Review Openingmolecules Up the Toolbox: Synthesis and Mechanisms of Phosphoramidates

Emeka J.Review Itumoh 1,2,3, Shailja Data 1,3 and Erin M. Leitao 1,3,*

1 SchoolOpening of Chemical Sciences, up the The Toolbox:University of Auckland, Synthesis 23 Symonds and Street, Mechanisms Auckland 1010, Newof Zealand; Phosphoramidates [email protected] (E.J.I.); [email protected] (S.D.) 2 Department of Industrial Chemistry, Ebonyi State University, Abakaliki 480001, Ebonyi State, Nigeria 3 The MacDiarmidEmeka J. Itumoh Institute1,2,3 for, Shailja Advanced Data 1,3 Materialsand Erin and M. LeitaoNanotechnology,1,3,* Wellington 6140, New Zealand * Correspondence:1 School of Chemicalerin.leitao@ Sciences,auckland.ac.nz; The University Tel.: of Auckland, +64-9923-5567 23 Symonds Street, Auckland 1010, New Zealand; [email protected] (E.J.I.); [email protected] (S.D.) Academic Editor: Frederik Wurm 2 Department of Industrial Chemistry, Ebonyi State University, Abakaliki 480001, Ebonyi State, Nigeria 3 Received: 3 TheJuly MacDiarmid 2020; Accepted: Institute 11 for Augu Advancedst 2020; Materials Published: and Nanotechnology, 12 August 2020 Wellington 6140, New Zealand * Correspondence: [email protected]; Tel.: +64-9923-5567



Abstract:Academic This review Editor: Frederik covers Wurm the main synthetic routes to and the corresponding mechanisms
 of phosphoramidateReceived: 3 July formation. 2020; Accepted: The 11 August synthetic 2020; Published: routes 13can August be 2020separated into six categories: salt elimination,Abstract: oxidativeThis review cross-coupling, covers the main azide, synthetic reduction, routes to andhydrophosphinylation, the corresponding and phosphoramidate-aldehyde-dienophilemechanisms of phosphoramidate formation. (PAD). The Examples synthetic routesof some can be separatedimportant into compounds six synthesizedcategories: through salt elimination,these routes oxidative are provided. cross-coupling, As azide,an important reduction, class hydrophosphinylation, of organophosphorus and phosphoramidate-aldehyde-dienophile (PAD). Examples of some important compounds compounds,synthesized the applications through these of routesphosphoramid are provided.ate compounds, As an important are classalso ofbriefly organophosphorus introduced. compounds, the applications of phosphoramidate compounds, are also briefly introduced. Keywords: phosphoramidate; synthetic routes; mechanism; applications Keywords: phosphoramidate; synthetic routes; mechanism; applications

1. Introduction1. Introduction to Phosphoramidates to Phosphoramidates and and their their Applications PhosphoramidatesPhosphoramidates (P-N) (P-N) are are a aclass class of organophosphorusorganophosphorus compounds compounds known forknown the presence for the of presence of a singlea single covalent covalent bond between between the tetracoordinatethe tetracoor P(V)dinate atom P(V) and N(III)atom atom. and ThereN(III) are atom. generally There are three types of phosphoroamidates, which are distinguished according to the substitution on the P and generallyN atomsthree (Figuretypes 1of)[ 1phosphoroamidates,]. which are distinguished according to the substitution on the P and N atoms (Figure 1) [1]. O O O P H P R' R' RO N RO N RO P N RO H RO H RO R" I II III R = H, alkyl, aryl R', R" = alkyl, aryl, heteroaryl Figure Figure1. Three 1. Three types types of P-N of P-N based based on on the the substituents directly directly attached attached to the Pto and the N. P and N.

Another feature of these organophosphorous compounds, defined as (RO)2P(O)NR’2 (R, R’ = H, Anotheralkyl, aryl, feature heteroaryl), of these is a organophos stable phosphorylphorous bond (Pcompounds,=O). Both P and defined N atoms as are (RO) key2 physiologicalP(O)NR’2 (R, R’ = H, alkyl, aryl,elements heteroaryl), present in is genetic a stable material, phosphoryl energy transfer, bond enzymes, (P=O). Both and other P and biomolecules N atoms and are are key required physiological elementsfor present various lifein processes.genetic material, As such, molecules energy containingtransfer, P-Nenzymes, linkages and are foundother in biomolecules a large array of and are requiredbiologically for various active life natural processes. products As (such,1–7) (Figure molecules2)[ 2,3]. containing For example, P-N Microcin linkages C7 (1 )are (Figure found2) is in a large an antibiotic produced by Escherichia coli [4]. Dinogunellin (2) (Figure2), which is produced in the roe array ofof biologically some fishes, isactive a natural natural toxin [ 5products]. Phosphoarginine (1–7) (Figure and phosphocreatine 2) [2,3]. For (3 example,and 6) (Figure Microcin2) are C7 (1) (Figure important2) is an biologicalantibiotic molecules produced used by as sourcesEscherichia of stored coli energies[4]. Dinogunellin in invertebrates (2) and (Figure vertebrates, 2), which is producedrespectively in the roe [6 ].of Phosphoramidonsome fishes, is (a4) natura (Figurel2 ),toxin derived [5]. from PhosphoarginineStreptomyces tanashiensis and phosphocreatine, inhibits (3 and 6) the(Figure thermolysin 2) are enzyme, important which isbiological a key factor molecules in the development used ofas varioussources diseases of stored [7,8]. Lastly, energies in invertebratesphosmidosine and vertebrates, and agrocin 84 (respectively5 and 7) (Figure 2[6].) are Phosphoramidon nucleotide antibiotics isolated(4) (Figure from Streptomyces2), derived from Streptomyces tanashiensis, inhibits the thermolysin enzyme, which is a key factor in the development Molecules 2020, 25, 3684; doi:10.3390/molecules25163684 www.mdpi.com/journal/molecules of various diseases [7,8]. Lastly, phosmidosine and agrocin 84 (5 and 7) (Figure 2) are nucleotide antibiotics isolated from Streptomyces durhameusis and Agrobacterium radiobacter and are used to control gray mold disease and crown gall disease in plants, respectively [9,10].

Molecules 2020, 25, x; doi: FOR PEER REVIEW www.mdpi.com/journal/molecules Molecules 2020, 25, 3684 2 of 37 durhameusis and Agrobacterium radiobacter and are used to control gray mold disease and crown gall diseaseMolecules in 2020 plants,, 25, x FOR respectively PEER REVIEW [9,10 ]. 2 of 37

Figure 2. Phosphoramidate motifs in natural products: Microcin C7 (1), Dinogunellin (R = residue Figure 2. Phosphoramidate motifs in natural products: Microcin C7 (1), Dinogunellin (R = residue of of fatty acid) (2), Phosphoarginine (3), Phosphoramidon (4), Phosmidosine (5), Phosphocreatine (6), fatty acid) (2), Phosphoarginine (3), Phosphoramidon (4), Phosmidosine (5), Phosphocreatine (6), Agrocin 84 (7). Agrocin 84 (7). Due to the inherent physiochemical properties of the phosphorus atom including its polarizability, Due to the inherent physiochemical properties of the phosphorus atom including its multivalency, varying oxidation states, and low coordination number, a diverse range of compounds polarizability, multivalency, varying oxidation states, and low coordination number, a diverse range containing the P-N motifs have been synthesized [11]. These P-Ns are widely used in medicine for the of compounds containing the P-N motifs have been synthesized [11]. These P-Ns are widely used in control and treatment of various diseases, in agriculture as pesticides for crop protection, in industry as medicine for the control and treatment of various diseases, in agriculture as pesticides for crop novelprotection, fire-retardant in industry compounds as novel to fire-retardant delay the flammability compounds of to polymeric delay the compounds, flammability and of in polymeric the fields ofcompounds, analytical and and coordination in the fields chemistry. of analytical Therefore, and coordination synthetic P-N chemistry. compounds Therefore, are not only synthetic researched P-N outcompounds of academic are interest, not only but researched they also have out commercialof academic applications. interest, but Uses they for also P-Ns have can becommercial separated intoapplications. 5 main classes: Uses for agriculture, P-Ns can industry,be separated analytical into 5 chemistry,main classes: synthetic agriculture, chemistry, industry, and analytical medicinal chemistrychemistry, (Figure synthetic3)[12 chemistry,–18]. and medicinal chemistry (Figure 3) [12–18].

Molecules 2020, 25, x FOR PEER REVIEW 3 of 37 Molecules 2020, 25, 3684 3 of 37 Molecules 2020, 25, x FOR PEER REVIEW 3 of 37

FigureFigureFigure 3.3. 3. ApplicationsApplications Applications of ofof phosphoramidates. phosphoramidates. 1.1. Phosphoramidates in Agriculture 1.1.1.1. Phosphoramidat Phosphoramidates esin in Agriculture Agriculture This class of organophosphates (with common names such as cruformate, fenamiphos, ThisThis class class of oforganophosphates organophosphates (with (with commoncommon names suchsuch asas cruformate,cruformate, fenamiphos, fenamiphos, and and andfosthietan)fosthietan) fosthietan) has has been has been beenwidely widely widely used used in used in pest pest in management management pest management forfor crop for protectionprotection crop protection (Figure (Figure 3) 3) (Figure [19–21]. [19–21].3 )[P-Ns P-Ns19 –for21 for ]. P-Nspestpest control for control pest affect control affect the the a nervousff ectnervous the sy nervous systemstem of of system pests/insects pests/insects of pests by/insects inhibiting by inhibitingacetylcholinesteraseacetylcholinesterase acetylcholinesterase (AChE), (AChE), a a (AChE),majormajor neurotransmitter aneurotransmitter major neurotransmitter [22–25]. [22–25]. In [In22 addition, –addition,25]. In addition, thesthesee P-N these compounds P-N compounds havehave beenbeen have utilized utilized been as utilized as urease urease as ureaseinhibitorsinhibitors inhibitors [26,27]. [26,27]. [ 26Urease ,Urease27]. Urease is is a ani ni isckel-basedckel-based a nickel-based enzymeenzyme enzyme that catalyzes that catalyzes thethe hydrolysishydrolysis the hydrolysis of of urea urea of on urea on soil soil on soilsurfacessurfaces surfaces into into into volatile volatile volatile ammonia ammonia ammonia and and and carboncarbon carbon dioxiddioxid dioxidee (Scheme (Scheme 1)1)1)[ [28,29].[28,29].28,29]. ThTh Thus,us,us, on on inhibiting inhibitinginhibiting the thethe activityactivityactivity ofof thisofthis this metalloenzyme,metalloenzyme, metalloenzyme, thethe the availabilityavailability availability and andand performance performanceperformance ofof ureaurea is is enhanced, enhanced,enhanced, which whichwhich is is isa avitala vitalvital nitrogenousnitrogenousnitrogenous fertilizerfertilizer fertilizer forfor for plantplant plant growth.growth. growth.

SchemeScheme 1. 1.Hydrolysis Hydrolysis of of urea urea on on soil soil inin thethe presencepresence of urease. Scheme 1. Hydrolysis of urea on soil in the presence of urease. 1.2. Phosphoramidates in Industry 1.2. Phosphoramidates in Industry 1.2. PhosphoramidatesP-Ns have been in used Industry as additives in both oil and water-based lubricants (Figure3). It has P-Ns have been used as additives in both oil and water-based lubricants (Figure 3). It has been been proposed that phosphorus acts as a key element in enhancing the tribological properties of proposedP-Ns have that been phosphorus used as additives acts as ain key both element oil and inwater-based enhancing lubricantsthe tribological (Figure properties 3). It has beenof waterproposedwater/oil-based/oil-based that fluidsphosphorus fluids by by forming forming acts aas protectivea protectivea key element layer layer containing containing in enhancing phosphates the tribological and/or and/or polyphosphates. polyphosphates. properties of Thus,water/oil-basedThus, they they possess possess fluids anti-wear anti-wear by forming andand afriction-reducing friction-reducing protective layer pr containing propertiesoperties [18,30]. phosphates [18,30 Furthe]. Furthermore, rmore,and/or these polyphosphates. P-Ns these have P-Ns haveThus,been been they found foundpossess to be to anti-wear a be promising a promising and alternative friction-reducing alternative to halo togenated pr halogenatedoperties flame [18,30]. flameretardants Furthe retardants (FRs),rmore, which (FRs), these are whichP-Ns being have are beingbeenphased found phased out to as out be they asa promising theyhave been have recognizedalternative been recognized as to global halo asgenated contaminants global flame contaminants due retardants to their due ill (FRs), effects to their which on ill health eareffects andbeing on healthphasedthe andenvironment out the as they environment have[31]. beenP-N [31 recognizedfire]. P-N retardants fire as retardants global are less contaminants are volatile less volatile and due relatively andto their relatively thermallyill effects thermally onstable health with stable and withthe environment enhanced char [31]. formation, P-N fire and retardants they are are more less effi volatilecient and and sustainable relatively than thermally their halogenated stable with

Molecules 2020, 25, 3684 4 of 37 counterparts [32,33]. Recently, compounds containing both P and N atoms in combination have been reported to have a synergistic effect, as they can act in both vapor phase and condensed phase, thus offering improved flame retardancy on various substrates such as polyurethane foams, cotton, cellulose, epoxy resins, textiles, etc. [34–40]. For example, novel P-N-based intumescent flame retardants have been incorporated into polycarbonates (PC) to impart flame retardancy to the composite by forming an expandable protective char [41].

1.3. Phosphoramidates in Analytical Chemistry MALDI-TOF MS is a prominent tool for analyzing biomolecules (Figure3)[ 42]. For the detection of low molecular weight such as amino acids and peptides, conventional matrices yield a lot of matrix-related ions in the low m/z range of the spectrum, thus interfering with analyte signals. To tackle this, various approaches such as using additives in the organic matrix, high mass matrix molecules, or matrices based on inorganic compounds have been employed [43]. Furthermore, to improve analysis, synthesizing derivatives of small analyte molecules by N-phosphorylation labeling has been done. The neutral phosphoryl group attached at the N-terminal of amino acids suppresses the matrix signals and favors the transfer of energy from matrix to analyte for ionization by secondary ion-molecule reactions. Therefore, P-Ns have been used for analysis of biomolecules to improve the ionization efficiency and suppress matrix background signals [44]. In addition to this, P-Ns have found novel applications as task-specific ionic liquids (TSILs), which are tailored ionic liquids having a specific functionality to complex metal ions. Recently, these TSILs have been used for the efficient extraction of uranium metal, which is an important element in nuclear fuel, and the extraction of uranium metal from the spent/used nuclear fuel is vital for the sustainable economy [45]. The enhanced extraction capabilities using TSILs in contrast to liquid–liquid extraction could be attributed to synergistic effects as a result of complexation and H-bonding [17]. To this end, these tailored ionic liquids have been found to be selective for the micellar extraction of uranium metal from aqueous waste samples as even the ultra-trace levels of uranium are toxic [46].

1.4. Phosphoramidates in Synthetic Chemistry P-Ns act as 1,3-N,O-chelating ligands (e.g., Figure3, Ligand) and have diverse applications in the field of coordination chemistry for bond activation, catalysis, and metal ligand cooperativity [47–49]. For example, a P-N-tantalum complex has been developed as a pre-catalyst for hydroaminoalkylation reactions [50]. In addition, the synthesis of medium and large N-based heterocycles has been achieved with the aid of P-Ns, as the phosphoryl group improves intramolecular cyclization, and it can also be easily removed afterwards [51]. Furthermore, P-Ns have been used as directing groups for arylation reactions, as they selectively activate C-H bonds, and thus, desired functionality can be achieved [52].

1.5. Phosphoramidates in Pharmaceutical and Medicinal Chemistry P-Ns have garnered considerable interest in the field of biomedicine due to their potential applications as antimicrobial [53–55], antioxidant [56], anticancer [57], antimalarial [58], antiviral [59,60], and anti-HIV [61] drugs and prodrugs against various ailments (Figure3). The ProTide approach, pioneered by the McGuigan group in 1992 for drug delivery, is a powerful tool to enhance the efficacy, intracellular delivery, and therapeutic potential of the parent drugs [62,63]. Recently, remdesivir (Figure3, drug candidate), which has a P-N moiety, has been evaluated as a therapeutic option for the treatment of COVID-19-affected patients and has attracted a lot of attention in the clinical field [64]. Additionally, these P-N compounds have been used in gene therapy and nucleoside treatment [65–67]. Moreover, many P-Ns have been found to be hydrolytically degradable under acidic conditions and are comparatively stable at neutral and higher pHs. The acid labile P-N bond is selectively cleaved due to protonation at N, which then undergoes nucleophilic attack by a molecule of water to eliminate the corresponding phosphates and amines [68,69]. Thus, these pH responsive P-Ns have notable applications in controlled drug release [70,71]. For example, the P-N-based prodrug of l-Dopa has Molecules 2020, 25, 3684 5 of 37 been synthesized for its controlled release for the treatment of Parkinson’s disease [72]. Similarly, P-N derivatives of the antiherpetic drug, acyclovir (ACV), hydrolyses at pH 2 into ACV monophosphate and can be a promising antiviral drug due to increased cell penetration and therapeutic potential relative to the parent drug [73].

2. Synthetic Routes to Phosphoramidates Although P-N biomolecules such as phosphocreatine have been known since the work of Fiske and Subbarow in 1927, synthetic routes to P-N compounds prior to 1988 have been limited [74,75]. These early routes involve the preparation of and use of toxic reagents over multiple synthetic steps and often resulted in the elimination of stoichiometric waste. However, with an increase in the number of uses of P-Ns, the need to develop one-pot synthetic routes that are more environmentally benign has driven researchers to discover catalytic strategies. Accordingly, all the known synthetic routes to P-Ns can be separated into six categories: salt elimination, oxidative cross-coupling, azide, reduction, hydrophosphinylation, and phosphoramidate-aldehyde-dienophile (PAD). Each of the categories will be discussed in detail in the coming sections, with an emphasis on conditions, scope, and mechanism. This discussion will be preceded by a brief introduction to the early synthetic routes.

2.1. A Brief Historical Timeline of Phosphoramidate Synthesis Based on the available literature, one of the earliest syntheses of P-Ns involved the works of Audrieth and Toy[76,77]. Audrieth and Toytreated phosphoryl trichloride with phenol in the presence of pyridine to obtain a mixture of diphenylchlorophosphate (dPCP) and phenyl dichlorophosphate (PdCP). Upon reacting the mixture with gaseous or aqueous NH3 in 1941 or primary amine in 1942, P-N and N-P-N were formed (Scheme2 route A,R = Ph). In 1945, P-Ns were made by Atherton, Openshaw, and Todd through a salt elimination process using disubstituted H-phosphonates (H-P), amines, and chlorinating agents (Scheme2 route B)[78]. Subsequently, the Atherton-Todd group synthesized P-Ns via the same method using different polyhalogen solvents in 1947 [79] and using alternative phosphorylating agents in 1948 [80]. In 1951, Wagner-Jauregg et al. synthesized P-N compounds from diisopropylchlorophosphate (dPrCP) or tetraethylpyrophosphate (tEPyP) and amines (Scheme2 route A,R = i-Pr and route C, respectively) [81]. Sodium anilide or sodium diphenylamide was refluxed with triphenylphosphate (tPPO) to eliminate phenol and give diphenyl N-phenylphosphoramidate or diphenyl N,N-diphenylphosphoramidate in 1964 (Scheme2 route D)[82]. In 1965, Sundberg reacted 1-ethyl-2-nitrobenzene and triethyl phosphite to obtain a phosphorimidate-product (N=P) that was converted to P-N on silica or alumina columns [83]. Cadogan and coworkers reportedly synthesized and investigated the nucleophilicity of various P-Ns in 1967 [84]. Two years later, a mixture of N-arylphosphoramidates, dialkyl phosphoramidates, and phosphonates were obtained when nitroso- and nitro-compounds were reduced in the presence of (RO)3P (R = alkyl) [85]. In 1975, Appel and Einig [86] reported a new synthesis to P-Ns by reacting phosphoric acid and an amine in the presence of triphenylphosphine (tPP) and CCl4. The same year, phase-transfer catalysis was introduced by Zwierzak to synthesize P-Ns through the phosphorylation of amines [87]. The selective alkylation of (EtO)2P(O)NH2 via silylation was achieved by Zwierzak in 1982 using [n-Bu4N]Br catalyst (Scheme2 route E)[88]. In 1984, Zwierzak and Osowska-Pacewicka reported the synthesis of various P-Ns via inorganic salt elimination [89] and the direct conversion of phosphoric acid [90]. In 1985, Riesel et al. reacted primary amines or NH3 with (RO)3P (R = alkyl) and CCl4 as an effective route to P-Ns [91]. Nielsen and Caruthers reported the first iodine-mediated reaction of phosphite and n-butylamine to synthesize P-Ns in 1988 (Scheme2 route F)[92]. At about the same time, P-Ns were synthesized from a reaction of azide and (RO)3P (R = alkyl) in a one-pot process [93]. A magnesium chloride-catalyzed reaction of 2,6-dimethylphenol and phosphorus oxychloride was used to generate phosphorochloridate, which was used for the phosphorylation of amines to synthesize P-Ns [94]. Molecules 2020, 25, 3684 6 of 37 MoleculesMolecules 2020 2020, 25, 25, x, xFOR FOR PEER PEER REVIEW REVIEW 6 6of of 37 37

OO BB CC PP ++ NN RORO HH R'R' HH OO OO ++ N RORO R''R'' P 22 N HH RO P OO PP OROR R'R' RR = = alkyl, alkyl, Bn, Bn, RO OROR R''R'' ++ CClCCl R',R', R'' R'' = = H, H, alkyl alkyl 44 RR = = alkyl alkyl B = base ++ BB R', R'' = alkyl or H B = base -- NHR''RNHR''R R', R'' = alkyl or H -- BHClBHCl - (RO) P(O)OH - (RO)22P(O)OH - CHCl - CHCl33 OO O O AA N O O P + 22 R' N H R' N RO P Cl+ R' H RO P N R' P + NH D RO Cl RO N RO P OPh +R'R' H D R'' + - - PhOH RO OPh RO R'' - [NH2R'R'']+ [Cl]- RO R'' - PhOH R'' RO - [NH2R'R''] [Cl] RO R'' RO R'' R = alkyl, aryl RO R = alkyl, aryl R = Ph, R' = H, R'' = - R', R'' = alkyl or H 10 mol% nBu4NBr R = Ph, R' = H, R'' = - R', R'' = alkyl or H 10 mol% nBu4NBr I2 NaH I2 -R'''OH NaH -R'''OH R'-Br - NH R'-Br - NH3 EtOH O - 2 Me3 SiBr EtOH O - 2 Me3SiBr F P + N H 3 F OR'''+ R' N H 2 O RO P OR''' R' O RO R'' 2 + N E RO R'' P NH Me3Si N R'' RO RO P 2 + Me3Si R'' E RO NH2 SiMe RO 3 R = functional alkyl, R' = H R'' = alkyl, SiMe3 R = functional alkyl, R' = H R'' = alkyl, RO R''' = 2-cyano-1,1-dimethylethyl R = Et, R' = alkyl, aryl, R'' = H R''' = 2-cyano-1,1-dimethylethyl R = Et, R' = alkyl, aryl, R'' = H Scheme 2. Selected early synthetic routes to phosphoramidates. SchemeScheme 2.2. SelectedSelected earlyearly synthetic routes to phosphoramidates. The aforementioned syntheses demonstrate the diversity of organophosphorus synthons The aforementioned syntheses demonstrate the diversity of organophosphorus synthons available availableThe aforementioned for P-N chemistry syntheses up until demonstrate1988 and highlight the diversity the main ofpioneers organophosphorus in the field (Figure synthons 4). for P-N chemistry up until 1988 and highlight the main pioneers in the field (Figure4). The research availableThe research for P-N in chemistrythese initial up studiesuntil 1988 has and focused highlight on reducingthe main waste,pioneers limiting in the toxicfield (Figurereagents, 4). in these initial studies has focused on reducing waste, limiting toxic reagents, improving selectivity, Theimproving research selectivity, in these initialexpanding studies scope, has and focused searching on reducingfor effective waste, and limitingefficient toxiccatalytic reagents, P-N expandingimprovingbond-making scope, selectivity, solutions. and searching expanding for escope,ffective and and sear effichingcient catalyticfor effective P-N bond-makingand efficient solutions.catalytic P-N bond-making solutions.

