Six-Membered Ring Systems: Diazines and Benzo Derivatives

Six-Membered Ring Systems: Diazines and Benzo Derivatives

6.2

K. Alison Rinderspacher * Columbia University, New York, NY, United States *Corresponding author: E-mail: [email protected]

6.2.1

Introduction

In 2018, the trend toward more efficient, economical, and ecologically friendly syntheses continued, resulting in a wealth of publications, discussing the syntheses, reactions, and applications of diazines and their benzo derivatives. Due to their ubiquity in nature, their established biological activity and their electrochemical properties, these compounds continue to find use as building blocks for pharmaceuticals, semiconductors, low-band gap polymers, dyes, flavors, fragrances, and catalysts. The space limitations of this document permit only a selection of the advances in the studies of this class of compounds to be presented here. Among the reviews published in 2018, some examined the utility of pyridazinones for the generation of either other functional groups or heterocycles (18JOC1). Others reported on different approaches to the synthesis of a-(trifluoromethyl)pyridazine derivatives (18EJO3541), the formation of pyridazines and pyrimidines via Dielse Alder reactions (18EJO3618), and the breadth of biological applications of quinoxalines (18EJM542). Studies on the photophysical properties of quinoxalinecontaining iminodibenzyl and iminostilbene moieties (18CC13857), the effects of hydrogen and halogen bonding on the electronic properties of a pyrazine rotor (18JOC6142), and the differences in architecture and luminescence of metal complexes formed with group 11 metals and pyrimidine-based phosphine ligands (18AO16601) were published in 2018. A number of reports emerged discussing the chemistry and properties of cavitands containing either quinoxaline or pyrazine moieties. The synthesis of a new class of tetraquinoxaline-cavitand-based copolymers was published, and their pH-driven interconversion both in solution and in solid matrices was analyzed (18SL2503). Another group investigated the catalytic capability of gold cavitands, containing either quinoxaline- or pyrazine-based components in their cavitand wall, to hydrate alkynes selectively (18EJO5304). Patent applications that were filed in 2018 will not be discussed in this document, as they fall outside the scope of this review.

Progress in Heterocyclic Chemistry. https://doi.org/10.1016/B978-0-12-819962-6.00013-0 Copyright © 2020 Elsevier Ltd. All rights reserved.

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6.2.2 6.2.2.1

Progress in Heterocyclic Chemistry

Pyridazines and Benzo Derivatives Syntheses

In 2018, different approaches to the formation of the pyridazine ring employing hydrazines in combination with either carbonyl compounds or diols or alkynes were reported. Suchand and Satyanarayana prepared phthalazines and phthalazinones via a one-pot, palladium-catalyzed acylation reaction followed by a nucleophilic cyclocondensation (18EJO2233). Reaction of ketone 1 with an aldehyde resulted in the generation of a diketone, which upon exposure to hydrazine produced the corresponding phthalazine (Scheme 1A). Both aliphatic, aromatic, and heteroaromatic aldehydes were well tolerated by these reaction conditions. Treatment of ester 2 with an aldehyde followed by hydrazine gave the respective phthalazinone (Scheme 1B). Notably, further functionalization of the phthalazinone product could be achieved by employing an aryl hydrazine instead of hydrazine (Scheme 1C). Furthermore, the authors were able to apply their new methodology to the synthesis of PDE-4 inhibitor 3 (Scheme 2). Chakraborty and coworkers developed a one-pot synthesis of phthalazine, employing a nickel(II)-catalyzed, ligand redox-controlled tandem generation of azines. Treatment of an aromatic alcohol, in this case, 1,2-dibenzenemethanol, with hydrazine in the presence of nickel catalyst 4, potassium tert-butoxide, and 3-Å molecular sieves (MSs) in toluene at 125
C under aerobic conditions provided phthalazine in 52% yield (18JOC7771; Scheme 3). Dey and coworkers devised a Lewis-acid-catalyzed annulation of cyclopropane carbaldehydes and aryl hydrazines, yielding tetrahydropyridazines, which via a subsequent Lewis-acid-catalyzed [3 þ 2]-cycloaddition were converted into hexahydropyrrolo[1,2-b]pyridazines (18JOC5438). Treatment of cyclopropane carbaldehydes with aryl hydrazines in the presence of indium(III) chloride (20 mol %) provided the corresponding tetrahydropyridazines in moderate to good yields (Scheme 4). Subsequent [3 þ 2]-cycloaddition of the resulting tetrahydropyridazine with donore

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(A)

(B)

(C)

Scheme 1 One-pot, palladium-catalyzed synthesis of phthalazines and phthalazinones.

acceptor cyclopropanes (DACs), catalyzed by ytterbium(III) triflate (20 mol %), gave a diastereomeric mixture of the cycloadduct (Scheme 5). While the overall yields of this step were mostly good, the diastereomeric ratio was not. The best results were obtained with Ar ¼ 2-thiophenyl, which gave a diastereomeric ratio of 70:30 in favor of the cis isomer. Both reactions could be run in one pot, generating the intermediate tetrahydropyridazine in situ. Furthermore, to demonstrate the ability of this new methodology to access more hexahydropyrrolo[1,2-b]pyridazines, the authors monodecarboxylated one of the cycloadducts, 5a, with potassium hydroxide in refluxing methanol (Scheme 6). Monoacid 6 was obtained in 75% yield. Wang and collaborators developed a new synthesis of cinnolines and cinnolinium salts employing Rh(III)-catalyzed cascade oxidative coupling and cyclization reactions of Boc-protected aryl hydrazines and alkynes (18JOC10845; Scheme 7). To generate

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Scheme 2 Application of one-pot palladium-catalyzed acylation reaction and subsequent nucleophilic cyclocondensation to the synthesis of a PDE-4 inhibitor 3.

Scheme 3 Nickel-catalyzed one-pot synthesis of phthalazine from hydrazine hydrate and 1,2-benzenedimethanol.

Scheme 4 Lewis-acid-catalyzed annulation to form tetrahydropyridazines.

Scheme 5 Lewis-acid-catalyzed [3 þ 2]-cycloannulation to form hexahydropyrrolo[1,2-b] pyridazines.

the cinnoline derivatives, the starting materials were treated with the rhodium(III) catalyst, pentamethylcyclopentadienylrhodium(III) chloride [Cp*RhCl2]2 (5 mol %), and oxidant, Cu(OAc)2•H2O (3 equiv), in a 1:3 mixture of chlorobenzene and methylene

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Scheme 6 Monodecarboxylation of hexahydropyrrolo[1,2-b]pyridazine 5.

Scheme 7 Rh(III)-catalyzed synthesis of cinnolines and cinnolinium salts.

chloride at 80
C. The respective cinnolinium salts were formed by addition of a catalytic amount of silver hexafluoroantimonate(V) and two equivalents of silver tetrafluoroborate to the existing reaction conditions for the cinnoline product. Electrondonating and electron-withdrawing substituents were well tolerated on both the aryl hydrazine and the alkyne, providing the corresponding cinnolines and cinnolinium salts in good to high yields. Other groups introduced the characteristic azo group of the pyridazine ring by using either diazonium salts or a-diazo carbonyl compounds. Mahesha and collaborators developed a one-pot iridium-catalyzed [4 þ 2] annulation of 1-arylindazolones with a-diazo carbonyl compounds to yield indazolone-fused cinnolines (18OBC8585; Scheme 8). Treatment of 1-arylindazolones with either acyclic or cyclic a-diazo carbonyl compounds in the presence of bis(1,5-cyclooctadiene)diiridium(I) dichloride and silver hexafluoroantimonate(V) in 1,2-dichloroethane (DCE) at 110
C provided

Scheme 8 Synthesis of indazolone-fused cinnolines via an iridium-catalyzed [4 þ 2] annulation.

