It was in 1963 that Huisgen laid out the classification of 1,3-dipoles and the concepts for 1,3-dipolar cycloaddition reactions, although it was not until 1976 that the first intramolecular 1,3-dipolar cycloaddition reaction of an azomethine ylide was reported. Since then, impressive developments have been described in this area, with the establishment of various useful methods for the formation of azomethine ylides and the determination of the requirements for a successful intramolecular cycloaddition reaction. Use of this methodology for the synthesis of pyrrolidineand pyrrole-containing natural products has been expanding rapidly. This review aims to describe the background and mechanisms of azomethine ylide formation and intramolecular cycloaddition, giving a critical account including the very first example and covering to early 2005. It is hoped that this review will be a useful resource for chemists interested in cycloaddition reactions and will inspire further exciting developments in this area. Cycloaddition reactions are one of the most important class of reactions in synthetic chemistry. Within * Corresponding author. Tel: +44 (0)114 222 9428. Fax: +44 (0)114 222 9346. E-mail: i.coldham@sheffield.ac.uk. † University of Sheffield. ‡ Tripos Discovery Research Ltd. Iain Coldham (b. 1965) is a Reader in Organic Chemistry at the University of Sheffield. He obtained his undergraduate degree and Ph.D. from the University of Cambridge, completing his Ph.D. in 1989 under the supervision of Stuart Warren. After postdoctoral studies at the University of Texas with Philip Magnus, he joined the staff in 1991 at the University of Exeter, U.K. In 2003, he moved to the University of Sheffield where he is involved in research on chiral organolithium compounds and on dipolar cycloaddition reactions in synthetic organic chemistry.

Intramolecular dipolar cycloaddition reactions of azomethine ylides.

Thionation reactions of lawesson's reagents

Transition metal catalyzed denitrogenative transannulation of a triazole ring has recently received considerable attention as a new concept for the construction of diverse nitrogen-containing heterocyclic cores. This method allows a single-step synthesis of complex nitrogen heterocycles from easily available and cheap triazole precursors. In this Minireview, recent progress of the transition metal catalyzed denitrogenative transannulation of a triazole ring, which was discovered in 2007, is discussed.

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Transition-Metal-Catalyzed Denitrogenative Transannulation: Converting Triazoles into Other Heterocyclic Systems

Transition-metal-catalyzed annulations are widely used in the synthesis of heterocyclic compounds.[1] One of the most efficient methods for the construction of five-membered oxygen-containing heterocycles involves the annulation of diazocarbonyl compounds with alkynes and nitriles. Thus, Davies et al.[2] and Padwa et al.[3] have employed this method[4] for the synthesis of furans (X = CH), and Helquist et al.[5] for the preparation of oxazoles (X = N) [Eq. (1)]. In contrast, analogous transformations of α-imino diazo compounds, which may lead to the formation of pyrrole and imidazole rings, are unknown. Herein we report an efficient, direct, Rh-catalyzed transannulation of pyridotriazoles with alkynes and nitriles that leads to indolizines (X= CH) and imidazopyridines (X = N), respectively [Eq. (2)].




(1)





(2)


It has been shown that 2-pyridyl diazo compounds 1[6] transform into their cyclic triazole form 2[7] upon storage [Eq. (3)], and it is also known that some of these cyclic triazoles can still undergo transformations that are characteristic of diazo compounds.[8] This phenomenon has been attributed to the closed/open form equilibrium of N-fused triazoles in solution,[9] which can produce trace to significant amounts of 1. The position of this equilibrium depends on the temperature and the substitution pattern of the triazole.[9b] Thus, introduction of a halogen substituent at C7 (R1 = Cl) shifts the equilibrium to the left, which has been explained in terms of nonbonding repulsion between the lone pair of the halogen and that of the nitrogen in the peri position.[10]




(3)


To evaluate the feasibility of using triazoles as precursors of Rh carbenoids we investigated the reaction of triazoles 3a and 3b with triethylsilane in the presence of a catalytic amount of rhodium(II) acetate, which is a method developed by Doyle and coworkers[11] for the efficient trapping of Rh carbenoids [Eq. (4)]. Not surprisingly, pyridotriazoles 3a and 3b behave differently under these reaction conditions. Thus, while the 7-H derivative 3a remains unaffected, the 7-chloro-substituted compound 3b is smoothly converted into 4, which is the product of carbenoid insertion into the Si–H bond. These experiments clearly indicate that 7-halo-substituted pyridotriazoles can indeed serve as convenient precursors of Rh carbenoids.




