Synthetic Procedures Leading Towards Aminobisphosphonates

Review Synthetic Procedures Leading towards Aminobisphosphonates

Ewa Chmielewska * and Paweł Kafarski

Department of Bioorganic Chemistry, Faculty of Chemistry, Wrocław University of Science and Technology, Wrocław 50-370, Poland; [email protected] * Correspondence: [email protected]; Tel.: +48-71-320-29-77; Fax: +48-71-320-24-27

Academic Editor: György Keglevich Received: 30 September 2016; Accepted: 2 November 2016; Published: 4 November 2016

Abstract: Growing interest in the biological activity of aminobisphosphonates has stimulated the development of methods for their synthesis. Although several general procedures were previously elaborated to reach this goal, aminobisphosphonate chemistry is still developing quite substantially. Thus, innovative modiﬁcations of the existing commonly used reactions, as well as development of new procedures, are presented in this review, concentrating on recent achievements. Additionally, selected examples of aminobisphosphonate derivatization illustrate their usefulness for obtaining new diagnostic and therapeutic agents.

Keywords: bisphosphonates; bisphosphonylation procedures; Vilsmayer-Haack-like reactions; functionalization of aminoalkylbisphosphonates

1. Introduction Bisphosphonates are a class of compounds that are currently receiving significant attention. Over 50 new papers are seen each week when searching the literature with the keyword “bisphosphonate” via Web of Science. More than 17,000 various bisphosphonate structures have been synthesized and described in the literature [1]. Most papers concern their important subclass, namely aminobisphosphonates. This strong interest results from these compounds acting as strong inhibitors of bone resorption, with several representatives of this class already commercialized as drugs of choice for the treatment of osteoporosis, skeletal complications of malignancy, Paget’s disease, multiple myeloma, hypercalcemia and fibrous dysplasia [2–7] Consequently, most of the papers are devoted to various clinical aspects of the anti-resorptive effects that bisphosphonates exert towards bone tissues; however, there is also a growing interest in their applications as anticancer and antibacterial agents [5–7]. Additionally, aminobisphosphonic acids have found important industrial applications, largely as inhibitors of scale formation and as corrosion inhibitors, actions which result from their ability to complex metal ions [8–10]. Thus, simple and effective procedures for their synthesis are becoming increasingly important. However, only a few general reactions leading to these compounds have been described to date and are only partially reviewed in the literature [11,12]. Novel reports are mostly concentrated on modifications and improvement of these procedures, and there are only a few papers aiming at new reactions, which results from the commonly applied procedures being simple, economical and effective. In this paper, we comprehensively review the recent studies (supplemented by older papers if necessary) on reactions applied to synthesize the most important class of bisphosphonates— aminobisphosphonates—and discuss their scope and limitations.

Molecules 2016, 21, 1474; doi:10.3390/molecules21111474 www.mdpi.com/journal/molecules Molecules 2016, 21, 1474 2 of 26

2. Overview of Synthetic Procedures There are contradictory reports of the origin of bisphosphonates [13]. Most likely, the ﬁrst one was obtained in the 19th century by Nikolay Menschutkin and/or Theodor Saltzer as an impurity in reactionsMolecules designed 2016, 21 to, 1474 obtain different compounds. It was further identiﬁed by Hans von2 Baeyerof 25 and

Wilhelm2. HeideprimOverview of asSynthetic 1-hydroxyethanebisphosphonic Procedures acid. There are only a few general methods for the synthesis of aminobisphosphonates. However, there There are contradictory reports of the origin of bisphosphonates [13]. Most likely, the first one are many individual procedures described for their preparation [11,12]. In this review, the following was obtained in the 19th century by Nikolay Menschutkin and/or Theodor Saltzer as an impurity in generalreactions reactions designed are presented: to obtain different (i) starting compounds. from carboxylic It was further acids identified and (ii) by their Hans amides;von Baeyer (iii) and reactions using nitrilesWilhelm and Heideprim (iv) isonitriles as 1-hydroxyethanebisphosphonic as substrates; (v) syntheses acid. based on addition of phosphites to oxophosphonates;There are (vi) only three-component a few general methods condensation for the synthesis of of amines, aminobisphosphonates. trialkyl orthoformates However, there and dialkyl phosphites;are many (vii) individual addition procedures of amines described to vinylidenebisphosphonates; for their preparation [11,12]. In and this (viii)review, functionalization the following of simple bisphosphonatesgeneral reactions are treatedpresented: as (i) building starting from blocks carboxylic for the acids preparation and (ii) their of amides; more complex (iii) reactions structures. using nitriles and (iv) isonitriles as substrates; (v) syntheses based on addition of phosphites to Additionally,oxophosphonates; some speciﬁc (vi) three-component and non-conventional condensation procedures of amines, trialkyl that haveorthoformates been elucidated and dialkyl will be presentedphosphites; in this review. (vii) addition of amines to vinylidenebisphosphonates; and (viii) functionalization of simple bisphosphonates treated as building blocks for the preparation of more complex structures. 2.1. SynthesisAdditionally, from Carboxylic some specific Acids and non-conventional procedures that have been elucidated will be presented in this review. 1-Hydroxyethylidene-1,1-bisphosphonic acids are perhaps the oldest group of bisphosphonates. They are2.1. standardly Synthesis from prepared Carboxylic by Acids a large-scale, one-step reaction of carboxylic acids with phosphorus trichloride and phosphorous or phosphoric acids, followed by hydrolysis with water; the procedure 1-Hydroxyethylidene-1,1-bisphosphonic acids are perhaps the oldest group of bisphosphonates. was optimizedThey are standardly by Kieczykowski prepared by eta large-scale, al. [14]. one- Thestep reactionreaction of iscarboxylic carried acids out with in selectedphosphorus solvents (phenylsulphonictrichloride and acid, phosphorous various phenols, or phosphoric chlorobenzene, acids, followed diphenyl by hydrolysis ether with or ionic water; liquids) the procedure with sulfone and methanesulphonicwas optimized by acidKieczykowski being preferred et al. [14]. choices The reaction [11,15– 20is ].carried Despite out manyin selected theories solvents [19 ,21–23], the exact(phenylsulphonic mechanism of acid, this reactionvarious phenols, is not fullychlorobenzen understood;e, diphenyl however, ether or the ionic formation liquids) with of acid sulfone chloride as a ﬁrst intermediateand methanesulphonic has been acid undoubtedly being preferred demonstrated choices [11,15–20]. (Scheme Despite1). This many intermediate theories [19,21–23], may reactthe with exact mechanism of this reaction is not fully understood; however, the formation of acid chloride as methanesulphonica first intermediate acid (whenhas been used undoubtedly as a solvent), demonstrated and the (Scheme formed 1). mixedThis intermediate anhydride may is react also with considered a potentialmethanesulphonic intermediate acid for (when the next used step as a solvent), [24], which and the is anformed Arbuzov-like mixed anhydride reaction is also of considered phosphorus a acid or one ofpotential its several intermediate derivatives for the (including next step [24], anhydrides which is an Arbuzov-like of variable structurereaction of phosphorus [17]) formed acid during or the reaction.one The of formedits several derivative derivatives of (including ketophosphonate anhydrides is of a substratevariable structure for the [17]) addition formed reaction during ofthe trivalent P-OH species,reaction. The and formed bisphosphonate derivative of ketophosphonate is obtained (Scheme is a substrate1). It for has the also addition been reaction documented of trivalent that the P-OH species, and bisphosphonate is obtained (Scheme 1). It has also been documented that the use of use of phosphorous acid could be omitted if water was added to the reaction medium, and thus this phosphorous acid could be omitted if water was added to the reaction medium, and thus this compoundcompound was formed was formed in situ. in situ.

PO3H2 1./ SOCl2 O 1./ PCl3/H3PO3 or CH SO H O OH 3 3 R R OH 2./ H2O PO3H2 2./ H2O R OH 1

CH3SO3H PCl3 SOCl2 O R = H N n n =1-5 O O 2 R Cl S R O O R1 R1 R2 P HO P O OH R2 R Cl R1 O HO R1 PH O O P R R2 2 S R R O O O

1 PO3H2 R 2 OH R P R 1 PO3H2 OH R = Cl, OH 1 R2 = Cl, OPR1R2 Scheme 1. Presumable mechanism of the synthesis of 1-hydroxy-1,1-bisphosphonic acids. Scheme 1. Presumable mechanism of the synthesis of 1-hydroxy-1,1-bisphosphonic acids. This reaction was commonly used for the preparation of a wide variety of anti-osteoporotic Thisbisphosphonic reaction was acids commonly containing free used amino for gr theoups preparation (so called dronic of a acids, wide compound variety of1). In anti-osteoporotic this case, bisphosphonicfree unblocked acids amino containing acids are free used amino as substrates, groups and (so the called final neutralization dronic acids, of compoundreaction mixtures1). In to thisa case, pH of approximately 4 causes precipitation of the desired products, which are formed in satisfactory free unblocked amino acids are used as substrates, and the ﬁnal neutralization of reaction mixtures to a pH of approximately 4 causes precipitation of the desired products, which are formed in satisfactory Molecules 2016, 21, 1474 3 of 26

Molecules 2016, 21, 1474 3 of 25 yieldsMolecules and 2016 are, 21 of, 1474 good purity [16,23–26]. Because of its technological importance, this reaction3 of 25 is yields and are of good purity [16,23–26]. Because of its technological importance, this reaction is still still quite intensively studied and optimized; however, most of the studies are done in industrial yieldsquite intensively and are of studied good purity and optimized; [16,23–26]. however, Because most of it sof technological the studies are importance, done in industrial this reaction laboratories, is still laboratories, and their results are mostly disseminated as patents. Consequently, it is difficult, if not quiteand their intensively results studiedare mostly and disseminated optimized; however, as patents. most Consequently, of the studies areit is done difficult, in industrial if not impossible, laboratories, to impossible, to determine which conditions are optimal for the synthesis of individual drugs. It is anddetermine their results which areconditions mostly aredisseminated optimal for as the patents. synthesis Consequently, of individual it drugs. is difficult, It is important if not impossible, because, toas important because, as in the case of any multicomponent reaction, a synthetic course is strongly determinein the case which of any conditions multicomponent are optimal reaction, for the synthesisa synthetic of individualcourse is drugs.strongly It isdependent important onbecause, applied as dependent on applied conditions and molar ratios of reagents. For example, one of the patents reports inconditions the case and of anymolar multicomponent ratios of reagents. reaction, For example, a synthetic one ofcourse the patents is strongly reports dependent that the omissionon applied of thatconditionsphosphorus the omission and chloride molar of phosphorus ratiosin the ofreaction reagents. chloride of For4-aminobutyric in example, the reaction one acid ofof the as 4-aminobutyric patentsthe substrate reports in that acid methanesulphonic the as omission the substrate of inphosphorusacid methanesulphonic provides chloride mixtures acid in ofthe provides anhydrides reaction mixtures of as 4-aminobutyric final of products anhydrides acid(compounds as finalthe substrate products2 and 3 ,in Scheme (compounds methanesulphonic 2) [11].2 Thisand 3, Schemeacidcorresponds provides2)[11]. well This mixtures to corresponds the knownof anhydrides tendency well to as the offinal knownphosphonic products tendency acids (compounds ofto phosphoniccyclize. 2 and 3 acids, Scheme to cyclize. 2) [11]. This corresponds well to the known tendency of phosphonic acids to cyclize. O OH OH O HO P O O P O OH H2O3P OH NH2 H N O P 2 HO P O OH O PO O H2N H O P POPO PO3H2 NH O 2 3 O 2 H N OHP 2 OH 3 HO 2 PO H2N OP PO3H2 O O OH 2 3 HO SchemeScheme 2. 2.Cyclic Cyclic productsproducts ofof thethe reactionreaction between carboxylic carboxylic acids acids and and phosphorous phosphorous acid acid in in methanesulphonicSchememethanesulphonic 2. Cyclic acid. acid.products of the reaction between carboxylic acids and phosphorous acid in methanesulphonic acid. Among modifications of this procedure are (i) replacement of phosphorus trichloride with Among modifications of this procedure are (i) replacement of phosphorus trichloride with thionyl thionylAmong chloride modifications to generate ofacid this chloride procedure in the are firs (i)t reaction replacement step [11]; of phosphorus(ii) replacement trichloride of acid bywith its chloride to generate acid chloride in the first reaction step [11]; (ii) replacement of acid by its chloride thionylchloride chloride or anhydride to generate [11] oracid (iii) chloride t-butyl in ester the firs[27];t reaction (iv) blocking step [11]; the (ii)amino replacement moiety in of the acid case by itsof or anhydride [11] or (iii) t-butyl ester [27]; (iv) blocking the amino moiety in the case of α-amino chlorideα-amino oracids anhydride [28]; and [11] (v) applicationor (iii) t-butyl of microwave-assisted ester [27]; (iv) blocking procedures the amino [29]. moiety in the case of acids [28]; and (v) application of microwave-assisted procedures [29]. α-amino acids [28]; and (v) application of microwave-assisted procedures [29]. 2.2. Synthesis from Amides 2.2. Synthesis from Amides 2.2. SynthesisAlthough from studies Amides on the biological activity of 1-amino-1,1-bisphosphonic acids are scarce, a Although studies on the biological activity of 1-amino-1,1-bisphosphonic acids are scarce, significantAlthough number studies of procedures on the biological for their activitypreparation of 1-amino-1,1-bisphosphonic have been described. They acidshave arerecently scarce, been a a significant number of procedures for their preparation have been described. They have recently significantreviewed by number Romanenko of procedures and Kukhar for [12].their Amides, preparation bein ghave highly been stable described. and easily They available have recently compounds, been beenreviewedare reviewedsubstrates by Romanenkoby of Romanenkochoice, andand Kukhar the and most Kukhar [12]. commonly Amides, [12]. bein Amides, appliedg highly procedures being stable highly and are easily stable simple available and modifications easily compounds, available of compounds,arethose substrates elaborated are of substrates forchoice, carboxylic and of the choice,acids. most Th commonly ande most the straightforward most applied commonly procedures are appliedreactions are simple procedures of N modifications-acylamines are simpleand of modificationsthoseN-formylamines elaborated of those withfor carboxylic phosphorus elaborated acids. fortrichloride carboxylicThe most and straightforward acids.phosphorous The most acid are straightforward[30–32],reactions phosphorus of N-acylamines are tribromide reactions and of N-acylaminesN[33],-formylamines or triphosgene and withN [34],-formylamines phosphorus which pr ovidetrichloride with a wide phosphorus and structural phosphorous trichloride variety acid of 1-amino-1,1-bisphosphonic[30–32], and phosphorous phosphorus acidtribromide [acids30–32 ], phosphorus[33],(compound or triphosgene tribromide 4, Scheme [34], 3). [33which They], or arepr triphosgeneovide based a onwide modification [structural34], which ofvariety the provide first of 1-amino-1,1-bisphosphonicprocedure a wide elaborated structural by variety Plöger acids of 1-amino-1,1-bisphosphonic(compoundet al. with formamide 4, Scheme as3). a They acidssubstrate are (compound based [35]. on modification4, Scheme3). of They the first are basedprocedure on modification elaborated by of Plöger the first procedureet al. with elaborated formamide by as Plöger a substrate et al. [35]. with formamide as a substrate [35]. O 1 PCl /H PO PO3H2 R 3 3 4 H2O3P R O N R1 N 2 1 PCl /H PO PO3H2 R R 3 3 4 H2O3P R R N R2R1 R= CH phenyl 4 N R2 3, R R1= H, alkyl R2 4 R=R2= CH alkyl,3, phenyl aryl, heteroaryl, cycloalkyl R1= H, alkyl 2 Scheme R3. =Bisphosphonylation alkyl, aryl, heteroaryl, cycloalkyl of amides.

