Among the latter, 87 is a good illustration. There are examples of q1: A similar bridging coordination Sec. Complex 88 [94JCS D ], for which there is no X-ray structural proof, and complex 89, in which the furan heterocycle is within a macrocyclic ligand, are possible examples [95ICA ].
Stabilization of structures 88 and 89 is perhaps related to chelate and macrocyclic effects 94CCR39; 96MI4. Furan gives rise to organometallic compounds with M-C and M-0 frameworks M Complexes of thiophene in which the coordination bond is localized at the sulfur atom are represented by a variety of structures, e. The selenium atom of selenophene may also participate in coordination, e.
A similar coordination mode may be observed in the complexes of tellurium heterocycles with chlorides and carbonyl chlorides of mono- and trivalent rhodium 90POL Benzothiophene and dibenzothiophene form the ql- C complexes and , respectively M,M Up to the majority of publications on five-membered monoheterocycles were on phospholes. Since , thiophene has become the ligand of the year.
A series of coordination modes and the reaction ability of thiophenes in transition metal complexes compose the first group of reviews 87CCR;; 91PIC;95BSB To present the modern state of affairs,especially on such an exciting subject as the reactivity pattern of free and differently coordinated thiophene and some of its derivatives, we would need a review of the same size as this one.
Herein we attempt to cover the recent data that show the variety of coordination modes. Thus, the sulfur atom is an electrophilic center in the q5-complexes M The reaction with various metal carbonyls or sandwich complexes proceeds differently depending on the nature of the attacking agent. A similar situation is observed for the interaction with Re2 CO lo,although there is no cluster formation in this case, but a Re C0 4-Re CO 5 moiety ql-bound to the sulfur atom. The other ring-insertion reaction is the interaction of benzo[b]thiophene with Pt PEt, ,, leading to the addition product containing the platinum-sulfur bond in the metallocycle 96MI Similarly, the q6coordinated complexes of benzo[b]thiophene BT possess various reactivity patterns.
The nature of the complexes of tellurophene and its benzo analogs depends on the type of metal carbonyl. A similar reaction is observed for dibenzotellurophene. Indeed, azines and their P and As analogs form the n- - complexes as well. Reference data on the X-ray structural analysis of the complexes of pyridine [Py,. MX,] are generalized in Elsenbroich et al. In the same publication evidence for the existence of the complex of pyridine with zerovalent nickel in solution, [NiPy4] is provided.
A similar coordination is observed in [96AX C ]. The vl- a- coordination is characteristic for the cobalt 0 bis pyridy1 complex prepared by a gas-phase synthesis 81IC and for azines containing two nitrogen atoms in the heteroring, e. A good deal of research is devoted to the study of the reactivity of chelates, e.
I- complexes are known for a series of phosphorus- and arsenic-containing analogs of pyridine-phosphabenzene and arsabenzene and 90MI1. They are also able to form the 2-organozinc derivatives that in turn form the ql-bound W CO 5 complexes M Molybdenum sandwiches of 2,6-lutidine [96JOM ] are known. Other Coordination Modes In the metal-carbonyl complexes W the phosphorus atom retains its donor properties, which gives rise to the q1: An q2-pyridylmoiety bound to zirconium is known M The pyridine ligand is a sixelectron donor in the first of the clusters, whereas it is oxidized and bonded in a ortho-metallated mode in the second [95ICA ].
The p N,C bridging coordination mode is described in the anthracene-containing supramolecular pyridine complexes of osmium clusters [96JCS D ]. They form mainly complexes with coordination via the pyridinic N atom 1. Azoles may be monodentate or bridging ligands. Because only the LT- N coordination has so far been proven structurally, it is possible to subdivide the azole complexes according to the type of the endocyclic heteroatoms.
C plexes and are considered elsewhere. In the binuclear rhodium complex , the pyrazole ligand fulfills mono- and bidentate functions simultaneously. A similar situation is achieved in the mixed: It possible to prepare complexes of compositions MX,.
Advances in Heterocyclic Chemistry, Volume 72
C12 66AX , MX,. The structures of and are of interest, as is that of the adducts of the metal chelates with imidazole and Complexes with the bridging imidazolate framework may be represented by Complexes of imidazolium derivatives in which both nitrogen atoms bear a substituent are famous because they form carbenes [95JOM 1], among them the titanium and [95ICA ] and palladium [95AG E ] carbenes.
Another illustration is a series of bis 1methylimidazoly1 aurate compounds [96JOM ]. However complexes 28 [Sec. Rhodium is coordinated via the N-4 atom of the hetarene ligand in the complex of 3-pyridyl-S-phenyl-l,2,4-triazole The N-1 atom of the pyridine type participates in coordination in the complex of 5 6 methyl[l,2,4]triazolo[l,5-a]pyrimidine 89POL This coordination mode is realized in the trans-octahedral complex of l-phenyltetrazole However, when the solvent is removed, the bridging coordination mode is realized.
However, in the absence of the X-ray data the structure is insecure. I P I65 r I C 1- The possibility of using pentazole as a ligand is discussed in literature based on quantum-chemical or other theoretical reasoning. Thus, pentazole, pentazolate anion, or azidopentazole were identified as aromatic species 96IC In contrast to azoles, their phosphorus analogs tend to form 7'complexes or the species with a mixed coordination mode 88CRV The ruthenium sandwich containing the mixed phosphorus, antimony analog of pyrazole belongs to the series of exotic products [96JCS CC l].
The possibility of 0 coordination is less likely. Examples of the C-coordinated derivatives of oxazole and isoxazole are known [89JOM ]. X-ray studies indicate that only the N-M coordination is realized. The same mode is characteristic for the complexes of 1,2,3-thiadiazole and 1,2,3-selenadiazole However, the X-ray analysis shows that the coordination via the A atom cannot be excluded, e. Such a coordination mode may be related to a high donor activity of the tellurium atom 96MI It is important to obtain the X-ray data on the metal carbony1 complexes of benzothiazole and benzoselenazole, for which in solu- 32 A.
Boroles are famous for their multidecker complexes. The triple-deckers are formed even for the complexes with organolithium compounds [95JOM 67]. Generally, boron analogies of pyrrole, pyridine, and azoles give rise to the following n--complex types: The five-membered hetarenes and diborafulvenes with several boron atoms may serve as T - q5- ligands, e.
The studies in this field have reached the stage of directed synthesis, e. The six-membered boron-nitrogen heterocycles form the widely represented complexes of borazines 77CCR The representatives of the 7- q5- complexes of the ligands containing boron and sulfur silicon ring atoms are [80AG E ;85JOM and 82CB The silole and germole dianions possess delocalized v-systems. Monoanions of germole contain pyramidal germanium atoms and the delocalized Complexes in which diene portion of the ring [96AG E ,96JA]. E mainly characterized by v4- coordination 9OCRV as a result of metal bonding to the two double bonds of the heteroring, e.
For germole the first q5-complex has been prepared [93AG E ].
Introduction
Complexes of Amino Derivatives of Heterocycles Amino heterocycles exist mainly as the amino tautomers 91H For the complexes of and structures may be proposed. The common coordination mode is via the nitrogen atom of the pyridine type Sec. The study of the complexes with copper acetate by X-ray analysis and IR spectroscopy provided the reason for the decrease in the stretching vibrations of the NH2 group.
