Nucleophilic Substitution at Tetracoordinate Phosphorus

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Article Nucleophilic Substitution at Tetracoordinate Phosphorus. Stereochemical Course and Mechanisms of Nucleophilic Displacement Reactions at Phosphorus in Diastereomeric cis- and trans-2-Halogeno-4-methyl-1,3,2-dioxaphosphorinan-2-thiones: Experimental and DFT Studies

Marian Mikołajczyk 1,* , Barbara Ziemnicka 1, Jan Krzywa ´nski 1, Marek Cypryk 2,* and Bartłomiej Gosty ´nski 2

1 Department of Organic Chemistry, Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, Sienkiewicza 112, 90-363 Łód´z,Poland; [email protected] (B.Z.); [email protected] (J.K.) 2 Department of Structural Chemistry, Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, Sienkiewicza 112, 90-363 Łód´z,Poland; [email protected] * Correspondence: [email protected] (M.M.); [email protected] (M.C.); Citation: Mikołajczyk, M.; Tel.: +48-42-680-3221 (M.M.); +48-42-680-3314 (M.C.) Ziemnicka, B.; Krzywański,J.; Cypryk, M.; Gostyński,B. Abstract: Geometrical cis- and trans- isomers of 2-chloro-, 2-bromo- and 2-fluoro-4-methyl-1,3,2- Nucleophilic Substitution at dioxaphosphorinan-2-thiones were obtained in a diastereoselective way by (a) sulfurization of Tetracoordinate Phosphorus. III Stereochemical Course and corresponding cyclic P -halogenides, (b) reaction of cyclic phosphorothioic acids with phosphorus IV Mechanisms of Nucleophilic pentachloride and (c) halogen–halogen exchange at P -halogenide. Their conformation and configu- 1 31 Displacement Reactions at ration at the C4-ring carbon and phosphorus stereocentres were studied by NMR ( H, P) methods, Phosphorus in Diastereomeric cis- X-ray analysis and density functional (DFT) calculations. The stereochemistry of displacement reac- and trans-2-Halogeno-4-methyl-1,3,2- tions (alkaline hydrolysis, methanolysis, aminolysis) at phosphorus and its mechanism were shown dioxaphosphorinan-2-thiones: to depend on the nature of halogen. Cyclic cis- and trans-isomers of chlorides and bromides react Experimental and DFT Studies. − − with nucleophiles (HO , CH3O , Me2NH) with inversion of configuration at phosphorus. DFT Molecules 2021, 26, 3655. https:// calculations provided evidence that alkaline hydrolysis of cyclic thiophosphoryl chlorides proceeds doi.org/10.3390/molecules26123655 according to the SN2-P mechanism with a single transition state according to the potential energy surface (PES) observed. The alkaline hydrolysis reaction of cis- and trans-fluorides afforded the Academic Editor: Vadim same mixture of the corresponding cyclic thiophosphoric acids with the thermodynamically more V. Negrebetsky stable major product. Similar DFT calculations revealed that substitution at phosphorus in fluorides

Received: 9 April 2021 proceeds stepwise according to the A–E mechanism with formation of a pentacoordinate intermediate Accepted: 10 May 2021 since a PES with two transition states was observed. Published: 15 June 2021 Keywords: 2-halogeno-4-methyl-1,3,2-dioxaphosphorinan-2-thiones; alkaline hydrolysis; mecha- Publisher’s Note: MDPI stays neutral nism; stereochemistry; DFT calculations with regard to jurisdictional claims in published maps and institutional afﬁl- iations. 1. Introduction The stereochemistry and mechanisms of nucleophilic substitution reactions at the phosphorus atom have been the major points of interest of many research groups since Copyright: © 2021 by the authors. the middle of the last century [1]. The stereochemical course of nucleophilic displacement Licensee MDPI, Basel, Switzerland. reactions at phosphorus has also been a subject of our early systematic studies, which This article is an open access article have employed, in the ﬁrst stage, optically active acyclic thiophosphonic acids 1 and their distributed under the terms and derivatives, as for example the enantiomeric thiophosphonyl chlorides 2 (Figure1). conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

