Dong Wang
email: wangdong@tust.edu.cn

Laurent Désaubry

Gaoyu Li

Mindong Huang

Shixin Zheng

Dr Laurent

Recent Advances in the Synthesis of C2-Functionalized Pyridines

Keywords: Nitrogen heterocycles, Synthetic methods, Nitrogen oxides, C-H activation, Fused-ring systems Scheme 1. Functionalization

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Introduction

Pyridines and quinolines are among the most prevalent heterocyclic structural units in medicinal chemistry and materials science, with numerous bioactive C2-functionalized pyridines and quinolines already identified (Figure 1). Directly functionalizing pyridines is a central challenge in modern synthetic organic chemistry due to the poor selectivity and reactivity associated with the low energy π-system. Despite rapid developments over the past ten years, the direct functionalization of pyridines remains difficult due to the limited number of accessible functional groups (primarily carbon-based) and poor regioselectivity (Scheme 1). [1] In general, these reactions display C2 selectivity, although C4-and C3-functionalized products (2b and 2c, respectively) have been obtained. [2] Moreover, harsh activation conditions are required for increasing pyridine reactivity, such as the use of strong acids for Minisci reactions. One effective approach for addressing these problems involves the use of pyridine N-oxides 1, which are easily accessible and more reactive than pyridines (Scheme 1). The oxygen-directed functionalization of these compounds results in excellent regioselectivity. In addition, numerous activating reagents have been developed that allow the synthesis of C2-functionalized pyridines and quinolines under mild conditions. There are excellent reviews related to the use of activated pyridines and quinolines in heterocycle synthesis. For example, a 2012 review by Charette and coworkers detailed the synthesis of pyridine and dihydropyridine derivatives by selective addition to N-activated pyridines (including N-oxides), [3] and Wang and Zhang published an update on the chemistry of heteroaromatic N-oxides in 2015. [4] Nevertheless, a comprehensive review on the application of N-oxide chemistry to the synthesis of fused pyridine derivatives and functionalization at the C2-benzylic position of pyridine N-oxides is lacking. In addition, there have been notable advancements in the synthesis of simple C2-functionalized pyridines/quinolines from pyridine/quinoline Noxides. Accordingly, an updated and comprehensive review of this field is essential.

This work describes recent advances in the C2-Hfunctionalization of pyridine/quinoline N-oxides as follows: (1) simple C2-H-functionalization, (2) annulation of C3-substituted azine N-oxides, and (3) functionalization at the C2-benzylic position of pyridine/quinoline N-oxides. The significant progress made by Fagnou, He, Larionov, Londregan, Singh, Tomkinson, Wang, Wu, Zhao, and many others are detailed. As reviews related to simple C2-Hfunctionalization are available, only the seminal work published in the past five years and earlier representative achievements are described in this review. The major achievements for the remaining two topics are exhaustively discussed.

Along with the two general reviews concerning Noxide chemistry mentioned above, several types of reactions have been reviewed. Reactions related to Grignard additions were reviewed by Almqvist and colleagues in 2011. [5] Transition-metal-catalyzed functionalization of N-oxides was reviewed by Yan and coworkers in 2014. [6] The photochemistry of N-oxides was reviewed by Poole in 2017. [7] Loska reviewed pyridine N-oxide cycloadditions in 2015 [START_REF] Loska | Targets Heterocycl[END_REF] and 2017 [9] . Quinoline N-oxide alkenylations were reviewed by Kouznetsov and coworkers in 2020. [10]

Synthesis and Reduction

There are a number of commercially available and inexpensive azine N-oxides. Pyridine or quinoline Noxides 3 can be easily prepared by oxidation of the corresponding nitrogen heterocycles with known reagents (Scheme 2). [11] The standard laboratory oxidant for small scale reactions is mCPBA, but column purification is required to remove the 3chlorobenzoic acid byproduct. Hydrogen peroxide is remarkably effective and more commonly used in industry as no purification is needed. Unfortunately, recovering the product from the aqueous phase is difficult due to the good solubility of N-oxides in water. Peroxytrifluoroacetic acid, usually generated in situ by the reaction of urea hydrogen peroxide with TFAA, is practical for electron-deficient nitrogen heteroaromatics. In addition, some pyridine/quinoline N-oxides can be prepared by ring-closing reactions. [4,12] Scheme 2. Common methods for oxidizing pyridines/quinolines and reducing N-oxides.

Non-deoxygenative N-oxide functionalization requires the reduction of product 4 (Scheme 2). Although several reductants are applicable, such as TFAA [13] and Pd/C, [14] the most commonly employed and effective reagent is PCl 3 . [15] Recently, two studies also investigated the visible-light-photocatalyzed deoxygenation of heterocyclic N-oxides. [16] Scheme 3. Selective heteroaryl N-oxidation.

The selective oxidation of N-heteroarenes in the presence of amines was first achieved in 2018. The N-oxides were selectively formed in the presence of more reactive secondary and tertiary amines using an in situ protonation strategy and an iminium salt organocatalyst 8 (Scheme 3). [17] Hilinski's team initially investigated the reaction using traditional peracid oxidants under acidic conditions, but only the undesired tertiary amine oxide was formed. The group then employed trifluoromethyl iminium salt 8, which they previously developed for use in catalytic oxaziridinium-mediated oxidation. Encouragingly, they obtained the desired product 7 in good yield. This method was also successfully applied to the onestep synthesis of quinine N-oxide 7c.

Mechanisms of N-oxide Chemistry

N-oxide chemistry has evolved with modern organic chemistry, resulting in the discovery of novel heterocyclic N-oxide reactions. There are primarily four mechanisms governing the C2-functionalization of pyridine/quinoline N-oxides (Scheme 4). Reissert discovered the first path in 1905. [18] The coordination of an activating agent to the N-oxide enhances the electrophilicity of the C2 position in 9, allowing nucleophilic attack and subsequent deprotonation/aromatization to give the C2substituted product 11 (Scheme 4A). Numerous Reissert-type reactions have been explored since 1905 and the synthesis remains popular to this day. The next reaction path for the C2-functionalization of N-oxides was identified by Hamana and coworkers in 1983. [19] Pyridine/quinoline N-oxides are natural 1,3dipoles, making them viable substrates for dipolar cycloaddition to a wide variety of unsaturated carbon-carbon or carbon-heteroatom bonds (Scheme 4B). However, the low reactivity of these N-oxides, likely due to the stability of the aromatic system, renders them capable of reacting only with strong, electron-deficient dipolarophiles or highly reactive ones, such as benzyne. The cycloaddition product 12 is generally unstable owing to the disruption of aromaticity, and restoration of the conjugated system drives cleavage of the N-O bond to afford 13.

In 2005, Fagnou and coworkers reported a novel direct arylation of pyridine N-oxides catalyzed by Pd(OAc) 2 , [14] which has attracted considerable attention. The aryl-palladium intermediate 14 forms via coordination of the palladium atom to the N-oxide and subsequent electrophilic attack at the C2 carbon atom (Scheme 4C). Transfer of the functional group onto 14 produces 15, which is converted to 4 via reductive elimination. [20] Minisci reactions, in which radicals add to pyridines under oxidizing and strongly acidic (usually TFA) conditions, are an effective method for the direct functionalization of pyridines. [21] Although this approach has undergone extensive development, it is primarily limited to the used of carbon-based radicals, such as alkyl, acyl, and aryl radicals. [21b, 21c] Wu's group recently reported the synthesis of 2acetoxylated quinolines under oxidizing conditions via Cu-catalyzed radical addition to quinoline Noxide. [22] This displayed a fourth reaction path, Minisci-type reactions, for the C2-functionalization of N-oxides (Scheme 4D). Notably, metal catalysis is not essential for the reactions, and several methods can be used for quenching the radical cation species 16 to afford product 4 or 5. This novel reaction class is superior to standard Minisci reactions as a variety of radicals can be employed, likely due to the lower activation energy of the N-oxide reagents. In addition, the reaction is amenable to a wider substrate scope since it is performed under neutral conditions. Scheme 4. Primary reaction mechanisms for pyridine/quinoline N-oxide reactions.

Simple C2-H-Functionalization

Various functional groups have been introduced at the C2 position of pyridines/quinolines in high efficiency under mild conditions. The reactants and activating reagents used for deoxygenative functionalization are summarized in Table 1.

P/Q NOs PyBroP R 1 R 2 NH Q NOs HP(O)(O i Pr) 2 R 1 R 2 R 3 N Q NOs HP(O)(OEt) 2 R 1 R 2 NH P/Q NOs TFAA DABCO then NuH Q NOs Tf 2 O R 1 R 2 NH Q NOs CuCl b PhCO 2 N R 1 R 2 6 -NHR Q NOs AgBF 4 b RNCS P/Q NOs - RCON 3 7 -NHAr P/Q NOs CH 3 CN + ArN 2 BF 4 8 -NHC(O)R Q NOs (COCl) 2 RC(O)NH 2 Q NOs BAIL-1
[c] BAIL-1 is 1-(1- propylsulfonic)-3-methylimidazolium chloride.

