Heterocycles, five membered

Five-membered heterocycles with two heteroatoms connected in 2-position also form two step redox systems of the Weitz type which may be described as hetero-tetrasubstituted ethylenes on the level of RED . The great significance of tetrathia (selena) flilvalenes 17 as a basis for organic metals has already been discussed  

In this rapidly developing field the crystal stmcture of the specific donor-acceptor pair dominates the solution bound redox potentials which are discussed here. 

The long-known dibenzo-tetrathiafulvalene i SRED can also be oxidized reversibly in two separate steps with Ej = +0.72 V, E2 = +1.06 V (vers. Ag/AgCl in acetonitrile) and Ksem = 5.6 10 The influence of different heteroatoms can be read from the systems 19—21 which are better isolated in the oxidized form. 

The effect of an increasing number of vinylene groups in the general type A should be of special interest. The separation of the end groups X which carry an appreciable amount of positive charge on the level SEM and OX increases as the rr-system is enlarged. 

Extension of this scheme to nonaromatic heterocycles and saturated side chains has also been described [94H(37)2051]. See Section IV,D. 

Degenerate Ring Transformations Involving Participation of One Atom of a Side Chain 

3- Exoannular CC exchange. The ehemistry of this type of ring eonver-sion is extensively diseussed in the last part of Section IV,B (see Sehemes IV.34-39). 

For five-membered, electron-rich heterocycles, the utility of electrophilic substitutions is much greater. Heterocycles such as pyrrole, thiophene and furan undergo a range of electrophilic substitutions with great ease, at either type of ring position, but with a preference for attack adjacent to the heteroatom - at their a-positions. 

These substitutions are facilitated by electron release from the heteroatom pyrroles are more reactive than furans, which are in turn more reactive than thiophenes. Quantitative comparisons of the relative reactivities of the three heterocycles vary from electrophile to electrophile, but for trifluoroacetylation, for example, the pyrrole furan thiophene ratio is 5 x 10 1.5 x 10 I in formylation, furan is 12 times more reactive than thiophene, and for acetylation, the value is 9.3. In hydrogen exchange (deuteriodeproton-ation), the partial rate factors for the a and p positions of A-methylpyrrole are 3.9 x 10 ° and 2.0 x 10 ° respectively for this same process, the values for furan are 1.6 x 10 and 3.2 x l(f and for thiophene, 3.9 X 10 and 1.0 x 10 respectively, and in a study of thiophene, a P ratios ranging from 100 1 to 1000 1 were found for different electrophiles. Relative substrate reactivity parallels positional selectivity i.e. the a P ratio decreases in the order furan thiophene pyrrole. ° Nice illustrations of these relative reactivities are found in acylations of compounds containing two different systems linked together.  

The positional selectivity of attack on pyrroles can be completely altered by the presence of bulky gronps on nitrogen l-(t-butyldimethylsilyl)pyrrole and l-(tri-i-propylsilyl)pyrrole are attacked exclusively at their P-positions.  

Each of the simple five-membered heterocycles—furan, pyrole, and thiophene—can be regarded as dienes with varying degrees of aromaticity. They have the (4n 4- 2)7t electronic systems where two of the necessary six electrons are supplied by the heteroatom. Of these, furan appears the least aromatic and hence most dienelike. Furan 141 alone reacts with maleic anhydride under ordinary conditions to form an adduct 142. The reaction occurs under mild conditions to give quantitative yields. The structure of the adduct 142 has been verified by converting it to phthalic anhydride. 

A number of furan derivatives, e.g., 2-methylfuran, 3-methylfuran, 2,5-dimethylfuran, 3-bromofuran, and 2-aminofuran, have been investigated.Furan derivatives with 2 or 3 cyano, carbethoxy, and nitro substituents fail to undergo the addition reaction. However, when a double bond is exocyclic to a furan ring, interestingly, the adduct formed is predominantly the one involving the external olefin as known in the case 

MA adducts formed from furan derivatives are generally labile and dissociate in solution. The extent of dissociation depends on the nature of 

It may be of interest to note that not all dienophiles react with furan to give the DA adduct. Thus, furan and 2-methylfuran react with acrolein, crotonaldehyde, methylvinyl ketone, and phenylvinyl ketone to yield substitution products. 