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Figure 1. 1. StructuresStructures of ofoptically optically active active acyclic acyclic thiophosphonic thiophosphonic acid acid(1) and (1) the and corresponding the corresponding Figure 1. Structures of optically active acyclic thiophosphonic acid (1) and the corresponding thiophosphonyl chloride (2) used in studies of nucleophilicnucleophilic substitutionsubstitution atat phosphorus.phosphorus. thiophosphonyl chloride (2) used in studies of nucleophilic substitution at phosphorus. These early investigations resulted, among others, in elaborationelaboration of a Walden cyclecycle for thiophosphonic thiophosphonicThese early acids acids investigations 11 (interconversion(interconversion resulted, of of the the enantiomers enantiomers among ofothers, of 1) 1[2,3])[2, 3and ]in and inelaboratio inproviding provid- n of a Walden cycle unequivocaling unequivocal proof proof for forthe the inversion inversion of ofconf conﬁgurationiguration at at phosphorus phosphorus occurring occurring in in thethe forchloride thiophosphonic exchange reactionreaction acids betweenbetween 1 (interconversion radioactiveradioactive chloride chloride anion ofanion the ( 36(36 ClenantiomersCl−−)) and and optically of active 1) [2,3] and in providing unequivocalthiophosphonyl chloride proof 2for [4].[4]. theIt has inversion also beenbeen demonstrateddemonstrated of configuration thatthat alkalinealkaline at hydrolysishydrolysisphosphorus ofof occurring in the chlorideoptically active exchange chlorides reaction 2 proceeds between with inversion radioactive atat thethe PP atomatom chloride [[5].5]. anion (36Cl−) and optically active The secondsecond mostmost important important question question about about the the mechanisms mechanisms of displacement of displacement reac- thiophosphonylreactionstions at phosphorus at phosphorus chloride was, was, and and it 2 isit [4]. is still, still It whether, whetherhas also these these been reactions reactions demonstrated occuroccur synchronouslysynchronously that alkaline hydrolysis of opticallyaccording to active the SN 2-P2-Pchlorides mechanism 2 proceeds via a single with transition inversion state (TS) at orthe stepwise P atom by [5]. thethe addition–eliminationThe second mechanismmechanismmost important (A–E) (A–E) involving inquestionvolving formation formation about of an unstable,theof anmechanisms pentacoor-unstable, of displacement pentacoordinatedinate phosphorus phosphorus intermediate intermediate (trigonal (trigo bipyramidalnal bipyramidal intermediate, intermediate, TBPI). It TBPI). is formed It is reactionsformedin the ﬁrst in reactionthe at phosphorusfirst stepreaction by addition step was, by of andaddition the nucleophilicit is of still the , nucleophilicwhether reagent (N) these reagent to the reactions electrophilic (N) to the occur synchronously phosphorusaccordingelectrophilic substrate phosphorusto the andSN substrate2-P decomposes mechanism and indecomp the second viaoses a in step single the by second the transition departure step by ofthe state the departure leaving (TS) or stepwise by the addition–eliminationofgroup the leaving (L) to the group reaction (L) to product the reactionmechanism (see Scheme product1 ). (see(A–E) Scheme in 1).volving formation of an unstable, pentacoordinate phosphorus intermediate (trigonal bipyramidal intermediate, TBPI). It is formed in the first reaction step by addition of the nucleophilic reagent (N) to the electrophilic phosphorus substrate and decomposes in the second step by the departure of the leaving group (L) to the reaction product (see Scheme 1).

Scheme 1. MechanismsMechanisms of ofnucleophilic nucleophilic substitution substitution reactions reactions at phosphorus at phosphorus and andstructures structures of of possible pentacoordinate phosphorusphosphorus intermediatesintermediates (TBPI)(TBPI) formedformed byby thethe A–EA–E mechanism.mechanism.

