molecules

Review Synthesis and Chemical Properties of 3-Phosphono-coumarins and 1,2-Benzoxaphosphorins as Precursors for Bioactive Compounds

Ana I. Koleva , Nevena I. Petkova-Yankova and Rositca D. Nikolova *

Department of Organic Chemistry and Pharmacognosy, Faculty of Chemistry and Pharmacy, Sofia University “St. Kliment Ohridski”, 1 J. Bouchier Buld., 1164 Sofia, Bulgaria; [email protected] (A.I.K.); [email protected]fia.bg (N.I.P.-Y.) * Correspondence: [email protected]fia.bg; Tel.: +359-2-8161-392



Academic Editors: Salvatore Genovese, Serena Fiorito and Vito Alessandro Taddeo
 Received: 24 April 2019; Accepted: 27 May 2019; Published: 28 May 2019

Abstract: Coumarins are an important class of natural heterocyclic compounds that have attracted considerable synthetic and pharmacological interest due to their various biological activities. This review emphasizes on the synthetic methods for the preparation of dialkyl 2-oxo-2H-1-benzo- pyran-3-phosphonates and alkyl 1,2-benzoxaphosphorin-3-carboxylates. Their chemical properties as acceptors in conjugate addition reactions, [2+2] and [3+2] cycloaddition reactions are discussed.

Keywords: coumarins; 2-oxo-2H-1-benzopyrans; 2-oxo-2H-chromenes; 1,2-bezoxaphosphorines; 1,2-bezoxaphosphorines-3-phosphonic acid; 1,2-phosphorinines; conjugate addition; [2+2] cycloaddition; [3+2] cycloaddition

1. Introduction Drug discovery plays an important role in the development of modern society as well as the growth of the pharmaceutical and chemical industry. A key step in this process is the identification of the compound properties and activities while planning its molecular structure. The pyran group is characteristic of a great diversity of compounds possessing different pharmacological properties. Coumarins, 2-oxo-2H-1-benzopyrans or 2-oxo-2H-chromenes are an important class of natural heterocyclic compounds. The coumarin moiety could be found in different plants’ secondary metabolites. They play a major role in the proper functioning of the individual plant parts. Moreover, coumarin derivatives have gained considerable synthetic and pharmacological interest due to their various biological activities like antitumor, anti-HIV, antimicrobial, anti-cancer, serine protease inhibition, vasorelaxant and antioxidant activity [1–5]. Phosphorus-containing structures such as 1 and its analogue 2, presented in Figure1, are of a great importance in the areas of pharmacology, chemistry and agriculture due to the similarity of phosphorus compounds to the naturally occurring carboxylic acid derivatives and their possible application in diverse biological systems. Many research papers have illustrated that the chemical behavior of coumarins depends mainly on the substituent at position C-3 in the lactone ring. A phosphoryl group in this position should enhance the biological activities of the resulting 3-phosphonocoumarins as well as influence the chemical properties owing its electron-withdrawing characteristic. Therefore, the combination of the two fragments—a coumarin system containing a phosphoryl group—could open a route to a new class of compounds, which structures might possess wide spectrum of biological activities due to the presence of the different functional groups. In fact, the biological activity of the two represented isomers on Figure1 is less studied. The great interest to these compounds is due to their application as important precursors for compounds with proven pharmacological

Molecules 2019, 24, 2030; doi:10.3390/molecules24112030 www.mdpi.com/journal/molecules Molecules 2019, 24, 2030 2 of 38 MoleculesMolecules 20192019,, 2424,, 20302030 22 ofof 3838 proven pharmacological properties. Structures of compoundscompounds possessingpossessing pharmacophore fragments properties.and exhibiting Structures anti-cancer, of compounds anti-inflammatory, possessing pharmacophore anti-arthritic fragments and anticonvulsant and exhibiting activity anti-cancer, are anti-inflammatory,presented in Figure anti-arthritic 2 [6–13]. and anticonvulsant activity are presented in Figure2[6–13].

Figure 1. Phosphorus-containing structures 1 and its phosphoroheterocyclic analogueanalogue 22...

Figure 2. Biologically active compounds and drugs. Figure 2. Biologically active compounds and drugs. The Knoevenagel reaction was the first to be applied in the synthesis of phosphonocoumarins as The Knoevenagel reaction was the first to be applied in the synthesis of phosphonocoumarins many other 3-substituted coumarins. In the next decades the interest in those derivatives has increased as many other 3-substituted coumarins. In the next decades the interest in those derivatives has and new synthetic methods have been developed. The first 1,2-bezoxaphosphorines were obtained as increasedincreased andand newnew syntheticsynthetic methodsmethods havehave beenbeen dedeveloped. The first 1,2-bezoxaphosphorines were side products via lactonization conditions. Therefore, further procedures illustrate alternative routes for obtained as side products via lactonization conditions. Therefore, further procedures illustrate their preparation. Surprisingly, only one review paper, published in 2004 [14], appeared presenting some alternative routes for their preparation. Surprisingly, only one review paper, published in 2004 [14], of the properties of these compounds. The aim of this review is to emphasize on the synthetic methods appeared presenting some ofof thethe propertiesproperties ofof thesethese compoundcompounds. The aim of this review is to for dialkyl 2-oxo-2H-1-benzopyran-3-phosphonates and alkyl 1,2-benzoxaphosphorin-3-carboxylates emphasize on the synthetic methods for dialkyl 2-oxo-2H-1-benzopyran-3-phosphonates and alkyl preparation. The particular interest towards this class of organic compounds is due to their potential 1,2-benzoxaphosphorin-3-carboxylates preparation. The particular interest towards this class of application as acceptors in different organic reactions with nucleophillic reagents and 1,3-dipolar organic compounds is due to their potential application as acceptors in different organic reactions cycloaddition reactions as well as to their application as intermediates in the synthesis of products of with nucleophillic reagents and 1,3-dipolar cycloaddition reactions as well as to their application as practical interest proving their biological activity as new therapeutics. intermediatesintermediates inin thethe synthesissynthesis ofof productsproducts ofof practipractical interest proving their biological activity as new therapeutics. 2.new Synthesis therapeutics. and Some Reactions of Dialkyl 2-oxo-2H-1-benzopyran-3-phosphonates 1 2. Synthesis and Some Reactions of Dialkyl 2-oxo-2H-1-benzopyran-3-phosphonates 1 2.1.2. Synthesis Synthesis and of Dialkyl Some 2-oxo-2H-1-benzopyran-3-phosphonates Reactions of Dialkyl 2-oxo-2H-1-benzopyran-3-phosphonates1 1 1a 2.1. SynthesisSince the of firstDialkyl synthesis 2-oxo-2H-1-benzopyran-3-phosphonates of 3-diethylphosphonocoumarin 1 ( ) by Robinson and Addison in 1966 [15], many research groups have been interested in its chemical behavior and various Since the first synthesis of 3-diethylphosphonocoumarin (1a) by Robinson and Addison in 1966 syntheticSince strategiesthe first synthesis to access of 3-diethylphosphonocoumarin this molecule have been presented. (1a) by Robinson There are and several Addison methods in 1966 [15], many research groups have been interested in its chemical behavior and various synthetic described[15], many in research the literature groups forhave the been synthesis interested of diethyl in its chemical 2-oxo-2H behavior-1-benzopyran-3-phosphonates and various synthetic strategies to access this molecule have been presented. There are several methods described in the 1strategiesand their to derivatives.access this molecule These protocolshave been can presented. be grouped There according are several to methods the method described or reaction in the literature for the synthesis of diethyl 2-oxo-2H-1-benzopyran-3-phosphonates 1 and their usedliterature into Knoevenagelfor the synthesis condensations of diethyl [15 –2-oxo-221], applicationsH-1-benzopyran-3-phosphonates of phosphoryl ketenimines 1 and [ 22their] or derivatives. These protocols can be grouped according to the method or reaction used into vinylphosphonatesderivatives. These [23protocols–27] as precursors, can be groupedcatalytic according [28–32] or electrochemicalto the method [ 33or– 35reaction] phosphorylation, used into Knoevenagel condensations [15–21], applications of phosphoryl ketenimines [22] or protocolsKnoevenagel using condensations three-component [15–21], and tandem applicatio couplingns reactionsof phosphoryl [36–38] or throughketenimines rearrangement [22] or vinylphosphonates [23–27] as precursors, catalytic [28–32] or electrochemical [33–35] processesvinylphosphonates [39]. [23–27] as precursors, catalytic [28–32] or electrochemical [33–35]

Molecules 2019, 24, 2030 3 of 38 Molecules 2019, 24, 2030 3 of 38 phosphorylation, protocols using three-component and tandem coupling reactions [36–38] or Molecules 2019, 24, 2030 3 of 38 throughphosphorylation, rearrangement protocols processes usin g[39]. three-component and tandem coupling reactions [36–38] or through rearrangement processes [39]. 2.1.1. Synthetic Protocols A Applyingpplying Knoevena Knoevenagelgel Reaction 2.1.1. Synthetic Protocols Applying Knoevenagel Reaction 3-Diethylphosphonocoumarin ((1a1a)) waswas obtained obtained via via a a Knoevenagel Knoevenage condensationl condensation reaction reaction [15 [15]] of 3-Diethylphosphonocoumarin (1a) was obtained via a Knoevenagel condensation reaction [15] ofsalicylaldehyde salicylaldehyde (3) with(3) with triethyl triethyl phosphonoacetate phosphonoacetate (4) under (4) under basic conditions.basic conditions. However, However, the formed the of salicylaldehyde (3) with triethyl phosphonoacetate (4) under basic conditions. However, the productformed product could not could be purified not be due purified to its highdue boilingto its high point boiling and the point structure and ofthe1a structurewas determined of 1a was on formed product could not be purified due to its high boiling point and the structure of 1a was determinedthe basis of theon the hydrolyzed basis of the product hydrolyzed5 (Scheme product1). 5 (Scheme 1). determined on the basis of the hydrolyzed product 5 (Scheme 1).

Scheme 1. KnoevenagelKnoevenagel condensation condensation reaction reaction of of salicylaldehyde salicylaldehyde ( (3a3a)) with with triethyl triethyl phosphono- phosphono- Scheme 1. Knoevenagel condensation reaction of salicylaldehyde (3a) with triethyl phosphono- acetate (4). acetate (4). In 1985 Singh and Rogers [[16]16] reported a modifiedmodified procedure for the synthesissynthesis of substituted 3-diethylphosphonocoumarinsIn 1985 Singh and Rogers by[16] usingus reporteding triethyl a modi phosphonoacetatefied procedure (4 for) and the series synthesis of salicylaldehydes of substituted 3a3-diethylphosphonocoumarins–f (Scheme(Scheme2 , Method2, Method A). TheA). by reaction usTheing reactiontriethyl was accomplished phosphonoacetate was accomplished in 18 ( h4) using andin series titanium18 h of salicylaldehydesusing tetrachloride titanium/ pyridinetetrachloride/pyridine3a–f (Scheme as a catalytic2, Method as systema catalyticA). andThe system tetrahydrofuran reaction and tetrahydrofuranwas asaccomplished a solvent. as a Theinsolvent. 18 structures h The using structures of titanium isolated of isolated3-dialkylphosphonocoumarinstetrachloride/pyridine 3-dialkylphosphonocoumarins as a catalytic1a–f were system 1a characterized–f were and characterized tetrahydrofuran for the first for timethe as firsta by solvent. 31timeP-NMR by The 31P-NMR spectra structures andspectra forof 31 1bandisolatedby for1H-NMR. 1b 3-dialkylp by 1H-NMR.hosphonocoumarins 1a–f were characterized for the first time by P-NMR spectra and for 1b by 1H-NMR.

Scheme 2. DifferentDifferent synthetic methods for the form formationation of 3-dialkylphosphonocoumarins 11.. Scheme 2. Different synthetic methods for the formation of 3-dialkylphosphonocoumarins 1. Bouyssou and Chenault studied the formation of coumarins 1a and 1g under liquidliquid/liquid/liquid phaseBouyssou transfer conditionsand Chenault at lowlow studied temperaturestemperatures the formation [[1818].]. The of condensationcoumarins 1a reactionand 1g betweenunder liquid/liquid acetylated hydroxyaromaticphase transfer conditions aldehydes at 6alowand temperatures6g with triethyl [18]. phosphonoacetateThe condensation (reaction4) was carried between out acetylated applying

MoleculesMolecules 20192019,, 2424,, 20302030 44 ofof 3838 hydroxyaromaticMoleculeshydroxyaromatic2019, 24, 2030 aldehydesaldehydes 6a6a andand 6g6g withwith triethyltriethyl phosphonoacetatephosphonoacetate ((44)) waswas carriedcarried outout applyingapplying4 of 38 sodiumsodium hydroxidehydroxide asas aa basebase (Scheme(Scheme 2,2, MethodMethod B).B). TheThe KnoevenagelKnoevenagel condensationcondensation productsproducts 1a1a andand 1g1g werewere isolatedisolated inin goodgood yieldsyields (Scheme(Scheme 2,2, MethodMethod B).B). sodiumFalsoneFalsone hydroxide et.et. al.al. as [19][19] a base applappl (Schemeiedied piperidinepiperidine2, Method acetate/acetate/ B). Theββ Knoevenagel-alanine-alanine asas catalystcatalyst condensation forfor thethe products initiationinitiation1a andofof thethe1g lactonizationwerelactonization isolated process. inprocess. good yields TheThe reactionreaction (Scheme betweenbetween2, Method substitutedsubstituted B). salicylaldehydessalicylaldehydes 3a3a––bb,, 3g3g––hh andand triethyltriethyl β phosphonoacetatephosphonoacetateFalsone et al. (( [4419,, ]SchemeScheme applied 2,2, piperidine MethodMethod C)C) acetate resultedresulted/ -alanine inin thethe asformationformation catalyst forofof 3-diethylphosphono-3-diethylphosphono- the initiation of the coumarinslactonizationcoumarins 1a1a,, process.bb andand 1h1h, The,ii inin high reactionhigh yields.yields. between TheThe appliedapplied substituted catalystcatalyst salicylaldehydes demonstrateddemonstrated 3aexcellentexcellent–b, 3g– hactivityactivityand triethyl inin thethe KnoevenagelphosphonoacetateKnoevenagel condensationcondensation (4, Scheme inin2, comparison Methodcomparison C) resulted withwith thth inee theotherother formation catalyticcatalytic of systemssystems 3-diethylphosphono- usedused inin MethodMethod coumarins AA andand Method1aMethod,b and B.B.1h ,i in high yields. The applied catalyst demonstrated excellent activity in the Knoevenagel condensationChenChen andand in comparisoncoauthorscoauthors [17][17] with werewere the other thethe catalyticfirstfirst toto systemsreportreport usedthethe formation information Method Aofof and alkylalkyl Method 1,2-benzoxa-1,2-benzoxa- B. phosphorin-3-carboxylatesphosphorin-3-carboxylatesChen and coauthors [2172 ]viavia were KnoevenagelKnoevenagel the first to reportcondensation.condensation. the formation TheThe reactionreaction of alkyl 1,2-benzoxa-ofof triethyltriethyl phosphonoacetatephosphorin-3-carboxylatesphosphonoacetate ((44)) andand2 electron-donatingelectron-donatingvia Knoevenagel condensation. group-substitutedgroup-substituted The reaction salicylaldehydessalicylaldehydes of triethyl phosphonoacetate 3e3e andand 3i3i,,jj waswas catalyzed(catalyzed4) and electron-donating byby freshlyfreshly preparedprepared group-substituted piperidiniumpiperidinium salicylaldehydes acetate.acetate. Thus,Thus,3e and notnot3i ,jonlyonlywas catalyzedthethe correspondingcorresponding by freshly 3-diethylphosphonocoumarinsprepared3-diethylphosphonocoumarins piperidinium acetate. 1e1e Thus, andand not1h1h,,ii only werewere the isolatedisolated corresponding andand characterized,characterized, 3-diethylphosphonocoumarins butbut alsoalso theirtheir analoguesanalogues1e 2aand2a––cc 1h inin, iwhichwhichwere isolatedaa P-atomP-atom and replacedreplaced characterized, thethe αα-pyronyl-pyronyl but also carboncarbon their analogues atomatom (Scheme(Scheme2a–c in 3).3). which InIn SectionSection a P-atom 33.. ofof replaced thethe articlearticle the α thethe-pyronyl specificspecific carbon methodsmethods atom for (Schemefor thethe 3synthesissynthesis). In Section ofof3 .1,2-1,2- of thebenzoxaphosphorinesbenzoxaphosphorines article the specific methods andand theirtheir for thederivativesderivatives synthesis are ofare discussed.1,2-benzoxaphosphorinesdiscussed. and their derivatives are discussed.

SchemeScheme 3. 3. KnoevenagelKnoevenagel condensation condensation reaction reaction with with piperidine piperidine as as catalyst. catalyst.

FewFew yearsyears laterlaterlater another anotheranother approach approachapproach presented presentedpresented the thth synthesisee synthesissynthesis of 3-diethylphosphonocoumarines ofof 3-diethy3-diethylphosphonocoumarineslphosphonocoumarines and and1,2-benzoxaphosphorinesand 1,2-benzoxaphosphorines1,2-benzoxaphosphorines applying applyingapplying various variousvarious CH-acidic CH-acidicCH-acidic components. components.components. Bojilova Bojilova etBojilova al. [20 ]etet performed al.al. [20][20] performedtheperformed Knoevenagel thethe KnoevenagelKnoevenagel reaction under reactionreaction modified underunder conditionsmodifiedmodified conditionsconditions using both usingusing organic bothboth and organicorganic inorganic andand inorganicinorganic catalysts catalysts(Tablecatalysts1, Scheme (Table(Table 4 1,).1, TheSchemeScheme main 4).4). contribution TheThe mainmain ofcontributioncontribution the study was ofof thethe analysisstudystudy waswas of the thethe ratio analysisanalysis between ofof thethe tworatioratio betweenchemoisomersbetween thethe twotwo and chemoisomerschemoisomers the possible mechanismandand thethe possiblepossible of the mechanismmechanism reaction. ofof thethe reaction.reaction.

SchemeScheme 4. 4. KnoevenagelKnoevenagel condensationcondensation reactionreaction wi withwithth organic organic and and inorganic inorganic catalysts. catalysts.

3-Diethylphosphonocoumarines3-Diethylphosphonocoumarines 1a1a1a––ccc,,,jjj andand 1,2-benzoxaphosphorines 1,2-benzoxaphosphorines 2b2b––fff werewere prepared prepared in in 1 solutionsolution (toluene (toluene andand ethanol)ethanol) andand inin thethe presencepresence ofof anan organicorganic basebase (Method(Method A,A, AA 11,, , C,C, C, D;D; D; TableTable Table 11).1).). Different adsorbents (Al O zeolites, molecular sieves and Florisil) or titanium tetrachloride (Method DifferentDifferent adsorbentsadsorbents (Al(Al222OO3,3, zeolites, zeolites, molecularmolecular sievessieves andand FlorisilFlorisil)) oror titaniumtitanium tetrachloridetetrachloride (Method(Method B;;B; Table TableTable1 ) 1)1) were werewere also alsoalso applied appliedapplied as asas catalysts catalystscatalysts and andand the thethe only onlyonly isolated isolatedisolated product productproduct was waswas the thethe corresponding correspondingcorresponding substituted 3-diethylphosphonocoumarin. 3-diethylphosphonocoumarin.

Molecules 2019, 24, 2030 5 of 38

Table 1. Reaction conditions for the preparation of 1a–c,j and 2b–f using different catalysts.

R1 X R Method Overall Yield 1 a 2 a A 51 33 11 Me COOEt H A1 56 27 21 B 20 20 0 A 87 70 9 A1 98 84 14 Et COOEt H B 50 50 0 C 74 66 8 A 59 47 8 Et COOSi(Me)3 H C 28 20 2 D 73 57 9 A 69 45 24 A1 52 17 35 Et CN H B 49 49 0 C 55 47 8 D 60 42 18 A 98 77 19 Et COOEt 6-Br B 81 81 0 C 50 40 4 A 78 65 9 Et COOEt 6-Cl B 71 71 0 C 67 41 20 A 81 64 17 Et COOEt 7-NEt2 B 3 3 0 C 86 71 15 Method A: Toluene/piperidine/Dean-Stark trap; Method A1: Toluene/piperidine/Dean-Stark short distance trap; Method B: THF/TiCl4/pyridine; Method C: Toluene/β-alanine/piperidine acetate/Dean-Stark short path trap; Method D: Toluene/piperidine/mol. siev. 4A, reflux. a Isolated yields.

The detailed results and information are presented in Table1 where the di fferent reaction conditions, the comparisons of the ratios between the two products and the influence of the substituent R are illustrated. The optimized conditions revealed that the crucial step for the condensation is the azeotropic removal of water. For example the overall yield of 98%, and 84% for 1a, was achieved when toluene/piperidine and a Dean-Stark short path trap were used for the reaction between triethyl phosphonoacetate and salicylaldehyde. The effective condensation reaction depends on the used CH-acidic component and the electronic effect of the substituent in the aromatic aldehydes. The observed regioselectivity is explained on the base of the configuration of the two possible intermediates I-1 and I-3 (Scheme5) which are formed in the addition step. Subsequent trans-elimination of a water molecule leads to formation of intermediates E-I-2 and Z-I-4. The following intermolecular pre-esterification of the phosphoryl or ester group resulted in ring closure to the corresponding 3-diethylphosphonocoumarines or 1,2-benzoxaphosphorines. The preferred E-configuration of the intermediate E-I-2 was due to the strong steric interaction between the bulky phosphoryl group and the hydroxyphenyl substituent that could be observed in the intermediate I-3. The predominant isolation of 3-diethylphosphonocoumarines over 1,2-benzoxaphosphorines is a result of the formation of the stable E-isomer in that reaction conditions. Molecules 2019, 24, 2030 6 of 38 Molecules 2019, 24, 2030 6 of 38 Molecules 2019, 24, 2030 6 of 38 Molecules 2019, 24, 2030 6 of 38

Scheme 5. Different reaction paths explaining the ratio of the products 1 and 2. Scheme 5. Different reaction paths explaining the ratio of the products 1 and 2. Scheme 5. DifferentDifferent reaction paths explainingexplaining the ratio ofof thethe productsproducts 11 andand 22.. The complete regioselectivity of the reaction in the presence of titanium tetrachloride (Method B) orThe adsorbents complete wasregioselectivity explained byof thea chelate-complex reaction in the presenceformation, of titaniumFigure 3, tetrachloride involving 4 (Methodand the The completecomplete regioselectivityregioselectivity ofof the the reaction reaction in in the the presence presence of of titanium titanium tetrachloride tetrachloride (Method (Method B) B)titanium or adsorbents salt. An analogouswas explained orientation by a ofchelate-complex the reactants on formation, the surface Figure of the adsorbent3, involving might 4 and also the be orB) adsorbentsor adsorbents was was explained explained by a chelate-complexby a chelate-complex formation, formation, Figure 3Figure, involving 3, involving4 and the 4 titaniumand the titaniumassembled salt. in Anthat analogous case. Due orientation to the strong of the steric reactants effect on between the surface the ofphosphoryl the adsorbent and mightthe aromatic also be salt.titanium An analogous salt. An analogous orientation orientation of the reactants of the onreactants the surface on the of thesurface adsorbent of the mightadsorbent also might be assembled also be assembledgroup, the formationin that case. of intermediateDue to the strongI-5 was steric favored effect and between since this the steric phosphoryl interaction and could the appeararomatic in inassembled that case. in Duethat tocase. the Due strong to stericthe strong effect steric between effect the between phosphoryl the phosphoryl and the aromatic and the group, aromatic the group,the first the step formation of the process, of intermediate it could prevent I-5 was the favored formation and sinceof I-6 this. Therefore, steric interaction the reaction could took appear place asin formationgroup, the of formation intermediate of intermediateI-5 was favored I-5 was and favored since this and steric since interaction this steric could interaction appear could in the appear first step in thea preferential first step of stereoselective the process, it Ecould-olefination. prevent the formation of I-6. Therefore, the reaction took place as ofthe the first process, step of it the could process, prevent it could the formation prevent the of I-6formation. Therefore, of I-6 the. Therefore, reaction took the placereaction as atook preferential place as a preferential stereoselective E-olefination. stereoselectivea preferential stereoselectiveE-olefination. E-olefination.