Halogenation

A regioselective C2-bromination/chlorination of quinoline N-oxides under mild conditions was presented by Baran and coworkers in 2013 (Scheme 5). [23] This method employs tosic anhydride as the activating agent and tetra-n-butylammonium halide as the nucleophilic halide source. Although the regioselectivity is excellent, the highly dilute conditions (0.01 M) render this method impractical. To eliminate the use of activating agents in conventional Reissert-type reactions, our group successfully employed the Vilsmeier reagent as both the activator and nucleophilic halide source, resulting in a highly practical method for the regioselective halogenation of fused heterocyclic N-oxides, including quinolines, isoquinolines, and diazine Noxides (Scheme 6). [24] In contrast to conventional methods that require large volumes of POX 3 (usually as solvent), only a stoichiometric quantity is needed. Initial coordination of the in situ-generated Vilsmeier reagent to N-oxide 19 afforded the activated quinoline complex 22, which is converted to a quaternary ammonium salt 23 via intramolecular nucleophilic attack by the halide. Subsequent rearomatization affords the desired 2-halogenoarenes 20 or 21 and DMF, which proceeds into the next catalytic cycle. The regioselectivity of this reaction was found to be excellent for chlorides and moderate for bromides. Scheme 6. C2-halogenation of quinoline N-oxides under mild conditions. This strategy was used by two other groups. In 2015, Amgen scientists reported a highly efficient and regioselective halogenation of unsymmetrical pyridine N-oxides (24) under mild conditions (Scheme 7). [25] The C2/C6 regioselectivity is excellent, with the halide being incorporated at the electron-deficient side of most substrates. Compound 24 is first activated by oxalyl chloride. The C2 proton of the resulting pyridinium chloride 25 is extracted by triethylamine to generate a highly reactive carbene intermediate 26, which reacts with a halide anion to afford products 27 or 28. This transformation could also be performed at room temperature with similar regioselectivity but slightly lower yields. Guo and coworkers reported a regioselective chlorination of quinoline and isoquinoline N-oxides using PPh 3 /CCl 3 CN in refluxing toluene (Scheme 8). [26] Despite using several common brominating agents, no bromination products were obtained. Due to the low reactivity of the fluoride anion, the direct fluorination of aromatics and heteroaromatics remains problematic. Avid Radiopharmaceuticals developed a facile synthesis of 2-fluoropyridines via 2-pyridyltrialkylammonium salts 29 generated from N-oxides 3 (Scheme 9). [27] This method benefits from the simplified preparation and separation of 29, which was limited in previous methods.

Amination

Both deoxygenative and non-deoxygenative aminations of pyridine/quinoline N-oxides have been reported. Activating reagents or electron-deficient dipolarophiles are typically required for deoxygenative aminations, whereas transition-metal catalysts are commonly used for non-deoxygenative aminations.

2.2.1

Organic Reagent/Base-Promoted Deoxygenative Amination

In contrast with C2-halogenation, C2-amination of pyridines or quinolines is challenging due to the competitive reaction between the amine and activating agent. Merck scientists successfully solved this problem using an attenuated ammonia surrogate, t BuNH 2 , which retained the capacity to be deprotected (Scheme 10). [28] However, the specificity of this amine substrate is too limited to find broad applicability.

Scheme 10. One-pot amination of pyridine/quinoline Noxides.

Scheme 11. C2-amination of 3,5-disubstituted pyridine Noxides.

Similarly, inexpensive and commercially available saccharin was employed by Amgen scientists for the regioselective amination of unsymmetrical 3,5disubstituted pyridine N-oxides (24, Scheme 11). [29] In situ deprotection under acidic conditions allows for a one-pot process.

Phosphorous-based activating reagents are particularly attractive because the formation of the P=O bond provides a strong thermodynamic driving force for the reaction. In 2010, Londregan and colleagues at Pfizer identified PyBroP, a commercially available phosphonium salt, as an excellent activating reagent for the amination of both pyridine and quinoline N-oxides with a variety of amines (Scheme 12). [30] The reaction likely proceeds via the activated pyridine complex 36. Nucleophilic attack of the amine at the C2 position of 36 yields 37. Base-mediated rearomatization affords the desired 2aminopyridine 35 and phosphoryltripyrrolidine, the only significant organic byproduct of the reaction. It should be noted that PyBroP is a universal activating reagent for the functionalization of N-oxides and has been widely used for reactions with various nucleophiles, including amines, phenols, sulfonamides, sulfoximines, malonates, pyridones, thiols, and silyl ketene acetals. Scheme 12. General method for the mild C2-amination of pyridine and quinoline N-oxides.

Another notable phosphorous-based activating agent was developed by Zhao's group and used for the synthesis of a series of 2-(dialkylamino)quinolines through the direct reaction of quinoline N-oxides with trialkylamines in the presence of diisopropyl H-phosphonate 38 and CCl 4 (Scheme 13). [31] This activating reagent is more efficient than PyBroP for the synthesis of (dialkylamino)quinolines, but cannot be used with pyridine N-oxides or primary amines. This group extended the substrate scope to include ammonia, a variety of primary and secondary amines, and reactive methylene compounds. The use of such a wide range of nucleophiles was enabled by activation with diethyl H-phosphonate 44 and K 2 CO 3 in CCl 4 and DMF (Scheme 14). [32] The method has proved less effective for pyridine N-oxides and large excesses of amines are required. Notably, the C4aminated product (43e) predominates when pyridine N-oxide substrates are employed.

Introduction of piperazine to the C2 position of pyridines/quinolines is desirable as several bioactive pyridine/quinoline derivatives contain this functionality. Using a similar strategy to that of Avid Radiopharmaceuticals, [27] Karchava's team developed a simple, one-pot synthesis of piperazinefunctionalized 49 and 51. Under the activation of TFAA, initial reaction of N-oxides 3 with DABCO followed by in situ treatment of the resultant 2pyridyltrialkylammonium salts 48 or 50 with nucleophiles provides the desired ring-opening products (Scheme 15). [33] The amination of quinoline N-oxides with various amines was also realized under the activation of trifluoromethanesulfonic anhydride (Tf 2 O). [34] Scheme 15. One-pot synthesis of substituted N-(2-pyridyl) -N′-ethylpiperazines.

He's group recently reported a non-Reissert-type synthesis of 2-aminoquinolines 52 via AgBF 4catalyzed 1,3-dipolar cycloaddition with isothiocyanates (Scheme 16). [35] This reaction is unfortunately not amenable to pyridine N-oxides. In 2020, Kim's group described a similar transformation with isocyanate via a Curtius rearrangement from the starting acyl azide (Scheme 17). [36] Despite the harsh reaction conditions, this reaction is applicable to pyridine N-oxides, as well as more complex molecules, such as quinidine and fasudil, with products obtained in moderate yields.

Scheme 18. Three-component reaction of N-oxides, aryldiazonium salts, and acetonitrile. Sharma's group disclosed a microwave-assisted synthesis of 2-anilinoquinolines 59 via threecomponent reaction (Scheme 18A). [37] Aryldiazonium tetrafluoroborate 58 reacted with acetonitrile under microwave heating to produce 60, which then underwent [3+2] cycloaddition with 3 to provide 61. Interestingly, 2-arylquinoline N-oxides 63 afforded 3hydroxy-2-arylquinolines 64 under the identical reaction conditions (Scheme 18B). The reaction may proceed through intermediate 61, which on 1,3oxygen transfer followed by rearomatization gave 66.

Metal-Catalyzed Amination

In 2013, Li's team conducted Cu(II)-catalyzed reactions for the amination and amidation of quinoline N-oxides in refluxing benzene (Scheme 19A). [38] Ag 2 CO 3 was used to oxidize the generated CuOAc into the active catalyst. Utilizing O-benzoyl hydroxylamines as the nitrogen source, the same catalyst system was also successfully applied to the synthesis of 68 at lower temperatures (Scheme 19B). [39] Cu(I)-catalyzed amination under milder conditions was also developed, which included atmospheric oxidation of the Cu(I) catalyst to the active Cu(III) complex (Scheme 20). [40] Deoxygenative amination through metal catalysis is also reported (Scheme 21). [41] Notably, DCE serves as both the solvent and reductant in this transformation. O-benzoyl hydroxylamine 73 was reduced by Cu + to generate an aminyl radical, which reacted with 19 to produce intermediate 74. Subsequently, 74 underwent the reaction with DCE to give 75, which released ClCH 2 CHO to form radical 76. Finally, 76 was oxidized by Cu 2+ and further rearomatized to afford 43. Patel's group reported another Cu(I)-catalyzed deoxygenative amination of quinoline N-oxides with N-(2-(arylthio)aryl)cyanamides through an autoreduction process. [42] Scheme 19. Cu-catalyzed amination/amidation of quinoline N-oxides with cyclamines/lactams or O-benzoyl hydroxylamines.

Scheme 20. Cu-catalyzed amination with secondary amines.

Scheme 21. Cu-catalyzed deoxygenative amination with O-benzoyl hydroxylamines. Note: this reaction mechanism is suggested based on our understanding and, thus, slightly differs from the original paper.

Amidation

N-acylated 2-Aminopyridines and 2-Aminoquinolines

Isocyanate was first shown to be a suitable reagent for the C2-amidation of quinoline/isoquinoline Noxides by Couturier and coworkers in 2006 (Scheme 22). [43] In this reaction, isocyanate 79, generated via an in situ reaction between the primary amide and oxalyl chloride, undergoes 1,3-dipolar cycloaddition with quinoline N-oxide 19, followed by decarboxylative aromatization of the adduct to give 81. Unfortunately, the strongly acidic conditions and long reaction times (typically > 20 h) greatly limit the application of this reaction. The Tf 2 O-promoted amidation of pyridine, quinoline, and isoquinoline N-oxides with secondary amides in the presence of 2-fluoropyridine as the base was developed by Medley and Movassaghi in 2009 (Scheme 23). [44] Interestingly, mechanistic studies suggested the formation of a nitrilium ion 84. Scheme 23. C2-amidation of pyridine/quinoline N-oxides with secondary amides.

