Denitrogenative Transformations of Pyridotriazoles and Related Compounds: Synthesis of N‑Containing Heterocyclic Compounds and Beyond

Abstract

The high demand for new and efficient routes toward synthesis of nitrogen-containing heterocyclic scaffolds has inspired organic chemists to discover several methodologies over recent years. This Perspective highlights one standout approach, which involves the use of pyridotriazoles and related compounds in denitrogenative transformations. Readily available pyridotriazoles undergo ring–chain isomerization to produce uniquely reactive α-diazoimines. Such reactivity, enabled by metal catalysts, additives, or visible-light irradiation, can be applied in transannulation, insertion, cyclopropanation, and many other transformations.

Graphical Abstract

1. INTRODUCTION

N-Containing heterocyclic frameworks are ubiquitous in drugs, dyes, and high-performance materials.¹ Pyridines, fused pyridines, and other heterocyclic scaffolds possessing bridgehead nitrogens are important moieties present in several biologically active molecules and natural products.² Because of the broad and emergent applications of these families of molecules, new, efficient, and general methods for their synthesis are in constant demand. Several strategies involve the use of triazoles as nitrogen sources for synthesis of fused N-heterocyclic and carbocyclic compounds.³ Those employing N-sulfonyl-1,2,3-triazoles have emerged in the past few years and are summarized elsewhere.⁴ This Perspective will focus on denitrogenative transformations of pyridotriazoles and related compounds. This reaction class stands out as a single-step process featuring high efficiency and atom economy, as the only byproduct is molecular nitrogen.

Pyridotriazoles are essential building blocks in the pharmaceutical chemistry and material science.^3b,5 They are readily available either through the reaction of pyridin-2-yl acetates with 4-acetamidobenzenesulfonyl azides or the oxidative N–N coupling of in situ generated hydrazones from ketones.⁶

Cyclic triazoles are known to undergo ring–chain isomerization.⁷ In particular, pyridotriazole 1 in solution will undergo reversible ring–chain isomerization (Scheme 1) to produce diazo compound 2,⁸ or vice versa.⁹ The equilibrium of this isomerization can be influenced by reaction conditions, particularly by solvent and temperature. However, a crucial factor in shifting the equilibrium toward the open or closed isomer is the substitution pattern around the ring, specifically at C7.^8d For instance, introducing a halogen atom (R¹ = Cl) at this position shifts the equilibrium to the right, likely due to the nonbonding repulsion between the lone pairs of electrons at halogen atom with those at the nitrogen atom in the peri position of 1 (Scheme 1).¹⁰ Computational studies by the Bao group showed that the formation of the diazo tautomer 2 occurs readily, and even slightly exothermically, when R¹ = F.^8a

Scheme 1.

Ring–Chain Isomerism of Pyridotriazoles

In 2007, the Gevorgyan group disclosed the use of pyridotriazoles as stable precursors for rhodium carbenes.¹¹ It was shown that pyridotriazole 3b, which exists in equilibrium with pyridyl diazo compound 2b via ring–chain isomerism, reacted with rhodium catalyst to release molecular nitrogen and form rhodium carbene 4b.¹² Formation of the latter was confirmed by its smooth Si–H insertion reaction¹³ with triethylsilane to produce the corresponding product 5b (Scheme 2). Not surprisingly under the reaction conditions, pyridotriazoles 3a and 3b showed completely different reactivity, as no reaction was observed with 3a. This further illustrates the governing effect of the C7 substituent on the open–close form equilibrium between 3 and 2.

Scheme 2.

Rhodium(II)-Catalyzed Si–H Insertion

2. TRANSANNULATION OF PYRIDOTRIAZOLES

2.1. Rhodium-Catalyzed Transannulation.

Species 4 are unique as they possess an inherently electrophilic rhodium carbene moiety α to a nucleophilic imine group. Gevorgyan and co-workers first uncovered remarkable reactivity of these species in transannulation reaction with alkynes and nitriles toward synthesis of indolizines and imidazopyridines from readily available and inexpensive pyridotriazoles.¹¹

Initially, transannulation reaction of pyridotriazole 3b with phenyl acetylene in the presence of rhodium acetate yielded a mixture of the [2 + 1] and [3 + 2] cycloaddition products 6a and 7a, respectively (Scheme 3). Upon resubmission of isolated cyclopropene 6a to the reaction, no isomerization of the latter into indolizine 7a was observed, thus pointing out independent mechanisms for formation of 6 and 7. Notably, employment of more electrophilic Rh₂(pfb)₄ led to the highly chemoselective formation of indolizine 7a in 78% yield. Under the optimized reaction conditions, pyridotriazole 3b reacted smoothly with different aryl alkynes and enynes to give indolizines 7 in good to excellent yields. However, the reactions with aliphatic alkynes were much less efficient.

Scheme 3.