SchemeScheme 3.3. BisphosphonylationBisphosphonylation of of amides. amides. The exact reaction mechanism in this case is also not fully known; however, a Vilsmayer- Haack-likeThe exact route reaction via iminium mechanism ion is postulated in this case here is (Schemealso not 4).fully known; however, a Vilsmayer- The exact reaction mechanism in this case is also not fully known; however, a Vilsmayer- Haack-likeAnother route possibility via iminium is using ion is trialkyl postulated or trimet here (Schemehylsilyl 4).phosphites in reactions prompted by Haack-likephosphorylAnother route chloride possibility via iminium [36–39], is using iontrifluoromethanesulphonic is trialkyl postulated or trimet here (Schemehylsilyl anhydride 4phosphites). (Tf2O) in [40], reactions zinc chloride prompted [41] byor Another possibility is using trialkyl or trimethylsilyl phosphites in reactions prompted by phosphoryltrimethylsilyl chloride trifluoromethanesulfonate [36–39], trifluoromethanesulphonic [42,43]. Unfortunately, anhydride primary (Tf2O) [40],amides zinc are chloride not suitable [41] or phosphoryltrimethylsilylsubstrates for chloride thistrifluoromethanesulfonate reaction [36–39 [38].], triﬂuoromethanesulphonic The use of [42,43].triethyl phosphiteUnfortunately, anhydride and phosphoryl primary (Tf2 O)amides chloride [40], are zinc appeared not chloride suitable to be [41 ] orsubstratesespecially trimethylsilyl foruseful this triﬂuoromethanesulfonate when reaction lactams [38]. Thewere use used of triethylas [ 42substrates,,43 phosphite]. Unfortunately, resulting and phosphoryl in high primary yields chloride amides of aminomethylene- appeared are not suitable to be substratesespeciallygem-bisphosphonates for useful this reactionwhen (Scheme lactams [38]. The were5) [36–39]. use used of triethylas They substrates, we phosphitere readily resulting and hydrolyzed, phosphorylin high yields yielding chloride of aminomethylene- corresponding appeared to be especiallygembisphosphonic-bisphosphonates useful acids when (represe lactams(Schementative were5) [36–39]. usedexampleas They substrates, compound were readily resulting 5). On hydrolyzed, the in other high hand, yields yielding this of aminomethylene- correspondingreaction is not gembisphosphonicsuitable-bisphosphonates for the acidsconversion (Scheme(represe of ntativebenzoannulated5)[ 36 –example39]. They compoundlact wereams, and readily 5 ).mixtures On hydrolyzed, the otherof the hand,desired yielding this bisphosphonates reaction corresponding is not bisphosphonicsuitableand monophosphonates for the acids conversion (representative of of variable benzoannulated example structures compound lact wereams, obtained5 ).and On mixtures the (compounds other of hand, the desired6 this, 7, reaction8 and bisphosphonates 9, isScheme not suitable 5). forandIn the fact, monophosphonates conversion monophosphonates of benzoannulated of variableare usually structures lactams,major produc were and obtainedts, mixtures and the (compounds ofreaction the desired course 6, 7,bisphosphonates is8 anddependent 9, Scheme on the5). and In fact, monophosphonates are usually major products, and the reaction course is dependent on the

Molecules 2016, 21, 1474 4 of 26 monophosphonates of variable structures were obtained (compounds 6, 7, 8 and 9, Scheme5). In fact, Molecules 2016, 21, 1474 4 of 25 monophosphonatesMolecules 2016, 21, 1474 are usually major products, and the reaction course is dependent on the size4 of of 25 the substratesize of aliphaticthe substrate ring aliphatic [44]. Additionally, ring [44]. Additi theseonally, bisphosphonates these bisphosphona and monophosphonatestes and monophosphonates appeared to size of the substrate aliphatic ring [44]. Additionally, these bisphosphonates and monophosphonates beappeared unstable to upon be unstable acid hydrolysis upon acid andhydrolysis upon and storage, upon andstorage, undergo and undergo degradation degradation with cleavagewith cleavage of the appeared to be unstable upon acid hydrolysis and upon storage, and undergo degradation with cleavage carbon-to-phosphorusof the carbon-to-phosphorus bond (for bond example (for example compound compound10, Scheme 10, Scheme5). Thus, 5). Thus, corresponding corresponding acids acids have of the carbon-to-phosphorus bond (for example compound 10, Scheme 5). Thus, corresponding acids nothave yet beennot yet obtained. been obtained. have not yet been obtained.

PO H O Cl 3 2 PO3H2 O PCl3 O PO3H2 1 PO H R1 PCl Cl 1 O R 3 R2 1 1 3 R HP R N 1 1 R N R R N R1 R R N R R N HOHPOH R N2 R N R2 R N2 R R2 2 R HO OH 2 2 R R2 R R O HPO HOHPOH HO OH

PO3H2 H2O3P PO H1 H O P 3R 2 2 3 N R1 R N R R2 4 R2 4 Scheme 4. Bisphosphonylation of amides and the presumable mechanism of this reaction. SchemeScheme 4. 4.Bisphosphonylation Bisphosphonylationof of amidesamides and the presumable mechanism mechanism of of this this reaction. reaction.

POCl3/(EtO)3P HCl/H2O P(O)(OEt)2 PO3H2 POCl3/(EtO)3P HCl/H2O N O N P(O)(OEt)2 N PO3H2 P(O)(OEt) PO H HN O HN 2 HN 3 2 H H P(O)(OEt)2 H 5 PO3H2 5

1./ POCl3/(EtO)3P P(O)(OEt)2 1./ POCl /(EtO) P 3 3 N P(O)(OEt)2 + N O P(O)(OEt) N P(O)(OEt)2 H HN 2 + N O P(O)(OEt) N P(O)(OEt)2 H 6H 2 7 6 7 HCl/H2O HCl/H2O

N PO3H2 N PO3H2

1./ POCl3/(EtO)3P 1./ POCl /(EtO) P + 3 3 P(O)(OEt)2 N N + N P(O)(OEt)2 HN O HN P(O)(OEt)2 HN P(O)(OEt)2 P(O)(OEt) H O 89H P(O)(OEt)2 H 2 89 HCl/H2O HCl/H2O

COOH COOH NH2 10 NH2 10 Scheme 5. Representative reactions of lactams with triethyl phosphite prompted by phosphoryl chloride. SchemeScheme 5. 5.Representative Representative reactions reactions ofof lactamslactams with trieth triethylyl phosphite phosphite prompted prompted by by phosphoryl phosphoryl chloride. chloride. The formation of a Vilsmayer-Haack-like intermediate is also proposed in this case with the The formation of a Vilsmayer-Haack-like intermediate is also proposed in this case with the further addition of a nucleophilic phosphorus reagent. This assumption is additionally supported by furtherThe formationaddition of ofa nucleophilic a Vilsmayer-Haack-like phosphorus reagent. intermediate This assumption is also proposed is additionally in this supported case with by the studies on the use of structurally variable imine salts as substrates for synthesis of compounds 11 furtherstudies addition on the use of a of nucleophilic structurally phosphorusvariable imine reagent. salts as This substrates assumption for synthesis is additionally of compounds supported 11 (Scheme 6) [41–45]. by(Scheme studies on6) [41–45]. the use of structurally variable imine salts as substrates for synthesis of compounds 11

(Scheme6)[41–45]. OTMS F3CO2SO P(O)(OTMS)2 OEt OTMS + OTMS F CO SO P(O)(OTMS) The reactionOEt of dibutoxyphosphineCF3SO3TMS OTMS or bis(trimethylsiloxy)phosphineP 3 with2 dimethylformamides2 CF SO TMS +TMSO P OTMS R NH2 -CF3 SO3 R NH TMSO OTMS R NH in the presenceR NH2 of trimethylsilyl3 3 triﬂuoromethanesulfonate2 affords the2 corresponding R NH Cl -CF SO R NH2 Cl 2 3 3 Cl OTMS Cl OTMS aminomethylenebisphosphonites 12 in high yields (Scheme7)[ 41–43]. SimilarP products were TMSO P OTMS obtained by reactingTMS = Me3Si diethyl pivaloylphosphonite with dialkylformamides inTMSO the presenceOTMS of excess TMS = Me Si 3 -CF SO TMS CH OH 3 3 ethanol and catalyticH amounts2O3P PO3 ofH2 zinc chloride3 (TMSO) (Scheme2(O)P P(O)(OTMS)7). Pivaloylphosphonite2 -CF3SO3TMS decomposes in these H2O3P PO3H2 CH3OH (TMSO)2(O)P P(O)(OTMS)2 reaction conditions, yieldingR NH diethoxyphosphine,2 whichR NH is2 the real substrate of the reaction [41]. R NH R NH 11 2 2 N-Octylpyrrolidinone11 treated with LDA, followed by the addition of diethyl phosphorochloridite and oxidation of the reaction mixture with 30% hydrogen peroxide resulted in bisphosphonylated R = H, CH3, phenyl, , HO R = H, CH3, phenyl, N , HO lactam 13 with excellent yieldN (Scheme8). This reaction was then applied for the synthesis

Scheme 6. Imine salts as substrates for preparation of bisphosphonic acids. Scheme 6. Imine salts as substrates for preparation of bisphosphonic acids.

Molecules 2016, 21, 1474 4 of 25

size of the substrate aliphatic ring [44]. Additionally, these bisphosphonates and monophosphonates appeared to be unstable upon acid hydrolysis and upon storage, and undergo degradation with cleavage of the carbon-to-phosphorus bond (for example compound 10, Scheme 5). Thus, corresponding acids have not yet been obtained.

PO H O Cl 3 2 PO3H2 PCl3 O 1 1 1 R 1 R R HP R R N R N R N R N 2 HO OH 2 2 R R2 R R

O HP HO OH

PO H H O P 3 2 2 3 R1 N R R2 4 Scheme 4. Bisphosphonylation of amides and the presumable mechanism of this reaction.

POCl3/(EtO)3P HCl/H2O P(O)(OEt)2 PO3H2 N O N N H H P(O)(OEt)2 H PO3H2 5

1./ POCl3/(EtO)3P P(O)(OEt)2 N + N O P(O)(OEt) N P(O)(OEt)2 H H 2 6 7

HCl/H2O

N PO3H2

1./ POCl /(EtO) P 3 3 + P(O)(OEt)2 N N N H O H P(O)(OEt)2 H P(O)(OEt)2 89

Molecules 2016, 21, 1474 HCl/H2O 5 of 26

COOH of N-geranylated lactams 14 and 15 and linear amides, potential inhibitors of farnesyl:protein NH2 10 transferase [46]. In the case of cyclic imides, in which two equivalent positions for enolate formation Scheme 5. Representative reactions of lactams with triethyl phosphite prompted by phosphoryl chloride. areMolecules present 2016 on, 21 the, 1474 imide rings, and thus two carbon atoms may be phosphonylated, the structure5 of 25 of the productThe formation was dependent of a Vilsmayer-Haack-like on the mode of reaction.intermedia Ifte phosphonylation is also proposed wasin this carried case with out inthe one step,further twoThe carbonaddition reaction atoms of of a dibutoxyphosphine nucleophilic were phosphonylated phosphorus or bis(trim and reagent. vicinalethylsiloxy)phosphine This bisphosphonate assumption is withadditionally was dimethylformamides obtained. supported Step-by-step by reactioninstudies the resulted onpresence the use in the ofof structurally predomination trimethylsilyl variable of tri the imineﬂuoromethanesulfonate phosphonylation salts as substrates of one foraffords carbonsynthesis atom,the of compoundscorresponding and the desired 11 gem-bisphophonateaminomethylenebisphosphonites(Scheme 6) [41–45]. was the major product.12 in high yields (Scheme 7) [41–43]. Similar products were obtained by reacting diethyl pivaloylphosphonite with dialkylformamides in the presence of excess ethanol and catalytic amounts of zinc chloride (Scheme OTMS7). PivaloylphosphoniteF CO SO decomposesP(O)(OTMS) in these OEt OTMS + 3 2 2 CF3SO3TMS P reaction conditions, yielding diethoxyphosphine, TMSOwhich isOTMS the real substrate ofR theNH reaction2 [41]. R NH -CF SO R NH2 2 3 3 Cl Cl OTMS OMe OR RO OR P R1 P TMSO OTMS TMS = Me3Si P + MeO N RO R1 H OR 2 -ROH Molecules 2016, 21, 1474 R P -CFN3SO3TMS 5 of 25 H O P PO H CH3OH (TMSO) (O)P P(O)(OTMS) 2 3 3 2 2 2 OR R2 R = Et, Bu, SiMe R NH2 3 R NH 1 2 2 12 The reaction of dibutoxyphosphine11 R =R = CH3 or bis(trimethylsiloxy)phosphine with dimethylformamides in the presence of trimethylsilyl triﬂuoromethanesulfonate affords the corresponding R = H, CH , phenyl, , aminomethylenebisphosphonitesO 3 12HO in high yields (SchemeOEt 7) [41–43]. EtOSimilarOEt products were N OEt P OEt EtOH/ZnCl2 R1 obtained by reactingP diethyl pivaloylphosphoniteP with+ EtO dialkylformamidesN EtO in the presenceR1 of excess - t-BuCOOEt H OEt -EtOH P N ethanol and catalyticOEt amounts of zinc chloride (Scheme 7). PivaloylphosphoniteR2 decomposes in these OEt R2 SchemeScheme 6. 6.Imine Imine salts salts as as substratessubstrates for preparation of of bisphosphonic bisphosphonic acids. acids. reaction conditions, yielding diethoxyphosphine, which is the real substrate of the12 reaction [41]. 1 2 R = R = CH3, n-propyl, R1, R2 = -(CH ) -, -CH CH OCH CH - 2 5 2 2 2 2 OMe OR RO OR + R1 P Scheme 7. Reaction ofP diethoxyphoMeOsphineN with the acetal of dimethylformamide.1 H OR -ROH RO R R2 P N OR R2 N-Octylpyrrolidinone treatedR = withEt, Bu, LDA,SiMe3 followed by the addition of diethyl phosphorochloridite 1 2 12 and oxidation of the reaction mixtureR =R = CH with3 30% hydrogen peroxide resulted in bisphosphonylated lactam 13 with excellent yield (Scheme 8). This reaction was then applied for the synthesis of O OEt EtO OEt N-geranylated lactams 14 and 15 and linear amides,OEt potential inhibitors of farnesyl:proteinP transferase OEt EtOH/ZnCl2 R1 [46]. In the case of cyclicP imides, in which twoP equivalent+ EtO positionsN for enolateEtO formationR1 are present - t-BuCOOEt H OEt -EtOH P N OEt R2 on the imide rings, and thus two carbon atoms may be phosphonylated, the structureOEt R2 of the product 12 was dependent on1 the2 mode of reaction. If phosphonylation was carried out in one step, two carbon R = R = CH3, n-propyl, 1 2 atoms were phosphonylatedR , R = -(CH2) 5and-, -CH vicinal2CH2OCH bisphosphona2CH2- te was obtained. Step-by-step reaction resulted in the predomination of the phosphonylation of one carbon atom, and the desired gem-bisphophonate Scheme 7. Reaction of diethoxyphosphine with the acetal of dimethylformamide. was the majorScheme product. 7. Reaction of diethoxyphosphine with the acetal of dimethylformamide. N-Octylpyrrolidinone treated with LDA, followed by the addition of diethyl phosphorochloridite