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the corresponding indazolo[1,2-a]cinnolines in good to high yields. Both electrondonating and electron-withdrawing substituents in the para position of the aryl group of the 1-arylindazolone or at the C-5 position of the indazolone ring were well tolerated. The exceptions to this overall observation were p-CN, p-OH, p-CHO, p-NO2, pCOOEt, and m-NO2. The authors postulated the following mechanism: iridium-promoted NeH oxidative addition followed by CAreH activation and subsequent reaction with the a-diazo carbonyl compound leads to the generation of a carbene which inserts itself into the CAreIr bond (Fig. 1). Protodemetalation of the resulting intermediate gives rise to a new intermediate which via nucleophilic addition and subsequent dehydration provides the indazolo[1,2-a]cinnoline. The benefits of this methodology are that it lacks an oxidant and uses a cheaper catalyst. Ramanathan and coworkers prepared 2-methoxybenzo[c]cinnoline 7 in 85% yield from aryldiazonium salt 8 (1 equiv) and 1,3,5-trimethoxybenzene (1.1 equiv) via in situ formation of an N-arylnitrilium intermediate and subsequent intermolecular arylation (18JOC6133; Scheme 9). Bhattacharjee and coworkers synthesized benzo[c]cinnolines 9 in moderate to high yields from 2,20 -dinitrobiaryls 10, using the organosilicon reducing reagent N,N0 -bis(trimethylsilyl)-4,40 -bipyridinylidene (Si-DHBP) (4.0 equiv) in acetonitrile and subsequent heating at 100
C for 16 h (18CEJ11278; Scheme 10). Powers and coworkers applied their new methodology of employing a dinuclear nickel complex to form azoarenes from aryl azides via catalytic dimerization to the

Figure 1 Postulated mechanism for the synthesis of indazolone-fused cinnolines.

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Scheme 9 Formation of 2-methoxybenzo[c]cinnoline 10 from an aryldiazonium salt and 1,3,5-trimethoxybenzene, employing dry acetonitrile.

Scheme 10 Metal-free synthesis of benzo[c]cinnolines 9.

synthesis of benzo[c]cinnoline (11) (18JA4110). Treatment of 2,20 -diazido-1,10 biphenyl 12 (1.0 equiv) with nickel catalyst 13 (10 mol %) in deuterated benzene at 80
C for 2 h gave benzo[c]cinnoline (11) in 80% yield (Scheme 11). Lee and collaborators devised a new, simple synthesis of functionalized benzo[c] cinnolines 14 (18CS2092; Scheme 12). Treatment of 2,20 -diamino-1,10 -biaryls 15 with tert-butyl nitrite (3 equiv) as the diazotizing reagent in 2,2,2-trifluoroethanol (TFE) (0.01 M) at room temperature for 12e24 h furnished the corresponding benzo[c]cinnolines 14 in moderate to high yields. The choice of solvent and the low concentration used were crucial to the successful formation of the desired product. Both electron-donating and electron-withdrawing substituents on the aryl rings were well tolerated. These reaction conditions were scalable, and the authors were able to prepare benzo[c]cinnolines 14 on a gram scale.

Scheme 11 Nickel-catalyzed synthesis of benzo[c]cinnoline from 2,20 -diazido-1,10 -biphenyl 12.

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Scheme 12 Metal-free synthesis of benzo[c]cinnolines 14 from 2,20 -diamino-1,10 -biaryl 15.

6.2.2.2

Reactions

In 2018, numerous reports emerged describing different approaches to the CeH functionalization of pyridazines. Roudesly and collaborators developed a palladiumcatalyzed direct CeH alkenylation and allylation of diazine N-oxides via an allylation/isomerization cascade reaction (18OL2346; Scheme 13). Pyridazine-Noxide underwent C2-alkenylation with allyl acetate in the presence of palladium(II) acetate, tri-tert-butyl phosphonium tetrafluoroborate, and potassium fluoride in tetrahydrofuran (THF) at 100
C, giving the alkenylated product in 62% yield with the E isomer as the major product. The cinnamylation of pyridazine-N-oxide with cinnamyl acetate employed similar reaction conditions but had an extended reaction time of 40 h. Both the cinnamylated product (83%) and the respective isomerized adduct (17%) were formed. Three groups reported Minisci-type CeH functionalizations of phthalazines. Genovino and collaborators devised a metal-free method for the CeH alkylation of heterocycles, employing visible light (18OL3229). This approach was applied to the generation of alkylated phthalazines, pyrimidines, and pyrazines. Phthalazine was treated with isobutyric acid (3 equiv) under blue LED irradiation (lmax ¼ 455 nm) in the presence of [bis(trifluoracetoxy)iodo]benzene (PIFA) (2 equiv) and 9-mesityl10-methyl acridinium (MesAcr) (1 mol %) to give a mixture of the mono- and dialkylated phthalazines (Scheme 14). Zhang and coworkers also alkylated phthalazine, quinoxaline, and pyrimidine derivatives, employing metal-free conditions (18OL4686). A reaction mixture containing phthalazine (1.0 equiv), cyclohexanecarboxylic acid (4.0 equiv), and

Scheme 13 C2-direct alkenylation and allylation of diazine N-oxides.

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Scheme 14 Metal-free alkylation of phthalazine.

[bis(trifluoroacetoxy)iodo]benzene (2.0 equiv) in anhydrous acetonitrile was irradiated with 12 W blue LEDs for 12 h to yield 1,4-dicyclohexylphthalazine in 76% yield (Scheme 15). Sutherland and coworkers provided an alternative approach to the synthesis of 1,4-dicyclohexylphthalazine employing metal-, catalyst-, and light-free Minisci-type CeH alkylation conditions, which they also used to alkylate phthalazines, quinazolines, quinazolinones, and quinoxalines (18OL6863). Phthalazine (1 equiv) was treated with cyclohexanecarboxylic acid (10 equiv) in the presence of oxidant, ammonium persulfate (6 equiv), in a 600:1 mixture of dimethyl sulfoxide (DMSO) and water at 40
C providing 1,4-dicyclohexylphthalazine in 74% yield (Scheme 16). Several groups described the functionalization of phthalazin-1,4-dione derivatives with a-diazo carbonyl compounds. Karishma and collaborators described additive-driven, rhodium-catalyzed [4 þ 1]-, and [4 þ 2]- annulations of N-arylphthalazin-1,4-diones with a-diazo carbonyl compounds to yield hydroxy-dihydroindazolo [1,2-b]phthalazines and phthalazino[2,3-a]cinnolines, respectively (18JOC11661). Conditions for the rhodium-catalyzed [4 þ 1]-annulation of 2-aryl2,3-dihydrophthalazin-1,4-diones to hydroxy-dihydroindazolo[1,2-b]phthalazines were treatment of a 2-aryl-2,3-dihydrophthalazin-1,4-dione (1 equiv) with an a-diazo carbonyl compound (1.25 equiv) in the presence of pentamethylcyclopentadienylrhodium(III) chloride (2.5 mol %) and cesium acetate (50 mol %) in DCE at room temperature for 16e18 h (Scheme 17). With the exception of cyclic a-diazo carbonyl compounds and 2-aryl-2,3-dihydrophthalazin-1,4-diones bearing an m-NO2 or mCF3 or p-NO2 or p-COOEt or p-CN or o-Me or o-Cl substituent on the N-aryl ring,

Scheme 15 Metal-free synthesis of 1,4-dicyclohexylphthalazine.

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Scheme 16 Metal-, catalyst-, and light-free alkylation of phthalazine.