Rhodium(II)-Catalyzed Transannulation with Aryl and Alkenyl Acetylenes

Next, the Gevorgyan group demonstrated the efficient synthesis of N-fused imidazopyridines through the transannulation of pyridotriazoles 3 with nitriles 8 (Scheme 4). Electronically different aryl, alkenyl, and alkyl nitriles were proven to be capable reaction partners for pyridotriazoles 3 to produce the corresponding N-fused imidazopyridines 9 in moderate to good yields even in the presence of less electrophilic rhodium acetate catalyst. Diversely substituted pyridotriazoles such as 3-methoxycarbonyl, 3-aryl, 7-Br, and 7-OMe reacted well under these reaction conditions.

Scheme 4.

Rhodium(II)-Catalyzed Transannulation with Nitriles

Two alternative mechanisms were proposed by the authors for this transannulation reaction (Scheme 5). According to path a, pyridotriazole 3 reacts with rhodium catalyst via its in situ generated open form 2 to form the rhodium carbene species 10, followed by a direct nucleophilic attack¹⁴ of an alkyne or nitrile to produce the intermediate ylide 11. A subsequent cyclization leads to the corresponding products 7 or 9 via zwitterionic intermediates 12 (Scheme 5, path a). Alternatively (path b), upon [2 + 2] cycloaddition of rhodium carbene 10 with alkyne or nitrile, a rhodacyclobutene 13 is produced, which could also be formed from the cyclization of 11.¹⁵ Ring opening of rhodacyclobutene 13 would produce rhodium carbene species 14, which, upon 6π-electrocyclization and a subsequent reductive elimination, would yield the corresponding products 7 or 9. As previously stated, even though cyclopropene 16 was observed from [2 + 1] cycloaddition of pyridotriazole 3 with alkynes in the presence of rhodium(II) acetate, path c could be ruled out as no isomerization 16 → 7 was observed.

Scheme 5.

Proposed Mechanism for Rhodium(II)-Catalyzed Transannulation

Next, the Gevorgyan group reported a two-step method for a regiodivergent synthesis of 1,2- and 1,3-disubstituted indolizines from pyridotriazoles 3 and terminal alkynes.¹⁶ At the first step, an efficient access to a variety of 3-iminocyclopropenes 6 was readily achieved in the presence of Rh₂(S-DOSP)₄ (Scheme 6). This intermediate could be then subjected to the copper catalyst to selectively obtain 1,2-disubstituted indolizines 17 (Scheme 6a). Alternatively, using rhodium(I) catalyst, selective formation of 1,3-disubstituted indolizines 18 could be achieved (Scheme 6b). These protocols are remarkably regiodivergent, as regioisomeric indolizines 17 and 18 were obtained with >99% selectivity. These protocols are quite general with respect to the electronic nature of cyclopropenes used.

Scheme 6.

Regiodivergent Synthesis of N-Fused Heterocyclic Compounds

The authors proposed the following mechanisms for the regiodirvergent cycloisomerizations of cyclopropenes 6 into indolizines 17 and 18 (Scheme 7). For the rhodium-catalyzed method, upon ring opening of cyclopropene the most substituted rhodium carbene 19 forms.¹⁷ A nucleophilic attack by the nitrogen lone pair would then lead to a zwitterionic intermediate 20. A subsequent elimination of the rhodium would furnish the 1,3-regioisomeric product 18. Alternatively, in the presence Cu(I), formation of the less substituted copper carbene 21, followed by its cyclization to zwitterionic intermediate 22, occurs,^17d,18 eventually leading to the 1,2-regioisomeric product 17. The authors confirmed that isomeric carbenes 19 and 21 are not interconverted through the cycloaddition/cycloreversion equilibrium,^17a,d since no crossover product was observed upon addition of 5 equiv of the alkyne. Alternatively, regioisomers 17 and 18 could arise from the reductive elimination of aza-metalacyclic carbene intermediates 23 and 24.

Scheme 7.

Proposed Mechanisms for the Regiodivergent Copper(I)- and Rhodium(I)-Catalyzed Synthesis of Substituted Indolizines

Later, the Lee group expanded the transannulation chemistry to synthesis of 3-alkenylindolizines by employing 1,3-dienes (Scheme 8).¹⁹ In this one-pot, three-step protocol, pyridotriazoles 3 reacted with 1,3-dienes 25 in the presence of rhodium catalyst via [2 + 1]¹⁶ cycloaddition reaction to produce cyclopropane 27. The latter, upon Pd-catalyzed cycloisomerization, produced dihydroindolizine 28 (Scheme 8a). A subsequent oxidation with MnO₂ led to 3-alkenylindolizines 26. Under these conditions, pyridotriazoles 3 reacted very well with electronically different 1,3-dienes (E)-25 to produce 3-alkenylindolizines 26 in moderate to good yields (Scheme 8b).

Scheme 8.

Rhodium- and Palladium-Catalyzed Synthesis of 3-Alkenylindolizines

2.2. Copper-Catalyzed Transannulation.

Previously developed transannulation methods relied on rhodium catalysis, which required C7-substituted pyridotriazoles as precursors for the α-imino diazo compounds.^11,16 The Gevorgyan group reported a copper-catalyzed expansion of this reaction under aerobic conditions (Scheme 9).²⁰ This methodology does not require substitution at the C7 position, employment of electron-deficient pyridotriazoles, and use of expensive rhodium(II) catalysts. Employment of this method allowed to efficiently produce indolizines 30 with electronically diverse aryl acetylenes 29. Aliphatic and heteroaromatic alkynes also reacted well, which was not possible under the previously reported rhodium-catalyzed conditions.¹¹ Most notably, unsubstituted pyridotriazoles (R¹, R² = H) turned out to be the competent substrates for this reaction as well.