Figure 3. Titanium chelate-complex formation. Figure 3. TitaniumTitanium chelate-complex chelate-complex formation. Figure 3. Titanium chelate-complex formation. Regulating plant growth activity of a series of 3-diethylphosphonocoumarins and 1,2-benzoxaphosphorines,Regulating plant plant growth synthesized activity in thisof study,a seriesseries was oftested 3-diethylphosphonocoumarins3-diethylpho [40] as auxinssphonocoumarins of different plantand Regulating plant growth activity of a series of 3-diethylphosphonocoumarins and 1,2-benzoxaphosphorines,seeds. synthesizedsynthesized inin this this study, study, was was tested tested [40 ][40] as auxins as auxins of di ffoferent different plant seeds.plant 1,2-benzoxaphosphorines, synthesized in this study, was tested [40] as auxins of different plant seeds.During thethe investigationsinvestigations of of the the synthesis synthesis of new of new therapeutics, therapeutics, Budzisz Budzisz et al. performed et al. performed a reaction a seeds. reactionof 20-bromoacetoxyphenonesDuring of 2 the′-bromoacetoxyphenones investigations8a –ofe withthe 8asynthesis trimethyl–e with of phosphitetrimethyl new therapeutics, phosphite (9, Scheme 6(Budzisz9), and Scheme coumarin et 6)al. and performed compounds coumarin a During the investigations of the synthesis of new therapeutics, Budzisz et al. performed a reactionwerecompounds isolated of 2 ′were-bromoacetoxyphenones as minor isolated products as minor [21]. products8a The–e with authors [21]. trimethyl elaboratedThe authors phosphite on elaborated the (9 formation, Scheme on the6) of and Arbuzovformation coumarin type of reaction of 2′-bromoacetoxyphenones 8a–e with trimethyl phosphite (9, Scheme 6) and coumarin compoundsArbuzovCH-acidic compoundstype were CH-acidic isolated that proceeded ascompounds minor inproducts an intramolecularthat [21].proceeded The Knoevenagelauthors in an elaborated intramolecular condensation on the resulting formationKnoevenagel in theof compounds were isolated as minor products [21]. The authors elaborated on the formation of Arbuzovcondensationformation oftype1l resulting– pCH-acidic. in the compoundsformation of 1lthat–p . proceeded in an intramolecular Knoevenagel Arbuzov type CH-acidic compounds that proceeded in an intramolecular Knoevenagel condensation resulting in the formation of 1l–p. condensation resulting in the formation of 1l–p.

Scheme 6. Reaction of 2 ′0-bromoacetoxyphenones-bromoacetoxyphenones 8a8a––ee with trimethyl phosphite ( 9). Scheme 6. Reaction of 2′-bromoacetoxyphenones 8a–e with trimethyl phosphite (9). Scheme 6. Reaction of 2′-bromoacetoxyphenones 8a–e with trimethyl phosphite (9).

Molecules 2019, 24, 2030 7 of 38 Molecules 2019, 24, 2030 7 of 38

Alkylating eeffectffect andand cytotoxicity cytotoxicity of of several several phosphorylated phosphorylated coumarins coumarins have have been been studied studied [41 ][41] on someon some human human leukemia leukemia cell cell lines lines HL-60 HL-60 and and NALM-6. NALM-6. Substituents Substituents in thirdin third or fourth or fourth position position in the in lactonethe lactone ring ring were were essential essential for thefor increasedthe increased cytotoxicity. cytotoxicity.

2.1.2. Synthetic Procedure IncludingIncluding Phosphoryl Ketenimines In 1991,1991, BestmannBestmann and and Lehnen Lehnen [22 [22]] presented presented a synthesis a synthesis of 3-diethylphosphonocoumarin of 3-diethylphosphonocoumarin (1a) from (1a) compoundfrom compound10 (Scheme 10 (Scheme7). Instead 7). Instead of an unsymmetrical of an unsymmetrical CH-acidic CH-acidic component, component, they used they a multistep used a proceduremultistep includingprocedure methylendiphosphonate including methylendiphosphonate to prepare N-phenyl-bis(diethyl- to prepare phosphono)ketenimineN-phenyl-bis(diethyl- (phosphono)ketenimine10). In the next synthetic (10 step,). In sodiumthe next 2-formylphenolatesynthetic step, sodium (11) 2-formylphenolate was used as a Michael (11) donorwas used to form as a theMichael target donor molecule. to form the target molecule.

Scheme 7. Reaction with compound 10.

2.1.3. Synthetic Procedure Includingincluding Vinylphosphonates—Friedel-Crafts Alkylation ofof PhenolsPhenols Another approachapproach forfor thethe synthesis synthesis of of the the target target 3-diethylphosphonocoumarins 3-diethylphosphonocoumarins1 was 1 was applied applied by Janeckiby Janecki and and coworkers coworkers [23–27 [23–27],], using using strong strong acids as acid catalystss as catalysts for Friedel-Crafts for Friedel-Crafts alkylation alkylation of differently of substituteddifferently substituted phenols followed phenols by followed spontaneous by spontaneous lactonization lactonization (Scheme8). (Scheme 8). From the reactions of 2-diethoxyphosphorylacrylates 12 with substituted phenols or naphthols 13, series of substituted dialkyl 2-oxo-2H-1-benzopyran-3-phosphonates 1e,f, 1q–ad were isolated and characterized. The electrophilic addition was catalyzed by methanesulfonic acid or trifluoromethanesulphonic acid at room temperature. However, strong acidic promoter as trifluoroacetic acid was less effective in the described conditions. This synthetic procedure presents an alternative method in which in higher yields the target compounds 1e,f, 1q–ad were obtained but the conversion time for the reaction was long especially in the presence of methanesulfonic acid (Table2). The applied conditions were not suitable for the formation of 1t and 1z where the starting compound was α-naphthol. Scheme 8. Synthetic method uses vinylphosphonates and phenols.

TableFrom 2.theResults reactions from of the 2-diethoxyphosphorylacrylates reactions of 2-diethoxyphosphorylacrylates 12 with substituted12 with substituted phenols phenols or naphthols or 13, seriesnaphthols of substituted13 in the presence dialkyl of 2-oxo-2 strong acids.H-1-benzopyran-3-phosphonates 1e,f, 1q–ad were isolated and characterized. The electrophilic addition was catalyzed by methanesulfonic acid or trifluoromethanesulphonic1 R1 R2 Racid3 at roomR 4 temperature.R5 However,Reaction Timestrong [days] acidic Yields promoter Ref as trifluoroacetic1q H OMe acid was less effective H in the OMe described Hconditions. This 6d synthetic procedure 88% [presents23–25] an alternative1e H methodH in which H in higher OMeyields the target H compounds 10d 1e,f, 1q–ad were 81% obtained [24,25 ]but 1r H H -CH2OCH2- H 60d 73% [24,25] the 1fconversionH -CHtime=CH-CH for the=CH- reaction was Hlong especially H in the presence 10d of methanesulfonic 88% [24,25 acid] (Table1s 2).H The -CHapplied=C(OH)-CH conditions=CH- were not Hsuitable for H the formation 18dof 1t and 1z where 95% the [ 24starting,25] compound1t H wasH α-naphthol. H -CH=CH-HC=CH- 14d 9% [24] 1u Me H H OMe H 3d 81% [26,27] 1v Me OMe H OMe H 3d 69% [26] 1wTableMe 2. ResultsH from the reactions H of 2-diethoxyphosphorylacrylates -CH=CH-HC=CH- 12 3d with substituted 60% phenols [26or] 1xnaphtholsEt 13H in the presence H of strong acids. OMe H 3d 59% [26] 1y Et OMe H OMe H 3d 47% [26] 1z1 REt1 HR2 HR3 -CHR4 =CH-HCR=5 CH-Reaction Time 3d [days] Yields 26% Ref [26 ] 1aa1q n-BuH HOMe H H OMe OMe H H 6d 3d 88% 38% [23–25] [26] 1ab1e n-BuH OMeH H H OMe OMe H H 10d 3d 81% 31% [24,25] [26] 1ac Ph H H OMe H 3d 85% [26] 1r H H -CH2OCH2- H 60d 73% [24,25] 1ad Ph OMe H OMe H 3d 70% [26] 1f H -CH=CH-CH=CH- H H 10d 88% [24,25] 1s H -CH=C(OH)-CH=CH- H H 18d 95% [24,25] 1t H H H -CH=CH-HC=CH- 14d 9% [24]

Molecules 2019, 24, 2030 7 of 38

Alkylating effect and cytotoxicity of several phosphorylated coumarins have been studied [41] on some human leukemia cell lines HL-60 and NALM-6. Substituents in third or fourth position in the lactone ring were essential for the increased cytotoxicity.

2.1.2. Synthetic Procedure Including Phosphoryl Ketenimines In 1991, Bestmann and Lehnen [22] presented a synthesis of 3-diethylphosphonocoumarin (1a) from compound 10 (Scheme 7). Instead of an unsymmetrical CH-acidic component, they used a multistep procedure including methylendiphosphonate to prepare N-phenyl-bis(diethyl- phosphono)ketenimine (10). In the next synthetic step, sodium 2-formylphenolate (11) was used as a Michael donor to form the target molecule.

Scheme 7. Reaction with compound 10. Molecules 2019, 24, 2030 8 of 38 2.1.3. Synthetic Procedure including Vinylphosphonates—Friedel-Crafts Alkylation of Phenols Table 2. Cont. Another approach for the synthesis of the target 3-diethylphosphonocoumarins 1 was applied 1u Me H H OMe H 3d 81% [26,27] Moleculesby Janecki2019 , and24, 2030 coworkers [23–27], using strong acids as catalysts for Friedel-Crafts alkylation8 ofof 38 differently1v substitutedMe phenolsOMe followedH by spontaneous OMe lactonization H (Scheme3d 69%8). [26] 1w Me H H -CH=CH-HC=CH- 3d 60% [26] 1x Et H H OMe H 3d 59% [26] 1y Et OMe H OMe H 3d 47% [26] 1z Et H H -CH=CH-HC=CH- 3d 26% [26] 1aa n-Bu H H OMe H 3d 38% [26] 1ab n-Bu OMe H OMe H 3d 31% [26] 1ac Ph H H OMe H 3d 85% [26] 1ad Ph OMe H OMe H 3d 70% [26] SchemeScheme 8.8. Synthetic method uses uses viny vinylphosphonateslphosphonates and and phenols. phenols. In all performed reactions, a full regioselectivity to C-addition products was observed, which furtherInFrom allundergo the performed reactions intermolecular reactions,of 2-diethoxyphosphorylacrylates acyclization full regioselectivity resulting 12 to within C-addition substitutedthe formation products phenols of was or substitutednaphthols observed, which3-diethylphosphonocoumarins13, series further of substituted undergo dialkyl intermolecular in 2-oxo-2 moderateH-1-benzopyran-3-phosphonates cyclization to very good resulting yields. in the 1e formation,f, 1q–ad ofwere substituted isolated 3-diethylphosphonocoumarinsand characterized. The electrophilic in moderate addition to very goodwas yields.catalyzed by methanesulfonic acid or 2.1.4.trifluoromethanesulphonic Phosphorylation of Coumarins acid at room temperature. However, strong acidic promoter as 2.1.4.trifluoroacetic Phosphorylation acid was of less Coumarins effective in the described conditions. This synthetic procedure presents Catalytic Phosphorylation an alternative method in which in higher yields the target compounds 1e,f, 1q–ad were obtained but Catalytic Phosphorylation the conversionThe direct timeC-H forfunctionalization the reaction was appeared long espe tocially be an in atom-economical the presence of methanesulfonicand environmentally acid friendly(TableThe 2). synthetic direct The applied C-H method. functionalization conditions Lately were manganese(III) appeared not suitable to be acetate for an atom-economicalthe hasformation been introduced of 1t and and environmentally 1z as where a new the reagent starting friendly for syntheticinitiationcompound method.of was phosphorus α-naphthol. Lately manganese(III) radicals. Zou acetate and hascoauthors been introduced [28] presented as a new reagenta new forapproach initiation for of phosphorusphosphonocoumarins radicals. Zou using and direct coauthors phosphonation [28] presented of C-H a new bond approach to sp2-hybridized for phosphonocoumarins carbon (Scheme using 9). Table 2. Results from the reactions of 2-diethoxyphosphorylacrylates2 12 with substituted phenols or directThe reaction phosphonation of coumarin of C-H 14 bondwith todiethylphosphite sp -hybridized carbon(15a) in (Scheme the presence9). The of reaction Mn(OAc) of coumarin3 for 30 min14 naphthols 13 in the presence of strong acids. withgave diethylphosphite3-diethylphosphonocoumarin (15a) in the presence 1v as ofa Mn(OAc)product of3 for regioselective 30 min gave 3-diethylphosphonocoumarinα-phosphonation in yield of

1v87%as 1(Scheme a productR1 9, of Method regioselectiveR2 A). TheR3α -phosphonation selectivityR4 of the inR yieldreaction5 ofReaction 87% to (Schemeα-phosphorylation Time [days]9, Method Yields A). product The selectivity Ref was not ofonly the1q a reaction resultH of toOMe αdialkylphosphonyl-phosphorylation H productradicals OMe wasformation H not only but a resultalso 6d ofdue dialkylphosphonyl to the 88%differentiation [23–25] radicals of formationα-position1e H butin arylalkene alsoH due to as the a H dihigh fferentiation electron OMe density of α-positionH center inand arylalkene 10dstabilization as a highof 81%the electron benzyl[24,25] densityradical centergenerated1r andH after stabilization theH attack of at the the benzyl -CHα-position.2OCH radical2- generatedH after the attack 60d at the α-position. 73% [24,25] 1f H -CH=CH-CH=CH- H H 10d 88% [24,25] 1s H -CH=C(OH)-CH=CH- H H 18d 95% [24,25] 1t H H H -CH=CH-HC=CH- 14d 9% [24]

SchemeScheme 9.9. Catalytic phosphorylation with Mn(OAc)Mn(OAc)33.

The same group of authors [[29]29] reported a modifiedmodified procedure for the synthesis of a series of substituted coumarincoumarin systems. systems. The The presented presented method method displayed displayed a regioselectivity a regioselectivity for the C-3for positionthe C-3 in the coumarin and formation of compounds 1a, 1e, 1p, 1v, 1ae–ah in yields of 63 to 87%, (Scheme9,

Method B). Substituents on the phenyl ring or at position C-4 at the benzopyran had no significant impact on the yields of the target molecules. Molecules 2019, 24, 2030 9 of 38

Moleculesposition2019 in ,the24, 2030coumarin and formation of compounds 1a, 1e, 1p, 1v, 1ae–ah in yields of 63 to 987%, of 38 (Scheme 9, Method B). Substituents on the phenyl ring or at position C-4 at the benzopyran had no significant impact on the yields of the target molecules. MoleculesOne 2019 year, 24, 2030 later, Wu andand coworkerscoworkers [[30]30] reportedreported aa newnew protocolprotocol forfor selectiveselective synthesis9 of of38 substituted dialkyldialkyl 2-oxo- 2-oxo-2H-1-benzopyran-3-phosphonates2H-1-benzopyran-3-phosphonates1a, 1e 1a, 1af, ,1e1ai, –1afan,via 1ai a direct–an via Pd-catalyzed a direct phosphonationPd-catalyzedposition in the phosphonation coumarin of coumarins and (Schemeof formation coumarins 10 ).of (Schemecompounds 10). 1a , 1e, 1p, 1v, 1ae–ah in yields of 63 to 87%, (Scheme 9, Method B). Substituents on the phenyl ring or at position C-4 at the benzopyran had no significant impactR1 on the yields of the target molecules. 10 mol% PdCl2 R1 O R H 30 mol% bipyridine 2One year later, Wu and coworkersRO OR [30] reported a new protocol for selective synthesis of 3 equiv K S O R2 P 2 equiv P 2 2 8 OR substituted dialkyl 2-oxo-2H-1-benzopyran-3-phosphonates 1a, 1e, 1af, 1ai–an ORvia a direct O CH CN, 100 oC Pd-catalyzedR3 phosphonationO O of coumarins (Scheme3 10). 5-24 h, air R3 O O

14 R1 15a R=Et 1a R1 =R2 =R3 =H 10 mol% PdCl2 R O 15b R=Me 1e R1 =R2 =H,R1 3 =OMe R H 30 mol% bipyridine 2 RO15c R=ORi-Pr 1af R =R =H,R =Me R2 1 3 P2 2 equiv P 3 equiv K2S2O8 15d R=nBu 1ai R1 =R2 =H,R3 =OEtOR OR 15e R=sec-Bu o 1aj R1 =Me,R2 =OMe,R3 =H R O O O CH3CN, 100 C 3 15f R=i-Bu 1ak R =H,R =R =OMe 5-24 h, air R3 1 O 2 O3 1al R1 =R2 =H,R3 =OBn 1am R1 =R2 =H,R3 =OH 14 15a R=Et 1a R1 =R2 =R3 =H 1an R1 =R3 =H,R2 = CHO 15b R=Me 1e R1 =R2 =H,R3 =OMe 15c R=i-Pr 1af R1 =R3 =H,R2 =Me Scheme 10.15d CatalyticR=nBu phosphorylation with Pd-complexes.1ai R 1 =R2 =H,R3 =OEt 15e R=sec-Bu 1aj R1 =Me,R2 =OMe,R3 =H 15f R=i-Bu 1ak R1 =H,R2 =R3 =OMe The reactions were performedperformed byby usingusing 2,22,20′-bipyridine as aa ligand,ligand, PdClPdCl22 as a transition-metaltransition-metal 1al R1 =R2 =H,R3 =OBn source, potassiumpotassium peroxodisulfate peroxodisulfate as as an an oxidant oxidant and and acetonitrile acetonitrile as a solventas 1ama solventR media.1 =R2 =H,Rmedia. Diff3erent=OH Different dialkyl Hdialkyl-phosphonates H-phosphonates15a–f were 15a– testedf were in tested the optimized in the optimized reaction reaction conditions conditions1an andR1 the=R and di-3 =H,R isothe-propyl 2di-= CHOiso-propyl (yield 56%)(yield and 56%) di- secand-butyl di-sec (yield-butylScheme 59%) (yield 10.H -phosphonatesCatalytic 59%) phosphorylationH-phosphonates displayed with better displayed Pd-complexes. C-H phosphonation better C-H phosphonation activity toward theactivity unsubstituted toward the coumarin unsubstituted in comparison coumarin with in comp the otherarison dialkyl with the phosphonates other dialkyl (R phosphonates= Me 44%; R =(REt = 48%;Me 44%;The R = nRreactions-Bu = Et 47%; 48%; were R R= =i-Bu performedn-Bu 51%). 47%; The Rby = coumarins usingi-Bu 51%). 2,2′-bipyridine bearing The coumarins electron-donating as a ligand, bearing PdCl electron-donating groups2 as a reacted transition-metal faster groups and gavereactedsource, better fasterpotassium yields and thangave peroxodisulfate their better analogues yields asthan possessingan their oxidant analogues electron-withdrawing and acetonitrile possessing aselectron-withdrawing a groups. solvent Substituents media. Different groups. as Me andSubstituentsdialkyl OMe H-phosphonates at positionas Me and C-6 OMe 15a in– the fat were position benzene tested C-6 ring in in the showed th optimizede benzene significant reactionring showed influence conditions sign onificant theand phosphorylation theinfluence di-iso-propyl on the reactionphosphorylation(yield 56%) yielding and reaction1di-insec 52%-butyl yielding and (yield 63%. 1 in The59%) 52% coumarins H and-phosphonates 63%.1aj Theand coumarins 1kdisplayedwere prepared1aj better and 1kC-H in were 10% phosphonation lowerprepared yields in than10%activity lower1e. toward yields the than unsubstituted 1e. coumarin in comparison with the other dialkyl phosphonates (R = Me 44%;It is worthR = Et noting48%; R that = n-Bu the reaction47%; R = conditions i-Bu 51%). were The tolerantcoumarins of systemsbearing withelectron-donating hydroxyl and groups formyl groups,reacted faster even thoughand gave the better yields yields were than low, their 34% analogues and 27%, possessing respectively. electron-withdrawing Use of a radical scavenger groups. (2,2,6,6-tetramethylpiperidin-1-yl)oxidanylSubstituents as Me and OMe at position C-6 (TEMPO) in the benzene provided ring evidence showed for sign a possibleificant influence mechanism on the of thephosphorylation reaction. In the reaction performed yielding parallel 1 inreactions 52% and the63%. formation The coumarins of the 3-diethylphosphonocoumarin 1aj and 1k were prepared in allowed10% lower the yields possibility than 1e of. a radical mechanism to be discarded (Scheme 11).

Scheme 11. Proposed mechanism for the synthesis of substituted dialkyl 2-oxo-2H-1-benzopyran-3-phosphonates.

It is worth noting that the reaction conditions were tolerant of systems with hydroxyl and formyl groups, even though the yields were low, 34% and 27%, respectively. Use of a radical scavengerSchemeScheme (2,2,6,6-tetramethylpiperidin-1-yl)oxi 11. 11.Proposed Proposed mechanism mechanism for the synthesisfordanyl ofthe (TEMPO) substituted synthesis provided dialkyl of 2-oxo-2 substitutedevidenceH-1-benzopyran- for dialkyla possible 3-phosphonates.2-oxo-2H-1-benzopyran-3-phosphonates.

It is worth noting that the reaction conditions were tolerant of systems with hydroxyl and formyl groups, even though the yields were low, 34% and 27%, respectively. Use of a radical scavenger (2,2,6,6-tetramethylpiperidin-1-yl)oxidanyl (TEMPO) provided evidence for a possible

Molecules 2019,, 24,, 20302030 10 of 38 mechanism of the reaction. In the performed parallel reactions the formation of the Moleculesmechanism2019, 24of, 2030 the reaction. In the performed parallel reactions the formation of10 ofthe 38 3-diethylphosphonocoumarin allowed the possibility of a radical mechanism to be discarded (Scheme 11). 2 An eefficientfficient regioselectiveregioselective silver-catalyzedsilver-catalyzed directdirect CspCsp2-H radicalradical phosphorylationphosphorylation ofof coumarinscoumarins waswas presentedpresented byby MaoMao etet al.al. [[31]31].. Phosphorus-containingPhosphorus-containing compounds compounds 1a1a,, 1e,, 1af–ag, 1am–ar werewere preparedprepared inin aa reactionreaction ofof coumarinscoumarins 1414 withwith didifferentfferent dialkyldialkyl HH-phosphonates-phosphonates 15a–d,, 15f–h under mild reactionreaction conditionsconditions inin thethe presence presence of of catalyst catalyst AgNO AgNO3/Mg(NO3/Mg(NO3)32)2 × 6H6H22O (Scheme(Scheme 1212).). TheThe × metal-promoted synthetic protocol derived the expected products 1 with moderate to good yields (45–65%).(45–65%).

Scheme 12.12. Ag-catalyzed phosphorylation reaction.

According to the proposed mechanism (Scheme 1313)) Ag(I) promotes thethe initiationinitiation ofof phosphorylphosphoryl radicalsradicals whichwhich impliedimplied thatthat the C-HC-H phosphorylationphosphorylation ofof coumarins—experiencecoumarins—experience a radicalradical reactionreaction path.path. Indeed, formation of 3-dialkylphosphonocoumar 3-dialkylphosphonocoumarinin was not observed in the presence of radical scavenger TEMPOTEMPO thatthat provedproved thethe radicalradical mechanismmechanism ofof thethe process.process.

Scheme 13. The proposed radical mechanism of the Ag-catalyzed phosphorylation reaction.

InIn thethe conditions conditions of radicalof radical phosphonation phosphonation coumarins coumarins with electron-donating with electron-donating groups proceeded groups withproceeded better resultswith better than results their analogs than their having analogs electron-withdrawing having electron-withdra substituents.wing Thesubstituents. diethylamino The groupdiethylamino was found group to bewas a substituentfound to be that a substituent activated thethat coumarin activated system the coumarin toward system the C-P toward formation, the thus, highest yields were observed in this case—65%. The electron-withdrawing effect of the nitro group slightly deactivated the benzopyran system and therefore product 1ao was obtained in yield of Molecules 2019, 24, 2030 11 of 38 Molecules 2019, 24, 2030 11 of 38 C-P formation, thus, highest yields were observed in this case—65%. The electron-withdrawing effect of the nitro group slightly deactivated the benzopyran system and therefore product 1ao was obtained45%. Interestingly, in yield coumarinof 45%. Interestingly,1am was afforded coumarin in nearly 1am doubled was afforded yield comparing in nearly with doubled the previous yield procedure.comparing Thewith di- isothe-propyl previous (60%) procedure. and dimethyl The (62%) di-isoH-phosphonates-propyl (60%) displayedand dimethyl better activity(62%) Hfor-phosphonates the coumarin displayed1a in comparison better activity with the for other the coumarin dialkyl phosphonates 1a in comparison (R = Etwith 55%; the R other= n-Bu dialkyl 49%; phosphonatesR = i-Bu 54%; R(R= =n Et-Pr 55%; 50%; R R = =n-Bun-pentyl 49%; R 45%). = i-Bu 54%; R = n-Pr 50%; R = n-pentyl 45%). A year later, Mao etet. al.al. reportedreported [[32]32] aa modifiedmodified selectiveselective protocol forfor thethe phosphorylationphosphorylation of coumarins using N-heterocyclic carbene palladium complexes. The The catalytic catalytic activity activity of of different different NHC-complexes was implied in the reaction. The complex presented in Scheme 14 showed the best catalytic efficiency efficiency in the phosphorylationphosphorylation reaction. A A wide range of of dialkyl H-phosphonates-phosphonates 15a15a––dd,, 15f–h reactedreacted smoothlysmoothly with coumarins 14 resulting in the complete regioselective synthesis of the target molecules 1a, 1e, 1af, 1am–ar inin moderatemoderate toto highhigh yields.yields.