1./ LDA (2 equiv.) H O and oxidation of the reaction mixture with 30% hydrogen peroxide2 2 resultedN in bisphosphonylated 2./ ClP(OEt)2 (2 equiv.) N N lactam 13 with excellent yield (Scheme 8). This reacOtion was then appliedO for the synthesis of O (EtO)2P P(OEt)2 (EtO)2(O)P P(O)(OEt)2 N-geranylated lactams 14 and 15 and linear amides, potential inhibitors of farnesyl:protein13 transferase [46]. In the case of cyclic imides, in which two equivalent positions for enolate formation are present

on the imide rings, and thus two carbonO atoms may be phosphonylated, the structure of the product

was dependent on the mode of reaction.N If phosphonylation was carried out in one step, two carbon

atoms were phosphonylated and vicinalO bisphosphonate was obtained. Step-by-step reaction resulted 1./ LDA (1 equiv.) 2./ ClP(OEt) (1 equiv.) in the predomination1./ of LDA the (2 equiv.) phosphonylation of one carbon atom, and2 the desired gem-bisphophonate 3./ H2O2 was the major product.2./ ClP(OEt) 2 (2 equiv.) 3./ H2O2

1./ LDA (1 equiv.) O 1./ LDA (2 equiv.) H O 2./ ClP(OEt)2 22 (1 equiv.) N 2./ ClP(OEt)2 (2 equiv.) N N N 3./ H2O2 (EtO)2(O)P 14 O O O O (EtO)2P P(OEt)2 (EtO)2(O)P P(O)(OEt)2 (EtO) (O)P 2 O 13 (EtO)2(O)P N (EtO) (O)P O 2 15 O N Scheme 8. Synthesis of bisphosphonate lactams. Scheme 8.OSynthesis of bisphosphonate lactams. 1./ LDA (1 equiv.) 2./ ClP(OEt) (1 equiv.) 1./ LDA (2 equiv.) 2 3./ H2O2 2.3. Synthesis from Nitriles2./ ClP(OEt) 2 (2 equiv.) 3./ H2O2 1-Aminoalkylidene-1,1-bisphosphonic acids could also be prepared from nitriles by applying 1./ LDA (1 equiv.) the same procedures as inO syntheses starting from amides. Despite being readily available substrates, 2./ ClP(OEt)2 (1 equiv.) N 3./ H2O2 (EtO)2(O)P 14 O (EtO) (O)P 2 O (EtO)2(O)P N (EtO)2(O)P 15 O Scheme 8. Synthesis of bisphosphonate lactams.

2.3. Synthesis from Nitriles 1-Aminoalkylidene-1,1-bisphosphonic acids could also be prepared from nitriles by applying the same procedures as in syntheses starting from amides. Despite being readily available substrates,

Molecules 2016, 21, 1474 6 of 26

2.3. Synthesis from Nitriles 1-Aminoalkylidene-1,1-bisphosphonic acids could also be prepared from nitriles by applying the Molecules 2016, 21, 1474 6 of 25 same procedures as in syntheses starting from amides. Despite being readily available substrates, there thereis limited is limited literature literature on their on their use use for thatfor that purpose. purpos Thee. The most most popular popular route route is is the the reaction reaction ofof nitrilesnitriles with phosphorousphosphorous acid, in somesome casescases promptedprompted byby phosphorusphosphorus trichloridetrichloride andand phenylsulphonicphenylsulphonic or methylsulphonic acids [12,31,47,48]. [12,31,47,48]. The The conditions conditions of of this this reaction are sufficiently sufﬁciently delicate to use peptidyl nitriles as substrates,substrates, which was demonstrated using cyanoethylcyanoethyl derivatives of dipeptides (for example, peptidepeptide 16,, SchemeScheme9 9))[ [49].49].

PO H PO3H2 H H H2N 3 2 H NC HN COOH PCl /H PO 2 N COOH NC N N COOH PCl3/H3PO3 N N COOH N 3 3 3 H2O3P N H 2 3 H H O S O S O S 16 16 Scheme 9. RepresentativeRepresentative example of the synthesis of peptidylbisphosphonates from nitriles.

Recently, elegant,elegant, mild, and atomatom economicaleconomical doubledouble phosphonylation of nitriles in the presence of titanocenetitanocene hashas beenbeen described.described. This This proced procedureure used induced phosphorus-centered radicals mediated by titanocene dichloride (Cp2TiCl2) (Scheme 10) and provided a wide structural variety of mediated by titanocene dichloride (Cp2TiCl2)) (Scheme (Scheme 10)10) and and provided provided a a wide structural variety of aminobisphosphonates 1717 [50].[50]. This This is is a a double radical transfer reaction initiated by the reaction of titanocene with zinc dust and the transfer of the obtainedobtained radical to epoxypropaneepoxypropane by cleavage of its oxirane ring, followed by transfer of this radical to diethyl phosphite, which in turn reacts with nitrile (Scheme 1010).). The reaction carried out withoutwithout epoxide,epoxide, under microwave stimulation, also results in the desired bisphosphonates,bisphosphonates, althoughalthough itit isis accompaniedaccompanied byby formationformation ofof manymany sideside products.products.

O Zn O Cp2TiCl2 Zn Cp2TiCl2 Cp2TiCl2 Cp2TiCl2 O(Cl)TiCp2 O(Cl)TiCp2

H Cl H Cl HP(O)(OEt) Cp2TiCl2 = Ti HP(O)(OEt)2 Cp2TiCl2 = Ti 2 Cl Cl O(Cl)TiCp2 O(Cl)TiCp2

O (EtO)2(O)P P(O)(OEt)2 RCN O (EtO)2(O)P P(O)(OEt)2 RCN P OEt P OEt R NH2 OEt R NH2 OEt 17 17 Ph Ph R = alkyl, cycloalkyl, halogenoalkyl, aryl, HOOC-CH2-,CH3-CH2CH2-, N R = alkyl, cycloalkyl, halogenoalkyl, aryl, HOOC-CH2-,CH3-CH2CH2-, Ph N Ph Scheme 10. Radical procedure for the synthesis of bisphosphonates from nitriles. Scheme 10. Radical procedure for the synthesis of bisphosphonates from nitriles. 2.4. Synthesis from Isonitriles 2.4. Synthesis from Isonitriles Isonitriles, which are quite common substrates, especially in multicomponent reactions [51], have Isonitriles, which are quite common substrates, es especiallypecially in multicomponent reactions [[51],51], have been seldom used for the preparation of aminobisphosphonates 18. Their reactions with H-phosphine been seldom used for the preparationpreparation of aminobisphosphonates 18. Their reactions with H-phosphine oxides carried out in the presence of typical palladium catalysts (Pd2dba3) afforded the product 19 oxides carried out out in in the the presence presence of of typical typical palladium palladium catalysts catalysts (Pd (Pd2dbadba3) afforded) afforded the the product product 19 of monophosphonylation, whereas the use of various rhodium catalysts2 3 afforded products of 19of ofmonophosphonylation, monophosphonylation, whereas whereas the the use use of of va variousrious rhodium rhodium catalysts catalysts afforded afforded products products of diphosphonylation (Scheme 11) [52]. diphosphonylation (Scheme 1111))[ [52].52]. Far simpler is the addition of diethyl phosphite to isonitriles. This reactionO is carried out with 1 O H O O R1 H an excess of hydrogen1 O chloride in aprotic solvents. UnderO 1 theseRh cat. conditions,R P nitrileN is converted to R1 Pd cat. R1 Rh cat. 2P N R R P N Pd cat. RNC + HPR R2 R 2P N R RNC + HP2 R an onium salt, andR2 after additionR of the ﬁrst phosphiteR molecule,2 iminium saltP is formed, a substrate R R O P R1 19 O 2R1 for the addition of a second19 phosphite molecule (Scheme 12)[53]. Using this procedure,R2 two distinct 18 libraries of bisphosphonates 20 and 21 haveEt been prepared [54–56]. 18 R = , , Et , R = , , N , Et 1 R1 = CH3, t-butyl, cyclohexyl, aryl R2 = CH3, t-butyl, cyclohexyl, aryl R2 = CH3, t-butyl, cyclohexyl, aryl R = CH3, t-butyl, cyclohexyl, aryl Scheme 11. Addition of H-phosphine oxides to isonitriles catalyzed by metallocatalysts.

Molecules 2016, 21, 1474 6 of 25 there is limited literature on their use for that purpose. The most popular route is the reaction of nitriles with phosphorous acid, in some cases prompted by phosphorus trichloride and phenylsulphonic or methylsulphonic acids [12,31,47,48]. The conditions of this reaction are sufficiently delicate to use peptidyl nitriles as substrates, which was demonstrated using cyanoethyl derivatives of dipeptides (for example, peptide 16, Scheme 9) [49].

PO3H2 H H2N H NC N COOH PCl /H PO N COOH N 3 3 3 H O P N H 2 3 H O S O S 16 Scheme 9. Representative example of the synthesis of peptidylbisphosphonates from nitriles.

Recently, elegant, mild, and atom economical double phosphonylation of nitriles in the presence of titanocene has been described. This procedure used induced phosphorus-centered radicals mediated by titanocene dichloride (Cp2TiCl2) (Scheme 10) and provided a wide structural variety of aminobisphosphonates 17 [50]. This is a double radical transfer reaction initiated by the reaction of titanocene with zinc dust and the transfer of the obtained radical to epoxypropane by cleavage of its oxirane ring, followed by transfer of this radical to diethyl phosphite, which in turn reacts with nitrile (Scheme 10). The reaction carried out without epoxide, under microwave stimulation, also results in the desired bisphosphonates, although it is accompanied by formation of many side products.

Zn O Cp2TiCl2 Cp2TiCl2 O(Cl)TiCp2

H Cl HP(O)(OEt) Cp2TiCl2 = Ti 2 Cl O(Cl)TiCp2

O (EtO) (O)P P(O)(OEt) RCN 2 2 P OEt R NH2 OEt 17 Ph R = alkyl, cycloalkyl, halogenoalkyl, aryl, HOOC-CH2-,CH3-CH2CH2-, N Ph Scheme 10. Radical procedure for the synthesis of bisphosphonates from nitriles.

2.4. Synthesis from Isonitriles Isonitriles, which are quite common substrates, especially in multicomponent reactions [51], have been seldom used for the preparation of aminobisphosphonates 18. Their reactions with H-phosphine oxides carried out in the presence of typical palladium catalysts (Pd2dba3) afforded the product 19

Moleculesof monophosphonylation,2016, 21, 1474 whereas the use of various rhodium catalysts afforded products7 of of 26 diphosphonylation (Scheme 11) [52].

O O O R1 H 1 Pd cat. R1 Rh cat. P N R P N RNC + HP R2 R 2 R 2 R R P O R1 Molecules 2016, 21, 1474 19 R2 7 of 25 18 Et Far simpler is theR = addition, of diethyl, Nphosphite, to isonitriles. This reaction is carried out with an Et excess of hydrogen chloride1 in aprotic solvents. Under these conditions, nitrile is converted to an R = CH3, t-butyl, cyclohexyl, aryl onium salt, and after2 addition of the first phosphite molecule, iminium salt is formed, a substrate for R = CH3, t-butyl, cyclohexyl, aryl the addition of a second phosphite molecule (Scheme 12) [53]. Using this procedure, two distinct libraries ofScheme bisphosphonates 11. Addition 20 of and H-phosphine 21 have been oxides prepared to isonitriles [54–56]. catalyzed by metallocatalysts.

R R N N HCl P(OEt)3 OEt RNC RNC H OEt H P H P OEt Cl OEt O OEt Cl R = alkyl, Ph(CH2)n- HCl n = 0-3

R NH R H Cl P(OEt)3 N OEt (EtO)2(O)P P(O)(OEt)2 H P OEt 20 O

R HCl/P(OEt) C=N N=C 3 (EtO)2(O)P HN NH P(O)(OEt)2 (EtO)2(O)P 21

X = n n , , , R1 R1

, , n n , -(CH2)m-

n =0, 1 m = 6 X= -CH2-, -CH2CH2-, O, S, SO2 1 R = H, OCH3

Scheme 12. Addition of phosphites to isonitriles.