Scheme 9.

Copper-Catalyzed Transannulation

The following mechanism was proposed for the copper-catalyzed transannulation of pyridotriazoles into indolizines (Scheme 10a). First, terminal acetylene 29 reacts with the copper catalyst to generate copper acetylide 31, which upon reaction with diazo compound 2 generates the copper–carbene complex 33 (path a). The latter could also be generated by the reaction of copper carbene 32 and alkyne 29 (path b). Next, a migratory insertion of the alkynyl group into the carbene 33 would produce intermediate 34.²¹ Generation of intermediate 37 from 34 could occur via a nucleophilic attack of the pyridine nitrogen at the triple bond, likely activated by the electrophilic copper complex.²² On the other hand, the in situ generated propargylic intermediate 35 or allenic intermediates 36 could also lead to the formation of 37, protodecupration of which would deliver indolizine product 30. Importantly, no reaction was observed when copper acetylide 31a and pyridotriazole 3c were subjected to the reaction conditions without copper catalyst (Scheme 10b). This suggests that electrophilic copper²² (Cu(MeCN)₄PF₆) is indeed required for activation of the triple bond during the cyclization step (34 → 37).

Scheme 10.

Proposed Mechanism for Copper-Catalyzed Transannulation of Pyridotriazoles with Alkynes

In continuation of their work on the synthesis of N-heterocyclic structures via transannulation chemistry, the Gevorgyan group reported assembly of diverse polycyclic frameworks via the copper-catalyzed intramolecular transannulation reaction (Scheme 11).²³ Pyridotriazoles 38 tethered with internal alkynes participate well in this intramolecular transannulation reaction to produce in a single step the corresponding tri-, tetra-, and pentacyclic fused indolizines 39 in moderate to good yields (Scheme 11a). Interestingly, it was uncovered that this reaction can also be catalyzed by Lewis acids, such as In(OTf)₃ and TIPSOTf (Scheme 11b).

Scheme 11.

Copper-Catalyzed Intramolecular Transannulation

Copper-catalyzed intramolecular transannulation was proposed to proceed through the in situ generated copper carbene intermediate 41 (Scheme 12), which upon a [3 + 2] cycloaddition reaction would produce indolizine 39.¹¹ The latter could also be formed via a direct [2 + 1] cycloaddition to produce the cyclopropene intermediate 42, followed by cycloisomerization.¹⁶ Another pathway could involve carbene alkyne metathesis²⁴ of the copper carbene intermediate 43. The Lewis acid catalyzed version was envisioned to operate via the cationic intermediate 45, which could be formed through the denitrogenative cyclization of a Lewis acid adduct 44. A subsequent cyclization with the loss of the metal would produce indolizine 39. Alternatively, a nucleophilic attack of the α-imino carbon at the Lewis acid activated triple bond could form intermediate 46. Extrusion of dinitrogen, followed by the aza-Nazarov-type cyclization, produces 48,²⁵ which upon metal loss would deliver the indolizine product 39.

Scheme 12.

Mechanism of Copper- and Lewis Acid Catalyzed Intramolecular Transannulation

In 2016, Adimurthy and co-workers reported aerobic copper-catalyzed transannulation of pyridotriazoles with benzylamines into aza-heterocyclic compounds.²⁶ Pyridotriazoles 3 reacted efficiently with different substituted benzyl amines to produce the imidazopyridines 49a–h in high yields (Scheme 13a). Heteroaromatic and cyclic amines reacted well; however, no reaction was observed with aza-heterocyclic or aliphatic amines. α-Amino acids reacted smoothly with pyridotriazoles 3 in a decarboxylative manner to produce the corresponding products 49i–m in high yields (Scheme 13b).

Scheme 13.

Copper(I)-Catalyzed Transannulation with Benzylamines and α-Amino Acids

It was proposed that in the presence of copper catalyst the carbene intermediate 32 forms (Scheme 14).^20,23 A migratory insertion of the latter with the N–H bond of benzylamine generates pyridine 50. The following consecutive single electron transfer events would produce benzylic cation 53,²⁷ which exists in equilibrium with aza-allene 54. A subsequent cyclization–oxidation would furnish imidazopyridine 49.

Scheme 14.

Proposed Mechanism of Copper(I)-Catalyzed Transannulation with Benzylamines and α-Amino Acids

2.3. Cobalt-Catalyzed Transannulation.

Recently, the Chattopadhyay group reported a cobalt(II)-catalyzed radical transannulation and cyclopropanation reactions.²⁸ Employment of pyridotriazoles or 2-(diazomethyl)pyridines in the presence of Co(TPP) catalyst and alkyne partners resulted in the synthesis of N-containing heterocycles (Scheme 15). The in situ generated N-tosylhydrazones underwent transannulation with various substituted aryl, heteroaryl, and alkyl alkynes in the presence of Co(TPP) to produce the indolizines 57 in good to excellent yields (Scheme 15a). In a similar fashion, the use of alkenes in place of alkynes provided substituted cyclopropanes 58 in high yields and good diastereoselectivity (Scheme 15b). The potential application of this radical transannulation was demonstrated in two-step synthesis of (±)-monomorine 59 (Scheme 15c).