Figure 4. Timeline illustrating the pioneers who discovered the first syntheses of phosphoramidates. Figure 4. Timeline illustrating the pioneers who discovered the first syntheses of phosphoramidates.

Figure 4. Timeline illustrating the pioneers who discovered the first syntheses of phosphoramidates.

Molecules 2020, 25, 3684 7 of 37

Molecules 2020, 25, x FOR PEER REVIEW 7 of 37 2.2. Salt Elimination Route 2.2.Molecules Salt 2020Elimination, 25, x FOR Route PEER REVIEW 7 of 37 2.2.1. Modifications to the Atherton–Todd Reaction 2.2.1.2.2. Salt Modifications Elimination Routeto the Atherton–Todd Reaction A synthetic P-N was fortuitously prepared by Atherton, Openshaw, and Todd in 1945 by the salt2.2.1. eliminationA Modifications synthetic P-N method to was the Atherton–Toddfortuitously using H-phosphonates prepared Reaction by Athert (H-P)on, Openshaw, ((RO)2P(O)H; and Todd R = inEt, 1945i-Pr, by Bn)the and ammoniasalt elimination in the presence method using ofa H-phosphonates base (Scheme (H-P)2 route ((RO)B2P(O)H;)[78]. R The= Et, scopei-Pr, Bn) of and this ammonia method in was A synthetic P-N was fortuitously prepared by Atherton, Openshaw, and Todd in 1945 by the investigatedthe presence using of dia ffbaseerent (Scheme amines 2 (e.g.,route morpholine,B) [78]. The scope cyclohexylamine, of this method 1-phenylethan-1-amine was investigated using and differentsalt elimination amines method (e.g., morpholine,using H-phosphonates cyclohexyl (H-P)amine, ((RO) 1-phenylethan-1-amine2P(O)H; R = Et, i-Pr, Bn) and and benzylamine, ammonia in benzylamine, 4-methylmorpholine) or a mixture of aniline and N,N-dimethylcyclohexanamine, as well 4-methylmorpholine)the presence of a base or (Scheme a mixture 2 ofroute aniline B) [78].and NThe,N-dimethylcyclohexanamine, scope of this method was asinvestigated well as different using as different solvents (e.g., CCl4, Cl3CCCl3, and HCl2CCCl3). Isolated yields of 62–92% were obtained. solventsdifferent (e.g.,amines CCl (e.g.,4, Cl 3CCClmorpholine,3, and HClcyclohexyl2CCCl3).amine, Isolated 1-phenylethan-1-amine yields of 62–92% were and obtained.benzylamine, The in situ d The Atherton–ToddAtherton–Todd4-methylmorpholine) method method or wasa wasmixture prominent prominent of aniline for for itsand itsin N situ,N-dimethylcyclohexanamine, generationgeneration of (RO) of (RO)2P(O)Cl2P(O)Cl as(d ACPwell ( ;asACP; R different = alkyl, R = alkyl, benzyl),benzyl),solvents which which(e.g., eliminates CCleliminates4, Cl the3CCCl usethe3, ofanduse moisture- HClof moisture-2CCCl and3). air-sensitiveIsolatedand air-sensitive yieldsdACP. of d62–92% However,ACP. However,were the obtained. major the drawbacksmajor The Atherton–Todd method was prominent for its in situ generation of (RO)2P(O)Cl (dACP; R = alkyl, of thedrawbacks method include of the method the use include of halogen the use sources of halogen such assources CCl4 ,such Cl3CCCl as CCl3,4 and, Cl3CCCl HCl23CCCl, and HCl3 and2CCCl extensive3 work-upandbenzyl), /purificationextensive which work-up/purification eliminates of the products. the use In of 2020, themoisture- Chenproduc etandts. al. In reportedair-sensitive 2020, Chen a modified dACP.et al. reportedHowever, Atherton–Todd a themodified major reaction for theAtherton–Todddrawbacks synthesis of of the P-Nsreaction method using for include the air synthesis as the a radical use ofof P-Ns initiatorhalogen using sources (Scheme air as such a 3radical)[ as95 CCl]. initiator The4, Cl modified3CCCl (Scheme3, and method 3) HCl [95].2CCCl The explored3 and extensive work-up/purification of the products. In 2020, Chen et al. reported a modified P-N synthesismodified usingmethod (H-P) explored ((RO) P-NP(O)H; synthesis R = Et, usingi-Pr, (H-P) Bu, i-Bu) ((RO) and2P(O)H; benzylamine R = Et, withi-Pr, Bu, yields i-Bu) in theand range Atherton–Todd reaction for the2 synthesis of P-Ns using air as a radical initiator (Scheme 3) [95]. The of 30–75%.benzylamine Although with yields this method in the range offered of 30–75%. advantages Although such this as usingmethod air offered as a radical advantages initiator such atas room usingmodified air methodas a radicalexplored initiator P-N synthesis at room using temperature, (H-P) ((RO) 2P(O)H;the use R of= Et,relatively i-Pr, Bu, expensivei-Bu) and temperature, the use of relatively expensive 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (DBU) as 2,3,4,6,7,8,9,10-octahydrbenzylamine with yieldsopyrimido[1,2-a]azepine in the range of 30–75%. (DBU) Although as a base this in the method process, offered the elimination advantages ofsuch large as a baseamountsusing in the air process,of asstoichiometric a theradical elimination waste,initiator and ofat largecomparativroom amounts temperature,ely lower of stoichiometric yieldsthe useof productsof waste,relatively are and some comparativelyexpensive of the lowerlimitations.2,3,4,6,7,8,9,10-octahydr yields of productsopyrimido[1,2-a]azepine are some of the limitations. (DBU) as a base in the process, the elimination of large amounts of stoichiometric waste, and comparatively lower yields of products are some of the limitations.

SchemeScheme 3. A 3. modifiedA modified Atherton–Todd Atherton–Todd reaction for for the the synthesis synthesis of phosphoramidates. of phosphoramidates.

2.2.2.2.2.2. Direct Direct ConversionScheme Conversion 3. A of modified of Diethyl Diethyl Atherton–Todd Hydrogen Hydrogen Phosphate reaction for the synthesis of phosphoramidates. With reference to the limitations (such as low yield and the formation of organophosphorus 2.2.2.With Direct reference Conversion to the of Diethyllimitations Hydrogen (such as Phosphate low yield and the formation of organophosphorus anhydridesanhydrides side side products) products) in in the the methodmethod reportedreported by by Appel Appel and and Einig Einig [86], [86 Zwierzak], Zwierzak and and Osowska-PacewickaOsowska-PacewickaWith reference [ 90 to[90] ]the proposed proposedlimitations an an(such alternativealternative as low yield method method and thethat thatformation uses uses −OH of organophosphorusOHgroup group activator, activator, anhydrides side products) in the method reported by Appel and Einig −[86], Zwierzak and hexamethyltriaminodibromophosphoranehexamethyltriaminodibromophosphorane ((Me ((Me22N)3PBrPBr2).2). In In the the reported reported method, method, (Me (Me2N)32PBrN)23 PBrwas2 was preparedOsowska-Pacewicka in situ in a one-pot[90] proposed two-step synthesisan alternative of P-Ns method from (EtO) that2P(O)OH uses −andOH amines group (Scheme activator, 4) prepared in situ in a one-pot two-step synthesis of P-Ns from (EtO)2P(O)OH and amines (Scheme4)[ 90]. hexamethyltriaminodibromophosphorane ((Me2N)3PBr2). In the reported method, (Me2N)3PBr2 was The synthesis[90]. The wassynthesis explored was usingexplored various using amines various such amines as aniline, such as phenylmethanamine, aniline, phenylmethanamine, dibutylamine, dibutylamine,prepared in situ butan-1-amin in a one-pote, two-step dipropylamine, synthesis and of P-Ns hept-1-en-2- from (EtO)amine.2P(O)OH This methodand amines was (Scheme favorable 4) butan-1-amine, dipropylamine, and hept-1-en-2-amine. This method was favorable with improved with[90]. improvedThe synthesis yields was of exploredP-N products using (59–91%) various afteramines workup such asand aniline, eliminated phenylmethanamine, the route(s) for yields of P-N products (59–91%) after workup and eliminated the route(s) for anhydride formation. anhydridedibutylamine, formation. butan-1-amin Nevertheless,e, dipropylamine, the method and used hept-1-en-2- potentiallyamine. harmful This bromine method in was a multi-step favorable Nevertheless,tediouswith improved process the method withyields low usedof atom P-N potentially economy. products harmful(59–91%) bromineafter workup in a multi-stepand eliminated tedious the processroute(s) with for low atomanhydride economy. formation. Nevertheless, the method used potentially harmful bromine in a multi-step tedious process with low atom economy.

Scheme 4. One-pot two-step synthesis of phosphoramidates via (Me2N)3PBr2.

SchemeScheme 4. One-pot 4. One-pot two-step two-step synthesis synthesis ofof phosphoramidates via via (Me (Me2N)23N)PBr32PBr. 2.

Molecules 2020, 25, 3684 8 of 37 Molecules 2020, 25, x FOR PEER REVIEW 8 of 37

2.2.3. Inorganic Salt Elimination

In another salt elimination route, this time using inorganic bases and [n-Bu4N]Br as a catalyst, In another salt elimination route, this time using inorganic bases and [n-Bu4N]Br as a catalyst, Zwierzak and Osowska-Pacewicka synthesized P-Ns from (EtO)2P(O)H (diethyl H-P) and various Zwierzak and Osowska-Pacewicka synthesized P-Ns from (EtO)2P(O)H (diethyl H-P) and various amines (Scheme(Scheme5 5a)a) [ 89[89].]. AromaticAromatic aminesamines suchsuch asas anilineaniline andand 4-chloroaniline,4-chloroaniline, aliphaticaliphatic aminesamines suchsuch as cyclohexylamine,cyclohexylamine, n-butylamine,-butylamine, and ethanamine,ethanamine, and alkanolaminesalkanolamines such asas 2-aminoethan-1-ol,2-aminoethan-1-ol, 3-aminopropan-1-ol, and bis(2-(-ethoxy)ethyl)amine were explored to demonstrate the broad scopescope of this synthetic synthetic transformation. transformation. The The P-Ns P-Ns were were isol isolatedated in 83–100% in 83–100% yield yield after after recrystallization. recrystallization. In a similar synthesis, using [BnEt3N]Cl as the catalyst instead of [n-Bu4N]Br, Zwierzak accomplished the In a similar synthesis, using [BnEt3N]Cl as the catalyst instead of [n-Bu4N]Br, Zwierzak accomplished phosphorylation of amines using dialkyl H-phosphonate (RO)2P(O)H (R = Et, Bn, t-Bu; Scheme 5b) the phosphorylation of amines using dialkyl H-phosphonate (RO)2P(O)H (R = Et, Bn, t-Bu; Scheme[87]. A5 b)range [ 87 ].of A amines, range of such amines, as suchaniline, as aniline, benzylamine, benzylamine, cyclohexylamine, cyclohexylamine, ethylamine, ethylamine, and anddiethylamine diethylamine were were used. used. The The crude crude P-Ns P-Ns were were recr recrystallizedystallized to toafford afford pure pure products products in in 35–93% yield.yield. Due Due to to the the difficulty difficulty encountered in phosphorylating aromatic amines, as mentioned by Zwierzak [[87,89],87,89], LukanovLukanov etet al.al. proposedproposed a similarsimilar syntheticsynthetic routeroute usingusing NN-phenylformamide-phenylformamide oror 2-chloro-NN-phenylacetamide-phenylacetamide as as the the N-source, N-source, which which offered offered less stericless steric hindrance hindrance and better and N-Hbetter acidity N-H (Schemeacidity 5(Schemec) [ 96]. Derivatives5c) [96]. Derivatives of N-phenylformamide of N-phenylformamide or 2-chloro-N-phenylacetamide or 2-chloro-N-phenylacetamide (R’R”NC(O)R”’) were(R’R’’NC(O)R’’’) used containing were a used wide contai rangening of aryl-substituents a wide range of (e.g., aryl-substituents R” = Ph, 4-MeOPh, (e.g., R’’ 4-ClPh, = Ph, 2-MeOPh,4-MeOPh, 4-ClPh, 2-MeOPh, 2,3-Cl2Ph, 2-MePh, and 2,6-(C2H5)2Ph and 2,6-(CH3)2Ph). Either column 2,3-Cl2Ph, 2-MePh, and 2,6-(C2H5)2Ph and 2,6-(CH3)2Ph). Either column chromatography (on silica) orchromatography recrystallization (on were silica) used or torecrystallization purify the P-Ns were to obtain used to isolated purify yields the P-Ns in the to obtain range ofisolated 30–80%. yields in the range of 30–80%.

Scheme 5. Phosphoramidate syntheses via the inorganic salt elimination route. (a) Using [n-Bu N]Br Scheme 5. Phosphoramidate syntheses via the inorganic salt elimination route. (a) Using [n-Bu44N]Br as a catalyst, (b) using [BnEt N]Cl as a catalyst and (c) using [BnEt N]Br as a catalyst. as a catalyst, (b) using [BnEt33N]Cl as a catalyst and (c) using [BnEt33N]Br as a catalyst. Inorganic salt elimination methods stimulated an era of catalytic transformations of dialkyl Inorganic salt elimination methods stimulated an era of catalytic transformations of dialkyl H-P H-P ((RO)2P(O)H; R = alkyl) to (RO)2P(O)Cl (dACP; R = alkyl) in the presence of readily available ((RO)2P(O)H; R = alkyl) to (RO)2P(O)Cl (dACP; R = alkyl) in the presence of readily available inorganic bases, thereby eliminating the use of Et3N. However, this method has limitations including inorganic bases, thereby eliminating the use of Et3N. However, this method has limitations including a pre-functionalization step, the production of large amounts of stoichiometric waste, and the use of a pre-functionalization step, the production of large amounts of stoichiometric waste, and the use of hazardous halogenating reagents. hazardous halogenating reagents.

Molecules 2020, 25, x FOR PEER REVIEW 9 of 37

2.3. Oxidative Cross-Coupling Route

2.3.1. Using Chlorinating Agents A one-pot synthesis of P-Ns was reported by Gupta et al. (Scheme 6a) [97]. According to the authors, the chlorination of (RO)2P(O)H (R = Me, Et, Pr, i-Pr; 3 eq.) to afford (RO)2P(O)Cl (dACP; R = alkyl) was possible upon reacting with trichloroisocyanuric acid (tCiC-A; 1 eq.), which was then treated with an equal mixture of amines, R’R’’NH (R’ = Me, Et, Pr; R’’ = H) and Et3N, to form the P-N in 82–92% yield, which was determined as conversions by 31P NMR spectroscopy. However, the isolation of (RO)2P(O)NR’R” (R = Et, R’, R” = Et, Pr) product gave 79% yield. A similar method, under base-free reaction conditions, was achieved by Kaboudin et al. (Scheme 6b) [98]. The scope of Molecules 2020, 25, 3684 9 of 37 the synthesis was explored with (H-P) ((RO)2P(O)H; R = Et, i-Pr) and amine (e.g., N-methylaniline, naphthalen-1-amine, 2-phenylethan-1-amine, 3-chloro-2-methylaniline, 3-nitroaniline, benzylamine, or aniline). The crude product was purified by column chromatography (on silica) to yield isolated 2.3. Oxidative Cross-Coupling Route pure products in the range of 22–92%. 2.3.1. UsingJang and Chlorinating coworkers Agentsreported a facile synthetic route to form P-Ns using diphenyl phosphoric acid (dPPA) and an amine in the presence of both a chlorinating agent (Cl3CCN) and a base (Et3N), whichA one-pot was added synthesis to ofsequester P-Ns was the reported acid formed by Gupta during et al. (Schemethe reaction6a) [ 97 (Scheme]. According 6c) to[99]. the authors,The theapplicability chlorination of of (RO)the 2P(O)Hmethod (R =wasMe, Et,explored Pr, i-Pr; 3using eq.) toprop-2-en-1-amine, afford (RO)2P(O)Cl (ddiethylamine,ACP; R = alkyl ) was2-methylpropan-2-amine, possible upon reacting cyclohexylamine, with trichloroisocyanuric piperidine, acid morpholine, (tCiC-A; 1 and eq.), aniline. which The was crude then treatedproduct with anwas equal purified mixture by column of amines, chromatography R’R”NH (R’ =(onMe, silica) Et, Pr;to obtain R” = H) isolated and Et yields3N, to of form P-N theproducts P-N in in 82–92% the yield,range which of 53–93%. was determined A similar chlorination as conversions method by 31 Preacting NMR spectroscopy.an amine (e.g., However, aniline, thehexylamine, isolation of (RO)diethylamine,2P(O)NR’R” and (R methanamine)= Et, R’, R” = Et,with Pr) phosphoric product gave acid 79% ((R yield.2P(O)OH; A similar R = OEt, method, OBu, underOBn) in base-free the reactionpresence conditions, of triphenylphosphine was achieved and by KaboudinCCl4 was also et al. used (Scheme to synthesize6b) [ 98]. P-Ns The scope (Scheme of the 6d) synthesis [86]. The was exploredisolated withyields (H-P) of the ((RO) products2P(O)H; in th Ris= caseEt, iwere-Pr) andin the amine range (e.g., of 30–75%.N-methylaniline, naphthalen-1-amine, 2-phenylethan-1-amine,P-N synthesis via 3-chloro-2-methylaniline,oxidative cross-coupling using 3-nitroaniline, chlorinating benzylamine, agents offers or a aniline). short reaction The crude producttime, low was temperature purified by synthesis, column chromatographyand a diverse choice (on of silica) phosphorylating to yield isolated reagents. pure Nevertheless, products in the rangethe methods of 22–92%. use hazardous chlorinating agents such as CCl4 and Cl3CCN, generate large stoichiometric wastes, and involve a pre-functionalization step in the synthetic process.

Scheme 6. Phosphoramidate synthesis via oxidative cross-coupling route using different chlorinating agents, (a) trichloroisocyanuric acid and a base, (b) trichloroisocyanuric acid under base-free conditions, Scheme 6. Phosphoramidate synthesis via oxidative cross-coupling route using different (c) Cl3CCN, and (d) CCl4. chlorinating agents, (a) trichloroisocyanuric acid and a base, (b) trichloroisocyanuric acid under Jangbase-free and coworkersconditions, ( reportedc) Cl3CCN, a and facile (d) syntheticCCl4. route to form P-Ns using diphenyl phosphoric acid (dPPA) and an amine in the presence of both a chlorinating agent (Cl CCN) and a base (Et N), which was 2.3.2. Using Iodinating Agents 3 3 added to sequester the acid formed during the reaction (Scheme6c) [ 99]. The applicability of the method was exploredThe synthesis using of prop-2-en-1-amine, P-Ns from amines (aromatic diethylamine, and aliphatic) 2-methylpropan-2-amine, and symmetrical trialkyl cyclohexylamine, phosphite piperidine,(P(OR)3; R= morpholine, Me, Et, i-Pr) andin the aniline. presence The I2 was crude reported product by was Chen purified et al. [100]. by column Crude products chromatography were (onpurified silica) by to column obtain isolatedchromatography yields of (on P-N silica) products and resulted in the rangein yields of in 53–93%. the range A similarof 0–95%. chlorination For the methodlow yielding reacting derivatives, an amine (e.g., the aniline, reaction hexylamine, was more diethylamine, selective to and three methanamine) identified withby-products, phosphoric H-phosphonate, trialkyl phosphate, and tetraalkyl diphosphate, as well as some other unidentified acid ((R2P(O)OH; R = OEt, OBu, OBn) in the presence of triphenylphosphine and CCl4 was also used to synthesize P-Ns (Scheme6d) [ 86]. The isolated yields of the products in this case were in the range of 30–75%. P-N synthesis via oxidative cross-coupling using chlorinating agents offers a short reaction time, low temperature synthesis, and a diverse choice of phosphorylating reagents. Nevertheless, the methods use hazardous chlorinating agents such as CCl4 and Cl3CCN, generate large stoichiometric wastes, and involve a pre-functionalization step in the synthetic process.