2.5. Synthesis via Ketophosphonates Presumably, the addition of phosphites to ketophosphonates was the first procedure for Presumably, the addition of phosphites to ketophosphonates was the first procedure for preparation of dialkyl 1-hydroxy-1,1-bisphosphonates [16,19,57]. Starting ketophosphonates are preparation of dialkyl 1-hydroxy-1,1-bisphosphonates [16,19,57]. Starting ketophosphonates are obtained by the Arbuzov reaction of acyl chlorides with trialkyl phosphites and used as substrates in the obtained by the Arbuzov reaction of acyl chlorides with trialkyl phosphites and used as substrates in the next step, namely, the addition of dialkyl phosphite to carbonyl double bonds (a representative example next step, namely, the addition of dialkyl phosphite to carbonyl double bonds (a representative example for preparation of tetramethyl pamidronate 22 is shown in Scheme 13). Since ketophosphonates are for preparation of tetramethyl pamidronate 22 is shown in Scheme 13). Since ketophosphonates unstable species [58], the desired bisphosphonates are usually obtained via one-pot procedures are unstable species [58], the desired bisphosphonates are usually obtained via one-pot procedures applying mixtures of trialkyl- and dialkylphosphonates at elevated temperature [59]. Additionally, in applying mixtures of trialkyl- and dialkylphosphonates at elevated temperature [59]. Additionally, in situ generation of dialkyl- from trialkyl phosphites is possible by the addition of a protic solvent to the situ generation of dialkyl- from trialkyl phosphites is possible by the addition of a protic solvent to reaction mixture. A useful modification of this procedure is the application of tris(trimethylsilyl) the reaction mixture. A useful modification of this procedure is the application of tris(trimethylsilyl) phosphite, followed by the easy removal of ester groups by methanolysis [23,60,61]. This was used to phosphite, followed by the easy removal of ester groups by methanolysis [23,60,61]. This was used prepare a wide variety of 1-hydroxy-1,1-bisphosphonates containing amino groups [19,23,61–63]. to prepare a wide variety of 1-hydroxy-1,1-bisphosphonates containing amino groups [19,23,61–63]. Additionally, the use of bis((trimethylsilyl)oxy)phosphine generated from ammonium hypophosphite Additionally, the use of bis((trimethylsilyl)oxy)phosphine generated from ammonium hypophosphite was applied to prepare hydroxybisphosphinic acids (also presented in Scheme 13) [64]. Another was applied to prepare hydroxybisphosphinic acids (also presented in Scheme 13)[64]. Another modification was the use of acyl phosphonamidates readily prepared from phosphoramidite type modification was the use of acyl phosphonamidates readily prepared from phosphoramidite type reagents and a range of acid chlorides, followed by reaction with trimethyl phosphite in the presence of pyridinium perchlorate [65].

Molecules 2016, 21, 1474 8 of 26 reagents and a range of acid chlorides, followed by reaction with trimethyl phosphite in the presence ofMolecules pyridinium 2016, 21, perchlorate1474 [65]. 8 of 25 Molecules 2016, 21, 1474 8 of 25

O HO O P(O)(OMe) O P(OMe) O HP(O)(OMe) HO 2 3 2 P(O)(OMe)2 P(OMe)3 H N P(O)(OMe) HP(O)(OMe)2 H2N H2N Cl 2 2 P(O)(OMe) H2N P(O)(OMe)2 H2N 2 H2N Cl P(O)(OMe)2 22 O 22 O N Cl NH Cl H HO or 1./ P(OSiMe3)3 P(O)(OH) or 1./ P(OSiMe ) HO 2 O 3 3 P(O)(OH)2 O N 2./ MeOH NH P(O)(OH)2 B 2./ MeOH P(O)(OH) N O B H 23 2 NH O 23 H Scheme 13. Representative syntheses via ketophosphonates. Scheme 13. Representative syntheses via ketophosphonates. Recently, a one-pot synthesis was described reacting carboxylic acids with catecholborane, followed Recently, a aone-pot one-pot synthesis synthesis was was described described reacting reacting carboxylic carboxylic acids with acids catecholborane, with catecholborane, followed by the treatment of the formed acyloxy-benzodioxaborolane with tris(trimethylsilyl)phosphite byfollowed the treatment by the treatment of the of formed the formed acyloxy-benzodio acyloxy-benzodioxaborolanexaborolane with with tris(trimethylsilyl)phosphite tris(trimethylsilyl)phosphite (Scheme 13) [66]. The efficiency of that simple methodology was proved by the syntheses of alendronate (Scheme 1313))[ [66].66]. The The efficiency efficiency of of that simple meth methodologyodology was proved by the syntheses of alendronate and N-methyl pamidronate (compound 23) without additional steps for the protection/deprotection and N-methyl pamidronate (compound 23)) withoutwithout additionaladditional stepssteps forfor thethe protection/deprotectionprotection/deprotection of their amine functions. of their amine functions. 2.6. Three-Component Condensation of Amines with Triethyl Orthoformate and Diethylphosphite 2.6. Three-Component Condensation of Amines with Triethyl OrthoformateOrthoformate andand DiethylphosphiteDiethylphosphite Simple three-component condensation of stoichiometric ratios of amines, diethyl phosphite Simple three-component condensation of stoichiometricstoichiometric ratios of amines, diethyl phosphite and triethyl orthoformate, first reported in patent literature by Suzuki [67] and further extended by and triethyl triethyl orthoformate, orthoformate, first first reported reported in in patent patent literature literature by by Suzuki Suzuki [67] [67 and] and further further extended extended by Maier [68], is perhaps the most common procedure for the preparation of a wide variety of Maierby Maier [68], [68 is], perhaps is perhaps the the most most common common procedur proceduree for for the the preparation preparation of of a a wide wide variety of aminomethylenebisphosphonic acids (Scheme 14). Since this reaction usually gives a complex mixture aminomethylenebisphosphonic acids (Scheme 1414).). Sinc Sincee this reaction usually gives a complex mixture of products [56] that are difficult to separate, the resulting esters are not isolated but rather, the crude of products [56] [56] that are difficult difficult to separate, the resulting esters are not isolated isolated but rather, rather, the crude reaction mixtures are hydrolyzed, yielding bisphosphonic acids that are isolated after the hydrolytic reaction mixtures are hydrolyzed, yielding bisphosphonicbisphosphonic acids that are isolated after the hydrolytic step. Some modifications of this classic procedure have also been reported. They include the use of a step. Some modifications modifications of this classic procedure havehave also been reported. They include the use of a solvent-free, microwave-assisted reaction [69–71] and reactions catalyzed by titanium dioxide [72] and solvent-free, microwave-assisted reactionreaction [[69–71]69–71] and reactions catalyze catalyzedd by titanium dioxide [72] [72] and by crown ethers (increasing the selectivity of the process by 10%–20%) [73]. Additionally, a reaction by crown ethers (increasing the selectivity of the process by 10%–20%) [[73].73]. Additionally, a reaction carried out in a micellar environment was described [74]. carried out in a micellar environment was described [[74].74].

1./ PO3H2 1./ PO3H2 R NH2 + H-C(OEt)3 + HP(O)(OEt)2 R R NH2 + H-C(OEt)3 + HP(O)(OEt)2 2./ HCl/H2O R N PO3H2 2./ HCl/H2O NH PO3H2 H R = over 300 structurally variable substituents R = over 300 structurally variable substituents Scheme 14. Condensation of amines with triethyl orthoformate and diethyl phosphite. Scheme 14. Condensation of amines with triethyl orthoformate and diethyl phosphite. The three-component reaction was applied to synthesize a large series of physiologically active The three-component reaction was applied to synthesize a large series of physiologically active compounds,The three-component in some cases reactionof very complex was applied chemical to synthesize structures, a large including series bone of physiologically antiresorptive active drug compounds, in some cases of very complex chemical structures, including bone antiresorptive drug compounds,candidates [75–82]; in some bone cases imaging of very [83,84], complex antiprotozoal chemical structures, [85–88], antibacterial including bone [72,89–92], antiresorptive anti-HIV drug [93] candidates [75–82]; bone imaging [83,84], antiprotozoal [85–88], antibacterial [72,89–92], anti-HIV [93] candidatesand anti-inflammatory [75–82]; bone [94] imaging agents; [ 83herbicides,84], antiprotozoal [95–97]; and [85 –complex88], antibacterial ones for various [72,89–92 metals], anti-HIV [10,98]. [93 ] and anti-inflammatory [94] agents; herbicides [95–97]; and complex ones for various metals [10,98]. and anti-inﬂammatoryIn some cases, this [reaction94] agents; appears herbicides to be [quit95–97e capricious]; and complex and affords ones for unexpected various metals side-products [10,98]. In some cases, this reaction appears to be quite capricious and affords unexpected side-products alongIn with some the cases, expected this reactionaminomet appearshylenebisphosphonates to be quite capricious (see represen and affordstative unexpected examples in side-products Scheme 15), along with the expected aminomethylenebisphosphonates (see representative examples in Scheme 15), alongthe compositions with the expected of which aminomethylenebisphosphonates are dependent on the applied (see conditions representative (molar examples ratio inof Schemesubstrates, 15), the compositions of which are dependent on the applied conditions (molar ratio of substrates, thetemperature compositions and reaction of which time). are dependent Most often, on alkylation the applied (for conditions example, compounds (molar ratio 24 of and substrates, 25) or temperature and reaction time). Most often, alkylation (for example, compounds 24 and 25) or temperatureformylation (compound and reaction 26) time).of amine Most moieties often, is alkylationobserved [71,99], (for example, while in selected compounds cases24 theand formation25) or formylation (compound 26) of amine moieties is observed [71,99], while in selected cases the formation formylationof aminomethylenebisphosphonic (compound 26) of amine acid moieties (compound is observed 27) [is71 ,observed.99], while inBecause selected this cases compound the formation was of aminomethylenebisphosphonic acid (compound 27) is observed. Because this compound was ofpreviously aminomethylenebisphosphonic prepared by acid hydrolysis acid of (compound N-benzhydrylaminomethylenebis27) is observed. Becausephosphonic this compound acid [83,100], was previously prepared by acid hydrolysis of N-benzhydrylaminomethylenebisphosphonic acid [83,100], previouslyit may be that prepared it is formed by acid upon hydrolysis hydrolysis of N of-benzhydrylaminomethylenebisphosphonic N-aryl derivatives. acid [83,100], it may be that it is formed upon hydrolysis of N-aryl derivatives. it may be that it is formed upon hydrolysis of N-aryl derivatives.

Molecules 2016, 21, 1474 9 of 26 Molecules 2016, 21, 1474 9 of 25

Molecules 2016, 21, 1474 H H 9 of 25 N PO3H NH2 N PO3H HC(OEt)3 H H N PO3H2 N N PO3H2 N PO3H NH2HP(O)(OEt)2 N PO3H HC(OEt)3 N PO H N N PO3H2 24 3 2 HP(O)(OEt)2 24 P(O)(OEt)2 P(O)(OEt)2 P(O)(OEt)2 HC(OEt)3 + + NH2 NP(O)(OEt)P(O)(OEt)2 2 HP(O)(OEt)2 N P(O)(OEt)P(O)(OEt)2 2 N P(O)(OEt)P(O)(OEt)2 2 HC(OEt)3 H + + NH2 ON HP(O)(OEt)2 HP(O)(OEt)2 N P(O)(OEt)2 N P(O)(OEt)2 H 25 26 O H 25 26 PO H 3 2 PO H + 3 2 NH HC(OEt)3 PO3H2 2 N PO3H2 PO3H2 H + H2N PO3H2 NH HP(O)(OEt)HC(OEt)3 2 2 N PO3H2 27 H H2N PO3H2 HP(O)(OEt)2 27 Scheme 15.15. Representative side side products of the three-componentthree-component procedure for the synthesis of Scheme 15. Representative side products of the three-component procedure for the synthesis of aminomethylenebisphosphonicaminomethylenebisphosphonic acids.acids. aminomethylenebisphosphonic acids.

31 The mechanism of this useful reaction had been thoroughly studied by using 31P-NMR and by The mechanism of this useful reaction had been thoroughly studied by using31 P-NMR and by isolationThe of mechanismall intermediates of this [71,72,99]useful reaction and identi had beenfying thoroughly interrelations studied between by using them P-NMR(Scheme and 16) by [99]. isolationisolation of of all all intermediates intermediates [ 71[71,72,99],72,99] andand identifyingidentifying interrelations interrelations between between them them (Scheme (Scheme 16) 16 [99].)[99 ]. The mechanism appeared to be quite complex because the intermediates exist in thermodynamic TheThe mechanism mechanism appeared appeared to to be be quite quite complexcomplex becausebecause the intermediates intermediates exist exist in in thermodynamic thermodynamic equilibrium. Thus, its course is strongly dependent on the properties of the used amine and applied equilibrium.equilibrium. Thus, Thus, its its course course is is strongly strongly dependentdependent on the the properties properties of of the the used used amine amine and and applied applied reaction conditions. reactionreaction conditions. conditions.

OEt H NH2 HC OEt HN OEt R NH2 HC OEt R N OEt R OEt - EtOH R EtOEtO - EtOH OEtOEt

R-NH R-NH22 -- 22 EtOHEtOH -- EtOH EtOH

HH NN HH RR NN NN H RR RR EtOEtO P EtO P OEt O

H H H N P(O)(OEt)2 R-NH2 NH P(O)(OEt)2 RN P(O)(OEt)2 R-NH R N P(O)(OEt) R 2 R 2 HN OEt HN R OEt R

-R-NH - EtOH 2 - EtOH -R-NH2

N P(O)(OEt)2 R N P(O)(OEt) R 2 H EtO PH OEt EtO OP OEt R = NO2 O

R = NO2

H N P(O)(OEt)2 R H N P(O)(OEt) R P(O)(OEt)2 2 P(O)(OEt) Scheme 16. Mechanism of the three-component reaction of2 amines with orthoformates and phosphites. Scheme 16. Mechanism of the three-component reaction of amines with orthoformates and phosphites. Scheme 16. Mechanism of the three-component reaction of amines with orthoformates and phosphites.