In analogy withwith thethe SSNN2 substitution at carbon, the SSNN2-P reactions also occur withwith inversion ofof conﬁguration.configuration. However, However, the the relationship relationship between between the the stereochemistry stereochemistry and and the A–Ethe A–E mechanism mechanism is more is complicated. more complicated. It is now generallyIt is now accepted generally that accepted the stereochemical that the stereochemicaloutcome of such outcome stepwise of reactions such stepwise depends reac mainlytions depends on the disposal mainly of on the the attacking disposalN of and the attackingleaving L N groups and leaving in a short-living L groups in intermediate a short-living TBPI. intermediate Thus, the diapicalTBPI. Thus, or diequatorialthe diapical ordisposal diequatorial of N and disposal L should of leadN and to inversion L should of lead conﬁguration to inversion at phosphorus of configuration while theat phosphorusstereochemical while outcome the stereochemical of the apical-equatorial outcome substitutionof the apical-equatorial is predicted tosubstitution be retention. is predicted to be retention. Moreover, these three different TBPIs may be formed as primary

Scheme 1. Mechanisms of nucleophilic substitution reactions at phosphorus and structures of possible pentacoordinate phosphorus intermediates (TBPI) formed by the A–E mechanism.

In analogy with the SN2 substitution at carbon, the SN2-P reactions also occur with inversion of configuration. However, the relationship between the stereochemistry and the A–E mechanism is more complicated. It is now generally accepted that the stereochemical outcome of such stepwise reactions depends mainly on the disposal of the attacking N and leaving L groups in a short-living intermediate TBPI. Thus, the diapical or diequatorial disposal of N and L should lead to inversion of configuration at phosphorus while the stereochemical outcome of the apical-equatorial substitution is predicted to be retention. Moreover, these three different TBPIs may be formed as primary

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intermediates or as a result of their pseudorotation. In this connection, it is necessary to emphasizeMoreover, these a great three importance different TBPIsof the mayWestheim be formeder’s concept as primary [6]and intermediates his rules (apical or as a resultentry of theirN, apical pseudorotation. departure of In thisL, microscopic connection, itreversibility is necessary and to emphasizepseudorotation a great of importance TBPI) for understandingof the Westheimer’s many conceptaspects of [6 nucleophilic] and his rules subs (apicaltitution entry at phosphorus of N, apical as departurewell as at other of L, heteroatomsmicroscopic reversibilitysuch as sulfur and pseudorotation[7]. The results of of TBPI) his forcareful understanding studies on many acid-catalyzed aspects of bidirectionalnucleophilic substitutionhydrolysis at phosphorusof methyl as wellethylene as at otherphosphate heteroatoms 3 (2-methoxy-1,3,2- such as sulfur [7]. Thedioxaphospholan-2-one) results of his careful an studiesd the onconcurrent acid-catalyzed rapid bidirectional16O/18O oxygen hydrolysis exchange of methylin the phosphorylethylene phosphate group of3 (2-methoxy-1,3,2-dioxaphospholan-2-one)3 provided arguments for the A–E mechanism and the involving concurrent transient rapid 16formationO/18O oxygen of a trigonal exchange bipyramidal in the phosphoryl intermed groupiate (TBPI-a) of 3 provided with the arguments five-membered for the A–Ering occupyingmechanism the involving energetically transient most formation favorable of a trigonalapical-equatorial bipyramidal position intermediate and its (TBPI-a) Berry withpseudorotation the five-membered (BPR). ring occupying the energetically most favorable apical-equatorial positionAlthough and its methyl Berry pseudorotation ethylene phosphate (BPR). 3 is an achiral molecule, an inspection of the pathwayAlthough for the methyl external ethylene hydrolysis phosphate of 3 and3 is the an oxygen achiral molecule,16O/18O exchange an inspection proposed of theby pathwayWestheimer for strongly the external suggested hydrolysis that in of cyc3 andlic five-membered the oxygen 16O/ phos18Ophorus exchange compounds proposed the by Westheimernucleophilic stronglydisplacement suggested reactions that inshould cyclic five-memberedoccur with retention phosphorus of configuration compounds at the P. Thisnucleophilic was found displacement to be the case reactions [8]. Using should the occur geometrical with retention cis and oftrans configuration isomers of 2-chloro- at P. This was4,5-dimethyl-1,3,2-dioxaphospholan-2-thiones found to be the case [8]. Using the geometrical 4 ascis andmodeltrans compounds,isomers of 2-chloro-4,5- we have demonstrateddimethyl-1,3,2-dioxaphospholan-2-thiones that the replacement of chloride4 as model anion compounds,in trans-4 by we nucleophilic have demonstrated reagents Nthat takes the place replacement with retention of chloride of configuration anion in trans at -phosphorus.4 by nucleophilic This stereochemical reagents N takes outcome place withof the retention reaction ofwas configuration best rationalized at phosphorus. in terms Thisof the stereochemical A–E mechanism outcome shown of in the Scheme reaction 2 wasand bestprovided rationalized experimental, in terms stereochemical of the A–E mechanism evidence shownin support in Scheme of the2 andWestheimer’s provided concept.experimental, stereochemical evidence in support of the Westheimer’s concept.