2.3.2. Using Iodinating Agents The synthesis of P-Ns from amines (aromatic and aliphatic) and symmetrical trialkyl phosphite (P(OR)3;R= Me, Et, i-Pr) in the presence I2 was reported by Chen et al. [100]. Crude products were purified by column chromatography (on silica) and resulted in yields in the range of 0–95%. For the low yielding derivatives, the reaction was more selective to three identified by-products, H-phosphonate, trialkyl phosphate, and tetraalkyl diphosphate, as well as some other unidentified Molecules 2020, 25, x FOR PEER REVIEW 10 of 37 by-products. Important compounds such as phosphoryl amino acid esters (8–11) were synthesized using the iodine-mediated method (Figure 5).

Molecules 2020, 25, 3684 10 of 37

Molecules 2020, 25, x FOR PEER REVIEW 10 of 37 by-products.Figure Important5. Structures compounds of suchbenzyl as phosphoryl(diethoxyphosphoryl)- amino acid estersD-prolinate (8–11 ) were(8), synthesizedethyl usingby-products.(diethoxyphosphoryl)- the iodine-mediated Important compoundsL-phenylalaninate method (Figure such as5). phosphoryl amino(9 ),acid esters (8–11) weretetraethyl synthesized using((1S,3S)-cyclohexane-1,3-diyl)bis(phosphoramidate) the iodine-mediated method (Figure 5). (10), diethyl ((1S,3S)-3-aminocyclohexyl)phosphoramidate (11) synthesized by iodinating agents.

Iodine (I2) has also been used as a catalyst under solvent-free conditions to couple aryl amines (PhNH2 and derivatives containing OH, OEt, CN, OMe, NO2, F, Cl, or Br substituents on Ph) with (RO)2P(O)H (dialkyl H-P; R = Me, Et) affording dialkyl P-Ns (Scheme 7b) [101]. Then, the crude products were purified by column chromatography (on silica) to obtain yields of product in 0–88%.

The best yielding conditions were shorter reaction times without solvent. Reactions performed in FigureFigure 5. Structures5. Structures of benzyl of (diethoxyphosphoryl)- benzyl (diethoxyphosphoryl)-d-prolinate (8), ethylD-prolinate (diethoxyphosphoryl)- (8), ethyl polar non-protic solvents (e.g., CH2Cl2), non-polar solvents (e.g., hexane), or protic solvents (e.g., l-phenylalaninate (9), tetraethyl ((1S,3S)-cyclohexane-1,3-diyl)bis(phosphoramidate) (10), diethyl MeOH)(diethoxyphosphoryl)- all suffered from Lreduced-phenylalaninate efficiency and selectivity. Furthermore,(9), aniline withtetraethyl substituents ((1S,3S)-3-aminocyclohexyl)phosphoramidate (11) synthesized by iodinating agents. at ortho((1S,3S)-cyclohexane-1,3-diyl)bis(phosphoramidate)- and meta-positions were observed to have reacted faster (and10), were higher yieldingdiethyl than ((1S,3S)-3-aminocyclohexyl)phosphoramidate (11) synthesized by iodinating agents. aniline containing substituents at the para-position. Iodine (I2) has also been used as a catalyst under solvent-free conditions to couple aryl amines I2 was used in the presence of H2O2 as a catalyst at 20 °C for the dehydrogenative cross-coupling (PhNHIodine2 and (I derivatives2) has also been containing used as OH, a catalyst OEt, CN, under OMe, solvent-free NO2, F, Cl, conditions or Br substituents to couple aryl on Ph) amines with of diethyl H-P and amine or sulfoximines to form P-Ns (Scheme 7c) [102]. Purification of the (RO)(PhNH2P(O)H2 and (dialkylderivatives H-P; containing R = Me, Et)OH, a ffOEt,ording CN, dialkyl OMe, NO P-Ns2, F, (Scheme Cl, or Br7b) substituents [ 101]. Then, on thePh) crudewith products by column chromatography (on silica) afforded P-Ns with isolated yields of 31–96%, with products(RO)2P(O)H were (dialkyl purified H-P; by columnR = Me, chromatographyEt) affording dialkyl (on silica) P-Ns to(Scheme obtain yields7b) [101]. of product Then, the in 0–88%.crude the lower yielding products reported from sulfoximine. Both alkyl and aryl H-P ((RO)2P(O)H, R = Et, Theproducts best yielding were purified conditions by column were shorter chromatography reaction times (on without silica) to solvent. obtain Reactionsyields of product performed in in0–88%. polar i-Pr, Ph) were used as the substrate along with cyclic aromatic secondary amines (e.g., indole), non-proticThe best yielding solvents conditions (e.g., CH2Cl were2), non-polar shorter reacti solventson times (e.g., hexane),without orsolvent. protic Reactions solvents (e.g., performed MeOH) in all derivatives of heterocyclic amines (e.g., furfurylamine), aliphatic cyclic secondary amines (e.g., supolarffered non-protic from reduced solvents effi ciency(e.g., CH and2Cl selectivity.2), non-polar Furthermore, solvents (e.g., aniline hexane), with substituents or protic solvents at ortho (e.g.,- and 1-benzhydrylpiperazine), tertiary amines (e.g., N-methylhomopiperazine), or sulfoximine. metaMeOH)-positions all suffered were observedfrom reduced to have efficiency reacted and faster sele andctivity. were Furthermore, higher yielding an thaniline anilinewith substituents containing According to the article, using other sources of I2 such as KI or N-bromosuccinimide (NBS) for the substituentsat ortho- and at meta the -positionspara-position. were observed to have reacted faster and were higher yielding than reactionaniline containingresulted in substituents decreased yield at the and para trace-position. quantities of the desired products, respectively. I2 was used in the presence of H2O2 as a catalyst at 20 °C for the dehydrogenative cross-coupling of diethyl H-P and amine or sulfoximines to form P-Ns (Scheme 7c) [102]. Purification of the products by column chromatography (on silica) afforded P-Ns with isolated yields of 31–96%, with the lower yielding products reported from sulfoximine. Both alkyl and aryl H-P ((RO)2P(O)H, R = Et, i-Pr, Ph) were used as the substrate along with cyclic aromatic secondary amines (e.g., indole), derivatives of heterocyclic amines (e.g., furfurylamine), aliphatic cyclic secondary amines (e.g., 1-benzhydrylpiperazine), tertiary amines (e.g., N-methylhomopiperazine), or sulfoximine. According to the article, using other sources of I2 such as KI or N-bromosuccinimide (NBS) for the reaction resulted in decreased yield and trace quantities of the desired products, respectively.

SchemeScheme 7. Iodine-mediatedIodine-mediated synthesis synthesis of of phosphoramidates phosphoramidates using using iodine iodine as a catalystas a catalyst (a) with (a a) solvent,with a b c solvent,( ) under (b a) under solvent-free a solvent-free conditions, conditions, and ( ) in and the (c presence) in the presence of H2O2 .of H2O2.

I was used in the presence of H O as a catalyst at 20 C for the dehydrogenative cross-coupling of Iodine-mediated2 oxidative cross-coupling2 2 methods ◦offer better routes to P-N compounds by diethyl H-P and amine or sulfoximines to form P-Ns (Scheme7c) [ 102]. Purification of the products by eliminating toxic halogenating agents such as CCl4 in the synthetic processes. The method also uses column chromatography (on silica) afforded P-Ns with isolated yields of 31–96%, with the lower yielding inexpensive oxidants without additives and generates water or alkanol as stoichiometric waste. products reported from sulfoximine. Both alkyl and aryl H-P ((RO) P(O)H, R = Et, i-Pr, Ph) were used However, the synthetic routes are prone to the formation of many2 undesired side products, suffer as the substrate along with cyclic aromatic secondary amines (e.g., indole), derivatives of heterocyclic from low yields, and sometimes have limited applicability. amines (e.g., furfurylamine), aliphatic cyclic secondary amines (e.g., 1-benzhydrylpiperazine), tertiary amines (e.g., N-methylhomopiperazine), or sulfoximine. According to the article, using other sources Scheme 7. Iodine-mediated synthesis of phosphoramidates using iodine as a catalyst (a) with a of I2 such as KI or N-bromosuccinimide (NBS) for the reaction resulted in decreased yield and trace quantitiessolvent, of ( theb) under desired a solvent-free products, conditions, respectively. and (c) in the presence of H2O2. Iodine-mediated oxidative cross-coupling methods offer better routes to P-N compounds by Iodine-mediated oxidative cross-coupling methods offer better routes to P-N compounds by eliminating toxic halogenating agents such as CCl4 in the synthetic processes. The method also eliminating toxic halogenating agents such as CCl4 in the synthetic processes. The method also uses uses inexpensive oxidants without additives and generates water or alkanol as stoichiometric waste. inexpensive oxidants without additives and generates water or alkanol as stoichiometric waste. However, the synthetic routes are prone to the formation of many undesired side products, suffer from However, the synthetic routes are prone to the formation of many undesired side products, suffer low yields, and sometimes have limited applicability. from low yields, and sometimes have limited applicability.

Molecules 2020, 25, 3684 11 of 37

2.3.3. UsingMolecules Transition 2020, 25, x FOR Metal PEER CatalystsREVIEW 11 of 37

The2.3.3. aerobic Using oxidative Transition couplingMetal Catalysts of amines and disubstituted H-phosphonates (H-P) (RO)2P(O)H (R = Me, Et, i-Pr; 1 eq.) in the presence of copper catalysts to synthesize P-Ns was reported by Hayes The aerobic oxidative coupling of amines and disubstituted H-phosphonates (H-P) (RO)2P(O)H and coworkers(R = Me, Et, (Table i-Pr; 11, eq.) route in the a) presence [ 103]. The of copper authors cataly reportedsts to synthesize that the P-Ns ligands was reported on the copperby Hayes catalyst were importantand coworkers in the (Table reaction, 1, route but a) not [103]. the initialThe author oxidations reported state that of the copper ligands catalyst, on the copper and that catalyst the primary amineswere coupled important better in than the reaction, the secondary but not the and initia tertiaryl oxidation amines state due of copper to the catalyst, reduced and steric that hindrance.the The methodprimary was amines slightly coupled modified better for than the the synthesis secondary of and some tertiary important amines phosphoryl due to the reduced amino steric compounds such ashindrance. ethyl (diethoxyphosphoryl)glycinate, The method was slightly modified etc. for the (12 –synthesis15) (Figure of some6). important phosphoryl amino compounds such as ethyl (diethoxyphosphoryl)glycinate, etc. (12–15) (Figure 6).

Table 1.TableOxidative 1. Oxidative cross-coupling cross-coupling using using transition transition me metaltal catalysts catalysts to form to form phosphoramidates. phosphoramidates.

Reaction Yield RouteRoute CatalystCatalyst Reaction Conditions RR R’, R”R’, R’’ Yield Range/%Ref. Conditions Range/% a 20 mol% CuI MeCN, 55 ◦C Me, Et, i-Pr H, alkyl 16–98 [103] Me, Et, H, Ph, ba 5 mol% 20 mol% CuBr CuI EtOAc, MeCN, 20 C 55 °C Et, i-Pr, Bu H, alkyl 20–94 16–98 [103] [104] ◦ i-Pr functional Ph 15 mol% Et, i-Pr, H, Ph,H, Bn, Ph, cb 5 mol% CuBr CCl4 EtOAc,, 20 ◦C 20 °C Et, i-Pr 52–8520–94 [104] [105] Fe3O4@MgO Bu cycloalkylfunctional Ph 200 mol% Acetone, Cs CO , Me, Et, d 15 mol% 2 3 H,H, alkyl Ph, Bn, 25–93 [106] c CuCl2 20CCl◦C 4, 20 °C Pr, i-Pr Et, i-Pr 52–85 [105] 10Fe mol%3O4@MgO Toluene, K CO , Me, Et, cycloalkyl e 2 3 RCOR a 52–99 [107] Cu(OAc)200 mol%2 mol.Acetone, sieve, 80 Cs◦C2CO3,20 i-Pr, BuMe, Et, d Me, Et, i-Pr, H, alkyl,H, alkyl 25–93 [106] f 2 mol%CuCl CuBr2 EtOAc, 25 °CC Pr, i-Pr 86–96 [108] ◦ Bu, Ph cycloalkyl, R b 10 mol% Toluene, K2CO3, Me, Et, e 5 mol% c RCORd a 52–99 [107] g Cu(OAc)2 MeOH,mol. NaN sieve,3, 20 ◦ C80 °C Et i-Pr, Bu R-B(OH)2 67–93 [109] Cu(OAc)2 Me, Et, a urea, oxazolidinone, indole, pyrrolidinone, lactam, and sulfonamide derivatives;H, alkyl, b methyl alaninate; c triethyl f d 2 mol% CuBr EtOAc, 25 °C i-Pr, Bu, 86–96 [108] Moleculesphosphite; 2020, 25, xphenylboronic FOR PEER REVIEW acid and phenylboronic ester derivatives. cycloalkyl, R b 12 of 37 Ph 5 mol% g MeOH, NaN3, 20 °C Et c R-B(OH)2 d 67–93 [109] Cu(OAc)2 a urea, oxazolidinone, indole, pyrrolidinone, lactam, and sulfonamide derivatives; b methyl alaninate; c triethyl phosphite; d phenylboronic acid and phenylboronic ester derivatives.

FigureFigure 6. 6.Structures Structures of ethyl of (diethoxyphosphoryl)glycinate ethyl (diethoxyphosphoryl)glycinate (12), methyl ((((2R,3S,5S)-5-(((tert-(12), methyl ((((2R,3S,5S)-5-(((tert-butyldimethylsilyl)oxy)methylbutyldimethylsilyl)oxy)methyl)-2-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)tetrahydrofuran-)-2-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1( 2H)-yl)tetrahydrofuran-3-yl)oxy)(metho3-yl)oxy)(methoxy)phosphoryl)-D-phenylalaninatexy)phosphoryl)-D-phenylalaninate (13), methyl (diethoxyphosphoryl)- (13l-phenylalaninate), methyl (diethoxyphosphoryl)-(14), (2R,3S,5S)-5-(((tert-butyldimethylsilyl)oxy)methyl)-2-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-L-phenylalaninate (14), (2R,3S,5S)-5-(((tert-butyldimethylsilyl)oxy)methyl1(2H)-yl)tetrahydrofuran-3-yl methyl benzylphosphoramidate)-2-(5-methyl-2,4-dioxo-3, (15) synthesized4-dihydropyrimidin-1(2 by aerobic oxidative H)-yl)tetrahydrofuran-3-ylcross coupling. methyl benzylphosphoramidate (15) synthesized by aerobic oxidative cross coupling.

Another copper-catalyzed aerobic oxidative cross-coupling reaction reported by Wang et al. in 2013 involved the coupling of aryl amines (1.5 eq.) and dialkyl H-phosphonates (RO)2P(O)H (R = Et, i-Pr, Bu; 1 eq.) in the presence of CuBr (5 mol%) to give P-Ns (Table 1, route b) [104]. Although para- or meta-substituted aryl amines were very effective substrates in this reaction, the conversions observed with ortho-substituted aryl amines or aryl amines with strong electron-withdrawing substituents (e.g., 4-nitroaniline) as well as alkylamines were very poor. The effectiveness of the reaction with diaryl H-phosphonates was not reported. In 2015, Fe3O4@MgO nanoparticles were used as a catalyst to synthesize P-N from primary amines and H-P via the Atherton–Todd coupling reaction with CCl4 (Table 1, route c) [105]. After column chromatography (on silica), P-Ns were isolated in 52–85% yield. The Fe3O4@MgO nanoparticles were recycled by washing successively with H2O and MeOH and drying before reuse. Although the scope of the transformation was not challenged by investigating aromatic H-Ps, this route offers some advantages, such as the use of a low-cost reusable catalyst with proven activity for up to four consecutive reactions. Purohit et al. reported a one-pot synthesis of P-Ns from (RO)2P(O)H (R = Et, Pr, i-Pr; 1 eq.) and amine in the presence of CuCl2 and Cs2CO3 (Table 1, route d) [106]. The reported yields for the variety of desired products were in the range of 25–93% as determined by 31P NMR spectroscopy. A Cu(II) catalyst, a base, and air as an oxidant were used to synthesize N-acylphosphoramidates (AcP-N) from (RO)2P(O)H (R = Me, Et, i-Pr, Bu) and an amide via an oxidative cross-coupling reaction according to Mizuno et al. (Table 1, route e) [107]. The scope of the reaction was investigated by changing the R substituent as well as the nitrogen nucleophiles (e.g., urea, oxazolidinone, indole, pyrrolidinone, lactam, and sulfonamide derivatives). Column chromatography (on silica) using different solvent mixtures was used to purify the desired P-Ns in 52–99% yield. Through the reagent screening, Mizuno et al. [107] found that Cu(OTf)2 gave similar cross-coupling results as Cu(OAc)2, while other Cu catalysts such as CuCl2 and CuSO4 and other transition metal catalysts (e.g., Co(OAc)2.4H2O, Fe(OAc)2) were not selective or completely ineffective. Another copper-catalyzed synthesis of P-N at 20 °C in the presence of air, reported by Zhou et al., involved reacting (RO)2P(O)H (R = Me, Et, i-Pr, Ph) with primary or secondary amines

Molecules 2020, 25, 3684 12 of 37

Another copper-catalyzed aerobic oxidative cross-coupling reaction reported by Wang et al. in 2013 involved the coupling of aryl amines (1.5 eq.) and dialkyl H-phosphonates (RO)2P(O)H (R = Et, i-Pr, Bu; 1 eq.) in the presence of CuBr (5 mol%) to give P-Ns (Table1, route b) [ 104]. Although para- or meta-substituted aryl amines were very effective substrates in this reaction, the conversions observed with ortho-substituted aryl amines or aryl amines with strong electron-withdrawing substituents (e.g., 4-nitroaniline) as well as alkylamines were very poor. The effectiveness of the reaction with diaryl H-phosphonates was not reported. In 2015, Fe3O4@MgO nanoparticles were used as a catalyst to synthesize P-N from primary amines and H-P via the Atherton–Todd coupling reaction with CCl4 (Table1, route c) [ 105]. After column chromatography (on silica), P-Ns were isolated in 52–85% yield. The Fe3O4@MgO nanoparticles were recycled by washing successively with H2O and MeOH and drying before reuse. Although the scope of the transformation was not challenged by investigating aromatic H-Ps, this route offers some advantages, such as the use of a low-cost reusable catalyst with proven activity for up to four consecutive reactions. Purohit et al. reported a one-pot synthesis of P-Ns from (RO)2P(O)H (R = Et, Pr, i-Pr; 1 eq.) and amine in the presence of CuCl2 and Cs2CO3 (Table1, route d) [ 106]. The reported yields for the variety of desired products were in the range of 25–93% as determined by 31P NMR spectroscopy. A Cu(II) catalyst, a base, and air as an oxidant were used to synthesize N-acylphosphoramidates (AcP-N) from (RO)2P(O)H (R = Me, Et, i-Pr, Bu) and an amide via an oxidative cross-coupling reaction according to Mizuno et al. (Table1, route e) [ 107]. The scope of the reaction was investigated by changing the R substituent as well as the nitrogen nucleophiles (e.g., urea, oxazolidinone, indole, pyrrolidinone, lactam, and sulfonamide derivatives). Column chromatography (on silica) using different solvent mixtures was used to purify the desired P-Ns in 52–99% yield. Through the reagent screening, Mizuno et al. [107] found that Cu(OTf)2 gave similar cross-coupling results as Cu(OAc)2, while other Cu catalysts such as CuCl2 and CuSO4 and other transition metal catalysts (e.g., Co(OAc)2.4H2O, Fe(OAc)2) were not selective or completely ineffective. Another copper-catalyzed synthesis of P-N at 20 ◦C in the presence of air, reported by Zhou et al., Moleculesinvolved 2020 reacting, 25, x FOR (RO) PEER2P(O)H REVIEW (R = Me, Et, i-Pr, Ph) with primary or secondary amines (butylamine,13 of 37 dibutylamine, hexylamine, cylohexylamine, and methyl alaninate; Table1, route f) [ 108]. The crude (butylamine,P-Ns were extracted dibutylamine, and then hexylamine, concentrated cylohexylamine, under vacuum and to obtainmethyl purealaninate; products Table with 1, excellentroute f) [108].isolated The yields crude (86–96%). P-Ns were Similar extracted to other and copper-catalyzedthen concentrated P-N under synthesis, vacuum the to authorsobtain pure reported products a low withyield excellent (21%) when isolated dibutylamine yields (86–96%). and diisopropyl Similar H-Pto other were copper-catalyzed used as substrates, P-N which synthesis, could bethe attributed authors reportedto steric eaff lowects. yield In addition, (21%) when the method dibutylamine was not and effective diisopropyl when diphenylphosphine H-P were used as substrates, oxide (dPPO) which was couldreacted be with attributed butylamine to (13%steric isolated effects. yield) In dueaddition, to oxidative the conversionmethod was to phosphonic not effective acid (whenPP-A). diphenylphosphineUsing this aerobic copper-catalyzed oxide (dPPO) was dehydrocoupling reacted with butylamine method, Zhou(13% is etolated al. synthesized yield) due ato phosphoryl oxidative conversionamino compound to phosphonic (16) (Figure acid7). (PP-A). Using this aerobic copper-catalyzed dehydrocoupling method, Zhou et al. synthesized a phosphoryl amino compound (16) (Figure 7).