Scheme 15.

Cobalt(II)-Catalyzed Transannulation and Cyclopropanation

Control experiments showed TEMPO-trapping products 60 in the absence of alkyne and a complete shutdown of the reaction in the presence of phenylacetylene (Scheme 16a). On the basis of these data, the following radical mechanism was proposed (Scheme 16b). The produced in situ N-tosylhydrazone 56′ upon exposure to the base produces pyridotriazole 61, which exists in equilibrium with α-imino diazo compounds 62. The latter would be converted into the α-Co^III-pyridyl radical intermediate 63 in the presence of Co^II(TPP) catalyst.²⁹ A radical addition to phenylacetylene would produce γ-Co^III-vinyl radical intermediate 64. A subsequent cyclization would produce indolizine 57. Alternatively, formation of indolizine could result from the ring expansion of cyclopropene intermediate 65, obtained via radical recombination process. However, based on the fact that this intermediate was never observed in the reaction mixtures, the authors ruled out this pathway.

Scheme 16.

Proposed Mechanism of Cobalt(II)-Catalyzed Radical Transannulation

2.4. Lewis Acid Catalyzed Transannulation.

The Adimurthy group reported a general metal-free transannulation reaction of pyridotriazoles for synthesis of imidazopyridines.³⁰ The authors utilized BF₃·OEt₂ as a Lewis acid catalyst and pyridotriazoles 3 as precursors for α-imino diazo compounds 4 (Scheme 17). It is believed that coordination of BF₃·OEt₂ to pyridine nitrogen atom stabilizes the open forms of pyridotriazole 67 and its vinyl diazonium form 68. In one scenario, a direct [3 + 2] cycloaddition (path a) of benzonitrile generates intermediate 69, which upon elimination of dinitrogen and BF₃ produces imidazopyridine 66 (Scheme 17a). Alternatively, an intramolecular nucleophilic addition of intermediate 70 and a subsequent elimination of BF₃ delivers the product (path b). Pyridotriazoles reacted well with electron-donating, withdrawing, and neutral aromatic and heteroaromatic nitriles. Notably, aliphatic nitriles are also competent substrates for this transformation (Scheme 17b).

Scheme 17.

BF₃·OEt₂-Catalyzed Transannulationp

Later, the same group extended this protocol for reactions of electron-rich arenes. Thus, transannulation of pyridotriazoles was successful in the presence of catalytic amounts of In(OTf)₃ and trifluoroacetic acid as an additive.³¹ A somewhat unusual mechanism was proposed by the authors that involved indium–carbene intermediate 73, which was generated from In(OTf)₃ and pyridotriazoles 3 (Scheme 18a). Next, insertion of electron-rich arenes onto the indium–carbene³² leads to the metalated aza-Nazarov-type intermediate 74.^25a,33 Upon elimination of In(OTf)₃ under acidic conditions, the biscationic intermediate 75 is produced.^33,34 It was reasoned that at high temperature the phenyl ring in this sterically congested intermediate would come close to the pyridine ring to generate intermediate 76 via C–H amination. The pyridoindole 72 is produced upon a subsequent proton loss. DFT calculations supported the proposed mechanism.

Scheme 18.

In(OTf)₃-Catalyzed Transannulation

2.5. Brønsted Acid Mediated Transannulation.

Xu and Dong proposed an unusual synthesis of pyridoindoloindolizines through a Brønsted acid mediated transannulation.³⁵ It is likely that TsOH stabilizes diazo–diazonium intermediates 79 ↔ 80, which upon nucleophilic attack of 7-azaindole (77) produce intermediate 81 (Scheme 19a). A subsequent cyclization with the loss of TsOH generates 82. An oxidation with AIBN completes synthesis of pyridoindoloindolizine 78. As exemplified in Scheme 19b, this Brønsted acid mediated transannulation is quite general with respect to the pyridotriazole and pyridoindole components used.

Scheme 19.

PTSA-Mediated Transannulation

3. PYRIDOTRIAZOLE INSERTION

3.1. Rhodium-Catalyzed N–H Insertion.

In 2014, the Gevorgyan group reported the rhodium-catalyzed N-H insertion reactions of pyridotriazoles.³⁶ Various 2-picolylamine derivatives 83 were obtained from the corresponding pyridotriazoles and NH-containing amides, anilines, amines, and enamines in the presence of Rh₂(esp)₂ catalyst (Scheme 20a). After developing the N–H insertion reaction with various amides, a formal transannulation using a combination of Brønsted acid with rhodium catalyst was accomplished. This one-pot protocol allows for efficient synthesis of a wide variety of imidazopyridines possessing alkyl, aryl, benzyl, and alkenyl substituents at the C3 position of the heterocycle (Scheme 20b).

Scheme 20.