Scheme 2. StructureStructure of of methyl methyl ethylene ethylene phosphate phosphate 3 and3 and stereochemical stereochemical course course of displacement of displacement reactions at phosphorus in trans-2-chloro-4,5-dimethyl-1,3,2-dioxaphospholan-2-thione-2-chloro-4,5-dimethyl-1,3,2-dioxaphospholan-2-thione 44..

In thethe case ofcase cyclic of ﬁve-membered cyclic five-membe phosphorusred compoundsphosphorus (1,3,2-dioxaphospholanes), compounds (1,3,2- dioxaphospholanes),the ring occupies apical the andring equatorialoccupies apical position and in equatorial the intermediate position adduct in the intermediate (TBPI) since adductits diequatorial (TBPI) since arrangement its diequatorial would arrangemen cause a larget would steric straincause [a6 ].large This steric led to strain the question [6]. This ledof the to effectthe question of a six-membered of the effect ringof a six-me in 1,3,2-dioxaphosphorinanesmbered ring in 1,3,2-dioxaphosphorinanes on the stereochemical on thecourse stereochemical and the mechanism course and of the substitution mechanism at phosphorus.of substitution In at this phosphorus. case, the diequatorial In this case, or apical-equatorial positions of the ring in the TBPI are equally probable and are not the diequatorial or apical-equatorial positions of the ring in the TBPI are equally probable connected with the essential strain energy changes [9].The stereochemistry of the displace- and are not connected with the essential strain energy changes [9].The stereochemistry of ment reactions at phosphorus was intensively investigated using the geometrical cis- and the displacement reactions at phosphorus was intensively investigated using the trans-isomers of the structurally diverse 1,3,2-dioxaphosphorinanes shown in Figure2. In geometrical cis- and trans-isomers of the structurally diverse 1,3,2-dioxaphosphorinanes this place, it is interesting to note that 1,3,2-dioxaphosphorinanes may be considered as shown in Figure 2.In this place, it is interesting to note that 1,3,2-dioxaphosphorinanes oversimpliﬁed analogues of cyclic nucleotides-adenosine 30,50-phosphate (c-AMP) and may be considered as oversimplified analogues of cyclic nucleotides-adenosine 3′,5′- thiophosphate (c-AMPS). The elucidation of the mechanism of substitution at phosphorus phosphate (c-AMP) and thiophosphate (c-AMPS). The elucidation of the mechanism of could shed light on enzymatic hydrolytic processes of cyclic nucleotides.

