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Review
. 2020 Aug 13;25(16):3684.
doi: 10.3390/molecules25163684.

Opening up the Toolbox: Synthesis and Mechanisms of Phosphoramidates

Emeka J Itumoh  1   2   3 , Shailja Data  1   3 , Erin M Leitao  1   3
Affiliations
Review

Opening up the Toolbox: Synthesis and Mechanisms of Phosphoramidates

Emeka J Itumoh et al. Molecules. .

Abstract

This review covers the main synthetic routes to and the corresponding mechanisms of phosphoramidate formation. The synthetic routes can be separated into six categories: salt elimination, oxidative cross-coupling, azide, reduction, hydrophosphinylation, and phosphoramidate-aldehyde-dienophile (PAD). Examples of some important compounds synthesized through these routes are provided. As an important class of organophosphorus compounds, the applications of phosphoramidate compounds, are also briefly introduced.

Keywords: applications; mechanism; phosphoramidate; synthetic routes.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Three types of P-N based on the substituents directly attached to the P and N.
Figure 2
Figure 2
Phosphoramidate motifs in natural products: Microcin C7 (1), Dinogunellin (R = residue of fatty acid) (2), Phosphoarginine (3), Phosphoramidon (4), Phosmidosine (5), Phosphocreatine (6), Agrocin 84 (7).
Figure 3
Figure 3
Applications of phosphoramidates.
Scheme 1
Scheme 1
Hydrolysis of urea on soil in the presence of urease.
Scheme 2
Scheme 2
Selected early synthetic routes to phosphoramidates.
Figure 4
Figure 4
Timeline illustrating the pioneers who discovered the first syntheses of phosphoramidates.
Scheme 3
Scheme 3
A modified Atherton–Todd reaction for the synthesis of phosphoramidates.
Scheme 4
Scheme 4
One-pot two-step synthesis of phosphoramidates via (Me2N)3PBr2.
Scheme 5
Scheme 5
Phosphoramidate syntheses via the inorganic salt elimination route. (a) Using [n-Bu4N]Br as a catalyst, (b) using [BnEt3N]Cl as a catalyst and (c) using [BnEt3N]Br as a catalyst.
Scheme 6
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, (c) Cl3CCN, and (d) CCl4.
Figure 5
Figure 5
Structures of benzyl (diethoxyphosphoryl)-d-prolinate (8), ethyl (diethoxyphosphoryl)-l-phenylalaninate (9), tetraethyl ((1S,3S)-cyclohexane-1,3-diyl)bis(phosphoramidate) (10), diethyl ((1S,3S)-3-aminocyclohexyl)phosphoramidate (11) synthesized by iodinating agents.
Scheme 7
Scheme 7
Iodine-mediated synthesis of phosphoramidates using iodine as a catalyst (a) with a solvent, (b) under a solvent-free conditions, and (c) in the presence of H2O2.
Figure 6
Figure 6
Structures of ethyl (diethoxyphosphoryl)glycinate (12), methyl ((((2R,3S,5S)-5-(((tert-butyldimethylsilyl)oxy)methyl)-2-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)tetrahydrofuran-3-yl)oxy)(methoxy)phosphoryl)-D-phenylalaninate (13), methyl (diethoxyphosphoryl)-l-phenylalaninate (14), (2R,3S,5S)-5-(((tert-butyldimethylsilyl)oxy)methyl)-2-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)tetrahydrofuran-3-yl methyl benzylphosphoramidate (15) synthesized by aerobic oxidative cross coupling.
Figure 7
Figure 7
Structure of methyl (isopropoxy(((2S,5R)-5-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2,5-dihydrofuran-2-yl)oxy)phosphoryl)-d-alaninate (16) synthesized by aerobic copper-catalyzed oxidative cross coupling.
Scheme 8
Scheme 8
Visible light and organic dye-catalyzed synthesis of phosphoramidates.
Scheme 9
Scheme 9
Oxidative cross-coupling reaction of amines and H-phosphonates to form phosphoramidates in the presence of LiI/TBHP.
Scheme 10
Scheme 10