Figure 7. Structure of methyl (isopropoxy(((2S,5R)-5-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)- Figure 7. Structure of methyl 2,5-dihydrofuran-2-yl)oxy)phosphoryl)-d-alaninate (16) synthesized by aerobic copper-catalyzed oxidative (isopropoxy(((2S,5R)-5-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2,5-dihydrofuran-2-yl)o cross coupling. xy)phosphoryl)-D-alaninate (16) synthesized by aerobic copper-catalyzed oxidative cross coupling. Phenylboronic acid or ester-based substrates were converted in situ to an organic azide using Phenylboronic acid or ester-based substrates were converted in situ to an organic azide using a a Cu-based catalyst and subsequently used for the synthesis of P-Ns via a coupling reaction, according Cu-based catalyst and subsequently used for the synthesis of P-Ns via a coupling reaction, according to Dangroo et al. (Table1, route g) [ 109]. Triethyl and trimethyl phosphate were used as the P-sources to Dangroo et al. (Table 1, route g) [109]. Triethyl and trimethyl phosphate were used as the while phenylboronic acids or esters with substituents such as CN, NO2, OH, OMe and halides P-sources while phenylboronic acids or esters with substituents such as CN, NO2, OH, OMe and halides were used for azide conversion. The reaction was very tolerant to compounds with unsaturated boron–carbon bonds giving isolated yields of 67–93%. However, this reaction is not effective for compounds containing saturated boron–carbon bonds such as butyl boronic acid or cyclopentyl boronic acid. Transition metal-catalyzed oxidative cross-coupling methods for P-N synthesis have become attractive in recent years because of the advantages of using readily available inexpensive catalysts, for example CuXn (X = Cl, Br, (OAc), etc., n = 1, 2), and air as an oxidant. In addition, this route uses environmentally friendly H-P (RO)2P(O)H (R = alkyl, Ph) and amines as starting materials in a one-pot single-step process without any need for purification of the starting material, thereby making the process cost- and time-effective. Apart from eliminating hazardous starting materials, the method uses fewer chemical additives and generates mainly water as a stoichiometric waste. Furthermore, the methods offer a possibility of catalyst recycling, which is an important attribute for any green chemical process in terms of mass production. However, a notable limitation of the synthetic route is the formation of various undesired by-products from the reactivities of H-P and amine with the catalysts under oxidative conditions [103].

2.3.4. Using an Organophotocatalyst Guo et al. used visible light and organic dyes as catalysts for the dehydrogenative cross-coupling reaction of (EtO)2P(O)H (H-P) and amines (aniline, aniline derivatives with CN, X, Me, OMe and 1-naphthylamine) to form the corresponding P-Ns (Scheme 8) [110]. After an extraction, the pure product was formed with isolated yield in the range of 0–99%. It is noteworthy that the method was not effective when vinylaniline and 2-aminothiazole were used because of their radical sensitivity making them prone to either polymerization or decomposition in the reaction media, respectively. Although no product was formed when secondary aliphatic amines were used, moderate yields of up to 59% were obtained from primary or tertiary aliphatic amines, while a complex mixture of products was formed when an aromatic H-P was used.

Molecules 2020, 25, 3684 13 of 37 were used for azide conversion. The reaction was very tolerant to compounds with unsaturated boron–carbon bonds giving isolated yields of 67–93%. However, this reaction is not effective for compounds containing saturated boron–carbon bonds such as butyl boronic acid or cyclopentyl boronic acid. Transition metal-catalyzed oxidative cross-coupling methods for P-N synthesis have become attractive in recent years because of the advantages of using readily available inexpensive catalysts, for example CuXn (X = Cl, Br, (OAc), etc., n = 1, 2), and air as an oxidant. In addition, this route uses environmentally friendly H-P (RO)2P(O)H (R = alkyl, Ph) and amines as starting materials in a one-pot single-step process without any need for purification of the starting material, thereby making the process cost- and time-effective. Apart from eliminating hazardous starting materials, the method uses fewer chemical additives and generates mainly water as a stoichiometric waste. Furthermore, the methods offer a possibility of catalyst recycling, which is an important attribute for any green chemical process in terms of mass production. However, a notable limitation of the synthetic route is the formation of various undesired by-products from the reactivities of H-P and amine with the catalysts under oxidative conditions [103].

2.3.4. Using an Organophotocatalyst Guo et al. used visible light and organic dyes as catalysts for the dehydrogenative cross-coupling reaction of (EtO)2P(O)H (H-P) and amines (aniline, aniline derivatives with CN, X, Me, OMe and 1-naphthylamine) to form the corresponding P-Ns (Scheme8)[ 110]. After an extraction, the pure product was formed with isolated yield in the range of 0–99%. It is noteworthy that the method was not effective when vinylaniline and 2-aminothiazole were used because of their radical sensitivity making them prone to either polymerization or decomposition in the reaction media, respectively. Although no product was formed when secondary aliphatic amines were used, moderate yields of up to 59% were obtained from primary or tertiary aliphatic amines, while a complex mixture of products Molecules 2020, 25, x FOR PEER REVIEW 14 of 37 was formed when an aromatic H-P was used.

Scheme 8. Visible light and organic dye-catalyzed synthesis of phosphoramidates. Scheme 8. Visible light and organic dye-catalyzed synthesis of phosphoramidates. 2.3.5. Using Alkali–Metal Catalyst 2.3.5. Using Alkali–Metal Catalyst An oxidative cross-coupling reaction of amines and (EtO)2P(O)H (H-P) in the presence of lithium iodide-tert-butylAn oxidative hydroperoxide cross-coupling (LiI /reTBHP)action was of usedamines for theand synthesis (EtO)2P(O)H of P-N (H-P) and otherin the compounds presence byof Reddylithium et iodide-tert-butyl al. (Scheme9)[ 111 hydroperoxide]. The crude products (LiI/TBHP) were was purified used by for column the synthesis chromatography of P-N and (on silica)other withcompounds isolated by yields Reddy of 65%et al. and (Scheme 31% for 9) the [111]. use ofThe benzylamine crude products and 4-chloroaniline, were purified respectively.by column Otherchromatography amines were (on not silica) investigated. with isolated Although yields the of method 65% and uses 31% an inexpensivefor the use catalystof benzylamine and oxidant, and the4-chloroaniline, applicability ofrespectively. the process Other was not amines explored were using not diverseinvestigated. H-P and Although amines. the method uses an inexpensive catalyst and oxidant, the applicability of the process was not explored using diverse H-P and amines.

Scheme 9. Oxidative cross-coupling reaction of amines and H-phosphonates to form phosphoramidates in the presence of LiI/TBHP.

2.4. Azide Route

Many conventional routes to P-N synthesis as discussed above have used H-P (RO)2P(O)H (R = alkyl, Bn, Ph) or (RO)2P(O)Cl (dACP; R = alkyl, Bn, Ph) and amine as the P- and N-sources, respectively. As a result, derivatives of P-N compounds synthesized through these routes are limited mainly to substituents on the amine starting materials. Due to increased applicability, it has become necessary to synthesize P-N compounds with diverse functionalities. In order to achieve this, nitrene insertion from organic azides is becoming a popular one because the route uses phosphoryl azide, which acts a dual source of P and N. In this case, it is possible to add (or insert) diverse molecules on the P-N moiety through C-N bond formation.

2.4.1. Nitrene Insertion from Organic Azide A route to P-N formation through C–N bond formation was explored by Chang, Kim, and coworkers (Scheme 10a) [112]. The P-N was synthesized in the presence of an Ir(III)-based catalyst using an amide or a ketone and a phosphoryl azide. The product was purified by column chromatography (on silica) with isolated yields in the range 41–99%. The scope of the synthesis was explored using phosphoryl azide substituted with binaphthyl, aryl, and alkyl groups, while the phenone had substituents such as phenyl, methyl, and isobutane groups. Furthermore, 4-methoxy, 4-CF3, and tert-butyl were some of the substituents on the benzamide. Biologically active phosphoramidates (17 and 18) were synthesized through this method (Figure 8).

Molecules 2020, 25, x FOR PEER REVIEW 14 of 37

Scheme 8. Visible light and organic dye-catalyzed synthesis of phosphoramidates.

2.3.5. Using Alkali–Metal Catalyst

An oxidative cross-coupling reaction of amines and (EtO)2P(O)H (H-P) in the presence of lithium iodide-tert-butyl hydroperoxide (LiI/TBHP) was used for the synthesis of P-N and other compounds by Reddy et al. (Scheme 9) [111]. The crude products were purified by column chromatography (on silica) with isolated yields of 65% and 31% for the use of benzylamine and 4-chloroaniline, respectively. Other amines were not investigated. Although the method uses an inexpensiveMolecules 2020, 25catalyst, 3684 and oxidant, the applicability of the process was not explored using diverse14 H-P of 37 and amines.

Scheme 9. Oxidative cross-coupling reaction of amines and H-phosphonates to form phosphoramidates Scheme 9. Oxidative cross-coupling reaction of amines and H-phosphonates to form in the presence of LiI/TBHP. phosphoramidates in the presence of LiI/TBHP. 2.4. Azide Route 2.4. Azide Route Many conventional routes to P-N synthesis as discussed above have used H-P (RO)2P(O)H Many conventional routes to P-N synthesis as discussed above have used H-P (RO)2P(O)H (R = (R = alkyl, Bn, Ph) or (RO)2P(O)Cl (dACP; R = alkyl, Bn, Ph) and amine as the P- and N-sources, alkyl,respectively. Bn, Ph) As or a result,(RO)2P(O)Cl derivatives (dACP; of P-N R = compounds alkyl, Bn, synthesizedPh) and amine through as the these P- routes and N-sources, are limited respectively.mainly to substituents As a result, on derivati the amineves of starting P-N compounds materials. Duesynthesized to increased through applicability, these routes it has are becomelimited mainlynecessary to substituents to synthesize on P-N the compounds amine starting with materials. diverse functionalities. Due to increased In order applicability, to achieve it this,has become nitrene necessaryinsertion fromto synthesize organic azidesP-N compou is becomingnds with a populardiverse functionalities. one because the In route order uses to achieve phosphoryl this, nitrene azide, whichinsertion acts from a dual organic source azides of P and is becoming N. In this a case, popu itlar is possibleone because to add the (or route insert) uses diverse phosphoryl molecules azide, on whichthe P-N acts moiety a dual through source C-Nof P bondand N. formation. In this case, it is possible to add (or insert) diverse molecules on the P-N moiety through C-N bond formation. 2.4.1. Nitrene Insertion from Organic Azide 2.4.1. Nitrene Insertion from Organic Azide A route to P-N formation through C-N bond formation was explored by Chang, Kim, and coworkers (SchemeA route 10a) [to112 P-N]. The formation P-N was synthesizedthrough C–N in thebond presence formation of an was Ir(III)-based explored catalyst by Chang, using Kim, an amide and coworkersor a ketone (Scheme and a phosphoryl 10a) [112]. azide. The P-N The was product synthesize was purifiedd in the by presence column chromatographyof an Ir(III)-based (on catalyst silica) withusing isolated an amide yields or ina theketone range and 41–99%. a phosphoryl The scope ofazide. the synthesisThe product was exploredwas purified using phosphorylby column chromatographyazide substituted (on with silica) binaphthyl, with isolated aryl, and yields alkyl in groups, the range while 41–99%. the phenone The scope had of substituents the synthesis such was as exploredphenyl, methyl, using phosphoryl and isobutane azide groups. substituted Furthermore, with binaphthyl, 4-methoxy, 4-CFaryl, 3and, and alkyl tert-butyl groups, were while some the of phenonethe substituents had substituents on the benzamide. such as Biologicallyphenyl, methyl active, and phosphoramidates isobutane groups. (17 Furthermore,and 18) were synthesized4-methoxy, 4-CF3, and tert-butyl were some of the substituents on the benzamide. Biologically active Moleculesthrough 2020 this, 25 method, x FOR PEER (Figure REVIEW8). 15 of 37 phosphoramidates (17 and 18) were synthesized through this method (Figure 8).

SchemeScheme 10. 10. PhosphoramidatePhosphoramidate synthesis synthesis vi viaa nitrene nitrene insertion insertion using, using, (a (a) )5 5 mol% mol% Ir(III)-based Ir(III)-based catalyst, catalyst, ((bb)) 5 5 mol% mol% Ru RuIVIV-porphyrin-catalyst,-porphyrin-catalyst, and and (c ()c )4 4mol% mol% Ir(III)-based Ir(III)-based catalyst. catalyst.

Figure 8. Structures of (1R,2R,5R)-5-isopropyl-2-methylcyclohexyl phenyl (2-(tert-butylcarbamoyl)phenyl)phosphoramidate (17), (3S,5S,8R,9S,10S,13R,14S,17R)-10,13-dimethyl-17-((R)-6-methylheptan-2-yl)hexadecahydro-1H-cyclo penta[a]phenanthren-3-yl phenyl (2-(tert-butylcarbamoyl)phenyl)phosphoramidate (18) synthesized by nitrene insertion from organic azide.

Che and coworkers later introduced a RuIV-porphyrin-catalyst to synthesize N-acylphosphoramidates (AcP-N) from aldehydes and phosphoryl azide through nitrene insertion (Scheme 10b) [113]. The product was isolated by column chromatography (on silica). The observed product conversions were in the range 56–99%. Aromatic and aliphatic aldehydes such as 2-naphthaldehyde, benzo[d][1,3]dioxole-5-carbaldehyde, 5,6-dihydro-2H-pyran-3-carbaldehyde and 3-methylbut-2-enal were used in the reaction along with aromatic and aliphatic phosphoryl azide such as 3-nitrophenyl (4-nitrophenyl) phosphorazidate, bis(2,2,2-trichloroethyl) phosphorazidate, and diethyl phosphorazidate. However, lower yields were obtained from aliphatic aldehydes when compared with the aromatic aldehydes, suggesting that the synthetic procedure favors electron-rich aromatic aldehydes.

Molecules 2020, 25, x FOR PEER REVIEW 15 of 37

Scheme 10. Phosphoramidate synthesis via nitrene insertion using, (a) 5 mol% Ir(III)-based catalyst, Molecules 2020, 25, 3684 15 of 37 (b) 5 mol% RuIV-porphyrin-catalyst, and (c) 4 mol% Ir(III)-based catalyst.

Figure 8. Structures of (1R,2R,5R)-5-isopropyl-2-methylcyclohexyl phenyl (2-(tert-butylcarbamoyl)phenyl) Figure 8. Structures of (1R,2R,5R)-5-isopropyl-2-methylcyclohexyl phenyl phosphoramidate (17), (3S,5S,8R,9S,10S,13R,14S,17R)-10,13-dimethyl-17-((R)-6-methylheptan-2-yl) (2-(tert-butylcarbamoyl)phenyl)phosphoramidate (17), hexadecahydro-1H-cyclopenta[a]phenanthren-3-ylphenyl(2-(tert-butylcarbamoyl)phenyl)phosphoramidate (3S,5S,8R,9S,10S,13R,14S,17R)-10,13-dimethyl-17-((R)-6-methylheptan-2-yl)hexadecahydro-1H-cyclo (18) synthesized by nitrene insertion from organic azide. penta[a]phenanthren-3-yl phenyl (2-(tert-butylcarbamoyl)phenyl)phosphoramidate (18) synthesized byChe nitrene and insertion coworkers from organic later azide. introduced a RuIV-porphyrin-catalyst to synthesize N-acylphosphoramidates (AcP-N) from aldehydes and phosphoryl azide through nitrene Che and coworkers later introduced a RuIV-porphyrin-catalyst to synthesize insertion (Scheme 10b) [113]. The product was isolated by column chromatography (on silica). N-acylphosphoramidates (AcP-N) from aldehydes and phosphoryl azide through nitrene insertion The observed product conversions were in the range 56–99%. Aromatic and aliphatic aldehydes such (Scheme 10b) [113]. The product was isolated by column chromatography (on silica). The observed as 2-naphthaldehyde, benzo[d][1,3]dioxole-5-carbaldehyde, 5,6-dihydro-2H-pyran-3-carbaldehyde product conversions were in the range 56–99%. Aromatic and aliphatic aldehydes such as and 3-methylbut-2-enal were used in the reaction along with aromatic and aliphatic phosphoryl azide 2-naphthaldehyde, benzo[d][1,3]dioxole-5-carbaldehyde, 5,6-dihydro-2H-pyran-3-carbaldehyde such as 3-nitrophenyl (4-nitrophenyl) phosphorazidate, bis(2,2,2-trichloroethyl) phosphorazidate, and 3-methylbut-2-enal were used in the reaction along with aromatic and aliphatic phosphoryl and diethyl phosphorazidate. However, lower yields were obtained from aliphatic aldehydes when azide such as 3-nitrophenyl (4-nitrophenyl) phosphorazidate, bis(2,2,2-trichloroethyl) compared with the aromatic aldehydes, suggesting that the synthetic procedure favors electron-rich phosphorazidate, and diethyl phosphorazidate. However, lower yields were obtained from aliphatic aromatic aldehydes. aldehydes when compared with the aromatic aldehydes, suggesting that the synthetic procedure A nitrene insertion route in the presence of Ir(III)-based catalyst was also used to synthesize favors electron-rich aromatic aldehydes. P-Ns by Zhu et al. (Scheme 10c) [114]. The P-Ns were synthesized under an inert environment and the isolated yield of the products was in the range of 52–77%. The scope of the synthesis was investigated using diethyl phosphorazidate and diphenyl phosphorazidate along with 2-phenylpyridine or pyrazole derivatives with substituents such as Me, OMe, CF3, Cl, F, Ph, and COOMe at ortho-, meta-, and para-positions as well as benzo[h]quinoline. Although nitrene insertion provides a viable route to P-N synthesis and generates N2 gas as the only stoichiometric by-product, the process uses expensive catalysts in addition to many chemical additives. Moreover, apart from the hazards associated with the handling of phosphoryl azide, the route requires a long reaction time, high temperature, and does not favor electron-deficient starting materials.

2.4.2. Via In Situ Azide Generation

An organic azide was generated in situ from organic halides and was coupled with (RO)3P (R = alkyl) for the synthesis of P-N by Sangwan et al. (Scheme 11) The crude product was purified by column chromatography (on silica) to afford isolated products in the range of 52–96% yield. A broad scope of the reaction was tested; 3-bromoprop-1-yne, 3-bromoprop-1-ene, 1-bromopropane alkyl or (un)substituted aromatic halide such as (bromomethyl)benzene, 1-(bromomethyl)-2-nitrobenzene, 1-(chloromethyl)-4-nitrobenzene, (chloromethyl)benzene, 1-(bromomethyl)-3,5-dimethoxybenzene, or 3-(4-(bromomethyl)-1H-1,2,3-triazol-1-yl)benzyl acetate were reacted with dimethyl or diethyl H-P. Molecules 2020, 25, x FOR PEER REVIEW 16 of 37

MoleculesA 2020 nitrene, 25, x FORinsertion PEER REVIEWroute in the presence of Ir(III)-based catalyst was also used to synthesize16 of 37 P-Ns by Zhu et al. (Scheme 10c) [114]. The P-Ns were synthesized under an inert environment and theA isolated nitrene yield insertion of the route products in the was presence in the ofrange Ir(III)-based of 52–77%. catalyst The scope was alsoof the used synthesis to synthesize was P-Nsinvestigated by Zhu et usingal. (Scheme diethyl 10c) phosphorazidate [114]. The P-Ns wereand synthesizeddiphenyl phosphorazidateunder an inert environment along with and the2-phenylpyridine isolated yield ofor thepyrazole products derivatives was in with the substiturange ofents 52–77%. such as The Me, scopeOMe, ofCF 3the, Cl, synthesis F, Ph, and was investigatedCOOMe at orthousing-, meta diethyl-, and para phosphorazidate-positions as well asand benzo[h]quinoline. diphenyl phosphorazidate along with Although nitrene insertion provides a viable route to P-N synthesis and generates N2 gas as the 2-phenylpyridine or pyrazole derivatives with substituents such as Me, OMe, CF3, Cl, F, Ph, and COOMeonly stoichiometric at ortho-, meta by-product,-, and para -positionsthe process as uses well expensive as benzo[h]quinoline. catalysts in addition to many chemical additives. Moreover, apart from the hazards associated with the handling of phosphoryl azide, the Although nitrene insertion provides a viable route to P-N synthesis and generates N2 gas as the route requires a long reaction time, high temperature, and does not favor electron-deficient starting only stoichiometric by-product, the process uses expensive catalysts in addition to many chemical materials. additives. Moreover, apart from the hazards associated with the handling of phosphoryl azide, the route2.4.2. requires Via In Situ a long Azide reaction Generation time, high temperature, and does not favor electron-deficient starting materials. An organic azide was generated in situ from organic halides and was coupled with (RO)3P (R = 2.4.2.alkyl) Via for In theSitu synthesis Azide Generation of P-N by Sangwan et al. (Scheme 11) The crude product was purified by column chromatography (on silica) to afford isolated products in the range of 52–96% yield. A broad scopeAn oforganic the reaction azide was tested;generated 3-bromoprop-1-yn in situ from organice, 3-bromoprop-1-ene, halides and was 1-bromopropane coupled with (RO) alkyl3P or (R = alkyl)(un)substituted for the synthesis aromatic of halideP-N by such Sangwan as (bromo et al.methyl)benzene, (Scheme 11) Th 1-(bromoe crudemethyl)-2-nitrobenzene, product was purified by column1-(chloromethyl)-4-nitrobenzene, chromatography (on silica) (chloromethyl)benzene, to afford isolated products 1-(bro inmomethyl)-3,5-dimethoxybenzene, the range of 52–96% yield. A broad scopeor 3-(4-(bromomethyl)-1H-1,2,3-triazol-1-yl)benzyl of the reaction was tested; 3-bromoprop-1-yn acetatee, 3-bromoprop-1-ene, were reacted with 1-bromopropane dimethyl or diethyl alkyl or (un)substitutedH-P. aromatic halide such as (bromomethyl)benzene, 1-(bromomethyl)-2-nitrobenzene, 1-(chloromethyl)-4-nitrobenzene,A similar method of P-N synthesis (chloromethyl)benzene, via in situ azide 1-(bro generationmomethyl)-3,5-dimethoxybenzene, from organic halides was reported by Dar [115], following the procedure previously reported by Sangwan et al. (Scheme 11) Moleculesor 3-(4-(bromomethyl)-1H-1,2,3-triazol-1-yl)benzyl2020, 25, 3684 acetate were reacted with dimethyl or diethyl16 of 37 H-P.[116]. The yield range of the isolated P-Ns, in this case, was 60–96%. Phosphoramidate-derived bioactiveA similar compound method (19 of) was P-N synthesized synthesis usingvia in the situ proposed azide methodgeneration (Figure from 9). organic halides was reported by Dar [115], following the procedure previously reported by Sangwan et al. (Scheme 11) [116]. The yield range of the isolated P-Ns, in this case, was 60–96%. Phosphoramidate-derived bioactive compound (19) was synthesized using the proposed method (Figure 9).