This coordination mode stems from the quantum-chemical interpretation of the regioselective coordination in the metal complexes of 2-aminoazoles 95IZV,95MIll; 96KK This is a continuation of the calculations on the free ligands 88KK that estimated the relative thermodynamic stability of linkage isomers The predominant coordination of the proton and BH3 via the pyridine nitrogen atom follows from the results of these calculations 95KK Localization of the coordination bond at the N atom is characteristic of the adducts of 1-methylaminobenzimidazole with chelates of tridentate Schiff bases in which the intramolecular hydrogen N-H E bond is formed , Structures and for the complexes of aminoisoxazoles were not confirmed by X-ray analysis.
Bridging is followed by the deprotonation of the NH group of the imidazole ring and formation of the tetranuclear v6-benzene-ruthenium II cluster [93ICA 15]. For guanine, coordination as in is common, but other coordination modes are known 92IC In the complex of 9-methylguanine with ethylenediaminoplatinum II , structure is realized.
The 0 coordination of cytosine in is unexpected 90IC ; the ligand here is in the enolate anion form. There are complexes of amino heterocycles in which a ligand is bonded to both donor sites, the nitrogen atom of the pyridine type and the unchanged or deprotonated amino group. The metal clusters contain the deprotonated amino group. Among the complexes with such an N-H group are both mono- and polynuclear complexes. In clusters , the NR nitrogen atom may be bonded simultaneously to two metal atoms, forming the trinuclear clusters Compounds in which the NH2 hydrogen atoms are replaced by a metal are known for some other heterocycles, for instance cytosine and 3-aminopyridine 90JA E nium cluster of the same pattern is known, and its reaction ability has been studied in detail [96JOM ].
Involvement of two nucleophilic nitrogen atoms is thus typical for the amino heterocycles. The mutual disposition of the pyridine and amine nitrogen atoms allows the formation of chelate structures for the cobalt complexes of purine, and Another coordination mode can be found in the complexes of 4-amino-3,5-bis pyridinyl -l,2,4-triazole, or [92IC; 93ICA 41]. Isomer is the product of interaction of the ligand and Ru C0 2C12 in methanol, and is obtained when LiBr is added to the reaction mixture.
Complexes of Hydroxyhetarenes A variety of the structures is observed for the complex compounds prepared from ligands and containing the 0 OH exocyclic framework. Compared to the amino heterocycles, they are characterized predominantly by the chelate structures and This ligand is capable of forming mono- ,di- , and tri- , nuclear complexes. The chelate structures and represent complexes of 2-mercapto Zthione derivatives of the aromatic nitrogen heterocycles. Adducts 54 are formed in the presence of bases pyridine, bipyridine, o-phenanthroline, and diphenylphosphinomethane.
The transformation of to may be achieved by electrosynthesis and similarly for the zero-valent lanthanides samarium, yttrium in THF by the chemical means [95JOM ]. One of the sulfur atoms is bonded to one metal atom; the other is attached to two different metal centers 96IC The presence of N- and E-donor sites and prototropic tautomerism led to different structures of the complexes of mercaptoazoles and mercaptoazines Complexes prepared from l-methyl-2 3H -imidazoline thione , quinolinethione and 4,6-dimethylpyrimidinethione are known.
The number of complexes having structure is much less. The thiol form of the ligand does not lead to chelate structures. A Mononuclear complex formation was confirmed for the adduct of zinc I1 salt with 2-mercaptobenzothiazole and o-phenanthroline The vl-S coordination is observed in the complexes of triphenylphosphine gold with 2-mercaptomethylimidazole 88JOM , 8mercaptotheophilline 91IC , 2-mercaptobenzoxazole [94AX C ], and purinethiol 94AJC Depending on the nature of the A.
E I' H solvent, temperature, and pH, the same ligand may form the mono-Scoordinated adducts and with the thione tautomeric form, as well as binuclear complex , in which the thiol and bridging N,S-bonding modes operate simultaneously. Complex compounds of 2-mercaptohetarenes coordinated in the q2 N,S: The fragment occurs in the hexanuclear complex of copper I with 4,6-dimethylmercaptopyrimidine. The pyridinic nitrogen is protonated and participates in intermolecular hydrogen bonding. Complexes of the selenium-containing ligands and are scarce.
Mercury complex of 2-pyrineselenol has a chelate structure 94IC , whereas in the cadmium dimer, chelate and bridging coordination modes coexist All the complexes are octahedral. Divalent nickel, cobalt, copper, zinc, and cadmium form the bis-thioxinates. The mixed-valent complexes of vanadyl with 8-mercaptoquinoline are known 92AG In the complexes the chelate structure is com- A.
However, for complexes with phenylmercury- and triphenylphosphine gold frameworks , the less common mode is postulated: Complexes of Chelating Hetarene Ligands Data have accumulated on the influence of heteroannulation and introduction of the heteroaromatic substituents to the chelating ligands on the structure of the complex compounds. Annulation of the heterocycles leads to chelates and Complex has a pyramidal structure, whereas copper chelates have a distorted tetrahedral structure. Zinc complex is tetrahedral.
Complexes are tetrahedral, although generally cis-planar structures are expected. Thus, in aromatic complexes the five- but not the six-membered metal rings are formed.
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Application of nitrogen-containing heteroaromatic rings as substituents in the chelating ligands leads to the structural changes. This is characteristic for the complexes of hetarylamino oxy azo 46 A. For the hetaryl amino azo compounds ,the structure with two five-membered metal rings is known; the pyridinic N atom participates in coordination.
The same coordination mode is observed in the chelates of hetarylformazanes. In contrast to the planar aromatic analogs with a six-membered metal ring , octahedral polyhedra with two five-membered coordination units are formed 53 89ZOB; 92KK In both structures the distances M-Npy are enhanced compared to the normal values and unusual polyhedra are formed, such as one- or double-capped tetrahedra. Additional metal cyclic structures are formed upon introduction of an azole framework to the hydrazone systems 92MI8 ,in which the imino tautomer of the benzothiazole is fixed.
Other Chelating Hetarene Ligand Systems. Here only some recent examples and trends to study the reaction ability of metal chelates leading to new products and important materials are presented. An exotic chelate was prepared by the reaction of an N-functionalized lithium agent with FeC12 M Cluster [96JOM 27] is of interest. The methyl- and arylpalladium I1 cations containing the coordinated N- 2-picolyl -N,Nr, N'-trimethylenediamine were used as reactants in a CO insertion reaction that provided a series of acetyl- and aroylpalladium I1 cations The 1-naphthoylpalladium complex is the first representative M Depending on the reaction conditions, 2-benzoylpyridine forms a variety of chelates on reaction with rhodium II1 chloride 95AJC A series of 2pyridinecarboxamides when reacted with [Rh cod C1I2in a basic medium yield complexes whose ligands reveal their bidentate function and coordinate via the pyridine and deprotonated amide nitrogen atoms [96 JOM However, it does not necessarily fulfill the chelate function.
Often both functions are simultaneous.
The pyrrole ring participates in the formation of hetaryl chelates as a part of porphyrines, phthalocyanines 93MI2 , corroles, corrines, and other macrocyclic ligands L87MI. However, their detailed consideration is beyond the limits of this publication. The bulk of information on the coordination compounds of pyrazolylborates was recently reviewed in Kitajima and Tolman 95PIC Conclusion We have attempted to cover the problems of the chemistry of u-and Tcoordinated five- and six-membered heteroaromatic compounds.
Omitted are the nitrogen-, phosphorus- 78S. The problem of competitive coordination for such upligands is not well studied. The possibility of application of the five- and six-membered metal-containing ligands is of interest 84MI1, 84M The problem of the interaction of amino- oxy-, mercapto- derivatives of the five-membered heterocycles subject to tautomerism 84MI3, 84MI4 with metal salts has not been studied extensively.