Scheme 17 Rh-catalyzed [4 þ 1]-annulation of 2-arylphthalazin-1,4-diones with a-diazo carbonyl compounds.

which did not provide the desired product, all of the prepared hydroxy-dihydroindazolo[1,2-b]phthalazines were obtained in good to high yields. For the [4 þ 2]-annulation of 2-aryl-2,3-dihydrophthalazin-1,4-diones with a-diazo carbonyl compounds to give phthalazino[2,3-a]cinnolines, 2-aryl2,3-dihydrophthalazin-1,4-diones (1 equiv) were stirred with the respective a-diazo carbonyl compounds (1.25 equiv) in the presence of pentamethylcyclopentadienylrhodium(III) chloride (2.5 mol %) and silver hexafluoroantimonate(V) (10 mol%) in DCE at 110
C under nitrogen for 14e18 h (Scheme 18). While most of the resulting phthalazino[2,3-a]cinnolines were obtained in good to high yields, the yields for phthalazino[2,3-a]cinnolines generated from 2-aryl2,3-dihydrophthalazin-1,4-diones with either an m-NO2 or a p-NO2 substituent on the N-aryl ring were low. Starting materials that did not result in the formation of the desired product were a-diazo diketones, diethyl 2-diazomalonate, and 2-aryl-2,3-dihydrophthalazin-1,4-diones with either an m-CF3 or p-COOEt or pCN or o-Me or o-Cl substituent on the N-aryl ring. Cai and coworkers developed an iridium(III)-catalyzed CeH activation and annulation of 2-aryl-2,3-dihydrophthalazin-1,4-diones with cyclic 2-diazo-1,3-diketones to

Scheme 18 Rh-catalyzed [4 þ 2]-annulation of 2-arylphthalazin-1,4-diones with a-diazo carbonyl compounds.

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form phthalazino[2,3-a]cinnolin-8,13-diones in good to high yields, using pentamethylcyclopentadienyliridium dichloride (2 mol %) and silver hexafluoroantimonate(V) (20 mol %) as the catalyst (18AO14575; Scheme 19). Electron-donating and electronwithdrawing substituents on the N-aryl ring were well-tolerated by these conditions as were ortho-substituents. Furthermore, five-membered cyclic and acyclic 1,3-dicarbonyl-2-diazo compounds could also be used as starting materials, giving the corresponding phthalazino[2,3-a]cinnoline derivatives in high yields. Other reported functionalizations of the pyridazine ring involved modifications of substituents on the pyridazine ring. Mukherjee and collaborators developed a method to activate heteroaryl sulfonyl fluorides with calcium triflimide, so that they may react with amines, which was applied to pyridazines (18OL3943). Treatment of 6-methylpyridazin-3-sulfonyl fluoride (1 equiv) with 1-[6-(trifluoromethyl)pyridine2-yl]piperazine (2 equiv) in the presence of calcium triflimide (1 equiv) and tert-amyl alcohol (0.2 M) at 60
C provided 3-methyl-6-((4-(6-(trifluoromethyl)pyridine-2-yl) piperazin-1-yl)sulfonyl)pyridazine in 90% yield (Scheme 20). A number of groups employed three-component strategies to functionalize pyridazine and benzo derivatives. Li and collaborators discovered that treatment of electronpoor phthalazine (1 equiv) with carbon tetrachloride (15 equiv) and 2-(trimethylsilyl) phenyl triflate (1.5 equiv), as an aryne precursor, in the presence of cesium fluoride (2 equiv) in acetonitrile at 65
C for 6 h led to the insertion of the C]N bond of phthalazine and C^C bond of the benzyne into the CeCl bond of carbon tetrachloride, generating 2-(2-chlorophenyl)-1-(trichloromethyl)-1,2-dihydrophthalazine in 57% yield (18OL4545; Scheme 21). Wang and coworkers prepared 3-methyl-6-(methylthio)pyridazine in 85% yield, employing a three-component approach, by stirring 3-chloro-6-methylpyridazine (1 equiv) with potassium thioacetate (3 equiv) and dimethyl carbonate (DMC) (5 equiv) in DMSO at 120
C, using palladium(II) acetate (5 mol %) and triphenylphosphine (10 mol %) as the catalyst and potassium tert-butoxide (3 equiv) as the base (18OL6193; Scheme 22). An enantioselective functionalization of the pyridazine ring was described by Buchwald and coworkers, who developed an asymmetric copper(II)-catalyzed 1,4-dearomatization/functionalization/reoxidation of pyridazines (18JA5057; Scheme 23). The pyridazines were dearomatized with a chiral copper hydride complex, (PhBPE)CuH, and functionalized with an aryl alkene. Subsequent reoxidation with

Scheme 19 Ir-catalyzed CeH activation and subsequent annulation to generate phthalazino [2,3-a]cinnolin-8,13-diones.

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Scheme 20 Calcium triflimideepromoted pyridazyl sulfonyl fluoride activation.

Scheme 21 Functionalization of electron-poor phthalazine with carbon tetrachloride and arynes.

Scheme 22 Three-component generation of 3-methyl-6-(methylthio)pyridazine.

Scheme 23 Asymmetric copper(II)-catalyzed 1,4-aromatization of pyridazines.

oxygen or air in toluene at room temperature gave the resulting pyridazine derivatives in moderate to high yields with excellent enantiomeric excess (ee). Ahles and collaborators described an amine group transfer promoted by aromaticity via a diastereoselective inverse-electron-demand DielseAlder reaction of phthalazine

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Scheme 24 Generation of 1-amino-1,2-dihydronaphthalenes via a diastereoselective inverseelectron-demand DielseAlder reaction.

with aldehydes in the presence of amines, yielding 1-amino-1,2-dihydronaphthalenes in low to high yields (18OL7034; Scheme 24). Phthalazines were treated with aldehydes and amines in the presence of a bidentate Lewis-acid catalyst, 5,10-dimethyl5,10-dihydroboranthrene (5 mol %), in THF at 60
C for 15 h. The authors postulate that after the extrusion of nitrogen, an o-quinodimethane intermediate is formed, which is attacked by another molecule of the amine (Fig. 2). The final generation of the product may occur in one step by loss of the first amine or in a stepwise fashion proceeding through a zwitterionic species, then a proton transfer from the second amine group to the first causes the elimination of the protonated first amine group, and the desired 1-amino-1,2-dihydronaphthalene derivative is obtained. Xue and coworkers reported the synthesis of 2-aminonaphthalenes and 2-aminoanthracenes in good to high yields from phthalazines and ynamides via a metal-free inverse-electron-demand DielseAlder reaction with triflic anhydride in DCE at 100
C (18OL6055; Scheme 25).

Figure 2 Mechanism for the formation of 1-amino-1,2-dihydronaphthalenes from the o-quinodimethane intermediate.

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Scheme 25 Generation of 2-aminonaphthalenes and 2-aminoanthracenes from phthalazine and ynamides via an inverse-electron-demand DielseAlder reaction.

Furthermore, a report emerged in 2018, describing the novel use of benzo[c]cinnoline as a catalyst for an organocatalytic oxidation, exploiting the ability of diazenes to reoxidize fairly easily. Stone and coworkers employed a benzo[c]cinnoline-catalyzed Kornblum oxidation to convert alkyl halides into aldehydes (18AC(I)12494; Scheme 26). The resulting aldehydes were obtained in moderate to excellent yields. The authors performed additional experiments to support their postulated mechanism and recorded the changes in the color of the solution for each step: (1) nucleophilic substitution to add the benzyl group to the benzo[c]cinnoline catalyst in the presence of silver(I) triflate in anhydrous methylene chloride (dark-yellow solution); (2) deprotonation of the resulting triflate salt with H€ unig’s base (deep purple solution); and (3) hydrolysis with 1N HCl to give 5,6-dihydrobenzo[c]cinnoline and the corresponding aldehyde (orange solution) (Scheme 27).

6.2.2.3

Applications

In 2018, numerous reports, describing the biological activity of pyridazine-based compounds, emerged. Reilly and collaborators explored diazaspiro cores as substitutes for the piperazine ring in the structure of olaparib, and identified phthalazin-1(2H)-one 16 with an IC50 of 12.6  1.1 nM as a potent poly(ADP-ribose) polymerase inhibitor (PARPi), which did not show any DNA damage at drug levels similar to those of olaparib (18JMC5367; Fig. 3).