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Molecules 2021, 26, 3655 substitution at phosphorus could shed light on enzymatic hydrolytic processes of cyclic4 of 30 nucleotides.substitution at phosphorus could shed light on enzymatic hydrolytic processes of cyclic nucleotides.

Figure 2. Structures of 1,3,2-dioxaphosphorinanes most often used in studies of displacement reac- tionsFigure at phosphorus. 2. StructuresStructures of of 1,3,2-dioxaphosphorinanes 1,3,2-dioxaphosphorinanes most most often often used used in studies in studies of displacement of displacement reac- reactionstions at phosphorus. at phosphorus. The results of these very extensive studies on the stereochemistry of nucleophilic substitutionThe results reactions of thesethese at phosphorus veryvery extensiveextensive in 1, studiesstudie3,2-dioxaphosphorinanes,s onon thethe stereochemistrystereochemistry including ofof nucleophilicnucleophilic also the synthesissubstitution of geometrical reactionsreactions at atisomers phosphorus phosphorus and determ in in 1,3,2-dioxaphosphorinanes, 1,ination3,2-dioxaphosphorinanes, of their conformation, including including were also summa- also the syn-the rizedthesissynthesis in ofa comprehensive geometrical of geometrical isomers reviewisomers and paper determinationand determentitledination “Stereochemical of their of conformation,their conf Aspectsormation, were of summarizedPhosphorus- were summa- in Containingarized comprehensive in a Cyclohexanes”comprehensive review paper publishedreview entitled paper in “Stereochemical1979 entitl [10].ed “Stereochemical Aspects of Aspects Phosphorus-Containing of Phosphorus- Cyclohexanes”ContainingIn general, Cyclohexanes” the published displacement in published 1979 [reactions10]. in 1979 in [10]. 1,3,2-dioxaphosphorinanes investigated were foundIn general,general, to occur the the with displacement displacement both inversion reactions reactions and in retention 1,3,2-dioxaphosphorinanesin 1,3,2-dioxaphosphorinanes at phosphorus. The investigated stereochemical investigated were found to occur with both inversion and retention at phosphorus. The stereochemical out- outcomewere found depended to occur on with many both factors inversion like theand natureretention of atthe phosphorus. entering and The leaving stereochemical group, come depended on many factors like the nature of the entering and leaving group, solvent, solvent,outcome added depended salts and on reactionmany factors conditions. like the However, nature ofin spitethe entering of the fact and that leaving rich exper- group, added salts and reaction conditions. However, in spite of the fact that rich experimental imentalsolvent, material added hadsalts been and reactionaccumulated, conditions. it was However,not possible in atspite that of time the factto draw that firmrich exper-con- material had been accumulated, it was not possible at that time to draw ﬁrm conclusions clusionsimental on material the mechanism had been ofaccumulated, the displacement it was notreactions possible investigated. at that time The to draw results firm were con- on the mechanism of the displacement reactions investigated. The results were explained explainedclusions byon assumingthe mechanism operation of the of displacementeither the SN2 reactionsor A–E mechanisms. investigated. The The best results recapit- were by assuming operation of either the S 2 or A–E mechanisms. The best recapitulation of the ulationexplained of the by results assuming obtained operation in this of early Neither period the S mayN2 or be A–E found mechanisms. in one of the The many best papers recapit- results obtained in this early period may be found in one of the many papers devoted to devotedulation to of the the problem results obtained and is as in follows: this early “The period interpretation may be found of our in resultsone of the is not many a simple papers the problem and is as follows: “The interpretation of our results is not a simple matter and matterdevoted and to should the problem be accepted and is only as follows: as a starting “The interpretationpoint for further of our investigations” results is not [11]. a simple should be accepted only as a starting point for further investigations” [11]. matterIn our and studies should on be the accepted nucleophilic only as subs a startingtitution point reactions for further at phosphorus, investigations” the cis [11].- and In our studies on the nucleophilic substitution reactions at phosphorus, the cis- and trans-isomersIn our studiesof 2-chloro- on the nucleophilicand 2-bromo-4-me substitutionthyl-1,3,2-dioxaphosphorinan-2-ones reactions at phosphorus, the cis - (and5) trans-isomers of 2-chloro- and 2-bromo-4-methyl-1,3,2-dioxaphosphorinan-2-ones (5) were trans-isomers of 2-chloro- and 2-bromo-4-methyl-1,3,2-dioxaphosphorinan-2-ones (5) wereused used as model as model compounds compounds (Figure (Figure3). 3). were used as model compounds (Figure 3).