Saturated heterocycles are important ligands. They are flexible models for the problem of competitive coordination of the hard and soft acids with the nonconjugated donor sites. Analysis of these problems is of interest for the chemistry of complex and heteroaromatic compounds.
A , Nauk SSSR , Nauka, Moscow, in Russian. Majoral, Synthesis 5,57 Dekker, New York, A A35, B B36, Dobryakova, Polyhedron 3, Wiley, New York, Actu 98, L21 Khimiya, Moscow, in Russian. C C42, Actu l24, Library, Elsevier, Amsterdam, Nuuk SSSR , Santos, and A, M. Hursthouse, Polyhedron 7, Tagiev, Polyhedron 8, Steel, Polyhedron 8, Tiripicchio, Polyhedron 8, Sousa, Polyhedron 8, C C46, Verlag Chemie, Stuttgart, Vosif, Polyhedron 9, Basolo, Polyhedron 9, Ni, Synthesis 89 London 15, 23 London , Karelson, and R A. Hams, Heterocycles 32, Actu , 7 World Scientific, Singapore, Eduardo, Organometallics 10, Angelici, Organometallics 10, Dyachenko, Polyhedron 10, Byriel, Polyhedron 10, Thesis, Novosibirsk University, Novosibirsk Acta , Tocher, Polyhedron 11,13 E Williams, Angew Chem , C C49, Nauk SSSR ,54 Garnovskii, R i m J.
Ricard, and E Mathey, Organometallics 12,98 Metz, Organometallics It, Merob, Organomerallics 12, Pritchard, Polyhedron 12, Thesis, Philips University, Marburg, Germany C C50, C CSO, Acta , 73 Riera, Organometallics 13, Strahle, Polyhedron 13, Tertis, Polyhedron l3, Sousa, Polyhedron 13, Deeming, Polyhedron 13, Olive, Polyhedron 13, Lavrenova, Polyhedron 13, Christon, Polyhedron 13, El Shahawy, and A. C C51, Le Floch, and F. Martelli, Farmaco 50, Actu , Acfa , Sneddon, Organometallics 14, Ruffo, Organometallics 14, Zanello, Organometallics 14, Joubran, Organometallics 14, Vittal, Organometallics 14, Wigley, Organometallics 14, Zubieta, Polyhedron 14,17 Maichee-Mossmer, Polyhedron 14, Knuuttila, Polyhedron 14, Wenger, Polyhedron 14, Kleine, Polyhedron 14, C C52, Acta , 47 Le Grel, and W.
Kairn, Organometallics 15, Angelici, Organometallics 15, De Sanctis, Organometallics 15, Bickelhaupt, Organometallics 15, Messerle, Organometallics 15, Gray, Organometallics 15, Angelici, Organornetallics 15, Cheung, Organometallics 15, Puddephatt, Organometallics 15, Mak, Organometallics 15, Kirchner, Organometallics 15, Chiang, Organornetallics 15, Drommi, E Faraone, M.
Tiripicchio, Orgunometallics 15, Chaudret, Organometallics 15, Russell, Organometallics 15, Ricard, Organometallics 15, Moms, Organornetallics 15, Terreros, Organometallics 15, Lamertz, Organometallics 15, Satyanarajana, Polyhedron 15,63 Bovio, Polyhedron 15, Thornton, Polyhedron 15, Granifo, Polyhedron 15, Yu, Polyhedron 15, Scott, Polyhedron 15, Veszpremi, Phosphorus, Sulfur Silicon Relat.
Wolmershauser, Phosphorus, Sulfur Silicon Relat. Zenneck, Phosphorus Sulfur Silicon Relat. Selenium Tellurium, 7th, Germany, Synthesis of Annulated 3-Aminofurans. Synthesis of Monocyclic 3-Aminothiophenes. Synthesis of Annulated 3-Aminothiophenes. Introduction One of the most convenient methods for the synthesis of functionalized amino heterocycles especially five-membered heteroaromatics 4 , is the Thorpe-Ziegler cyclization Scheme 1. There are two principal routes to precursors 1: Thorpe-Ziegler cyclizations are mostly catalyzed by bases, although acid catalysis e.
A num79 Copyright 0 by Academic Press All rights of reproduction in any form reserved. Some are devoted to applications of the Thorpe-Ziegler reaction for synthesizing five-membered heterocycles 8OC; 85MI1. A recent review on 3-cyanopyridine-2 1H -ones, -thiones and -selenones 92MI1 contains numerous examples of Thorpe-Ziegler syntheses of furo-, thieno-, and selenophenopyridines. The present review covers the Thorpe-Ziegler syntheses of 3-aminofurans, 3-aminopyrroles, 3-aminothiophenes, 3-aminoselenophenes, and diverse aminoazoles as well as the corresponding annulated systems that appeared from to but excludes examples considered in the 3-cyanopyridine review 92MI1.
Moreover, examples are included that do not report a separate Thorpe-Ziegler cyclization but are likely to involve this type of reaction e. Special attention is paid to synthetic aspects, although some reaction mechanisms are discussed too. Synthesis of 3-Aminofurans A. The starting materials 9 were accessible either from 3-hydroxyacrylonitriles 7 or from 3-chloroacrylonitriles 8 Scheme 2. Lithium diisopropyl amide LDA assisted Thorpe-Ziegler cyclization of cyanoenolethers 11 was used to synthesize the ribose-C-glycoside 12, which was further transformed into a furo[3,2-d] pyrimidine 86TL; 90MI1.
A were not suitable for this furan formation Scheme 3. Thus, 0-alkylation of 16 followed by Thorpe-Ziegler cyclization of the intermediates 17 in the presence of K2C03 smoothly yields the 2-acylaminobenzofurans 18, which are the starting compounds for the synthesis of benzofuro[3,2-b] pyridines B [81IJC B ] Scheme 5.
Hal-COR 16 - a: It was claimed that quinoxaline rings were sufficiently electron withdrawing to enable a Thorpe-Ziegler cyclization affording 3-aminoquinoxalinyl-benzofuranes 25 91EGP Scheme 6. Further cyclization of the assumed 3-aminO2-cyanobenzofuran 27 with the Vilsmeier reagent afforded benzofuro[3,2-d]pyrimidine 28 in poor yield, 91JHC Scheme 7. The authors 83JPR attribute this difference in reactivity to the higher electrophilicity of the cyano group in intermediates 30 as compared with The starting 2-cyanohydroxybenzothiophene35 was obtained from methyl 2-thiohydroxybenzoate and chloroacetonitrile.
The role that Vilsmeier conditions play in the mechanism of the Thorpe-Ziegler cyclization of 36 still remains unclear. Eventually intermediate 2-azachloro-propeniminium salts are formed by the addition of the formamide chloride to one of the cyano groups 88S A great number of furo[2,3-b] pyridines were synthesized by O-alkylation of 3-cyano-pyridineonesfollowed by base-catalyzed Thorpe-Ziegler which were often not cyclization of the resulting 2-alkoxycyanopyridines, isolated 82JPR; 85M12; 87IZV; 89PS1; 92MI1; 95M For example, the interaction of condensed pyridine-Zones 39 with halo carbonyl compounds followed by cyclization of 40 in the presence of EtONa afforded annulated aminofuropyridines 41 in high yields 82JPR;89PS1; 95M Scheme The latter can serve as starting materials for annulated pyrimidines 95M Because amide 44 resisted the basecatalyzed Thorpe-Ziegler cyclization, probably due to amide deprotonation, prior methylation of the amide was necessary formation of 45 95H Synthesis of 3-Aminopyrroles A.