(4)


Next, to test our hypothesis regarding the annulation of α-imino diazo compounds with alkynes to form a pyrrole ring, we treated triazole 3b with phenylacetylene in the presence of rhodium(II) acetate. This reaction proceeded smoothly to produce a mixture of cyclopropene 5 and indolizine 6a with yields of 68% and 28% of isolated product, respectively [Eq. (5)]. Surprisingly, cyclopropene 5 does not undergo further isomerization into indolizine 6a under these reaction conditions.[12] The ratio of these products remained constant throughout the course of the reaction, thereby suggesting an independent path for the formation of 6a.




(5)


We found, however, that the selectivity of the transannulation (6 over 5) could be dramatically improved by using rhodium(II) heptafluorobutyrate as catalyst.[13] Thus, transannulation of 3b with a series of aryl and alkenyl alkynes[14] proceeded highly chemoselectively (90:10 to 95:5 vs. cyclopropene) to produce indolizines 6[15] in good yields (Table 1). Electron-rich, electron-deficient, and sterically hindered aryl alkynes were nearly equally effective in this reaction.



Table 1

Rhodium(II)-catalyzed transannulation of triazole 3b with alkynes.



Inspired by the successful formation of an N-fused pyrrole ring from the transannulation of triazoles with alkynes, we examined the formation of an N-fused imidazole ring in the reaction of 3 with nitriles and found that pyridotriazoles 3 react smoothly with a variety of aryl, alkyl, and alkenyl nitriles in the presence of Rh2(OAc)4 (1 mol%) in toluene at 60°C (Table 2) to afford N-fused imidazopyridines 7 in reasonable to high yields.



Table 2

Rhodium(II)-catalyzed transannulation of triazoles with nitriles.



Both 3-carbomethoxy-(Table 2, entries 1–9) and 3-aryl-(Table 2, entry 10) pyridotriazoles are equally efficient in this reaction. Moreover, 7-bromo-(Table 2, entry 11) and even 7-methoxy-substituted (Table 2, entry 12) triazoles proved to be good substrates for this transannulation reaction.

We propose the following mechanism for this novel Rh-catalyzed transformation (Scheme 1). First, pyridotriazole 3 undergoes closed/open form equilibrium[9] to produce small amounts of diazo compound 1 which, upon reaction with rhodium(II) carboxylate, generates the Rh-carbenoid species I. A direct nucleophilic attack[18] of alkyne or nitrile 8 on species I produces ylide species II, according to path A, which then cyclizes to form 6 or 7 via cyclic zwitterion III. Alternatively (path B), [2+2] cycloaddition of I and 8 leads to metallacyclobutene IV, which can also be formed by cyclization of II.[19] Rhodacycle IV then undergoes metathesis to produce Rh carbenoid V which, upon 6π-electrocyclization and subsequent reductive elimination, furnishes product 6 or 7. [2+1] Cycloaddition of I with 8 (path C) accounts for the formation of cyclopropene 5 in the presence of rhodium(II) acetate [see Eq. (5)]. As discussed above, 5 does not transform into heterocycle 6 under these reaction conditions.[12]



Scheme 1

Plausible mechanisms for the Rh-catalyzed transannulation of pyridotriazoles with alkynes and nitriles. Y=N, CR″.



In summary, we have developed an efficient Rh-catalyzed transannulation of pyridotriazoles for the formation of pyrrolo- and imidazopyridines, which are important fused heterocyclic scaffolds.[20] We have also demonstrated that some of these pyridotriazoles can serve as stable[13] and convenient[21] precursors of Rh carbenoids.