Scheme 26 Benzo[c]cinnoline-catalyzed oxidation of alkyl halides to aldehydes.

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Scheme 27 Reactions run in support of proposed mechanism.

Cheung and coworkers reported the discovery of clinical candidate pyridazinebased branaplam (17), a small-molecule modulator of survival motor neuron-2 (SMN2) to treat spinal muscular atrophy (SMA) (18JMC11021; Fig. 3). Barlaam and coworkers developed a series of 3-cinnoline carboxamides as selective ataxia telangiectasia mutated (ATM) kinase inhibitors, which are both orally bioavailable and potent (18AMCL809; Fig. 3). Their most potent compound, 18, with an IC50 ¼ 2.8 nM, also had favorable physicochemical and pharmacokinetic properties.

6.2.3 6.2.3.1

Pyrimidines and Benzo Derivatives Syntheses

In 2018, numerous groups employed the reaction of aryl or heteroaryl amines with carbonyl compounds to furnish the pyrimidine ring. Kim and coworkers prepared

Figure 3 Biologically active pyridazine-based compounds.

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pyrimidine- and quinazoline-fused benzimidazol-4,7-diones in low to good yields by treating b-bromo-a,b-unsaturated aldehydes or 2-bromobenzaldehydes with 4,7-dimethoxy-1H-benzo[d]imidazole-2-amines in the presence of potassium carbonate under microwave irradiation, followed by oxidation with cerium(IV) ammonium nitrate (CAN) in a mixture of acetonitrile and water at 0
C (18AO17456; Scheme 28). Arcadi and collaborators prepared indolo[1,2-c]quinazolines from 2-alkynylaniline via a palladium(0)-catalyzed indole formation followed by a dimethylformamide dimethyl acetal (DMFDMA)-promoted cyclization (18BJO2411; Scheme 29). Treatment of o-(o-aminophenylethynyl)trifluoroacetanilides (1.0 equiv) with arylboronic acids (2.0 equiv) in the presence of palladium(II) acetate (0.05 equiv), 1,3-bis(diphenylphosphino)propane (dppp) (0.05 equiv), and potassium phosphate (2 equiv) provided 2-(o-aminophenyl)-3-arylindoles, which upon subsequent exposure to DMFDMA (5 equiv) at 100
C formed the respective indolo[1,2-c]quinazolines. While 12-arylindolo[1,2-c]quinazolines were obtained in low to good yields, the yields for 12-unsubstituted indolo[1,2-c]quinazolines were good to high. The latter were prepared using only 1.2 equivalents of DMFDMA. A number of three-component strategies were employed to generate the pyrimidine ring. Hoang and coworkers developed a three-component coupling reaction for the formation of polysubstituted pyrazolo[1,5-a]pyrimidines from 3-aminopyrazoles, aldehydes, and sulfoxonium ylides (18JOC15347). Treatment of aminopyrazole 19 (1 equiv) with the respective aldehyde (2 equiv) and b-keto sulfoxonium ylide (1.5 equiv) in the presence of tris(acetonitrile)pentamethylcyclopentadienylrhodium(III) hexafluoroantimonate (10 mol %), potassium acetate, pivalic acid (4 equiv), and 3 Å molecular sieves in dioxane (0.4 M) provided the corresponding pyrazolo[1,5-a]pyrimidine in low to high yields (Scheme 30). The reaction conditions tolerated an array of aromatic, heteroaromatic, and aliphatic aldehyde and sulfoxonium ylide starting materials. Use of unsubstituted and 5-substituted 3-aminopyrazoles resulted in slightly lower yields. Two groups reported the construction of the pyrimidine ring via acceptorless dehydrogenative coupling reactions. Sultana Poly and collaborators devised a one-pot, acceptorless dehydrogenative synthesis of 2,4,6-trisubstituted pyrimidines from three components: amidines and secondary and primary alcohols (18AC11330). The reaction of amidines with primary and secondary alcohols in the presence of platinum on carbon and potassium tert-butoxide in refluxing toluene afforded the resulting trisubstituted pyrimidines in excellent yields (Scheme 31). Alkyl, aryl, and heteroaryl substituents were all well tolerated.

Scheme 28 Preparation of pyrimidine- and quinazoline-fused benzimidazole-4,7-diones via cyclocondensation and subsequent oxidation.

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Scheme 29 Preparation of indolo[1,2-c]quinazolines.

Scheme 30 Synthesis of functionalized pyrazolo[1,5-a]pyrimidines.

Scheme 31 One-pot acceptorless dehydrogenative synthesis of 2,4,6-trisubstituted pyrimidines.

Scheme 32 Synthesis of polysubstituted quinazolines via nickel-catalyzed dehydrogenative coupling reactions.

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Parua and coworkers developed two nickel-catalyzed acceptorless dehydrogenative coupling reactions for the preparation of multifunctionalized quinazolines (18JOC11154; Scheme 32). The first method coupled 2-aminobenzylamines with benzyl alcohols in the presence of nickel tetramethyltetraaza[14]annulene (MeTAA) and potassium tert-butoxide in xylene at 140
C. The second method employed 2-aminobenzyl alcohols and benzonitriles. In both cases, the resulting quinazolines were obtained in low to high yields. While aryl and heteroaryl substituents were well tolerated, attempts at synthesizing 2-butylquinazoline from either 1-pentanol and 2-aminobenzylamine or valeronitrile and 2-aminobenzyl alcohol resulted in yields of only 25% and 30%, respectively. No detrimental effects on the synthesis of the desired quinazoline derivatives were observed with either electron-donating or electron-withdrawing groups on either the 2-aminobenzylamine or the 2-aminobenzyl alcohol.

6.2.3.2

Reactions

In 2018 numerous reports described the synthesis of pyrimidine-based heterobiaryls. Hilton and coworkers prepared heterobiaryls via metal-free CeC contractive coupling reactions (18SCI799). The first step for the synthesis of pyrimidine 20 involved a phosphorus ligand coupling reaction between 2-(propylthio)pyrimidine and 2-(diphenylphosphanyl)-4-methylquinoline in the presence of triflic anhydride and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (Scheme 33). Exposure of the resulting salt to an acidic alcohol at 80
C furnished the heterobiaryl bond, giving pyrimidinebased heterobiaryl 20 in 37% yield. Markovic and collaborators prepared heterocyclic allylsulfones to function as latent heteroaryl nucleophiles in palladium-catalyzed cross-coupling reactions (18JA15916). This method was applied to pyrimidines, pyridazines, pyrazines, and quinoxalines. 5(Allylsulfonyl)-2,4-dimethoxypyrimidine and 2-(allylsulfonyl)pyrimidine underwent deallylative desulfinylative cross-coupling reactions with 1-bromo-4-methoxybenzene in the presence of potassium carbonate, palladium(II) acetate, and bis(1,1-dimethylethyl)methylphosphine to yield 2,4-dimethoxy-5-(4-methoxyphenyl)pyrimidine and 2-(4-methoxyphenyl)pyrimidine, respectively (Scheme 34). Gupta and coworkers devised a two-step protocol for the syntheses of 4-arylpyrimidines and unsymmetrical 4,6-disubstituted pyrimidines from

Scheme 33 Synthesis of heterobiaryls via CeC contractive coupling reaction.

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Scheme 34 Synthesis of polysubstituted pyrimidines from pyrimidinyl allylsulfones.

Scheme 35 Syntheses of 4-arylpyrimidine and 4,6-disubstituted pyrimidines from 4,6-dichloropyrimidine via SuzukieMiyaura reaction conditions.