Similar blocking of the enamine NH group was applied to the preparation of 4alkyl, 4-alkenyl, and 4-pyridylmethyl3-aminopyrroles 59 as potential immunosuppressants 91USP,91USP Scheme Substitution of one of the two alkylthio-leaving groups of bis-alkylthioacrylonitriles 60 by aminoacid derivatives yielded substituted enaminonitriles 61 , which cyclized to 3-aminopyrroles 62 when heated in ethanol in the presence of triethylamine 88JPR Scheme In the opinion of the authors of the present review, this reluctance is likely caused by NH acidity rather than CH acidity as needed for Thorpe-Ziegler reactions.
Another principal way to synthesize enaminonitriles 67 as precursors for Thorpe-Ziegler cyclizations to pyrroles 65 is the N-alkylation of enaminonitriles such as 66 93JPR Intermediates 67 were isolated and cyclized to 65 in the presence of NaOEt Scheme When 2-cyano3,3-diaminothioacrylanilide 68 was submitted to reactions with phenacyl bromides, the outcome depended on the conditions Scheme Triethylamine initiates an alkylation of the 3-amino group followed by Thorpe-Ziegler cyclization affording 2,4-diaminopyrroles In contrast, Salkylation rather than N-alkylation took place when 68 reacted with phenacyl bromides in the presence of toluenesulfonic acid, leading to 1,4thiazepines 70 95JHC,95JHC or to mixtures of 69 and Alkylation of the 3-amino group was followed by substitution of the methylthio group by the carbonyl oxygen atom, affording oxazolines 72 , which could also be ring transformed into Thorpe-Ziegler products 74 by ring opening via 73 in the presence of sodium alkoxides Scheme They could be obtained from the corresponding 1,3-dicarbonyl compounds 75 and afford via 77 intermediate 3-aminopyrroles 78 , which condensed to bisethoxycarbonylvinylamino-pyrroles 79 and then intramolecularity cyclized into pyrrolopyridines 80 85JHC83;90JHC Scheme The formation of the 3Hmorpholinopyrrole 82 from the cyanoazabutadiene 81 also involves a Thorpe-Ziegler type cyclization Scheme 21 for a further example in the tetrahydroindole series and the mechanism see Scheme 26 87HCA In the aromatic indole series such as 92 83JHC , precursors 91 for Thorpe-Ziegler cyclization were synthesized by alkylation of the corresponding o-aminobenzonitriles A number of investigations were allotted to the pyrrolizine synthesis by the Thorpe-Ziegler reaction.
Thus, lactam acetal could be condensed with acidic nitriles to give semicyclic enamino nitriles , which cyclized under basic conditions e. This method also was applied to the synthesis of pyrrolopyridines and pyrroloazepines 94KFZ15 Scheme Thorpe-Ziegler reaction of enaminonitriles was also possible in the presence of dimethylformamide diethylacetal, giving amidines 87KGS Scheme The resulting enamino nitriles such as were further N-alkylated with ethyl bromoacetate or phenacyl bromides, yielding intermediates such as , which cyclize in the presence of NaOEt to the final products [e.
No intermediates were isolated when phase transfer catalysis was applied in the alkylation step. The synthesis of pyrrolo[l,2-a]pyridines starting from l-benzyl-2methylthiopyridinium salts could be achieved by replacement of the 2-methylthio group by malononitrile and Thorpe-Ziegler cyclization Scheme 31 85JHC The CH-acidifying effect of aryl substituents was sufficient for the ring closure when LDA was used as a base.
When 2cyanomethylidenepyridines W ,structural analogs of , were submitted to Diels-Alder cycloaddition with N-phenylmaleinimide prior to Thorpe- H2NQ:: Substitution of chloride in o-chloronitriles or by glycine derivatives followed by Thorpe-Ziegler cyclization of the resulting o-aminonitrile structures was used to synthesize the 1-methylmethoxycarbonyl-3aminonitro-pyrrolo[2,3-b]pyridine Scheme 33 96KFZ36 and the pyrrolo[2,3-d]pyrimidines Scheme 34 , 88LA respectively.
Structural analogs of with a hydrogen atom instead of a methyl group resisted cyclization. Synthesis of 3-Aminothiophenes There are numerous applications of the Thorpe-Ziegler reaction for the synthesis of thiophenes and annulated thiophenes. Only seIected examples can be covered here.
Thus, one sulfur atom was methylated formation of ;the other was alkylated: The alkylation sequence could also be changed, that is, first introduction of the acidic alkyl substituent with usage of formation of followed by Thorpe-Ziegler reaction to 3-aminothiohydroxythiophenes and final S-methylation,giving Scheme 36 90LA With a-haloketones or a-bromoesters an alternative cyclization was observed: Nucleophilic attack of the anilino substituent at the carbonyl group of the intermediate alkylation product led to 1,3-thiazolidineones 91AP or 1,3-thiazolines Scheme 37 [91AP;92JCR S ].
In some cases this problem could be circumvented by using a-bromooximes rather than ketones, affording corresponding oximes of 2-benzoylaminothiophenes. The dithiooxalester amide was used to generate the 3-thiohydroxyacrylonitrile by condensation, allowing the synthesis of 3-aminothiophenes with a thioamide function in position 5 87AP43 Scheme Substituted 3-dimethylamino and 3-alkylthioacrylonitrites used as precursors for Thorpe-Ziegler cyclization to 3-aminothiophenes such as Scheme 39 C , Scheme 40 , and Scheme 41 84S; 87PS; 92M were obtained by substitution reactions with CH-acidic methyl thiols in which OH ,EtO la or ,chloride served as leaving groups in the starting acrylonitriles.
The addition of a second molecule of thioglycolate formation of in the course of the formation of the C-nucleoside also took place 8UOC Finally, cyanoalkynes also were used as precursors for 3-aminothiophenes 86JHC Presumably,this synthesis starts with the addition of cyanomethylthiolate, affording intermediate P-cyanomethylthioacrylonitriles similar to that finally undergo Thorpe-Ziegler cyclization to Scheme By applying phase transfer catalysis and stepwise addition of different alkylating reagents, the asymmetrically substituted product was obtained 92PS15 Scheme When ethyl cyanoacetate was used in place of malonodinitrile, Thorpe-Ziegler cyclization and Dieckmann cyclizations occurred after reaction with two equivalents of ethyl chloroacetate, affording mixtures of thieno[2,3-b]thiophenes and 92PS Thus, the substitution pattern shown in Scheme 48 gave unambiguously the Thorpe-Ziegler cyclization products Alternatively,the acidic methylthio group was introduced by substitution of a suitable leaving group OAlkyl,SMe, Halo, NOz in a cyanoheterocycle or cyanocarbocycle to obtain precursors for Thorpe-Ziegler cyclizations.
This strategy was also followed in a stepwise way, first by thiolysis and subsequently by S-alkylation to synthesize the benzo[b]thiophenes from 95MI1 Scheme In the syntheses of 3arninobenzo[b]-thiophenes via , Scheme 53 81ZC and Scheme 54 80LA , precursors and were generated by Dimroth rearrangement of 2-aminothiopyranes or by nucleophilic ring opening of benzoisothiazoles respectively. However, investigations of the mechanism revealed the formation of intermediate disulfides rather than the expected S-alkylation products The former are attacked at the cyano group by the nitromethane anion and close the thiophene ring by intramolecular disulfide cleavage via [86JCS P1 ].