Phosphoramidate synthesis via nitrene insertion using, (a) 5 mol% Ir(III)-based catalyst, (b) 5 mol% RuIV-porphyrin-catalyst, and (c) 4 mol% Ir(III)-based catalyst.
Figure 8
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-cyclopenta[a]phenanthren-3-yl phenyl (2-(tert-butylcarbamoyl)phenyl)phosphoramidate (18) synthesized by nitrene insertion from organic azide.
Scheme 11
Scheme 11
Phosphoramidate synthesis from organic azide and (RO)3P.
Figure 9
Figure 9
Structure of (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl (dimethoxyphosphoryl)glycinate (19) synthesized via in situ azide generation.
Scheme 12
Scheme 12
Phosphoramidate synthesis via two-step organic azide generation.
Scheme 13
Scheme 13
Phosphoramidate synthesis from organic azide and amine.
Scheme 14
Scheme 14
Synthesis of N-arylphosphoramidates from nitrobenzene and (RO)3P (R = alkyl).
Scheme 15
Scheme 15
Synthesis of phosphoramidates from organic azide derivatives and (RO)3P after Lewis acid-catalyzed rearrangement.
Scheme 16
Scheme 16
A 1,2-hydrophosphinylation of nitriles to form phosphoramidates.
Scheme 17
Scheme 17
Phosphoramidate synthesis via the PAD process.
Scheme 18
Scheme 18
Atherton–Todd mechanism proposed for the formation of phosphoramidates.
Scheme 19
Scheme 19
Modified Atherton–Todd mechanism proposed in the formation of phosphoramidates.
Scheme 20
Scheme 20
Proposed mechanism of direct conversion of diethyl hydrogen phosphate to form phosphoramidates.3.1.3. Inorganic Salt Elimination.
Scheme 21
Scheme 21
Potential mechanism for the formation of phosphoramidates using a salt elimination route.
Scheme 22
Scheme 22
Proposed mechanism for the base-free synthesis of phosphoramidates using a chlorinating agent.
Scheme 23
Scheme 23
Proposed mechanism for the synthesis of phosphoramidates from phosphoric acid and amine in the presence of phosphine and CCl4.
Scheme 24
Scheme 24
Proposed mechanism for the iodine-mediated synthesis of phosphoramidates.
Scheme 25
Scheme 25
Proposed mechanism for the iodine-mediated synthesis of phosphoramidates.
Scheme 26
Scheme 26
Proposed mechanism for the hypoiodous acid-mediated synthesis of phosphoramidates.
Scheme 27
Scheme 27
Proposed mechanism for the copper catalyzed oxidative cross-coupling of disubstituted H-phosphonates and amines to produce phosphoramidates.
Scheme 28
Scheme 28
Proposed mechanism for the Fe3O4@MgO nanoparticle-mediated synthesis of phosphoramidates.
Scheme 29
Scheme 29
Proposed mechanism for the Cu-mediated synthesis of phosphoramidates.
Scheme 30
Scheme 30
Proposed mechanism of the Cu-catalyzed synthesis of phosphoramidates from phenylboronic acid/ester-based substrates and trialkyl phosphite.
Scheme 31
Scheme 31
Proposed mechanism for the visible light and organic dye-catalyzed synthesis of phosphoramidates.
Scheme 32
Scheme 32
Proposed mechanism for the synthesis of phosphoramidates using alkali–metal catalyst.
Scheme 33
Scheme 33
Proposed mechanism for the Ir-catalyzed synthesis of phosphoramidates.
Scheme 34
Scheme 34
Proposed mechanism to phosphoramidates via azide generation.
Scheme 35
Scheme 35
Proposed mechanism for an organic azide route to phosphoramidates.
Scheme 36
Scheme 36
Proposed mechanism for reduction of the nitro-group route to phosphoramidates.
Scheme 37
Scheme 37
Proposed mechanism for the catalyst-free Staudinger reduction and Lewis-acid catalyzed rearrangement route to phosphoramidates.
Scheme 38
Scheme 38
Proposed mechanism for hydrophosphinylation route to phosphoramidates.
Scheme 39
Scheme 39
Proposed mechanism for the synthesis of phosphoramidates via the phosphoamidate-aldehyde-dienophile (PAD) route.
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