Pyrrole derivatives fail to give normal adducts and instead give substitution products as illustrated with iV-methylpyrrole 147 below.  

Many other heterobifunctional chiral auxiliaries have also been employed to alford P-stereogenic heterocycles. Some of them are discussed here. 

The first step was a thermodynamically controlled process towards the more stable exo isomer of 66 (shown in the scheme) although at shorter reaction times the endo isomer was also observed. Compound 66 is a liquid that is only stable at low temperatures, whereas 67 is a crystalline solid that was used to prepare P-stereogenic phosphines, as detailed in Chapter 4, Section 4.S.2.2. Analogues of 67 with other groups instead of phenyl were also prepared. 

Compound 68 was prepared by Stelzer and co-workers from (—)-pina-nediol as a single isomer, but the absolute configuration at the P atom was not determined. Benetsky and co-workers prepared compounds 69-71 from dichlorophosphine precursors and commercially available or easily obtainable diols. Phosphite 71 was obtained in low optical purity (32% de), but for both 69 and 70 the de exceeded 90% and one of them (70, R = NEt2) was prepared in 

Thus far only eight different types of five-membered heterocycles with two heteroatoms, one of these being tellurium, are known. Of special interest are those containing S,Se, or Te as the second heteroatom in the ring. Such compounds afford electron-donor components of charge-transfer complexes or radical cation salts, exhibiting properties of the so-called organic metals. 

Isotellurazoles 4 were obtained in low yields (3-11%) by the one-pot reaction of alkynyl ketones with hydroxylamino-O-sulfonic acid and K2Te in aqueous solution containing sodium acetate (83S824 87H1587). A plausible mechanism of the reaction includes formation of the oxime derivative and subsequent nucleophilic addition of telluride anion to the triple bond followed by cyclization to 4. The reaction is accompanied by the formation of telluro bis(alkenyl ketones) 5 in yields approximately equal to those of 4. When alkynyl aldehydes are used instead of ketones, the single reaction products are the tellurobis(alkenyl nitriles) 6 (83S824). 

As demonstrated above, nitro derivatives of five-membered heterocycles have found extensive use as antiinfective agents. It is therefore of interest that the nitro derivative of a substituted thiazole was at one time used as an antitrichomonal agent. Bro-mination of 2-aminothiazole (136) (obtained from condensation of thiourea with chloroacetaldehyde) gives the 4-bromo derivative (138) this is then acetylated to 139. Treatment of 139 with nitric acid leads to an interesting displacement of bromine by a nitro group to afford aminitrazole (140) 

A thiazole derivative that incorporates a fragment of the amphetamine molecule shows some CNS stimulant activity more specifically, the compound antagonizes the depression caused by overdoses of barbiturates and narcotics. Reaction of benzalde-hyde with sodium cyanide and benzenesulfonyl chloride gives the toluenesulfony1 ester of the cyanohydrin (141). Reaction of this with thiourea leads directly to aminophenazole (143) It is probable the reaction proceeds by displacement of the tosylate by the thiourea sulfur to give 142 addition of the amino group to the nitrile followed by tautomerization affords the observed product.  

Acylation of benzamidoxlme (144) with chloropropionyl chloride gives the 0-acylated derivative (145). Reaction of that intermediate with diethylamine serves first to cyclize the molecule to the 1,2,4-oxadiazole heterocycle subsequent displacement of the halogen on the side chain gives oxolamine (146),a drug with antltussive and spasmolytic activity. 

Shifting the side chain to the 4 position (with the necessary tautomeric change) affords an agent with local anesthetic and coronary vasodilator activity. Cycllzation of compound 147 by means of phosphorus oxychloride gives the amino-l,2,4-oxodiazole (148). Alkylation of that compound with 2-chlorotriethylamine in the presence of sodium hydroxide proceeds via the tautomer, 

rather than the fully conjugated isomer. There is thus obtained imolamine (150) 

The rapid s)mthesis of 4-thiazohdinones by the MCR of an amine, aldehyde and mercaptoacetic acid has been developed under microwave-assisted conditions [73-75]. Irradiation of the three components in ethanol at 120 °C in the presence of molecular sieves [73] or in toluene at reflux imder atmospheric conditions [74] in a single-mode microwave s)mthesizer gave the 

State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences, Lanzhou, China 

Stereoselective Multiple Bond-Forming Transformations in Organic Synthesis First Edition. Edited by Jean Rodriguez and Damien Bonne. 