Appropriate reaction conditions were determined for different Y groups to match the CH acidity in these precursors. In addition to the transformation to thienopyridines the 2,4-bisalkylthiopyridines formed from , also allowed the annulation of a second thiophene ring by the Thorpe-Ziegler reaction, affording the bisthienopyridine [92JCR S ] Scheme The formation of tetracyclic thiophene via by the Thorpe-Ziegler reaction in the presence of N-bromsuccinimide NBS represents a special case, because the pyrimidinethione also served as precursor for the CH-acidic alkylation agent 95H Scheme The formation of N-substituted thieno[2,3-b]pyridines such as were reported to be the result of the reaction of dimeric malodinitrile with phenyl isothiocyanate and alkylating reagents such as ethyl chloroacetate 92M Scheme Similarly, by the formation of both a six-membered ring and a thiophene ring, the benzo-annulated N-substituted thienopyridinone 91EUP , and the thienobenzodithiines 84S were synthesized starting from methyl o-cyanomethylbenzoate or the o-chlorophenylsulfone via , ,respectively Scheme In this way all the other isomeric thienopyridines also were accessible 87JHC85 Scheme This method also allowed two thiophene rings 94H to be constructed when two o-chloronitrile units were present in the starting material Scheme Moreover, a 3-aminophenylthieno[2,3-c]pyridineanalogous to was readily formed with benzylmercaptan in the presence of NaOEt in spite of the weak CH acidity of the benzylthio group 83T Thienopyridines and could also be prepared from the corresponding bromocyanopyridines and ethyl thioglycolate under irradiation and in the presence of t-BuOK 83T The thieno[2,3blpyrazine 89JA could be obtained in a similar manner from the corresponding o-chloronitrile precursor Scheme The formation of thieno[2,3d]pyrimidine Scheme 68 does not follow general path of Scheme 64 because the Thorpe-Ziegler precursor was generated by ring opening of the starting aminoisothiazole in the presence of chloroacetone as alkylating reagent [88JCR S 46].
The unstable 3-selenylcinnamonitrile was not isolated. The substituted methylselenopyridines are more prone to ThorpeZiegler cyclization than the corresponding methylthiopyridines 94KGS Scheme The dihydroselenophen0[2,34]pyridine was obtained in the same way 91ZOB Scheme Synthesis of Aminoazoles Thorpe-Ziegler cyclization can also be applied to the synthesis of azoles 1 with X or Y as N atoms see Scheme 1.
Thus, semicyclic cyanamidine structures could by alkylated at the ring N atom in the presence of a base e. N-Cyanoisothioamide, precursors for the synthesis of 4-amino-1,3thiazoles, are available by various routes. Sometimes no extra base was necessary for the synthesis of the thiazoles according to route A. Alternatively, 4-amino-l,3-thiazoles could be by synthesized according to route B, on substitution of the methylthio group in Smethylisothioamides by a-mercaptocarbonyl compounds 86LA; ; Scheme Thorpe-Ziegler cyclization of thiooximes of acylcyanides gave access to 4-aminoisothiazoles such as 82EUP Scheme The former were obtained from the corresponding O-tosyloximes and mercaptoacetate.
In the same manner the C-glycoside was obtained 93JOC The interaction of ethyl diazoacetate with benzylcyanides opened a straightforward way to aminopyrazoles 84FES ,probably via azo intermediates Scheme Gewald, Chimia 34, Stezhko, Thesis, Moscow Klein, Tetrahedron Len 22,25 EP 48, [CA 97, l. Boudet, Tetrahedron 39, DD , [CA , ].
Tanaka, Heterocycles 22, see I , Liebscher, Synthesis, Janietz, Synthesis, JP 60 28, [85 28, [CA , l. JP 60 51, [85 51, [CA , l. JP 60 51, [85,51,] [CA , ]. Shestopalov, Synthesis, 98 Wagner, Pharmazie 41, Taipei 33, [CA , l. Beller, Phosphorus Sulfur 29, Ihrke, Synthesis, Kuhn, Synthesis, Imanishi, Synthesis, Eilingsfeld, Synthesis, DD , [CA , l.
Bartroli Rivas, East Ger. EP , [CA , l. Hongo, Heterocycles 28, 51 Abdel Hafez, and A. Attallah, Phosphorus, Sulfur Silicon Relat. Ramiz, Phosphorus, Sulfur Silicon Relat. Kelin, Nucleosides Nucleotides 9, Taipei 37, [CA , l. Weinheim, Gex , E P , [CA , l. Wagner, Pharmazie 46,51 Strohscheidt, Pharmazie 46, Bakhite,Phosphorus, Sulfur Silicon Relat. Geies, Phosphorus, Sulfur Silicon Relat. Mahgoub, Phosphorus, Sulfur Silicon Relat.
B 46, Hongo, Heterocycles 33, Alarab, Heterocycles 34, B 31B, La Mattina and R. Zeit , Azucar 26,56 [ C A , l. Dumke, Phurmuzie 47, 11 Mohamed, Phosphorus, Sulfur Silicon Relar. Kirsch, Phosphorus, Sulfur Silicon Relat. Quintela, Heterocycles 38, Radwan, Phosphorus, Sulfur Silicon Relat.
Dapporto, Heterocycles 41, Sherif, Heterocycles 41, Ji, Youji Huawue 15, [CA , l. Introduction This chapter reviews the chemistry, biological significance, and uses of 1,2,4-triazolo- and tetrazolo[x,y-zlpyrimidines. The arrangement of each ring follows the order of the site of fusion on the pyrimidine ring, denoted by the letter t,and the site of fusion on the triazole ring, denoted by the letters x and y. The classification of the subdivisions is dependent upon the extent of published work.
Azido-tetrazolo isomerization was reviewed 69CRV; 73S The present chapter reviews the work on the title compounds from to the end of Chemical Abstract volume with some additional earlier references. All of them have a bridgehead nitrogen atom. A characteristic feature in these triazolopyrimidines is the ease of a Dimroth rearrangement 99AHC in two systems; this results in the Copyright 0 by Academic Press AII rights of reproduction in any form reserved. The 3- and 5-amino-l,2,4-triazoles are alternative precursors that can act as a source of three carbons to complete the pyrimidine ring.
Synthesis from 1 -Aminopyrimidines Cyclization of 1- acy1amino pyrimidine hydroiodides 1 with alkyl ammonium acetates gave 3H,5H-1,2,4-triazolo[1,5-a]pyrimidines 2 87 EGP; 89ZC Condensation of the 1- acy1amino pyrimidinium salt 3 with hydrazine hydrate gave 4, which upon cyclization with acetic acid in the presence of perchloric acid afforded the 3-amino-1,2,4-triazolo [1,5-a]pyrimidinium salt 5 89EGP Scheme 2. The 1-aminohydrazinopyrimidine6 can be cyclized with triethyl orthoformate to 7 85USP Scheme 3. The synthesis of triazolopyrimidines may be achieved by the cyclization of 2-aminopyrimidines by fusion of a C-N fragment.
In the case of 2aminomethylpyrimidine as a starting compound, cyclization involved either an N-1 or N-3 atom of the pyrimidine, whereby both isomers were formed in a ratio of 1: Treatment of 2- aroy1amino pyrimidines 18 , prepared from 15 and aroyl chlorides with PCI5 followed by azidolysis in aqueous acetone, gave the tetrazoles 19, whose subsequent pyrolysis afforded 2-aryl-1,2,4- E.