He's group developed a facile and eco-friendly approach for the production of various N-acylated 2aminoquinolines from quinoline N-oxides and nitriles in acidic ionic liquid (Scheme 24). [45] Beneficially, the ionic liquid could be recycled for several reactions. A similar amidation of quinoline N-oxides can be achieved by heating at high temperatures in TsOH rather than acidic ionic liquid. [46] Notably, He's group reported another efficient protocol operating through a radical activation pathway, with nitriles used as the amide source and methyl carbazate as both the radical activating reagent and oxygen source (Scheme 25). [47] First, methyl carbazate was oxidized by Selectfluor to generate a carbon-centered ester radical with the release of molecular nitrogen, HF, and tetrafluoroborate. The ester radical reacted with 19 to produce a radical intermediate, 87, which was further oxidized to give a quinolinium intermediate, 88. Subsequent transformations would afford 81. Although the previous three methods are facile and efficient, the high-temperature conditions render them impractical for complex molecules. Scheme 25. Amidation of quinoline N-oxides with nitriles via radical activation. Note: this reaction mechanism is suggested based on our understanding and, thus, slightly differs from the original paper.

Scheme 26. Cu-catalyzed amidation of quinoline N-oxides.

Cu(I)-catalyzed non-deoxygenative amidation of quinoline N-oxides was efficiently achieved with hydrazinecarboxamides 91 and TBHP (Scheme 26). [48] Scheme 27. Amidation of pyridine N-oxides with dialkylcyanamides.

Kukushkin and coworkers reported the synthesis of useful pyridine-2-yl substituted urea, 96, via a 1,3dipolar cycloaddition pathway utilizing pyridine Noxides 1 and dialkylcyanamides 95 under acidic and solvent-free conditions (Scheme 27). [49] Notably, the C5-functionalized product, 100, predominated when the reaction was performed with 2-methoxypyridine N-oxide. This method was later applied to the synthesis of pharmaceutically privileged oxadiazole-substituted urea, 102 (Scheme 28). [50] All the synthesized targets had cLogP values of <3, which complies with the "lead-like" criteria. In 2019, He's team disclosed the Cu-catalyzed synthesis of quinolin-2-yl substituted ureas in water (Scheme 29). [51] which was initiated by a [3+2] cycloaddition between quinoline N-oxides and carbodiimides. The reaction is exceptionally green because it involves 100% atom economy, water as solvent, and easy operation.

Sulfoximination and Sulfonamidation

In 2016, Bolm's group developed a nondeoxygenative sulfoximination of quinoline N-oxides with NH-sulfoximines (Scheme 30). [52] The process is catalyzed by CuBr in air and proceeds by dual C-H/N-H activation. However, this reaction is not applicable to pyridine N-oxides. Scheme 30. Cu-catalyzed sulfoximination of quinoline Noxides.

The deoxygenative sulfoximination of both pyridine and quinoline N-oxides was achieved by Singh's team under PyBroP activation conditions (Scheme 31). [53] The reaction conditions were also suitable for use with enantiopure substrates and furnished products without any racemization. In addition, the method was successfully applied to the sulfoximination of azine-based functional molecules, such as 2,2′-bipyridine, 1,10-phenanthroline, and quinine. The nucleophilic addition of sulfonamides had not been achieved until recently because of the poor nucleophilicity of these compounds. Bao's group developed a new method to synthesize quinoline sulfonamides 111 from quinoline N-oxides, sulfonamides, PhI(OAc) 2 , and PPh 3 (Scheme 32). [54] The method is applicable to a variety of quinoline Noxides and sulfonamides. Sulfonamides react with PhI(OAc) 2 to produce sulfonyl imino iodo arene 112 and acetic acid. Ni-catalyzed sulfonamidation using Nfluorobenzenesulfonimide (NFSI, 95) as the amidating reagent was an efficient method described by Wu's group in 2019 (Scheme 33). [55] Two tentative reaction mechanisms were proposed based on control experiments. Interestingly, the 1,2dihydro-2-iminoquinoline products, 111 ′ , are tautomers of 2-sulfonylaminoquinolines 111. Scheme 33. Ni-catalyzed sulfonamidation of quinoline N-oxides.

Hydroxylation

Traditional methods for synthesizing 2-pyridones and 2-quinolinones 120 involve refluxing N-oxides in acetic anhydride and hydrolyzing the resulting acetylated products. Our group developed a mild and efficient alternative, employing sodium acetate, water, and PyBroP as the activating agent (Scheme 34). [56] Notably, this method has a wide substrate scope, including both electron-rich and electron-poor quinolines, pyridines, and isoquinolines. He's group later described an efficient, rapid, and environmentally benign route to 2-quinolinones 122 that relies on the activation of quinoline N-oxides by MsCl in water. The desired products crystallized in situ and were isolated via simple filtration to afford analytically pure compounds without the need for further purification (Scheme 35). [57] Nevertheless, this method is ineffective for pyridine and quinoxaline Noxides.

Scheme 35. Aqueous synthesis of 2-quinolinones.

Wu and coworkers serendipitously identified a unique pathway involving azodicarboxylates. Based on several carbonylative transformations with diethyl azodicarboxylate catalyzed by palladium, they assumed that the carbonylation product 123 (Scheme 36) should be formed. However, 2-quinolinones 122 were produced, with DIAD acting as both the activating agent and the oxidant in the Pd(II)catalyzed transformation of quinoline N-oxides. [58] Intermediate 124 was oxidized by either air or DIAD to generate radical cation 125, which reacted with the carboxylic radical generated in situ from the decomposition of DIAD. Importantly, the reaction proceeded under mild conditions and without the need for a dry or inert environment.

Scheme 36. PdCl 2 -catalyzed synthesis of 2-quinolinones. Note: this reaction mechanism is suggested based on our understanding and, thus, slightly differs from the original paper.

Alkoxylation and Aryloxylation

In 2011, Londregan and colleagues reported a mild, one-pot synthesis of 2-aryloxypyridines 129 from pyridine N-oxides and phenols (Scheme 37A). [59] The conditions were identical to their previous amination method, [30] with PyBroP used as the activating agent. The group later reported the synthesis of 2alkoxypyridines 130 by reaction of non-aromatic alcohols with N-oxides (Scheme 37B). [60] Minimal product was obtained using the conditions employed for the synthesis of 2-aryloxypyridine. However, changing the base from DIPEA to sodium carbonate resulted in a dramatic improvement in the yield, likely due to an increase in the lifetimes of both PyBroP and the activated intermediate 36 (Scheme 12). A similar strategy using silver carbonate allowed for the introduction of fluoroalkoxy groups onto quinolines, isoquinolines, and pyridines (Scheme 38). [61] Two byproducts, viz. 2-bromoquinoline and 2quinolinone, were detected when DIPEA was used as the base. Yield was improved dramatically upon switching the base to sodium carbonate. The best yield was obtained when silver carbonate was used as the base, which suppressed the formation of 2bromoquinoline by forming a precipitate with the bromide ion derived from PyBroP. The 2-quinolinone byproduct was suppressed by using molecular sieves. This is a promising strategy as the addition of fluorinated groups can improve the lipophilicity, bioavailability, and metabolic stability of organic molecules, which is highly significant for preclinical drug development. Tomkinson's team developed a three-component reaction involving electron-deficient pyridine Noxides, acyl chlorides, and cyclic ethers in the presence of triethylamine to afford 2-alkoxylated pyridines 134 in low to medium yields (Scheme 39). [62] This system employs the cyclic ether as both the reactant and solvent and is proposed to occur via formation of carbene intermediate 136.

Scheme 39. Alkoxylation of pyridine N-oxides with cyclic ethers and acyl chlorides.

Sulfonylation

Metal-Catalyzed Sulfonylation

In 2013, Wu's group showed that CuI could catalyze the non-deoxygenative sulfonylation of quinoline N-oxides using aryl sulfonyl chlorides (Scheme 40). [63] Both electron-rich and electron-poor phenyl sulfonyl chlorides are compatible with this process. However, the reaction is not amenable to pyridine/pyrazine/pyrimidine N-oxides. Unlike the above-mentioned Cu(I)-catalyzed nondeoxygenative sulfonylation, deoxygenative sulfonylation occurs in the presence of Cu(II)catalysts or oxidizing reagents. Pan's group introduced a unique, regioselective, Cu-catalyzed deoxygenative sulfonylation of quinoline N-oxides using sodium sulfinates 142 in the presence of the radical initiator K 2 S 2 O 8 (Scheme 41). [64] Electron-rich aromatic sulfinates generally performed better than electron-poor reagents. Mechanistic studies suggest that the reaction proceeds through a Minisci-type radical coupling step involving a sulfonyl radical, 144, formed via the Cu(II)-or K 2 S 2 O 8 -mediated oxidation of sodium sulfinate, 142. Quinoline displayed expectedly poorer reactivity, being unable to react under the standard conditions in control experiments. FeCl 3 and TBHP were also successfully employed for the deoxygenative sulfonylation of quinoline Noxides (Scheme 42). [65] Wang's group enabled the same transformation by generating a sulfonyl radical, 149,

through the reaction of DABSO [DABCO•(SO 2 ) 2 ]
and aryldiazonium tetrafluoroborate using Cu(I) salt as a catalyst (Scheme 43). [66] Scheme 41. Cu-catalyzed deoxygenative sulfonylation of quinoline N-oxides. Iron (III)-catalyzed, oxidant-free reactions at higher temperatures are possible for deoxygenative sulfonylation (Scheme 44). [67] These reactions include a broad range of substrates and proceed with good regioselectivity and functional group tolerance. In general, sodium arylsulfinates bearing electrondonating substituents showed superior reaction efficiency to those substituted with electronwithdrawing groups. Unfortunately, aliphatic sodium sulfinates were found to be unsuitable under the current conditions. Although the reaction mechanism is not fully understood, mechanistic studies suggest a non-radical pathway.