Scheme 14. PhosphorylationPhosphorylation reactions reactions by N-heterocyclic carbene palladium complexes.

The optimized conditions for the selective phosphorylation of coumarins 14 included a combination of catalysts—Pd-bearing component and and Ag(I) salts—thus, the highest yields were reported. Substituents Substituents at at C-7 C-7 or or C-4 in the benzop benzopyranyran system favored the phosphorylation reaction (86–89%), thoughthough substituents substituents at position at position C-6, either C-6, electron-withdrawing either electron-withdrawing (41%) or electron-donating (41%) or electron-donatinggroups (36%), resulted groups in (36%), lower resulted yields. in The lower results yields. for The the coumarinresults for 1atheremained coumarin higher1a remained using higherdi-iso-propyl using (70%) di-iso and-propyl dimethyl (70%) (68%) andH-phosphonates dimethyl (68%) than otherH-phosphonates dialkyl phosphonates than other (R = dialkylEt 64%; phosphonatesR = n-Bu 44%; (R R = = iEt-Bu 64%; 46%; R R= n=-Bun-Pr 44%; 46%; R R= =i-Bun-pentyl 46%; R 52%). = n-Pr 46%; R = n-pentyl 52%).

Electrochemical Phosphorylation The preparationpreparation ofof 3-dialkylphosphonocoumarins 3-dialkylphosphonocoumarins through through a direct a direct phosphorylation phosphorylation of C-H of bondC-H bondof the of aromatic the aromatic system system remains remains one of theone used of the synthetic used synthetic approaches approaches that corresponds that corresponds to the principals to the principalsof green chemistry–atom of green chemistry economy, – atom single economy, step processes, single low step amounts processes, of waste low products, amounts etc. of Recentwaste products,approaches etc. for theRecent synthesis approaches of 3-dialkylphosphonocoumarins for the synthesis of 3-dialkylphosphonocoumarins include electrochemical initiation include of electrochemicalthe phosphorylation. initiation A newof the method phosphorylation. for C-P bond A new formation method atfor position C-P bond C-3 formation in the benzopyran at position C-3system in the was benzopyran reported in system 2016 by was Khrizanforov reported in et 2016 al. [33by, 34Khrizanforov]. The synthetic et al. protocol [33,34]. wasThe basedsynthetic on protocolan oxidation was processbased on of an aromatic oxidatio compoundsn process of14 aromaticand diethyl compounds phosphonate 14 and (15a diethyl) in the phosphonate presence of (bimetallic15a) in the catalytic presence systems of bimetallic (Scheme catalytic 15). Two systems bimetallic (Scheme systems 15). as Two the bimetallic pairs MnCl systems2bipy/Ni(BF as the4) 2pairsbipy and MnCl bipy/CoCl bipy were used where 2,2 -bipyridine was an additional ligand. The reaction MnCl2bipy/Ni(BF2 4)2bipy2 and MnCl2bipy/CoCl20bipy were used where 2,2′-bipyridine was an additionaltook place ligand. at room The temperature reaction took by place applying at room equimolar temperature ratio betweenby applying the equimolar coumarin ratio and thebetween used phosphonatethe coumarin15a and. Coumarins,the used phosphonate bearing electron-donating 15a. Coumarins, groups, bearing gave electron-donating better yields in phosphonation groups, gave betterreactions yields in comparison in phosphonation with the reactions unsubstituted in compar benzopyranison with system the unsubstituted (Scheme 15). benzopyran system (Scheme 15).

Molecules 2019, 24, 2030 12 of 38 Molecules 2019,, 24,, 20302030 12 of 38 Molecules 2019, 24, 2030 12 of 38

Scheme 15. Electrochemical phosphorylation of coumarins with diethyl H-phosphonate. Scheme 15. Electrochemical phosphorylation of coumarins with diethyl HH--phosphonate.phosphonate. Subsequent investigations by Khrizanforov et al. [35] for the preparation of coumarin phosphonatesSubsequent in investigations theinvestigations presence byof Khrizanforovby MnCl Khrizanforov2bipy/Ni(BF et al. [4et35)2bipy ]al. for the[35]showed preparation for changesthe preparation of coumarinin the electrochemical phosphonatesof coumarin parametersinphosphonates the presence by inapplying of the MnCl presence2 bipythree/ Ni(BF ofdialkyl MnCl4)2 bipy2Hbipy/Ni(BF-phosphonates showed4) changes2bipy (Scheme showed in the 16).changes electrochemical In this in studythe electrochemical parameters di-iso-propyl by phosphonateapplyingparameters three by resulted dialkyl applyingH in-phosphonates yieldsthree dialkylof up (Schemeto H 70%.-phosphonates 16An). Ininteresting this study(Scheme circumstance di-iso 16).-propyl In this phosphonateis thatstudy the di- yields resultediso-propyl were in yieldsobtainedphosphonate of upafter to resulted 70%.one-day An in interestingreaction yields ofmixture circumstance up to 70%.storage An is thatbefore interesting the electrolysis, yields circumstance were obtainedwhich iswas afterthat necessary one-daythe yields reactionfor were the formationmixtureobtained storage after of the one-day before metal electrolysis, phosphonatereaction mixture which comp wasstoragelex. necessary Full before conversion forelectrolysis, the formationof the which dialkyl of thewas H metal-phosphonate necessary phosphonate for wasthe observedcomplex.formation Fullunder of the conversion the metal described phosphonate of the conditions. dialkyl compH-phosphonate lex. Full conversion was observed of the under dialkyl the describedH-phosphonate conditions. was observed under the described conditions.

Scheme 16. Electrochemical phosphorylatio phosphorylationn of coumarins with dialkyl H-phosphonate. Scheme 16. Electrochemical phosphorylation of coumarins with dialkyl H-phosphonate. 2.1.5. Synthetic Protocols Involving Coupling Reactions 2.1.5. Synthetic Protocols Involving Coupling Reactions DifferentDifferent approach for thethe synthesissynthesis ofof thethe targettarget 3-dialkylphosphonocoumarins3-dialkylphosphonocoumarins includes three-componentDifferent approach coupling for of the arynes, synt hesisdimeth dimethyl of ylthe formamide target 3-dialkylphosphonocoumarins (DMF) and CH-acidic component includes 4 (Schemethree-component 1717).). coupling of arynes, dimethyl formamide (DMF) and CH-acidic component 4 (Scheme 17).

Scheme 17. Synthesis of 3-diethylphosphonoco 3-diethylphosphonocoumarinumarin under coupling reaction. Scheme 17. Synthesis of 3-diethylphosphonocoumarin under coupling reaction. The reported protocol [[36]36] represents a reaction between an in situ ge generatednerated benzyn benzynee fragment (SchemeThe 1818)reported) andand anan protocol active active methylene methylene[36] represents compound compound a reaction bearing bearing between a diethylphosphoryla diethylphosphoryl an in situ generated group group benzyn in DMFin DMFe fragment at 80at ◦80C. The°C.(Scheme The compound compound 18) and1a anwas 1a active was produced producedmethylene in 74% in compound 74% yield yield (Scheme (Schemebearing 17). a17). diethylphosphoryl group in DMF at 80 °C. The compound 1a was produced in 74% yield (Scheme 17).

Scheme 18. Possible mechanism of the reaction involving ortho-quinone methide. Scheme 18. Possible mechanism of the reaction involving ortho-quinone methide.

Molecules 2019, 24, 2030 13 of 38 Molecules 2019, 24, 2030 13 of 38 Molecules 2019, 24, 2030 13 of 38 The course of the reaction was switched when th thee solvent was changed. The The nucleophilic nucleophilic attack attack The course of the reaction was switched when the solvent was changed. The nucleophilic attack of the carbonyl oxygen of DMF DMF molecule molecule to benzyne benzyne was was a a probable probable initiator initiator of the the reaction reaction followed followed of the carbonyl oxygen of DMF molecule to benzyne was a probable initiator of the reaction followed by the formation of ortho-quinone methide intermediate (Scheme 1818).). by the formation of ortho-quinone methide intermediate (Scheme 18). Currently several utilized methods of C-P bond construction as an electrophilic phosphorus Currently several utilized methods of C-P bond construction as an electrophilic phosphorus reagent and transition-metal-catalyzed cross-coupling cross-coupling synthetic synthetic protocols protocols for for the formation of reagent and transition-metal-catalyzed cross-coupling synthetic protocols for the formation of phosphorus-containing coumarin systems are listed listed.. Another Another approach approach relied relied on a domino reaction phosphorus-containing coumarin systems are listed. Another approach relied on a domino reaction via an an intermolecular intermolecular addition addition of of P-centered P-centered radicals radicals to toalkynes alkynes followed followed by byfast fast cyclization cyclization onto onto the via an intermolecular addition of P-centered radicals to alkynes followed by fast cyclization onto the aromaticthe aromatic π-systemπ-system [37]. [37 The]. The tandem tandem radical radical phosphorylation-cyclization phosphorylation-cyclization reaction reaction of of readily aromatic π-system [37]. The tandem radical phosphorylation-cyclization reaction of readily prepared phenyl alkynoates 17 with diethyl H-phosphonate substrate substrate 15a was investigated in the prepared phenyl alkynoates 17 with diethyl H-phosphonate substrate 15a was investigated in the presence of combination ofof AgAg22CO33, Mg(NO 3))22x6Hx6H22OO in in CH CH33CNCN for for 12 12 h h to to afford afford the the corresponding corresponding presence of combination of Ag2CO3, Mg(NO3)2x6H2O in CH3CN for 12 h to afford the corresponding 3-dialkylphosphonocoumarins 1l, 1as–bj (Scheme 1919).). 3-dialkylphosphonocoumarins 1l, 1as–bj (Scheme 19).

Scheme 19. Transition-metal-catalyzedTransition-metal-catalyzed cross-coupling cross-coupling synthetic synthetic protocol protocol for for the the formation of Scheme 19. Transition-metal-catalyzed cross-coupling synthetic protocol for the formation of phosphorus-containing coumarin systems. phosphorus-containing coumarin systems.

Scheme 20. The suggested mechanism of the observed cross-coupling transformation. Scheme 20. The suggested mechanism of the obse observedrved cross-coupling transformation. The steric effect had strong impact on the accomplishing of the radical tandem reaction. For The steric eeffectffect hadhad strongstrong impactimpact onon thethe accomplishingaccomplishing ofof thethe radicalradical tandemtandem reaction.reaction. For example, the formation of compound 1bb was not observed due to the hindrance of the methyl example, thethe formationformation of of compound compound1bb 1bbwas was not not observed observed due due to the to hindrancethe hindrance of the of methyl the methyl group group on the ortho-position of the phenoxy ring in 17. By applying aryl alkynoates bearing 4-Me, group on the ortho-position of the phenoxy ring in 17. By applying aryl alkynoates bearing 4-Me, 4-OMe or 4-Cl substituents at the para-position in the phenoxy ring the authors studied the 4-OMe or 4-Cl substituents at the para-position in the phenoxy ring the authors studied the

Molecules 2019, 24, 2030 14 of 38 Molecules 2019, 24, 2030 14 of 38 Molecules 2019, 24, 2030 14 of 38 regioselectivityon the ortho-position of the of reaction. the phenoxy Products ring in1bc17/1bd. By applyingand 1ae/1af aryl were alkynoates produced bearing in a 4-Me,mixture 4-OMe of two or isomers.4-Clregioselectivity substituents Product of at1ac the the was reaction.para formed-position Products inin high the 1bcyield phenoxy/1bd (78%) and ring with 1ae the / authorscomplete1af were studied regioselectivityproduced the regioselectivityin a mixtureof the process. of of two the Thereaction.isomers. products Product Products formation 1ac1bc was/1bd was formedand as 1aea resultin/1af highwere of yield cyclization produced (78%) withreaction in a mixturecomplete preferably of regioselectivity two occurring isomers. Product atof the the opposite process.1ac was siteformedThe ofproducts the in substituent. high formation yield (78%) was with as completea result of regioselectivity cyclization reaction of the process.preferably The occurring products at formation the opposite was assite a of resultThe the cascadesubstituent. of cyclization reaction reaction was preferably accomplished occurring smoothly at the oppositewith dimethyl site of the H substituent.-phosphonate and di-isoThe-butyl cascadecascade H-phosphonate reaction reaction was yieldingwas accomplished accomplished the corresponding smoothly smoothly with product dimethyl with 1l indimethylH 70%-phosphonate and H90%,-phosphonate andrespectively. di-iso-butyl and A seriesHdi--phosphonateiso-butyl of controlled H-phosphonate yielding experiments the yielding corresponding using the correspondingTEMPO product as 1la productinradical 70% and1lscavenger in 90%, 70% respectively.and and 90%, experiments respectively. A series with ofA deuteriumcontrolledseries of controlled experimentslabelling wereexperiments using executed TEMPO using asto ahighlight radicalTEMPO scavenger theas mechanisma radical and experiments scavenger of the observed withand deuteriumexperiments transformation labelling with (Schemeweredeuterium executed 20). labelling The to highlightresults were demonstrated executed the mechanism to thathighlightof the the cl observedeavagethe mechanism of transformationthe C-H of bond the onobserved (Scheme the phenoxy 20transformation). The ring results was notdemonstrated(Scheme involved 20). inThe thatthe results rate-determining the cleavage demonstrated of thestep. that C-H the bond cleavage on the of phenoxythe C-H bond ring wason the not phenoxy involved ring in was the rate-determiningnot involvedA photochemical in the step. rate-determining technique for the step. synthesis of derivative 1l uses a cascade radical addition of phosphorusA photochemical nucleophiles technique technique to aryl for forpropiolates. the the synthesis synthesis Xu of et of derivative al. derivative [38] employed 1l1l usesuses a cascade acatalytic cascade radical quantities radical addition addition of the of commerciallyofphosphorus phosphorus nucleophiles available nucleophiles Eosin to to arylY aryl(EY) propiolates. propiolates.as a photocatalyst Xu Xu et etal. al.and [38] [38 tert ]employed employed-butyl-hydroperoxide catalytic catalytic quantities quantities as an oxidant of of the (Schemecommercially 21). available Eosin Y (EY) as a photocatalystphotocatalyst and terttert-butyl-hydroperoxide-butyl-hydroperoxide as an oxidantoxidant (Scheme 2121).).

Scheme 21. Cascade-radical approach for the formation of 3-functionalized coumarin. Scheme 21. Cascade-radical approach for the form formationation of 3-functionalized coumarin. 2.1.6. Rearrangement Reactions 2.1.6. Rearrangement Reactions 2.1.6.CH-acidic Rearrangement component Reactions as diethyl cyanomethylphosphonate (7c) was used in a reaction with someCH-acidic α- and β-monohalocarbonyl componentcomponent as as diethyl diethyl compounds cyanomethylphosphonate cyanomethylphosphonate [39]. As a result of (7c nucleophilic)(7c was) was used used in aromatic a reactionin a reaction substitution with somewith α β ansome- andintermediate α- and-monohalocarbonyl β-monohalocarbonyl A was formed compounds from compounds 4-chlorocoumarin [39]. [39]. As a As result a(14 result) ofwith nucleophilic of 7c nucleophilic in the presence aromatic aromatic of substitution an substitution equimolar an amountintermediatean intermediate of NaHA was A wasin formed THF, formed from Scheme from 4-chlorocoumarin 4-chlorocoumarin22. Tautomerization (14) with (14)7c withtoin the vinylphosphonate7c presencein the presence of an equimolar of18 an or equimolar thermal amount rearrangementofamount NaH inof THF, NaH Schemeto thein THF,3-diethylphosphonocoumarin 22. Tautomerization Scheme 22. Tautomerization to vinylphosphonate 1bk were to vinylphosphonatenext18 or steps thermal in rearrangementthe intermediate18 or thermal to theA transformation.3-diethylphosphonocoumarinrearrangement to the 3-diethylphosphonocoumarin1bk were next steps in the1bk intermediate were next Astepstransformation. in the intermediate A transformation.

Scheme 22. RearrangementRearrangement reaction of intermediate A.A. Scheme 22. Rearrangement reaction of intermediate A. The observed rearrangement is expected becaus becausee the chemical properties of 3-substituted coumarinsThe observed frequently rearrangement are pursued by is suchexpected benzopyran-2-oxochroman because the chemical transformationtransformation properties of [[42–46].423-substituted–46]. coumarins frequently are pursued by such benzopyran-2-oxochroman transformation [42–46]. 2.2. Reaction Reaction of of Dialkyl Dialkyl 2-ox 2-oxo-2H-1-benzopyran-3-phosphonateso-2H-1-benzopyran-3-phosphonates 1 2.2. ReactionThe presence of Dialkyl of a 2-ox conjugateconjugateo-2H-1-benzopyran-3-phosphonates ππ-system-system inin thethe lactone lactone ring ring 1 of of 2-oxo-2 2-oxo-2HH-1-benzopyran-1-benzopyran derivatives derivatives1 implies their involvement in nucleophilic addition reactions (Figure4). Various factors as substituents 1 impliesThe presence their involvement of a conjugate in πnucleophilic-system in the addition lactone ringreactions of 2-oxo-2 (FigureH-1-benzopyran 4). Various derivativesfactors as in the lactone ring, the strength of the used nucleophile, the solvent, etc. influence the reaction rate, the substituents1 implies their in the involvement lactone ring, in the nucleophilic strength of thadditione used nucleophile,reactions (Figure the solvent, 4). Various etc. influence factors theas type and the yields of the obtained products. There are many examples in the literature presenting a reactionsubstituents rate, in the the type lactone and ring, the yieldsthe strength of the ofob thtainede used products. nucleophile, There the are solvent, many etc.examples influence in the coumarin structure as an excellent Michael acceptor [42,47–49] producing adducts of type B as a main literaturereaction rate, presenting the type a andcoumarin the yields structure of the as obantained excellent products. Michael There acceptor are many [42,47–49] examples producing in the product (Figure4). adductsliterature of presenting type B as a a main coumarin product structure (Figure as4). an excellent Michael acceptor [42,47–49] producing adducts of type B as a main product (Figure 4).

Molecules 2019, 24, 2030 15 of 38 Molecules 2019, 24, 2030 15 of 38 Molecules 2019, 24, 2030 15 of 38

Figure 4. Nucleophilic addition reactions to 3-dialkylphosphonocoumarin. Figure 4. NucleophilicNucleophilic addition addition reactions to 3-dialkylphosphonocoumarin. 2.2.1. Reactions with Nucleophilic Reagents 2.2.1. Reactions with Nucleophilic Reagents 2.2.1.Chemical Reactions withproperties Nucleophilic of diethylReagents 2-oxo-2H-1-benzopyran-3-phosphonate (1a), diethyl 2H 1a 3,4-dihydro-2-oxo-Chemical propertiesproperties2H-1-benzopyran-3-phosphonate of diethylof diethyl 2-oxo- 2-oxo--1-benzopyran-3-phosphonate2H -1-benzopyran-3-phosphonate(19), 2-oxo-2H-1-benzopyran-3-phosphonic ( ), diethyl ( 3,4-dihydro-2-1a), diethyl 2H 19 2H 5 acid3,4-dihydro-2-oxo-oxo- (5)-1-benzopyran-3-phosphonate and diethyl2H 7-N,N-diethylamino-2-oxo--1-benzopyran-3-phosphonate ( ), 2-oxo-2H-1-benzopyran-3-phosphonate-1-benzopyran-3-phosphonic (19), 2-oxo-2H-1-benzopyran-3-phosphonic acid(1j, Figure ( ) and 5) diethyl were 2H 1j theacid7-N,N-diethylamino-2-oxo- (object5) and ofdiethyl experimental 7-N,N-diethylamino-2-oxo- and-1-benzopyran-3-phosphonate theoretical 2Hre-1-benzopyran-3-phosphonateactivity parameter ( , Figure studies5) were distinguishing (1j, the Figure object 5) were ofthe theelectrophilicityexperimental object of and ofexperimental theoreticalthe center reactivityinand the theoretical coumarin parameter syreactivitystem studies by distinguishingparameteratomic electrostatic studies the electrophilicity distinguishingpotential and of XPSthe electrophilicitybindingcenter in energies the coumarin of while the electroniccenter system in by localizationthe atomic coumarin electrostatic was sy examinedstem by potential atomicon the and baseelectrostatic XPSof atomic binding potential Fukui energies indices and while [50].XPS bindingTheelectronic calculated energies localization electronic while was electronic examinedstructures localization on have the basecharacterized was of examined atomic Fukuiwith on the indiceslarge base negative [ 50of ].atomic The charge calculated Fukui on indices C-3-atom electronic [50]. Thewhereasstructures calculated C-4 have atomic characterizedelectronic charge structures has with values large have negativeclose characterized to chargezero. Obtained on with C-3-atom large 2p-binding whereasnegative C-4energiescharge atomic onfor chargeC-3-atom P-atoms has whereasdescribedvalues close C-4 identical to atomic zero. local Obtained charge environment 2p-bindinghas values for energies closethe coumar to forzero. P-atomsins. Obtained On describedcontrary, 2p-binding in identical 7-diethylamino energies local environment for substituted P-atoms for describedcompoundthe coumarins. identical energy On contrary,waslocal low environment probably in 7-diethylamino due for theto interact coumar substitutedionins. between On compound contrary, N- and energy in P-substituents7-diethylamino was low probably displayed substituted due as to compoundhigherinteraction electronegativity betweenenergy was N- andlow at P-substituentsP-atom.probably Calculated due to displayed interact atomicion as higherelectrostatic between electronegativity N- potentialsand P-substituents also at P-atom. showed displayed Calculated that the as higherelectrophilicityatomic electronegativity electrostatic of the potentials reactionat P-atom. also centers Calculated showed in thatthe atomic thecoumarin electrophilicity electrostatic system potentials increases of the reaction alsoin theshowed centers presence that in the of electrophilicityphosphoniccoumarin system group, of increases theespecially reaction in the in presence centerscoumarin-3-phosphonic ofin phosphonicthe coumarin group, acid system especially5. Electron increases in donating coumarin-3-phosphonic in the grouppresence at C-7 of phosphonicincreasedacid 5. Electron electrophilicity group, donating especially groupof the in atC-7 C-7coumarin-3-phosphonic carbon increased but at electrophilicity the same timeacid of C-35 the. Electron and C-7 O-2 carbon donatingatoms but from at thegroup the same lactoneat timeC-7 increasedringC-3 andincreased O-2 electrophilicity atoms their fromnucleophilicity. the of the lactone C-7 carbon ring increased but at the their same nucleophilicity. time C-3 and O-2 atoms from the lactone ring increased their nucleophilicity.