Rhodium-Catalyzed N–H Insertion

The authors proposed that rhodium carbenes 4 formed from the in situ generated α-imino diazo compounds react with amides to form an ylide intermediate 85 (Scheme 21). Regeneration of the rhodium catalyst produces 2-picolylamines 83. An acid-assisted intramolecular dehydrative condensation furnishes imidazopyridine product 84.

Scheme 21.

Rhodium-Catalyzed N–H Insertion Mechanism

3.2. Metal-Free C(sp³)–N Bond Formation.

Recently, Alami and Hamze reported interesting metal-free C(sp³)–N bond formation of pyridotriazoles with weakly nucleophilic aniline derivatives (Scheme 22a).³⁷ On the basis of control experiments, it was proposed that first water reacts with α-imino diazo compounds 2 to produce diazonium intermediate 88. Next, the nucleophilic substitution by bromine from TBAB (tetrabutylammonium bromide) produces benzyl bromide 89, which upon alkylation of amine and a subsequent dehydro-bromination delivers the reaction product 87. Different pyridotriazoles reacted well under these conditions with diversely substituted anilines to produce the pyridyl alkyl amines 87 in good to excellent yields (Scheme 22b).

Scheme 22.

Metal-Free C(sp³)–N Bond Formation

3.3. Rhodium(III)-Catalyzed C–H Insertion.

In 2015, Strassert and Glorius reported rhodium(III)-catalyzed directing group assisted C–H activation of pyridine derivatives 91 followed by reaction with pyridotriazoles 3 toward synthesis of fused fluorescent scaffolds 92 (Scheme 23).³⁸ In this protocol, the pyridine moiety plays a dual role by acting as a directing group in the C–H activation step as well as a nucleophile at the cyclization step. The fluorescent properties of the obtained molecules and their complexes with metal salts were studied.

Scheme 23.

Rhodium(III)-Catalyzed C–H Insertion

The proposed mechanism starts with the reversible coordination of cationic rhodium with 2-phenylpyridine 91 to produce via C–H activation a cationic rhodacycle 93 (Scheme 24). Next, it reacts with the diazo compound 4, which upon release of dinitrogen produces carbene intermediate 94. A migratory insertion of pyridyl carbene leads to 95, which undergoes protoderhodation to afford 96. A nucleophilic addition of pyridine at the activated carbonyl group of the ester produces 97. A subsequent elimination of alcohol and the catalyst yields the reaction product 92.

Scheme 24.

Proposed Mechanism of Rhodium(III)-Catalyzed C–H Insertion

Later, the Lee group reported related a sulfoximine-directed C–H functionalization method,³⁹ which provides expeditious access to 1,2-benzothiazines from the corresponding sulfoximines and pyridotriazoles in the presence of Rh(III) catalyst and sodium acetate (Scheme 25a). Mechanistically, this reaction (Scheme 25b) follows a path similar to that of the above-mentioned method (Scheme 24). A variety of 1,2-benzothiazines were efficiently synthesized via this domino C–H activation/cyclization/elimination protocol from readily available sulfoximines and pyridotriazoles.

Scheme 25.

Rhodium(III)-Catalyzed C–H Insertion with Sulfoximines

The Dong group expanded this chemistry to the Rh(III)-catalyzed C–H activation of N-phenylbenzimidamides, followed by a subsequent coupling with pyridotriazoles/cyclization to access the corresponding 3H-indoles 106 (Scheme 26).⁴⁰ Recently, the Xu group reported that N-acetyl-substituted sulfonamide 107 derivatives under similar conditions produce the C–H insertion product 108 exclusively (Scheme 27).⁴¹

Scheme 26.

Rhodium(III)-Catalyzed C–H Insertion with N-Phenylbenzimidamides

Scheme 27.

Rhodium(III)-Catalyzed C–H Insertion with N-Acetyl-Substituted Sulfonamides

3.4. Copper-Catalyzed P(O)–H Insertion.

In 2018, the Shen group reported denitrogenative synthesis of phosphorylated picolyl derivatives via the C–P bond formation.⁴² As proposed in Scheme 28a, the formed copper carbene 111 reacts with 109′, the P–OH tautomer of 109 (P(O)–H), to produce 112, which after 1,2-phosphorus migration (113) and protodecupration delivers the reaction products 110. Under these conditions, various H-phosphonates, H-phosphinates, and H-phosphine oxides reacted well with pyridotriazoles to efficiently produce 2-picolylphosphoryl derivatives (Scheme 28b).

Scheme 28.

Copper(II)-Catalyzed P(O)–H Insertion

3.5. Metal-Free Nucleophile Insertion Reactions.

Very recently, Dehaen reported an acid-mediated metal-free insertion reaction of methoxylated triazoloisoquinolines into weakly nucleophilic Nu–H bonds.⁴³ This method operates via an acid-mediated denitrogenative ring-opening of triazoloisoquinoline 114, followed by the trapping with weak nucleophiles (Scheme 29). C-Nucleophiles, arenes, and heteroarenes such as veratrole, naphthalene, and thiophene in the presence of HBF₄·OEt₂ produced mixtures of regioisomers (115a–c). Conversely, reaction with N-methylindole produced a single regioisomer (115d) exclusively (Scheme 29a) in the presence of triflic acid TfOH. Unlike their nonpolar counterparts, polar nucleophiles, such as amines, alcohols, and thiols smoothly reacted in the presence of triflic acid TfOH under slightly modified conditions to give the corresponding products 116a–e in good yields (Scheme 29b). The authors commented on the importance of a methoxy substituent at the isoquinoline moiety, which is crucial for a facile ring-opening step.