Scheme

44.

Iron-catalyzed, regioselective arylsulfonylation of quinoline N-oxides.

Organic Reagent/Base-Promoted Deoxygenative Sulfonylation

Zhao's group developed a procedure superior to high-temperature, metal-catalyzed sulfonylation for building a large variety of both 2-(aryl/alkyl sulfonyl)pyridines and 2-(aryl/alkyl sulfonyl)quinolines. Their method employed the direct C-H functionalization of pyridine/quinoline Noxides with sulfonyl chlorides or sodium sulfinates by activation with H-phosphonates at ambient temperatures (Scheme 45). [68] Remarkably, the Hphosphonates play a dual role in the reaction, generating both the functioning activating agent, diisopropyl chlorophosphate (39), and the sulfonyl anion, 154. Another efficient metal-free sulfonylation was accomplished using N-oxides and sulfonyl hydrazides through activation by hypoiodite, generated in situ from NaI and TBHP (Scheme 46A). [69] Unfortunately, the reaction is not effective for most pyridine Noxides. One alternative to this method uses iodine and H 2 O 2 to induce the rapid sulfonylation of N-oxides (Scheme 46B). [70] A gram-scale reaction was conducted through this route and resulted in only a slight loss of product. A similar transformation, but without in situ generation of a sulfonyl anion, was achieved through a direct reaction with sodium sulfinates in the presence of I 2 and TBHP at room temperature (Scheme 47A). [71] Interestingly, Zhao's group found that this reaction could even be performed without TBHP. Moreover, I 2 is an effective activating agent and can be regenerated by air oxidation of the iodide ion produced in the reaction (Scheme 47B). [72] Scheme 47. Iodine/(TBHP)-promoted sulfonylation of Noxides with sodium sulfinates. Scheme 48. Ultrasound-accelerated sulfonylation of quinoline N-oxides in water.

In 2017, an efficient, ultrasound-accelerated onepot synthesis of 2-sulfonylquinolines in water was developed by He's group (Scheme 48). [73] Ultrasound irradiation aided in the zinc-dust-mediated reduction of the sulfonyl chloride to a zinc bissulfinate compound, 164. Quinoline N-oxide 19 coordinates with 164 to generate the reactive intermediate, 165, which undergoes intramolecular nucleophilic addition to form the sulfonated product, 143, with subsequent release of zinc hydroxide. Compared with conventional heating conditions, the ultrasoundassisted techniques improved efficiency and minimized side reactions. The group later reported a TsCl-promoted aqueous sulfonylation that proceeds via the traditional Reissert-type mechanism (Scheme 49). [74] Beneficially, this reaction is suitable for both alkyl and aryl sulfinates.

Scheme

49.

TsCl-promoted sulfonylation of quinoline/pyridine N-oxides.

He's team also developed a Minisci-type reaction for the sulfonylation of quinoline N-oxides with sodium sulfinates (Scheme 50). [75] Sodium sulfinates 166 play a dual role of the sulfonylation source and the activating reagent. Mechanistic studies suggest that the in situ generation of sulfonyl radicals 149 is a key factor in obtaining the deoxygenative sulfonated products. In contrast, the similar reaction developed by Pan's team allowed for lower temperature conditions but necessitated the use of CuBr 2 as a catalyst (Scheme 41). [64] Scheme 50. Metal-free deoxygenative sulfonylation of quinoline N-oxides.

Sulfonyl radicals 149 have been generated and employed in two additional methods. Visible-lightinduced deoxygenative C2-sulfonylation of quinoline N-oxides with sulfinic acids was described using an organic dye, 171, as the catalyst (Scheme 51). [76] The generation of 149 using this method is eco-friendly and mild, employing ambient air as the sole oxidant. Xia's group developed a three-component sulfonylation using quinoline N-oxides, sodium metabisulfite, and aryldiazonium tetrafluoroborates 172 to provide C2-sulfonylated products 169 in moderate to good yields (Scheme 52). [77] The aryldiazonium tetrafluoroborates decompose to generate an aryl radical, which subsequently attacks Na 2 S 2 O 5 to give sulfonyl radical 131. Electrochemistry is an emerging, environmentally benign strategy for modern organic synthesis as no oxidant or reductant is required. One application of this technology is exemplified by Lei's sulfonylation of quinoline N-oxides using sodium sulfinates via a Minisci-type mechanism (Scheme 53). [78] Sodium sulfinates 142 act as both the sulfonylation source and the activating agent.

Alkylation

Metal-Catalyzed Non-Deoxygenative Alkylation

In 2013, Fu's group reported a Pd-catalyzed alkylation of pyridine/quinoline N-oxides using secondary, and even tertiary, alkyl bromides (Scheme 54). [79] The reaction is convenient but requires two Noxide equivalents.

Scheme 54. Pd-catalyzed alkylation of quinoline/pyridine N-oxides with alkyl bromides.

Another Pd-catalyzed system was developed by Wu's group utilizing ethers or thioethers as both the reactant and solvent and TBHP as an oxidant (Scheme 55). [80] Interestingly, Pd(III) species 178 are formed via reaction of 176 with radical 177, which is generated in situ through TBHP-initiated hydrogenatom abstraction.

Scheme

55.

Pd-catalyzed C2-alkylation of quinoline/pyridine N-oxides with ethers.

Scheme

56.

Cu-catalyzed C2-alkylation of quinoline/pyridine N-oxides with N-tosylhydrazones.

N-tosylhydrazone is an efficient alkylating reagent for Cu-catalyzed reactions under basic conditions and high temperatures (Scheme 56). [81] Diazo compound 181 is generated in situ from N-tosylhydrazone 179 in the presence of t BuOLi. Notably, copper-carbene species 183 are produced by the reaction of 181 and metalated intermediate 182. Migratory insertion of C2-carbon to the carbenic carbon produces 184, which upon protonation affords 180 and regenerates the CuI catalyst.

A photoredox-catalyzed direct C2-alkylation of pyridine N-oxides using alkyltrifluoroborate and hypervalent iodine(III) oxidant (BIOAc) under acidic conditions was developed by Xu's group in 2017 (Scheme 57A). [82] The mild reaction proceeds by a Minisci-type mechanism and was successfully applied to the synthesis of the antifungal ciclopirox (Scheme 57B).

Scheme

58.

Ni-catalyzed C2-alkylation of quinoline/pyridine N-oxides with cyclobutanone oximes.

A nickel-catalyzed direct C2-H cyanoalkylation of heteroaromatic N-oxides with cyclobutanone oximes was reported by Guo and coworkers (Scheme 58). [83] Mechanistic studies suggest the formation of a radical intermediate, 196, and single-electron transfer from the Ni complex.

Organic Reagent/Base-Promoted Alkylation

In 2015, Wang and coworkers developed a novel and efficient radical addition of ethers to pyridine Noxides in the presence of TBHP (Scheme 59). [84] A similar approach was reported with quinoline Noxides. [85] Peroxide 202 was employed as a methyl radical precursor for the alkylation of both pyridine and quinoline N-oxides, resulting in the formation of both monomethylated and dimethylated products (203 and 204, respectively) from pyridine substrates (Scheme 60). [86] Scheme 59. Alkylation of pyridine N-oxides with ethers. Scheme 60. Methylation of pyridine/quinoline N-oxides with peroxide.

Pyridine N-oxides can also be alkylated by the traditional Reissert-type mechanism. One such example is the synthesis of α-(2-azaheteroaryl) acetates 207 or 209 from the reaction between 1 and silyl ketene acetals 206 or 208, respectively, activated by PyBroP (Scheme 61). [87] It should be noted that the hexafluorophosphate counteranion of PyBroP is an important reaction component as it initiates the silicon-oxygen cleavage necessary for ketene acetal addition. Another example of a Reissert-type alkylation is the one-pot, three-component synthesis of α-pyridyl, α-substituted amino acid derivatives 212. Readily available azlactones 210 were chosen as appropriate nucleophiles for the activated pyridine N-oxides because their pK a values were similar to those of the carbon acids or phenols studied by Londregan. The reaction proceeds via TsCl-activated direct alkylation of pyridine N-oxides with 210 and subsequent ring opening with diverse nucleophiles (Scheme 62). [88] Notably, the regioselectivity favors the C4 isomers for pyridine and 3-methylpyridine N-oxides.

Alkenes have also been used for pyridine N-oxide alkylations. Sharma and coworkers reported the first example with the synthesis of quinoline-substituted α-hydroxy carboxylic derivatives 213 from the reaction of quinoline N-oxides with electron-deficient olefins under catalyst-and solvent-free conditions at elevated temperatures (Scheme 63). [89] The reaction proceeds through 1,3-dipolar cycloaddition, followed by cleavage of the N-O bond. Competition experiments with electronically distinct quinoline Noxides suggested that electron-rich N-oxides are favored.

Scheme 63. Alkylation of quinoline N-oxides with alkenes.