Figure 5.5.Structures Structures of phosphorus-containingof phosphorus-containing coumarins coum thatarins were that object were of theoretical object of investigations. theoretical Figureinvestigations. 5. Structures of phosphorus-containing coumarins that were object of theoretical As a result the the phosphorus-containing coumarins C-3 atoms in these chemical structures were investigations. definedAs a as result soft centers. the the Indeed,phosphorus-containing Fukui indices showed coumarins increased C-3 atoms values in forthese C-3, chemical especially structures when a werephosphorylAs defined a result and as softthe diethylphosphoryl centers.the phosphorus-containing Indeed, groupFukui indices is bound, coum showed andarins characterized increased C-3 atoms values in the these centerfor C-3, chemical as especially hard. structures Actually, when wereaphosphorus-containing phosphoryl defined asand soft diethylphosphoryl centers. substituents Indeed, Fukui didgroup not indices is influence bound, showed and the characterized increased electron localization values the centerfor C-3, at as the especially hard. C-3 atomActually, when like aphosphorus-containingwithdrawing phosphoryl and groups diethylphosphoryl but substituents were most likedidgroup not a hydrogen is influenc bound,e atomand the characterized electron due to the localization similar the center electronegativity at asthe hard. C-3 atomActually, of like H- phosphorus-containingwithdrawingand P-atoms. Indicesgroups forbut substituents thewere carbon most atoms likedid anotcharacterized hydrogen influenc atome the C-3 dueelectron atoms to the as localization hard similar centers electronegativity at compared the C-3 atom with of likeC-2. H- withdrawingandFurthermore, P-atoms. groupsIndices the studied butfor thewere parameters carbon most likeatoms anticipated a hydrogen characterized the atom reactivity C-3 due atoms into the as lactonesimilar hard centers ringelectronegativity accounting compared for ofwith theH- andC-2.lower P-atoms.Furthermore, nucleophilicity Indices the offorstudied the the O-2 carbon parame atom atoms comparedters anticipated characterized to C-3, the and reactivityC-3 moreover, atoms in as thethe hard participationlactone centers ring compared accounting in 1,2-addition with for C-2.thereactions lowerFurthermore, with nucleophilicity nucleophiles. the studied of theparame O-2 tersatom anticipated compared the to reactivity C-3, and in moreover, the lactone the ring participation accounting forin 1,2-additionthe lower nucleophilicity reactions with ofnucleophiles. the O-2 atom compared to C-3, and moreover, the participation in 2.2.2. Reactions with Hydrides 1,2-addition reactions with nucleophiles. 2.2.2.The Reactions chemical with behavior Hydrides of diethyl 2-oxo-2H-1-benzopyran-3-phosphonate (1a) in hydrogenation/ 2.2.2.acylationThe Reactions reactionschemical with underHydridesbehavior diff erent of conditionsdiethyl was2-oxo- studied2H-1-benzopyran-3-phosphonate [51] and high regioselectivity (1a for) thein C-acylation product 20 was observed. Two reaction paths presented in Scheme 23 demonstrate the hydrogenation/acylationThe chemical behavior reactions of underdiethyl differ 2-oxo-ent 2Hconditions-1-benzopyran-3-phosphonate was studied [51] and(1a ) highin advantage of one-pot reactions versus the multistep routes. The first path shown as Method A involved hydrogenation/acylationregioselectivity for the C-acylation reactions productunder differ20 wasent observed.conditions Two was reaction studied paths [51] presented and high in deprotonation of 3,4-dihydroadduct 19 by NaH or DMAP and formation of enolate ion which reacted regioselectivityScheme 23 demonstrate for the C-acylationthe advant ageproduct of one-pot 20 was reacti observed.ons versus Two the reaction multistep paths routes. presented The first in with anhydride to form the acylated product 20a. However, the yields were rather unsatisfactory, 31 or Schemepath shown 23 demonstrate as Method A the involved advant agedeprotonation of one-pot ofreacti 3,4-dihydroadductons versus the multistep19 by NaH routes. or DMAP The firstand 38%. The second approach, Method B, presented a one-pot reaction with in situ generated enolate ion formationpath shown of asenolate Method ion A which involved reacted deprotonation with anhydride of 3,4-dihydroadduct to form the acylated 19 byproduct NaH 20aor DMAP. However, and formationthe yields ofwere enolate rather ion unsatisfactory, which reacted with31 or anhydride 38%. The tosecond form theapproach, acylated Method product B,20a presented. However, a the yields were rather unsatisfactory, 31 or 38%. The second approach, Method B, presented a

Molecules 2019, 24, 2030 16 of 38 Molecules 2019, 24, 2030 16 of 38 Molecules 2019, 24, 2030 16 of 38 one-pot reaction with in situ generated enolate ion followed by its trapping with a series of one-potfollowedanhydrides reaction by produced its trapping with the in with expectedsitu a seriesgenerated products of anhydrides enolate 20a–d ionin produced higher followed yields the expectedby (Scheme its trapping products 23). with20a –ad inseries higher of anhydridesyields (Scheme produced 23). the expected products 20a–d in higher yields (Scheme 23).

Scheme 23. One-pot tandem hydrogenation/acylation reactions with 3-diethylphosphonocoumarin Scheme1a. 23. One-pot tandemtandem hydrogenationhydrogenation/acylation/acylation reactions reactions with with 3-diethylphosphonocoumarin 3-diethylphosphonocoumarin1a. 1a. The yieldsyields ofof productsproducts 20a20a––dd dependeddepended stronglystrongly onon thethe solvent—pyridine—andsolvent—pyridine—and the catalyst—DMPA—usedThe yields of products in in the the process. process.20a–d Duringdepended During the the opstronglytimization optimization on ofthe the of solvent—pyridine—andreaction the reaction conditions, conditions, the ratiothe catalyst—DMPA—usedratiobetween between the anhydrides the anhydrides in theand process. andDMAP DMAP Duringvaried varied thefrom fromop timization3:1 3:1 to to 3:2.2. 3:2.2. of the Acetic, Acetic, reaction propionic propionic conditions, and the butyricbutyric ratio betweenanhydrides the resultedresulted anhydrides inin C-acylatedC-acylated and DMAP productsproducts varied inin 90%,90%, from 65%65% 3:1 andand to 72%72%3:2.2. yieldyield Acetic, afterafter 2.52.5propionic hh atat –4°4 ◦ andC. For butyric bulky − anhydridesacylating reagents resulted such in C-acylated as iso-propyl products anhydride,anhydride, in 90%, running 65% and the 72% reaction yield at after room 2.5 temperature h at –4° C. For enhancedenhanced bulky acylatingthethe yieldyield ofreagentsof20d 20dfrom from such 47 47 as to toiso 72%. 72%.-propyl The The stericanhydride, steric hindrance hindrance running between between the reaction the the newly newlyat room incorporated incorporated temperature acyl acyl groupenhanced group and theand phosphorylyield the phosphoryl of 20d group from group 47 at positionto at 72%. position C-3The determined stericC-3 determined hindrance the outcome thebetween outcome of the the of newly reaction. the reaction. incorporated acyl group and theProducts phosphoryl of subsequent group at position acylation C-3 21 determined or further the hydrogenation outcome of the22 andreaction. 23 were also isolated, (Figure(FigureProducts6 ).6). The The of predominant predominant subsequent presence acylationpresence of of dihydro21 dihydroor further adduct adduct hydrogenation19 when19 when the the reaction22 reactionand was23 werewas carried carriedalso out isolated, in out THF in (FigureconfirmedTHF confirmed 6). theThe importance predominant the importance of thepresence usedof the solvent, of used dihydro solvent, and furtheradduct and hydrogenation 19further when hydrogenation the reaction of 19 resulted was of carried19 in resulted formation out inin THFofformation derivatives confirmed of derivatives22 theand importance23. 22 and 23of. the used solvent, and further hydrogenation of 19 resulted in formation of derivatives 22 and 23.

Figure 6. Products isolated from acylation reaction. Figure 6. Products isolated from acylation reaction. 2.2.3. Reactions with Organometallic Reagents 1a 2.2.3.The Reactions firstfirst reactionreaction with Organometallic ofof 3-diethylphosphonocoumarin3-diethylphosphonocoumarin Reagents 1a with a Grignard reagent was reported by Bestmann and Lehnen [22]. Product 24 was isolated as a result of Michael-type addition reaction BestmannThe first and reaction Lehnen of [22]. 3-diethylphosphonocoumarin Product 24 was isolated as 1a a with result a Grignardof Michael-type reagent addition was reported reaction by (Scheme 24). Though, the reaction took place as stereospecific cis-addition to the C3=C4 double bond Bestmann(Scheme 24). and Though, Lehnen the [22]. reaction Product took 24 placewas isolatedas stereospecific as a result cis -additionof Michael-type to the C addition3=C4 double reaction bond and the product was characterized by X-ray spectroscopy, no yields from the performed reactions were (Schemeand the product24). Though, was characterizedthe reaction took by X-rayplace asspectr stereospecificoscopy, no cis yields-addition from to the the performed C3=C4 double reactions bond given in the article. andwere the given product in the was article. characterized by X-ray spectroscopy, no yields from the performed reactions were given in the article.

Molecules 2019, 24, 2030 17 of 38 Molecules 2019, 24, 2030 17 of 38 Molecules 2019, 24, 2030 17 of 38

Scheme 24. Reaction of 3-diethylphosphonocoumarin 1a with Grignard reagent. Scheme 24. Reaction of 3-diethylphosphonocoumarin3-diethylphosphonocoumarin 1a with Grignard reagent. A productive study on the option of applying 3-dialkylphosphonocoumarins 1q–t as key intermediatesA productive for the study study formation on on the theof optionα-methylene option of ofapplying applyingδ-lactones 3-dialkylphosphonocoumarins 3-dialkylphosphonocoumarinswas reported by Janecki and 1q co-workers–t1q as– tkeyas key[23–25,52].intermediates intermediates Compounds for the for formation thelike formationα-alkylidene of α-methylene of γα-lactones,-methylene δ-lactones α-alkylideneδ-lactones was reported δ-lactones was by reported Janecki and their byand analogs Janecki co-workers with and co-workerslactam[23–25,52]. ring Compounds [display23–25,52 pharmacological]. Compounds like α-alkylidene like propertiesα γ-alkylidene-lactones, and α inγ-alkylidene-lactones, particular αδ -alkylidene-lactonesstrong anti-cancer andδ-lactones their analogsactivity. and theirwithThe analogsmajoritylactam ring withof the display lactam synthesized pharmacological ring display δ-lactones pharmacological wereproperties tested andon properties human in particular leuk andemia instrong cell particular lines anti-cancer NALM-6 strong activity. anti-cancerand HL-60 The activity.asmajority well as The of MCF-7 the majority synthesized breast of thecancer synthesizedδ-lactones and HT-29 wereδ-lactones colon tested cancer wereon human cells. tested leuk on humanemia cell leukemia lines NALM-6 cell lines and NALM-6 HL-60 andas well HL-60In asorder MCF-7 as wellto obtainbreast as MCF-7 cancerthe phosphorus-contain breast and cancerHT-29 andcolon HT-29 cancering adducts colon cells. cancer for the cells. Horner–Wadsworth–Emmons olefinationInIn orderorder α-(diethoxyphosphoryl)- toto obtainobtain thethe phosphorus-containingphosphorus-containδ-lactones 25ing were adductsadducts prepared forfor thethe by Horner–Wadsworth–EmmonsHorner–Wadsworth–Emmons a 1,4-conjugate addition of olefinationorganometallicolefination α-(diethoxyphosphoryl)- compounds to substiδtuted-lactones-lactones 3-diethylphosphonocoumarins 25 were prepared by a 1,4-conjugate1,4-conjugate 1q–t in the presence additionaddition ofof organometalliccatalytic amount compounds of CuI (Scheme to substitutedsubsti 25). tutedThe reaction 3-diethylphosphonocoumarinss proceeded in a fully diastereoselective 1q–tt in the presencepresence manner ofof catalyticwhile the amount time for of CuIconversionCuI (Scheme(Scheme depended 2525).). The reactionsreactionstronglys proceededon the substituents in aa fullyfully diastereoselectiveondiastereoselective the benzene ring. mannermanner For whileexample,while thethe timewhen time for thefor conversion interactionconversion depended was depended performed strongly strongly with on the 1hon substituents (Ythe = substituents8-OMe) on using the benzeneon MeMgI the benzene ring. as a Fornucleophile ring. example, For whentheexample, reaction the interactionwhen time the was interaction was 2.5h performed and wasthe yieldperformed with of1h 25(Y was=with8-OMe) 73%. 1h (Y However, using = 8-OMe) MeMgI when using as the a MeMgI nucleophile same asconditions a thenucleophile reaction were timeappliedthe reaction was for 2.5 coumarin time h and was the 1e2.5h yield (Y and= of7-OMe) 25thewas yield the 73%. oftime 25 However, forwas its 73%. conversion when However, the was same when 48h conditions theand same the additionwere conditions applied product were for coumarinwasapplied obtained for1e coumarin(Y in= a7-OMe) yield 1e of the(Y 69%. = time 7-OMe) In forgeneral, its the conversion time using for iso wasits-propyl conversion 48 h and and n the -butylmagnesiumwas addition 48h and product the additionha waslide obtained the product yields in awerewas yield obtained in of the 69%. range in In a general,yieldof 51 toof using69%.93%, Inwhereasiso general,-propyl for andusing methn-butylmagnesium isoylmagnesium-propyl and haliden-butylmagnesium halide the the results yields were were halide between in the the yields range 68– of85%.were 51 toinInterestingly, 93%,the range whereas of 51 forthe to methylmagnesium 93%,structures whereas offor halide methisolatedylmagnesium the resultscompounds were halide between were the results 68–85%.characterized were Interestingly, between as 68–the structurestrans85%.- β-substitutedInterestingly, of isolated isomers. compoundsthe structures were characterizedof isolated ascompounds the trans-β-substituted were characterized isomers. as the trans-β-substituted isomers.

Scheme 25. 1,4-conjugate addition reactions with organometallic compounds.

Scheme 25. 1,4-conjugate addition reactions with 25organometallic compounds. Fundamental research on th thee synthesis of compounds 25 was presented by by Nikolova Nikolova et et al. al. [53]. [53]. In this study, ultrasonic waves were used as a promoter of the reaction—Method B, Scheme 25. The In thisFundamental study, ultrasonic research waves on thweree synthesis used as ofa promotercompounds of the25 was reaction—Method presented by Nikolova B, Scheme et 25.al. [53].The sonication method provides an unusual mechanism to generate high-energy chemistry due to the sonicationIn this study, method ultrasonic provides waves an were unusual used mechanis as a promoterm to generateof the reaction—Method high-energy chemistry B, Scheme due 25. to Thethe extraordinary temperatures and pressure generated by the collapse of cavitation bubbles, while it can extraordinarysonication method temperatures provides andan unusualpressure mechanis generatedm byto generatethe collapse high-energ of cavitationy chemistry bubbles, due while to the it accelerate organic reactions involving metal-mediated processes because of the metal surface activation canextraordinary accelerate temperaturesorganic reactions and involvingpressure generated metal-mediated by the processescollapse of because cavitation of the bubbles, metal whilesurface it and the particle size reduction, producing modified metal surfaces and at the same time speeding activationcan accelerate and theorganic particle reactions size reduction, involving produc metal-ingmediated modified processes metal surfaces because and of the at themetal same surface time up the formation of organometallic reagents. The reaction between 3-diethylphosphonocoumarin 1a speedingactivation andup thethe particle formation size reduction, of producorganometaing modifiedllic reagents. metal surfaces The andreaction at the samebetween time and the organomagnesium compound was completed as Michael-type addition and the formation of 3-diethylphosphonocoumarinspeeding up the formation 1a andof theorganometa organomagnesiumllic reagents. compound The wasreaction completed between as Michael-type3-diethylphosphonocoumarin addition and the formation1a and the of trans-organomagnesiumisomers of products compound 25 were wasobserved. completed Methods as Michael-type addition and the formation of trans-isomers of products 25 were observed. Methods

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Molecules 2019, 24, 2030 18 of 38 trans-isomers of products 25 were observed. Methods for initiating the reaction—thermal or ultrasonic, werefor initiating furtherinvestigated the reaction—thermal and a relationship or ultrasonic between, were theyields further and investigated the reaction and time a as relationship well as the appliedbetween technique the yields was and indicated the reaction in Tabletime 3as. well as the applied technique was indicated in Table 3.

TableTable 3.3. ComparisonComparison betweenbetween thethe resultsresults forfor reactionreaction ofof 1a1a withwith organomagnesiumorganomagnesium reagentsreagents underunder thermalthermal andand ultrasonicultrasonic initiation.initiation.

RefluxReflux US US Substituent R1 SubstituentReaction R1 TimeReaction [min] Time YieldYield [%] Reaction Time [min]Yield Yield [%] Reaction Time [min] [min] [%] [%] Et 50 64 10 89

n-PrEt 6050 7764 10 30 89 94 i-Prn-Pr 8060 6977 30 50 94 74

PhCH2 i-Pr 12580 3869 50 90 74 53

CH2COOt-BuPhCH2 75125 7838 90 30 53 95 CH2COOt-Bu 75 78 30 95

TheThe mainmain disadvantagedisadvantage of thethe thermalthermal initiationinitiation was the lack ofof reproducibilityreproducibility of thethe obtainedobtained results.results. By By applying applying the the sonication sonication method method this obstacle was overcome.overcome. The The data data in in Table 33 unambiguously showe the impact of sonication on thethe decrease of reaction time to 10–4010–40 min,min, andand thethe increaseincrease ofof thethe yieldsyields ofof thethe targettarget molecules.molecules. The studied reaction was specifiedspecified withwith aa completecomplete regioselectivityregioselectivity forfor thethe 4-substituted4-substituted 3,4-dihydrophosphonocoumarins3,4-dihydrophosphonocoumarins 2525.. A comparison between Method A and Method B displayed distinctly shorter reaction times for thethe sonicatedsonicated reactionsreactions andand absenceabsence of requirementsrequirements as useuse aa specificspecific catalyst,catalyst, inertinert atmosphereatmosphere andand high excess ofof thethe GrignardGrignard reagentsreagents used.used. Applying Method B to Reformatsky reagentsreagents aaffordedfforded product of typetype 25 [[53].53]. However, underunder ultrasound irradiation,irradiation, using using di ffdifferenterent organozinc organozinc compounds, compounds, the dimeric the dimeric systems systems26 were obtained26 were inobtained high yields in high [54 ]yiel (Schemeds [54] 26 (Scheme). 26).

Scheme 26. Reactions with organozinc reagents.

Obviously, thethe processesprocesses inin SchemeScheme 2626 areare characterizedcharacterized byby twotwo didifferentfferent mechanisms.mechanisms. WhenWhen compound 25 was formed,formed, the reactionreaction isis classifiedclassified asas aa Michael-typeMichael-type additionaddition ofof C-nucleophilesC-nucleophiles to electron-deficientelectron-deficient systems. However, the formation of product 26 cannot be explainedexplained by a MichaelMichael addition reaction. Therefore, Niko Nikolovalova et. et al.al. investigated the mechanism of the process and it waswas assumed a radicalradical intermediateintermediate formation and a subsequentsubsequent couplingcoupling betweenbetween thethe initiatedinitiated radicalsradicals (Scheme(Scheme 2727).). During the investigationsinvestigations on the mechanismmechanism of the reaction,reaction, thethe authorsauthors triedtried toto synthesizesynthesize heterodimers byby combining combining coumarin coumarin systems systems with with varied varied reactivity. reactivity. However, However, the approaches the approaches were notwere successful not successful and the assumptionand the assumption was that the was reaction thatconditions the reaction favored conditions just the homodimerizationfavored just the processhomodimerization whereas the process used solventwhereas played the used a major solven rolet played in the a reaction major role path. in the Products reaction26 werepath. isolatedProducts and 26 characterizedwere isolated asandmeso characterized-form structures as meso due-form to the structures obtained analyticdue to the data obtained from X-ray analytic and NMRdata from spectroscopy. X-ray and NMR spectroscopy.

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Scheme 27. Radical homodimerization mechanism. SchemeScheme 27.27. Radical homodimerization mechanism.mechanism. Applying 4-substituted 3-diethylphosphonocoumarins 1u–ad (Scheme 28), as Michael acceptorsApplyingApplying another 4-substituted4-substituted approach 3-diethylphosphonocoumarinstoward 3-diethylphosphonocoumarins the investigation of the1u regioselectivity– ad1u(Scheme–ad (Scheme(Scheme 28 of), asthe Michael28), 28),reaction asas acceptors MichaelandMichael the possibilityanotheracceptors approach another for incorporation approach toward oftoward the a second investigation the alkylinvestigation substituent of the of regioselectivity thein δ regioselectivity-lactones 27 was of of the presented the reaction reaction [26,27]. and and The thethe possibilitystudypossibility was foraccomplished for incorporation incorporation with of of a asecondseries second of alkyl organomagnesium alkyl substituent substituent in δ in -lactones-lactonesreagentsδ-lactones 27(ethyl-, was27 was presented iso- presentedpropyl-, [26,27]. n-butyl-, [26 ,The27]. Thecyclohexylmagnesiumstudy study was accomplished was accomplished chlorides, with a with series allylmagnesium a of series organomagnesiumorganomagnesium of organomagnesium iodide reagentsreagentsand benzylmagnesium reagents (ethyl-,(ethyl-, iso-iso- (ethyl-,propyl-, isobromide) -propyl-,n-butyl-,-butyl-, 4,4-disubstitutedncyclohexylmagnesium-butyl-, cyclohexylmagnesium 3-dietho chlorides,xyphosphoryl-3,4-dihydro-2 chlorides, allylmagnesium allylmagnesium iodideH-chroman-2-ones iodide and and benzylmagnesium benzylmagnesium 27 were isolated bromide) in moderate4,4-disubstituted4,4-disubstituted to good 3-diethoxyphosphoryl-3,4-dihydro-2 yields3-dietho in xyphosphoryl-3,4-dihydro-2a mixture of trans- and cisH- -chroman-2-onesisomers.H-chroman-2-ones-chroman-2-ones Only in 27three were 2727 cases isolatedwerewere the product inisolatedisolated moderate was inin foundtomoderate good to yields be to a good single in a mixtureyields trans -isomer.in of a transmixture - and ofcis trans-trans-- isomers. and cis Only-- isomers.isomers. in three OnlyOnly cases inin the threethree product casescases was thethe foundproductproduct to bewaswas a singlefoundfound transtoto bebe-isomer. aa singlesingle transtrans-isomer.-isomer.

Scheme 28. 1,4-conjugate addition reactions to 4-substituted 3-diethylphosphonocoumarins. Scheme 28. 1,4-conjugate addition reactions to 4-substituted 3-diethylphosphonocoumarins. Scheme 28. 1,4-conjugate addition reactions to 4-substituted 3-diethylphosphonocoumarins. 2.2.42.2.4. Three-ComponentThree-component ReactionsReactions ofof Diethyl Diethyl 2-oxo-2 2-oxo-2H-1-benzopyran-3-phosphonateH-1-benzopyran-3-phosphonate (1a) with(1a) with Compounds2.2.4 Three-component Bearing Carbonyl Reactions and Aminoof Diethyl Groups 2-oxo-2 H-1-benzopyran-3-phosphonate-1-benzopyran-3-phosphonate ((1a)) withwith Compounds Bearing Carbonyl and Amino Groups Conjugate additionaddition reactions reactions to 3-diethylphosphonocoumarin to 3-diethylphosphonocoumarin1a using asymmetric1a using nonstabilizedasymmetric nonstabilizedazomethineConjugate ylides azomet addition werehine investigated ylidesreactions were byto investigated Moshkin3-diethylphosphonocoumarin3-diethylphosphonocoumarin et al.by [55Moshkin,56]. The et developedal. [55,56].1a usingusing approach The asymmetricasymmetricdeveloped for the approachsynthesisnonstabilized for of productsthe azomet synthesishine28 and ofylides products29 utilized were 28 asandinvestigated starting 29 utilized material by as Moshkin starting the in material situet al. formed [55,56]. the in ylide situ The derivedformed developed ylide from derivedcyclohexanoneapproach from for the cyclohexanone and synt N-methylglycinehesis of productsand N-methylglycin (Scheme28 andand 29 29 utilizedutilized).e (Scheme The asas structure startingstarting 29). The material ofmaterial compoundsstructure thethe inin of situsitu29 compounds resembleformedformed ylideylide the29 resembleskeletonderived from ofthe adrenoceptor skeleton cyclohexanone of adrenoceptor antagonists and N-methylglycin andantagonists are good ande precursors(Scheme are good 29). forprecursors The new structure pharmaceutical for new of pharmaceuticalcompounds agents for29 prostaticagentsresemble for hyperplasia.the prostatic skeleton hyperplasia. of adrenoceptor antagonists and are good precursors for new pharmaceutical agents for prostatic hyperplasia.

Scheme 29. Reaction of 1a with cyclohexanone and N-methylglycine. Scheme 29. Reaction of 1a withwith cyclohexanonecyclohexanone andand N-methylglycine.N-methylglycine. The reaction can be illustrated as 1,3-dipolar cycloaddition to the 3-diethylphosphonocoumarin 1a, thereforeThe reaction productproduct can 29 29be was wasillustrated thethe expectedexpected as 1,3-dipolar adduct.adduct. cycloaddition Surprisingly,Surprisingly, the theto the pyrrolidonepyrrolidone 3-diethylphosphonocoumarin28 28was was alsoalso formed.formed. 1a,, thereforetherefore productproduct 29 waswas thethe expectedexpected adduct.adduct. SuSurprisingly, the pyrrolidone 28 was also formed..

Molecules 2019, 24, 2030 20 of 38 MoleculesMolecules 2019 2019, ,24 24, ,2030 2030 20 20of of38 38

DueDue toto thethe stericsteric hindrance,hindrance, the deactivation ofof the the cationic cationic center center and and the the loss loss of of the the dipolar dipolar propertiesproperties ofof thethe azomethineazomethine structurestructure 30 anan initial initial Michael MichaelMichael addition additionaddition fo followedfollowedllowed by by an an intramolecular intramolecularintramolecular cyclizationcyclization leading leading toto thethe formationformation of the heterocyclic heterocyclic compound compoundcompound 28 2828 was waswas observed observedobserved (Scheme (Scheme(Scheme 30). 3030). ).The The participationparticipation of ofof cyclohexanone cyclohexanonecyclohexanone in thein the formation formation of pyrrolidone ofof pyrrolidonepyrrolidone28 was 2828 identified was was identified identified by additional by by additional additional reactions. Withoutreactions.reactions. the Without Without presence thethe of presencepresence cyclohexanone of cyclohexanone no interaction nono wasinteractioninteraction observed, was was therefore observed, observed, it therefore played therefore a majorit itplayed played role a in a themajormajor formation role role in in the the of 28 formationformationas catalyst of 28 for as the catalyst described forfor thethe domino describeddescribed reaction. domino domino reaction. reaction.