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A completely different, important type of synthesis, which was developed more recently, takes advantage of the electrophilicity of nitrogen-containing 1,3-dipolar compounds rather than the nucleophilicity of amines or enamines. Such compounds add to multiple bonds, e.g. C—C, C C, C—O, in a [2 + 3 -cycioaddition to form five-membered heterocycles. 

A few typical examples indicate the large variety of five-membered heterocycles, which can be synthesized efficiently by [2 + 3]-cycloadditions. [2 + 2]-Cycloadditions are useful in the synthesis of certain four-membered heterocycles (H. Ulrich, 1967), e.g. of 8-lactams (J.R. 

The strain energies of these five-membered heterocycles are relatively small with values of 23.5, 24.8 and S.SkJmoF estimated for tetrahydrofuran, pyrrolidine and tetrahy-drothiophene respectively (74PMH(6)199). The closeness of the values for the two former compounds reflects the almost identical covalent radii of oxygen (0.66 A) and nitrogen (0.70 A) atoms. The sulfur atom with a much larger covalent radius of 1.04 A causes a... 

Table 32 Conformational Preference of 2-Substituted Five-membered Heterocycles...

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. 

Some examples of ring opening reactions with carbanions leading to five-membered heterocyclic ring formation are shown in Scheme 85. Pyrrole syntheses from functionally substituted oxiranes and amines are often described and typical examples are shown in Scheme 86. 

The conversion of furans by oxidative acetylation or methoxylation to 2,5-diacetoxy- or 2,5-dimethoxy-2,5-dihydrofurans respectively, and their subsequent hydrogenation to the corresponding tetrahydrofurans, provides a useful source of protected 1,4-dicarbonyl compounds capable of conversion inter alia into the other five-membered heterocycles [Pg.142]

Furans, thiophenes and pyrroles have all been obtained by addition of alkynic dienophiles to a variety of other five-membered heterocycles, as illustrated in Scheme 104. As the alkynic moiety provides carbons 3 and 4 of the resulting heterocycle, this synthetic approach provides an attractive way of introducing carbonyl containing substituents at these positions, especially as many of the heterocyclic substrates are readily generated. Such reactions do... 

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. 

In Table 29 the u(C=0) and other characteristic bands are given for some saturated five-membered heterocycles, and compared with the corresponding absorption frequencies for cyclopentanone. Adjacent NH groups and sulfur atoms have the expected bathochromic effect on r (C=0), whereas an adjacent oxygen atom acts in the reverse direction. The CHa vibrations of cyclopentanone are repeated to a considerable extent in the heterocyclic analogs. 

Table 33 Solubilities of Some Five-membered Heterocycles in Water at 20 °C°...

Saturated five-membered heterocyclic compounds are non-planar, existing in half-chair or envelope conformations. The far-IR spectra of THE and 1,3-dioxolane (127) show both to have barriers of ca. 0.42 kJ moP ... 

Scheme 1 General reaction schemes tor the synthesis of five-membered heterocycles containing two or more heteroatoms by aldol-related reactions...

As shown in Scheme 2, two heteroatom-carbon bonds are constructed in such a way that one component provides both heteroatoms for the resultant heterocycle. By variation of X and Z entry is readily obtained into thiazoles, oxazoles, imidazoles, etc. and by the use of the appropriate oxidation level in the carbonyl-containing component, further oxidized derivatives of these ring systems result. These processes are analogous to those utilized in the formation of five-membered heterocycles containing one heteroatom, involving cyclocondensation utilizing enols, enamines, etc. 

Many of the acyclic functional groups used for the synthesis of the five-membered system discussed in Section 4.03.2.2.1 may also be incorporated into five-membered heterocyclic systems, thus providing a convenient means of annulation of a second ring. 

Thus, reaction of a 1,2-binucleophile with a 1,3-bielectrophile would lead to a five-membered heterocycle, as would the reaction of a 1,4-binucleophile with a 1,1-bielectrophile. Considering the reactions in this manner has several advantages and provides a convenient framework for considering synthetic approaches to target heterocycles. 

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. 