The photocatalyzed alkylation of pyridine N-oxides with neutral alkenes was later reported by Murakami and coworkers (Scheme 64). [90] The coupling step was initiated by the radical cation intermediate, 215, generated by photoirradiation of an alkene in the presence of a photocatalyst. This strategy was successfully applied to reactions between various Noxides and alkenes, yielding pyridines with benzyl and secondary alkyl groups at the ortho position. Interestingly, when a similar visible-light-catalyzed system was applied to alkynes and pyridine N-oxides, either the alkylated product 218 or the acylated product 219 was obtained in moderate to excellent yields, depending on whether the reaction was performed under an inert atmosphere (Scheme 65). [91] The reaction under nitrogen proceeds via mechanism similar to the one for the reaction with alkenes. In an atmosphere of O 2 or air, singlet oxygen is produced via energy transfer between the light-excited photocatalyst and 3 O 2 . Then, the enol form, 218, of the alkylation product reacts with 1 O 2 to yield 220, which collapses to afford 219 and the carboxylic acid byproduct. More recently, Zhou's team presented a visiblelight-induced alkylation of heterocyclic N-oxides with N-hydroxyphthalimide esters 221 using organic dye Eosin Y as the photocatalyst (Scheme 66). [92] Remarkably, this transformation is amenable to a wide range of primary, secondary, and tertiary alkyl groups and is applicable to several complex heterocyclic N-oxides. In 2016, an unprecedented, base-promoted deborylative primary alkylation of N-oxides with 1,1diborylalkanes was reported by Cho's group (Scheme 67). [93] The yield was higher for quinoline and pyridine substrates than for isoquinoline and quinoxaline substrates. The α-boryl carbanion intermediate, 225, is initially generated by the reaction of a 1,1-diborylalkane with MeONa. Later, the same group disclosed a secondary alkylation protocol through a similar approach at higher temperatures. [94] Kim and coworkers employed Wittig reagents for the alkylation of N-oxides (Scheme 68). [95] Although the reaction requires a strong base and high temperatures, it proceeds well with both excellent positional-selectivity and functional-group compatibility. Phosphonium ylide was generated, which subsequently underwent intermolecular

Alkenylation

In 2008, Chang's group developed a Pd(OAc) 2catalyzed non-deoxygenative method for the alkenylation of pyridine N-oxides using silver carbonate as the oxidant (Scheme 69A). [15a] While this method is efficient, its requirement for a large excess of N-oxides renders it impractical. The arylation of pyridine N-oxides with unactivated arenes like benzene is also realized under similar conditions, while a large excess of arenes (40 equiv) is required. Another Pd-catalyzed alkenylation is Poli's reaction with allyl acetate, which proceeds via an allylation/isomerization cascade to generate products 231 in low to moderate yields (Scheme 69B). [96] When cinnamyl acetate 230b is used, the same catalytic system promotes C2-cinnamylation of pyridine N-oxides without subsequent isomerization. Considering N-oxides as prototypical oxidants, Wu and coworkers developed a Pd-catalyzed deoxygenative alkenylation of quinoline N-oxides that eliminates the use of external oxidants and ligands (Scheme 70). [97] Using this approach, quinoline N-oxide, and derivatives bearing electrondonating methyl groups at positions 3, 4, and 6, were smoothly alkenylated with acrylate at the C2 position in high yields. In contrast, electron-withdrawing substituents reduced the reactivity, and no desired product was obtained using 4-nitroquinoline-N-oxide as the substrate. Notably, the catalyst plays a direct role in deoxygenative functionalization, the final step of which involves the oxidation of palladium hydride by N-oxide intermediate 236. In 2017, the same group reported an I 2 -catalyzed alkenylation of azaheterocycle N-oxides, including quinoline, isoquinoline, and quinoxaline N-oxides (Scheme 71). [98] Interestingly, the HI and HIO generated in the last step react to regenerate iodine for the next catalytic cycle.

The alkenylation of N-oxides can also be achieved under acidic conditions. In 2016, Wang and coworkers reported the synthesis of 2alkenylquinoline 242 by AcOH-promoted reductive olefination of quinoline N-oxide (Scheme 72). [99] The protocol relies on a thermally promoted [3+2] cycloaddition between an N-oxide and an alkene to generate an isoxazolidine 243. The Brønsted acid then promotes N-O cleavage and dehydration to afford the target compound, 242. Catalytic TsOH•H 2 O has also been employed for this transformation (Scheme 73). [100] Scheme 72. AcOH-promoted C2-alkenylation of quinoline N-oxides. Scheme 73. Acid-catalyzed C2-alkenylation of pyridine, quinoline, and isoquinoline N-oxides.

Scheme 74. Lewis-acid-catalyzed alkenylation of quinoline N-oxides.

In 2017, Liang's group reported an efficient, Lewis-acid-catalyzed synthesis of medically valuable 2-(quinolin-2-yl)prop-2-en-1-ones 248 via dehydrogenative coupling of propargylic alkynols 247 with quinoline N-oxides (Scheme 74). [101] Importantly, the reaction was efficiently scalable to gram quantities.

Arylation

Pd(OAc) 2 / t Bu 3 P was identified as an effective system for the coupling of N-oxides and phenyl bromides by Fagnou in 2005 (Scheme 75). [14] Although the reaction is efficient, four equivalents of N-oxides are required. Improved methods have been developed, including the coupling of N-oxides with unactivated arenes [15a] and aryl or alkenyl tosylates and mesylates. [102] Wei developed another Pdcatalyzed system for the arylation of pyridine Noxides using potassium aryl-and heteroaryltrifluoroborates 254 (Scheme 76). [103] Importantly, this method provides the desired biaryl products in moderate to high yields with good functional group tolerance and high regioselectivity. The mechanism involves ortho-C-H activation, transmetalation, and reductive elimination. Additional metal-catalyzed direct arylations of Noxides have been described. Cu-catalyzed deoxygenative C2-arylation of pyridine N-oxides with arylboronic esters 258 was reported in 2014 (Scheme 77). [104] In contrast to the above examples, which use a large excess of N-oxides, this reaction requires an excess of the coupling partner 258 (2 equiv). The mechanism may involve arylation of the pyridine N-oxides with arylboronic esters followed by deoxygenation of the resultant arylated pyridine N-oxides with an organoboron reagent to produce the 2-aryl pyridines 259. Scheme 77. Cu-catalyzed arylation of pyridine N-oxides with boronic esters.

Liu reported an Au-catalyzed reaction between 8alkylquinoline N-oxides 260 and vinyldiazo carbonyl compounds 261 to yield 2-furanyl-quinoline products 267 (Scheme 78). [105] The nucleophilic attack of 261 on the Au(I)-bound oxide complex 262 generates 263, which undergoes dehydration to form species 264. Gold complexes then activate diazo decomposition of species 264 to yield gold carbenes 265, which undergo an oxa-Nazarov cyclization to form furanylium cation 266 and ultimately 267. This mechanism is highly speculative, and additional work is required for its confirmation. Scheme 78. Au-catalyzed α-furanylations of quinolone N-oxides with alkenyldiazo carbonyl species.

Arylation using Grignard reagents is another powerful tool for the construction of 2-arylpyridines. It had been reported that Grignard reagents react with heterocyclic N-oxides to afford a mixture of nondeoxygenative addition and ring-opening products, which can be converted to 228 following treatment with dehydrating reagents. [5] In 2014, Larionov's group described the direct synthesis of various 2alkyl-, aryl-, and alkenyl-substituted pyridines and quinolines using Grignard reagents and N-oxides (Scheme 79). [106] This approach utilizes both copper catalysis and activation by lithium fluoride or magnesium chloride. The utility of this method for the late-stage modification of complex Nheterocycles is exemplified by the facile syntheses of novel structural analogs of several antimalarial, antimicrobial, and fungicidal agents. Visible-light-promoted non-deoxygenative arylation of pyridine and quinoline N-oxides has been realized with diaryliodonium tetrafluoroborate using Eosin Y as a photocatalyst. [107] Transition-metal-free arylation of N-oxides has also been achieved via a Reissert-type mechanism. In 2015, Wu's group described a base-promoted cross-dehydrogenative coupling between quinoline N-oxides and 1,3-azoles 268 under air (Scheme 80). [108] The mechanism involves the formation of intermediates 270 and 271 and the release of LiOH. While the arylation of pyridine N-oxides with arylboronic acids requires AgNO 3 for catalysis, [109] Antonchick and coworkers achieved both the arylation and alkenylation of quinoline N-oxides by directly reacting quinoline N-oxides with boronic acids 272 in hot DMSO (Scheme 81). [110] Coordination of boronic acid 272 to the N-oxide brings the reactants into close proximity. Similar to a Petasis reaction, aryl migration of the boronic acid proceeds via nucleophilic attack at the C2 position to yield 275. Concerted rearomatization and elimination of boric acid results in the deoxygenative formation of functionalized quinoline 273.

The arylation of quinoline N-oxides has also been achieved electrochemically. One application of this technology is exemplified by Lei's arylation of quinoline N-oxides with aryl sulfonyl hydrazide through a Minisci-type mechanism (Scheme 82). [111] The aryl radical is produced from sulfonyl hydrazide through the loss of three protons and electrons and the subsequent release of N 2 and SO 2 .

Scheme 82. Electrochemical deoxygenative C2-arylation of quinoline N-oxides.

Trifluoromethylation

Despite the importance of fluoroalkyl-substituted heterocycles in medicinal and agricultural chemistry, the trifluoromethylation of N-oxides was not achieved until 2014. Larionov's group investigated reactions between heterocyclic N-oxides and perfluoroalkylsilanes affording 2-perfluoroalkyl/arylsubstituted heterocycles 277 in good to excellent yields (Scheme 83). [112] This reaction was also exploited for the syntheses of new analogs of the antimicrobial drug chlorquinaldol. Although this method is efficient for quinoline and isoquinoline Noxides, low yields were obtained for pyridine N-oxide substrates.

Scheme 83. Perfluoroalkylation of heterocyclic N-oxides.