Scheme 30. Proposed ylide structure 30 and subsequent interactions. Scheme 30. Proposed ylide structure 30 and subsequent interactions. When the used carbonyl compound was changed to paraformaldehyde (Scheme 31, Reaction When the used carbonyl compound was changed to paraformaldehyde (Scheme 31, Reaction (1)), (1)),When and the the reaction used carbonyl was carried compound out in benzenewas change withd azeotropicto paraformaldehyde removal of water,(Scheme Moshkin 31, Reaction and and the reaction was carried out in benzene with azeotropic removal of water, Moshkin and coworkers (1)),coworkers and the observed reaction wasthe formationcarried out of in benzopyranopyrrolidine benzene with azeotropic derivative removal of31 .water, The lactoneMoshkin ring and observed the formation of benzopyranopyrrolidine derivative 31. The lactone ring conformation in the coworkersconformation observed in the formedthe formation product ofconfirmed benzopyranopyrrolidine the synchronicity ofderivative the reaction 31. ofThe nonstabilized lactone ring formed product confirmed the synchronicity of the reaction of nonstabilized azomethine ylides with conformationazomethine ylides in the withformed 3-diethylphosphonocoumarin product confirmed the synchronicity 1a resulted ofin the the reaction cis-fusion of nonstabilizedin the new 3-diethylphosphonocoumarin 1a resulted in the cis-fusion in the new pyrrolidine structure. azomethinepyrrolidine structure.ylides with 3-diethylphosphonocoumarin 1a resulted in the cis-fusion in the new Further investigation on the 1,3-dipolar cycloaddition of the ylide, derived from proline and pyrrolidineFurther structure. investigation on the 1,3-dipolar cycloaddition of the ylide, derived from proline and formaldehyde, using diethyl 2-oxo-2H-1-benzopyran-3-phosphonate 1a as a trapping dipolarophile, formaldehyde,Further investigation using diethyl on 2-oxo-2 the 1,3-dipolarH-1-benzopyran-3-phosphonate cycloaddition of the ylide, 1a as aderived trapping from dipolarophile, proline and 32 resultedformaldehyde,resulted inin thethe formationusingformation diethyl ofof pyrrolizidines pyrrolizidines2-oxo-2H-1-benzopyran-3-phosphonate 32 as a a major product product (Scheme (Scheme 1a as 31, a31 trapping ,Reaction Reaction dipolarophile,(2), (2), n n= =1),1), a a 1 minorresultedminor diastereomer diastereomer in the formation33 33,, andand of thethepyrrolizidines presencepresence of the 32 as other other a major isomers isomers product 3434 andand (Scheme 3535 werewere 31, determined determined Reaction by(2), by 1H- nH- =and 1), and a 31 minor31P-NMRP-NMR diastereomer spectroscopy.spectroscopy. 33, and the presence of the other isomers 34 and 35 were determined by 1H- and 31P-NMR spectroscopy.

SchemeScheme 31. Domino reaction reaction with with azomethine azomethine ylides. ylides.

Scheme 31. Domino reaction with azomethine ylides.

MoleculesMolecules 20192019,, 2424,, 20302030 2121 ofof 3838

Different selectivity of the cyclization process was observed when pipecolic acid (Scheme 31, ReactionDifferent (2), n selectivity = 2) was ofimplied the cyclization in the reaction process mixture. was observed The increase when pipecolic of the endo- acidcycloaddition (Scheme 31, Reactionproduct 35 (2), might n = 2) be was due implied to the insize the and reaction the flexibility mixture. of The the increase azomethine of the ylide’sendo-cycloaddition cyclic moiety product and the 35absencemight of be steric due tohindrance the size and in the the transition flexibility state. of the azomethine ylide’s cyclic moiety and the absence of stericA large hindrance number in theof pyrrolizidines transition state. were observed when benzaldehyde was used as a carbonyl componentA large and number only two of pyrrolizidines of the isomers were were observed isolated and when characterized benzaldehyde as being was usedthe major as a carbonylproducts component36 and 37 (Scheme and only 31, two Reaction of the isomers(3)). were isolated and characterized as being the major products 36 andPhosphorylated37 (Scheme 31 ,azaheterocycles Reaction (3)). were synthesized [57] by three-component reaction between 3-diethylphosphonocoumarinPhosphorylated azaheterocycles 1a withwere acetone, synthesized cyclopentanone [57] by or three-component cyclohexanone and reaction benzylamine. between 3-diethylphosphonocoumarinThese compounds are promising1a with precursors acetone, for cyclopentanone the preparation or of cyclohexanone polycyclic δ-lactams and benzylamine. possessing Thesepotential compounds biological are activity. promising precursors for the preparation of polycyclic δ-lactams possessing potentialThe biologicalreaction of activity. 3-diethylphosphonocoumarin 1a with benzylamine and acetone, proceeded at roomThe temperature reaction of within 3-diethylphosphonocoumarin one day and the desired product1a with benzylamine38 was isolated and as acetone, a single proceededdiastereomer at roomin 87% temperature yield (Scheme within 32). one The day structure and the and desired absolu productte configuration38 was isolated of the as product a single was diastereomer determined in 87%by single yield crystal (Scheme X-ray 32). crystallography. The structure and absolute configuration of the product was determined by singleInterestingly, crystal X-ray only crystallography. one product was observed when 3-diethylphosphonocoumarin 1a reacted withInterestingly, cyclopentanone only and one benzylamine product was observedat room whentemperature 3-diethylphosphonocoumarin at benzene as a solvent.1a reactedThe isolated with cyclopentanoneproduct 39 was and identified benzylamine as benzoxazocine at room temperature isomer at with benzene H-C(10), as a solvent. H-C(9)- The trans isolated and productH-C(9), 39H-C(9a)-was identifiedcis relative as benzoxazocine configuration. isomer Using with X-ray H-C(10), analysis H-C(9)- a 3aR*,9R*,9aR*,10R*trans and H-C(9), H-C(9a)-configurationcis relative was configuration.assigned (Scheme Using 32). X-ray analysis a 3aR*,9R*,9aR*,10R* configuration was assigned (Scheme 32). ItIt shouldshould bebe notednoted thatthat thethe reactionreaction ofof 1a1a withwith benzylaminebenzylamine andand cyclohexanonecyclohexanone waswas notnot stereoselectivestereoselective likelike thethe previouslypreviously mentionedmentioned reactionsreactions andand aa mixturemixture ofof fourfour isomersisomers 4040::4141::4242::4343 inin aa ratioratio ofof 1:0.25:0.25:0.11:0.25:0.25:0.1 werewere isolated.isolated.

(EtO)2(O)P H O H Ph 1 equiv Ph NH2 N

acetone, 24h, r.t. CH O 3

38 87%

O H Ph (EtO)2(O)P O 1 equiv Ph NH 10 2 H N 9 P 2 equiv cyclopentanone 9a 3a OEt OEt H O O benzene, 24h, r.t. O 1a 39 85%

3aR*,9R*,9aR*,10R*

O O O H Ph H Ph Ph (EtO)2(O)P (EtO)2(O)P (EtO)2(O)P 11 3 11 1 equiv Ph NH H N H N H N 2 9 4 9 9a 4a 9a 4a 2 equiv cyclohexanone 4a H H H O OH O benzene, 48h, r.t. 40 40% 41 5% 42/43

4aR*,9R*,9aR*,11R* 3R*,4R*,4aR* 4aR*,9R*,9aR* SchemeScheme 32.32. SynthesisSynthesis ofof polycyclicpolycyclic δδ-lactams.-lactams.

TheThe authorsauthors usedused enantiomericallyenantiomerically purepure ((RR)-)- andand ((SS)-phenylamines)-phenylamines asas reagentsreagents inin orderorder toto determinedetermine thethe absolute absolute stereochemical stereochemical course course of of the th reactions.e reactions. However, However, even even under under this this approach approach the unambiguouslythe unambiguously assignment assignment of the of relative the relative configuration configuration of the stereogenic of the stereogenic centers C-9centers and C-9aC-9 and in 39 C-9a–43

Molecules 2019, 24, 2030 22 of 38 Molecules 2019, 24, 2030 22 of 38 wasin 39 not–43 achieved. was not When achieved. adducts wereWhen transformed adducts were into their transformed corresponding intoα -methylene-their correspondingδ-lactams theα-methylene- configurationδ-lactams was distinguished. the configuration was distinguished.

Reactions with CH-acidic Compounds CH-acidic compounds were also used as nucleophilesnucleophiles in conjugateconjugate additionaddition reactions with 3-diethylphosphonocoumarin 1a 1aand and its its derivatives. derivatives. For For example, example, Janecki Janecki et al. [et52 ]al. applied [52] applied the sodium the saltsodium of nitromethane salt of nitromethane as an alternative as an alternative reagent in areagent Michael in type a Michael addition type reaction addition to give reaction coumarin to give1a. Thecoumarin reaction 1a. proceededThe reaction in proceeded 58% conversion in 58% of conversion the starting of material the starting and material product 44andwas product isolated 44 aswas a singleisolated diastereomer as a single diastereomer with a pseudo-axial with a pseudo-axial disposition of disposition the phosphoryl of the andphosphoryl nitro groups and nitro (Scheme groups 33, Method(Scheme A).33, Method A).

Scheme 33. Michael-type addition of nitromethane under didifferentfferent reactionreaction conditions.conditions.

The interactioninteraction between between coumarin coumarin1a and1a and nitromethane nitromethane using using different different bases (KF, bases Et3 N,(KF, C5 HEt113N)N, inC5H a11 proticN) in solventa protic (EtOH)solvent (EtOH) led to formation led to formation of compounds of compounds45 and 4546 and(Scheme 46 (Scheme 33, Method 33, Method B) [58 B)]. Product[58]. Product45 was 45 isolatedwas isolated in an in overall an overall yield yield of 74% of as74% a mixtureas a mixture of two oftrans two-isomers trans-isomers in 1:1.25 in 1:1.25 ratio whenratio when potassium potassium fluoride fluoride was used was as used a base. as Thea base. transformation The transformation involved involved a 1,4-conjugate a 1,4-conjugate addition ofaddition nitromethane of nitromethane to the activated to the activated double bond double in coumarinbond in coumarin1a and a 1a subsequent and a subsequent attack of attack a solvent of a moleculesolvent molecule to the carbonyl to the groupcarbonyl of thegroup lactone of the ring. lactone However, ring. when However, using piperidinewhen using or piperidine propylamine or anpropylamine additional product 1-hydroxy-4-(2an 0-hydroxyphenyl)-2,5-dioxopyrrolidin-3-yl-phosphonateadditional product (46) was1-hydroxy-4-(2 isolated as′-hydroxyphenyl)-2,5-dioxopyrrolidin-3-yl-phosphonate a single isomer. The mechanism of formation of 46, shown(46) was in isolated Scheme as34 a, wassingle a resultisomer. of The a base-catalyzed mechanism of tautomeric formation transformationof 46, shown in of Scheme the Michael-type 34, was a result adduct of 44a base-catalyzedfollowed by a Nef-reactiontautomeric transformation rearrangement. of the Michael-type adduct 44 followed by a Nef-reaction rearrangement.

Molecules 2019, 24, 2030 23 of 38 Molecules 2019, 24, 2030 23 of 38 Molecules 2019, 24, 2030 23 of 38

Scheme 34. Proposed mechanism for the formation of 45 and 46. Scheme 34. Proposed mechanism for the formation of 45 and 46. The subsequentsubsequent syntheticsynthetic protocol, protocol, Method Method C, C, Scheme Scheme 33, 33, illustrated illustrated the conjugatethe conjugate reaction reaction with withnitromethaneThe nitromethane subsequent in free syntheticin solventfree solvent protoc conditions. conditions.ol, Method The The resultsC, Schemeresults emphasized emphasized 33, illustrated the influencethe theinfluence conjugate of the of basesthe reaction bases on the on withthereaction nitromethane reaction path path and in and onfree on the solvent the product product conditions. ratio. ratio. The TheThe primary primary results amineemphasized amine led led to to the productproduct influence 4747,, whereaswhereas of the bases secondary on theamines reaction promotedpromoted path and formation formationon the product of of46 46and ratio. and47 The47. Compound. Compound primary amine46 46was was led isolated toisolated product as an as only47 an, whereasonly product product secondary in very in goodvery aminesyieldsgood promoted yields when when triethylamine formation triethylamine of was 46 usedandwas 47used in. theCompound in reaction. the reaction. 46 The was productThe isolated product of as Michael-type ofan Michael-type only product addition addition in very44 still 44 goodstillremained yields remained when as a as major triethylamine a major product product inwas the in used presencethe presencein the of reaction. potassium of potassium The fluoride product fluoride as of a trans asMichael-type a trans--isomer.isomer. addition 44 still remainedA diastereoselective as a major product Michael in the ad addition ditionpresence of enolizable of potassium ketones fluoride to 3-diethylphosphonocoumarin 3-diethylphosphonocoumarin as a trans-isomer. 1a1a,, 1cA and diastereoselective 1h promoted by by Michael 1,5,7-triazabicyclo 1,5,7-triazabicyclo addition of enolizable[4.4.0]dec-5-ene [4.4.0]dec-5-ene ketones (TBD) (TBD) to 3-diethylphosphonocoumarin was was performed performed in inthe the next next work 1a work, of 1c andKrawczykof Krawczyk 1h promoted et etal. al. [59,60]by [ 591,5,7-triazabicyclo,60 (Scheme] (Scheme 35). 35 ). Due[4.4.0]dec-5-ene Due to to the the equilibrium equilibrium (TBD) was of of performedthe the process, process, in the the nextreactions work wereof Krawczykperformed et inal.in the [59,60]the presence presence(Scheme of an excess35).of anDue of excess theto usedthe ofequilibrium ketone the andused theof ketone TBDthe process, base. and The the electron-withdrawing reactionsTBD base. were The performedelectron-withdrawingand electron-donating in the presence substituentsand electron-donatingof an equally excess influenced of substituents the 3-diethylphosphono-used equallyketone influeand ncedthe coumarins 3-diethylphosphono-TBD 1cbase.and 1hTheand electron-withdrawingcoumarinscontributed 1c to and their 1h and high and electron-donating reactivity.contributed to their substituents high reactivity. equally influenced 3-diethylphosphono- coumarins 1c and 1h and contributed to their high reactivity. O O O O excess O OEt O P excess 1.5 equiv TBD OEt OEt R P 1.5 equiv TBD OEt 1h, r.t. R O O 1h, r.t. O O Y 48 96-98% O 48 96-98% Y O O Y O O n 1.5 equiv Y O 5 equiv O 2' O n OEt O O n OEt 1.5 equiv O P 5 equiv O 2' OEt O P 2 equiv n TBD OEt OEt 2 equiv TBD O P OEt OEt OEt R P 4 3 OEt R P 2 equiv TBD OEt 2 equiv TBD R P CH2Cl2, 1h, r.t. CH2Cl2, 24h, r.t. OEt R O O 4 3 OEt R O O CH Cl 1h, r.t. CH Cl 24h, r.t. R O O 2 Y=H,4'-OMe2, 1aO, 1c, O1h 2 2, O O R = H, 6-Cl, 8-OMe O 49 O 83-88% 51 Y=H,4'-OMe 1a, 1c, 1h n = 1, 83-88% R = H, 6-Cl, 8-OMe 49 83-88% 51 O n = 1,n = 2, 83-88% 61-72% X O n = 2, 61-72% X = O, 3 equiv X X=CH 15 equiv O O X = O, 3 equiv2, X OEt O X=CH2, 15 equiv O P 1.5 equiv X Cs2CO3 OEt OEt R P 1.5 equiv Cs2CO3 OEt CH2Cl2, 48h, r.t. R O O CH2Cl2, 48h, r.t. O 50 O X =50 O, 84% X = O,X=CH 84%2,72-82% X=CH2,72-82% Scheme 35. Michael addition of enolizable ketones to 3-diethylphosphonocoumarin 1 using TBD and

SchemeCsScheme2CO 35.3. Michael 35. Michael addition addition of enolizable of enolizable ketones ketones to 3-diethylp to 3-diethylphosphonocoumarinhosphonocoumarin 1 using1 TBDusing and TBD Cs2COand3. Cs 2CO3. Ketones as acetone, cyclopenatanone and 1-indanone have shown high stereoselectivity for the additionKetones productsas acetone, 48 cyclopenatanone, 49, 51. In theand 1-indanocase of necyclohexanone, have shown high a stereoselectivitymixture of unidentified for the addition products 48, 49, 51. In the case of cyclohexanone, a mixture of unidentified

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MoleculesKetones 2019, 24 as, 2030 acetone, cyclopenatanone and 1-indanone have shown high stereoselectivity for24 of the 38 Molecules 2019, 24, 2030 24 of 38 addition products 48, 49, 51. In the case of cyclohexanone, a mixture of unidentified phosphorus- containing products was afforded and the use of cesium carbonate (Cs2CO3) resolved2 the3 problem, phosphorus-containingphosphorus-containing productsproducts was afforded and the useuse ofof cesiumcesium carbonatecarbonate (Cs (Cs2COCO3) )resolved resolved producingthethe problem, problem,50 producing inproducing very good 5050 yields. inin veryvery goodgood yields. All of the α-phosphono-δ-lactonic products 48–51 were isolated as a mixture of C 3-C 4 cis- and AllAll ofof thethe αα-phosphono--phosphono-δδ-lactonic-lactonic products 48–51 werewere isolatedisolated asas aa mixturemixture of of C C3-C-C44 cis- cis- and and transtranstrans-isomers-isomers-isomers withwith with predominant predominantpredominant formation formationformation ofof thethe transtrans-product.-product.-product. A AA synclinal synclinalsynclinal transition transitiontransition state statestate might mightmight be bebe formedformedformed when when the the process process was was carriedcarried out out with with prochiral prochiral ketones.ketones. ketones. InIn In thethe the described described described case case case the the the Re-face Re-face Re-face of of ofthethe the enolateenolate enolate approachesapproaches approaches thethe the Re-faceRe-face Re-face of of the the 3-diet 3-diethylphosphonocoumarinhylphosphonocoumarin (Fig(Fig (Figureureure 7)77)) leading leadingleading to toto thethe formationformationformation ofof of aa a single singlesingle C CC444-C-C22--synsyn diastereomerdiastereomer (Scheme 35).35).35).

FigureFigureFigure 7.7. ProposedProposed synclinal transitiontransitiontion state state formation. formation.

InInIn tandemtandemtandem Michael-intermolecularMichael-intermolecularMichael-intermolecular Horner-Wadsworth-EmmonsHorner-Wadsworth-Emmons reactions reactionsreactions involving involvinginvolving 3-diethylphosphonocoumarin3-diethylphosphonocoumarin3-diethylphosphonocoumarin 1a1a1a andand its substituted its substituted analogues analogues 1c1c andand 1c1h 1h (Schemeand (Scheme1h 36), (Scheme36), an an alternative alternative 36), an alternativeCH-acidicCH-acidic compound, CH-acidiccompound, compound, 2,5-hexanedione,2,5-hexanedione, 2,5-hexanedione, was applied was [61].[61]. applied TheThe performedperformed [61]. The performed reactionsreactions were were reactions catalyzed catalyzed were catalyzedbyby a a stoichiometric stoichiometric by a stoichiometric amountamount ofof amount TBD at ofroom TBD temper at roomature. temperature. TheThe quenchingquenching The of quenchingof thethe process process of resulted theresulted process in in resultedthethe formationformation in the formationofof thethe transtrans of-isomer-isomer the trans of-isomer product of 52 product andand thethe52 correspondingcorrespondingand the corresponding hydroxyacidhydroxyacid hydroxyacid 53 53 in in almost almost53 in almostequimolarequimolar equimolar amounts. amounts. amounts. TheThe formationformation The formation of product of 53 product waswas inin53 aa resultwasresult in ofof a subsequentsubsequent result of subsequent hydrolysis hydrolysis hydrolysiscatalyzed catalyzed catalyzedbyby the the presencepresence by the presenceofof TBDTBD ofof of thethe TBD formed of the formedbenzolactone benzolactone adduct.adduct. adduct. ModifiedModified Modified conditionsconditions conditions utilizing utilizing utilizing a a protic protic a proticsolventsolvent solvent (MeOH), (MeOH), (MeOH), werewere appliedapplied were applied toto favor to the favor formation the formation ofof 5353 asas a ofa solesole53 as product.product. a sole However, product.However, However,the the products products the productsofof type type 53 53 of were were type isolatedisolated53 were asas isolated theirtheir methylmethyl as their trans methyl-cyclopentencarboxylatetrans-cyclopentencarboxylate derivatives.derivatives. derivatives.

Scheme 36. Michael addition of enolizable ketones to 3-phosphonocoumarin 1 using TBD. SchemeScheme 36.36. Michael addition of enolizable ketones to 3-phosphonocoumarin3-phosphonocoumarin 11 usingusing TBD.TBD. Then the dione system was changed to cyclohexane-1,3-dione [62] products 54 were observed (SchemeThen 36) the and dione later system used aswas adducts changed in a to subseq cyclohexane-1,3-dioneuent domino transesterification-cyclodehydration [62] products 54 were observed (Schemeprocess 36)that and resulted later used in theas adductsformation in aof subseq methyluent 2-(diethoxyphosphoryl)-2-(1-oxo-2,3,4,9-tetra- domino transesterification-cyclodehydration process that resulted in the formation of methyl 2-(diethoxyphosphoryl)-2-(1-oxo-2,3,4,9-tetra-

Molecules 2019, 24, 2030 25 of 38

Then the dione system was changed to cyclohexane-1,3-dione [62] products 54 were observed (SchemeMolecules 2019 36), 24 and, 2030 later used as adducts in a subsequent domino transesterification-cyclodehydration25 of 38 process that resulted in the formation of methyl 2-(diethoxyphosphoryl)-2-(1-oxo-2,3,4,9-tetra- hydro-1H-xanthen-9-yl)acetates. Products 54 were isolated as single diastereomers with hydro-1H-xanthen-9-yl)acetates. Products 54 were isolated as single diastereomers with anti-disposition anti-disposition of the bulky groups. of the bulky groups. A functionalization of the indole structure was performed by a conjugate addition of A functionalization of the indole structure was performed by a conjugate addition of substituted substituted indoles to 3-diethylphosphonocoumarins 1a, 1c, 1h and 1bl [63]. The reaction was indoles to 3-diethylphosphonocoumarins 1a, 1c, 1h and 1bl [63]. The reaction was carried out in the carried out in the presence of TBD in CH2Cl2 at room temperature and products 55 were isolated as a presence of TBD in CH Cl at room temperature and products 55 were isolated as a mixture of cis- mixture of cis- and trans-2 2diastereomers, the applied conditions favored the formation of the and trans-diastereomers, the applied conditions favored the formation of the trans-adducts. In the trans-adducts. In the presence of TBD, substituted 3-diethylphosphonocoumarins 1c, 1h and 1bl presence of TBD, substituted 3-diethylphosphonocoumarins 1c, 1h and 1bl participated with high participated with high efficiency in the Michael-type addition process regardless the presence of efficiency in the Michael-type addition process regardless the presence of electron-withdrawing or electron-withdrawing or electron-donating groups in the benzene moiety. electron-donating groups in the benzene moiety.

3. Synthesis and Some Reactions of Alky Alkyll 1,2-benzoxaphosphorin-3-carboxylates 2

3.1. Synthesis of Substituted Alkyl 1,2-benzoxaphosphorin-3-carboxylates 2

3.1.1. Synthetic Protocols Involving Knoevenagel Condensation ReactionReaction. The synthesis, isolation and characterization of the phosphoroheterocyclic analogue of 3-dialkylphosphonocoumarin, the the corresponding corresponding alkyl alkyl 1,2-benzoxaphosphorin-3-carboxylates 1,2-benzoxaphosphorin-3-carboxylates2a– f2avia–f Knoevenagelvia Knoevenagel lactonization lactonization were were previously previously discussed discussed [17, 20[17,20]] in Section in Section2. 2. A synthetic protocol including the formation of dialkyl 1,2-benzoxaphosphorin-3-phosphonates 55a–f [[64]64] underunder KnoevenagelKnoevenagel reaction conditionsconditions (Scheme 3737)) waswas performedperformed byby usingusing substitutedsubstituted salicylaldehydes 3a–c,e,i,k and tetraethyl methylenebisphosphonate ( 7d). The The products 55a–f were isolated in yields from 6969 toto 92%.92%.

