic compound 10 is formed from 9 by an intramolecular cycloaddition in 80% yield ... 

Similar cycloadditions between thiirene dioxides and 1,3-dipoles generated in situ give heterocycles which result from either loss of sulfur dioxide or from the three-membered ring opening of the initially formed adduct (e.g. 174). Such cycloadditions with nitrilium imides (173a) and nitrile ylids (173b) are illustrated in equation 69175. 

The 1,3-dipolar cycloadditions are a powerful kind of reaction for the preparation of functionalised five-membered heterocycles [42]. In the field of Fischer carbene complexes, the a,/ -unsaturated derivatives have been scarcely used in cyclo additions with 1,3-dipoles in contrast with other types of cyclo additions [43]. These complexes have low energy LUMOs, due to the electron-acceptor character of the pentacarbonyl metal fragment, and hence, they react with electron-rich dipoles with high energy HOMOs. 

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