Although the wide diversity of structural types illustrated in Scheme 6 suggests that numerous examples of their application to five-membered heterocycles would be known,... 

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). 

In comparison to N—S bond formation, O—N bond formation by essentially oxidative procedures has found few applications in the synthesis of five-membered heterocycles. The 1,2,4-oxadiazole system (278) was prepared by the action of sodium hypochlorite on A(-acylamidines (277) (76S268). The A -benzoylamidino compounds (279) were also converted into the 1,2,4-oxadiazoles (280) by the action of r-butyl hypochlorite followed by base. In both cyclizations A -chloro compounds are thought to be intermediates (76BCJ3607). 

A versatile method for the synthesis of a variety of five-membered heterocycles and their ring-fused analogs involves the reaction of a neutral 47r-electron-3-atom system with a 27T-electron system, the dipolarophile, which is usually electron deficient in nature. Available evidence, e.g. retention of dipolarophile stereochemistry in the product and solvent polarity exerting only a moderate influence on the reaction, indicates that the cycloaddition proceeds via a concerted mechanism 63AG(E)565, 63AG(E)633, 68JOC2291) and may be represented in general terms by the expression in Scheme 8. 

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. 

Dipolarophiles utilized in these cycloadditions leading to five-membered heterocycles contain either double or triple bonds between two carbon atoms, a carbon atom and a heteroatom, or two heteroatoms. These are shown in Scheme 9 listed in approximate order of decreasing activity from left to right. Small rings containing a double bond (either C=C or C=N) are also effective dipolarophiles, but these result in six- and seven-membered ring systems. 

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. 

Just as in the Diels-Alder reaction, 1,4-dipolar cycloadditions lead to six-membered rings. Their principal use in five-membered heterocycles is for ring annulations giving [5,6] ring-fused systems. 

Azetidines under analogous reaction conditions to those above result in six-membered ring formation. However, diketene (472), an oxetan-2-one, offers considerable promise for five-membered heterocycle formation. With hydroxylamine the 3-methylisoxazolin-5-one (473) was formed. Phenylhydrazine gave the corresponding 3-methyl-l-phenylpyrazolin-5-one. 

Unusual heterocyclic systems can be obtained by photodimerizations and for five-membered heterocycles with two or more heteroatoms such dimerizations need be effected on their ring-fused derivatives. Cyclobutanes are usually obtained as in the photodimerization of the s-triazolo[4,3-a]pyridine (540) to the head-to-head dimer (541). These thermally labile photodimers were formed by dimerization of the 5,6-double bond in one molecule with the 7,8-double bond in another (77T1247). Irradiation of the bis( 1,2,4-triazolo[4,3-a]pyridyl)ethane (542) at 300 nm gave the CK0ifused cyclobutane dimer (543). At 254 nm the cage-like structure (544) was formed (77T1253). 

Utilization of carbenes in the synthesis of five-membered heterocycles with two or more heteroatoms has not been featured prominently in the synthetic strategies developed for these ring systems. The following illustrations show their considerable promise. 

A theoretical, comparative study of the tautomerism of 56 five-membered heterocyclic rings announced in (76AHC(Sl)l) has appeared (81MI40402). The stabilities of the three forms for 5-pyrazolones, 5-pyrazolethiones and 5-aminopyrazoles have been calculated by a simple Hiickel o) iterative method. The relative energies and the substituent and solvent effects are in agreement with the experimental results. 

Polymers with a backbone of five-membered heterocyclic rings have been developed in the new area of thermally stable materials during the last 10 years (B-80MI40408). The simple polypyrazole (741) is prepared by condensation of polydiethynylbenzene with hydrazine in pyridine with yields of 60-97%. 

A Hiickel model used for calculating aromaticity indicated that the isoxazole nucleus is considerably less aromatic than other five-membered heterocycles, including oxazole and furan. SCF calculations predicted that isoxazole is similar to oxazole. Experimental findings are somewhat difficult to correlate with calculations (79AHC(25)147). PRDDO calculations were compared with ab initio values and good agreement for the MO values was reported... 

Prototropic tautomerism of isoxazole derivatives has been well studied over a number of years and has recently been reviewed in context with similar behavior in other five-membered heterocycles (70C134, 76AHC(Sl)l, 79AHC(25)147, p. 202). Several generalizations are summarized below. 

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