Scheme 36 Functionalization of 4-chloro-6-substituted pyrimidines using SuzukieMiyaura reaction conditions.

Scheme 37 Hydrodechlorination of 6-chloropyrimidines.

4,6-dichloropyrimidine, employing SuzukieMiyaura and hydrodechlorination conditions (18H1549; Schemes 35e37). Treatment of 4,6-dichloropyrimidine with an arylboronic acid in the presence of tetrakis(triphenylphosphine)palladium(0), and sodium carbonate in refluxing isopropanol resulted in the formation of monoarylated pyrimidines and, in some cases, a mixture of both mono- and diarylated pyrimidines (Scheme 35). Subsequent dehydrochlorination with hydrogen and 5% palladium on carbon in the presence of triethylamine in ethanol allowed the separation of the mono- and diarylated products. Furthermore, it offered another approach to the synthesis of 4-arylpyrimidines (Scheme 37). Unsymmetrical 4,6-diarylpyrimidines were prepared by treating 4-chloro-6-substituted pyrimidines with an arylboronic acid, using similar

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SuzukieMiyaura reaction conditions as those employed for the generation of the monoarylated product (Scheme 36). The same group explored the ability of pyrimidine to act as an aryl CeH activating group (18OL3745). Arylation of 4-arylpyrimdines via pyrimidine-promoted ortho CeH activation occurred with para-substituted iodobenzene in the presence of palladium(II) acetate and silver(I) trifluoroacetate in propionic acid at 170
C for 15 h (Scheme 38a). The arylated products were obtained in low to good yields. Iodination of 4-arylpyrimidines with N-iodosuccinimide (NIS) in the presence of palladium(II) acetate in dioxane at 100
C for 6e24 h afforded the desired ortho-iodinated products in moderate to good yields (Scheme 38b). Further modifications of the ortho-iodinated products involved exposure to either SuzukieMiyaura or Sonogashira reaction conditions to give the corresponding arylated or alkynylated products, respectively (Scheme 39). Acetoxylation was effected via treatment of the starting 4-arylpyrimidine with (diacetoxyiodo)benzene and palladium(II) acetate in a 1:1 mixture of acetic acid and acetic anhydride at 100
C for 18 h (Scheme 38c). The resulting acetoxylated products were obtained in moderate to high yields. All of the reactions allowed gram-scale scale-ups. Two groups reported the synthesis of pyrimidine-based fused ring systems. Zinchenko and collaborators developed a one-pot synthesis of 6-aminopyrido[2,3-d] pyrimidin-7-ones from methyl N-(4-methoxybenzylidene)glycinate and 4-amino

(A)

(B)

(C)

Scheme 38 Function of pyrimidine as an aryl CeH activating group; (A) arylation, (B) iodination, and (C) acetoxylation.

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Scheme 39 Further functionalization of the iodination product.

Scheme 40 One-pot synthesis of 6-aminopyrido[2,3-d]pyrimidin-7-ones.

substituted 6-chloropyrimidin-5-carbaldehydes in two steps (18EJO6519; Scheme 40). The first step furnished the respective pyrido[2,3-d]pyrimidin-7-one, which upon heating with acetic acid gave rise to the corresponding 6-aminopyrido[2,3-d]pyrimidin7-one in high yield. The latter could be modified further. Hence, to examine the utility of their intermediate, the authors performed a number of nucleophilic aromatic substitution reactions and acylation reactions (Scheme 40). Kobayashi and coworkers prepared 5-hydroxythieno[2,3-d]pyrimidin-6(5H)-ones from 4,6-dichloro(methylsulfanyl)pyrimidine (DCSMP) (18H1248; Scheme 41). Treatment of DCSMP with lithium diisopropylamide (LDA) provided 4,6-dichloro5-lithio-2-(methylsulfanyl)pyrimidine, which was then exposed to a-ketoesters, furnishing 2-[4,6-dichloro-2-(methylsulfanyl)pyrimidin-5-yl]alkanoates. Subsequent cyclization of the latter with sodium hydrogensulfide yielded the respective 4-chloro-5-hydroxy-2-(methylsulfanyl)thieno[2,3-d]pyrimidin-6(5H)-ones in moderate yields. Further modification of the 2-[4,6-dichloro-2-(methylsulfanyl)pyrimidin5-yl]alkanoates either via treatment with sodium methoxide or secondary amines or

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Scheme 41 Synthesis of 5-hydroxythieno[2,3-d]pyrimidin-6(5H)-ones.

thiols resulted in the formation, after cyclization, of either 4-methoxythieno[2,3-d]pyrimidin-6(5H)-ones, in moderate yields, or 4-(dialkylamino)thieno[2,3-d]pyrimidin-6(5H)-ones, in good yields, or 4-(ethyl(or phenyl)sulfanyl)thieno[2,3-d] pyrimidin-6(5H)-ones, in low yields. New approaches to the functionalization of the pyrimidine ring were reported in 2018. As sulfonic acids can be used as linkers in coordination polymers, Kahrs and collaborators functionalized pyrimidine rings with benzenesulfonic acid to allow their incorporation into polymers (18EJO6499). To this effect, 5-bromopyrimidine was treated with boronic acid 21 in the presence of tetrakis(triphenylphosphine)palladium

Scheme 42 Functionalization of pyrimidine rings with benzenesulfonic acid.

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487

(0) and potassium carbonate in a 1:1 mixture of toluene and water at 140
C for 18 h (Scheme 42). The resulting 5-(4-tert-butylthiophenyl)pyrimidine was converted into 5-(acetylthiophenyl)pyrimidine with boron tribromide in a 4:1 mixture of toluene and acetyl chloride. Subsequent hydrolysis with potassium hydroxide in methanol gave 5-(4-mercaptophenyl)pyrimidine, which was oxidized to 4-(5-pyrimidyl)benzenesulfonic acid with aqueous hydrogen peroxide in methanol. Analogous conditions were employed when preparing the diacid, 5-(5-pyrimidyl)benzene-1,3-disulfonic acid. The authors also synthesized pyrimdine-based mono- and disulfonic acids with ethynyl linkers. Using Sonogashira reaction conditions, 5-ethynylpyrimidine was treated with neopentyl sulfonate 22, diisopropylamine, copper(I) iodide, and bis(triphenylphosphine)palladium(II) dichloride in anhydrous THF at 100
C for 18 h to afford neopentyl 4-(5-pyrimidylethynyl)benzenesulfonate (Scheme 43). Subsequent stirring of the latter in refluxing DMF for 21 h gave 4-(5-pyrimidylethynyl)benzenesulfonic acid. Analogous conditions were employed for the diacid. Tinson and coworkers examined the nucleophilic addition of Grignard reagents to 4-amino-5-cyano-2-methylpyrimidine in THF at varying temperatures, yielding aketo-2-methyl-4-aminopyrimidines as well as their unexpected C6-substituted analogs (18AO8937; Table 1). At lower temperatures, [1,2]-dihydropyrimidines (type C) appeared to be the favored product, while at higher temperatures, a-keto-2-methyl4-aminopyrimidines (type A) were formed more preferentially. Yet, when either methylmagnesium halide or ethylmagnesium halide was used at higher temperatures, the corresponding [1,2]dihydropyrimidines were the major product. Use of Grignard reagents with a bulky R group was also observed to give the [1,2]dihydropyrimidines primarily. The authors hypothesized that pyrimidine products of type B formed as a result of rearomatization of unstable [1,2]-dihydropyrimidines. The authors proposed the following mechanism for the generation of [1,2]dihydropyrimidine 23 (Scheme 44):

6.2.3.3

Applications

Advances have been made in the discovery and optimization of pyrimidine-based biologically active compounds. Koltun and coworkers prepared 5-(thiophen-2-yl)pyrazolo[1,5-a]pyrimidine-based calmodulin-dependent protein kinase II (CAMKII) inhibitors 24a and 24b, which showed good activity in rat ventricular myocytes, selectivity for CAMKII isoforms in cardiac cells, and essentially no inhibition of human

Scheme 43 Synthesis of 4-(5-pyrimidylethynyl)benzenesulfonic acid.