Wu's team recently described a Ni-catalyzed trifluoromethylation of pyridine N-oxides in low to medium yields using Togni's reagent (Scheme 84). [113] Beneficially, the reaction is easily scaled to gram quantities and has been applied to the late-stage trifluoromethylation of hydroquinine. While the mechanism is not fully understood, a radical pathway was proposed based on control experiments. Interestingly, utilizing the same trifluoromethylation source, Gao and coworkers developed a visible-light-promoted nondeoxygenative trifluoromethylation of quinoline Noxides in moderate to good yields (Scheme 85). [114] This reaction proceeds via a Minisci-type radical addition.

Scheme 85. Visible-light-promoted trifluoromethylation of quinoline N-oxides.

Miscellaneous

In 2013, Wu's team reported a CuOTf-catalyzed non-deoxygenative acetoxylation of quinoline Noxides using aldehydes (Scheme 86). [22] In contrast to traditional esterifications, this reaction uses TBHP as an oxidant and copper (I) salt as a catalyst to synthesize the target product directly under mild and environmentally friendly conditions. Scheme 86. Acetoxylation of quinoline N-oxides using aldehydes.

Few methods are available for the acylation of Noxides. In 2018, Singh and coworkers reported a practical method for the Ag-catalyzed acylation of Noxide using alkynes and K 2 S 2 O 8 as the oxidant (Scheme 87). [115] Mechanistic studies indicated that the reaction proceeds through a Minisci-type radical addition and Wolff rearrangement of ketene 291 to produce 292. In 2018, Zhao, Wu, and coworkers reported a Cucatalyzed non-deoxygenative thiolation of N-oxides with disulfides (Scheme 88). [116] During the reaction, N-oxide undergoes a facile C-H cleavage to produce the aryl Cu(II) intermediate, 296. The subsequent reaction with a thiyl radical forms the Cu(III) complex, 297, which undergoes reductive elimination to yield the desired product, 295, along with Cu(I) species. The active Cu(OAc) 2 catalyst is regenerated by the action of disulfides and air.

Tomkinson's team described a regioselective, three-component coupling reaction between pyridine N-oxide, acyl chloride, and thioether in the presence of triethylamine to give 2-thiolated pyridine 298a and 298b via carbene 300 (Scheme 89). [117] The reaction follows path A to give 298a for less strained sulfide, whereas more strained sulfide expedites the elimination of 4-nitrobenzoate, followed by recombination through ring opening to give 298b. Scheme 89. Three-component thiolation of pyridine/quinoline N-oxides.

Two groups achieved the trifluoromethylthiolation of N-oxides using distinct activating reagents (Scheme 90). Kuninobu and coworkers identified 2,4dinitrobenzenesulfonyl chloride as the best activating agent following extensive studies with various sulfonyl chlorides. [118] This method was applied to the synthesis of a quinidine derivative. Qing's group found that the combination of Ts 2 O and TBAI activates the reaction of quinoline and isoquinoline N-oxides with AgSCF 3 . [119] This reaction was shown to proceed via the traditional Reissert-type mechanism, with TBAI activating AgSCF 3 to generate the nucleophilic SCF 3 anion.

Scheme 90. Trifluoromethylthiolation of azine N-oxides.

A neat, high-temperature azidation of azine Noxides with DPPA was accomplished by Keith in 2006 (Scheme 91). [120] This method is more efficient than azidations using sulfonyl azide generated in situ by TMSN 3 and TsCl. In 2015, Li and coworkers reported a nondeoxygenative azidation of quinoline N-oxides with TMSN 3 that occurred within 10 min at room temperature (Scheme 92). [121] The quinoline N-oxide 19 would undergo single electron oxidation by an azide radical to generate the radical cation, 305 or 305. The reaction appears to involve a novel, carbene-stabilized N-O radical intermediate, 306, which undergoes single-electron transfer to TMSN 3 to give the C2-azidation product, 308. In 2014, Wu's group reported the phosphonation of N-oxides at elevated temperatures by direct reaction with H-phosphonates 309, which play a dual role of the activating agent and the nucleophilic source (Scheme 93A). [122] The reaction mechanism was rationalized by DFT studies calculated at the B3LYP/6-31G (d, p) level of theory (Scheme 93B). [123] The H-phosphonates exist as mixtures of two tautomers 309 and 309, both of which can react to form 312 via intermediates 311 and 311, respectively. The second stage is the dehydration process, for which three possible reaction pathways are proposed: 309-assisted dehydration, 309-assisted dehydration, and direct dehydration. The direct dehydration pathway is ruled out due to the very unfavorable activation barrier (35.40 kcal/mol). Although the 309-assisted pathway is more energyfavorable, 309 lies 6.24 kcal/mol above 309 in the energy profile, leading to a similar energy barrier. Therefore, both the reaction pathways can proceed under the experimental conditions.

One of the earliest studies to introduce functional groups at the C2 position of pyridines involved cyanation of pyridine N-oxides via Reissert reaction. [124] In 1983, Fife reported a popular cyanation method utilizing TMSCN as the cyanide source with the activation of dimethylcarbamyl chloride (Scheme 94A). [125] It has also been reported that pyridine N-oxides can react directly with TMSCN at high temperatures without using any activating reagent (Scheme 94B). [126] Triethylamine is required to neutralize the HCN formed. This reaction was revisited in 2019 by two research groups. Sun and coworkers found that the reaction with quinoline N-oxides can be activated by the eco-friendly and inexpensive hypervalent reagent PhI(OAc) 2 (PIDA, Scheme 95). [127] The reaction proceeds quickly, but is not efficient enough for pyridine N-oxides. Das's group successfully prepared 2-cyanated pyridines and quinolines 317 under neat conditions at high temperatures either by conventional heating or microwave treatment (Scheme 96). [128] Scheme 94. Cyanation of pyridine N-oxides, as reported in 1983.

Annulation of C3-Substituted Pyridine/Quinoline N-oxides

Fused pyridine derivatives are extremely important due to their abundance in various biologically active natural products and synthetic pharmaceuticals (Figure 2). While some of these structures are underexplored, likely due to synthetic intractability, they have emerged as promising targets because their isosteric phenyl analogs have been designated privileged structures in drug development. [129] Traditional synthetic approaches to 323 largely rely on nucleophilic aromatic substitution reactions (S N Ar) with 2-halogen-or hydroxyl-substituted pyridine derivatives 324, which are themselves difficult to access (Scheme 97). Although 324 can be prepared from N-oxides 322 by the hydroxylation or chlorination methods described above, regioselectivity issues render this transformation impractical. Departing from traditional methods, our group envisioned new synthetic strategies to access fused pyridine derivatives (Scheme 97). The naturally abundant, commercially available nicotinic acid derivatives 321 were selected as the starting material and converted to 322 by conventional methods. Direct functionalization of the C2-H bond in 322 allowed access to 323.

Although azacoumarins 330 are promising targets, their synthesis had been confined to electron-rich pyridines. [130] In 2017, our group presented a facile and general synthesis of 8-azacoumarins from transacrylic acid-functionalized pyridine N-oxides 325 (Scheme 98). [131] Multiple transformations were involved in the key lactonization reaction, including conjugate addition, S N Ar, and elimination. Importantly, the double bond geometry is converted from trans to cis without the need for irradiation. In addition, this method is amenable to both electronrich and electron-poor pyridine/quinoline N-oxides. Building on this work, we developed a practical synthetic method for 8-azachromones 332 from readily available nicotinates in only three steps. The key intramolecular O-heteroarylation reaction was achieved by PyBroP-or Ac 2 O-activated nucleophilic addition of enolates to the C2 position of N-oxides 331 (Scheme 99). [132] Scheme 99. Synthesis of 8-azachromones.

Emery's team reported a method for the metal-free synthesis of furo[2, 3-b]pyridines 336 (also known as 7-azabenzofuran) at ambient temperatures (Scheme 100). [133] 3-Ethylcarboxylate pyridine N-oxides 335 react with acyl chloride or anhydride to form ethyl acetoacetate derivatives 337, which undergo carbonyl deprotonation and cyclization to generate 338. Finally, deprotonation and rearomatization provide the target products, 336. Our group applied this method to the efficient synthesis of the potent HCV NS5B polymerase inhibitor, 341 (Scheme 101), [134] providing six times greater total yield than that obtained through the original synthesis developed by BMS scientists, [135] who used Pd-catalyzed cyclization to construct the 7-azabenzofuran core. Emery's method is confined to the synthesis of 3carboxylate-substituted 7-azabenzofurans. Our group has greatly extended the accessible targets utilizing 342 as substrates under two different conditions (Scheme 102). [136] Scheme 102. Synthesis of 2,3-substituted furo[2, 3b]pyridine. Scheme 103. Synthesis of 7-azaindoles.

In contrast to the conventional Pd-catalyzed synthesis of 7-azaindoles, we described a one-pot, transition-metal-free synthesis of 7-azaindoles involving amination of pyridine N-oxides 342 to yield 346 and intramolecular enamine formation (Scheme 103). [137] Although the conditions are mild and allow for a wide substrate scope, the yield is generally moderate due to regioselectivity between C2-and C6functionalization.

Scheme 104. Synthesis of 1,8-naphthyridones.

The highly regioselective amination (C2 vs. C6) of azine N-oxides was successfully applied to the synthesis of 349, which were converted to 1,8naphthyridones 350 smoothly under acidic conditions in nearly quantitative yield (Scheme 104). [138] Interestingly, enamines 349a were formed from 348a (Scheme 104A), whereas 349b were formed on substrates with non-methyl R 1 groups (Scheme 104B), likely due to steric hindrance precluding enamine formation. Enamine 348c was found to be appropriate substrate with non-aliphatic amines, including ammonia and aromatic amines.