Scheme 11. Phosphoramidate synthesis from organic azide and (RO)3P. Scheme 11. Phosphoramidate synthesis from organic azide and (RO)3P. A similar method of P-N synthesis via in situ azide generation from organic halides was reported by Dar [115], following the procedure previously reported by Sangwan et al. (Scheme 11)[116]. The yield range of the isolated P-Ns, in this case, was 60–96%. Phosphoramidate-derived bioactive compound (19) wasScheme synthesized 11. Phosphoramidate using the proposed synthesis method from organic (Figure azide9). and (RO)3P.

Figure 9. Structure of (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl (dimethoxyphosphoryl)glycinate (19) synthesized via in situ azide generation.

2.4.3. Via Two-Step Organic Azide Generation Figure 9. Structure of (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl (dimethoxyphosphoryl)glycinate (19) FigureIn 1988, 9. StructureKoziara reportedof (1R,2S,5R)-2-isopropyl-5-methy a two-step P-N syntheticlcyclohexyl route via (dimethoxyphosphoryl)glycinateorganic azide generation using a synthesized via in situ azide generation. [n-Bu(194)N]Br synthesized catalyst via (Scheme in situ azide12) [93]. generation. The crude product was purified by crystallization or vacuum 2.4.3.distillation Via Two-Step with 50–93% Organic isolated Azide Generationyield. The organic halides used were (3-bromopropyl)benzene, 2.4.3.(2-bromoethyl)benzene, Via Two-Step Organic Azide1-bromohexane, Generation bromocyclohexane, 1-bromobutane, or bromocyclopentane.In 1988, Koziara reported a two-step P-N synthetic route via organic azide generation using In 1988, Koziara reported a two-step P-N synthetic route via organic azide generation using a aMolecules [n-BuRoutes4 N]Br2020, 25 catalystvia, x FORorganic PEER (Scheme azide REVIEW 12generation)[ 93]. The use crude readily product available, was less purified toxic organic by crystallization halides and or (RO) vacuum173 Pof 37 [n-Bu4N]Br catalyst (Scheme 12) [93]. The crude product was purified by crystallization or vacuum distillation(R = alkyl) with relative 50–93% to other isolated routes yield. and generate The organic N2 as halidesstoichiometric used werewaste. (3-bromopropyl)benzene, However, the method distillationrelies on the with pre-functionalization 50–93% isolated yield. and Thepreparation organic ofhalides hazardous used wereazide (3-bromopropyl)benzene,precursors in multi-step (2-bromoethyl)benzene, 1-bromohexane, bromocyclohexane, 1-bromobutane, or bromocyclopentane. (2-bromoethyl)benzene,processes. 1-bromohexane, bromocyclohexane, 1-bromobutane, or bromocyclopentane. Routes via organic azide generation use readily available, less toxic organic halides and (RO)3P (R = alkyl) relative to other routes and generate N2 as stoichiometric waste. However, the method

Scheme 12. Phosphoramidate synthesis via two-step organic azide generation. Scheme 12. Phosphoramidate synthesis via two-step organic azide generation. Routes via organic azide generation use readily available, less toxic organic halides and (RO) P 2.4.4. Transition Metal-Free Synthesis from Organic Azide 3 (R = alkyl) relative to other routes and generate N2 as stoichiometric waste. However, the method relies on theTransition pre-functionalization metal-free synthesis and preparation of P-N from of hazardous phosphoryl azide azide precursors and amines in multi-stepwas accomplished processes. by Chen et al. [117]. The synthetic process uses the nitrogen atom available from the amine rather than 2.4.4.from Transitionthe azide Metal-Free(Scheme 13). Synthesis The residue from Organicwas puri Azidefied by column chromatography (on silica) to affordTransition the isolated metal-free product synthesis in 52–92% of P-N yield. from Th phosphoryle scope of the azide reaction and amines was examined was accomplished by using bydiphenyl Chen et and al. [diisopropyl117]. The synthetic phosphor processyl azide uses along the with nitrogen primary atom amines available (e.g., from isopropylamine the amine rather and thant-butylamine), from the azide substituted (Scheme 13).primary The residue amines was purified (e.g., by columnthiophen-2-ylmethylamine chromatography (on silica)and to4-chlorobenzylamine), afford the isolated product and heterocyclic in 52–92% amines yield. The(e.g., scope pyrrolidine of the reactionand morpholine). was examined Although by using the diphenylmethod circumvents and diisopropyl the use phosphoryl of metal azidecatalysts along in the with synthesis, primary the amines use (e.g.,of a hazardous isopropylamine azide and t-butylamine),high temperature substituted are its limitations. primary amines (e.g., thiophen-2-ylmethylamine and 4-chlorobenzylamine), and heterocyclic amines (e.g., pyrrolidine and morpholine). Although the method circumvents the use of metal catalysts in the synthesis, the use of a hazardous azide and high temperature are its limitations.

Scheme 13. Phosphoramidate synthesis from organic azide and amine.

2.5. Reduction Route

2.5.1. Via Nitro-Group Reduction Beifuss et al. reported a microwave-assisted synthesis of N-arylphosphoramidates from nitrobenzene and (RO)3P (R = alkyl) (Scheme 14) [118]. The crude residue product was purified by column chromatography (on silica) resulting in pure P-Ns with 52–79% isolated yield. The scope of the synthesis was investigated using trimethyl or triethyl phosphite along with nitrobenzene, and mono- or di-substituted nitrobenzenes with substitution such as Me, OMe, Cl, Br, or CN groups. This method is attractive because it provides a different route to P-Ns using nitro compounds instead of the conventional amines. Nonetheless, the high temperature and amount of energy required during the synthesis are the obvious limitations.

Scheme 14. Synthesis of N-arylphosphoramidates from nitrobenzene and (RO)3P (R = alkyl).

Molecules 2020, 25, x FOR PEER REVIEW 17 of 37 Molecules 2020, 25, x FOR PEER REVIEW 17 of 37 relies on the pre-functionalization and preparation of hazardous azide precursors in multi-step processes.

Scheme 12. Phosphoramidate synthesis via two-step organic azide generation. Scheme 12. Phosphoramidate synthesis via two-step organic azide generation.

2.4.4. Transition Metal-Free Synthesis from Organic Azide Transition metal-free synthesis of P-N from phosphoryl azide and amines was accomplished by Chen et al. [117]. The synthetic process uses the nitrogen atom available from the amine rather than from the azide (Scheme 13). The residue was purified by column chromatography (on silica) to afford the isolated product in 52–92% yield. The scope of the reaction was examined by using diphenyl and diisopropyl phosphoryl azide along with primary amines (e.g., isopropylamine and t-butylamine), substituted primary amines (e.g., thiophen-2-ylmethylamine and 4-chlorobenzylamine), and heterocyclic amines (e.g., pyrrolidine and morpholine). Although the Molecules 2020, 25, 3684 17 of 37 method circumvents the use of metal catalysts in the synthesis, the use of a hazardous azide and high temperature are its limitations.

Scheme 13. Phosphoramidate synthesis from organic azide and amine. Scheme 13. Phosphoramidate synthesis from organic azide and amine. 2.5. Reduction Route 2.5. Reduction Route 2.5.1. Via Nitro-Group Reduction 2.5.1. Via Nitro-Group Reduction Beifuss et al. reported a microwave-assisted synthesis of N-arylphosphoramidates from Beifuss et al. reported a microwave-assisted synthesis of N-arylphosphoramidates from nitrobenzeneBeifuss et and al. (RO) reported3P (R = aalkyl) micr (Schemeowave-assisted 14)[118 synthesis]. The crude of residueN-arylphosphoramidates product was purified from by nitrobenzene and (RO)3P (R = alkyl) (Scheme 14) [118]. The crude residue product was purified by columnnitrobenzene chromatography and (RO)3P (R (on = silica)alkyl) resulting(Scheme 14) in pure[118]. P-Ns The withcrude 52–79% residue isolated product yield. was purified The scope by column chromatography (on silica) resulting in pure P-Ns with 52–79% isolated yield. The scope of ofcolumn the synthesis chromatography was investigated (on silica) usingresulting trimethyl in pure or P-Ns triethyl with phosphite 52–79% isolated along withyield.nitrobenzene, The scope of the synthesis was investigated using trimethyl or triethyl phosphite along with nitrobenzene, and andthe synthesis mono- or was di-substituted investigated nitrobenzenes using trimethyl with or substitution triethyl phosphite such as Me, along OMe, with Cl, nitrobenzene, Br, or CN groups. and mono- or di-substituted nitrobenzenes with substitution such as Me, OMe, Cl, Br, or CN groups. Thismono- method or di-substituted is attractive becausenitrobenzenes it provides with asubsti differenttution route such to P-Nsas Me, using OMe, nitro Cl, compoundsBr, or CN groups. instead This method is attractive because it provides a different route to P-Ns using nitro compounds ofThis the method conventional is attractive amines. because Nonetheless, it provides the high a temperaturedifferent route and amountto P-Ns ofusing energy nitro required compounds during instead of the conventional amines. Nonetheless, the high temperature and amount of energy theinstead synthesis of the are conventional the obvious limitations.amines. Nonetheless, the high temperature and amount of energy required during the synthesis are the obvious limitations.

Molecules 2020Scheme, 25, x 14.FORSynthesis PEER REVIEW of N-arylphosphoramidates from nitrobenzene and (RO)3P (R = alkyl). 18 of 37 Scheme 14. Synthesis of N-arylphosphoramidates from nitrobenzene and (RO)3P (R = alkyl). Scheme 14. Synthesis of N-arylphosphoramidates from nitrobenzene and (RO)3P (R = alkyl). 2.5.2. Via Catalyst-Free Staudinger Reduction and Lewis-Acid Catalyzed Rearrangement 2.5.2. Via Catalyst-Free Staudinger Reduction and Lewis-Acid Catalyzed Rearrangement

Hackenberger et al. synthesized P-N compounds from organic azide derivatives and Hackenberger et al. synthesized P-N compounds from organic azide derivatives and (RO)3P (R (RO) P (R = alkyl) after Lewis acid-catalyzed rearrangement (Scheme 15)[119]. The crude = alkyl)3 after Lewis acid-catalyzed rearrangement (Scheme 15) [119]. The crude product was product was concentrated under reduced pressure, and the desired product was isolated concentrated under reduced pressure, and the desired product was isolated (63–98% yield) through (63–98% yield) through column chromatography (on silica). Triethyl or trimethyl phosphite column chromatography (on silica). Triethyl or trimethyl phosphite were used as the P-source along were used as the P-source along with organic azide derivatives such as (azidomethyl)benzene, with organic azide derivatives such as (azidomethyl)benzene, azidocyclohexane, azidocyclohexane, (2-azidopropan-2-yl)benzene, azidobenzene, ethyl 2-azidoacetate, 1-azidodecane, (2-azidopropan-2-yl)benzene, azidobenzene, ethyl 2-azidoacetate, 1-azidodecane, (azidomethylene)dibenzene, and (3-azidoprop-1-en-1-yl)benzene. (azidomethylene)dibenzene, and (3-azidoprop-1-en-1-yl)benzene.

Scheme 15. Synthesis of phosphoramidates from organic azide derivatives and (RO) P after Lewis Scheme 15. Synthesis of phosphoramidates from organic azide derivatives and (RO)3P after Lewis acid-catalyzed rearrangement. acid-catalyzed rearrangement. 2.6. Hydrophosphinylation Route 2.6. Hydrophosphinylation Route Zimin et al. reported the 1,2-hydrophosphinylation of alkyl nitriles (R’-CN, R’ = alkyl, Ph, Bn) Zimin et al. reported the 1,2-hydrophosphinylation of alkyl nitriles (R’-CN, R’ = alkyl, Ph, Bn) using sodium dialkyl phosphite ((RO)2PONa, R = Et, Pr) to achieve the formation of a P-N featuring using sodium dialkyl phosphite ((RO)2PONa, R = Et, Pr) to achieve the formation of a P-N featuring a P-C-N-P linkage in which the dialkyl phosphite group of (RO)2PONa was added to the carbon and anitrogen P-C-N-P atoms linkage of thein which nitriles the (Scheme dialkyl 16 phosphite)[120]. group of (RO)2PONa was added to the carbon and nitrogen atoms of the nitriles (Scheme 16) [120].

Scheme 16. A 1,2-hydrophosphinylation of nitriles to form phosphoramidates.

2.7. Phosphoramidate-Aldehyde-Dienophile (PAD) Route Chabour et al. reported a diastereoselective P-N synthesis via the PAD process using a TsOH acid catalyst and a dienophile, maleimide (Scheme 17) [1]. Flash chromatography was used to isolate the desired product in 40–88% yield. The scope of the synthesis was explored with maleimide derivatives with substituents such as 4-FC6H4CH2, C6H4CH2, C6H4COCH3, 4-BrC6H4, phenyl, and methyl. The unsaturated aldehyde derivatives that were used were 3,7-dimethylocta-2,6-dienal, 3-methylbut-2-enal, pent-2-enal, and hex-2-enal. This newest route for P-N synthesis uses inexpensive catalysts, generates only H2O as a by-product in stoichiometric amounts, and demonstrates an important route to the synthesis of polyfunctionalized P-N compounds.

Scheme 17. Phosphoramidate synthesis via the PAD process.

Molecules 2020, 25, x FOR PEER REVIEW 18 of 37 Molecules 2020, 25, x FOR PEER REVIEW 18 of 37 2.5.2. Via Catalyst-Free Staudinger Reduction and Lewis-Acid Catalyzed Rearrangement 2.5.2. Via Catalyst-Free Staudinger Reduction and Lewis-Acid Catalyzed Rearrangement Hackenberger et al. synthesized P-N compounds from organic azide derivatives and (RO)3P (R Hackenberger et al. synthesized P-N compounds from organic azide derivatives and (RO)3P (R = alkyl) after Lewis acid-catalyzed rearrangement (Scheme 15) [119]. The crude product was = alkyl) after Lewis acid-catalyzed rearrangement (Scheme 15) [119]. The crude product was concentrated under reduced pressure, and the desired product was isolated (63–98% yield) through concentrated under reduced pressure, and the desired product was isolated (63–98% yield) through columncolumn chromatography chromatography (on (on silica). silica). TriethylTriethyl oror trimethyltrimethyl phosphite were usedused asas thethe P-sourceP-source along along withwith organicorganic azideazide derivativesderivatives suchsuch as (azidomethyl)benzene, azidocyclohexane,azidocyclohexane, (2-azidopropan-2-yl)benzene,(2-azidopropan-2-yl)benzene, azidobenzene,azidobenzene, ethyl 2-azidoacetate, 1-azidodecane,1-azidodecane, (azidomethylene)dibenzene,(azidomethylene)dibenzene, and and (3-azidoprop-1-en-1-yl)benzene.(3-azidoprop-1-en-1-yl)benzene.

SchemeScheme 15. 15. Synthesis Synthesis of of phosphoramidatesphosphoramidates fromfrom organicorganic azide derivatives andand (RO)(RO)33PP afterafter LewisLewis acid-catalyzedacid-catalyzed rearrangement. rearrangement.

2.6.2.6. Hydrophosphinylation Hydrophosphinylation Route Route ZiminZimin et et al. al. reported reported thethe 1,2-hy1,2-hydrophosphinylationdrophosphinylation of alkyl nitriles (R’-CN,(R’-CN, R’R’ == alkyl,alkyl, Ph,Ph, Bn) Bn) usingusing sodium sodium dialkyl dialkyl phosphite phosphite ((RO)((RO)22PONa,PONa, RR == Et, Pr) to achieve the formationformation ofof aa P-NP-N featuring featuring Molecules 2020, 25, 3684 18 of 37 a aP-C-N-P P-C-N-P linkage linkage in in which which the the dialkyl dialkyl phosphitephosphite group of (RO)2PONa waswas addedadded toto thethe carbon carbon and and nitrogennitrogen atoms atoms of of the the nitriles nitriles (Scheme (Scheme 16)16) [120].[120].

Scheme 16. A 1,2-hydrophosphinylation of nitriles to form phosphoramidates. SchemeScheme 16. 16. A A 1,2-hydrophosphinylation 1,2-hydrophosphinylation of nitriles to form phosphoramidates.phosphoramidates. 2.7. Phosphoramidate-Aldehyde-Dienophile (PAD) Route 2.7.2.7. Phosphoramidate-Aldehyde-Dienophile Phosphoramidate-Aldehyde-Dienophile (PAD)(PAD) RouteRoute Chabour et al. reported a diastereoselective P-N synthesis via the PAD process using a TsOH Chabour et al. reported a diastereoselective P-N synthesis via the PAD process using a TsOH acidChabour catalyst andet al. a reported dienophile, a diastereoselective maleimide (Scheme P-N 17synthesis)[1]. Flash via the chromatography PAD process using was a used TsOH to acid catalyst and a dienophile, maleimide (Scheme 17) [1]. Flash chromatography was used to isolate acidisolate catalyst the desired and a productdienophile, in 40–88% maleimide yield. (Scheme The scope 17) [1]. of the Flash synthesis chromatography was explored was with used maleimide to isolate the desired product in 40–88% yield. The scope of the synthesis was explored with maleimide thederivatives desired withproduct substituents in 40–88% such yield. as The 4-FC scope6H4CH of2,C the6H synthesis4CH2,C 6wasH4COCH explored3, 4-BrC with6H maleimide4, phenyl, derivatives with substituents such as 4-FC6H4CH2, C6H4CH2, C6H4COCH3, 4-BrC6H4, phenyl, and derivativesand methyl. with The unsaturatedsubstituents aldehydesuch as 4-FC derivatives6H4CH2, that C6H were4CH2 used, C6H were4COCH 3,7-dimethylocta-2,6-dienal,3, 4-BrC6H4, phenyl, and methyl. The unsaturated aldehyde derivatives that were used were 3,7-dimethylocta-2,6-dienal, methyl.3-methylbut-2-enal, The unsaturated pent-2-enal, aldehyde and hex-2-enal.derivatives Thisthat newest were used route forwere P-N 3,7-dimethylocta-2,6-dienal, synthesis uses inexpensive 3-methylbut-2-enal, pent-2-enal, and hex-2-enal. This newest route for P-N synthesis uses 3-methylbut-2-enal,catalysts, generates only pent-2-enal, H2O as a by-product and hex-2-enal. in stoichiometric This newest amounts, route and demonstratesfor P-N synthesis an important uses inexpensive catalysts, generates only H2O as a by-product in stoichiometric amounts, and inexpensiveroute to the synthesiscatalysts, of generates polyfunctionalized only H2O P-N as compounds. a by-product in stoichiometric amounts, and demonstratesdemonstrates an an important important route route toto thethe syntsynthesishesis of polyfunctionalizedized P-NP-N compounds.compounds.

Scheme 17. Phosphoramidate synthesis via the PAD process. Scheme 17. PhosphoramidatePhosphoramidate synthesi synthesiss via via the the PAD PAD process. 3. Mechanistic Considerations

A wealth of information on the mechanisms for the synthetic routes to P-Ns is available. For each of the main categories highlighted above, researchers have provided mechanistic insight into the reaction by determining the main sources of oxidation as well as electronic and steric factors provided from the substituents that influence the reaction rate. Several examples of postulated catalytic cycles will be provided below, illustrating the key steps, similarities, and differences between them.

3.1. Salt Elimination Route

3.1.1. Atherton–Todd Reaction Atherton, Openshaw and Todd suggested that the two-step mechanistic process for the salt elimination could involve the formation of dialkyl or dibenzyl (trichloromethyl)phosphonate in the first step, from a reaction of (RO)2P(O)H (H-P; R = alkyl) and CCl4 in the presence of Et3N[78]. The desired product is formed in the second step when the (trichloromethyl)phosphonate reacts with amine, forming also CHCl3 in the process (Scheme 18). Although this mechanism is plausible, evidence by NMR spectroscopy suggests that in the first step, a reaction of the base and CCl4 results in salt + formation [Et3NCl] [CCl3]− [121]. The H-P is deprotonated by [CCl3]− to form CHCl3 and anionic + phosphite, which reacts further with [Et3NCl] to form (RO)2P(O)Cl (dACP; R = alkyl). In the second step, dACP reacts with amine to give the product. Molecules 2020, 25, x FOR PEER REVIEW 19 of 37 Molecules 2020, 25, x FOR PEER REVIEW 19 of 37

3.3. MechanisticMechanistic ConsiderationsConsiderations AA wealthwealth ofof informationinformation onon thethe mechanismsmechanisms forfor thethe syntheticsynthetic routesroutes toto P-NsP-Ns isis available.available. ForFor eacheach ofof thethe mainmain categoriescategories highlightedhighlighted above,above, reresearcherssearchers havehave providedprovided mechanisticmechanistic insightinsight intointo thethe reactionreaction byby determiningdetermining thethe mainmain sourcessources ofof oxidationoxidation asas wellwell asas electronicelectronic andand stericsteric factorsfactors providedprovided fromfrom thethe substituentssubstituents thatthat influenceinfluence ththee reactionreaction rate.rate. SeveralSeveral examplesexamples ofof postulatedpostulated catalyticcatalytic cyclescycles willwill bebe providedprovided below,below, illustratingillustrating thethe keykey stepsteps,s, similarities,similarities, andand differencesdifferences betweenbetween them.them.