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Table 1 Yields of Grignard Addition Products.

entry

R

T (8C)

% Yield

% Yield

% Yield

1

Me

0e40

50

2

Me

40

3

Et

0e40

4

Et

40

5

Pr

0e40

6

Pr

0e25

7

Pr

40

8

Bu

0e40

9

Bu

0e25

87

10

i-Pr

0e25

56

11

t-Bu

40

42

12

Ph

0e40

13

Ph

0e25

81

14

vinyl

40

76

85 68

27 80

16

20 67

22 18

25

40

ether-a-go-go-related gene (hERG) potassium channels at concentrations below 30 mM. In addition, they exhibited acceptable in vitro and in vivo absorption, distribution, metabolism, and excretion/pharmacokinetic (ADME/PK) profiles, qualifying them for further pharmacological studies (18BMCL541; Fig. 4). Reich and collaborators reported the discovery and synthesis of a pyrimidine-based selective mitogen-activated protein kinase interacting kinases (MNKs) 1/2 dual inhibitor, 25 (eFT508), with an IC50 for MNK1 of 2.4 nM and for MNK2 of 1 nM, which displayed in vivo antitumor activity in solid tumors and large cell B-cell lymphoma and has entered phase 2 clinical trials (18JMC3516; Fig. 4). Waszkowycz and collaborators discovered and optimized cell-active 2,4-dioxo-quinazolin-6-sulfonamide-based inhibitors of DNA-damage repair enzyme poly(ADP-ribose) glycohydrolase (PARG) (18JMC10767; Fig. 4). Compound 26 with good toxicity, metabolic stability, and selectivity profiles emerged as a new lead.

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489

Scheme 44 Proposed mechanism for the generation of [1,2]dihydropyrimidine 23.

Li and collaborators discovered 5-(2,3-dihydro-1H-indol-5-yl)-7H-pyrrolo[2,3-d] pyrimidin-4-amines as a new class of receptor-interacting protein kinase 1 (RIPK1) inhibitors (18JMC11398; Fig. 4). The most potent compound, 27, was found to have an IC50 of 0.011  0.001 mM. Fell and collaborators reported the discovery of tetrahydropyridopyrimidines as irreversible covalent inhibitors of KRAS-G12C, a driver mutation commonly seen in lung cancer, with in vivo activity (18AMCL1230; Fig. 4). Structureeactivity relationship (SAR) studies resulted in the identification of compound 28 with an IC50 of 70 nM and demonstrated on-target potency as a new lead. Hobson and collaborators reported the discovery of selective dual inhibitors of Rhoassociated kinases 1 and 2 (ROCK1 and ROCK2), identifying 2-((S)-3-(aminomethyl) piperidin-1-yl)-N-((R)-1-(3-methoxyphenyl)ethyl)-4-(pyrimidin-4-yl)benzamide (29) as a potent selective dual ROCK1 and ROCK2 inhibitor with an IC50 of 120 nM for ROCK1 and 14 nM for ROCK2 and a favorable predicted ADME-tox profile (18JMC11074; Fig. 4).

6.2.4 6.2.4.1

Pyrazines and Benzo Derivatives Syntheses

In 2018, numerous variations of the pyrazine ring formation from the reaction of amine starting materials with carbonyl compounds were reported. Two groups constructed the pyrazine ring via the reaction of ortho-phenylenediamines with diketones. Shukla and coworkers developed a copper-catalyzed, TEMPO-mediated, one-pot cross-dehydrogenative thienannulation of b-naphthols with a-enolic dithioesters, leading to the formation of 2,3-disubstituted naphtho[2,1-b]thiophen-4,5-diones, which upon treatment with ortho-phenylenediamine formed benzo[a]thieno[3,2-c]phenazines in excellent yields via an L-proline-catalyzed cross-dehydrogenative coupling reaction at 100
C (18JOC2173; Scheme 45). B€aumler and Kempe reported the preparation of quinoxalines in good to high yields from 2-nitroanilines and diketones via an iron-catalyzed selective nitroarene hydrogenation (18CEJ8989; Scheme 46). Advantages of this synthesis are the stability, selectivity, and reusability of the FeeSiCN nanocomposite catalyst used. Two groups reported the use of manganese catalysts for the construction of the pyrazine ring via dehydrogenative coupling reactions. Daw and coworkers prepared

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Figure 4 Biologically active pyrimidine-based compounds.

quinoxalines and 2,5-dialkyl-substituted symmetrical pyrazines, employing manganese-catalyzed dehydrogenative coupling reactions (18AC7734; Scheme 47). The pyrazines were synthesized via reaction of two molecules of b-amino alcohols in the presence of catalyst 30 and potassium hydride in toluene at 150
C. Analogous reaction conditions were employed for the synthesis of the quinoxalines. The starting

Six-Membered Ring Systems: Diazines and Benzo Derivatives

491

Scheme 45 Formation of benzo[a]thieno[3,2-c]phenazines.

Scheme 46 Iron-catalyzed formation of quinoxalines via selective nitroarene hydrogenation.

materials for this conversion, however, were 1,2-diaminobenzenes and 1,2-diols. In both cases, the products were obtained in moderate to high yields. The authors proposed the following mechanistic steps for the formation of the respective pyrazines and quinoxalines (Scheme 48): Das and coworkers also devised a manganese-catalyzed dehydrogenative synthesis of pyrazines and quinoxalines (18CC10582; Scheme 49). The reaction conditions for the syntheses of the quinoxaline and the pyrazine derivatives included treatment of 1,2-diamines with 1,2-diols in the presence of manganese catalyst 31 and potassium hydroxide as the base at 140
C for 20 h. The products were obtained in moderate to high yields. In contrast to the method developed by Daw et al., which used toluene as the solvent, this reaction was run neat.

Scheme 47 Manganese-catalyzed formation of pyrazines and quinoxalines.

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Scheme 48 Mechanistic intermediates for the manganese-catalyzed dehydrogenative synthesis of pyrazines and quinoxalines.

Scheme 49 Another approach to the manganese-catalyzed dehydrogenative formation of pyrazines and quinoxalines.

One group reported the use of a TEMPO-initiated PicteteSpengler reaction to furnish the pyrazine moiety within a fused ring system. Huo and coworkers prepared pyrrolo[1,2-a]quinoxalines and 5,6-dihydroindolo[1,2-a]quinoxalines by employing a metal-free, TEMPO-oxoammonium-salt-aided approach (18S2727; Scheme 50). The TEMPO-oxoammonium-salt-initiated PicteteSpengler reaction of 2-(1H-pyrrol-1-yl) aniline with aldehydes in acetonitrile furnished the corresponding pyrrolo[1,2-a]quinoxalines in good to high yields. 5,6-Dihydroindolo[1,2-a]quinoxalines were obtained in high yields, when 2-(1H-indol-1-yl)anilines were treated with aldehydes using

Six-Membered Ring Systems: Diazines and Benzo Derivatives

493

Scheme 50 Metal-free synthesis of pyrrolo[1,2-a]quinoxalines.