Functionalization at C2-Benzylic Position of Pyridine/Quinoline N-Oxides

Unlike the non-specific benzylic C-H activation of pyridines and benzenes, the C-H bond of an alkyl group α to nitrogen heteroaromatics can be specifically activated for functionalization (Figure 3). This activation is achieved by the well-established Boekelheide reaction, which is frequently used in heterocyclic chemistry for the formation of acylated products 354 by introducing oxygen onto alkyl groups α to nitrogen heteroaromatics (Scheme 105). [139] The mechanism involves a [3,3]-sigmatropic rearrangement of 353. An improved procedure was reported in 1995 by replacing Ac 2 O with TFAA, which allows the reaction to occur at room temperature and, after saponification, generally provides the hydroxylated compounds 357 in good to excellent yields (Scheme 106). [140] Although this reaction was developed in the 1950s, only recently have non-hydroxy functional groups been introduced at the C2-benzylic position. In 2006, Rádl and coworkers reported the sulfonyloxylation of 2-methylpyridine N-oxide 358 by sulfonic anhydride, providing 359 as a salt in moderate yields via a mechanism similar to the Boekelheide reaction (Scheme 107A). [141] Soulé's group later developed a mild, base-promoted reaction using benzene-sulfonyl chlorides (Scheme 107B). [142] Scheme 107. Sulfonyloxylation at the α position of Nheterocycles.

This group also developed a scalable acyloxylation of 2-alkylpyridine N-oxides 360 with aromatic aldehydes via a Cu-catalyzed tandem reaction involving oxidative esterification followed by O-atom transfer of the resultant Boekelheide intermediates 369 (Scheme 108). [143] Notably, this method enables the desymmetrization of 2,6-dialkylpyridines for the efficient synthesis of pincer ligands.

The benzylic amination of quinoline N-oxides was accomplished by a one-pot protocol using the sulfonated Boekelheide intermediate, 371 (Scheme 109). [144] Unfortunately, 2-picoline N-oxides were not amenable to the reaction conditions. In 2017, Zhao's group reported the synthesis of Nheteroarylmethyl phosphates 375 by a novel, heteroatom [3,3]-sigmatropic rearrangement (Scheme 110A). [145] This method was also successfully applied to reactions of nitrones 376 and dialkyl Hphosphonates 374 (Scheme 110B).

The direct thiolation at the α position of 2-picoline N-oxides to produce pyridine-2-ylmethyl thioethers 378 is critical, as these compounds are widely used as the most advanced commercial intermediates for several important drugs, such as omeprazole, pantoprazole, lansoprazole, and rabeprazole. Our group developed a metal-and base-free, one-pot protocol involving a TFAA-mediated Boekelheide rearrangement of pyridine N-oxides and TBABcatalyzed direct conversion of the trifluoroacetates to thioethers (Scheme 111A). [146] Notably, this reaction is regiospecific for the C2 methyl group and has been successfully applied to the synthesis of omeprazole sulfide and rabeprazole sulfide in good yields without the need for TBAB catalysis (Scheme 111B). Two plausible reaction pathways for the second step have been proposed. For highly electron-rich 2-picoline Noxides, the reaction proceeds via direct S N 2 through a six-membered ring transition state (Pathway 2, Scheme 111). For other N-oxides, the trifluoromethyl group of 382 is replaced with a bromine atom to obtain the more reactive bromoformate intermediate 383 and CF 3 -, which abstracts a proton from R 1 SH to produce R 1 S -and trifluoromethane. Nucleophilic addition of R 1 S -to 383 affords 378 and carbon dioxide and regenerates the bromide to complete the catalytic cycle. Benzylic C-H activation was also used in Fagnou's Pd-catalyzed direct arylation of 2-alkylpyridine Noxides 351 (Scheme 112). [147] The reaction conditions can be tuned to allow for site-selective arylation. The functionalization of 2-alkenylpyridine Noxides has also been achieved. Liang and coworkers reported an efficient difunctionalization of 386 to afford 388 through the tandem addition/Boekelheide rearrangement of intermediate 390 (Scheme 113). [148] This method benefits from a 100% atom economy, constructing several bonds simultaneously under mild reaction conditions. Some examples of C2-benzylic heteroatomfunctionalization have been reported. Makhova's group recently described the BF 3 -catalyzed preparation of hetaryl carbamates 392 by condensation of 2-aminohetarene N-oxide 391 with trimethyl orthoformate followed by intramolecular Noxide oxygen transfer (Scheme 114). [149] Scheme 114. Functionalization of aminopyridine N-oxides.

Applications to the Synthesis of Complex Azaheterocycles

Various applications of N-oxide chemistry in the synthesis of complex molecules have been reported previously. In 2016, Ji's group developed an efficient cycloaddition reaction between quinoline N-oxides and ynones 394 or 401, resulting in remarkably complex quinoline derivatives 400 or 404, respectively, in moderate to excellent yields (Scheme 115). [150] Preliminary studies suggest these compounds have potential as metal ion probes, with a high binding constant measured for Hg 2+ in acetonitrile.

Scheme 115. Synthesis of complex quinoline derivatives.

Wang's group investigated reactions between 1,4diynes 405 or 1-en-4-yn-3-ones 407 and (iso)quinoline N-oxides 19 that result in the formation of complex molecules 406 or 408 respectively, via cascade C=O/C=C/C-N bond formation (Scheme 116). [151] These novel fluorophores were found to display green-blue fluorescence. Interestingly, the synthesis of 413 through the reaction of (iso)quinoline N-oxides with 1,4-diyn-3ones 412 can proceed with or without copper catalysis (Scheme 117). [152] However, the copper catalyst promotes the final cyclization in 415 by activation of the carbon-carbon triple bond, providing better yields under milder conditions.

The Wang group also reported the synthesis of both 3-(2-quinolyl) chromones 417 and azachromones 418 from 2-hydroxyl-or aminosubstituted ynones 416 and quinoline N-oxides via a similar mechanism under acidic conditions (Scheme 118). [153] Their study primarily focused on reactions with quinoline and isoquinoline N-oxides and is not applicable to pyridine N-oxides. Cheng and coworkers were able to eliminate the need for acid by using the more reactive 2-fluoro ynones 419 (Scheme 119A). [154] This method was also applied to pyridine, quinoline and isoquinoline N-oxides under basic conditions (Scheme 119B). C2-functionalization methods have been applied to the synthesis of several natural products. For example, the 2,3′-bipyridyl framework of complanadines A and B was elegantly constructed by direct C2 arylation [14,147] of pyridine N-oxide 423 with 3-bromopyridine derivative 424 (Scheme 120). [155] Interestingly, both 423 and 424 were assembled from the same Nprotected lycodine. Reduction of 425 afforded complanadine A (426) and benzylic acetylation afforded 427, which was converted to complanadine B (428) in three steps.

In comparison, Sarpong and coworkers constructed complanadine B via the Suzuki cross-coupling of pinacolboronic ester 432 with 430, which was prepared by the chlorination of pyridine N-oxide 429 (Scheme 121). [156] Unlike the direct coupling between N-oxide and aryl bromide (Scheme 120), in this protocol, 430 and 432 must be prepared in one step from 429 and 431, [157] respectively, thereby adding two additional steps to the overall process.

Conclusions and Perspectives

In summary, heterocyclic N-oxide reactions remain one of the most powerful tools for the C2functionalization of nitrogen heteroaromatics. Although the chemistry of N-oxides has been explored for more than a century, the majority of reaction paths have only recently been discovered, with much of this progress made in the past five years. Advancements in modern organic chemistry technologies, such as photoredox catalysis with visible light and electrochemistry, have enabled access to previously challenging reactions, although further improvements are still necessary. There is a definitive need in green chemistry for the development of reactions involving catalytic quantities of activating reagents that produce water as the sole byproduct. Additional improvements should focus on functionalization at other positions, particularly at the rarely functionalized C3 position. One such attempt is exemplified by the metaselective alkyne oxyarylation with pyridine Noxides. [158] Functionalization at C8 position of quinoline N-oxides is another promising area. [159] Finally, there is great anticipation for the wide application of N-oxide chemistry to the synthesis of complex nitrogen-containing heterocycles.

Figure 1 .

 1 Figure 1. Representative, bioactive C2-functionalized pyridines and quinolines.

Scheme 5 .

 5 Scheme 5. C2-bromination/chlorination of quinoline Noxides.

Scheme 7 .

 7 Scheme 7. Regioselective C2-halogenation of pyridine Noxides.

Scheme 8 .

 8 Scheme 8. C2-chlorination of quinoline N-oxides using PPh 3 /CCl 3 CN.

Scheme 9 .

 9 Scheme 9. Facile synthesis of 2-fluoropyridines and 2fluoroquinolines.

Scheme 16 .

 16 Scheme 16. AgBF 4 -catalyzed deoxygenative C2-amination.

Scheme 22 .

 22 Scheme 22. C2-amidation of quinoline N-oxides with primary amides.

Scheme 28 .Scheme 29 .

 2829 Scheme 28. Synthesis of oxadiazole-substituted Npyridinylurea.

Scheme 31 .

 31 Scheme 31. Sulfoximination of heteroaromatic N-oxides under PyBroP activation conditions.

  Scheme 32. Hyperiodine-mediated sulfonamidation of quinoline N-oxides.

Scheme 34 .

 34 Scheme 34. Hydroxylation of pyridine/quinoline N-oxides with water and PyBroP.

Scheme 37 .