Rh‐Catalyzed Transannulation of Pyridotriazoles with Alkynes and Nitriles

Data on the synthetic routes to substituted 1,2,3-triazoles, including those containing functional groups, based on cyclisation of various nitrogen compounds published during the last 15 years are described. Examples of using new triazole derivatives in agrochemistry, medicine and engineering are given.

https://iopscience.iop.org/article/10.1070/RC2005v074n04ABEH000893/pdf

1,2,3-Triazole and its derivatives. Development of methods for the formation of the triazole ring

Molecular rearrangements of 4-iminomethyl-1,2,3-triazoles. Replacement of 1-aryl substituents in 1H-1,2,3-triazole-4-carbaldehydes

5-Chloro-1,2,3-thiadiazole-4-carbaldehyde, prepared in four steps from 1,3-dichloroacetone, reacts with alkyl- and aryl-amines in alcohol solution to give 1,2,3-triazole-4-thiocarboxamides 9a–f Similarly, hydrazine and N-aminomorpholine furnish the 1,2,3-triazole-4-thiohydrazides 9g and 9h, whereas phenylhydrazine and hydroxylamine yield unrearranged products 8i and 8j These, however, are transformed into 1,2,3-triazole-4-carboxylic acids 14i and 14j upon storage in dimethyl sulphoxide solution The mechanism of the rearrangement is discussed

Ring transformations of 5-chloro-1,2,3-thiadiazole-4-carbaldehyde with amines, hydrazines and hydroxylamine

Imines derived from 1,2,3-thiadiazole-4-carbaldehyde 4 rearrange thermally into 1,2,3-triazole-4-thiocarbaldehydes 6 which were trapped with anthracene or 2.3-dimethylbutadiene. In two cases, 1,2,3-thiadiazole-4-thiocarbaldehyde 9 was intercepted as the Diels–Alder adduct 11. 5-Phenyl-1,2,3-thiadiazole-4-carbaldehyde 14 reacts with amines to give 4-benzoyl-1,2,3-triazoles 17via the intermediate 4-thiobenzoyltriazoles 16, whose existence has been demonstrated by NMR. The reactions of 5-tert-butylthio-1,2,3-thiadiazole-4-carbaldehyde 18 with amines yield either 1,2,3-triazole-4-dithio esters 20 or 1,2,3-triazole-4-thioamides 21. In solution, the dithioesters 20 equilibrate with the imines 19 when the R-substituent is aryl. From the reaction conditions we conclude that the facility of rearrangement of the title compounds depends on the nucleophilicity of the imine nitrogen and on the 5-substituent in the order ButS > Ph > H.

Thermal rearrangement of 4-iminomethyl-1,2,3-thiadiazoles

A general method is described to transform the readily available title compounds into tri- and tetra-cyclic heterocycles, first by substituting the chlorine atom by an unsaturated thiolate or alkoxide, and then by modifying the aldehyde function into a 1,3-dipole. As 1,3-dipoles, nitrile oxide, nitrone, nitrile imine, azomethine ylide and azomethine imine groups were generated from the 5-allylsulfanyl-4-formylpyrazole 7, which resulted in Intramolecular cycloaddition and formation of the heterocycles shown in Scheme 2. The other pyrazoles 22, 23, 26, 30 and 33 were converted via intramolecular nitrile oxide cycloaddition (INOC) into fused dihydroisoxazoles. A limitation to the method is the Claisen rearrangement which occurs when the allyl ether 26 or the prop-2-ynyl ether 30 is used.

Gerrit L'abbé

Papers

Molecular rearrangements of 4-iminomethyl-1,2,3-triazoles. Replacement of 1-aryl substituents in 1H-1,2,3-triazole-4-carbaldehydes

Ring transformations of 5-chloro-1,2,3-thiadiazole-4-carbaldehyde with amines, hydrazines and hydroxylamine

Thermal rearrangement of 4-iminomethyl-1,2,3-thiadiazoles

5-Chloropyrazole-4-carbaldehydes as synthons for intramolecular 1,3-dipolar cycloadditions

Study of the diazoimine/triazole equilibria for substituted thiazoles and thiadiazoles