Molecules 2016, 21, 1474 10 of 26

Molecules 2016, 21, 1474 10 of 25

MoleculesModification 2016, 21, 1474 of this procedure and the use of ethyl diethoxymethyl-H-phosphinate10 insteadof 25 of diethylModification phosphite of allowed this procedure obtaining and structurally the use of ethyl variable diethoxymethyl- bisphosphinatesH-phosphinate28 (Scheme instead 17)[ of101 ]. diethyl phosphite allowed obtaining structurally variable bisphosphinates 28 (Scheme 17) [101]. Better Better resultsModification were obtained of this procedure if the reaction and the was use carried of ethyl out diethoxymethyl- under nitrogenH (air-phosphinate oxidizes substrates instead of and results were obtained if the reaction was carried out under nitrogen (air oxidizes substrates and products).diethyl phosphite Notably, aromaticallowed obtaining amines providedstructurally the variable desired bisphosphinates bisphosphinates 28 (Scheme in high yields17) [101]. (78%–92%), Better products). Notably, aromatic amines provided the desired bisphosphinates in high yields (78%–92%), whereasresults the were reaction obtained yields if the when reaction using was cyclic carried and aliphaticout under derivatives nitrogen (air were oxidizes lower. substrates Interestingly, and of whereasproducts). the Notably, reaction aromatic yields when amines using provided cyclic theand desired aliphatic bisphosphinates derivatives were in highlower. yields Interestingly, (78%–92%), of many methods for the synthesis of corresponding acids 29, acidolysis of the obtained esters 28 appeared manywhereas methods the reaction for the yieldssynthe whensis of correspondingusing cyclic and acids aliphatic 29, acidolysis derivatives of the were obtained lower. esters Interestingly, 28 appeared of to be optimal. The use of other conditions, including mild transesterification with trimethylsilyl tomany be methodsoptimal. forThe the use synthe of othersis of conditions,corresponding including acids 29 ,mild acidolysis transesterification of the obtained with esters trimethylsilyl 28 appeared bromide followed by methanolysis, resulted in the formation of side products 30 and 31. bromideto be optimal. followed The by use methanolysis, of other conditions, resulted in including the formation mild oftransesterification side products 30 withand 31 trimethylsilyl. bromide followed by methanolysis, resulted in the formation of side products 30 and 31. R1 R2 OEt H OEt N OEt N + HC(OEt) + H R1 R2 R1 R2 3 EtO OEtP H OEt EtO OEtP N P OEtOEt O H 1 N 2 + HC(OEt)3 + EtO O O OEt R R EtO P EtO P P OEt OEt 28 O EtO O O OEt 1./ Me3SiBr/CH2Cl2/N2 2./ aq. NH3 28 HBr/CH3COOH/rt 1./ Me3SiBr/CH2Cl2/N2 2./ aq. NH3 H HBr/CH3COOH/rt R1 H 1 R O N H R1 R2 N H R1 H + 1 + H N P N H H H R OH 2 P N P P P R1 R2 N O OHH H H HO O O OH + + P N P H H HOH O O OHH H2N P P P P P HOH O O OHH 29 30 31O OH HO O O OH HO O O OH P 29P HO O O OH 31 1 29 30 R = aryl, cycloalyk, alkyl 29 R2 = H, i-Pr R1 = aryl, cycloalyk, alkyl R2 = H, i-Pr SchemeScheme 17. 17.Three-component Three-component synthesis of of aminobisphosphonates. aminobisphosphonates. Scheme 17. Three-component synthesis of aminobisphosphonates. 2.7. Addition of Amines to Vinylidenebisphosphonates 2.7. Addition of Amines to Vinylidenebisphosphonates 2.7. AdditionTetraethyl of Amines vinylidenebisphosphonate to Vinylidenebisphosphonates 32 is a versatile synthon useful for preparation of a wide Tetraethyl vinylidenebisphosphonate 32 is a versatile synthon useful for preparation of a wide varietyTetraethyl of bisphosphonates. vinylidenebisphosphonate Its usefulness is32 ais subj a versatileect of recent synthon comprehensive useful for preparation review [102]. of a As wide an variety of bisphosphonates. Its usefulness is a subject of recent comprehensive review [102]. As an electron-deficientvariety of bisphosphonates. alkene, it canIts usefulnessundergo conjugate is a subject addition of recent of strongcomprehensive and mild review nucleophiles, [102]. As with an electron-deficient alkene, it can undergo conjugate addition of strong and mild nucleophiles, with amineselectron-deficient belonging alkene,to the latter it can class. undergo Primary conjugate amines additionundergo ofsmooth strong Michael and mild addition nucleophiles, (Scheme with 18), amines belonging to the latter class. Primary amines undergo smooth Michael addition (Scheme 18), however,amines belonging the obtained to the compounds latter class. 33Primary must beamines quickly undergo purified smooth and hydrolyzedMichael addition since (Schemethey tend 18), to however,undergohowever, the a the retro-Michael obtained obtained compounds compounds reaction [103,104].33 33must must Fortunately, bebe quicklyquickly purifiedfree purified acids and and34 arehydrolyzed hydrolyzed substantially since since more they they stable. tend tend to to undergo a retro-Michael reaction [103,104]. Fortunately, free acids 34 are substantially more stable. undergo a retro-Michael reaction [103,104]. Fortunately, free acids 341./ MeareSiBr substantially more stable. (EtO)2(O)P P(O)(OEt)2 RNH2/CH2Cl2 (EtO)2(O)P P(O)(OEt)2 3 H2O3P PO3H2 r.t. 2./ MeOH (EtO) (O)P P(O)(OEt) RNH /CH Cl (EtO) (O)P P(O)(OEt)R 1./ Me3SiBr H O P PORH 2 2 2 2 2 2 N 2 2 3 N 3 2 32 r.t. H 2./ MeOH H R R 33N 34N 32 H H R = alkyl, cyckloalkyl, heterocycloalkyl, benzyl 33 34 R = alkyl, cyckloalkyl,Scheme heterocycloalkyl, 18. Michael addition benzyl of amines to vinylidenebisphosphonate. Scheme 18. Michael addition of amines to vinylidenebisphosphonate. The reactivityScheme of vinylidenebisphosphonates 18. Michael addition of amines has been to vinylidenebisphosphonate. used for the synthesis of derivatives of variousThe analogues reactivity ofof fluoroquinolvinylidenebisphosphonatesone antibacterial has agents been [105,106], used for heteroaromaticsthe synthesis of withderivatives potential of pharmaceuticalvariousThe reactivity analogues applications of of vinylidenebisphosphonates fluoroquinol [107,108],one simple antibacterial antiplasmodial hasagents been agents[105,106], used [103,104], forheteroaromatics the HIV synthesis reverse with transcriptase of potential derivatives of variousinhibitorspharmaceuticalanalogues [59,93], applications potential of fluoroquinolone [107,108],anti-osteoporotic simple antipl antibacterial agentsasmodial [109,110], agents agents and [103,104], N [105-alkylated,106 HIV], heteroaromaticsreverseantitumor transcriptase pyridines with potential[111].inhibitors Some pharmaceutical [59,93], representatives potential applications of anti-o thesesteoporotic compounds [107,108 agents], (35 simple–39 )[109,110], are antiplasmodial shown and in Scheme N-alkylated agents 19. [antitumor103,104], HIVpyridines reverse transcriptase[111].Another Some inhibitors representatives example, [59 ,albeit93 of], these potential far compoundsless anti-osteoporoticdeveloped, (35–39 )is are the shown agents addition in [109 Scheme ,110of organometallic], 19. and N-alkylated amines antitumor to pyridinesvinylidenebisphosphonateAnother [111]. Someexample, representatives albeit 22 (Scheme far lessof 20) thesedeveloped, [112]. compounds Huisgen is thecopper-catalyzed (35addition–39) are of shown 1,3-dipolarorganometallic in Scheme cycloaddition amines 19. ofto this bisphosphonate to azides was used to obtain substrate 40 for a “click reaction”. This reaction vinylidenebisphosphonateAnother example, albeit 22 (Scheme far less 20) developed, [112]. Huisgen is copper-catalyzed the addition of 1,3-dipolar organometallic cycloaddition amines of to yielded compounds that may be considered aza-analogues 41 of zoledronate (Scheme 20) [113]. vinylidenebisphosphonatethis bisphosphonate to azides22 (Scheme was used 20)[ to112 obtain]. Huisgen substrate copper-catalyzed 40 for a “click reaction”. 1,3-dipolar This cycloaddition reaction Similar substrates could also be obtained by addition of propargylamine to the double bond of of thisyielded bisphosphonate compounds that to azides may be was considered used to obtain aza-analogues substrate 4140 offor zoledronate a “click reaction”. (Scheme This20) [113]. reaction vinylidenebisphosphonate [114]. yieldedSimilar compounds substrates could that may also bebe consideredobtained by aza-analoguesaddition of propargylamine41 of zoledronate to the (Schemedouble bond 20)[ of113 ]. vinylidenebisphosphonate [114]. Similar substrates could also be obtained by addition of propargylamine to the double bond of vinylidenebisphosphonate [114].

Molecules 2016, 21, 1474 11 of 26 Molecules 2016, 21, 1474 11 of 25 Molecules 2016, 21, 1474 11 of 25 Molecules 2016, 21, 1474 O 11 of 25 HOOC F O O PO3H2 HOOC F H HOOC N FN PO3H2 N POPO3H23H2 N H PO3H2 PO H HN N N PO3H23 2 N N N PO3H2 36, antiprotozoal agentPO3H2 N PO3H2 N PO3H2 35, analog of CiprofloxacinPO3H2 36, antiprotozoal agent 36, antiprotozoal agent 35, analog of Ciprofloxacin PO H 35, analog of Ciprofloxacin H 3 2 H2N N N N POPOH 3H2 H H H PO3H2 H 3 2 H2N N H2N N N N PO3H2 37, potential antiosteoporoticNH NH agentPO3H2 H H 37, potential antiosteoporotic agent 37, potential antiosteoporotic agent PO3H2 PO3H HN

N POPO3H23H2 POPO3H 3H2 HN N PO3H2 PO3H HN N PO3H2 F N PO3H2 S N N N PO3H2 PO3H2 N F 38, anticancer agent 39, inhibitorS N of HIVN reverse transcriptase F S N N 38, anticancer agent 39, inhibitor of HIV reverse transcriptase 38, anticancer agent 39, inhibitor of HIV reverse transcriptase Scheme 19.19. RepresentativesRepresentatives of of useful useful bisphosphonates bisphosphonates obtained obtained via via addition addition of amines to vinylidenebisphosphonate. vinylidenebisphosphonate.Scheme 19. Representatives of useful bisphosphonates obtained via addition of amines to vinylidenebisphosphonate. (EtO)2(O)P P(O)(OEt)2 (EtO)2(O)P P(O)(OEt)2 + H2N HN (EtO) (O)P P(O)(OEt) (EtO)2(O)P P(O)(OEt)2 (EtO)2(O)P P(O)(OEt)2 + H2N (EtO)2(O)P P(O)(OEt)2 2 222 + H2N 40 HN HN 22 40 22 40 N3

N3 N3

(EtO)2(O)P P(O)(OEt)2

(EtO)2(O)PHN P(O)(OEt)2 (EtO)2(O)P P(O)(OEt)2 HN HNN N N N N N41N N N 41 Scheme 20. An example of the synthesis of novel bisphosphonates41 via “click chemistry”. Scheme 20. An example of the synthesis of novel bisphosphonates via “click chemistry”. 2.8. Miscellaneous Procedures 2.8. Miscellaneous The desire to Procedures obtain new aminobisphosphonate scaffolds for biological studies has stimulated numerous studies on general methods of their synthesis. The methods discussed here are mostly The desire to obtain newnew aminobisphosphonateaminobisphosphonate scaffolds for biological studies has stimulated designed to prepare specific scaffolds or are applicable only to specific, if not unusual, substrates. numerous studies on general methods of their synthesis.synthesis. The The methods discussed here are mostly Only some of them may be considered as novel, general procedures. designed to prepare specific speciﬁc scaffolds or are applic applicableable only to specific, speciﬁc, if not unusual, substrates. substrates. Radical addition of sodium hypophosphite to terminal alkynes in the presence of triethylborane, Only some of them may be considered as novel, generalgeneral procedures.procedures. which produced 1-alkyl-1,1-bis-H-phosphinates in moderate yields, gives access to a wide structural Radical addition of sodium hypophosphite to terminal alkynes in the presence of triethylborane, variety of bisphosphonates [115]. When using propargylamino acids, the corresponding bisphosphinates which produced produced 1-alkyl-1,1-bis- 1-alkyl-1,1-bis-H-phosphinatesH-phosphinates in moderate in moderate yields, yields, gives access gives to access a wide to structural a wide were obtained in satisfactory yields (a representative example is given in Scheme 21 for analogue 42 varietystructural of bisphosphonates variety of bisphosphonates [115]. When using [115]. propargylamino When using propargylamino acids, the corresponding acids, the bisphosphinates corresponding of pamidronate). Bisphosphinates are easily converted to bisphosphonates by ozonolysis. werebisphosphinates obtained in were satisfactory obtained yields in satisfactory (a representa yieldstive (a representativeexample is given example in Scheme is given 21 infor Scheme analogue 21 for42 of pamidronate). Bisphosphinates are easily converted to bisphosphonates by ozonolysis. ofanalogue pamidronate).42 of pamidronate). Bisphosphinate Bisphosphinatess are easily converted are easily to converted bisphosphonatesP(O)(OH)(ONa) to bisphosphonates by ozonolysis. by ozonolysis. NaH2PO2 H2N Et B H2N P(O)(OH)(ONa)P(O)(OH)(ONa) NaH32PO2 P(O)(OH)(ONa) H N NaH2PO2 H2N H N 42P(O)(OH)(ONa) 2 Et3B H2N P(O)(OH)(ONa) Et3B 2 42 Scheme 21. Procedure for the synthesis of bisphosphinates and42 their conversion into bisphosphonates. Scheme 21. Procedure for the synthesis of bisphosphinates and their conversion into bisphosphonates. Scheme1-(N-acylamino)alkylphosphonates, 21. Procedure for the synthesis of easily bisphosphinates accessible and from theirconversion N-acyl-α into-amino bisphosphonates. acids using a two-step transformation, underwent electrophilic activation at the α-carbon by electrochemical 1-(N-acylamino)alkylphosphonates, easily accessible from N-acyl-α-amino acids using a α-methoxylation1-(N-acylamino)alkylphosphonates, in methanol in a process easily mediated accessible by fromNaCl.N -acyl-Attemptsα-amino to carry acids out using a Michaelis- a two-step two-step transformation, underwent electrophilic activation at the α-carbon by electrochemical transformation,Arbuzov-like reaction underwent of the electrophilic obtained diethyl activation 1-(N at-acetylamino)-1-methoxy- the α-carbon by electrochemicalalkylphosphonatesα-methoxylation with α-methoxylation in methanol in a process mediated by NaCl. Attempts to carry out a Michaelis- triethyl phosphite failed; however, they readily reacted with triphenylphosphine (Scheme 22) [116]. Arbuzov-like reaction of the obtained diethyl 1-(N-acetylamino)-1-methoxy-alkylphosphonates with The resulting diethyl 1-(N-acetylamino)-1-triphenylphosphoniumalkylphosphonate tetrafluoroborates triethyl phosphite failed; however, they readily reacted with triphenylphosphine (Scheme 22) [116].