Scheme 29.

Acid-Mediated Nucleophilic Insertions

4. MISCELLANEOUS REACTIONS OF PYRIDOTRIAZOLES

Hong reported the palladium-catalyzed arylation of alkyl-substituted pyridotriazoles with aryl bromides.⁴⁴ Interestingly, two different products were obtained from the same starting material, depending on the choice of the base used (Scheme 30). In the presence of potassium carbonate, the reaction leads to the C3-arylation products 118 mostly possessing an exomethylene fragment. However, under modified semi one pot conditions employing potassium tert-butoxide, C3 and C7-arylation products 119 were produced in high yields (Scheme 30b).

Scheme 30.

Palladium-Catalyzed Arylation

On the basis of the control experiments, the authors proposed the following mechanism (Scheme 31a). Initially, the ^tBuOK-promoted palladium-catalyzed C–H arylation of pyridotriazole occurs at the C7-position to produce 120. Next, the nickel salt enables ring-opening of pyridotriazoles and stabilizes the diazo compounds through the coordination with the pyridine nitrogen atom (121). The palladium carbene complex 122 is subsequently formed from the reaction of intermediate 121 with Pd(II), which is generated via the oxidative addition with aryl halides. Then, 122 undergoes aryl migratory insertion, followed by the β-hydride elimination to give the exocyclic double bond containing compounds 119. The endocyclic product 118h originates from the 1,2-hydride shift of C7-methoxy diazo compound 118h′, without the need for palladium catalysis, to afford the pyridyl styrene derivative (118h″). Finally, Heck reaction leads to the corresponding product 118h (Scheme 31b).

Scheme 31.

Proposed Mechanism for Palladium-Catalyzed Arylation

Xu and Hu reported a formal [4 + 1] cycloaddition of pyridotriazoles with propargyl alcohols for synthesis of pyridyl-substituted 2,5-dihydrofuran derivatives 125 (Scheme 32).⁴⁵ In this reaction, propargyl alcohol 124 reacts with rhodium carbene to form the oxonium ylide 126, which is in equilibrium with rhodium enolate 127. The following intramolecular nucleophilic addition of the C-enolate at the triple bond of alkyne in the 5-endo-dig fashion produces zwitterion 128, which upon protoderhodation delivers the reaction product 125 (Scheme 32a). Moderate to high yields of pyridyl-substituted 2,5-dihydrofurans were obtained using this method (Scheme 32b). In the case of secondary and tertiary alcohols, the reaction led to the formation of allene products 125g,h, which was explained via [2,3]-sigmatropic rearrangement from the oxonium ylide 126. Notably, Rh₂(esp)₂ was the only selective catalyst toward dihydrofurans 125. Employment of other rhodium sources, such as Rh₂(OAc)₄, Rh₂(oct)₄, as well as copper and palladium catalysts, led to mixtures of O–H insertion (129), [2,3]-sigmatropic rearrangement (130), and formal [4 + 1] cycloaddition products (125).

Scheme 32.

Rhodium-Catalyzed [4 + 1] Cycloadditions

Adimurthy reported oxidation of pyridotriazoles into arylated benzoyl pyridines 131,⁴⁶ which was achieved through palladium-catalyzed C–H arylation, and silver-mediated aerobic oxidation of readily available pyridotriazoles and haloarenes (Scheme 33a). Iodoarenes produced higher yields compared to their bromo and chloro counterparts (131a–c). Later, the same group reported the acetoxylative version of this reaction using acetic anhydride as a solvent.⁴⁷ Interestingly, both the acetyl and acetoxy groups of acetic anhydride were incorporated in the molecule to form the 2-oxo-1-phenyl-1-(pyridin-2-yl)propyl acetate 132. Aryl- and naphthyl-substituted pyridotriazoles smoothly underwent this reaction to produce 132 in good yields (Scheme 33b).

Scheme 33.

Palladium-Catalyzed Aerobic Oxidation

Product formation was proposed to occur via the following sequence (Scheme 34a). Upon initial Pd-catalyzed directed C–H arylation, the diazo compound 134 is formed, which is converted to silver carbene 135. The latter upon oxidation (136) produces 6-aryl 2-benzoylpyridines 131. The acetylace-toxylation reaction was proposed to occur via the formation of palladium carbene 137 (Scheme 34b). The following reaction with acetic anhydride would generate the ylide intermediate 138, which presumably via acyl group migration and reductive elimination of palladium catalyst produces 132. Similar to Hong’s method described above,⁴⁴ the pyridotriazole moiety plays a dual role both as a directing group for the C–H functionalization and as a carbene precursor. The Driver group also reported conversion of pyridotriazoles into picolyl alcohol derivatives under heating with HCl or AcOH.⁴⁸

Scheme 34.