Scheme 37.37.Synthesis Synthesis of dialkylof dialkyl 1,2-benzoxaphosphorin-3-phosphonates 1,2-benzoxaphosphorin-3-phosphonates55 via Knoevenagel55 via Knoevenagel reaction. reaction. The optimized reaction conditions were elaborated on the reaction of salicylaldehyde (3a) andThe tetraethyl optimized methylenebisphosphonate reaction conditions were (7d elabor) in theated presence on the reaction of different of salicylaldehyde catalysts—piperidine, (3a) and piperidinetetraethyl /AcOH,methylenebisphosphonate piperidine/ClCH2COOH (7d) andin the piperidine presence acetate of /βdifferent-alanine. catalysts—piperidine, The best results were obtainedpiperidine/AcOH, by slow addition piperidine/ClCH of the used2COOH catalyst and – piperidinepiperidine oracetate/ combinationβ-alanine. of piperidineThe best results/acetic were acid. Theobtained low activity by slow of addition the methylenebisphosphonate of the used catalyst – piperidine7d as a participating or combination CH-acidic of piperidine/acetic component was acid. the reasonThe low for activity the used of excess the methylenebisphosphonate of salicylaldehyde in comparison 7d as a with participating the amount CH-acidic used for thecomponent Knoevenagel was reactionsthe reason in for the presencethe used ofexcess phosphonoacetate of salicylaldehyde4. in comparison with the amount used for the KnoevenagelIn the described reactions conditions, in the presence the aromatic of phosphonoacetate aldehydes bearing 4. electron-donating groups showed highIn reactivity the described toward conditions, the condensation the aromatic reaction, aldehydes whereas, bearing moderate electron-donating yields were obtainedgroups showed in the presencehigh reactivity of electron-withdrawing toward the condensation groups inreaction, the benzene whereas, moiety moderate (45–69%). yields were obtained in the presence of electron-withdrawing groups in the benzene moiety (45–69%). 3.1.2. Synthetic Protocols Including Intermolecular Horner-Wadsworth-Emmons Reaction 3.1.2.Similar Synthetic conditions Protocols Including were used Intermolecular in the reaction Horner-Wadsworth-Emmons of salicylaldehyde Reaction (3a) with ethyl diphenylphosphonoacetateSimilar conditions were in the presenceused in of DBUthe andreaction different of saltssalicylaldehyde (NaI, LiCl, KI, MgBr(3a) 2)with as catalytic ethyl diphenylphosphonoacetate in the presence of DBU and different salts (NaI, LiCl, KI, MgBr2) as catalytic systems (Scheme 38). A process involving intermolecular Horner-Wadsworth-Emmons reaction instead of Knoevenagel condensation resulted in the formation of ethyl 1,2-oxaphosphorine-3-carboxylate (2d). The best results were obtained by applying NaI as a catalyst

Molecules 2019, 24, 2030 26 of 38

systemsMoleculesMolecules 2019 (Scheme 2019, 24, ,24 2030, 382030 ). A process involving intermolecular Horner-Wadsworth-Emmons reaction instead26 26of 38of 38 of Knoevenagel condensation resulted in the formation of ethyl 1,2-oxaphosphorine-3-carboxylate (2d). Theandand bestthe the reaction results reaction werewas was performed obtained performed by at applying atlow low temp temp NaIeratures,eratures, as a catalyst thus thus affording andaffording the reactionthe the main main was product product performed 2d 2d in ina at yielda low yield temperatures,of of61% 61% [65]. [65]. thusA Aprocess aprocessffording involving involving the main HWE productHWE reaction reaction2d in ainstead yieldinstead of of 61% ofKnoevenagel [Knoevenagel65]. A process condensation condensation involving HWE was was reactionpostulated,postulated, instead otherwise otherwise of Knoevenagel the the more more condensationstable stable erythro erythro was-aldol-aldol postulated, adduct adduct should otherwiseshould give give thethe the more E-alkene E-alkene stable anderythro and therefore therefore-aldol adductthethe corresponding corresponding should give the3-diethylphosphonocoumarin 3-diethylphosphonocoumarinE-alkene and therefore the corresponding 1a 1a. The. The less less 3-diethylphosphonocoumarinstable stable threo threo-aldol-aldol intermediate—the intermediate—the1a. The lessZ-alkene,Z-alkene, stable affordedthreo afforded-aldol the intermediate—thethe ethyl ethyl 1, 2-oxaphosphorine-3-carboxylate1,2-oxaphosphorine-3-carboxylateZ-alkene, afforded the ethyl 2d 2d (the 1,2-oxaphosphorine-3-carboxylate (the intermediates intermediates were were discussed discussed 2din inSection(the Section intermediates 2, 2,Scheme Scheme were5). 5). A discussedAreacti reactionon of in oftriethyl Section triethyl2 phosphonoacetate, Schemephosphonoacetate5). A reaction 4, 4salicylaldehyde, of salicylaldehyde triethyl phosphonoacetate (3a (3a) and) and DBU DBU 4under,under salicylaldehyde refluxing refluxing toluene toluene (3a) and was was DBU carried carried under out out refluxingto totest test the toluenethe proposed proposed was transformation carried transformation out to testpath. path. the Neither Neither proposed the the transformation3-dialkylphosphonocoumarin3-dialkylphosphonocoumarin path. Neither 1a the 1a nor 3-dialkylphosphonocoumarin nor the the 1,2-oxaphosphorine 1,2-oxaphosphorine 2d 2d 1awere werenor registered, the registered, 1,2-oxaphosphorine therefore therefore on on the2d the werebasebase registered,of ofthe the made made therefore comparison comparison on the erythro baseerythro of-aldol the-aldol madeadduct adduct comparison was was accepted acceptederythro as -aldol asintermediate intermediate adduct was in inthe accepted the applied applied as intermediateconditions.conditions. in the applied conditions.

SchemeScheme 38. 38. Horner-Wadsworth-EmmonsHorner-Wadsworth-Emmons Horner-Wadsworth-Emmons reaction reaction catalyzed catalyzed by by DBU. DBU.

In In the the samesame same conditions,conditions, conditions, thethe the performedperformed performed reactionsreacti reactionsons underwent underwent as as aa KnoevenagelKnoevenagela Knoevenagel condensationcondensation condensation (Scheme(Scheme5 5)) in 5)in theinthe the presencepresence presence of of piperidine ofpiperidine piperidine or or as oras HWE asHWE HWE whenwhen when DBUDBU DBU waswas was usedused used (Scheme(Scheme (Scheme 38 38).). 38). Therefore,Therefore, Therefore, thethe the outcomeoutcome of of the the transformation transformation depended depended stronglystro stronglyngly onon on thethe the basebase base appliedapplied applied inin theinthe the reaction.reaction. reaction.

3.1.3.3.1.3. Synthetic Synthetic Protocols Protocols on on the the Reaction Reaction of of Oxaphospholes Oxaphospholes with with Terminal Terminal AcetylenesAcetylenes Acetylenes SubstitutedSubstituted alkyl alkyl 1,2-benz 1,2-benzoxaphosphorins 1,2-benzoxaphosphorinsoxaphosphorins of of oftype type 2, , 2Figure , Figure 88,, were8,were were obtainedobtained obtained inin reactioninreaction reaction ofof of 2,2,2-trichlorobenzo-1,3,2-dioxaphosphole2,2,2-trichlorobenzo-1,3,2-dioxaphosphole (56 (56) with ) with phenyl- phenyl- and and alkylacety alkylacetylenes alkylacetyleneslenes [66,67] [66 [66,67],67] (Scheme (Scheme (Scheme 39).39 39).). TheThe obtained obtained 2,6-dichlorobezno[e]-1,2-oxaphosphinine-2-oxides2,6-dichlorobezno[ 2,6-dichlorobezno[e]-1,2-oxaphosphinine-2-oxidese]-1,2-oxaphosphinine-2-oxides 5757 57 were were converted converted to to esters esters in in subsequentsubsequent reactions reactions with with with methanol, methanol, methanol, ethanol ethanol ethanol or or ortr triethyliethyltriethyl orthoformate. orthoformate.orthoformate. The The The extensive extensive extensive research research research of of ofMironovMironov Mironov and and and coworkers coworkers was was summarized summarizedsummarized in inina aarevi reviewreviewew paper paperpaper [68] [68[68] ]presenting presenting presenting the the the synthesis synthesis of of numerousnumerous halophosphorinines. halophosphorinines.

Figure 8. 2 FigureFigure 8. The8. The structures structures of ofobtained obtained 1,2-benzophosphorins 1,2-benzophosphorins of of type type 2. 2. The described method combined the properties of P,P,P-trihalobenzodioxaphospholes derived TheThe described described method method combined combined the the properties properties of ofP,P,P-trihalobenzodioxaphospholes P,P,P-trihalobenzodioxaphospholes derived derived from 1,2-benzoquinones with a phosphorus trihalide. It is known that compounds like fromfrom 1,2-benzoquinones 1,2-benzoquinones with with a phosphorusa phosphorus trihalide. trihalide. It isIt isknown known that that compounds compounds like like P(V) P(V) halides halides P(V) halides interact with C C bond to form P-C bonda. During this transformation, the interactinteract with with C ≡CC≡ Cbond bond to toform ≡form P-C P-C bonda. bonda. During During this this transformation, transformation, the the phosphorus phosphorus atom atom phosphorus atom changed from a five- to four-coordinated state. Using the properties of the changedchanged from from a five-a five- to tofour-coordinated four-coordinated state. state. Using Using the the properties properties of ofthe the dioxaphospholes dioxaphospholes the the dioxaphospholes the reactions with terminal aryl- and alkylacetylenes were performed affording reactionsreactions with with terminal terminal aryl- aryl- and and alkylacety alkylacetyleneslenes were were performed performed affording affording series series of of series of 2,6-dichlorobezno[e]-1,2-oxaphosphinine-2-oxides (57) (Scheme 39). The regioselectivity of 2,6-dichlorobezno[e]-1,2-o2,6-dichlorobezno[e]-1,2-oxaphosphinine-2-oxidesxaphosphinine-2-oxides (57 (57) (Scheme) (Scheme 39). 39). The The regioselectivity regioselectivity of ofthe the the reaction depended not only on the substituents on the phosphorus atom but also in the aromatic reactionreaction depended depended not not only only on on th eth substituentse substituents on on the the phosphorus phosphorus atom atom but but also also in inthe the aromatic aromatic moietymoiety of ofthe the P,P,P-trihalobenzodioxaphospholes P,P,P-trihalobenzodioxaphospholes 56 56 as aswell well as assubstituents substituents on on the the alkynyl alkynyl component.component. In Inall all reaction reaction conditions, conditions, a halogenationa halogenation of ofthe the aromatic aromatic fragment fragment from from the the released released halogenhalogen of ofthe the phosphole phosphole occurred. occurred. In Inmost most of ofthe the performed performed reactions, reactions, a amixture mixture of of 2-halo-1,2-phosphorinines2-halo-1,2-phosphorinines 57a 57a and and 57b 57b was was produced produced and and the the regiochemistry regiochemistry of ofthe the process process is isstill still

Molecules 2019, 24, 2030 27 of 38

moietyMolecules of2019 the, 24 P,P,P-trihalobenzodioxaphospholes, 2030 56 as well as substituents on the alkynyl component.27 of 38 In all reaction conditions, a halogenation of the aromatic fragment from the released halogen of the phospholenot identified. occurred. Several In mostreaction of the mechanisms performed reactions,were proposed a mixture based of 2-halo-1,2-phosphorinines on the obtained results 57aby Molecules 2019, 24, 2030 27 of 38 anddifferent57b was researchers produced utilizing and the variousl regiochemistryy substituted of the starting process compounds. is still not identified. Several reaction mechanismsnot identified. were Several proposed reaction based onmechanisms the obtained were results proposed by different based researchers on the obtained utilizing variouslyresults by substituteddifferent researchers starting compounds. utilizing variously substituted starting compounds.

Scheme 39. Reactions involving oxaphospholes.

In subsequent papers, [69–72] the electronic effect of donor and acceptor substituents at the SchemeScheme 39. 39.Reactions Reactions involving involving oxaphospholes. oxaphospholes. arylacetylenes on the reaction rate was tested. With the enhancement of the electron-donor propertiesInIn subsequent subsequent of the substituent, papers, papers, the [69–72]the electronic reaction the e ff electronicrateect ofin donorcreased. effect and Moreover, of acceptor donor substituentsdonorand acceptor and acceptor at substituents the arylacetylenes effect of at the the onsubstituentsarylacetylenes the reaction at ratefourthon wasthe position testedreaction [69in –therate72]. 1,2-oxaphosp Withwas thetested enhancement.hinine With ringthe of influencedenhancement the electron-donor the electrophilicityof the properties electron-donor of the substituent,phosphorusproperties of theatom. the reaction substituent, rate increased. the reaction Moreover, rate increased. donor Moreover, and acceptor donor effect and of acceptor the substituents effect of atthe fourthsubstituentsThe position 2-halo-1,2-phosphorinine at in fourth the 1,2-oxaphosphinine position in theadducts 1,2-oxaphosp ring 57a influenced,b werehinine converted the ring electrophilicity influenced into acids, the of amides theelectrophilicity phosphorus and salts atom.ofwith the differentphosphorusThe 2-halo-1,2-phosphorininecounterions atom. with the sole adducts purpose57a to, bapplywere them converted as promising into acids, additives amides andfor polymers, salts with diligandsfferentThe for counterions 2-halo-1,2-phosphorinine metal complex with the catalysis sole purpose and adducts etc. to apply57a,b themwere asconverted promising into additives acids, amides for polymers, and salts ligands with fordifferent metal complex counterions catalysis with and the etc. sole purpose to apply them as promising additives for polymers, 3.1.4. Synthetic Protocols on A Reaction of Dialkyl Benzylphosphonates with Methyl Salicylate ligands for metal complex catalysis and etc. 3.1.4. Synthetic Protocols on A Reaction of Dialkyl Benzylphosphonates with Methyl Salicylate A multistep synthesis of 3-aryl 4-hydroxy-1,2-oxaphosphorines 62 and 3-arylphospha- chroman-2,4-diones3.1.4.A Synthetic multistep Protocols synthesis 61 was on presented A of Reaction 3-aryl by of 4-hydroxy-1,2-oxaphosphorinesFu Dialkyl and coworkers Benzylphosphonates [73,74]. It began with62 with Methyland the 3-arylphospha- preparationSalicylate of chroman-2,4-diones 61 was presented by Fu and coworkers [73,74]. It began with the preparation of dialkylA benzylphosphonates multistep synthesis in yiofelds 3-aryl of 80–85%. 4-hydroxy-1,2-oxaphosphorines The obtained benzylphosphonates 62 and were3-arylphospha- converted dialkyl benzylphosphonates in yields of 80–85%. The obtained benzylphosphonates were converted tochroman-2,4-diones the more reactive halogenides 61 was presented 59 and by in Fua subsequent and coworkers reaction [73,74]. with It methyl began withsalicylate the preparation afforded the of to the more reactive halogenides 59 and in a subsequent reaction with methyl salicylate afforded the correspondingdialkyl benzylphosphonates phosphonates in 60 yi eldsin veryof 80–85%. good Theyields obtained (75–82%). benzylphosphonates The third step were included converted a corresponding phosphonates 60 in very good yields (75–82%). The third step included a P-heterocyclic P-heterocyclicto the more reactive compound halogenides formation 59 andin the in apresen subsequentce of KOH reaction in drywith pyridine. methyl salicylate The product afforded of the the compound formation in the presence of KOH in dry pyridine. The product of the cyclization process was cyclizationcorresponding process phosphonates was a mixture 60 in of very two goodtautomers yields with (75–82%). predominate The third keto stepvs. enol-form,included a a mixture of two tautomers with predominate keto vs. enol-form, compounds 61 and 62 (Scheme 40). compoundsP-heterocyclic 61 andcompound 62 (Scheme formation 40). in the presence of KOH in dry pyridine. The product of the cyclization process was a mixture of two tautomers with predominate keto vs. enol-form, compounds 61 and 62 (Scheme 40).

Scheme 40. Multistep procedure for obtaining P-heterocyclic products.

Compounds ofof type type61 61(Figure (Figure9) were 9) were obtained obtained by a rearrangement by a rearrangement reaction andreaction their alkylatingand their Scheme 40. Multistep procedure for obtaining P-heterocyclic products. ealkylatingffect and effect cytotoxicity and cytotoxicity was tested was on tested some on human some human leukemia leukemia cell lines cellHL-60 lines HL-60 andNALM-6 and NALM-6 [41]. They[41]. They haveCompounds have shown shown highof typehigh alkylating 61alkylating (Figure activity activity9) were in respectin obtainedrespect to to both byboth a cell cellrearrangement lines lines but but were were reactionless less activeactive and thentheir 1l p 3-dialkylphosphonocoumarinsalkylating effect and cytotoxicity 1l–– wasp.. tested on some human leukemia cell lines HL-60 and NALM-6 [41]. They have shown high alkylating activity in respect to both cell lines but were less active then 3-dialkylphosphonocoumarins 1l–p.

Molecules 2019, 24, 2030 28 of 38 Molecules 2019, 24, 2030 28 of 38 Molecules 2019, 24, 2030 28 of 38

Figure 9. Another example of compounds 61. FigureFigure 9.9. Another example of compounds 6161.. 3.1.5. Synthetic Protocols onon forfor ReactionsReactions ofof 2-Ethoxyvinylphosphonic2-Ethoxyvinylphosphonic Dichloride Dichloride with with Substituted 3.1.5. Synthetic Protocols on for Reactions of 2-Ethoxyvinylphosphonic Dichloride with Substituted SubstitutedPhenols Phenols Phenols The 1,2-oxaphosphorines 64a–c and 65a–c were isolated in low yields during the synthesis of The 1,2-oxaphosphorines 64a–c and 65a–c were isolated in low yields during the synthesis of macrocyclic P-containingP-containing phenolsphenols [ 75[75].]. The The method method utilized utilized 2-ethoxyvinylphosphonic 2-ethoxyvinylphosphonic dichloride dichloride (63) macrocyclic P-containing phenols [75]. The method utilized 2-ethoxyvinylphosphonic dichloride and(63) resorcinolsand resorcinols13g–i in13g ratio–i in 1:2 ratio as starting 1:2 as materialsstarting materials and trifluoroacetic and trifluoroacetic acid as catalyst acid (Scheme as catalyst 41). (63) and resorcinols 13g–i in ratio 1:2 as starting materials and trifluoroacetic acid as catalyst The(Scheme ratio 41). between The ratio the 1,2-oxaphosphorinebetween the 1,2-oxaphosphorine adducts 64a adductsand the 64a macrocyclic and the macrocyclic compound wascompound found (Scheme 41). The ratio between the 1,2-oxaphosphorine adducts 64a and the macrocyclic compound towas be found 1:1, whereas, to be 1:1, compound whereas, compound65a was isolated 65a was in aisolated yield of in only a yield 5%. of In only a subsequent 5%. In a subsequent paper [76] was found to be 1:1, whereas, compound 65a was isolated in a yield of only 5%. In a subsequent thepaper reaction [76] the was reaction carried was out carried in dioxane out in as dioxane a solvent as ata solvent 60 ◦C thus at 60 resulting °C thus inresulting reduction in reduction of the yield of paper [76] the reaction was carried out in dioxane as a solvent at 60 °C thus resulting in reduction of ofthe 1,2-oxaphosphorine yield of 1,2-oxaphosphorine64a. One of64a the. One possible of the explanations possible explanatio for the observedns for the reaction observed course reaction was the yield of 1,2-oxaphosphorine 64a. One of the possible explanations for the observed reaction thecourse formation was the of formation the halogenide of the of halogenide oxaphosphorine of oxaphosphorine as the main intermediate as the main in intermediate the synthesis in of the course was the formation of the halogenide of oxaphosphorine as the main intermediate in the macrocyclessynthesis of andthe macrocycles the corresponding and the oxaphosphorine corresponding64a oxaphosphorinewas formed as 64a a result was offormed a parallel as ainteraction. result of a synthesis of the macrocycles and the corresponding oxaphosphorine 64a was formed as a result of a Therefore,parallel interaction. a modified Therefore, procedure a was modified published procedure in 2015 representingwas published [77 ]in a condensation2015 representing method [77] for a parallel interaction. Therefore, a modified procedure was published in 2015 representing [77] a preparationcondensation only method of 1,2-oxaphosphorines for preparation only64c ofand 1,2-oxaphosphorines65b,c in toluene as a64c solvent and media65b,c in under toluene reflux as ina condensation method for preparation only of 1,2-oxaphosphorines 64c and 65b,c in toluene as a yieldssolvent of media 75–85%. under reflux in yields of 75–85%. solvent media under reflux in yields of 75–85%.

Scheme 41. Condensation of a phosphorus-bearing component with substituted phenols. Scheme 41. Condensation of a phosphorus-bearing component with substituted phenols. 3.1.6. Synthetic Protocols for Gold-CatalyzedGold-catalyzed Hydroarylation Hydroarylation of of Aryl Aryl Alkynylphosphonates Alkynylphosphonates 3.1.6. Synthetic Protocols for Gold-catalyzed Hydroarylation of Aryl Alkynylphosphonates An alternative approach [[78]78] for the preparation of thethe targettarget 1,2-oxaphosphorines1,2-oxaphosphorines involved an An alternative approach [78] for the preparation of the target 1,2-oxaphosphorines involved an intramolecular hydroarylation ofof a series of substitutedsubstituted aryl alkynylphosphonates in the presence of intramolecular hydroarylation of a series of substituted aryl alkynylphosphonates in the presence of gold catalysts, silver salts and a protic acid.acid. Difffferenterent gold compounds were appliedapplied for optimizingoptimizing gold catalysts, silver salts and a protic acid. Different gold compounds were applied for optimizing the reaction conditions. The The highest highest results results (yield (yield of of84%) 84%) were were observed observed when when a combination a combination of ofthe Ph reaction3P-AuCl, conditions. AgOTf and The TfOH highest was results utilized (yield for of the 84%) activation were observed of the triple when bond a combination (Scheme 42 of). Ph3P-AuCl, AgOTf and TfOH was utilized for the activation of the triple bond (Scheme 42). Ph3P-AuCl, AgOTf and TfOH was utilized for the activation of the triple bond (Scheme 42). Conditions where the reaction mixture was heated at 80 ◦°CC or the process was performed at room Conditions where the reaction mixture was heated at 80 °C or the process was performed at room temperature, were both applicable.applicable. However, the best results for the hydroarylationhydroarylation were obtainedobtained temperature, were both applicable. However, the best results for the hydroarylation were obtained at roomroom temperature.temperature. Substituted Substituted diphen diphenylyl and and ethyl phenyl alkynylphosphonates 6666 affordedafforded a at room temperature. Substituted diphenyl and ethyl phenyl alkynylphosphonates 66 afforded a broad range of 1,2-ox 1,2-oxaphosphorineaphosphorine adducts adducts 6767 inin yields yields of of 60-95%. 60–95%. Elaborating Elaborating on on the the mechanism mechanism of broad range of 1,2-oxaphosphorine adducts 67 in yields of 60-95%. Elaborating on the mechanism of ofthe the reaction, reaction, alkynylphosphonates alkynylphosphonates with with substituents substituents on the on thephenyl phenyl ring ring attached attached to oxygen to oxygen was wasalso the reaction, alkynylphosphonates with substituents on the phenyl ringR2 attached to oxygen was also alsoexamined. examined. A relationship A relationship between between the thesteric steric effect eff ectof ofthe the group group R2 andand the the obtained obtained yields for examined. A relationship between the steric effect of the group R2 and the obtained yields for 1,2-benzoxaphosphorines 67 67was was noted, noted, when when the the hindrance hindrance e ffeffectect of of the the group group increased increased the the yields yields of 671,2-benzoxaphosphorinesdecreased from 94 (R2 = 67Ph) was to noted, 60% (R when2 = n-Bu the or hindrance C H Cl). effect of the group increased the yields of 67 decreased from 94 (R2 = Ph) to 60% (R2 = n-Bu or C3 3H66Cl). of 67 decreased from 94 (R2 = Ph) to 60% (R2 = n-Bu or C3H6Cl).

Molecules 2019, 24, 2030 29 of 38 Molecules 2019,, 24,, 20302030 29 of 38 Molecules 2019, 24, 2030 29 of 38

Scheme 42. Gold-catalyzed hydroarylation of aryl alkynylphosphonates. Scheme 42. Gold-catalyzed hydroarylation of aryl alkynylphosphonates.