The resulting diethyl 1-(N-acetylamino)-1-triphenylphosphoniumalkylphosphonate tetrafluoroborates

Molecules 2016, 21, 1474 12 of 26 in methanol in a process mediated by NaCl. Attempts to carry out a Michaelis-Arbuzov-like reaction of the obtained diethyl 1-(N-acetylamino)-1-methoxy-alkylphosphonates with triethyl phosphite

Moleculesfailed; however,2016, 21, 1474 they readily reacted with triphenylphosphine (Scheme 22)[116]. The resulting12 of 25 diethylMolecules 1-2016(N, -acetylamino)-1-triphenylphosphoniumalkylphosphonate21, 1474 tetraﬂuoroborates 43 reacted12 of 25 43smoothly reacted smoothly with trialkyl with phosphites, trialkyl phosphites, dialkyl dialkyl phosphonites phosphonites or alkyl or alkyl phosphinites phosphinites in the in the presence presence of 43 reacted smoothly with trialkyl phosphites, dialkyl phosphonites or alkyl phosphinites in the presence ofHünig’s Hünig’s base base and and methyltriphenylphosphonium methyltriphenylphosphonium iodide iodide asas catalysts.catalysts. ThisThis gavegave bisphosphonatesbisphosphonates 44,44, of Hünig’s base and methyltriphenylphosphonium iodide as catalysts. This gave bisphosphonates 44, 1-phosphinylalkylphosphonates oror 1-phosphinoylalkylphosphonates 1-phosphinoylalkylphosphonates in in good good yields. yields. This This reaction reaction has 1-phosphinylalkylphosphonates or 1-phosphinoylalkylphosphonates in good yields. This reaction potentialhas potential to become to become a general a general procedure. procedure. has potential to become a general procedure.

O R O R O R PPh3/HBF4 O R 1./ MeOH O R PPh /HBF O R 1./ MeOH 3 4 H3C N COOH -2e/-CO2 H3C N OCH3 H3C N PPh3 H3C HN COOH -2e/-CO2 H3C HN OCH3 H3C HN PPh3 H H H BF4 43 BF4 43

P(OEt)3 P(OEt)3

O R PPh BF O O 3 4 PPh /HBF R OMe O R R PPh3 BF4 3 4 O R OMe MeOH/NaCl O R H C N P(O)(OEt) PPh3/HBF4 MeOH/NaCl 3 2 H3C N P(O)(OEt)2 H C N P(O)(OEt) H3C HN P(O)(OEt)2 H C HN P(O)(OEt) 3 2 H 3 2 H3C HN P(O)(OEt)2 H H P(O)R1R2R3 P(O)R1R2R3

R = H, CH O R P(O)R1R2 3 O 1 2 R1 = = H, OEt, CH Ph3 R P(O)R R +Ph3PR3BF4 1 R2 = OEt, Ph H C N P(O)(OEt) +Ph3PR3BF4 R = OEt, CH , Ph 3 2 2 3 H3C HN P(O)(OEt)2 R3 = CHOEt,, CHEt 3, Ph H 3 3 R = CH3, Et 44 44 Scheme 22.22. TransformationTransformation of of diethyl diethyl 1-( N1-(-acetylamino)-1-alkylphosphonatesN-acetylamino)-1-alkylphosphonates into into bisphosphoric bisphosphoric acid Scheme 22. Transformation of diethyl 1-(N-acetylamino)-1-alkylphosphonates into bisphosphoric acidesters esters via the via corresponding the corresponding phosphonium phosphonium salts. salts. acid esters via the corresponding phosphonium salts. Alkylation of tetraalkyl methylenebisphosphonate 45, a classical method for synthesizing variable Alkylation of tetraalkyl methylenebisphosphonate 45, a classical method for synthesizing variable bisphosphonic acids, has been rarely used for the synthesis of amino derivatives. Thus, its direct bisphosphonic acids, has been rarely used for thethe synthesissynthesis ofof aminoamino derivatives.derivatives. Thus, its direct amination with the hydroxylamine ester of diphenylphosphinic acid, followed by its bromoacetylation amination with the hydroxylamine esterester of diphenylphosphinic acid, followed by its bromoacetylation (Scheme 23), provided substrate 46 for functionalization into glycopeptide antibiotics, in the hope (Scheme 2323),), providedprovided substrate substrate46 46for for functionalization functionalization into into glycopeptide glycopeptide antibiotics, antibiotics, in the in hopethe hope that that they will find an application as medication for osteomyelitis [117]. Another classical example is theythat they will findwill find an application an application as medication as medication for osteomyelitis for osteomyelitis [117 ].[117]. Another Another classical classical example example is the is the monoalkylation of tetraisopropyl methylenebisphosphonate with 1,6-dibromohexane, followed by monoalkylationthe monoalkylation of tetraisopropylof tetraisopropyl methylenebisphosphonate methylenebisphosphonate with with 1,6-dibromohexane, 1,6-dibromohexane, followedfollowed by fluorination with Selectofluor and conversion of the remaining bromide into amine, which resulted in fluorinationfluorination with SelectofluorSelectofluor and conversion of the remaining brom bromideide into amine, which resulted in compound 47 (Scheme 23) [118]. compound 47 (Scheme 2323))[ [118].118].

O 1./ NaH/DMF O (EtO)2(O)P P(O)(OEt)2 (EtO)2(O)P P(O)(OEt)2 (EtO)2(O)P P(O)(OEt)2 Br 1./ NaH/DMF Br (EtO)2(O)P P(O)(OEt)2 (EtO)2(O)P P(O)(OEt)2 2./ Ph P(O)ONH (EtO)2(O)P P(O)(OEt)2 Br 45 2 2 Br HN 2./ Ph2P(O)ONH2 NH2 Br 45 NH HN 2 O Br 46O Br 46 Br Br Br O P(O)(Oi-Pr)2 P(O)(Oi-Pr)2 O Selectofluor P(O)(Oi-Pr)2 P(O)(Oi-Pr)2 F + NK Br P(O)(Oi-Pr) Selectofluor Br F + 2 Br P(O)(Oi-Pr)2 NK Br P(O)(Oi-Pr) P(O)(Oi-Pr) 2 2 O O

O P(O)(Oi-Pr)2 O P(O)(Oi-Pr) P(O)(OH)2 F 2 H2NNH2 P(O)(OH)2 N F F H2NNH2 N P(O)(Oi-Pr)2 H2N F P(O)(Oi-Pr) P(O)(OH)2 2 H2N 47 O P(O)(OH)2 47 O Scheme 23. Synthesis of aminobisphosphonates via alkylation of tetraalkyl methylenebisphosphonates. SchemeScheme 23. 23. SynthesisSynthesis of of aminobisphosphonates aminobisphosphonates via alkyl alkylationation ofof tetraalkyltetraalkyl methylenebisphosphonates.methylenebisphosphonates. An unusual procedure is metallacarbenoid insertion of aromatic amines into tetraethyl An unusual procedure is metallacarbenoid insertion of aromatic amines into tetraethyl diphosphonodiazomethane 48, which yields corresponding aminomethylenebisphosphonates 49 diphosphonodiazomethane 48, which yields corresponding aminomethylenebisphosphonates 49 (Scheme 24) [119]. Among the tested catalysts, Rh2(NHCOCF3)4 was found to be the best. (Scheme 24) [119]. Among the tested catalysts, Rh2(NHCOCF3)4 was found to be the best.

Molecules 2016, 21, 1474 13 of 26

An unusual procedure is metallacarbenoid insertion of aromatic amines into tetraethyl diphosphonodiazomethane 48, which yields corresponding aminomethylenebisphosphonates 49 (SchemeMolecules 2016 24)[, 21119, 1474]. Among the tested catalysts, Rh2(NHCOCF3)4 was found to be the best. 13 of 25 Molecules 2016, 21, 1474 13 of 25 Molecules 2016, 21, 1474 13 of 25 1 (EtO) (O)P P(O)(OEt) (EtO)2(O)P P(O)(OEt)2 R R Rh2(NHCOCF3)4 2 2 + 1 N (EtO) (O)P P(O)(OEt) (EtO)2(O)P P(O)(OEt)2 R R Rh2(NHCOCF3)4 2 2 + 1 H toluene/ (EtO) (O)P N P(O)(OEt) R N R Rh2(NHCOCF3)4 (EtO)2(O)P1 N P(O)(OEt)2 2 2 2 + H toluene/ R R N N 1 N 482 H toluene/ R 49 R N 1 N 482 R 49 R 48 49 R = H, CH3 1 R = = H, Ph, CH3 OCH3 , NO2 , R1 = H, CH3 R = Ph, OCH3 , NO , R1 = Ph, 2 OCH3 , NO2 , Scheme 24. N-H insertion of the reaction of aromatic amines. Scheme 24. N-H insertion of the reaction of aromatic amines. Scheme 24. N-H insertion of the reaction of aromatic amines. A specific and unexpected reaction was the addition of silylated dialkyl phosphites to A speciﬁcspecific and unexpected reaction was the additionaddition of silylated dialkyldialkyl phosphites to 4-phosphono-1-aza-1,3-dienesA specific and unexpected 50 , reactionwhich resultedwas the inad γdition-phosphono- of silylatedα–aminobisphosphonates dialkyl phosphites 51to 4-phosphono-1-aza-1,3-dienes 5050,, which which resulted in γγ-phosphono--phosphono-α–aminobisphosphonates 51 (Scheme4-phosphono-1-aza-1,3-dienes 25) [120]. This reaction is50 interesting, which resultedin that, depending in γ-phosphono- on the stericα–aminobisphosphonates demand of the substituent 51 (Scheme 2525))[ [120].120]. This This reacti reactionon is interesting in that, depending on the steric demand of thethe substituentsubstituent present(Scheme on 25) nitrogen, [120]. This double reacti 1,2-additionon is interesting or tandem in that, 1,4-1,2-additiondepending on the with steric form demandation of of bisphosphonate the substituent present on nitrogen, double 1,2-addition or tandem 1,4-1,2-addition with form formationation of bisphosphonate present52occurred on nitrogen, (Scheme double25). 1,2-addition or tandem 1,4-1,2-addition with formation of bisphosphonate 52occurredoccurred (Scheme (Scheme 25).25). 52occurred (Scheme 25).

N HN (EtO) P(O)SiMe N 2 3 HN (EtO) P(O)SiMe (EtO) (O)P HN P(O)(OEt)2 (EtO)2(O)P N H 2 3 2 P(O)(OEt) (EtO)2P(O)SiMe3 (EtO) (O)P P(O)(OEt)2 2 (EtO)2(O)P H 2 50 (EtO) (O)P 51 P(O)(OEt)P(O)(OEt)2 2 (EtO)2(O)P H 2 50 51 P(O)(OEt)2 50 51

N (EtO)2(O)P N (EtO)2P(O)SiMe3 N (EtO)2(O)P N (EtO) P(O)SiMe (EtO) (O)P P(O)(OEt) (EtO) (O)P H 2 3 (EtO)2 2(O)P N 2 2 N (EtO) P(O)SiMe 2 3 (EtO)2(O)P P(O)(OEt)2 (EtO)2(O)P 50 H 52 (EtO) (O)P H (EtO)2(O)P P(O)(OEt)2 2 50 52 Scheme 25. Addition50 of phosphites to 4-phosphono-1-aza-1,3-dienes.52 Scheme 25. Addition of phosphites to 4-phosphono-1-aza-1,3-dienes. Scheme 25. Addition of phosphites to 4-phosphono-1-aza-1,3-dienes. Additionally, the addition of phosphites to iminophosphonate esters has been studied. This Additionally, the addition of phosphites to iminophosphonate esters has been studied. This reactionAdditionally, is limited tothe the specific addition addition substrates, of of ph phosphitesosphites and usually to toiminophosphonate iminophosphonatethe obtained bisphosphonates esters esters has been has 53 been studied.are unstable, studied. This reaction is limited to specific substrates, and usually the obtained bisphosphonates 53 are unstable, Thisandreaction phosphoryl reaction is limited is limited C-N to specifictransfer to speciﬁc substrates,to substrates,compounds and and usually54 usuallyis observed the the obtained obtained (Scheme bisphosphonates bisphosphonates 26), which may 5353 be areare considered unstable, unstable, and phosphoryl C-N transfer to compounds 54 is observed (Scheme 26), which may be considered andan example phosphorylphosphoryl of an C-NC-N aza-Perkov transfertransfer toreaction to compounds compounds [121–123].54 54is is observed observed (Scheme (Scheme 26 26),), which which may may be be considered considered an an example of an aza-Perkov reaction [121–123]. examplean example of anof aza-Perkovan aza-Perkov reaction reaction [121 [121–123].–123]. Cl

CCl CCl3 Cl P(O)(OEt) 3 Cl 2 HP(O)(OEt)2 (EtO)2(O)P Cl CCl3 SO Ar CCl3 SO2Ar P(O)(OEt)2 2 HP(O)(OEt) N Cl N (EtO)2(O)P CClN3 2 (EtO)(EtO)2(O)P(O)PCCl3 SO Ar P(O)(OEt)2 SO2Ar 2 H 2 (EtO)2Cl(O)P SO2Ar HP(O)(OEt)2 (EtO)2(O)P N N (EtO)2(O)P N SO Ar (EtO) (O)P SO2Ar 2 2 53 HN (EtO)2(O)P N SO2Ar (EtO)2(O)P N (EtO) (O)P 54 2 H (EtO)2(O)P SO2Ar Ar = Ph, 4-Me-C6H4 53 54 53 Ar = Ph, 4-Me-C6H4 54 Ar = Ph, 4-Me-CScheme6H4 26. Addition of phosphites to iminophosphonates. Scheme 26. Addition of phosphites to iminophosphonates. Scheme 26. Addition of phosphites to iminophosphonates. Finally, syntheses of rare aminomethyltrisphosphonates are presented in a recent review Finally, syntheses of rare aminomethyltrisphosphonates are presented in a recent review by RomanenkoFinally, syntheses and Kukhar of rare devoted aminomethyltrisphosphonates to applications of methylidynetrisphosphonates are presented in a recent [124]. review Two by RomanenkoFinally, syntheses and Kukhar of rare devoted aminomethyltrisphosphonates to applications of methylidynetrisphosphonates are presented in a recent [124]. review Two byprocedures Romanenko for theand synthesis Kukhar devotedof bis- and to applicationstrisphosphonates of methylidynetrisphosphonates 55 and 56 taken from this review[124]. Twoand proceduresby Romanenko for the and synthesis Kukhar of devotedbis- and totrisphosphonates applications of55 methylidynetrisphosphonatesand 56 taken from this review [ 124and]. proceduresdescribed in for patent the literaturesynthesis areof bis-depicted and trisphosphonatesin Scheme 27. 55 and 56 taken from this review and Twodescribed procedures in patent for literature the synthesis are depicted of bis- in and Scheme trisphosphonates 27. 55 and 56 taken from this review described in patent literature are depicted in Scheme 27. and described in patent literature are depicted in SchemeO 27. O Cl N P(OEt)3 O P(O)(OEt)2 O N Cl N P(OEt) 0 P(O)(OEt)2 Cl CH2Cl2/-403 C O N Cl (EtO) (O)PN P(O)(OEt)2 P(OEt)30 2 P(O)(OEt)2 O N Cl CH2Cl2/-40 C P(O)(OEt) Cl 0 (EtO)2(O)P55 2 Cl CH2Cl2/-40 C P(O)(OEt) Cl (EtO)2(O)P55 2 Cl 55

P(O)(OEt) Ar Cl Ar P(O)(OEt)2 HP(O)(OEt)2 Ar 2 P(OEt)3/ Ar N Cl Ar N P(O)(OEt)2 HP(O)(OEt) Ar N P(O)(OEt)P(O)(OEt)2 2 P(OEt) / 2 Ar Cl CH2Cl3 2 Ar P(O)(OEt) CH2Cl2/NaOH ArH P(O)(OEt)2 N Cl N P(O)(OEt)2 HP(O)(OEt)2 N P(O)(OEt)P(O)(OEt)2 2 P(OEt)3/ CH Cl /NaOH N Cl CH2Cl2 N P(O)(OEt) 2 2 H N P(O)(OEt)2 2 CH Cl /NaOH 56P(O)(OEt)2 Cl CH2Cl2 P(O)(OEt) 2 2 H 2 56P(O)(OEt)2 Scheme 27. Syntheses of aminomethyltrisphosphonates.56 Scheme 27. Syntheses of aminomethyltrisphosphonates. Scheme 27. Syntheses of aminomethyltrisphosphonates.