analogous reaction conditions. The authors applied their newly developed methodology to the synthesis of biologically active 5,6-dihydroindolo[1,2-a]quinoxaline 32 (Scheme 51). Another group constructed the pyrazine ring using a tandem Michael addition/azidation/cycloamination protocol (18JOC9422; Scheme 52). Wu and collaborators reported that the treatment of anilines with fluoroalkynes in methanol at room temperature, followed by cycloamination with (diacetoxyiodo)benzene (PIDA) and trimethylsilyl azide in the presence of potassium iodide in DMSO, furnished the respective quinoxalines in low to high yields. It was found that PIDA and potassium iodide formed an iodine(I) species, AcOI, which played a significant role in promoting the ring formation and aromatization of the pyrazine ring by providing the iodine, which either iodinates the original aniline nitrogen or the a-carbon next to the ester group prior to the nucleophilic attack by the azide. The authors proposed the following mechanism (Scheme 53): Another group devised a one-pot, phosphorus-radical-initiated cascade reaction to form the pyrazine ring and thereby furnish 2-phosphoryl-substituted quinoxalines from ortho-diisocyanoarenes and diarylphosphine oxides (18JOC11727; Scheme 54). Optimized reaction conditions for this conversion, reported by Liu and collaborators, included the use of silver nitrate in acetonitrile at 80
C for 12 h. The desired 2-phosphoryl-substituted quinoxalines were obtained in low to high yields. While both electron-donating and electron-withdrawing substituents were well tolerated at the meta position of the starting diarylphosphine oxide, electron-withdrawing substituents at the para position resulted in lower yields. The yields for the reactions with the two sole dialkylphosphine oxides that were tested, dimethylphosphine oxide and diethylphosphine oxide, were low. Electron-donating substituents on the starting ortho-diisocyanoarenes provided higher yields than those with electron-withdrawing groups. The regioselectivity of this reaction was determined to be low.

Scheme 51 Synthesis of biologically active 5,6-dihydroindolo[1,2-a]quinoxaline 32.

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Scheme 52 Synthesis of quinoxalines via a tandem Michael addition/azidation/cycloamination.

Scheme 53 Proposed mechanism for the azidation/cycloamination leading to the formation of the quinoxaline ring system.

Scheme 54 Generation of 2-phosphoryl-substituted quinoxalines via a phosphorus-radicalinitiated cascade reaction.

Two different approaches to the synthesis of phenazines were reported. Sheng and coworkers prepared phenazines in a regioselective fashion by treating benzoxadiazole with diaryliodonium salts in the presence of copper(I) bromide in DCE at 70
C for

Six-Membered Ring Systems: Diazines and Benzo Derivatives

495

24 h, and converting the resulting phenazine N-oxide to the respective phenazine via in situ reduction either with zinc and ammonium chloride or triethyl phosphite (18OL4458; Scheme 55). A wide range of substituents and substitution patterns were well tolerated by these reaction conditions. Nozawa-Kumada and coworkers reduced nitrofluorobenzenes with a pyridinederived super electron donor, 34, to prepare symmetrical phenazines in low to good yields (18OBC3095; Scheme 56). Super electron donor 34 was formed in situ from its precursor, 35, by treatment with sodium hydride (2.5 equiv) in DMF for 1 h. Subsequent addition of the respective nitrofluorobenzene resulted in the generation of the corresponding phenazine.

6.2.4.2

Reactions

Two groups described the use of pyrazine N-oxides as precursors for pyrazine derivatives. Kim and Lee prepared 2-phenylpyrazine in 55% yield from 2-phenylpyrazine N-oxide, using visible-light-photocatalyzed deoxygenation conditions by stirring the N-oxide with tris(2,20 -bipyridyl)dichlororuthenium(II) hexahydrate, styrene, and hydrazine hydrate in DMSO under irradiation by blue LEDs (18OL7712; Scheme 57). Frei and collaborators developed a light- and metal-free method for functionalizing heterocyclic N-oxides (18JOC1510). A thioalkyl group was introduced to the 4-position of pyrazine N-oxides, employing a cyclic thioether, 4-nitrobenzoyl chloride, and triethylamine (Scheme 58). 3-((4-Chlorobutyl)thio)pyrazine-2-carbonitrile and 2-chloro-3-((4-chlorobutyl)thio)pyrazine were prepared in 56% and 54% yields, respectively. This method was also applied to pyrimidine N-oxides. Decarboxylative alkylations and alkoxylations were common approaches to the functionalization of the pyrazine ring, described in 2018. Sun and coworkers developed a visible-light-promoted decarboxylative alkylation of heterocycles, which was applied to, among other heterocyclic pharmaceuticals, the synthesis of brimonidine (36), which was obtained in 11% yield (18OL3487; Scheme 59). Analogous reaction conditions were used to prepare 2-(tert-butyl)quinoxaline in 58% yield. Stirring of the respective quinoxaline with pyridine N-oxide as a redox auxiliary, and pivaloyl chloride in the presence of [4,40 -bis(1,1-dimethylethyl)-2,20 -bipyridine-N1,N1’]bis [2-(2-pyridinyl-N)phenyl-C]iridium(III) hexafluorophosphate in acetonitrile under irradiation by blue LEDs, gave the corresponding alkylation product. Yu and collaborators devised a metal-free decarboxylative alkoxylation method, which they applied to the synthesis of 2-(2-(2-chloroethoxy)ethoxy)quinoxaline (18OL6780; Scheme 60). The latter was prepared in 95% yield from quinoxaline-

Scheme 55 Regioselective preparation of phenazines from benzoxadiazole and diaryliodonium salt.

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Scheme 56 Formation of phenazines via reduction of nitrofluorobenzenes, employing an electron donor.

Scheme 57 Visible-light-photocatalyzed deoxygenation of 2-phenylpyrazine N-oxide.

Scheme 58 Functionalization of the 4-position of pyrazine N-oxides.

2-carboxylic acid and 1,4-dioxane in the presence of p-chloranil and tert-butyl hypochlorite under inert atmosphere at 110
C. Functionalizations of activated pyrazine rings were reported. Bhilare and coworkers developed a palladium-catalyzed method for etherifying chloroheteroarenes with

Six-Membered Ring Systems: Diazines and Benzo Derivatives

497

Scheme 59 Formation of brimonidine (36) and 2-(tert-butyl)quinoxaline via visible-lightmediated alkylation.

Scheme 60 Decarboxylative alkoxylation of quinoxaline-2-carboxylic acid.

phenols and applied it to pyrazines and quinoxalines (18JOC13088). 2-Chloropyrazine was converted to 2-(4-methoxyphenoxy)pyrazine in 90% yield by stirring the former with 4-methoxyphenol, palladium(II) acetate, PTABS, and potassium phosphate in DMF at 60
C for 2 h (Scheme 61). Balkenhohl and collaborators aminated phosphorodiamidate-substituted quinoxalines with magnesium amides R2NMgCl•LiCl to provide the corresponding 2-aminated quinoxalines in good to high yields (18OL8057; Scheme 62). Other approaches required radical-promoted activation of the pyrazine ring. RevilBaudard and collaborators devised a method for functionalizing heteroarenes via xanthate-assisted addition of tertiary alkyl radicals, which they used to alkylate pyrazines, pyrimidines, pyridazines, and quinoxalines (18OL3531). Pyrazines bearing different substitution patterns and quinoxaline were treated with (S)-tert-butyl O-ethyl

Scheme 61 Pd/PTABS-catalyzed etherification of 2-chloropyrazine.

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Scheme 62 Amination of phosphorodiamidate-substituted quinoxalines.

xanthate and dilauroyl peroxide (DLP) in DCE at 85
C (Scheme 63). Low to high yields of the desired products were obtained. Another group developed mild dehydrogenation conditions for the preparation of quinoxalines from tetrahydroquinoxalines (18OL4723). 2-Methylquinoxaline and 2-phenylquinoxaline were obtained in quantitative yield by Zumbr€agel and collaborators via treatment of the respective tetrahydroquinoxalines with vanadium catalyst (S)37 in water at 60
C for 48 h (Scheme 64). A report emerged in 2018, describing the use of phenazine radical cations instead of metal catalysts for aerobic oxidative homo- and cross-coupling reactions of amines (18JOC13481). The phenazine radical cations were prepared by Brisar and collaborators from N,N0 -disubstituted dihydrophenazines via oxidation with nitrosyl tetrafluoroborate (Scheme 65). Single electron transfer (SET) to the amine in the second step of the catalytic cycle reforms the dihydrophenazine. The benzylamine radical reacts with a hydroperoxyl radical to give the imine intermediate. The latter then, upon addition of a different amine, forms the cross-coupled imine, or the side product, the amide, which arises from the oxidation of either the first imine intermediate or the cross-coupled imine. Out of all of the phenazine radical cations generated and used for this methodology, the 5,10-dihydro-5,10-dimethylphenazine radical cation showed the highest reaction rates and best selectivity for the imine product (Table 2).