3.1.7. SyntheticSynthetic ProtocolsProtocols for for Pd-Catalyzed Pd-catalyzed Intramolecular Intramolecular Cross-Coupling Cross-coupling Reactions Reactions of of Ethyl 3.1.7. Synthetic Protocols for Pd-catalyzed Intramolecular Cross-coupling Reactions of Ethyl 2-(aryl)arylphosphonatesEthyl 2-(aryl)arylphosphonates 2-(aryl)arylphosphonates Intramolecular Pd-catalyzed Pd-catalyzed oxidative-cyclization oxidative-cyclization reaction reaction for for the the formation of Intramolecular Pd-catalyzed oxidative-cyclization reaction for the formation of 1,2-oxaphosphorine derivativesderivatives69 69involving involvinginvolving ethyl ethylethyl 2-(phenyl)phenylphosphonate 2-(phenyl)phenylphosphonate2-(phenyl)phenylphosphonate and substitutedandand substitutedsubstituted alkyl 1,2-oxaphosphorine derivatives 69 involving ethyl 2-(phenyl)phenylphosphonate and substituted alkyl2-(aryl)arylphosphonates 2-(aryl)arylphosphonates68 was 68 presented waswas presentedpresented by Lee etbyby al. LeeLee [79 ].etet The al.al. [79]. best[79]. reactionTheThe bestbest conditions reactionreaction conditions includedconditions a alkyl 2-(aryl)arylphosphonates 68 was presented by Lee et al. [79]. The best reaction conditions includedcombinationincluded aa combinationcombination of 10 mol % ofof Pd(OAc) 1010 mol%mol%2 and Pd(OAc)Pd(OAc) two equiv.22 andand PhI(OAc) twotwo equiv.equiv.2 with PhI(OAc)PhI(OAc) N-acetyl-L-leucine22 withwith N-acetyl-N-acetyl- as anL-leucine additional as included a combination of 10 mol% Pd(OAc)2 and two equiv. PhI(OAc)2 with N-acetyl-L-leucine as anligand additional for the Pd(II)–Pd(IV)ligand for the conversion.Pd(II)–Pd(IV) Substituted conversion. 1,2-oxaphosphorines Substituted 1,2-oxaphosphorines of type 69 were of isolated type 69 in an additional ligand for the Pd(II)–Pd(IV) conversion. Substituted 1,2-oxaphosphorines of type 69 wereyields isolated of 50–72%, in yields Scheme of 50-72%,43. Scheme 43. were isolated in yields of 50-72%, Scheme 43.

Scheme 43. IntramolecularIntramolecular Pd-catalyzPd-catalyz Pd-catalyzeded cyclization reaction. Scheme 43. Intramolecular Pd-catalyzed cyclization reaction. The study on the mechanism of the cyclization showed that the C-O bond formation was the The study on the mechanism of the cyclization showed that the C-O bond formation was the rate-determining step in which Pd(II)Pd(II)/Pd(IV)/Pd(IV) catalyticcatalytic cycle might bebe involvedinvolved (Scheme(Scheme 4444).). rate-determining step in which Pd(II)/Pd(IV) catalytic cycle might be involved (Scheme 44).

Scheme 44. ProposedProposed mechanism mechanism of the intramolecul intramolecularar Pd-catalyzed cyclization reaction. Scheme 44. Proposed mechanism of the intramolecular Pd-catalyzed cyclization reaction.

Molecules 2019, 24, 2030 30 of 38 Molecules 2019, 24, 2030 30 of 38 3.2. Chemical Reactions of Alkyl 1,2-benzoxaphosphorin-3-carboxylates 2 3.2.3.2. Chemical Chemical Reactions Reactions ofof AlkylAlkyl 1,2-benzoxaphosphorin-3-carboxylates1,2-benzoxaphosphorin-3-carboxylates 22 3.2.1. Reactions Resulting in the Formation of 4-O-substituted 1,2-benzoxaphosphorines 3.2.1. Reactions Resulting in the Formation of 4-O-substituted 1,2-benzoxaphosphorines 3.2.1.3-aryl-4-hydroxy-1,2-oxaphosphorine Reactions Resulting in the Formation ofcompounds 4-O-substituted 61a 1,2-benzoxaphosphorines–e and 3-arylphosphachroman-2,4- diones3-aryl-4-hydroxy-1,2-oxaphosphorine3-aryl-4-hydroxy-1,2-oxaphosphorine 62a–e were used [73] in reactions compoundswithcompounds acetic 61aanhydride, 61a–e and–e 3-arylphosphachroman-2,4-and methylsulfonyl 3-arylphosphachroman-2,4- chloride, diethyl diones phosphorochloridate62adiones–e were 62a–e used were [73used and] in p[73]-toluenesulfonyl reactions in reactions with with chloridate acetic acetic anhydride, anhydride,in the presence methylsulfonyl methylsulfonyl of K2CO3 in chloride, acetone diethyl(Scheme diethyl 45).phosphorochloridatephosphorochloridate The corresponding and and 4-O-subsp -toluenesulfonylp-toluenesulfonyltituted 1,2-benz chloridate chloridateoxaphosphorines in in the the presence presence 70 of wereof K2 KCO2 COisolated3 in3 in acetone acetone in yields (Scheme (Scheme of 82–45 ). 97%.The45). corresponding The corresponding 4-O-substituted 4-O-substituted 1,2-benzoxaphosphorines 1,2-benzoxaphosphorines70 were 70 were isolated isolated in yields in yields of 82–97%. of 82– 97%.

Scheme 45. FormationFormation of 1,2-benzoxaphosphorines 70.70. Scheme 45. Formation of 1,2-benzoxaphosphorines 70. The obtainedobtained compoundscompounds61a 61a–e–,e62a, 62a–e–ande and70 were70 were tested tested as inhibitors as inhibitors against against the enzyme the enzyme SHP-1, The obtained compounds 61a–e, 62a–e and 70 were tested as inhibitors against the enzyme SHP-1,a member a member of the protein of the tyrosineprotein tyrosine phosphatase phosphatase (PTP) family (PTP) responsible family responsible for the regulating for the regulating of numerous of SHP-1, a member of the protein tyrosine phosphatase (PTP) family responsible for the regulating of numerouscellular processes. cellular processes. Irregular functioningIrregular functioning of this protein of this family protein could family lead tocould cellular lead dysfunction to cellular numerous cellular processes. Irregular functioning of this protein family could lead to cellular dysfunctionand various and diseases, various thus, diseases, PTP-inhibitors thus, PTP-inhibitors could provide could potential provide therapeutic potential agents therapeutic against agents such dysfunction and various diseases, thus, PTP-inhibitors could provide potential therapeutic agents againstabnormalities. such abnormalities. Most of compounds Most70 ofexhibited compounds certain 70 membrane-permeable exhibited certain membrane-permeable PTP-inhibitor activity, against such abnormalities. Most of compounds 70 exhibited certain membrane-permeable PTP-inhibitorhowever, only activity, the 1,2-benzoxaphosphorines however, only the 1,2-benzoxaphosphorines bearing R3 = diethoxyphosphoryl bearing R3 = group, diethoxyphosphoryl R2 = Cl and R1 PTP-inhibitor activity, however, only the 1,2-benzoxaphosphorines bearing R3 = diethoxyphosphoryl group,= Et indicated R2 = Cl and better R1 inhibition= Et indicated properties. better inhibition properties. group, R2 = Cl and R1 = Et indicated better inhibition properties. TheThe same same mixture mixture of of tauromers tauromers 61a61a––e andand 62a–e waswas impliedimplied [74][74] [74] in in an an alkylation alkylation reaction reaction with with seriesseries of of alkylalkyl alkyl halides.halides. halides. ProductsProd Productsucts of ofof C- C-C- and andand O-alkylation O-alkylation70 70and andand71 7171were werewere isolated isolated isolated in in totalin total total yields yields yields of of 77–90% of 77– 77– 90%(Scheme (Scheme 46). The46). The ratio ratio of the of twothe two products products depended depended on the on stericthe steric effect effect of the of Rthe-substituent R2-substituent on theon 90% (Scheme 46). The ratio of the two products depended on the steric effect of the2 R2-substituent on thebenzenethe benzene benzene ring inring ring third inin position thirdthird positionposition of the oxaphosphorin ofof ththe oxaphosphorin systems. systems. Substituentssystems. SubstituentsSubstituents at ortho-position atat ortho ortho favored-position-position the favoredformationfavored the the of formation O-alkylatedformation of of O-alkylated product.O-alkylated The product.product. steric hindrance The steric e ff hindrancehindranceect of the effect alkyleffect halideof of the the alkyl wasalkyl alsohalide halide apparent. was was also also In apparent.theapparent. case of In CHIn the the3I thecase case ratio of of CHCH was33II shifted thethe ratioratio to was thewas C-alkylated shifted to thethe product C-alkylatedC-alkylated whereas productproduct with bulky whereas whereas alkyl with with groups bulky bulky the alkylproportionalkyl groups groups of the thethe proportion twoproportion products of of thth wasee twotwo almost productsproducts equal. was almost equal.equal.

SchemeScheme 46.46. AlkylationAlkylation reaction reaction to to productsproducts 70 70 and and 71. 71.71 . 3.2.2. Participation in Coupling Reactions 3.2.2.3.2.2. Participation Participation in in Coupling Coupling ReactionsReactions In order to construct a variety of complex structures, 4-tosylphosphacoumarins of type 70 were InIn order order to to construct construct a a variety variety ofof complexcomplex structures, 4-tosylphosphacoumarins4-tosylphosphacoumarins of of type type 70 70 were were applied [73] in Sonogashira and Suzuki coupling reactions in the presence of 10% mol PdCl22(PPh3 32)2 appliedapplied [73] [73] in in Sonogashira Sonogashira andand SuzukiSuzuki couplincoupling reactions inin thethe presencepresence of of 10% 10% mol mol PdCl PdCl(PPh2(PPh)3 )2 andand CuI CuI or or Et Et3N3N asas anan additiveadditive aaffordingffording the formation of of 4-aryl- 4-aryl- and and 4-alkynylderivatives 4-alkynylderivatives 7272 andand 7373 and CuI or Et3N as an additive affording the formation of 4-aryl- and 4-alkynylderivatives 72 and 73 (Scheme 47). (Scheme(Scheme 47). 47).

Molecules 2019, 24, 2030 31 of 38 MoleculesMolecules 2019 2019, ,24 24, ,2030 2030 3131 of of 38 38

SchemeScheme 47. 47. Conditions Conditions and and results results forfor thethe couplingcoupling reactions. reactions.

TheThe samesame researchresearchresearch groupgroupgroup [[80],80[80],], accomplishedaccomplishaccomplisheded NegishiNegishi cross-couplingcross-coupling reactionreaction ofof 4-tosylphosphacoumarins4-tosylphosphacoumarins 70 70 in inin the the the presence presence presence of of ofa a catalyti acatalyti catalyticcc system system system including including including 5 5 mol% mol% 5 mol Pd(PPh Pd(PPh % Pd(PPh33))44 and and3) 54 5 andmol%mol% 5 molPPh PPh %33 (Scheme (Scheme PPh3 (Scheme 47). 47). The The 47 expected expected). The expected products products products 74a 74a––kk were 74awere– kisolated isolatedwere isolated in in 64–85% 64–85% in 64–85% yield. yield. yield. AlkenylationAlkenylation [ 81[81][81]] of ofof 1,2-oxaphosphorines 1,2-oxaphosphorines1,2-oxaphosphorines of typeofof typetype75, Scheme 7575, , SchemeScheme 48, was 48,48, carried waswas carriedcarried out in Heck outout in reactionin HeckHeck conditionsreactionreaction conditionsconditions in the presence inin thethe of presencepresence Pd-catalyst. ofof Pd-catPd-cat The correspondingalyst.alyst. TheThe correspondingcorresponding 1,2-benzoxaphosphorines 1,2-benzoxaphosphorines1,2-benzoxaphosphorines76 were isolated 7676 inwerewere yields isolatedisolated of 45–95%. inin yieldsyields The reaction ofof 45–95%.45–95%. efficiency TheThe was reactireacti notonon dependable efficiencyefficiency on waswas the usednotnot dependable substituentsdependable onon the thethe aryl usedused or thesubstituentssubstituents styrene moieties. on on the the aryl aryl or or the the styrene styrene moieties. moieties.

SchemeScheme 48. 48. Palladium-catalyzed Palladium-catalyzed HeckHeck reaction.reaction.

Furthermore, compounds 76 were used as diene systems and underwent inverse Diels-Alder Furthermore,Furthermore, compoundscompounds 7676 werewere usedused asas dienediene systemssystems andand underwentunderwent inverseinverse Diels-AlderDiels-Alder reactions with enamines (Scheme 49). Subsequent 1,2-elimination/dehydrogenation afforded the reactionsreactions withwith enaminesenamines (Scheme(Scheme 49).49). SubsequentSubsequent 1,2-elimination/dehydrogenation1,2-elimination/dehydrogenation affordedafforded thethe fluorescent 1,2-benzoxaphosphorine structures of type 77a,b in very good yields (72–98%). fluorescentfluorescent 1,2-benzoxaphosphorine 1,2-benzoxaphosphorine structures structures of of type type 77a 77a,b,b in in very very good good yields yields (72–98%). (72–98%).

Molecules 2019, 24, 2030 32 of 38 Molecules 2019, 24, 2030 32 of 38 Molecules 2019, 24, 2030 32 of 38

Scheme 49. Accomplishing a Diels-Alder reaction with compounds 76. Scheme 49. Accomplishing a Diels-Alder reaction with compounds 7676.. 4. Reactions of [2+2] and [3+2] Cycloadditions of Dialkyl 2-oxo-2H-1-benzopyran-3-phosphonates 4. Reactions of [2[2+2]+2] and and [3+2] [3+2] Cycloadditions Cycloadditions of of Dialkyl Dialkyl 2-oxo-2H-1-benzopyran-3-phosphonates and2-oxo-2 AlkylH-1-benzopyran-3-phosphonates 1,2-benzoxaphosphorin-3-carboxylates and Alkyl 1,2-benzoxaphosphorin-3-carboxylates and Alkyl 1,2-benzoxaphosphorin-3-carboxylates 4.1. [2+2] [2+2] Cycloaddition Cycloaddition Reactions Reactions 4.1. [2+2] Cycloaddition Reactions The photochemicalphotochemical dimerization dimerization of coumarinsof coumarins is frequently is frequently used inused organic in organic synthesis. synthesis. The possible The The photochemical dimerization of coumarins is frequently used in organic synthesis. The possiblestereoisomers stereoisomers of the coumarin of the coumarin structure structure are given ar ine given Figure in 10 Figure, representing 10, representing different different C3=C4 double C3=C4 possible stereoisomers of the coumarin structure are given in Figure 10, representing different C3=C4 doublebond cyclization bond cyclization products. products. double bond cyclization products.

Figure 10. Cyclized stereoisomers. Figure 10. Cyclized stereoisomers. Alkyl 1,2-benzoxaphosphorine-3-carboxylates have shown similar behavior [82], [82], leading to the Alkyl 1,2-benzoxaphosphorine-3-carboxylates have shown similar behavior [82], leading to the formation ofof onlyonly anti-head-to-tailanti-head-to-tail dimersdimers78 78and and79 79(Scheme (Scheme 50 50).). The The reaction reaction was was accomplished accomplished in in a formation of only anti-head-to-tail dimers 78 and 79 (Scheme 50). The reaction was accomplished in aseries series of solventsof solvents from from which which protic protic polar polar solvents solvents accelerate accelerate the dimerization the dimerization process underprocess sunlight under a series of solvents from which protic polar solvents accelerate the dimerization process under sunlightirradiation. irradiation. Electron-withdrawing Electron-withdrawing substituents substituents in the benzene in the ring benzene of 2 stabilized ring ofthe 2 stabilized intermediates the sunlight irradiation. Electron-withdrawing substituents in the benzene ring of 2 stabilized the intermediatesformed during formed cyclization during and cyclization enhanced theand yield enha ofnced the stereoisomers,the yield of the whereas stereoisomers, electron-donating whereas intermediates formed during cyclization and enhanced the yield of the stereoisomers, whereas electron-donatinggroups such as diethylamino groups such did as notdiethylami favor theno performed did not favor interaction. the performed interaction. electron-donating groups such as diethylamino did not favor the performed interaction.

Scheme 50.50. [2+2][2+2] Cycloaddition Cycloaddition products. products. Scheme 50. [2+2] Cycloaddition products. Quantum-chemical calculationscalculations on theon mechanismthe mechanism of the dimerizationof the dimerization proposed an proposed asynchronous an Quantum-chemical calculations on the mechanism of the dimerization proposed an asynchronous[2+2] reaction with[2+2] dominant reaction head-to-tailwith dominant regioisomers head-to-tail due regioisomers to the formation due of to diradicals the formation or dipolar of asynchronous [2+2] reaction with dominant head-to-tail regioisomers due to the formation of diradicalsintermediate or dipolar through intermediate C3-C40 interaction through (Scheme C3-C4′ interaction50). (Scheme 50). diradicals or dipolar intermediate through C3-C4′ interaction (Scheme 50). The different chemical behavior of the two isomers 1 and 2 toward [2+2] cycloaddition reactions The different chemical behavior of the two isomers 1 and 2 toward [2+2] cycloaddition reactions was illustrated by their ability to form the corresponding dimers [20]. While was illustrated by their ability to form the corresponding dimers [20]. While

Molecules 2019, 24, 2030 33 of 38 Molecules 20192019,, 2424,, 20302030 3333 ofof 3838

1,2-benzoxaphosphorinesThe different chemical 2 behavior easily gave of the the two head-to-tail isomers 1 andaddu2cts,toward 3-diethylphosphonocoumarins [2+2] cycloaddition reactions 1 washave illustrated shown lack by of their reactivity ability in to the form described the corresponding transformation. dimers This [20]. observat While 1,2-benzoxaphosphorinesionion waswas duedue toto thethe moremore aromatic2 easily gave characteristic the head-to-tail of the adducts, C3=C4 3-diethylphosphonocoumarinsdouble bond inin thethe lactonelactone ringring1 have ofof thethe shown phosphonocoumarinphosphonocoumarin lack of reactivity moiety.in the described transformation. This observation was due to the more aromatic characteristic of the C3=C4 double bond in the lactone ring of the phosphonocoumarin moiety. 4.2. [3+2] Cycloaddition Reactions 4.2. [3+2] Cycloaddition Reactions Pyrazoline derivatives of 3-diethylphosphonocoumarin 80a,,b,, 1,2-benzoxa-1,2-benzoxa- phosphorine-3-carboxylatesPyrazoline derivatives and of 3-diethylphosphonocoumarin 1,2-benzoxaphosphorin-3-phosphonates80a,b, 1,2-benzoxa- 81 werewere preparedprepared phosphorine-3- [64][64] inin reactionscarboxylatesreactions withwith and ethylethyl 1,2-benzoxaphosphorin-3-phosphonates diazoacetate.diazoacetate. TheThe solventsolvent mimixture for the81 werethree preparedcoumarins [64 was] in different reactions based with onethyl their diazoacetate. solubility Theand solventthe solubility mixture of for the the products. three coumarins Benzene was and di ffchloroformerent based were on their preferred solubility as solventsand the solubility in the case of of the coumarins products. 1a Benzene and 1c andandand chloroform pyrazolinespyrazolines were 80a,,b preferred werewere isolatedisolated as solvents inin moderatemoderate in the case yieldsyields of (Schemecoumarins(Scheme 51).51).1a and 1c and pyrazolines 80a,b were isolated in moderate yields (Scheme 51).

SchemeScheme 51.51. [3+2][3[3+2]+2] CycloadditionCycloaddition reactionreaction ofof 3-diethylphosphonocoumarins3-diethylphosphonocoumarins 1a and 1c..

InIn general,general, 1,2-benzoxaphosphorines1,2-benzoxaphosphorines participateparticipate inin the the cycloaddition cycloaddition reactionreaction in in a a shortshort timetime giving higher yields due to the activated and more isolated double bond in the oxaphosphorine ringring (Scheme(Scheme 5252).52).). TheThe The outcomeoutcome fromfrom from thethe rere reactionaction of 1,2-benzoxaphosphorine 2d2d waswas a a mixture mixture of of twotwo epimeric pyrazolines 81a–c and 82a82a––cc ininin didifferentdifferentfferent ratios.ratios.ratios. The The ratio ratio was was influenced influencedinfluenced by by thethe solventsolvent polaritypolarity andand thethe desireddesired cycloadditioncycloaddition products were isolatedisolated inin goodgood toto excellentexcellent overalloverall yieldsyields rangingranging fromfromfrom 70% 70%70% (60 days;(60(60 benzenedays;days; benzene//benzene/n-hexane;n-hexane;-hexane; ratio 81: 82 ratioratio—1:0.25) 81:: to82—1:0.25) 95% (30 days; to CH95%2Cl 2(30/n-hexane; days; CHratio22Cl8122//n:82-hexane;-hexane;—1:0.14). ratioratio The 81::82 ether—1:0.14)./n-hexane The solventether/n-hexane-hexane mixture solventsolvent occurred mixturemixture to be occurredoccurred the best toto condition bebe thethe bestbest for 1,2-benzoxaphosphorin-3-phosphonatescondition for 1,2-benzoxaphosphorin-3-phosphonates55a–b affording 55a target–b affordingaffording products targettarget81b,c / products82bproducts,c in overall 81b,,c//82b yield,,c in ofin overall76% and yield 70%, of respectively. 76% and 70%, In all respectively the cases the.. In majorIn allall isomerthethe casescases was thethe81a majormajor–c with isomerisomercis-disposition waswas 81a– ofc Pwithwith=O cisgroupcis-disposition-disposition and substituent ofof P=OP=O grougrou at 3a-positionp and substituent (COOEt, at P(O)(OEt) 3a-position2). (COOEt, P(O)(OEt)22).).

SchemeScheme 52.52. [3+2][3[3+2]+2] CycloadditionCycloaddition reactionreaction of of 1,2-benzoxaphosphorines 1,2-benzoxaphosphorines 2d and 55a,,b..

5. Conclusions The interestinterest towardstowards dialkyldialkyl 2-oxo-22-oxo-2HH-1-benzopyran-3-phosphonates-1-benzopyran-3-phosphonates-1-benzopyran-3-phosphonates and and alkylalkyl 1,2-benzoxaphosphorin-3-carboxylates1,2-benzoxaphosphorin-3-carboxylates asas precursors precursors for for biologically biologically active active compounds compounds allowed allowed us us to tosummarizeto summarizesummarize the scientificthethe scientificscientific research researchresearch on their onon synthesistheirtheir synthesissynthesis and participation andand participationparticipation in conjugate inin conjugateconjugate addition reactions.additionaddition reactions.Inreactions. the beginning InIn thethe the beginningbeginning methods the forthe preparationmethodsmethods forfor of pr 3-dialkylphosphonocoumarinspreparation of 3-dialkylphosphonocoumarins were discussed, where were discussed,Knoevenagel where condensation Knoevenagel reactione, condensation application reacti ofone, phosphoryl application ketenimines of phosphoryl or vinylphosphonates, ketenimines or phosphorylationvinylphosphonates, of coumarins,phosphorylation three-component of coumarins, and tandem three-component coupling reactions and tandem or rearrangement coupling processes,reactionsreactions oror etc. rearrangementrearrangement were presented. processes,processes, The electronic etc.etc. werewere eff ect prespres ofented. the substituents The electronic on the effe usedct of substrates the substituents as well on the used substrates as well as the applied reactiontion conditionsconditions werewere accountedaccounted forfor byby presentingpresenting thethe mechanisms,mechanisms, wherewhere theythey werewere given,given, andand ththe corresponding results from the studies were

Molecules 2019, 24, 2030 34 of 38

as the applied reaction conditions were accounted for by presenting the mechanisms, where they were given, and the corresponding results from the studies were discussed. The comparisons between the developed methods highlighted the advantages and drawbacks in the selected research papers. The protocols for the synthesis of alkyl 1,2-benzoxaphosphorins were also summarized, where reactions of oxaphospholes with terminal acetylenes, dialkyl benzylphosphonates with methyl salicylate, etc. were analyzed. The chemical behavior of dialkyl 2-oxo-2H-1-benzopyran-3-phosphonates in conjugate addition reactions with different nucleophilic reagents—hydride ion, organometallic and CH-acidic compounds—as well as reactions of [2+2] and [3+2] cycloaddition were reviewed in details.

Author Contributions: Conceptualization, R.D.N., N.I.P.-Y. and A.I.K.; Writing-Original Draft Preparation, R.D.N., N.I.P.-Y. and A.I.K.; Writing-Review & Editing, R.D.N., N.I.P.-Y. and A.I.K.; Visualization, A.I.K. All authors have read and approved the final manuscript. Funding: The authors are grateful to the Materials Networking—Spreading Excellence and Widening Participation H2020-TWINN-2015 for the funding. A.I.K. acknowledges the financial support received from the program “Young scientists and Postdoctoral candidates” of the Bulgarian Ministry of Education and Science, MCD No. 577/17.08.2018 Acknowledgments: The work was assisted by University Scientific Fund (Grant No. 80-10-154/2019). Conflicts of Interest: The authors declare no conflict of interest.