Molecules 2016, 21, 1474 13 of 25

1 (EtO) (O)P P(O)(OEt) R R Rh2(NHCOCF3)4 (EtO)2(O)P P(O)(OEt)2 2 2 + N H toluene/ N N2 R1 R 48 49

R = H, CH3 1 R = Ph, OCH , NO , 3 2 Scheme 24. N-H insertion of the reaction of aromatic amines.

A specific and unexpected reaction was the addition of silylated dialkyl phosphites to 4-phosphono-1-aza-1,3-dienes 50, which resulted in γ-phosphono-α–aminobisphosphonates 51 (Scheme 25) [120]. This reaction is interesting in that, depending on the steric demand of the substituent present on nitrogen, double 1,2-addition or tandem 1,4-1,2-addition with formation of bisphosphonate 52occurred (Scheme 25).

N HN (EtO)2P(O)SiMe3 (EtO) (O)P P(O)(OEt)2 (EtO)2(O)P H 2 P(O)(OEt)2 50 51

N (EtO)2(O)P N (EtO)2P(O)SiMe3 (EtO)2(O)P P(O)(OEt)2 (EtO)2(O)P H 50 52 Scheme 25. Addition of phosphites to 4-phosphono-1-aza-1,3-dienes.

Additionally, the addition of phosphites to iminophosphonate esters has been studied. This reaction is limited to specific substrates, and usually the obtained bisphosphonates 53 are unstable, and phosphoryl C-N transfer to compounds 54 is observed (Scheme 26), which may be considered an example of an aza-Perkov reaction [121–123].

CCl CCl3 P(O)(OEt) 3 Cl 2 HP(O)(OEt)2 (EtO)2(O)P SO Ar SO2Ar 2 N N (EtO)2(O)P N (EtO) (O)P 2 H (EtO)2(O)P SO2Ar 53 54 Ar = Ph, 4-Me-C6H4 Scheme 26. Addition of phosphites to iminophosphonates.

Finally, syntheses of rare aminomethyltrisphosphonates are presented in a recent review by Romanenko and Kukhar devoted to applications of methylidynetrisphosphonates [124]. Two Moleculesprocedures2016 , for21, 1474the synthesis of bis- and trisphosphonates 55 and 56 taken from this review14 ofand 26 described in patent literature are depicted in Scheme 27.

O Cl P(OEt) N P(O)(OEt) O N 3 2 0 Cl CH2Cl2/-40 C P(O)(OEt) (EtO)2(O)P 2 Cl 55

P(O)(OEt) Ar Cl Ar P(O)(OEt)2 HP(O)(OEt)2 Ar 2 P(OEt)3/ N N N P(O)(OEt)2 CH2Cl2 CH2Cl2/NaOH H Cl P(O)(OEt)2 P(O)(OEt)2 56

Molecules 2016, 21, 1474 Scheme 27. Syntheses of aminomethyltrisphosphonates.aminomethyltrisphosphonates. 14 of 25

3. Functionalization Functionalization of of Aminobisphosphonates Aminobisphosphonates

Bisphosphonates are known for their afﬁnityaffinity to bone tissue, and thus their conjugation to various drugs has been quite intensivelyintensively studied; they are expected to serve as system-targetingsystem-targeting drugs [[6].6]. Because dronic acids are produced at industrial scale and are thus readily available and inexpensive, they are mostmost frequentlyfrequently usedused forfor thatthat purpose.purpose. However, their extremeextreme hydrophilichydrophilic character means that that they they are are practically practically insoluble insoluble in in most most organic organic solvents, solvents, which which limits limits the the use use of ofaqueous aqueous media media or orrequires requires their their conversion conversion into into phosphonate phosphonate esters esters prior prior to to functionalization. Unfortunately, the methods for direct esteriﬁcationesterification of phosphonate moieties are scarce and usually give unsatisfactory results; these esters mustmust generallygenerally bebe synthesizedsynthesized independently.independently. Methods for functionalizing aminobisphosphonic acids with structurally variable molecules were recently reviewed [[12];12]; therefore, in this review, thethe methodsmethods arbitrarilyarbitrarily chosen as the most representative areare reported.reported.

3.1. Direct Acylation of Aminobisphosphonic Acids Direct acylation of aminobisphosphonic acids is difﬁcultdifficult because this reaction is accompaniedaccompanied by the possible competitive acylation of phosphonic groups [[125,126]125,126] and hydroxylic groups when amino-1-hydroxy-1,1-bisphosphonic acids are substrates [[126,127].126,127]. A representative example of this reaction is given in Scheme 2828 forfor alendronicalendronic acidacid 5757..

O PO3H2 OH Cl + H2N PO3H2 57

aq. NaOH O

O O OH P O PO3H2 O PO3H2 OH + PO H H N OH 3 2 + 2 PO H N PO3H2 N 3 2 H H O O

Scheme 28. Direct acylation of alendronic acid with indication of possible side-products.

Acylation of dronic acid salts with acyl chlorides in sodium hydroxide in water or in Acylation of dronic acid salts with acyl chlorides in sodium hydroxide in water or in water/propanol water/propanol solutions is the simple Schotten-Baumann variant [127,128]. Acidification of the solutions is the simple Schotten-Baumann variant [127,128]. Acidification of the solution results in the solution results in the precipitation of the desired acids or their monosodium salts. To conjugate precipitation of the desired acids or their monosodium salts. To conjugate aminobisphosphonic acids aminobisphosphonic acids with molecules bearing carboxylic groups, classical coupling protocols with molecules bearing carboxylic groups, classical coupling protocols used in peptide synthesis have used in peptide synthesis have also been used. These include the activation of carboxylic groups also been used. These include the activation of carboxylic groups with N,N’-dicyclohexylcarbodiimide with N,N’-dicyclohexylcarbodiimide (DCC) [129,130]; the use of previously prepared succinimidate (DCC) [129,130]; the use of previously prepared succinimidate esters to obtain 21 extremely complex esters to obtain 21 extremely complex fluorescent imaging probes (representative examples of a fluorescent imaging probes (representative examples of a green fluorescent dye 58 and a red fluorescent green fluorescent dye 58 and a red fluorescent dye 59 are shown in Scheme 29) [131]; and dye 59 are shown in Scheme 29)[131]; and N,N’-dicarbonylimidazole, which was used to conjugate N,N’-dicarbonylimidazole, which was used to conjugate pamidronate to pullan (polysaccharide composed of maltotriose units) [132] to obtain a system for bone regeneration.

N O N

HO O O

SO3H

COOH O O O S O NH PO H N N HN 3 H OH OH N PO3H2 HO PO H H O P 3 2 3 OH 58, derivative of Carboxyfluorescein 59, derivative of Rhodamine Red -X Scheme 29. Representative fluorescent imaging probes obtained via acylation of bisphosphonic acids (green—carboxyfluoresceine fragment, red—rhodamine Red-X fragment).

Molecules 2016, 21, 1474 14 of 25

3. Functionalization of Aminobisphosphonates Bisphosphonates are known for their affinity to bone tissue, and thus their conjugation to various drugs has been quite intensively studied; they are expected to serve as system-targeting drugs [6]. Because dronic acids are produced at industrial scale and are thus readily available and inexpensive, they are most frequently used for that purpose. However, their extreme hydrophilic character means that they are practically insoluble in most organic solvents, which limits the use of aqueous media or requires their conversion into phosphonate esters prior to functionalization. Unfortunately, the methods for direct esterification of phosphonate moieties are scarce and usually give unsatisfactory results; these esters must generally be synthesized independently. Methods for functionalizing aminobisphosphonic acids with structurally variable molecules were recently reviewed [12]; therefore, in this review, the methods arbitrarily chosen as the most representative are reported.

3.1. Direct Acylation of Aminobisphosphonic Acids Direct acylation of aminobisphosphonic acids is difficult because this reaction is accompanied by the possible competitive acylation of phosphonic groups [125,126] and hydroxylic groups when amino-1-hydroxy-1,1-bisphosphonic acids are substrates [126,127]. A representative example of this reaction is given in Scheme 28 for alendronic acid 57.

O PO3H2 OH Cl + H2N PO3H2 57

aq. NaOH O

O O OH P O PO3H2 O PO3H2 OH + PO H H N OH 3 2 + 2 PO H N PO3H2 N 3 2 H H O O

Scheme 28. Direct acylation of alendronic acid with indication of possible side-products.

Acylation of dronic acid salts with acyl chlorides in sodium hydroxide in water or in water/propanol solutions is the simple Schotten-Baumann variant [127,128]. Acidification of the solution results in the precipitation of the desired acids or their monosodium salts. To conjugate aminobisphosphonic acids with molecules bearing carboxylic groups, classical coupling protocols used in peptide synthesis have also been used. These include the activation of carboxylic groups

Moleculeswith N,N2016’-dicyclohexylcarbodiimid, 21, 1474 e (DCC) [129,130]; the use of previously prepared succinimidate15 of 26 esters to obtain 21 extremely complex fluorescent imaging probes (representative examples of a green fluorescent dye 58 and a red fluorescent dye 59 are shown in Scheme 29) [131]; and pamidronateN,N’-dicarbonylimidazole, to pullan (polysaccharide which was used composed to conjugate of maltotriose pamidronate units) [ 132to ]pullan to obtain (polysaccharide a system for bonecomposed regeneration. of maltotriose units) [132] to obtain a system for bone regeneration.

N O N

HO O O

SO3H

COOH O O O S O NH PO H N N HN 3 H OH OH N PO3H2 HO PO H H O P 3 2 3 OH 58, derivative of Carboxyfluorescein 59, derivative of Rhodamine Red -X

Scheme 29. RepresentativeRepresentative ﬂuorescentfluorescent imaging probes obtained via acylationacylation ofof bisphosphonicbisphosphonic acidsacids (green—carboxyfluoresceine fragment, red—rhodamine Red-X fragment). Molecules(green—carboxyﬂuoresceine 2016, 21, 1474 fragment, red—rhodamine Red-X fragment). 15 of 25

Acylation of aminobisphosphonic acids with small ac acids,ids, such as acrylic acid [133], [133], chloroacetic acid [134] [134] or succinic acid [[135],135], provided useful substrates for further functionalization of larger molecules, such as macrocycles devised for lanthanide ion complexation,complexation, chitosan,chitosan, andand hyaluronan.hyaluronan.

3.2. Direct Acylation of Tetraethyl AminobisphosphonatesAminobisphosphonates Esters are far more suitable substrates for acylation than free phosphonic acids, with tetraethyl aminomethylenebisphosphonate being being the most popularpopular substrate. It It has has been been used used to obtain structurally variable variable conjugates conjugates with with estradiol estradiol (compounds (compounds 60, 6160 and, 61 62and in Scheme62 in Scheme 30) using 30 classical) using peptideclassical synthesis peptide synthesis coupling couplingagents such agents as suchDCC asand DCC DPPA and (diphenylphospho DPPA (diphenylphosphorylryl azide) [136]. azide) These [136]. Theseconjugates conjugates were synthesized were synthesized as bone-specific as bone-speciﬁc estrog estrogensens in the in thehope hope that that they they will will protect protect elderly elderly women from bone loss resulting fromfrom osteoporosis.osteoporosis.

O H2O3P O PO H O O PO3H2 O 3 2 NH N O H PO3H2

HO 60 61 HO

H2O3P O O

H2O3P N O H 62 Scheme 30. RepresentativeRepresentative structures of bone-specific bone-speciﬁc estrogens.

A derivative of raloxifene, a selective estrogen receptor or modulator, was obtained using a suitable A derivative of raloxifene, a selective estrogen receptor or modulator, was obtained using acid chloride as substrate [137], whereas radioligands, which are selectively bound to bone tissue, a suitable acid chloride as substrate [137], whereas radioligands, which are selectively bound to have been synthesized by using DCC/HOBt (hydroxybenzotriazol) activation [138] and antibacterial bone tissue, have been synthesized by using DCC/HOBt (hydroxybenzotriazol) activation [138] bisphosphonated benzoxazinorifamycin prodrugs using EDCl (1-ethyl-3-(3-dimethylaminopropyl) and antibacterial bisphosphonated benzoxazinorifamycin prodrugs using EDCl (1-ethyl-3-(3- carbodiimide) [139]. dimethylaminopropyl)carbodiimide) [139]. In this case, acylation of aminobisphosphonic acids with small acids was also applied as a In this case, acylation of aminobisphosphonic acids with small acids was also applied as a starting starting step to produce antibacterial agents against osteomyelitis [88] and bone imaging macrocycles step to produce antibacterial agents against osteomyelitis [88] and bone imaging macrocycles [81], [81], using acid chlorides as acylating agents. using acid chlorides as acylating agents.

H BnO N COOH P(O)(OEt)2 OH O + BnO H2N P(O)(OEt)2 22 HBTU

O P(O)(OEt) H 2 BnO N OH N H P(O)(OEt)2 O BnO 1./ H2/Pd-C 2./ TMSBr

O PO H H 3 2 HO N OH N H PO3H2 O HO

Fe3O4

O PO H H 3 2 O N OH Fe O N 3 4 H PO3H2 O O 63 Scheme 31. Synthesis of bisphosphonate functionalized magnetic nanoparticles.