Palladium-Catalyzed Oxidation Mechanism

Shen reported the metal-free method for C–C bond formation of pyridotriazoles with boronic acids toward substituted picolines (Scheme 35a).⁴⁹ α-Diazopyridine 141, generated from pyridotriazole upon heating, reacts either with boronic acid 139 (path a) or in situ generated boroxine 139′ (path b). Upon nucleophilic addition of 141 or 144 at the boron species, zwitterionic borates 142 or 145 are formed. A subsequent denitrogenative 1,2-R shift (143, 146), followed by protodeboration deliver the reaction product 140. Commercially available aryl and alkyl boronic acids reacted well with pyridotriazoles under these metal-free conditions to efficiently produce secondary and tertiary substituted picolines.

Scheme 35.

Metal-Free C–C Bond Formation

Very recently, the Rostovskii group disclosed an interesting rhodium-catalyzed reaction of pyridotriazoles 147 with azirines 148 to afford 1-(2-pyridyl)-2-azabuta-1,3-dienes 150 (Scheme 36).⁵⁰ First, the thermally generated rhodium carbene reacts with azirine 148 to form diazatriene 149, which upon reversible 1,6-electrocyclization delivers non-aromatic pyridopyrazine 150. This protocol was found to be efficient for synthesis of 1H-pyrazino[1,2-a]quinoline and 4H-benzo[4,5]oxazolo[3,2-a]pyrazine 150b,c. The configuration of the C=C bond of the diazatriene 149 was found to be an important thermodynamic factor for the position of the equilibrium between 149 and 150.

Scheme 36.

Rhodium-Catalyzed Dearomative Cyclization

5. PHOTOLYSIS OF PYRIDOTRIAZOLES

5.1. UV-Mediated Decomposition of Pyridotriazoles.

Formation of carbenes 152 under the UV photodecomposition of quinoline- and isoquinoline-based pyridotriazoles 151 was reported by Wentrup group in 1986 (Scheme 37).⁵¹ Later, Tomioka applied UV irradiation for the matrix photolysis of 3-methoxycarbonyl-1,2,3-pyridotriazoles into ketenes 156 (Scheme 38).⁵² The formation of ketenes was explained by the ring opening of pyridotriazoles 153a upon light irradiation (>300 nm) to form the diazo compound 154 and then carbene 155, which underwent Wolff rearrangement⁵³ into ketene 156 (Scheme 37). Later, the Wentrup group observed similar ketene and other side products from light irradiation of pyridotriazoles 153b,c (Scheme 38a).⁵⁴ However, in the case of ester derivative 153a, ketene 158 was observed as the major product, likely through an intramolecular C–H insertion of OCH₃ via singlet carbene intermediate 155a followed by fragmentation of the formed propiolactone 157 into ketene 158 and formaldehyde 159. The latter observation was supported by DFT calculations.⁵⁵ The Tidwell group reported formation of the ylide 160 upon photolysis of 3-pyridyl-substituted pyridotriazoles⁵⁶ (Scheme 38b).

Scheme 37.

Photolysis of Quinoline Triazoles

Scheme 38.

Photolysis of 3-Substituted Pyridotriazoles

The Zimmerman group utilized the UV-generated carbene intermediate from pyridotriazole 161 for cyclopropanation of cyclopentadiene 162,⁵⁷ which was employed as solvent to give a mixture of exo- and endo products 163 in moderate yield (Scheme 39). All of these photolysis reactions described above were carried out under UVC and UVB irradiations.

Scheme 39.

Cyclopropanation of Pyridotriazoles

5.2. Visible-Light-Induced Transformations of Unactivated Pyridotriazoles.

Recently, the Gevorgyan group reported UVA light induced denitrogenative transformations of unactivated pyridotriazoles at room temperature,⁵⁸ which were inspired by the observed sufficient absorption of pyridotriazoles at 390 nm (Scheme 40). Upon irradiation at 390 nm, 3-aryl pyridotriazoles 164 underwent ring–chain isomerization to produce α-diazoimines 165, which upon loss of dinitrogen were converted into carbene species 166.⁵⁹ The latter was efficiently utilized in several synthetic transformations. Thus, under these metal-free conditions, arylation of pyridotriazoles with boronic acids in the presence of K₂CO₃ was accomplished.⁶⁰ Different 3-aryl pyridotriazoles 164 reacted smoothly with a number of aryl and alkenyl boronic acids 167 to deliver triarylmethanes 168 in good to excellent yields at room temperature (Scheme 40b).

Scheme 40.

Visible-Light-Induced Transformations of Unactivated Pyridotriazoles

In addition to arylation reactions, 3-aryl pyridotriazoles underwent other visible-light-induced transformations, such as X–H (O–H, N–H, and CO₂–H) insertion reactions of alcohols, amines, and carboxylic acids, without any additives or catalysts, to produce heteroatom-substituted benzylpyridine derivatives 169 (Scheme 41a). Furthermore, 3-aryl-substituted pyridotriazoles also reacted with a variety of alkenes deliver the corresponding [2 + 1] cyclopropanation products 170 (Scheme 41b). Employment of this method for synthesis of biologically important molecules has been demonstrated. This method, however, is limited to C-3 aryl-substituted pyridotriazoles, which have adequate absorption at 390 nm. Other derivatives, such as 3-methyl pyridotriazoles, which are transparent in that area, did not react under these conditions at all. Overall, this method allows for efficiant formation of a broad spectrum of compounds from pyridotriazoles at room temperature in regular glassware without utilizing transition metals, Lewis acids, or harsh reaction conditions.