3.1.3.1. SaltSalt EliminationElimination RouteRoute

3.1.1.3.1.1. Atherton–ToddAtherton–Todd ReactionReaction Atherton,Atherton, OpenshawOpenshaw andand ToddTodd suggestedsuggested thatthat ththee two-steptwo-step mechanisticmechanistic processprocess forfor thethe saltsalt eliminationelimination couldcould involveinvolve thethe formationformation ofof dialkyldialkyl oror dibenzyldibenzyl (trichloromethyl)phosphonate(trichloromethyl)phosphonate inin thethe first step, from a reaction of (RO)2P(O)H (H-P; R = alkyl) and CCl4 in the presence of Et3N [78]. The first step, from a reaction of (RO)2P(O)H (H-P; R = alkyl) and CCl4 in the presence of Et3N [78]. The desireddesired productproduct isis formedformed inin thethe secondsecond stepstep whwhenen thethe (trichloromethyl)p(trichloromethyl)phosphonatehosphonate reactsreacts withwith amine, forming also CHCl3 in the process (Scheme 18). Although this mechanism is plausible, amine, forming also CHCl3 in the process (Scheme 18). Although this mechanism is plausible, evidence by NMR spectroscopy suggests that in the first step, a reaction of the base and CCl4 results evidence by NMR spectroscopy suggests that in the first step, a reaction of the base and CCl4 results in salt formation [Et3NCl]+[CCl3]− [121]. The H-P is deprotonated by [CCl3]− to form CHCl3 and in salt formation [Et3NCl]+[CCl3]− [121]. The H-P is deprotonated by [CCl3]− to form CHCl3 and Molecules 25 + anionic 2020phosphite,, , 3684 which reacts further with [Et3NCl] to form (RO)2P(O)Cl (dACP; R = alkyl).19 In of the 37 anionic phosphite, which reacts further with [Et3NCl]+ to form (RO)2P(O)Cl (dACP; R = alkyl). In the secondsecond step,step, ddACPACP reactsreacts withwith amineamine toto givegive thethe product.product.

Scheme 18. Atherton–Todd mechanism proposed for the formation of phosphoramidates. SchemeScheme 1818.. Atherton–ToddAtherton–Todd mechanismmechanism proposedproposed foforr thethe formationformation ofof phosphoramidates.phosphoramidates. For the modified Atherton–Todd reaction, the two-step mechanistic process involves the For the modified Atherton–Todd reaction, the two-step mechanistic process involves the deprotonationFor the modified of H-P by Atherton–Todd DBU, and the reaction, radical formedthe two-step is autoxidized mechanistic by Oprocess2 before involves it abstracts the deprotonation of H-P by DBU, and the radical formed is autoxidized by O2 before it abstracts chlorinedeprotonation from CHCl of H-P3 to by form DBU,dACP and (Scheme the radical 19)[95 formed]. The nucleophilicis autoxidized substitution by O2 before of dACP it abstracts by the chlorine from CHCl3 to form dACP (Scheme 19) [95]. The nucleophilic substitution of dACP by the aminechlorine aff ordsfrom theCHCl P-N3 to product. form dACP (Scheme 19) [95]. The nucleophilic substitution of dACP by the amineamine affordsaffords thethe P-NP-N product.product.

SchemeSchemeScheme 1919 19... ModifiedModifiedModified Atherton–ToddAtherton–Todd Atherton–Todd mechanismmechanism proposedproposed inin thethe formationformation of of phosphoramidates. phosphoramidates.

3.1.2.3.1.2.3.1.2. DirectDirect ConversionConversion ofofof DiethylDiethylDiethyl HydrogenHydrogenHydrogen Phosphate PhosphatePhosphate InInIn thethethe plausibleplausibleplausible mechanismmechanismmechanism forforfor thethethe directdirectdirect conversioncoconversionnversion ofofof diethyldiethyldiethyl hydrogenhydrogenhydrogen phosphate,phosphate,phosphate, hexamethyltriaminophosphinehexamethyltriaminophosphine P(NMeP(NMe2)3 is oxidizedoxidized toto hexamethyltriaminodibromophosphoranehexamethyltriaminodibromophosphorane hexamethyltriaminophosphine P(NMe22)3 is oxidized to hexamethyltriaminodibromophosphorane ((Me((Me2N)N)3PBr2)) which isis ionized ionized in in solution solution (Scheme (Scheme 20)[ 20)90 ].[90]. Subsequently,the Subsequently, ionized the ionized (Me N)(MePBr2N)3PBrand2 ((Me22N)33PBr22) which is ionized in solution (Scheme 20) [90]. Subsequently, the ionized2 (Me3 2N)23PBr2 Molecules 2020, 25, x FOR PEER REVIEW 20 of 37 diethyland diethyl hydrogen hydrogen phosphate phosphate undergo undergo ligand exchange ligand exchange in the presence in the of presence Et N to form of Et the3N intermediate,to form the and diethyl hydrogen phosphate undergo ligand exchange in the presence3 of Et3N to form the diethyl (phosphaneyloxy)phosphonate amino-hydrazine-bromide salt complex. Nucleophilic attack intermediate, diethyl (phosphaneyloxy)phosphonate amino-hydrazine-bromide salt complex. from the amine onto the positively charged P results in the diethyl phosphoramidate bromide salt, Nucleophilic attack from the amine onto the positively charged P results in the diethyl which reacts with Et3N to give the desired product with a concomitant elimination of triethylammonium phosphoramidate bromide salt, which reacts with Et3N to give the desired product with a bromide. Apart from the stoichiometric Et3N salt waste generated, the synthetic process is prone to concomitant elimination of triethylammonium bromide. Apart from the stoichiometric Et3N salt the formation of significant quantities of pyrophosphate or phosphanetetraamine bromide salt side waste generated, the synthetic process is prone to the formation of significant quantities of products, resulting in a low yield. pyrophosphate or phosphanetetraamine bromide salt side products, resulting in a low yield.

Scheme 20.20. ProposedProposed mechanism mechanism of of direct conversion of diethyl hydrogen phosphate to formform phosphoramidates.3.1.3. InorganicInorganic Salt Elimination.

The mechanistic steps for the synthesis of P-N via a salt elimination route were not proposed by Zwierzak et al. [89]; however, based on the roles of KHCO3, K2CO3, and [n-Bu4N]Br as outlined in the paper and a recently proposed mechanism for an Atherton–Todd type reaction, a probable mechanism can be postulated (Scheme 21) [121]. In the reacting system, the HCO3− migrates to the organic phase in the presence of [n-Bu4N]Br as the catalyst, where it is protonated and reacts with CCl4 to form anionic HCO3ClH− and cationic Cl3C+. The dialkyl H-phosphonate ((RO)2P(O)H, R = alkyl) is deprotonated by the cationic Cl3C+ to yield CHCl3 and anionic phosphate, (RO)2P(O)−. Next, the anionic phosphate reacts with HCO3ClH− to form (RO)2P(O)Cl (dACP; R = alkyl) and H2CO3. In the following step, a nucleophilic substitution between the amine and dACP results in the formation of the desired product. Meanwhile, K2CO3 serves as the dehydrating agent in the reacting system. The plausible mechanism is also similar when NaOH and [BnEt3N]Cl are used in place of KHCO3 and [n-Bu4N]Br, respectively.

Scheme 21. Potential mechanism for the formation of phosphoramidates using a salt elimination route.

Molecules 2020, 25, x FOR PEER REVIEW 20 of 37

intermediate, diethyl (phosphaneyloxy)phosphonate amino-hydrazine-bromide salt complex. Nucleophilic attack from the amine onto the positively charged P results in the diethyl phosphoramidate bromide salt, which reacts with Et3N to give the desired product with a concomitant elimination of triethylammonium bromide. Apart from the stoichiometric Et3N salt waste generated, the synthetic process is prone to the formation of significant quantities of pyrophosphate or phosphanetetraamine bromide salt side products, resulting in a low yield.

Scheme 20. Proposed mechanism of direct conversion of diethyl hydrogen phosphate to form Moleculesphosphoramidates.3.1.3.2020, 25, 3684 Inorganic Salt Elimination. 20 of 37

The mechanistic steps for the synthesis of P-N via a salt elimination route were not proposed by The mechanistic steps for the synthesis of P-N via a salt elimination route were not proposed by Zwierzak et al. [89]; however, based on the roles of KHCO3, K2CO3, and [n-Bu4N]Br as outlined in the Zwierzak et al. [89]; however, based on the roles of KHCO ,K CO , and [n-Bu N]Br as outlined in the paper and a recently proposed mechanism for an Atherton–Todd3 2 3 type4 reaction, a probable paper and a recently proposed mechanism for an Atherton–Todd type reaction, a probable mechanism mechanism can be postulated (Scheme 21) [121]. In the reacting system, the HCO3− migrates to the can be postulated (Scheme 21)[121]. In the reacting system, the HCO3− migrates to the organic phase in organic phase in the presence of [n-Bu4N]Br as the catalyst, where it is protonated and reacts with the presence of [n-Bu4N]Br as the catalyst, where it is protonated and reacts with CCl4 to form anionic 4 3 − 3 + 2 CCl to form anionic HCO ClH+ and cationic Cl C . The dialkyl H-phosphonate ((RO) P(O)H, R = HCO3ClH− and cationic Cl3C . The dialkyl H-phosphonate ((RO)2P(O)H, R = alkyl) is deprotonated 3 + 3 2 − alkyl) is deprotonated+ by the cationic Cl C to yield CHCl and anionic phosphate, (RO) P(O) . Next, by the cationic Cl3C to yield CHCl3 and anionic phosphate, (RO)2P(O)−. Next, the anionic phosphate the anionic phosphate reacts with HCO3ClH− to form (RO)2P(O)Cl (dACP; R = alkyl) and H2CO3. In reacts with HCO ClH to form (RO) P(O)Cl (dACP; R = alkyl) and H CO . In the following step, the following step,3 a nucleophilic− substitution2 between the amine and dACP2 3 results in the formation a nucleophilic substitution between the amine and dACP results in the formation of the desired product. of the desired product. Meanwhile, K2CO3 serves as the dehydrating agent in the reacting system. Meanwhile, K2CO3 serves as the dehydrating agent in the reacting system. The plausible mechanism The plausible mechanism is also similar when NaOH and [BnEt3N]Cl are used in place of KHCO3 is also similar when NaOH and [BnEt3N]Cl are used in place of KHCO3 and [n-Bu4N]Br, respectively. and [n-Bu4N]Br, respectively.

Scheme 21. Potential mechanism for the formation of phosphoramidates using a salt elimination route. Scheme 21. Potential mechanism for the formation of phosphoramidates using a salt elimination Lukanovroute. et al. suggested that the mechanistic cycle for their synthesis involves the deprotonation of dialkyl H-phosphonate ((RO)2P(O)H, R = alkyl) to form (RO)2P(O)Cl (dACP, R = alkyl) [96]. Then, the dACP reacts with N-phenylformamide or the 2-chloro-N-phenylacetamide derivative to form the product. Alternatively, the mechanism could proceed via a dialkyl (acetyl)(phenyl)phosphoramidate intermediate, which subsequently undergoes hydrolysis to afford the product.

3.2. Oxidative Cross-Coupling Route

3.2.1. Using Chlorinating Agents The mechanisms of P-N formation from Gupta et al. [97] and Kaboudin et al. [98] suggest that the dialkyl H-phosphonate ((RO)2P(O)H, R = alkyl) reacts with trichloroisocyanuric acid (tCiC-A) to form the intermediate (RO)2P(O)Cl (dACP; R = alkyl) and 1,3,5-triazinane-2,4,6-trione (tAtO) (Scheme 22). Following, a nucleophilic substitution between the dACP and the amine result in the P-N with HCl as the major by-product. MoleculesMolecules 2020 2020, ,25 25, ,x x FOR FOR PEER PEER REVIEW REVIEW 2121 of of 37 37

LukanovLukanov etet al.al. suggestedsuggested thatthat thethe mechanisticmechanistic cyclecycle forfor theirtheir synthesissynthesis involvesinvolves thethe deprotonationdeprotonation ofof dialkyldialkyl HH-phosphonate-phosphonate ((RO)((RO)22P(O)H,P(O)H, RR == alkyl)alkyl) toto formform (RO)(RO)22P(O)ClP(O)Cl ((ddACP,ACP, RR == alkyl)alkyl) [96].[96]. Then,Then, thethe ddACPACP reactsreacts withwith NN-phenylformamide-phenylformamide oror thethe 2-chloro-2-chloro-NN-phenylacetamide-phenylacetamide derivativederivative toto formform thethe product.product. AlternativelAlternatively,y, thethe mechanismmechanism couldcould proceedproceed viavia aa dialkyldialkyl (acetyl)(phenyl)phosphoramidate(acetyl)(phenyl)phosphoramidate intermediate,intermediate, whichwhich subsequentlysubsequently undergoesundergoes hydrolysishydrolysis toto affordafford thethe product.product.

3.2.3.2. OxidativeOxidative Cross-CouplingCross-Coupling RouteRoute

3.2.1.3.2.1. UsingUsing ChlorinatingChlorinating AgentsAgents TheThe mechanismsmechanisms ofof P-NP-N formationformation fromfrom GuptaGupta etet al.al. [97][97] andand KaboudinKaboudin etet al.al. [98][98] suggestsuggest thatthat thethe dialkyldialkyl H-phosphonateH-phosphonate ((RO)((RO)22P(O)H,P(O)H, RR == alkyl)alkyl) reactsreacts withwith trichloroisocyanurictrichloroisocyanuric acidacid ((ttCiC-A)CiC-A) toto formform thethe intermediateintermediate (RO)(RO)22P(O)ClP(O)Cl ((ddACP;ACP; RR == alkyl)alkyl) andand 1,3,5-triazinane-2,4,6-trione1,3,5-triazinane-2,4,6-trione ((ttAAttO)O) Molecules(Scheme(Scheme2020 22).22)., 25 Following,Following,, 3684 aa nucleophnucleophilicilic substitutionsubstitution betweenbetween thethe ddACPACP andand thethe amineamine resultresult 21 inin of thethe 37 P-NP-N withwith HClHCl asas thethe majormajor by-product.by-product.

Scheme 22. Proposed mechanism for the base-free synthesis of phosphoramidates using aSchemeScheme chlorinating 2222.. Proposed agent.Proposed mechanismmechanism forfor thethe base-freebase-free synthesissynthesis ofof phosphoramidatesphosphoramidates usingusing aa chlorinatingchlorinating agent.agent. The mechanism of the reaction by Jang et al. suggests that diphenyl phosphoric acid (dPPA) undergoesTheThe mechanismmechanism chlorination ofof in thethe the reactionreaction presence byby of aJangJang base, etet which alal.. suggestssuggests is subsequently thatthat diphenyldiphenyl attacked phosphoricphosphoric by the amine acidacid to ((d adPPA)ffPPA)ord theundergoesundergoes P-N product chlorinationchlorination [99]. Although inin thethe presencepresence the authors ofof aa base, didbase, not whichwhich propose isis subsequentlysubsequently any mechanism, attackedattacked they byby suggested thethe amineamine that toto nucleophilicaffordafford thethe P-NP-N attack productproduct on the [99].[99]. P atom AlthoughAlthough was consistent thethe authorauthor withss diddid aliphatic notnot proposepropose amines anyany resulting mechanism,mechanism, in a they higherthey suggestedsuggested yield of productsthatthat nucleophilicnucleophilic than the attack aromaticattack onon amines thethe PP atomatom because waswas aliphatic consisteconsiste aminesntnt withwith are aliphaticaliphatic more nucleophilic. aminesamines resultingresulting inin aa higherhigher yieldyieldThe ofof productsproducts mechanistic thanthan thethe step aromaticaromatic suggested aminesamines bybebecausecause Appel aliphaticaliphatic and aminesamines Einig areare involves moremore nucleophilic.nucleophilic. the formation of The mechanistic step suggested by Appel and Einig involves the formation of oxo-triphenyl-diphosphoxaniumThe mechanistic step suggested salt intermediate by Appel from aand deprotonation Einig involves of phosphoric the formation acid by CCl of4 inoxo-triphenyl-diphosphoxaniumoxo-triphenyl-diphosphoxanium the presence of phosphine (Scheme saltsalt intermediateintermediate 23)[86]. Nucleophilic fromfrom aa deprotonationdeprotonation substitution ofof from phosphoricphosphoric amineresults acidacid byby in CClCCl the44 desiredinin thethe presencepresence product of andof phosphinephosphine triphenylphosphate (Scheme(Scheme 23)23) as [86].[86]. the by-product. NuNucleophiliccleophilic substitutionsubstitution fromfrom amineamine resultsresults inin thethe desireddesired productproduct andand triphenylptriphenylphosphatehosphate asas thethe by-product.by-product.

SchemeScheme 23.2323.. ProposedProposed mechanismmechanism forfor thethe synthesissynthesis ofof phosphoramidatesphphosphoramidatesosphoramidates fromfrom phosphoricphosphoric acidacid andand

amineamine inin thethe presencepresence ofof phosphinephosphine and andand CCl CClCCl444..

3.2.2. Using Iodinating Agents 3.2.2.3.2.2. UsingUsing IodinatingIodinating AgentsAgents

In the suggested reaction mechanism by [100], iodine reacts with (RO)3P (R = alkyl) to form InIn thethe suggestedsuggested reactionreaction mechanismmechanism byby [100],[100], iodineiodine reactsreacts withwith (RO)(RO)33PP (R(R == alkyl)alkyl) toto formform trialkoxyiodophosphonium intermediate, which is further attacked by iodide ion to form dialkyl trialkoxyiodophosphoniumtrialkoxyiodophosphonium intermediate,intermediate, whichwhich isis furtherfurther attackedattacked byby iodideiodide ionion toto formform dialkyldialkyl phosphoriodidate (dAPPI) (Arbuzov reaction, Scheme 24). Then, the dAPPI is attacked by the amine to phosphoriodidatephosphoriodidate ((ddAPPI)APPI) (Arbuzov(Arbuzov reaction,reaction, SchemeScheme 24).24). Then,Then, thethe ddAPPIAPPI isis attackedattacked byby thethe amineamine give the desired P-N with an elimination of HI. N-phosphoryl amino acid esters and P-N with a free toto givegive thethe desireddesired P-NP-N withwith anan eliminationelimination ofof HI.HI. NN-phosphoryl-phosphoryl aminoamino acidacid estersesters andand P-NP-N withwith aa amino group were also synthesized using the iodine-mediated synthesis method. The challenges with freefree aminoamino groupgroup werewere alsoalso synthesizedsynthesized usinusingg thethe iodine-mediatediodine-mediated synthesissynthesis method.method. TheThe this iodine-mediated P-N formation is that many side products are formed, and the reaction procedure challengeschallenges withwith thisthis iodine-mediatediodine-mediated P-NP-N formationformation isis thatthat manymany sideside productsproducts areare formed,formed, andand thethe does not generate the desired product when N-iodosuccinimide (NIS) is used as the iodine source.

In addition, the reaction process is ineffective with aromatic H-phosphonates because the reaction is affected by steric effects on the substituents. In a mechanism of the I2-mediated P-N formation, according to Singh et al., H-P reacts with I2 to form an intermediate, which undergoes nucleophilic attack from the amine to generate a hydroxylated-dialkyl phenylphosphoramidate complex with an elimination of I2 (Scheme 25)[101]. The phosphoramidate complex further undergoes dehydrogenation to eliminate H2 in form of H2O and afford the desired products. The suggested mechanism of a similar reaction reported by Prabhu et al. instead involves the nucleophilic substitution of phosphoriodate intermediate after the electrophilic iodination of the H-P starting material (Scheme 26)[102]. Then, the iodide ion is oxidized to active catalyst, hypoiodous acid, in the presence of H2O2. Molecules 2020, 25, x FOR PEER REVIEW 22 of 37 reaction procedure does not generate the desired product when N-iodosuccinimide (NIS) is used as the iodine source. In addition, the reaction process is ineffective with aromatic H-phosphonates because the reaction is affected by steric effects on the substituents.

Molecules 2020, 25, x FOR PEER REVIEW 22 of 37

reaction procedure does not generate the desired product when N-iodosuccinimide (NIS) is used as the iodine source. In addition, the reaction process is ineffective with aromatic H-phosphonates because the reaction is affected by steric effects on the substituents.

Molecules 2020, 25, x FOR PEER REVIEW 22 of 37

reaction procedure does not generate the desired product when N-iodosuccinimide (NIS) is used as Molecules 2020, 25, 3684 22 of 37 the iodine source. In addition, the reaction process is ineffective with aromatic H-phosphonates Scheme 24. Proposed mechanism for the iodine-mediated synthesis of phosphoramidates. because the reaction is affected by steric effects on the substituents.

In a mechanism of the I2-mediated P-N formation, according to Singh et al., H-P reacts with I2 to form an intermediate, which undergoes nucleophilic attack from the amine to generate a hydroxylated-dialkyl phenylphosphoramidate complex with an elimination of I2 (Scheme 25) [101]. The phosphoramidate complex further undergoes dehydrogenation to eliminate H2 in form of H2O and afford the desired products. Scheme 24. Proposed mechanism for the iodine-mediated synthesis of phosphoramidates.

In a mechanism of the I2-mediated P-N formation, according to Singh et al., H-P reacts with I2 to form an intermediate, which undergoes nucleophilic attack from the amine to generate a hydroxylated-dialkyl phenylphosphoramidate complex with an elimination of I2 (Scheme 25) [101]. The phosphoramidate complex further undergoes dehydrogenation to eliminate H2 in form of H2O Scheme 24 24.. ProposedProposed mechanism for the iodine-med iodine-mediatediated synthesis of phosphoramidates. and afford the desired products. SchemeIn a mechanism 25. Proposed of the mechanism I2-mediated for P-N the formation, iodine-med accordingiated synthesisto Singh et of al phosphoramidates.., H-P reacts with I2 to form an intermediate, which undergoes nucleophilic attack from the amine to generate a Thehydroxylated-dialkyl suggested mechanism phenylphosphoramidate of a similar reaction complex reported with an eliminationby Prabhu of etI2 (Schemeal. instead 25) [101]. involves the The phosphoramidate complex further undergoes dehydrogenation to eliminate H2 in form of H2O nucleophilicand afford substitution the desired of products. phosphoriodate intermediate after the electrophilic iodination of the H-P starting material (Scheme 26) [102]. Then, the iodide ion is oxidized to active catalyst, hypoiodous acid,SchemeScheme in the 25.25 presence. ProposedProposed mechanismmechanism of H2O2. for for thethe iodine-mediatediodine-mediated synthesissynthesis ofof phosphoramidates.phosphoramidates.