A] 19 J". A pathway for the formation of 20 from 19 involved the elimination of a molecule of nitrogen from 19 followed by cyclization of the resulting nitrene intermediate 88BCJ Scheme 7. The 1,2,4-triazolo[l,5,-u]pyrimidiniumolates 23 were prepared by the sequential reaction of 2-methylaminopyrimidines 21 with phosgene to give 22 followed by Me3SiN3[87JCS CC ] Scheme 8. Synthesis from 5 3 -Amino-1,2,4-Triazoles 5-Arnino-lH-l,2,4-triazole and its derivatives are frequently used as precursors for this ring via their reaction with suitable carbonyl compounds.
The 5-amino-l,2,4-triazoles 27 ,prepared from calcium cyanide by hydrolysis to cyanamide followed by condensation with hydrazine 92MI4 , reacted with the appropriate acetophenone in presence of ZnClz to give the R I M. Thecyclization of 32 with methyl vinyl ketone in the presence of a base gave the tetrahydrotriazolopyrimidine 34,which was alternatively formed, from 33 by the action of alkali 94ZOR Scheme Similarly, the bis aminotriazo1yI methane 36 gave the bis triazolopyrimidy1 methane39 82UKZ The use of unsymmetrically substituted acetylacetone having a bulky electron-withdrawing group led to a mixture of triazolo[l,5-a]pyrimidine isomers.
Steric factors have a dominant influence in the regiochemical outcome. The ratio of products is influenced much more by the inductive effect of the substituent R in In the reaction with triacetylmethane and 3- 4-chlorobenzoyl acetylacetone,the elimination of a 1-acetyl group from the reactant gave the 6-acetyltriazolopyrimidine together with the deacetylated derivative.
A mixture of 5-methyl and 7methylacetyl-1,2,4-triazolopyrimidineisomers was formed from the reaction of ethoxymethyleneacetylacetone with A linear hept-2,4,6-trione behaved as a simple 1,3-diketone on reaction with 27 95JHC Scheme The triazolopyrimidinesulfonamides45 were prepared from the 1,2,4triazole 40 by reaction with phenyl chloroformate to give 41,whose chlorination gave 42, then transformed to the amide A the latter compound gave the lH-triazole sulfonamide 44,whose cyclization with 4-hydroxypentanone in dioxane gave 45 89EUP; 93JHC Heating 44 with unsymmetrical 1,3-dicarbonyl compounds such as 1-methoxyacetylacetone in the presence of acetic acid provided a mixture of 46 and 47 88GEP Similarly, 48 and 27 gave 53, 55, and A regioselective synthesis of the 5-methyl isomer took place exclusively in the presence of sodium ethoxide 89JHC or in aqueous base 91USP The proposed mechanism indicated that the P-ketoacetal 48 was initially converted to 3-oxobutanal 49 by hydrolysis under the acidic conditions.
ILA] the aminotriazole with 49; the amino group of the triazole can react with the aldehyde carbonyl group to give the 7-methyl isomers or with the keto group to give the 5-methyl isomers 89JHC Some of the product from this condensation 54 was formed when the ketoanil50 underwent a preliminary retro-anil reaction to yield 3-oxobutanal 49 prior to the condensation with The ratio of 52 to 54 was dependent on the catalyst identity. The carbocyclic analogs were prepared by the reaction of 5-aminotriazole 51 and 5-aminomethylthio-1,2,4-triazole 27b with 2-hydroxymethylenecyclopentanone 57 to furnish the angularly fused cyclopenta[e]triazolopyrimidines 61 and 62, respectively.
However, reaction of 2-hydroxymethylenecyclohexanone 58 with the aminoazoles 51 and 27b afforded both the linear and the angular cyclohexatriazolopyrimidines 65 and 66 and 68 and 69, respectively. The condensation of 60 with 27b afforded a mixture of a linearly fused product major and an angularly fused one minor. However, when the catalyst p-toluenesulfonic acid was replaced by anhydrous oxalic acid in the condensation of 60 with 27b, a high yield of the linearly fused compound 66 was obtained [79JCS P1 ] Scheme Reaction of 51 with the unsaturated ketone 76 was dependent upon the reaction conditions 90MI1.
A one 86 [67JCS C ]. The 7-oxotriazolopyrimidine 89 was prepared by cyclizing triazolylaminomethylenemalonate 88 by the action of polyphosphoric ester 93MI2 or by treatment of [ triazolylamino methylene]dioxanediones 90 with Na2C03 followed by saponification with HCl 91USP Scheme Cyclocondensation of the sodium salt of nitromalondialdehyde 86 KFZ , malonyl chloride or diethyl malonate 91USP , malonic acid in phosphorus oxychloride 89EUP; 93JHC , and pketoesters in AcOH 82MIP1; 90EGP with 27 gave the nitro derivative 91, the 5,7-dihydroxy derivative 92, the chloro derivative 93, and the hydroxy derivative 95, respectively.
Ring closure of 51 with ethyl benzoylacetate in the presence of NaOEt gave the triazolopyrimidine 98, a tautomer of 95 85JHC Alternatively, condensation of 27 with P-ketonitrile gave the amine 97 87GEP Reaction of 27 with a-arylazo derivatives of j3-ketoesters gave 85H; 91CCC A similar reaction using ethyl acetoacetate p-sulfonylphenylhydrazones with 51 provided the tautomer of , namelymethyl p-sulfonylphenylazo -1,2,4-triazolo[1,5a]pyrimidin-7 4H -one 95PHA The interaction of the phenylthiocarbamyl derivative 94 with 5-amino-1,2,4-triazoleresulted in the formation of triazolo[l,S-alpyrimidine 99 92JSC Scheme Condensation of the 4-allylaminotriazolewith ethyl acetoacetate by heating without a solvent gave the triazolopyrimidines a and a in compatible yields, whereas when glacial acetic acid was employed as a solvent only a was obtained.
Heating 51 with the acrylate derivative in acetic acid formed the dihydrotriazolopyrimidine 91CPB Scheme The Schiff base with the mixture of phosphorus oxychloride and dichloroacetic acid in DMF led to the triazolopyrimidinone instead of the expected 3,3-dichloroazetidinone derivative 88JHC Scheme Unsymmetrical vinamidinium salt can be cyclized with 51 at low temperature to give the 7-substituted isomer , but at higher temperature isomers and were both obtained. When the chloropropeniminium salt was used under similar conditions, compound was formed.
Similarly, the 6-substituted triazolopyrimidines were synthesized from 2-substituted vinamidinium salt 95H Scheme 26 4. Dimroth Rearrangement of 1,2,4Triazolo[4,3-a]pyrimidines Dimroth rearrangement of 1,2,4-triazolo[4,3-a]pyrimidines A gave the 1,2,4-triazolo[1J-a]pyrimidines B.
The triazolopyrimidines with various substituents on the ring, as in , , or , underwent rearrangement to give ,, and , respectively, upon treatment with acid, alkali, or triethyamine, or upon fusion 71CB; 75JHC; 77AJC; ; 87T; 89H; 94MI2; 98UP1. However, it is advantageous in cases in which the [1,5-a] ring system is required. Cyclization of the diamidine with acetyl- or benzoyl-acetone gave 1,2,4-triazolo[l,5-a]pyrimidine via the formation of 66CB; 79AP Alternatively, can be prepared by the reaction of with the diaminotriazole 66CB Scheme Reactivity of Ring Atoms Hydrolysis of 4,7-dihydrotriazolopyrimidine by hydrochloric acid gave the triazole 51 and the unsaturated ketone The 5- and 7-positions of the 1,2,4-triazolo[l,5-a]pyrimidine ring are very reactive toward nucleophilic substitution, the 7-position being the more reactive.