FigureFigure 3. 3.StructuresStructures of ofdiaste diastereomericreomeric 2-halogeno-4-methyl-1, 2-halogeno-4-methyl-1,3,2-dioxaphosphorinan-2-ones 3,2-dioxaphosphorinan-2-ones (5 (5) ) and and2-thionesFigure 2-thiones 3. Structures (6) ( prepared6) prepared of anddiaste and investigatedreomeric investigated 2-halogeno-4-methyl-1, by by our our group. group. 3,2-dioxaphosphorinan-2-ones (5) and 2-thiones (6) prepared and investigated by our group. It was found that methanolysis and aminolysis occur with a full or predominant inversion of conﬁguration [12]. The discussion of a possible mechanism of substitution at P was not conclusive and typical for all the papers at that time. Then, we prepared a new series of diastereomeric cyclic thiophosphoryl halogenides: trans-2-chloro-, trans-2- bromo- and cis-2-ﬂuoro-4-methyl-1,3,2-dioxaphosphorinan-2-thiones 6. In contrast to cyclic

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trans-chloride 6(Cl) and trans-bromide 6(Br), which reacted with nucleophilic reagents with inversion of configuration at phosphorus, cis-fluoride 6(F) was found to give, upon treatment with nucleophiles, a mixture of the corresponding isomeric products, the major one being formed with retention at phosphorus. These preliminary results reported in two short communications [13,14] did not allow us to unequivocally distinguish between a concerted SN2-P substitution and an addition–elimination (A–E) mechanism. In general, it is difficult or impossible to make this distinction based only on stereochemical results. For instance, the observation of inversion of configuration at phosphorus may be explained not only by the SN2-P mechanism but also by the A–E mechanism provided that the primarily formed trigonal bipyramidal phosphorane intermediate (TBPI) with nucleophilic reagent (N) and leaving groups (L) occupying apical positions undergoes decomposition to substitution product faster than pseudorotation. Quite recently, we were able to solve these fundamental mechanistic questions in parallel studies on nucleophilic substitution at tetracoordinate sulfur [15]. We found that the results of kinetic studies of the chloride–chloride exchange reaction in arenesulfonyl chlorides in combination with the DFT computations of this identity reaction gave convincing evidence for operation of the SN2-S mechanism with a single transition state. Similar DFT calculations for the fluoride exchange reaction in sulfonyl fluorides revealed that it proceeds stepwise according to the A–E mechanism with the formation of a pentacoordinate sulfur intermediate since a triple-well energy profile with two transition states was observed. The results mentioned above encouraged us to combine our stereochemical studies with theoretical calculations to definitely solve the question of the mechanism of substitution reactions at phosphorus (SN2-P or A–E) in isomeric 2-halogeno-4-methyl-1,3,2- dioxaphosphorinan-2-thiones 6. In the present paper we report the complete results of our studies on this class of compounds, including their stereospecific synthesis, stereochemical course of displacement reactions at phosphorus in 6 and the DFT calculations aimed at determination of the mechanisms of the substitution reactions.