The suggested mechanism of a similar reaction reported by Prabhu et al. instead involves the nucleophilic substitution of phosphoriodate intermediate after the electrophilic iodination of the H-P starting material (Scheme 26) [102]. Then, the iodide ion is oxidized to active catalyst, hypoiodous acid, in the presence of H2O2. Scheme 25. Proposed mechanism for the iodine-mediated synthesis of phosphoramidates.

The suggested mechanism of a similar reaction reported by Prabhu et al. instead involves the nucleophilic substitution of phosphoriodate intermediate after the electrophilic iodination of the H-P starting material (Scheme 26) [102]. Then, the iodide ion is oxidized to active catalyst, hypoiodous acid, in the presence of H2O2.

Scheme 26. Proposed mechanism for the hypoiodous acid-mediated synthesis of phosphoramidates. Scheme 26. Proposed mechanism for the hypoiodous acid-mediated synthesis of phosphoramidates. 3.2.3. Using Transition Metal Catalyst

3.2.3. Using InTransitionScheme a copper-catalyzed 26. Proposed Metal mechanismCatalyst oxidative for cross-couplingthe hypoiodous ac reaction,id-mediated Hayes synthesis et al. of phosphoramidates. proposed a reaction mechanism involving single-electron transfer oxidation of the copper catalyst, which favored the In formationa3.2.3. copper-catalyzed Using of theTransition Cu(II)-amine Metal oxidative complexCatalyst cross-coupling (Scheme 27)[103]. Thereaction, Cu(II)-amine Hayes complex et al. is furtherproposed oxidized a reaction mechanismto form involving the Cu(III)-amine-phosphonate single-electron transfer complex, oxidation which undergoes of the reductive copper elimination catalyst, ofwhich the copper favored the In a copper-catalyzed oxidative cross-coupling reaction, Hayes et al. proposed a reaction catalyst to yield the desired P-N. Although this mechanism seems plausible, it could not easily explain formationmechanism of the Cu(II)-amineinvolving single-electron complex transfer (Scheme oxidation 27) [103]. of the Thecopper Cu(II)-amine catalyst, which complex favored the is further the formation of the side products. formation of the Cu(II)-amine complex (Scheme 27) [103]. The Cu(II)-amine complex is further Scheme 26. Proposed mechanism for the hypoiodous acid-mediated synthesis of phosphoramidates.

3.2.3. Using Transition Metal Catalyst In a copper-catalyzed oxidative cross-coupling reaction, Hayes et al. proposed a reaction mechanism involving single-electron transfer oxidation of the copper catalyst, which favored the formation of the Cu(II)-amine complex (Scheme 27) [103]. The Cu(II)-amine complex is further

MoleculesMolecules 2020, 252020, x, FOR25, x FORPEER PEER REVIEW REVIEW 23 of23 37 of 37 oxidizedoxidized to form to form the Cu(III)-amine-phosphonatethe Cu(III)-amine-phosphonate co complex,mplex, which which undergoes reductive reductive elimination elimination of of the copperthe Moleculescopper catalyst 2020catalyst, 25to, 3684 yield to yield the the desired desired P-N. P-N. Althou Althoughgh this this mechanismmechanism seemsseems plausible, plausible, it23 couldit of could 37 not not easilyeasily explain explain the formation the formation of theof the side side products. products.

Scheme 27. Proposed mechanism for the copper catalyzed oxidative cross-coupling of disubstituted H-phosphonatesScheme 27. Proposed and amines mechanism to produce for the phosphoramidates. copper catalyzed oxidative cross-coupling of disubstituted Scheme 27H-phosphonates. Proposed mechanism and amines to for produce the copper phosphoramidates. catalyzed oxidative cross-coupling of disubstituted H-phosphonatesThere were and no aminessuggested to produce mechanisms phosphoramidates. for the reaction in the report by Wang et al. [104]. There were no suggested mechanisms for the reaction in the report by Wang et al. [104]. However, However,the results the of results the reagent of the screening reagent for screening the reaction for had the suggested reaction that had other suggested transition that metal other catalysts transition There were no suggested mechanisms for the reaction in the report by Wang et al. [104]. metal(e.g., catalysts CoBr ) and(e.g., other CoBr Cu2) catalystsand other (e.g., Cu Cu(OAc) catalystsH (e.g.,O) were Cu(OAc) inactive2·H or2O) ine werefficient inactive for the catalysis.or inefficient 2 2· 2 However,for theIt wasthe catalysis. furtherresults It suggestedof was the further reagent that suggested although screening a CuClthat for although catalyst the reaction enabled a CuCl reaction, hadcatalyst suggested itenabled was not reaction,that as e ffotherective it wastransition as not metalas catalysts effectiveCuBr and (e.g., as conducting CuBr CoBr and2) theconductingand reaction other underCuthe reaccatalysts anaerobiction under (e.g., conditions anaerobic Cu(OAc) (e.g., conditions2·H under2O) Nwere2) (e.g., did inactive not under lead Nor to2) the inefficientdid not for thelead catalysis.desired to the product.desired It was product. further suggested that although a CuCl catalyst enabled reaction, it was not In the Fe O @MgO nanoparticle-mediated synthesis of P-Ns as per the procedure reported as effectiveIn as the CuBr Fe3O and43@MgO4 conducting nanoparticle-mediated the reaction undersynthesis anaerobic of P-Ns conditionsas per the procedure (e.g., under reported N2) did by not by Habibi et al. [105], the mechanism involves the formation of the (RO) P(O)Cl (dACP; R = alkyl) lead toHabibi the desired et al. [105], product. the mechanism involves the formation of the (RO)2 2P(O)Cl (dACP; R = alkyl) intermediate from the reaction of dialkyl H-phosphonate ((OR) P(O)H, R = alkyl) with CCl (Scheme 28). intermediate from the reaction of dialkyl H-phosphonate ((OR)2 2P(O)H, R = alkyl) with4 CCl4 (Scheme In the Fe3O4@MgO nanoparticle-mediated synthesis of P-Ns as per the procedure reported by Following, the amine in the presence of Fe3O4@MgO nanoparticles couples with the dACP by 28). Following, the amine in the presence of Fe3O4@MgO nanoparticles couples with the dACP by Habibi etnucleophilic al. [105], substitutionthe mechanism to give theinvolves P-N product, the formation eliminating HCl.of the (RO)2P(O)Cl (dACP; R = alkyl) nucleophilic substitution to give the P-N product, eliminating HCl. intermediate from the reaction of dialkyl H-phosphonate ((OR)2P(O)H, R = alkyl) with CCl4 (Scheme 28). Following, the amine in the presence of Fe3O4@MgO nanoparticles couples with the dACP by nucleophilic substitution to give the P-N product, eliminating HCl.

Scheme 28. ProposedmechanismfortheFe3O4@MgOnanoparticle-mediatedsynthesisofphosphoramidates. Scheme 28. Proposed mechanism for the Fe3O4@MgO nanoparticle-mediated synthesis of phosphoramidates.

According the plausible two-step mechanism for the reaction by Purohit et al., (RO)2P(O)Cl (dACP; R = alkyl) is first generated from the electrophilic displacement of hydrogen on the dialkyl Scheme 28. Proposed mechanism for the Fe3O4@MgO nanoparticle-mediated synthesis of H-phosphonate ((OR)2P(O)H, R = alkyl) upon reacting with CuCl2 (Scheme 29a) [106]. The phosphoramidates.

According the plausible two-step mechanism for the reaction by Purohit et al., (RO)2P(O)Cl (dACP; R = alkyl) is first generated from the electrophilic displacement of hydrogen on the dialkyl H-phosphonate ((OR)2P(O)H, R = alkyl) upon reacting with CuCl2 (Scheme 29a) [106]. The

Molecules 2020, 25, 3684 24 of 37

According the plausible two-step mechanism for the reaction by Purohit et al., (RO) P(O)Cl Molecules 2020, 25, x FOR PEER REVIEW 2 24 of 37 (dACP; R = alkyl) is first generated from the electrophilic displacement of hydrogen on the dialkyl H-phosphonate ((OR)2P(O)H, R = alkyl) upon reacting with CuCl2 (Scheme 29a) [106]. phosphoramidateThe phosphoramidate is formed is in formed the insecond the second step stepby bycoupling coupling ddACPACP andand amine.amine. However, However, this 2 3 reportedthis mechanism reported mechanism could not could properly not properly explain explain the the role role ofof Cs Cs2COCO3 in thein couplingthe coupling of alkyl of alkyl chlorophosphatechlorophosphate and the and amine the amine to togive give the the P-N. This This is becauseis because the coupling the coupling reaction reaction was expected was to expected to eliminateeliminate other other products products alongalong with with CsCl CsCl such assu ach highly as reactivea highly CsH reactive and a carbonate. CsH and However, a carbonate. it is to be understood that the use of Cs2CO3 as the inorganic base was based on the poorly understood However, it is to be understood that the use of Cs2CO3 as the inorganic base was based on the poorly “caesium effect” in which the highly soluble caesium base selectively favors the formation of one understoodfunctional “caesium group ineffect” preference in towhich another the [122 highly,123]. soluble caesium base selectively favors the formation of one functional group in preference to another [122,123].

SchemeScheme 29. Proposed 29. Proposed mechanism mechanism for for the the Cu-media Cu-mediatedted synthesis synthesis of phosphoramidates. of phosphoramidates.

Mizuno et al. proposed a mechanism for the reaction in which K2CO3 first deprotonates the Mizunoamide, et aff al.ording proposed unpaired a electrons mechanism on a Cu-amide for the complex reaction [107 in]. Furthermore,which K2CO it was3 first suggested deprotonates that the amide, affordingit is possible unpaired that K2CO electrons3 deprotonates on a H-P Cu-amide or provides complex a medium [107]. for theFurthermore, H-P tautomer it to was further suggested complex with the Cu-amide complex. The Cu-amide-phosphite intermediate undergoes reductive that it is possible that K2CO3 deprotonates H-P or provides a medium for the H-P tautomer to further elimination to afford the desired product, while O re-oxidizes the reduced Cu species to regenerate complex with the Cu–amide complex. The Cu-ami2 de-phosphite intermediate undergoes reductive the active catalyst. Although the oxidation state of Cu in the reaction mechanism was not explained, eliminationthe authorsto afford suggested the desired that it couldproduct, be +2, while and the O fact2 re-oxidizes that the reaction the reduced produced Cu only species stoichiometric to regenerate the activeamounts catalyst. of the Although desired product the oxidation (relative to state the Cu of catalyst)Cu in the under reaction an inert mechanism atmosphere was was a supportnot explained, the authorsto the suggested re-oxidation that of the it could Cu species be +2, in air. and the fact that the reaction produced only stoichiometric amounts of Fromthe desired their experimental product (relative observations, to the Zhou Cu et catalyst) al. strongly under suggested an inert that theatmosphere oxidative was a support dehydrocouplingto the re-oxidation reaction of the for P-NCu species synthesis in using air. Cu-catalysts proceeds stereospecifically through an inversion of the configuration at P [108]. This stereospecific inversion chemistry was used as Froman argumenttheir experimental in the proposed observations, mechanism to support Zhou aet formation al. strongly of halogen–phosphate suggested that intermediate the oxidative dehydrocouplingwhen Cu catalyst reaction is reacted for P-N with synthesis H-phosphonate using (H-P). Cu-catalysts The amine proceeds (as a nucleophile) stereospecifically subsequently through an inversionattacks of the the intermediate configuration from behindat P [108]. to give This the product,stereospecific while the inversion Cu(I) catalyst chemistry is then reoxidized was used as an argumentby in O2 theto Cu(II) proposed in the presence mechanism of hydrogen to support halide formeda formation from the of process. halogen–phosphate Water is also formed intermediate as when Cua stoichiometriccatalyst is reacted waste (Scheme with H 29-phosphonateb). (H-P). The amine (as a nucleophile) subsequently attacks the intermediate from behind to give the product, while the Cu(I) catalyst is then reoxidized by O2 to Cu(II) in the presence of hydrogen halide formed from the process. Water is also formed as a stoichiometric waste (Scheme 29b). The mechanism as reported by Dangroo et al. involved transmetalation to form an azidocopper(II) species in the first step (Scheme 30) [109]. Similar transmetalation reactions involving the phenylboronic acid-based substrates and the azidocopper(II) species in the second step result in the formation of a phenyl–azidocopper(II) complex. The complex is oxidized in the presence of Cu(II) to a phenyl–azidocopper(III) complex, which results in the formation of the organic azide and forms Cu(I) after reductive elimination. From this, a reaction between the (RO)3P (R = alkyl) and the organic azide gives phosphorimidate (with loss of N2), which undergoes hydrolysis to afford the desired product, while the Cu(I) is reoxidized to Cu(II) in the catalytic cycle. Although the mechanism satisfies much of the observed results, the proposed second step, transmetalation, would have resulted in borazidic acid (i.e., N3-B(OH)2) and Cu(II)-phenyl species or Cu(OH)2 species when the azidocopper(II) species reacted with phenylboronic acid-based substrates, based on the exchange of ligands as in the first step.

Molecules 2020, 25, 3684 25 of 37

The mechanism as reported by Dangroo et al. involved transmetalation to form an azidocopper(II) species in the first step (Scheme 30)[109]. Similar transmetalation reactions involving the phenylboronic acid-based substrates and the azidocopper(II) species in the second step result in the formation of a phenyl–azidocopper(II) complex. The complex is oxidized in the presence of Cu(II) to a phenyl–azidocopper(III) complex, which results in the formation of the organic azide and forms Cu(I) after reductive elimination. From this, a reaction between the (RO)3P (R = alkyl) and the organic azide gives phosphorimidate (with loss of N2), which undergoes hydrolysis to afford the desired product, while the Cu(I) is reoxidized to Cu(II) in the catalytic cycle. Although the mechanism satisfies much of the observed results, the proposed second step, transmetalation, would have resulted in borazidic acid (i.e., N3-B(OH)2) and Cu(II)-phenyl species or Cu(OH)2 species when the azidocopper(II) species Moleculesreacted 2020, 25 with, x FOR phenylboronic PEER REVIEW acid-based substrates, based on the exchange of ligands as in the first step. 25 of 37

SchemeScheme 30. Proposed 30. Proposed mechanism mechanism of of the the Cu-catalyzedCu-catalyzed synthesis synthesis of phosphoramidates of phosphoramidates from from phenylboronic acid/ester-based substrates and trialkyl phosphite. phenylboronic acid/ester-based substrates and trialkyl phosphite. 3.2.4. Using an Organophotocatalyst 3.2.4. UsingIn an a Organophotocatalyst suggested mechanism for the organophotocatalytic synthesis of P-N, a photon from the In visiblea suggested light source mechanism is absorbed for by the organicorganophotocat dye to becomealytic an excitedsynthesis radical of (SchemeP-N, a photon31)[110]. from the By a single-electron transfer process, the excited dye-radical abstracts an electron from the N atom of the visible light source is absorbed by the organic dye to become an excited radical (Scheme 31) [110]. By amine to form an anionic dye radical and cationic amine radical. In the presence of O2, the anionic dye a single-electronradical is reoxidized transfer to process, the organic the dye, excited while the dye- anionicradical superoxide abstracts that is an formed electron in the processfrom the reacts N atom of the aminewith to diethyl form H-phosphonate an anionic (H-P)dye radical to generate and anionic cationic hydrogen amine peroxide radical. and aIn diethyl the presence phosphoryl of O2, the anionicradical. dye radical Then, theis reoxidized radical reacts to with the the organic cationic-amine dye, while radical the to anionic form a protonated superoxide P-N, that which is isformed in the processthen deprotonatedreacts with bydiethyl the anionic H-phosphonate hydrogen peroxide. (H-P) The to authorsgenerate reported anionic that hydrogen after an initial peroxide 74% and a isolated product, the organic dye catalyst was recycled a second time using an acid–base extraction, diethyl andphosphoryl 67% isolated radical. product wasThen, obtained the theradical second reacts time. with the cationic-amine radical to form a protonated P-N, which is then deprotonated by the anionic hydrogen peroxide. The authors reported that after an initial 74% isolated product, the organic dye catalyst was recycled a second time using an acid–base extraction, and 67% isolated product was obtained the second time.

Scheme 31. Proposed mechanism for the visible light and organic dye-catalyzed synthesis of phosphoramidates.

Molecules 2020, 25, x FOR PEER REVIEW 25 of 37

Scheme 30. Proposed mechanism of the Cu-catalyzed synthesis of phosphoramidates from phenylboronic acid/ester-based substrates and trialkyl phosphite.

3.2.4. Using an Organophotocatalyst In a suggested mechanism for the organophotocatalytic synthesis of P-N, a photon from the visible light source is absorbed by the organic dye to become an excited radical (Scheme 31) [110]. By a single-electron transfer process, the excited dye-radical abstracts an electron from the N atom of the amine to form an anionic dye radical and cationic amine radical. In the presence of O2, the anionic dye radical is reoxidized to the organic dye, while the anionic superoxide that is formed in the process reacts with diethyl H-phosphonate (H-P) to generate anionic hydrogen peroxide and a diethyl phosphoryl radical. Then, the radical reacts with the cationic-amine radical to form a protonated P-N, which is then deprotonated by the anionic hydrogen peroxide. The authors Molecules 2020 25 reported that, ,after 3684 an initial 74% isolated product, the organic dye catalyst was recycled a second26 of 37 time using an acid–base extraction, and 67% isolated product was obtained the second time.

Scheme 31. Proposed mechanism for the visible light and organic dye-catalyzed synthesis MoleculesScheme 2020, 2531, x. FORProposed PEER REVIEW mechanism for the visible light and organic dye-catalyzed synthesis of26 of 37 ofphosphoramidates. phosphoramidates. 3.2.5. Using Using Alkali–Metal Alkali–Metal Catalyst

In the overall mechanism suggested for the alkali–metalalkali–metal catalyzed oxidative cross-coupling reaction, a phosphoryl iodide intermediate and and LiOH LiOH are are generated in in the the first first step from a reaction of LiI and the H-phosphonate (H-P) in the presence of aq. TBHP (Scheme 32)32)[ [111].111]. The second step involves the removal of a proton from the amine by the LiOH to form lithium amide and H2O, and involves the removal of a proton from the amine by the LiOH to form lithium amide and H2O, and the thedesired desired product product is formed is formed in the in final the final step fromstep thefrom reaction the reaction of phosphoryl of phosphoryl iodide iodide and lithium and lithium amide. amide.

SchemeScheme 32 32.. ProposedProposed mechanism mechanism for for the the synthesis synthesis of of ph phosphoramidatesosphoramidates using using alkali-metal alkali–metal catalyst. catalyst.

3.3. Azide Route

3.3.1. Nitrene Insertion from Organic Azide The mechanism of the reaction of nitrene insertion according to Chang, Kim, and coworkers follows activation of the C-H bond cleavage on the amide or ketone substrate by the Ir(III)-based catalyst to generate an iridacyclic intermediate, which then reacts with the phosphoryl azide to produce a coordinated phosphoryl azide–iridacyclic adduct (Scheme 33) [112]. By intramolecular migratory insertion of C-N into the Ir-C bond, with removal of N2, or by nucleophilic attack from the azide group on the Ir-C bond to form the C-N bond with the elimination of N2, a complex of Ir-N-C bond is formed. Proto-demetallation of the Ir(III)-based catalyst affords the desired product while regenerating the catalyst. According to Zhu et al., the mechanistic steps involve activation of the Ir(III)-based catalyst in the presence of AgOAc and AgSbF6, which abstracts an H atom from the 2-phenylpyridine derivative to cyclo-(2-phenylpyridine)iridium(III) complex [114]. The complex further coordinates with phosphoryl azide to form a cyclo-(2-phenylpyridine)iridium(III)-phosphoryl azide complex, which undergoes migratory insertion to give a complex containing a C-N-Ir(III) bond, releasing N2. The Ir(III)-based catalyst is released through proto-demetallation to generate the desired product.

Molecules 2020, 25, 3684 27 of 37

3.3. Azide Route

3.3.1. Nitrene Insertion from Organic Azide The mechanism of the reaction of nitrene insertion according to Chang, Kim, and coworkers follows activation of the C-H bond cleavage on the amide or ketone substrate by the Ir(III)-based catalyst to generate an iridacyclic intermediate, which then reacts with the phosphoryl azide to produce a coordinated phosphoryl azide–iridacyclic adduct (Scheme 33)[112]. By intramolecular migratory insertion of C-N into the Ir-C bond, with removal of N2, or by nucleophilic attack from the azide group on the Ir-C bond to form the C-N bond with the elimination of N2, a complex of Ir-N-C bond is formed. Proto-demetallation of the Ir(III)-based catalyst affords the desired product while regenerating the catalyst. According to Zhu et al., the mechanistic steps involve activation of the Ir(III)-based catalyst in the presence of AgOAc and AgSbF6, which abstracts an H atom from the 2-phenylpyridine derivative to cyclo-(2-phenylpyridine)iridium(III) complex [114]. The complex further coordinates with phosphoryl azide to form a cyclo-(2-phenylpyridine)iridium(III)-phosphoryl azide complex, which undergoes (III) (III) migratory insertion to give a complex containing a C-N-Ir bond, releasing N2. The Ir -based catalyst is released through proto-demetallation to generate the desired product. For the nitrene insertion using RuIV-porphyrin-based catalyst, Che and coworkers proposed that a reactive intermediate RuIV-porphyrin-phosphorylimide species is first formed from the interaction of phosphoryl azide and the RuIV–porphyrin catalyst [113]. Then, the intermediate reacts with the aldehyde C-H bond through nitrene insertion to form a C-N bonded RuIV-porphyrin-phosphorylimide-aldehyde complex with the removal of N2. The desired N-acylphosphoramidates (AcP-N) product is formed Molecules 2020after, 25 proto-demetallation, x FOR PEER REVIEW of the RuIV-porphyrin catalyst, and the catalyst is regenerated in the process. 27 of 37

Scheme 33. Proposed mechanism for the Ir-catalyzed synthesis of phosphoramidates. Scheme 33. Proposed mechanism for the Ir-catalyzed synthesis of phosphoramidates.