Thus, the 7-substituted and 5,7-disubstituted triazolo[l,5-a]pyrimidines and were prepared by the reaction of 5,7-dichloro-1,2,4triazolo[l,5-a]pyrimidine with amines or hydrazines [81KFZ31; 88IJC B ; 91PHA Scheme The chlorine atoms at positions 5 and 7 can be displaced by alkoxide ions selectively. Thus, gave and then ,which by the action of alkali formed A Displacement of the chlorine atom in with sodium allyloxide in allyl alcohol gave 7-allyloxy-l,2,4-triazolo[1,5-a]pyrimidine This was followed by a thermal Claisen rearrangement to in addition to Allylation of with allyl bromide gave the two allylated products and 63CPB Scheme Reaction of the chloro derivative with thiourea gave the thiolo derivative [88IJC B ].
Displacement of the chlorine in with 2chlorothiophenol formed 2- arylthio -l,2,4-triazolo[lJ-a]pyrimidine 89EUP Scheme On increasing the amount of diethylaniline in is chlorination, major product was formed in addition to 91KGS Chlorination of 7hydroxynitrotriazolopyrimidine derivatives with P0Cl3 in the presence of N,N-dialkylanilines gave 88EGP together with as a side product, which upon heating with benzylamine in EtOH or DMF led to an unusual synthesis of 1-hydroxyphenylbenzylimino [4- dialkylamino phenyl]methylimidazole The arylation of was independent of the nature of the substituents on the triazole and pyrimidine rings, but the presence of a nitro group in position 6 is essential.
When the reaction was carried out in an alkaline solution, the pyrrolyl- and indolyltriazolopyrimidinium salts were obtained 90KFZ41 Scheme Reaction of 91 with malononitrile and ethyl cyanoacetate gave 9imino oxo nitro-4,9-dihydrotriazolopyridopyrimidine Malononitrile or ethyl cyanoacetate provided the C-C-N fragment for the pyridine ring. Nucleophilic additions of the acetonyl anion to 6-nitrotriazolopyrimidines 91 gave a-adducts ,whose acidification afforded the dihydro adduct 93KGS Direct addition of cyclic P-diketones such as dimedone and indanedione to 91 led to the adducts and , respectively 93ZOR Moreover, radical cyclizations predominantly conducted using Bu 3 SnH in the presence of azobisisobutyronitrile AIBN play a crucial role [15,16].
In order to meet increasing environmental and economic constraints, further efforts should be directed towards the development of mild and reagent-free methods [17,18]. In this context, electroorganic synthesis can provide an interesting and practical alternative to conventional methods for heterocycle synthesis [19,20]. Since toxic and hazardous redox reagents are either replaced by electric current direct electrolysis or generated in situ from stable and non-hazardous precursors indirect electrolysis , electrosynthesis is considered to be a safe and environmentally friendly methodology [].
A further interesting feature is that electrochemical reactions are feasible under very mild conditions; since the reaction rate is determined by the electrode potential, reactions with high activation energies can be conducted at low temperatures. The electrochemical synthesis of heterocyclic compounds can be considered as a mature discipline. Earlier reviews on different aspects of the electrochemistry of heterocyclic compounds are also available [].
However, recent innovations in electrosynthesis such as the cation pool method or the development of novel electron transfer mediators also have a significant impact on heterocyclic chemistry [30,31]. This review focuses upon both anodic and cathodic processes that lead to the formation of heterocyclic structures in view of these recent developments.
The intention is rather to provide the reader with a general insight than to give an exhaustive overview. Furthermore, one can distinguish between intramolecular and intermolecular cyclization. The intramolecular version typically involves two functional groups linked by a tether. The electrochemical reaction leads to an Umpolung of the functional group with the lower redox potential, triggering the ring-closure reaction between a nucleophilic and an electrophilic site. Another possibility for an intramolecular ring closure is represented by electrochemically induced radical cyclization.
Intermolecular cyclizations generally fall into two further categories. In the first scenario, an anodically generated nucleophile cathodically generated electrophile reacts with an electrophile nucleophile present in solution. Consequently, an intermediate is formed, which undergoes ring-closure reaction. The second scenario involves the electrochemical formation of a reactive species followed by cycloaddition in a concerted mechanism.
Common types of electrochemically induced cyclization reactions. The examples presented hereafter are classified according to the reaction type rather than to the resulting type of heterocycle. Among the intramolecular reactions, recent efforts in electrochemical heterocycle synthesis can mostly be differentiated into anodic olefin coupling section 1. On the other hand, cycloadditions section 2. Cases which do not fall into any of these categories are discussed in sections 1.
A further important aspect is the type of electron transfer involved in the reaction. With regard to selectivity, the direct method is often complementary to typical chemical oxidations and reductions, since electrochemical oxidation or reduction proceeds via discrete electron transfer steps rather than atom transfer. In contrast, the indirect process can either be initiated with a discrete electron transfer outer-sphere mechanism or proceed via bond formation inner-sphere mechanism , depending on the type of mediator [31].
In both cases, the electrode reaction proceeds at such a low potential that the substrate is electrochemically inactive. In many cases, undesired side-reactions can be avoided by using redox mediators, since reactive intermediates do not accumulate on the electrode surface. Moreover, the indirect approach is often used in order to inhibit electrode passivation caused by formation of polymer films. In the context of heterocycle synthesis, a number of mediators based on organic molecules, inorganic salts and metal complexes have been used recently and their use will be discussed later on the basis of the relevant examples.
Principle of indirect electrolysis. The reaction is initiated by single electron oxidation to generate intermediate 2 , which after cyclization and deprotonation gives radical 3. Further oxidation results in the formation of a cationic species which is trapped by methanol to yield product 4. Anodic intramolecular cyclization of olefines in methanol. This cyclization method is not restricted to hydroxy groups as trapping agents. The reactions can be carried out under galvanostatic conditions C.
The presence of a proton scavenger is necessary in order to obtain reasonable reaction rates. When the radical cation is trapped with a hydroxy group, the use of 2,6-lutidine is sufficient. However, a stronger base such as NaOMe is needed when tosylamines are converted in order to facilitate the cyclization reaction and to suppress intermolecular coupling. By using DMSO instead of methanol as nucleophilic co-solvent for electrolysis, a pool of alkoxysulfonium ions 7 is generated from tosylamine 5.
Analogously to Swern- and Moffat-type reactions, this key intermediate is then converted to ketone 8 by quenching with NEt 3 at slightly elevated temperatures under elimination of dimethyl sulfide. Alternatively, a tethered carboxy group can be used as the nucleophilic component, leading to the formation of lactone rings [39]. A further option is the hydrolysis of alkoxysulfonium species 7 with aqueous NaOH under formation of the corresponding secondary alcohol [40]. Among the numerous existing radical cyclization methods, the conversion of unsaturated alkyl halogenides represents one of the key-reactions for the synthesis of natural products containing aliphatic heterocycles.
Such ring-closing reactions are frequently carried out using toxic tri- n -butyltin hydride in combination with a radical initiator such as AIBN. Peters and co-workers described an electrochemical alternative using cathodically generated nickel I complexes as mediators [41,42]. Under potentiostatic conditions C. When 12 was electrolyzed in absence of mediator, significantly lower yields were obtained [42].
Cyclization of bromopropargyloxy ester The acidity of the reaction medium strongly influences the product distribution. Under aprotic conditions, the formation of 13 is favored, whereas in presence of HFIP 1,1,1,3,3,3-hexafluoroisopropanol as a proton donor, product 14 is formed exclusively. Proposed mechanism for the radical cyclization of bromopropargyloxy ester The cyclization reaction is initiated with the generation of radical 17 upon anodic oxidation of the potassium salt of However, increasing alkyl substitution leads to improved yields of the cyclization product; apparently, the cyclization rate is significantly enhanced in this case due to the Thorpe—Ingold effect [46].