References

1. Borges, F.; Roleira, F.; Milhazes, N.; Santana, L.; Uriarte, E. Simple coumarins and analogues in medicinal chemistry: Occurrence, synthesis and biological activity. Curr. Med. Chem. 2005, 12, 887–916. [CrossRef] [PubMed] 2. Riveiro, M.E.; De Kimpe, N.; Moglioni, A.; Vázquez, R.; Monczor, F.; Shayo, C.; Davio, C. Coumarins: Old compounds with novel promising therapeutic perspectives. Curr. Med. Chem. 2010, 17, 1325–1338. [CrossRef][PubMed] 3. Chen, S.; Cho, M.; Karlsberg, K.; Zhou, D.; Yuan, Y.-C. Biochemical and Biological Characterization of a Novel Anti-aromatase Coumarin Derivative. J. Biol. Chem. 2004, 279, 48071–48078. [CrossRef][PubMed] 4. Kulkarni, M.V.; Kulkarni, G.M.; Lin, C.-H.; Sun, C.-M. Recent Advances in Coumarins and 1-Azacoumarins as Versatile Biodynamic Agents. Curr. Med. Chem. 2006, 13, 2795–2818. [CrossRef][PubMed] 5. Al-Majedy, Y.; Kadhum, A.A.; Ibraheem, H.; Al-Amiery, A.; Moneim, A.A.; Mohamad, A.B. A Systematic Review on Pharmacological Activities of 4-Methylumbelliferon. Sys. Rev. Pharm. 2018, 9, 49–54. [CrossRef] 6. Kitson, R.; Millemaggi, A.; Taylor, R. The Renaissance of a-Methylene-g-butyrolactones: New Synthetic Approaches. Angew. Chem. Int. Ed. 2009, 48, 9426–9451. [CrossRef] 7. Zhang, S.; Won, Y.-K.; Ong, C.-N.; Shen, H.-M. Anti-Cancer Potential of Sesquiterpene Lactones: Bioactivity and Molecular Mechanisms. Curr. Med. Chem. Anti-Cancer Agents 2005, 5, 239–249. [CrossRef] 8. Janecka, A.; Wyr˛ebska,A.; Gach, K.; Fichna, J.; Janecki, T. Natural and synthetic α-methylenelactones and α-methylenelactams with anticancer potential. Drug Discov. Today 2012, 7, 561–572. [CrossRef] 9. Albrecht, L.; Albrecht, A.; Janecki, T. α-Alkylidene-γ- and δ-lactones and lactams. In Natural Lactones and Lactams: Synthesis, Occurrence and Biological Activity; Janecki, T., Ed.; Wiley-VCH: Weinheim, Germany, 2014; pp. 147–192, ISBN 9783527666911. 10. Perucca, E. The new generation of antiepileptic drugs: Advantages and disadvantages. Br. J. Clin. Pharmacol. 1996, 42, 531–543. [CrossRef] 11. Wong, M.; Defina, J.; Andrews, P. Conformational Analysis of Clinically Active Anticonvulsant Drugs. J. Med. Chem. 1986, 29, 562–572. [CrossRef] 12. Tasso, S.; Bruno-Blanch, L.; Moon, S.; Estiú, G. Pharmacophore searching and QSAR analysis in the design of anticonvulsant drugs. J. Mol. Struct. (Theochem) 2000, 504, 229–240. [CrossRef] 13. Hussain, H.; Hussain, J.; Al-Harrasi, A.; Krohn, K. The chemistry and biology of biscoumarins. Tetrahedron 2012, 68, 2553–2578. [CrossRef] 14. Budzisz, E. Synthesis, reactions and biological activity of phosphorus-containing derivatives of chromone and coumarin. Phosphorus Sulfur Silicon 2004, 179, 2131–2147. [CrossRef] Molecules 2019, 24, 2030 35 of 38

15. Robinson, C.N.; Addison, J.F. Condensation of Triethyl Phosphonoacetate with Aromatic Aldehydes. J. Org. Chem. 1966, 31, 4325–4326. [CrossRef] 16. Singh, R.K.; Rogers, M.D. An efficient synthesis of diethyl coumarin-3-phosphonates. J. Heterocycl. Chem. 1985, 22, 1713–1714. [CrossRef] 17. Chen, C.H.; Fox, J.L.; Lippert, E.K. Synthesis of phosphacoumarins and phosphonocoumarins. Two new classes of fluorescent dyes. J. Heterocycl. Chem. 1987, 24, 931–932. [CrossRef] 18. Bouyssou, P.; Chenault, J. Phosphonates and phosphine oxides as reagents in a one-pot synthesis of coumarins. Tetrahedron Lett. 1991, 32, 5341–5344. [CrossRef] 19. Falsone, G.; Cateni, F.; De Nardo, M.; Darai, M. Synthesis of 3-Alkylcoumarins and 3-Alkyl-α,β-unsaturated δ-Lactones from 3-Diethylphosphonocoumarins, 3-Diethylphosphonolactones and Aldehydes. Zeitschrift für Naturforschung B 1993, 48, 1391–1397. [CrossRef] 20. Bojilova, A.; Nikolova, R.; Ivanov, C.; Rodios, N.; Terzis, A.; Raptopoulou, C. A comparative study of the interaction of salicylaldehydes with phosphonoacetates under Knoevenagel reaction conditions. Synthesis of 1,2-benzoxaphosphorines and their dimers. Tetrahedron 1996, 52, 12597–12612. [CrossRef] 21. Kostka, K.; Pastuszko, S.; Kotynski, A.; Budzisz, E. 4-Derivatives Coumarin-3-Phosphonic Acids and Esters. Phosphorus Sulfur Silicon 1998, 134, 199–209. [CrossRef] 22. Bestmann, H.; Lehnen, H. Synthese und reaktionen des N-phenyl-bis(diethylphosphonato)-ketenimins. Tetrahedron Lett. 1991, 32, 4279–4282. [CrossRef] 23. Janecki, T.; Albrecht, A.; Koszuk, J.; Mondranka, J.; Slowak, D. A simple and effective synthesis of activated vinylphosphonates from 3-methoxy-2-diethoxyphosphorylacrylate. Tetrahedron Lett. 2010, 51, 2274–2276. [CrossRef] 24. Mondranka, J.; Albrecht, A.; Janecki, T. A Convenient Entry to 3-Methylidenechroman-2-ones and 2-Methylidenedihydrobenzochromen-3-ones. Synlett 2010, 19, 2867–2870. [CrossRef] 25. Mondranka, J.; Albrecht, A.; Jakubowski, R.; Krawczyk, H.; Rozalski, M.; Krajewska, U.; Janecka, A.; Wyrebska, A.; Rozalska, B.; Janecki, T. Synthesis and biological evaluation of α-methylidene-δ-lactones with 3,4-dihydrocoumarin skeleton. Biorg. Med. Chem. 2012, 20, 5017–5026. [CrossRef] 26. Jakubowski, R.; Romorska, D.; Dlugosz, A.; Janecka, A.; Krajewska, U.; Rozalski, M.; Mirowski, M.; Bartosik, T.; Janecki, T. Synthesis of 4,4-Disubstituted 3-Methylidenechroman-2-ones as Potent Anticancer Agents. Chem. Med. Chem. 2017, 12, 599–605. [CrossRef] 27. Pomorska, D.; Gach-Janczak, K.; Jakubowski, R.; Janecki, T.; Szymanski, J.; Janecka, A. Evaluation of anticancer properties of a new α-methylene-δ-lactone DL-249 on two cancer cell lines. Open Life Sci. 2017, 12, 178–179. [CrossRef] 28. Pan, X.; Zou, J.; Zhang, G.; Zhang, W. Manganese(III)-mediated direct phosphonation of arylalkenes and arylalkynes. Chem. Commun. 2010, 46, 1721–1723. [CrossRef] 29. Zhou, P.; Jiang, Y.; Zou, J.; Zhang, W. Manganese(III) Acetate Mediated Free-Radical Phosphonylation of Flavones and Coumarins. Synthesis 2012, 44, 1043–1050. [CrossRef] 30. Mi, X.; Huang, M.; Zhang, J.; Wang, C.; Wu, Y. Regioselective Palladium-Catalyzed Phosphonation of Coumarins with Dialkyl H-Phosphonates via C–H Functionalization. Org. Lett. 2013, 15, 6266–6269. [CrossRef] 31. Yuan, J.; Li, Y.; Yang, L.; Mai, W.; Mao, P.; Xiao, Y.; Qu, L. Silver-catalyzed direct Csp2-H radical phosphorylation of coumarins with H-phosphites. Tetrahedron 2015, 71, 8178–8186. [CrossRef] 32. Yang, L.; Zhang, X.; Yuan, J.; Xiao, Y.; Mao, P. Catalytic activity of chelating N-heterocyclic carbene palladium complexes towards selective phosphorylation of coumarins. J. Organomet. Chem. 2016, 818, 179–184. [CrossRef] 33. Strekalova, S.; Khrizanforov, M.; Gryaznova, T.; Khrizanforova, V.; Budnikova, Y.H. Electrochemical phosphorylation of coumarins catalyzed by transition metal complexes (Ni—Mn, Co—Mn). Russ. Chem. Bull. 2016, 65, 1295–1298. [CrossRef] 34. Grinenko, V.; Khrizanforov, M.; Strekalova, S.; Khrizanforova, V.; Kholin, K.; Gryaznova, T.; Budnikova, Y.H. Electrooxidative phosphorylation of coumarins by bimetallic catalytic systems Ni(II)/Mn(II) or Co(II)/Mn(II). Phosphorus Sulfur Silicon Relat. Elem. 2016, 191, 1660–1661. [CrossRef] 35. Khrizanforov, M.; Strekalova, S.; Kholin, K.; Khrizanforova, V.; Kadirov, M.; Gryaznova, T.; Budnikova, Y.H. Novel approach to metal-induced oxidative phosphorylation of aromatic compounds. Catal. Today 2017, 279, 133–141. [CrossRef] Molecules 2019, 24, 2030 36 of 38

36. Yoshida, H.; Ito, Y.; Ohshita, J. Three-component coupling using arynes and DMF: Straightforward access to coumarins via ortho-quinone methides. Chem. Commun. 2011, 47, 8512–8514. [CrossRef] 37. Mi, X.; Wang, C.; Huang, M.; Zhang, J.; Wu, Y.; Wu, Y. Silver-Catalyzed Synthesis of 3-Phosphorated Coumarins via Radical Cyclization of Alkynoates and Dialkyl H-Phosphonates. Org. Lett. 2014, 12, 3356–3359. [CrossRef] 38. Liu, D.; Chen, J.; Wang, X.; Xu, P. Metal-Free, Visible-Light-Promoted Synthesis of 3-Phosphorylated Coumarins via Radical C P/C C Bond Formation. ASC Commun. 2017, 359, 2773–2777. [CrossRef] − − 39. Abdou, W.; Shaddy, A. Application of Dialkyl Cyanomethylphosphonates in Synthesis of Biologically Active Phosphono-Substituted Heterocycles and Vinylphosphonates. Synth. Commun. 2006, 31, 1953–1964. [CrossRef] 40. Alexieva, V.; Karanov, E.; Nikolova, R.; Bojilova, A. Plant Growth Regulating Activity of Some Phosphorus Derivatives of Coumarin. Bulg. J. Plant Physiol. 1995, 21, 45–51. 41. Budzisz, E.; Brzezcnska, E.; Krajewska, U.; Rozatski, M. Cytotoxic effects, alkylating properties and molecular modelling of coumarin derivatives and their phosphonic analogues. Eur. J. Med. Chem. 2003, 38, 597–603. [CrossRef] 42. Bojilova, A.; Ivanov, C. Two new routes to esters of 2-oxochroman-4-acetic acid. Synthesis 1976, 4, 267–268. [CrossRef] 43. Ivanov, C.; Bojilova, A. Umwandlung von 2-oxo-2H-1-benzopyran-3-carbonsaureestern in 2-oxo-4- chromanessigsaureester—eine neue Umlagerung. Chem. Ber. 1978, 111, 3755–3763. [CrossRef] 44. Bojilova, A.; Rodios, N.; Nikolova, R.; Ivanov, C. Reactions of 3-acyl-substituted-2H-1-benzopyran-2-ones with acid anhydrides, II. Liebigs Ann. Chem. 1991, 12, 1279–1284. [CrossRef] 45. Bojilova, A.; Rodios, N.; Nikolova, R.; Ivanov, C. Potassium fluoride promoted reaction of 3-acylsubstituted 2H-1-benzopyran-2-ones with acid anhydrides. An improved method for the synthesis of 4-(2-oxoalkyl)-2H-chroman-2-ones. Part III. Synth. Commun. 1992, 22, 741–754. [CrossRef] 46. Bojilova, A.; Ivanov, C. On the Reaction of 3-Phenylcoumarin with Organomagnesium Compounds. Synthesis 1974, 708–709. [CrossRef] 47. Kasantsev, A.V.; Butyaikin, V.V.; Otrashchenkov, E.A.; Muldakhmetov, Z.M. Conjugated addition of lithium and magnesium derivatives of o-carboranes to 3-carbethoxycoumarin. Russ. Chem. Bull. 1995, 44, 1976–1977. [CrossRef] 48. Nikolova, R.D.; Bojilova, A.; Rodios, N.A. A new and efficient method for conjugate addition of trialkylphosphites to 3-acylsubstituted coumarins. Tetrahedron 2004, 60, 10335–10342. [CrossRef] 49. Desyatkln, V.G.; Beletskaya, I.P. Asymmetric Friedel–Crafts/Michael Reaction of Indoles and Pyrroles with Coumarin-3-carbonylates. Synthesis 2017, 49, 4327–4334. [CrossRef] 50. Petkova, N.I.; Nikolova, R.D.; Kostov, K.L.; Mineva, T.; Vayssilov, G.N. Theoretical and Experimental Local Reactivity Parameters of 3-Substituted Coumarin Derivatives. J. Phys. Chem. A 2014, 118, 11062–11073. [CrossRef] 51. Petkova, N.I.; Nikolova, R.D.; Bojilova, A.G.; Rodios, N.A.; Raptopoulou, C.P. Hydrogenation/Regioselective

C-Acylation Reaction of Diethyl Coumarin-3-phosphonate with NaBH4/Acid Anhydrides: A New One-Pot Tandem Reaction. Synth. Commun. 2006, 36, 509–524. [CrossRef] 52. Janecki, T.; W ˛asek,T. A Novel Route to Substituted 3-Methylidenechroman-2-ones and 3-Methylchromen- 2-ones. Tetrahedron 2004, 60, 1049–1055. [CrossRef] 53. Koleva, A.I.; Petkova, N.I.; Nikolova, R.D. Ultrasound-Assisted Conjugate Addition of Organometallic Reagents to 3-Diethylphosphonocoumarin. Synlett 2016, 27, 2676–2680. [CrossRef] 54. Koleva, A.I.; Petkova, N.I.; Nikolova, R.D. Ultrasound-Assisted Metal-Mediated Method for the Formation

of Tetrahydro-3,30-Disubstituted Biscoumarins. Molecules 2018, 23, 2810. [CrossRef] 55. Moshkin, V.S.; Sosnovskikh, V.Y.; Röschenthaler, G. Nucleophilic properties of a nonstabilized azomethine ylide derived from sarcosine and cyclohexanone. A novel domino reaction leading to substituted 4-aryl-2-pyrrolidones. Tetrahedron Lett. 2012, 53, 3568–3572. [CrossRef] 56. Moshkin, V.S.; Sosnovskikh, V.Y.; Röschenthaler, G. Synthesis of benzopyranopyrrolidines via 1,3-dipolar cycloaddition of nonstabilized azomethine ylides with 3-substituted coumarins. Tetrahedron 2013, 69, 5884–5892. [CrossRef] Molecules 2019, 24, 2030 37 of 38

57. Deredas, D.; Albrecht, Ł.; Maniukiewicz, W.; Wojciechowski, J.; Wolf, W.M.; Paluch, P.; Janecki, T.; Ró˙zalski,M.; Krajewska, U.; Janecka, A.; Krawczyk, H. Three-component reaction of 3-(diethoxyphosphoryl)coumarin, enolizable ketones and primary amines: Simple, stereoselective synthesis of benzo[1,3]oxazocine skeletons. RSC Adv. 2013, 3, 6821–6832. [CrossRef] 58. Ilieva, E.D.; Petkova, N.I.; Nikolova, R.D. Ring Opening Reactions of 3-Phosphonocoumarin under Michael Reaction Conditions. Phosphorus Sulfur Silicon 2012, 187, 39–50. [CrossRef] 59. Deredas, D.; Huben, K.; Maniukiewicz, W.; Krawczyk, H. Highly syn-diastereoselective Michael addition of enolizable ketones to 3-(diethoxyphosphoryl)coumarin. Tetrahedron 2014, 70, 8925–8929. [CrossRef] 60. Deredas, D.; Huben, K.; Janecka, A.; Długosz, A.; Pomorska, D.K.; Mirowski, M.; Krajewska, U.; Janecki, T.; Ró˙zalski,M.; Krawczyk, H. Synthesis and anticancer properties of 3-methylene-4-(2-oxoalkyl)- 3,4-dihydrocoumarins. MedChemComm 2016, 7, 1745–1758. [CrossRef] 61. Deredas, D.; Huben, K.; Maniukiewicz, W.; Krawczyk, H. Tandem Conjugate Addition–Intramolecular Horner–Wadsworth–Emmons Olefination Approach to the Synthesis of Cyclopentene[c]chroman-2-ones and Cyclopent-1-enecarboxylates. Synlett 2014, 25, 280–282. [CrossRef] 62. Deredas, D.; Ł ˛agiewka,B.; Maniukiewicz, W. A facile synthesis of novel 9-substituted 2,3,4,9-tetrahydro- 1H-xanthen-1-ones. Tetrahedron Lett. 2019, 60, 538–540. [CrossRef] 63. Deredas, D.; Krawczyk, H.; Huben, K. An efficient synthesis of 3-diethoxyphosphoryl-4-(1H-indol-3-yl)- 3,4-dihydrocoumarins: A convenient approach to 3-methylene-4-(indol-3-yl)-3,4-dihydrocoumarins. Arkivoc 2018, 120–133. [CrossRef] 64. Petkova, N.; Bojilova, A.; Nikolova, R.; Ivanov, C.; Rodios, N.; Kopf, J. Synthesis of Heterocyclic Methylenebisphosphonates by 1,3-Dipolar Cycloaddition of Ethyl Diazoacetate to 1,2-Benzoxaphosphorin- 3-phosphonates. Tetrahedron 2009, 65, 1639–1647. [CrossRef] 65. Takeuchi, Y.; Ueda, N.; Uesugi, K.; Abe, H.; Nishioka, H.; Harayama, T. Convenient Synthesis of a Simple Coumarin from Salicylaldehyde and Wittig Reagent. IV1a-c: Improved Synthetic Method of Substituted Coumarins. Heterocycles 2003, 59, 217–224. [CrossRef] 66. Mironov, V.F.; Bogdanov, A.V.; Nemtarev, A.V.; Shtyrlina, A.A.; Varaksina, E.N.; Cherkasov, V.K.; Dobrynin, A.B.; Krivolapov, D.B.; Musin, R.Z.; Litvinov, I.A.; et al. Reactions of 3,5-di(tert-butyl)-1,2- benzoquinone with terminal acetylenes in the presence of phosphorus trichloride. ipso-Substitution of the tert-butyl group. Russ. Chem. Bull. 2007, 56, 1900–1910. [CrossRef] 67. Nemtarev, A.V.; Mironov, V.F.; Varaksina, E.N.; Gubaidullin, A.T.; Krivolapov, D.B.; Musin, R.Z.; Litvinov, I.A. Reaction of arylenedioxytrihalophosphoranes with acetylenes 12. Alkylacetylenes in the reaction with 2,2,2-trihalobenzo-1,3,2-dioxaphospholes. Russ. Chem. Bull. 2014, 63, 149–177. [CrossRef] 68. Mironov, V.F.; Nemtarev, A.V. Reactions of Arylenedioxytrihalophosphoranes with Acetylenes: XV.1 Reaction of 2,2,2-Tribromo-4,6-di-tert-butylbenzo-1,3,2λ5-dioxaphospholedioxaphosphole with Pent-1-yne. Rev. J. Chem. 2011, 1, 27–55. [CrossRef] 69. Aniskin, A.S.; Nemtarev, A.V.; Baranov, D.S.; Mironov, V.F.; Vasilevskii, S.F. Effect of Electronic Nature of Substituents in Arylacetylene on the Rate of Reaction with 2,2,2-Trichloroareno-1,3,2-dioxaphosphols. Russ. J. Gen. Chem. 2013, 83, 1010–1012. [CrossRef] 70. Nemtarev, A.V.; Mironov, V.F.; Aniskin, A.S.; Baranov, D.S.; Mironova, E.V.; Krivolapov, D.B.; Musin, R.Z.; Vasilevskii, S.F.; Druzhkov, N.O.; Cherkasov, V.K. Reaction of arylenedioxytrihalophosphoranes with acetylenes 11. Electronic effect of the substituent in arylacetylene on the reaction rate. Russ. Chem. Bull. 2013, 62, 55–70. [CrossRef] 71. Mironov, V.F.; Nemtarev, A.V.; Varaksina, E.N.; Shtyrlina, A.A.; Gubaidullin, A.T.; Litvinov, I.A.; Dobrynin, A.B. Reactions of phenylenedioxytrihalophosphoranes with arylacetylenes: XIII. Reaction of 5-tert-butyl-2,2,2-trihalo-1,3,2λ5-benzodioxaphospholes with acetylenes. Russ. J. Org. Chem. 2014, 50, 864–887. [CrossRef] 72. Nemtarev, A.V.; Mironov, V.F.; Fayzullin, R.R.; Litvinov, I.A.; Musin, R.Z. Reactions of Arylenedioxytrihalophosphoranes with Acetylenes: XV.1 Reaction of 2,2,2-Tribromo-4,6-di-tert-butylbenzo- 1,3,2λ5-dioxaphospholedioxaphosphole with Pent-1-yne. Russ. J. Gen. Chem. 2018, 88, 2290–2295. [CrossRef] 73. Li, X.; Zhang, D.; Pang, H.; Shen, F.; Fu, H.; Jiang, Y.; Zhao, Y.Synthesis of a Diverse Series of Phosphacoumarins with Biological Activity. Org. Lett. 2005, 7, 4919–4922. [CrossRef][PubMed] 74. Li, X.; Wang, Y.; Fu, H.; Jiang, Y.; Zhao, Y. Alkylation reactions of phosphachroman-2,4-diones and 4-hydroxy phosphacoumarins. Bioorg Chem. 2006, 34, 105–113. [CrossRef][PubMed] Molecules 2019, 24, 2030 38 of 38

75. Burilov, A.R.; Knyazeva, I.R.; Kasymova, E.M.; Sadykova, Y.M.; Pudovik, M.A.; Habicher, W.D.; Sinyashin, O.G. New P-Containing Linear and Macrocyclic Polyphenols. Phosphorus Sulfur Silicon 2011, 186, 884–887. [CrossRef] 76. Sadykova, Y.M.; Dalmatova, N.V.; Burilov, A.R.; Pudovik, M.A.; Dobrynin, A.B. Reaction of 3-methoxy-2- methylphenol with 2-ethoxyvinylphosphonic dichloride. Russ. Chem. Bull. 2011, 60, 2078–2080. [CrossRef] 77. Sadykova, Y.M.; Sadikova, L.M.; Badrtdinova, A.R.; Dobrynin, A.B.; Burilov, A.R.; Pudovik, M.A. Condensation of 2-Ethoxyvinylphosphonic Acid Dichloroanhydride with 2,3,5-Trimethylphenol. Novel Method for Preparation of Phosphacoumarins. Phosphorus Sulfur Silicon 2015, 190, 2267–2272. [CrossRef] 78. Kim, C.-E.; Ryu, T.; Kim, S.; Lee, K.; Lee, C.-H.; Lee, P.H. Gold-Catalyzed Hydroarylation of Aryl Alkynylphosphonates for the Synthesis of Phosphacoumarins. Adv. Synth. Catal. 2013, 355, 2873–2883. [CrossRef] 79. Shin, S.; Kang, D.; Jeon, W.H.; Lee, P.H. Synthesis of ethoxy dibenzooxaphosphorin oxides through palladium-catalyzed C(sp2)–H activation/C–O formation. Beilstein J. Org. Chem. 2014, 10, 1220–1227. [CrossRef] 80. Li, X.; Shen, F.; Fu, H.; Jiang, Y.; Zhao, Y. Synthesis of 4-Substituted Phosphacoumarins via Cross-Coupling of 4-Tosylphosphacoumarins with Organozinc Reagents. Synlett 2006, 4, 630–632. [CrossRef] 81. Kim, C.-E.; Son, J.-Y.; Shin, S.; Seo, B.; Lee, P.H. Alkenylation of Phosphacoumarins via Aerobic Oxidative Heck Reactions and Their Synthetic Application to Fluorescent Benzophosphacoumarins. Org. Lett. 2015, 17, 908–911. [CrossRef] 82. Nikolova, R.; Vayssilov, G.N.; Rodios, N.; Bojilova, A. Regio- and Stereoselective [2+2] Photodimerization of 3-Substituted 2-Alkoxy-2-oxo-2H-1,2-benzoxaphosphorines. Molecules 2002, 7, 420–432. [CrossRef]

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