Scheme 41.

Visible-Light-Induced X–H Insertion and Cyclopropanation of Unactivated Pyridotriazoles

6. SYNTHESIS OF INDOLES FROM BENZOTRIAZOLES

In 2009, the Nakamura group reported the palladium-catalyzed denitrogenative synthesis of polysubstituted indoles from N-aroyl-1,2,3-benzotriazoles and internal alkynes (Scheme 42).⁶¹ 2-Iminobenzenediazonium species 174, formed under thermal decomposition of benzotriazoles 171,⁶² experiences oxidative addition with palladium into intermediates 175/175′ (Scheme 42b). A subsequent migratory insertion of internal alkyne 172 leads to palladacycle 176, and after reductive elimination delivers indole 173. A high reaction temperature (130 °C) was mandatory to induce ring opening of the benzotriazoles. Both the electron-withdrawing group on the N1-atom and the slightly electron-donating group at R² helped stabilize the in situ generated 2-iminobenzenediazonium species 174. A variety of benzotriazoles and internal alkynes smoothly reacted under these conditions to deliver the polysubstituted indoles 173 in moderate to good yields (Scheme 42b). Expectedly, in the case of unsymmetrical internal alkynes, a mixture of regioisomers 173c was observed. Terminal alkynes such as phenyl acetylene yielded only traces amount of product, and N-acetyl-substituted benzotriazole did not react at all. Very recently, Tang published a review on this topic.⁶³

Scheme 42.

Pd-Catalyzed Synthesis of Polysubstituted Indoles

7. CONCLUSIONS

In this Perspective, we have described the recent developments on denitrogenative transformations of pyridotriazoles. Suitably substituted pyridotriazoles undergo ring–chain isomerization to generate the α-diazoimines. The latter can then be trapped or stabilized by transition-metal catalysts, or Lewis and Brønsted acids, to generate the more reactive carbene species, which display diverse reactivity. Pyridotriazoles are surrogates of 1C and (aza)-3C synthons for transannulation, cyclopropanation, insertion followed by rearrangement, and other miscellaneous reactions with suitable nucleophiles, for synthesis of variety of N-containing heterocyclic compounds and beyond. Pyridine-containing biologically important heterocyclic cores can now easily be accessed from the corresponding pyridotriazoles in a one-pot fashion without loss of efficiency, which is a considerable improvement over existing methods. Pyridotriazoles are readily available from pyridyl ketones or aldehydes and hydrazines, as well as from other precursors.

Regardless of the substantial progress made, this chemistry still has room for further development. Some drawbacks include the requirement to utilize activated pyridotriazoles or harsh reaction conditions to induce the ring-opening and generate the reactive α-diazoimines. Recently, these limitations have been partially overcome by using visible light irradiation conditions at room temperature without any additives. In addition, stereo-selective denitrogenative transformations of pyridotriazoles and related compounds are hugely underdeveloped. We are hopeful that this methodology, once fully developed, will find broad applications in synthetic and medicinal chemistry.

Biographies

Dongari Yadagiri was born in Telangana, India. He received his Ph.D. in 2016 from the Indian Institute of Technology (IIT) Madras, India, with Dr. P. Anbarasan. In 2017, he joined the Gevorgyan group at the University of Illinois at Chicago as a postdoctoral fellow. Later, he moved to the University of Texas at Dallas along with his advisor. Here, his work is focused on the development of selective methods for C(sp³)–H functionalizations via photoexcited Pd catalysis, radical chemistry, and light-induced transformation of pyridyl carbenes.

Mónica Rivas was born and raised in Bogotá, Colombia. She received her B.S. from the University of Central Florida. In 2017, she joined the Gevorgyan group at the University of Illinois at Chicago as a Ph.D. student and later at the University of Texas at Dallas. Her work has focused on the development of mild and selective C(sp³)–H functionalization methods.

Vladimir Gevorgyan received his Ph.D. from the Latvian Institute of Organic Synthesis. After two years of postdoctoral research (1992–1994, JSPS- and Ciba-Geigy International Postdoctoral Fellowships) at Tohoku University, Japan, and a visiting professorship (1995) at CNR, Bologna, Italy, he joined the faculty at Tohoku University (Assistant Professor, 1996; Associate Professor, 1997–1999). In 1999, Vladimir moved to USA to join UIC (Associate Professor, 1999; Professor, 2003; LAS Distinguished Professor, 2012). In 2019, he joined the University of Texas at Dallas to become a Robert. A. Welch Distinguished Chair in Chemistry. Vladimir also holds a Professor position at the University of Texas Southwestern Medical Center. His group is interested in the development of novel synthetic methodology, particularly toward biologically relevant molecules.