Molecules 2016, 21, 1474 15 of 25

Acylation of aminobisphosphonic acids with small acids, such as acrylic acid [133], chloroacetic acid [134] or succinic acid [135], provided useful substrates for further functionalization of larger molecules, such as macrocycles devised for lanthanide ion complexation, chitosan, and hyaluronan.

3.2. Direct Acylation of Tetraethyl Aminobisphosphonates Esters are far more suitable substrates for acylation than free phosphonic acids, with tetraethyl aminomethylenebisphosphonate being the most popular substrate. It has been used to obtain structurally variable conjugates with estradiol (compounds 60, 61 and 62 in Scheme 30) using classical peptide synthesis coupling agents such as DCC and DPPA (diphenylphosphoryl azide) [136]. These conjugates were synthesized as bone-specific estrogens in the hope that they will protect elderly women from bone loss resulting from osteoporosis.

O H2O3P O PO H O O PO3H2 O 3 2 NH N O H PO3H2

HO 60 61 HO

H2O3P O O

H2O3P N O H 62

Molecules 2016, 21, 1474 Scheme 30. Representative structures of bone-specific estrogens. 16 of 26

A derivative of raloxifene, a selective estrogen receptor or modulator, was obtained using a suitable acid Usingchloride DCC as substrate as a coupling [137], agent, whereas diethyl radioligands, 1-(2-aminoethylamino)-1,1-ethylbisphosphonate which are selectively bound to bone tissue, was acylatedhave been by synthesized structurally by variable using DCC/HOBt natural acids, (hydroxybenzotriazol) such as folic acid [ 140activation,141], ursulonic [138] and and antibacterial betulinic acidsbisphosphonated [142], and trolox benzoxazinorifam [141,143]. ycin prodrugs using EDCl (1-ethyl-3-(3-dimethylaminopropyl) carbodiimide)Acylation [139]. of pamidronic acid ester 22 by using HBTU (2-(1H-benzotriazol-1-yl)-1,1,3,3- tetramethyluroniumIn this case, acylation hexaﬂuorophosphate) of aminobisphosphonic was used acids to prepare with small a catecholic acids was derivative, also applied which as was a thenstarting bound step to to the produce surface antibacterial of magnetic agents iron oxide against nanoparticles osteomyelitis (Scheme [88] and 31 bone)[144 imaging]. The particle macrocycles63 has been[81], using designed acid to chlorides remove uranylas acylating ions fromagents. blood.

H BnO N COOH P(O)(OEt)2 OH O + BnO H2N P(O)(OEt)2 22 HBTU

O P(O)(OEt) H 2 BnO N OH N H P(O)(OEt)2 O BnO 1./ H2/Pd-C 2./ TMSBr

O PO H H 3 2 HO N OH N Molecules 2016, 21, 1474 H PO3H2 16 of 25 O HO Using DCC as a coupling agent, diethyl 1-(2-aminoethylamino)-1,1-ethylbisphosphonate was Fe3O4 acylated by structurally variable natural acids, such as folic acid [140,141], ursulonic and betulinic O PO H acids [142], and trolox [141,143]. H 3 2 O N OH Acylation of pamidronic acid FeesterO 22 by using HBTUN (2-(1H-benzotriazol-1-yl)-1,1,3,3- 3 4 H PO3H2 O tetramethyluronium hexaﬂuorophosphate) Owas used to prepare a catecholic derivative, which was 63 then bound to the surface of magnetic iron oxide nanoparticles (Scheme 31) [144]. The particle 63 has been designedScheme to remove 31. Synthesis uranyl ions of bisphosphonate from blood. functionalizedfunctionalized magnetic nanoparticles.

3.3. Synthesis of Building Blocks for Polymer Chemistry Self-etching adhesives are polymeric materials co containingntaining phosphonate groups that have become popular in restorative dentistry because they allow strong bonds between dental hard tissues (enamel and dentin). One One possibility possibility for for their preparation is to obtain monomers containing phosphonic groups [[145].145]. SuchSuch methacrylamide methacrylamide monomers monomers64 and64 and65 were 65 synthesizedwere synthesized by acylation by acylation with suitable with acryloylchloridessuitable acryloylchlorides (Scheme 32(Scheme)[146]. Studies32) [146]. of theirStudies photopolymerization of their photopolymerization indicated that indicated they may that be suitablethey may for be potential suitable for use potential in dentistry. use in dentistry.

O O PO3H2 H H H2O3P N N PO3H2 N PO3H2 H H O P O O PO H 642 3 65 3 2 Scheme 32. Bisphosphonylated meth methacrylamideacrylamide monomers.

A similar monomer, acryloylated pamidronate, has been used to obtain a hyaluronic acid A similar monomer, acryloylated pamidronate, has been used to obtain a hyaluronic acid derivative that is dually polymerized with cross-linkable hydrazide groups and bisphosphonate derivative that is dually polymerized with cross-linkable hydrazide groups and bisphosphonate ligands. By mixing bisphosphonate polymer with calcium ions and aldehyde-derivatized hyaluronic ligands. By mixing bisphosphonate polymer with calcium ions and aldehyde-derivatized hyaluronic acid, a hybrid hydrogel was obtained, which quickly mineralizes [147]. Such a system is of interest as acid, a hybrid hydrogel was obtained, which quickly mineralizes [147]. Such a system is of interest as a mediator for fast bone regeneration. a mediator for fast bone regeneration. By dispersion copolymerization of three monomers (methacrylate bisphosphonate 66, By dispersion copolymerization of three monomers (methacrylate bisphosphonate 66, N-(3- N-(3-aminopropyl) methacrylamide 67, and tetra(ethylene glycol) diacrylate 68) (Scheme 33), aminopropyl) methacrylamide 67, and tetra(ethylene glycol) diacrylate 68) (Scheme 33), polymeric polymeric nanoparticles 69 were obtained [148]. Their size distribution was controlled by changing nanoparticles 69 were obtained [148]. Their size distribution was controlled by changing various various polymerization parameters. By covalent attachment of a drug and/or a dye to amino groups (such as a near IR fluorescent dye), a theranostic system may be obtained.

PO3H2 O PO3H2 O OH H O P x 2 3 PO H O PO3H2 NH2 3 2 66 O O PO3H2 H2O3P H2N NH NH 2 2 H2O3P O O 67 H2N PO3H2 H2O3P PO H O O NH2 3 2 O O H2O3P H N O 2 H2O3P O 4 PO3H2 68 69 Scheme 33. Synthesis of polymeric nanoparticles as potential dye and drug carriers.

Macromolecular co-conjugates of bisphosphonate and ferrocene were synthesized by means of Michael addition copolymerization of methylenebisacrylamide (MBA) with primary amines-6- amino-1-hydroxyhexylidene-1,1-bisphosphonate and 4-ferrocenyl-butamidopropylamine [149]. The mass percentage incorporation of ferrocene analogues was found to be between 4%–5%, and 10%–12% for bisphosphonate. Such polymers could be selectively bound to bone tissue and slowly release anticancer ferrocene derivatives at this target site.

Molecules 2016, 21, 1474 16 of 25

Using DCC as a coupling agent, diethyl 1-(2-aminoethylamino)-1,1-ethylbisphosphonate was acylated by structurally variable natural acids, such as folic acid [140,141], ursulonic and betulinic acids [142], and trolox [141,143]. Acylation of pamidronic acid ester 22 by using HBTU (2-(1H-benzotriazol-1-yl)-1,1,3,3- tetramethyluronium hexaﬂuorophosphate) was used to prepare a catecholic derivative, which was then bound to the surface of magnetic iron oxide nanoparticles (Scheme 31) [144]. The particle 63 has been designed to remove uranyl ions from blood.

3.3. Synthesis of Building Blocks for Polymer Chemistry Self-etching adhesives are polymeric materials containing phosphonate groups that have become popular in restorative dentistry because they allow strong bonds between dental hard tissues (enamel and dentin). One possibility for their preparation is to obtain monomers containing phosphonic groups [145]. Such methacrylamide monomers 64 and 65 were synthesized by acylation with suitable acryloylchlorides (Scheme 32) [146]. Studies of their photopolymerization indicated that they may be suitable for potential use in dentistry.

O O PO3H2 H H H2O3P N N PO3H2 N PO3H2 H H O P O O PO H 642 3 65 3 2 Scheme 32. Bisphosphonylated methacrylamide monomers.

A similar monomer, acryloylated pamidronate, has been used to obtain a hyaluronic acid derivative that is dually polymerized with cross-linkable hydrazide groups and bisphosphonate ligands. By mixing bisphosphonate polymer with calcium ions and aldehyde-derivatized hyaluronic acid, a hybrid hydrogel was obtained, which quickly mineralizes [147]. Such a system is of interest as a mediator for fast bone regeneration.

MoleculesBy 2016dispersion, 21, 1474 copolymerization of three monomers (methacrylate bisphosphonate17 of66 26, N-(3-aminopropyl) methacrylamide 67, and tetra(ethylene glycol) diacrylate 68) (Scheme 33), polymeric nanoparticles 69 were obtained [148]. Their size distribution was controlled by changing polymerizationvarious polymerization parameters. parameters. By covalent By covalent attachment atta ofchment a drug of and/or a drug a and/or dye to a amino dye to groups amino (such groups as a(such near as IR a ﬂuorescent near IR fluorescent dye), a theranostic dye), a theranostic system may system be obtained. may be obtained.

Macromolecular co-conjugates of bisphosphonate and ferrocene were synthesized by means Macromolecular co-conjugates of bisphosphonate and ferrocene were synthesized by means of Michael addition copolymerization of methylenebisacrylamide (MBA) with primary amines-6- of Michael addition copolymerization of methylenebisacrylamide (MBA) with primary amines-6- amino-1-hydroxyhexylidene-1,1-bisphosphonate and 4-ferrocenyl-butamidopropylamine [149]. The amino-1-hydroxyhexylidene-1,1-bisphosphonate and 4-ferrocenyl-butamidopropylamine [149]. mass percentage incorporation of ferrocene analogues was found to be between 4%–5%, and 10%–12% The mass percentage incorporation of ferrocene analogues was found to be between 4%–5%, for bisphosphonate. Such polymers could be selectively bound to bone tissue and slowly release and 10%–12% for bisphosphonate. Such polymers could be selectively bound to bone tissue and anticancer ferrocene derivatives at this target site. slowlyMolecules release 2016, 21,anticancer 1474 ferrocene derivatives at this target site. 17 of 25

3.4. 3.5. Miscellaneous Other means to functionalizefunctionalize aminoamino moietiesmoieties areare quitequite scarcescarce andand dispersed.dispersed. Classical ones include thethe formationformation ofof Schiff Schiff bases, bases, which which are are then then alkylated alkylated [150 [150]] or or reduced reduced [126 [126],], and and synthesis synthesis of thioureidoof thioureido derivatives derivatives as intermediatesas intermediates in thein th preparatione preparation of heterocyclicof heterocyclic compounds compounds [151 [151–153].–153]. The functionalization functionalization of polysaccharides of polysaccharides is the gateway is the gateway of aminobisphosphonates of aminobisphosphonates into nanoscience. into nanoscience.For example, Forphosphonated example, phosphonated cellulose was cellulose utilized was to utilizedobtain na tonocellulose obtain nanocellulose with good with thermal good thermalstability stabilityand potential and potentialintumescent intumescent properties. properties. It was synthesized It was synthesized from birch frompulp birchvia sequential pulp via sequentialperiodate oxidation periodate and oxidation reductive and reductiveamination aminationusing alendronate using alendronate 57 as a phosphonating57 as a phosphonating reagent reagent(Scheme (Scheme 34) [154]. 34)[ After154]. high-pressure After high-pressure homogeniza homogenization,tion, bisphosphonate bisphosphonate cellulose cellulose nanofibers nanoﬁbers or ornanocrystals nanocrystals of ofthe the general general formula formula 70 70werewere obtained, obtained, depending depending on on the the initial initial oxidation oxidation degree. degree.

OH OH H2O3P O NaIO4 O + OH O O H2N PO H O 3 2 HO OH O 57

BH3

OH O O HN HO H2O3P HO 70 H2O3P

SchemeScheme 34. 34. PeriodatePeriodate oxidation oxidation of of cellulose cellulose followed followed by reductive aminationaminationwith with sodium sodium alendronate. alendronate.

Alendronate was also bound to conjugates of pullulan and paclitaxel, which were bound to the polysaccharide by a cathepsin K-sensitive tetrapeptide spacer. This should ensure release of paclitaxel in bones. Then, bisphosphonate was covalently conjugated to the sugar chain via a polyethyleneglycol chain, using a technique similar to that described above (identical to those shown in Scheme 34) [155]. This system exhibited strong antiproliferative action against several cancer cell lines.

4. Conclusions Aminobisphosphonic acids are gaining significant interest as a class of compounds with promising physiologic activity, with some representatives already commercialized as bone resorption inhibitors, and therefore useful drugs against osteoporosis and related bone disorders. This leads to both the modification of existing and the elaboration of novel procedures for their preparation. There are several commonly used reactions for this purpose; however, they have also been modified in the last decade to be tailored to specific biological needs. A few novel procedures have also been developed. Functionalization of simple aminobisphosphonic acids is a difficult task because of their strongly polar character. However, successful examples of functionalization of the amino moieties of these compounds have provided promising diagnostics and novel therapeutic agents.

Acknowledgments: This work was supported by a statuary activity subsidy from the Polish Ministry of Science and Higher Education. Conflicts of Interest: The authors declare no conflict of interest.

References

Molecules 2016, 21, 1474 18 of 26

Alendronate was also bound to conjugates of pullulan and paclitaxel, which were bound to the polysaccharide by a cathepsin K-sensitive tetrapeptide spacer. This should ensure release of paclitaxel in bones. Then, bisphosphonate was covalently conjugated to the sugar chain via a polyethyleneglycol chain, using a technique similar to that described above (identical to those shown in Scheme 34)[155]. This system exhibited strong antiproliferative action against several cancer cell lines.

4. Conclusions Aminobisphosphonic acids are gaining significant interest as a class of compounds with promising physiologic activity, with some representatives already commercialized as bone resorption inhibitors, and therefore useful drugs against osteoporosis and related bone disorders. This leads to both the modification of existing and the elaboration of novel procedures for their preparation. There are several commonly used reactions for this purpose; however, they have also been modified in the last decade to be tailored to specific biological needs. A few novel procedures have also been developed. Functionalization of simple aminobisphosphonic acids is a difficult task because of their strongly polar character. However, successful examples of functionalization of the amino moieties of these compounds have provided promising diagnostics and novel therapeutic agents.

Acknowledgments: This work was supported by a statuary activity subsidy from the Polish Ministry of Science and Higher Education. Conﬂicts of Interest: The authors declare no conﬂict of interest.

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