For the nitrene insertion using RuIV-porphyrin-based catalyst, Che and coworkers proposed that a reactive intermediate RuIV-porphyrin-phosphorylimide species is first formed from the interaction of phosphoryl azide and the RuIV–porphyrin catalyst [113]. Then, the intermediate reacts with the aldehyde C-H bond through nitrene insertion to form a C-N bonded RuIV-porphyrin-phosphorylimide-aldehyde complex with the removal of N2. The desired N-acylphosphoramidates (AcP-N) product is formed after proto-demetallation of the RuIV-porphyrin catalyst, and the catalyst is regenerated in the process.

3.3.2. Organic Azide Generation Route In the reported mechanisms of the reaction for P-N synthesis via azide generation, organic azide is formed in the first step from nucleophilic substitution of the organic halide with the elimination of N2 gas. In the second step, the organic azide reacts with (RO)3P (R = alkyl) to form the P-N compound after rearrangement or hydrolysis (Scheme 34) [93,115,116].

Scheme 34. Proposed mechanism to phosphoramidates via azide generation.

According to the mechanism suggested by Chen et al., the amine reacts with phosphoryl azide through a nucleophilic substitution reaction to generate an azido (hydroxy)-phosphanamine complex intermediate in the first step [117]. In the second step, the azide anion departs as the leaving group to give a stable P-N product (Scheme 35). Although the mechanism looks highly plausible, it is noteworthy that N3 is highly nucleophilic because in its canonical structure, one of the nitrogen atoms carries a double negative charge (N≡N+ − N2−) [124], which makes it stable and a poor leaving group as N3 in the presence of amine [125]. In addition, the mechanism does account for the potentially explosive HN3 in a closed flask at 120 °C. However, it is possible that in the reaction process, the azide is first reduced or decomposed to a nitrene phosphonate radical ((RO)2P(O)N; R =

Molecules 2020, 25, x FOR PEER REVIEW 27 of 37

Scheme 33. Proposed mechanism for the Ir-catalyzed synthesis of phosphoramidates.

For the nitrene insertion using RuIV-porphyrin-based catalyst, Che and coworkers proposed that a reactive intermediate RuIV-porphyrin-phosphorylimide species is first formed from the interaction of phosphoryl azide and the RuIV–porphyrin catalyst [113]. Then, the intermediate reacts with the aldehyde C-H bond through nitrene insertion to form a C-N bonded RuIV-porphyrin-phosphorylimide-aldehyde complex with the removal of N2. The desired N-acylphosphoramidates (AcP-N) product is formed after proto-demetallation of the RuIV-porphyrinMolecules 2020, 25catalyst,, 3684 and the catalyst is regenerated in the process. 28 of 37

3.3.2.3.3.2. Organic Organic Azide Azide Generation Generation Route Route In theIn thereported reported mechanisms mechanisms ofof the the reaction reaction for P-Nfor P-N synthesis synthesis via azide via generation, azide generation, organic azide organic azideis formedis formed in the in first the step first from step nucleophilic from nucleoph substitutionilic substitution of the organic of halide the withorganic the elimination halide with of the eliminationN2 gas. Inof theN2 secondgas. In step, the second the organic step, azide the reactsorganic with azide (RO) 3reactsP (R = withalkyl) (RO) to form3P (R the = P-N alkyl) compound to form the P-N aftercompound rearrangement after rearrangement or hydrolysis (Scheme or hydrolysis 34)[93, 115(Scheme,116]. 34) [93,115,116].

Scheme 34. Proposed mechanism to phosphoramidates via azide generation. Scheme 34. Proposed mechanism to phosphoramidates via azide generation. According to the mechanism suggested by Chen et al., the amine reacts with phosphoryl azide throughAccording a nucleophilic to the mechanism substitution suggested reaction to by generate Chen et an al., azido the (hydroxy)-phosphanamine amine reacts with phosphoryl complex azide throughintermediate a nucleophilic in the first substitu step [117tion]. In thereaction second to step, generate the azide an anion azido departs (hydroxy)-phosphanamine as the leaving group complexto give intermediate a stable P-N in product the first (Scheme step [117]. 35). In Although the second the step, mechanism the azide looks anion highly departs plausible, as the it leaving is noteworthy that N3 is highly nucleophilic because in its canonical structure, one of the nitrogen atoms group to give a stable P-N product (Scheme+ 235). Although the mechanism looks highly plausible, it carries a double negative charge (N N N −)[124], which makes it stable and a poor leaving group is noteworthy that N3 is highly nucleophilic≡ − because in its canonical structure, one of the nitrogen as N3 in the presence of amine [125]. In addition, the mechanism does account for the potentially atoms carries a double negative charge (N≡N+ − N2−) [124], which makes it stable and a poor leaving explosive HN3 in a closed flask at 120 ◦C. However, it is possible that in the reaction process, the azide 3 groupisMolecules firstas N reduced 2020 in, 25 the, x or FOR decomposedpresence PEER REVIEW of toamine a nitrene [125]. phosphonate In addition, radical the ((RO) mechanism2P(O)N; R does= alkyl, account Ph),28 while offor 37 the potentiallyN2 is liberated. explosive In HN the second3 in a closed step, the flask electrophilic at 120 °C. nitrene However, phosphonate it is possible radical reactsthat in with the orreaction is process,substitutedalkyl, the Ph), azide while by theis firstN nucleophile2 is reduced liberated. amine or In decomp the to give secondosed the product.step, to a thenitrene electrophilic phosphonate nitrene radical phosphonate ((RO)2 P(O)N;radical R = reacts with or is substituted by the nucleophile amine to give the product.

SchemeScheme 35.35. Proposed mechanism for anan organicorganic azideazide routeroute toto phosphoramidates.phosphoramidates. 3.4. Reduction Route 3.4. Reduction Route 3.4.1. Via Nitro-Group Reduction 3.4.1. Via Nitro-Group Reduction The proposed mechanism of the reaction for the nitro-group reduction route involves the reduction The proposed mechanism of the reaction for the nitro-group reduction route involves the of nitrobenzene in the presence of (RO)3P (R = alkyl) to give nitrosobenzene with a phosphate side productreduction (Scheme of nitrobenzene 36)[118]. In in the the second presence step, of the (RO) nitrosobenzene3P (R = alkyl) is reduced to give further nitrosobenzene in the presence with ofa phosphate side product (Scheme 36) [118]. In the second step, the nitrosobenzene is reduced further another equivalent of (RO)3P, generating phenylnitride with another phosphate side product. A further in the presence of another equivalent of (RO)3P, generating phenylnitride with another phosphate reaction of (RO)3P (R = alkyl) with the basic phenylnitride generates a trialkyl phenylphosphorimidate intermediate,side product. A which further undergoes reaction of hydrolysis (RO)3P (R = to alkyl) give with the desiredthe basicN phenylnitride-arylphosphoramidate generates a product. trialkyl Experimentsphenylphosphorimidate to verify the intermediate, proposed mechanism which usingundergoes aniline hydrolysis in the presence to give of excessthe triethyldesired phosphiteN-arylphosphoramidate or triethyl phosphate product. did Ex notperiments yield the to desiredverify the product proposed under mechanism the optimized using conditions, aniline in the presence of excess triethyl phosphite or triethyl phosphate did not yield2 the desired product suggesting that the reaction proceeds via reduction of the nitro group to N − and that the product is notunder formed the optimized from phosphate. conditions, suggesting that the reaction proceeds via reduction of the nitro group to N2− and that the product is not formed from phosphate.

Scheme 36. Proposed mechanism for reduction of the nitro-group route to phosphoramidates.

3.4.2. Via Catalyst-Free Staudinger Reduction and Lewis-Acid Catalyzed Rearrangement The plausible two-step mechanistic process suggested by Hackenberger’s group for the synthesis involves the formation of phosphorimidate from the reduction of azide in the presence of (RO)3P (R = alkyl), eliminating N2, in the first step (Scheme 37) [119]. In the second step, BF3 activates the nitrogen site of the phosphorimidate by forming a coordinated complex. Electrophilic attack by a neighbouring alkyl group of phosphorimidate on the negatively charged N atom of the phosphorimidate-BF3 complex results in an ((alkyl)amino)trialkoxyphosphonium complex, cleaving off BF3. Nucleophilic attack on the trialkoxyphosphonium complex from a neighboring phosphorimidate completes the catalytic cycle, affording a P=O bond of the desired P-N product.

Molecules 2020, 25, x FOR PEER REVIEW 28 of 37

alkyl, Ph), while N2 is liberated. In the second step, the electrophilic nitrene phosphonate radical reacts with or is substituted by the nucleophile amine to give the product.

Scheme 35. Proposed mechanism for an organic azide route to phosphoramidates.

3.4. Reduction Route

3.4.1. Via Nitro-Group Reduction The proposed mechanism of the reaction for the nitro-group reduction route involves the reduction of nitrobenzene in the presence of (RO)3P (R = alkyl) to give nitrosobenzene with a phosphate side product (Scheme 36) [118]. In the second step, the nitrosobenzene is reduced further in the presence of another equivalent of (RO)3P, generating phenylnitride with another phosphate side product. A further reaction of (RO)3P (R = alkyl) with the basic phenylnitride generates a trialkyl phenylphosphorimidate intermediate, which undergoes hydrolysis to give the desired N-arylphosphoramidate product. Experiments to verify the proposed mechanism using aniline in the presence of excess triethyl phosphite or triethyl phosphate did not yield the desired product underMolecules the2020 optimized, 25, 3684 conditions, suggesting that the reaction proceeds via reduction of the29 nitro of 37 group to N2− and that the product is not formed from phosphate.

SchemeScheme 36 36.. ProposedProposed mechanism mechanism for for reduction reduction of th thee nitro-group route to phosphoramidates. 3.4.2. Via Catalyst-Free Staudinger Reduction and Lewis-Acid Catalyzed Rearrangement 3.4.2. Via Catalyst-Free Staudinger Reduction and Lewis-Acid Catalyzed Rearrangement The plausible two-step mechanistic process suggested by Hackenberger’s group for the synthesis The plausible two-step mechanistic process suggested by Hackenberger’s group for the involves the formation of phosphorimidate from the reduction of azide in the presence of (RO)3P synthesis involves the formation of phosphorimidate from the reduction of azide in the presence of (R = alkyl), eliminating N2, in the first step (Scheme 37)[119]. In the second step, BF3 activates (RO)3P (R = alkyl), eliminating N2, in the first step (Scheme 37) [119]. In the second step, BF3 activates the nitrogen site of the phosphorimidate by forming a coordinated complex. Electrophilic attack the nitrogen site of the phosphorimidate by forming a coordinated complex. Electrophilic attack by a by a neighbouring alkyl group of phosphorimidate on the negatively charged N atom of the neighbouring alkyl group of phosphorimidate on the negatively charged N atom of the phosphorimidate-BF3 complex results in an ((alkyl)amino)trialkoxyphosphonium complex, cleaving off phosphorimidate-BF3 complex results in an ((alkyl)amino)trialkoxyphosphonium complex, cleaving BF3. Nucleophilic attack on the trialkoxyphosphonium complex from a neighboring phosphorimidate off BF3. Nucleophilic attack on the trialkoxyphosphonium complex from a neighboring Molecules 2020, 25completes, x FOR PEER the catalytic REVIEW cycle, affording a P=O bond of the desired P-N product. 29 of 37 phosphorimidate completes the catalytic cycle, affording a P=O bond of the desired P-N product.

Scheme 37. SchemeProposed 37. Proposed mechanism mechanism for for thethe catalyst-free catalyst-free Staudinger Staudinger reduction and reduction Lewis-acid catalyzedand Lewis-acid rearrangement route to phosphoramidates. catalyzed rearrangement route to phosphoramidates. 3.5. Hydrophosphinylation Route 3.5. HydrophosphinylationFor the hydrophosphinylation Route route to P-Ns, Zimin et al. proposed that in the first step, sodium dialkyl phosphite ((RO)2PONa, R = Et, Ph) reacts with alkyl nitrile to form an imine For the hydrophosphinylation(C=N), which reacts further route with a to second P-Ns, equivalent Zimin et of al. (RO) proposed2PONa to that form in the the 1,1-addition first step, sodium dialkyl phosphiteproduct, ((RO) sodium2PONa, (1,1-bis(dialkoxyphosphoryl)alkyl)amide R = Et, Ph) reacts with alkyl (Scheme nitrile 38 )[to120 form]. In an the imine second step,(C=N), which sodium (1,1-bis(dialkyoxyphosphoryl)alkyl)amide undergoes hydrolysis and isomerization to give the reacts further with a second equivalent of (RO)2PONa to form the 1,1-addition product, sodium 1,2-addition phosphoramidate product containing a P-C-N-P bond, eliminating a sodium cation in (1,1-bis(dialkoxyphosphoryl)althe process. kyl)amide (Scheme 38) [120]. In the second step, sodium (1,1-bis(dialkyoxyphosphoryl)alkyl)amide undergoes hydrolysis and isomerization to give the 1,2-addition phosphoramidate product containing a P-C-N-P bond, eliminating a sodium cation in the process.

Scheme 38. Proposed mechanism for hydrophosphinylation route to phosphoramidates.

3.6. Phosphoramidate-Aldehyde-Dienophile (PAD) Route

Chabour et al. proposed a mechanism of the reaction in which (EtO)2P(O)NH2 reacts with (or is activated by) acetic anhydride to form diethyl acetylphosphoramidate and acetic acid (Scheme 39) [1]. Meanwhile, the aldehyde protonated in the presence of an acid catalyst, TsOH, reacts with the diethyl acetylphosphoramidate complex to give the cationic diethyl (alkene-acetamido)phosphonate complex intermediate. The unstable cationic complex undergoes rearrangement with a hydride shift and deprotonation in presence of TsO− to give a more stable diethyl acetyl(alk-1,3-diene)phosphoramidate. The subsequent direct addition of the maleimide derivative results in a P-N adduct intermediate, which is deacetylated in the presence of acetic acid to afford the desired product.

Molecules 2020, 25, x FOR PEER REVIEW 29 of 37

Scheme 37. Proposed mechanism for the catalyst-free Staudinger reduction and Lewis-acid catalyzed rearrangement route to phosphoramidates.

3.5. Hydrophosphinylation Route For the hydrophosphinylation route to P-Ns, Zimin et al. proposed that in the first step, sodium dialkyl phosphite ((RO)2PONa, R = Et, Ph) reacts with alkyl nitrile to form an imine (C=N), which reacts further with a second equivalent of (RO)2PONa to form the 1,1-addition product, sodium (1,1-bis(dialkoxyphosphoryl)alkyl)amide (Scheme 38) [120]. In the second step, sodium (1,1-bis(dialkyoxyphosphoryl)alkyl)amide undergoes hydrolysis and isomerization to give the Molecules 2020, 25, 3684 30 of 37 1,2-addition phosphoramidate product containing a P-C-N-P bond, eliminating a sodium cation in the process.

SchemeScheme 38 38.. ProposedProposed mechanism mechanism for for hydrophosphi hydrophosphinylationnylation route route to to phosphoramidates. phosphoramidates. 3.6. Phosphoramidate-Aldehyde-Dienophile (PAD) Route 3.6. Phosphoramidate-Aldehyde-Dienophile (PAD) Route Chabour et al. proposed a mechanism of the reaction in which (EtO)2P(O)NH2 reacts with (or is Chabour et al. proposed a mechanism of the reaction in which (EtO)2P(O)NH2 reacts with (or is activated by) acetic anhydride to form diethyl acetylphosphoramidate and acetic acid (Scheme 39)[1]. activated by) acetic anhydride to form diethyl acetylphosphoramidate and acetic acid (Scheme 39) Meanwhile, the aldehyde protonated in the presence of an acid catalyst, TsOH, reacts with the diethyl [1]. Meanwhile, the aldehyde protonated in the presence of an acid catalyst, TsOH, reacts with the acetylphosphoramidate complex to give the cationic diethyl (alkene-acetamido)phosphonate complex diethyl acetylphosphoramidate complex to give the cationic diethyl (alkene-acetamido)phosphonate intermediate. The unstable cationic complex undergoes rearrangement with a hydride shift and complex intermediate. The unstable cationic complex undergoes rearrangement with a hydride shift deprotonation in presence of TsO− to give a more stable diethyl acetyl(alk-1,3-diene)phosphoramidate. and deprotonation in presence of TsO− to give a more stable diethyl The subsequent direct addition of the maleimide derivative results in a P-N adduct intermediate, which acetyl(alk-1,3-diene)phosphoramidate. The subsequent direct addition of the maleimide derivative isMolecules deacetylated 2020, 25, x in FOR the PEER presence REVIEW of acetic acid to afford the desired product. 30 of 37 results in a P-N adduct intermediate, which is deacetylated in the presence of acetic acid to afford the desired product.

Scheme 39.39Proposed. Proposed mechanism mechanism for the for synthesis the ofsynthe phosphoramidatessis of phosphoramidates via the phosphoamidate- via the aldehyde-dienophilephosphoamidate-aldehyde-di (PAD) route.enophile (PAD) route.

5. Summary In this review, the applications, syntheses, and corresponding mechanisms of phosphoramidates have been discussed in depth. As demonstrated from the many categories for the uses of synthetic P-Ns, it is clear that the P-N bond motif has structural importance in diverse fields. Early synthetic routes to P-Ns are limited due to harsh reaction conditions, air and moisture-sensitive reagents, multi-step synthesis, and undesirable side reactions. The separation and purification of P-Ns is also a challenge. In particular, most of the synthetic strategies involve extraction and/or column chromatography, which not only requires large amounts of solvent, but also takes a significant amount of time. Therefore, unsurprisingly, extensive studies have been undertaken (with more to come in the future) for more sustainable, efficient, atom economic, selective, and milder synthetic procedures toward P-Ns. In addition, the discussed mechanisms require a deeper understanding of the associated phosphorus chemistry in order to have better synthetic control and to optimize the yield and selectivity toward P-N products. To overcome these challenges, it is predicted that better catalysts, improved reaction conditions, and new solvent solutions for separating the product from the by-products and potentially improving selectivity are in the forecast. For example, there is a sharp rise into synthetic research under solvent-free conditions or using ionic liquids (ILs) and deep eutectic solvents (DES). These can be environmentally benign, highly versatile, selective, and recoverable solvents for use in catalysis.

Author Contributions: Conceptualization, E.J.I. and E.M.L.; writing—original draft preparation, E.J.I. and S.D.; writing—review and editing, E.M.L.; supervision, E.M.L.; funding acquisition, E.M.L and E.J.I. All authors have read and agreed to the published version of the manuscript.

Funding: This research was funded by Tertiary Education Trust Fund (TETFund) Nigeria administered by Ebonyi State University Abakaliki, and The MacDiarmid Institute for Advanced Materials and Nanotechnology, Wellington, New Zealand.

Acknowledgments: We gratefully acknowledge Ebonyi State University Abakaliki and Tertiary Education Trust Fund (TETFund) Nigeria for E.J.I’s PhD Scholarship and The MacDiarmid Institute for Advanced Materials and Nanotechnology, Wellington, New Zealand for financial support.

Molecules 2020, 25, 3684 31 of 37

4. Summary In this review, the applications, syntheses, and corresponding mechanisms of phosphoramidates have been discussed in depth. As demonstrated from the many categories for the uses of synthetic P-Ns, it is clear that the P-N bond motif has structural importance in diverse fields. Early synthetic routes to P-Ns are limited due to harsh reaction conditions, air and moisture-sensitive reagents, multi-step synthesis, and undesirable side reactions. The separation and purification of P-Ns is also a challenge. In particular, most of the synthetic strategies involve extraction and/or column chromatography, which not only requires large amounts of solvent, but also takes a significant amount of time. Therefore, unsurprisingly, extensive studies have been undertaken (with more to come in the future) for more sustainable, efficient, atom economic, selective, and milder synthetic procedures toward P-Ns. In addition, the discussed mechanisms require a deeper understanding of the associated phosphorus chemistry in order to have better synthetic control and to optimize the yield and selectivity toward P-N products. To overcome these challenges, it is predicted that better catalysts, improved reaction conditions, and new solvent solutions for separating the product from the by-products and potentially improving selectivity are in the forecast. For example, there is a sharp rise into synthetic research under solvent-free conditions or using ionic liquids (ILs) and deep eutectic solvents (DES). These can be environmentally benign, highly versatile, selective, and recoverable solvents for use in catalysis.

Author Contributions: Conceptualization, E.J.I. and E.M.L.; writing—original draft preparation, E.J.I. and S.D.; writing—review and editing, E.M.L.; supervision, E.M.L.; funding acquisition, E.M.L and E.J.I. All authors have read and agreed to the published version of the manuscript. Funding: This research was funded by Tertiary Education Trust Fund (TETFund) Nigeria administered by Ebonyi State University Abakaliki, and The MacDiarmid Institute for Advanced Materials and Nanotechnology, Wellington, New Zealand. Acknowledgments: We gratefully acknowledge Ebonyi State University Abakaliki and Tertiary Education Trust Fund (TETFund) Nigeria for E.J.I’s PhD Scholarship and The MacDiarmid Institute for Advanced Materials and Nanotechnology, Wellington, New Zealand for financial support. Conflicts of Interest: The authors declare no conflict of interest.

List of Abbreviations Dialkyl chlorophosphate (dACP), dialkyl phosphoriodidate (dAPPI), H-phosphonate (H-P), phosphoramidate (P-N), trichloroisocyanuric acid (tCiC-A), 1,3,5-triazinane-2,4,6-trione (tAtO), N-acylphosphoramidates (AcP-N), diphenylphosphine oxide (dPPO), phosphonic acid (PP-A), N-bromosuccinimide (NBS), diphenyl phosphoric acid (dPPA), triphenylphosphine (tPP), diisopropylchlorophosphate (dPrCP), tetraethylpyrophosphate (tEPyP), triphenylphosphate (tPPO), 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (DBU), matrix-assisted laser desorption-ionization time-of-flight mass spectrometry (MALDI-TOF MS), task specific ionic liquid (TSIL), phosphorodiamidate (N-P-N), phenyl dichlorophosphate (PdCP), diphenylchlorophosphate (dPCP), tert-butyl hydroperoxide (TBHP).

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