Scheme 63 Xanthate-aided functionalization of pyrazines and quinoxaline with tertiary alkyl radicals.

Six-Membered Ring Systems: Diazines and Benzo Derivatives

499

Scheme 64 Vanadium-catalyzed dehydrogenation of tetrahydroquinoxalines.

Scheme 65 Catalytic cycle for the formation of phenazine radical cations and regeneration of dihydrophenazines.

6.2.4.3

Applications

Biologically active pyrazine-based molecules continue to be discovered, synthesized, analyzed, and optimized. Numerous reports, describing the identification, synthesis, and optimization of biologically active pyrazine-based compounds, were published in 2018. Ko and coworkers identified a new chemotype for histamine H4 receptor (H4R) antagonists (18JMC2949; Fig. 5). Of the pyrido[2,3-e]tetrazolo[1,5-a]pyrazine analogs prepared, lead compound 40 with an IC50 of 27 nM emerged as a highly active and selective H4R antagonist that has the desired properties, such as a favorable PK profile and oral bioavailability, of a clinical candidate for treatment of Alzheimer’s disease (AD). Ibrahim and collaborators prepared a series of [1,2,4]triazolo[4,3-a]quinoxalines and bis([1,2,4]triazolo)[4,3-a:30 ,40 -c]quinoxalines, which were tested against three tumor cell lines: HePG-2, Hep-2, and Caco-2 (18EJM117; Fig. 5). Their most promising compound, 41, inhibited restriction endonucleases Sal 1 enzymee and EcoR

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Table 2 Effect of the Functionalization of the Catalyst on the Conversion of the starting Material.

a

Catalyst

Conversion (mol %)

Selectivity (mol %)a

A

R¼H

99

81

B

R ¼ Me

99

97

C

R ¼ Ph

84

81

D

R ¼ 4-H3CeC6H5

71

90

E

R ¼ 4-F3CeC6H5

56

96

F

R ¼ 4-MeOeC6H5

55

98

Calculated by GC as (38a/(38aD39a))x100.

I-promoted DNA cleavage (IC50 ¼ 38.62 mM) and displayed topoisomerase II (Topo II) inhibitory activity (IC50 ¼ 0.85  0.06 mM). Qi and coworkers designed, prepared, and tested a new series of N-substituted 3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylic acid derivatives as inhibitors of tubulin polymerization, from which a new lead, 42, with an IC50 0f 3.97 mM, emerged (18EJM8; Fig. 5). Oyallon and collaborators synthesized and examined quinoxaline-2-carboxylic acids and their derivatives for their potential as human proviral integration site for Moloney murine leukemia virus-1 (Pim-1) kinase inhibitors (18EJM101; Fig. 5). Compound 43 with an IC50 of 74 nM, a favorable selectivity profile against a kinase panel of mammalian protein kinases, and antitumor activity in human chronic myeloid leukemia KU812 cells at micromolar concentrations, emerged as a new lead. Zhu and collaborators prepared and examined pyrazine and quinoxaline fluorophores for their potential as imaging tools for the in vivo detection of cerebral tau tangles in AD models (18CC11558; Fig. 5). Quinoxaline 44 met the requisite criteria, good brain kinetics, favorable emission wavelength, high affinity, and selectivity for tau aggregates, making it a potentially good, noninvasive imaging tool for in vivo and in vitro detection of cerebral tau tangles.

Six-Membered Ring Systems: Diazines and Benzo Derivatives

501

Figure 5 Biologically active pyrazine-based compounds.

References 18AC7734

P. Daw, A. Kumar, N.A. Espinosa-Jalapa, Y. Diskin-Posner, Y. Ben-David, D. Milstein, ACS Catal. 2018, 8, 7734. 18AC11330 S. Sultana Poly, S.M.A.H. Siddiki, A.S. Touchy, K.W. Ting, T. Toyao, Z. Maeno, Y. Kanda, K.-i. Shimizu, ACS Catal. 2018, 8, 11330. 18AG(I)12494 I.B. Stone, J. Jermaks, S.N. MacMillan, T.H. Lambert, Angew. Chem. Int. Ed. 2018, 57, 12494. 18AMCL809 B. Barlaam, E. Cadogan, A. Campbell, N. Colclough, A. Dishington, S. Durant, K. Goldberg, L.A. Hassall, G.D. Hughes, P.A. MacFaul, T.M. McGuire, M. Pass, A. Patel, S. Pearson, J. Petersen, K.G. Pike, G. Robb, N. Stratton, G. Xin, B. Zhai, ACS Med. Chem. Lett. 2018, 9, 809. 18AMCL1230 J.B. Fell, J.P. Fischer, B.R. Baer, J. Ballard, J.F. Blake, K. Bouhana, B.J. Brandhuber, D.M. Briere, L.E. Burgess, M.R. Burkard, H. Chiang, M.J. Chicarelli, K. Davidson, J.J. Gaudino, J. Hallin, L. Hanson, K. Hee, E.J. Hicken, R.J. Hinklin, M.A. Marx, M.J. Mejia, P. Olson, P. Savechenkov, N. Sudhakar, T.P. Tang, G.P. Vigers, H. Zecca, J.G. Christensen, ACS Med. Chem. Lett. 2018, 9, 1230. 18AO8937 R.A.J. Tinson, D.L. Hughes, L. Ward, G.R. Stephenson, ACS Omega 2018, 3, 8937. 18AO14575 P. Cai, E. Zhang, Y. Wu, T. Fang, Q. Li, C. Yang, J. Wang, Y. Shang, ACS Omega 2018, 3, 14575. 18AO16601 S. Kumar, D. Mondal, M.S. Balakrishna, ACS Omega 2018, 3, 16601. 18AO17456 D.Y. Kim, P.D. Quang Dao, C.S. Cho, ACS Omega 2018, 3, 17456. 18BJO2411 A. Arcadi, S. Cacchi, G. Fabrizi, F. Ghirga, A. Goggiamani, A. Iazzetti, F. Marinelli, Beilstein J. Org. Chem. 2018, 14, 2411.

502

18BMCL541

18CC10582 18CC11558 18CC13857 18CEJ8989 18CEJ11278 18CS2092 18EJM8 18EJM101

18EJM117

18EJM542 18EJO2233 18EJO3541 18EJO3618 18EJO5304 18EJO6499 18EJO6519 18H1248 18H1549 18JA4110 18JA5057 18JA15916 18JMC2949

18JMC3516

Progress in Heterocyclic Chemistry

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Six-Membered Ring Systems: Diazines and Benzo Derivatives

18JMC5367 18JMC10767

18JMC11021

18JMC11074

18JMC11398

18JOC1 18JOC1510 18JOC2173 18JOC5438 18JOC6133 18JOC6142 18JOC7771 18JOC9422 18JOC10845 18JOC11154 18JOC11661 18JOC11727

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504

18JOC13088 18JOC13481 18JOC15347 18OBC3095 18OBC8585 18OL2346 18OL3229 18OL3487 18OL3531 18OL3745 18OL3943

18OL4458 18OL4545 18OL4686 18OL4723 18OL6055 18OL6193 18OL6780 18OL6863 18OL7034 18OL7712 18OL8057 18S2727 18SCI799 18SL2503

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