 37 Scheme 37. C2-aryloxylation and alkoxylation of pyridine N-oxides.

Scheme 40 .

 40 Scheme 40. Non-deoxygenative sulfonylation of quinoline N-oxides.

Scheme 42 .

 42 Scheme 42. Iron-catalyzed deoxygenative sulfonylation of quinoline N-oxides.

Scheme 45 .Scheme 46 .

 4546 Scheme 45. Sulfonylation of quinoline/pyridine N-oxides by activation with H-phosphonates.

Scheme 51 .

 51 Scheme 51. Visible-light-induced sulfonylation of quinoline N-oxides.

Scheme 53 .

 53 Scheme 53. Electrochemical deoxygenative C2 sulfonylation of quinoline N-oxides.

Scheme 57 .

 57 Scheme 57. Visible-light-induced C2-alkylation of pyridine N-oxides.

Scheme 61 .

 61 Scheme 61. Alkylation of pyridine N-oxides with silyl ketene acetals.

Scheme 64 .Scheme 66 .

 6466 Scheme 64. Reductive C2-alkylation of pyridine N-oxides with alkenes.

Scheme 67 .

 67 Scheme 67. Alkylation of pyridine/quinoline N-oxides with diborylalkanes.

Scheme 68 .

 68 Scheme 68. Alkylation of pyridine/quinoline N-oxides with Wittig reagents.

Scheme 69 .

 69 Scheme 69. Pd-catalyzed non-deoxygenative alkenylation of N-oxides.

Scheme 70 .

 70 Scheme 70. Pd(OAc) 2 -catalyzed alkenylation of quinoline N-oxides.

Scheme 75 .

 75 Scheme 75. Pd-catalyzed arylation of pyridine N-oxides with phenyl bromides.

Scheme 79 .

 79 Scheme 79. Alkyl-, aryl-, and alkenylation of N-oxides by Cu-catalyzed Grignard addition.

Scheme 80 .

 80 Scheme 80. Cross-dehydrogenative coupling of quinoline N-oxides with 1,3-azoles.

Scheme 84 .

 84 Scheme 84. Ni-catalyzed trifluoromethylation of N-oxides.

Scheme 87 .Scheme 88 .

 8788 Scheme 87. Acylation of pyridine/quinoline N-oxides with alkynes.

Scheme 91 .

 91 Scheme 91. Azidation of azine N-oxides with DPPA.

Scheme 92 .Scheme 93 .

 9293 Scheme 92. Azidation of quinoline N-oxides.

Scheme 95 .Scheme 96 .

 9596 Scheme 95. Cyanation of quinoline N-oxides, as reported in 2019.

Scheme 97 .

 97 Scheme 97. Annulation via functionalization of C3substituted pyridine N-oxides.

Figure 2 .

 2 Figure 2. Representative, bioactive fused pyridine derivatives.

Scheme 98 .

 98 Scheme 98. Synthesis of 8-azacoumarins.

Scheme 100 .Scheme 101 .

 100101 Scheme 100. Synthesis of 3-ethylcarboxylate-furo[2,3- b]pyridine.

Figure 3 .Scheme 105 .

 3105 Figure 3. Activated C-H bonds in pyridine N-oxides and other aromatics.

Scheme 108 .Scheme 109 .Scheme 110 .

 108109110 Scheme 108. Acyloxylation of 2-alkylpyridine N-oxides with aldehydes.

Scheme 111 .

 111 Scheme 111. Thiolation of 2-picoline N-oxides.

Scheme 112 .Scheme 113 .

 112113 Scheme 112. Site-selective sp 2 and benzylic sp 3 arylation of 2-alkyl pyridine N-oxides.

Scheme 116 .Scheme 117 .

 116117 Scheme 116. Synthesis of 2,3-dihydro-1H-pyrido[1,2a]quinolines.

Scheme 119 .

 119 Scheme 118. Synthesis of 3-(2quinolyl)chromones/azachromones.

Scheme 120 .

 120 Scheme 120. Tsukano's total synthesis of complanadines A and B.

Table 1 .

 1 Deoxygenative C2-functionalization of pyridines/quinolines.

	Entry	-FG	Substrate(s) a	Activation	FG-L	Ref
	1	-F	P/Q NOs	TFAA	R 3 N then TBAF
			Q NOs	Ts 2 O		TBAX
	2	-Cl, -Br	Q NOs		POX 3 + DMF
			P NOs		(COX) 2
	3 4	-Cl -NH 2	Q NOs P/Q NOs P NOs	Ts 2 O TsCl	Ph 3 P + CCl 3 CN t BuNH 2 then TFA Saccharin then HCl
	5	-NR 1 R 2

  NOs: pyridine N-oxides; Q NOs: quinoline N-oxides.[b] These are promoters of the reaction.

	23	-CH=CHEWG	Q NOs	Pd(OAc) 2		CH 2 =CHEWG	97
	24	-CH=CHAr	Q NOs	I 2		CH 2 =CHAr	98
	25	-CH=CHR	Q NOs	AcOH or TsOH	CH 2 =CHR	99-100
	26	-Ar	P NOs Q NOs	Cu(acac) 2 ArSO 2 NHNH 2 + electrochemistry ArB(OR) 2	104 111
	27	-R (R = alkyl, alkenyl, aryl)	P/Q NOs	CuCl		RMgX•MgCl 2	106
	28	-R (R = alkenyl, aryl)	Q NOs	RB(OH) 2	110
	29	-CF 3	Q NOs P/Q NOs	CF 3 SiMe 3 + t BuOK NiCl 2 Togni's reagent	112 113
	30	-COR	P/Q NOs P NOs	AgNO 3 Mes-Acr + ClO 4	-	RC≡CH + K 2 S 2 O 8 RC≡CR 1	115 91
	31	-CH(EWG) 2	P NOs Q NOs	PyBroP HP(O)(OEt) 2		CH 2 (EWG) 2 CH 2 (EWG) 2	53 32
	32	-SCF 3	P/Q NOs	2,4-(NO 2 ) 2 PhSO 2 Cl Ts 2 O	AgSCF 3	118 119
	33	-SR	P NOs	PyBroP		RSH	53
	34	-P(O)(OR) 2	P/Q NOs	HP(O)(OR) 2	122
	35	-N 3	P/Q NOs		DPPA		120
			P NOs	ClCONMe 2			125
	36	-CN	P/Q NOs	microwave		TMSCN	128
			Q NOs	PhI(OAc) 2			127
	[a] P
				c or TsOH	RCN	45-46
			Q NOs	NH 2 NHCO 2 Me + Selectfluor	RCN
	9	-NR 1 C(O)R	P/Q NOs	Tf 2 O		RC(O)NHR 1
	10	-NHC(O)NR 2	P NOs	MeSO 3 H		R 2 NCN
	11	-NRC(O)NHR 1	Q NOs	CuSO 4 •5H 2 O b		RN=C=NR 1
	12	-NHSO 2 Ar	Q NOs Q NOs	PhI(OAc) 2 + Ph 3 P Ni(OAc) 2	ArSO 2 NH 2 FN(SO 2 Ar) 2
	13	-NRSO 2 Ar	P NOs	PyBroP		ArSO 2 NHR
			P/Q NOs	PyBroP		NaOAc + H 2 O
	14	-OH	Q NOs	MsCl		H 2 O
			Q NOs	DIAD + PdCl 2	H 2 O
	15	-OR	P/Q NOs	PyBroP		ROH	59-61
			Q NOs	CuBr 2		RSO 2 Na + K 2 S 2 O 8
			Q NOs	FeCl 3		RSO 2 Na + TBHP
			P/Q NOs	HP(O)(O i Pr) 2		RSO 2 Cl or ArSO 2 Na
	16	-SO 2 R	P/Q NOs	NaI + TBHP I 2 + H 2 O 2		RSO 2 NHNH 2	69-70
			P/Q NOs	I 2 (+ TBHP) TsCl		RSO 2 Na	71-72
			Q NOs	Zn + ultrasound	RSO 2 Cl
			Q NOs	FeNO 3 + microwave K 2 S 2 O 8	ArSO 2 Na
	17	-SO 2 Ar	Q NOs	CuOTf		ArN 2 BF 4 + DABSO
			Q NOs	Na 2 S 2 O 5		ArN 2 BF 4
	18	-CH 2 CO 2 Me	P NOs	PyBroP	CH=C(OTBS)OMe
	19	-CH 2 CH(OH)CO 2 R	Q NOs	-		CH 2 =CHCO 2 R
	20 21 22	-CH 2 R -CHRR 1 -Alkyl	P/Q NOs P/Q NOs P/Q NOs	RCH(Bpin) 2 + MeONa RR 1 C(Bpin) 2 + MeONa Alkyl-PPh 3 X + t BuOK

Scheme 24. Ionic-liquid-promoted amidation of quinoline N-oxides with nitriles.

Acknowledgements

We thank the National Key R&D Program of China (2018YFA0901700) for generous financial support. While we sought to prepare a comprehensive review of the existing literature, we sincerely apologize for any inadvertently omitted reports.

Gaoyu Li graduated from Puyang No.1 senior high school in 2014 and won the second prize of Henan Chemistry Competition when he was a junior high school student. He received his bachelor's degree from Henan University of Chinese Medicine in 2018. He participated in the Innovative Learning Projects for College Students and served as the team leader, and he won the second prize of The 1 st National Pharmaceutical College Pharmacy Students Innovation and Entrepreneurship and Experimental Teaching Reform Competition. In 2018, he joined Dr. Dong Wang's group, and has been researching in heterocyclic chemsitry.