Preparation of pyrrolidines and tetrahydrofurans via Kolbe-type electrolysis of unsaturated carboxylic acids Preparation of pyrrolidines and tetrahydrofurans via Kolbe-type electrolysis of unsaturated carboxy The cyclization is proposed to proceed via iminoxyl intermediate 22 , which is generated through deprotonation by cathodically generated methanolate and subsequent anodic oxidation.
Cyclization of radical 22 is followed by further oxidation and proton abstraction to afford isoxazol The reported method features a simple setup, mild conditions room temperature, low concentration of base and a broad scope. Anodic cyclization of chalcone oximes A well-studied method for generation of aliphatic N - and O -heterocycles is the intramolecular nucleophilic trapping of anodically formed iminium 23 or alkoxycarbenium species However, aliphatic ethers and amides generally exhibit high oxidation potentials, and a large number of functional groups are therefore not compatible with direct oxidation [48].
In this context, the use of silyl, stannyl and thioether groups is generally preferred, since these groups are typically cleaved off upon anodic oxidation. A number of intramolecular cyclizations of 23 - and 24 -type intermediates have been reported both in presence and absence of electroauxiliaries. Generation of N -acyliminium 23 and alkoxycarbenium species 24 from amides and ethers with and without the use of electroauxiliaries. Generation of N -acyliminium 23 and alkoxycarbenium species 24 from amides and ethers with and w In the course of their research on functionalized peptidomimetics, Moeller and co-workers found that the amide unit provides an excellent opportunity for oxidative modification of the peptide framework [50,51].
In order to construct constrained peptidomimetics, several electrochemical protocols for generation and cyclization of N -acyliminium species have been developed, resulting in the synthesis of a number of lactams and lactam-derived heterocycles [52].
Anodic cyclization of dipeptide While this reaction proved to be very useful for the cyclization of simple amino acid derivatives, major limitations were encountered when more complicated systems were oxidized [52]. As outlined before, amide groups exhibit rather high oxidation potentials in the order of 1.
In this context, the introduction of electroauxiliaries to the peptidomimetic structures and their use for site-selective oxidation was explored [52]. The cyclization was then accomplished in two steps, starting with the anodic oxidation of 27 in methanolic solution under galvanostatic conditions. Anodic cyclization of a dipeptide using an electroauxiliary. Generally, the anodic oxidation of aliphatic amines leads to the formation of radical anions which can undergo multiple reaction pathways, typically leading to complex product mixtures [54]. However, Okimoto et al. The hydroxy group tethered to the substrate serves for nucleophilic trapping of the iminium species under formation of oxazolidine or 1,3-oxazinane species The method provides access to a number of 2-aryl-1,3-oxazolidines and 2-aryl-1,3-oxazinanes.
Anodic cyclization of hydroxyamino compound An intriguing example for the intramolecular cyclization of alkoxycarbenium species has been reported recently by Suga, Yoshida et al. After formation of alkoxycarbenium ion 33 , cyclization proceeds and the resulting carbenium ion 34 is trapped by ArSSAr to give The use of tetrafluoroborate salts is associated with low yields due to fluorination of intermediate 34 and therefore has to be avoided. In contrast, good results are obtained when the reaction is carried out using Bu 4 NB C 6 F 5 4 as supporting electrolyte.
PhI OCH 2 CF 3 2 was generated anodically from iodobenzene in a solution of LiClO 4 in 2,2,2-trifluoroethanol and served as reagent for the oxidative intramolecular coupling of phenyl rings with amide or carbamate groups. With control experiments the authors demonstrated that this in situ generated reagent works more efficiently in such cyclizations than the more frequently used PIFA reagent.
The transformation represents the key-step of the synthesis of glycozoline 37 , an antifungal and antibacterial agent. Cyclization of biaryl 35 to carbazol 36 as key-step of the synthesis of glycozoline Electrosynthesis of 39 as part of the total synthesis of alkaloids 40 and In contrast to conventional Wacker-type cyclizations, where stoichiometric amounts of co-oxidant are employed at elevated temperatures, the electrochemical version proceeds smoothly at room temperature.
Among several electrolyte compositions, NaClO 4 in a 7: Halogen substituents on the phenol unit are tolerated under the described reaction conditions. Wacker-type cyclization of alkenyl phenols In view of the fact that the indole unit is present in a variety of natural products and biologically active compounds, Arcadi, Rossi et al. The cyanomethyl anion, a cathodically generated base which is formed upon reduction of the solvent CH 3 CN, triggers the cyclization reaction via deprotonation of the amide group.
According to the authors, the deprotonation is followed by ring closure on the C—C-triple bond, generating a carbanion intermediate which is then protonated by the solvent. Various alkynylanilines with different substituents on the aromatic ring and on the alkynyl group were cyclized in good to excellent yields.
When N -ethoxycarbonyl-substituted anilines are converted under the conditions described above, the carbamate group is cleaved and unprotected indoles are obtained. Cathodic synthesis of indol derivatives. An electrochemical method for the synthesis of oxindoles and 3-oxotetrahydroisoquinolines 47 via intramolecular cyclization under C—C-bond formation was reported by Atobe, Fuchigami et al. The latter serves as supporting electrolyte and as fluoride source for mediation of the reaction.
In absence of fluoride, the formation of the cyclization product was not observed. The authors proposed a mechanism, in which after initial one-electron oxidation the resulting radical cation 48 is attacked by a fluoride ion under formation of an S—F bond.
Advances in Heterocyclic Chemistry, Volume 72 (Hardcover)
Radical 49 is then further oxidized to the corresponding cationic species 50 , which undergoes elimination of HF under formation of cationic intermediate Finally, intramolecular trapping by the aromatic ring in a Friedel—Crafts type reaction leads to cyclization and formation of product A selectivity problem is caused by concurrent nucleophilic attack of fluoride ions on intermediate However, this undesired side reaction is suppressed when ultrasonic irradiation is applied during electrolysis.
The authors studied the product distribution under variation of stirring speed and temperature in order to determine whether improved mass transport or strong local heating is responsible for the improved selectivity. Whereas an increase of the stirring speed did not significantly affect the ratio between desired cyclization product 47 and fluorinated byproduct, higher temperatures lead to preferential formation of the desired cyclization product.
In the reported case, the use of ultrasonic radiation leads to significantly better results compared to conventional heating. These results suggest that the effect of ultrasound on the selectivity is attributable to strong local heating at the electrode surface, which increases the temperature sufficiently for cyclization. In contrast, such high temperatures are not available by conventional heating, where the reaction temperature is limited by the boiling point of the solvent. Zeng, Little et al. A two-phase system composed of a sodium carbonate buffer solution and dichloromethane is employed as electrolyte.
Synthesis of 2-substituted benzoxazoles from Schiff bases. A well-established strategy for the construction of certain six-membered heterocycles is the electrochemical generation of heterodienes for Diels—Alder cycloadditions [65,66]. In this context, electrosynthesis provides a significant advantage over conventional methods: Instable diene precursors which are difficult to synthesize by conventional means, can be conveniently generated in situ at low temperatures.
The electrogenerated intermediate is subjected to cycloaddition either by in situ trapping with the dienophile or by using the cation pool approach. These structures consist of a terpene element and a benzodihydropyran unit and feature antiviral activity.