2. Results and Discussion 2.1. Synthesis, Conformation and Configuration of Diastereomeric Trans- and cis-2-Halogeno-4-methyl-1,3,2-dioxaphosphorinan-2-thiones 6 Our initial investigations were focused on the efficient preparation and assignment of stereochemistry (ring conformation, configuration of the C4 and phosphorus stereocentres) to 2-chloro-, 2-bromo- and 2-fluoro-4-methyl-1,3,2-dioxaphosphorinan-2-thiones 6, which were intended to use as model compounds in subsequent studies of the stereochemistry of nucleophilic substitution at phosphorus. At first, trans-2-chloro-4-methyl-1,3,2-dioxaphosphorinan-2-thione 6(Cl) was prepared by treatment of trans-2-chloro-4-methyl-1,3,2-dioxaphosphorinan 7 [16–18] with acetyl- Molecules 2021, 26, x FOR PEER REVIEW ◦ 6 of 30 sulfenyl chloride. The reaction was carried out in ether at 0 C and afforded trans-6(Cl) as a pure diastereomer (31P-NMR assay) in 91% yield (Scheme3).

SchemeScheme 3. 3. StereospecificStereospeciﬁc synthesis synthesis of oftranstrans-2-chloro-4-methyl-1,3,2-dioxaphosphorinan-2-thione-2-chloro-4-methyl-1,3,2-dioxaphosphorinan-2-thione 66((ClCl).).

This reaction, as other reactions of PIII-compounds with sulfenyl chlorides [19], gave the desired product 6(Cl) in a stereospecific way with retention of configuration at phosphorus via the intermediate quasi-phosphonium chloride (A). Hence, the isomer of 6(Cl) obtained has the same trans-relation between the C4-methyl group and the chlorine atom as in the starting phosphorochloridite (7). To gain more detailed insight into the ring stereochemistry and conformation the 270 MHz 1H-NMR spectrum of trans-6(Cl) was recorded. It showed that all the resonance signals of the ring protons were well separated from each other, thus allowing the first order analysis of the spectrum without use of spin decoupling. In Table 1, all of the chemical shifts and coupling constants, derived from the spectrum, are summarized.

Table 1. 1H-NMR data for trans-2-chloro-4-methyl-1,3,2-dioxaphosphorinan-2-thione 6(Cl) in carbon tetrachloride solution at 270 MHz; atom numbering in the ring shown below.

Chemical Shift Coupling Constants (Hz) to: Proton (δ, ppm) CH3 5eq 5ax 6eq 6ax 4ax P CH3 1.26 n/a - - - - 6.2 2.6 5eq 1.59 - n/a 14.8 1.85 2.6 2.6 1.25 5ax 1.85 - 14.8 n/a 4.8 11.5 11.5 - 6eq 4.17 - 1.85 4.8 n/a 11.5 - 29.3 6ax 4.30 - 2.6 11.5 11.5 n/a - 4.4 4ax 4.54 6.2 2.6 11.5 - - n/a 3.3

These values and particularly very distinct differences between the long-range 31P- 1H couplings observed for axial and equatorial protons indicated that the dioxaphosphorinan ring in trans-6(Cl) adopts the chair conformation with the equatorial C4-methyl group and thiophosphoryl sulfur. Thus, the methyl protons appeared in the spectrum as a double doublet with coupling constants with the axial methine proton, 3JCH3-CH = 6.2 Hz, and with phosphorus, 4JCH3-P = 2.6 Hz. These values are diagnostic for equatorial position of the methyl group in the dioxaphosphorinan ring. The 31P-NMR spectrum of trans-6(Cl) showed the resonance signal shaped like a double multiplet at δP = 59.0 ppm (see Figure 4, which is characteristic and typical for the 1,3,2-dioxaphosphorinan ring with the methyl group and thiophosphoryl sulfur in equatorial positions.) Interestingly, almost the same shape of the 31P-spectrum was observed for the phosphoryl analogues of our compounds [12,20].

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Molecules 2021, 26,Scheme 3655 3. Stereospecific synthesis of trans-2-chloro-4-methyl-1,3,2-dioxaphosphorinan-2-thione 6 of 30 6(Cl).

This reaction, as other reactions of PIII-compounds with sulfenyl chlorides [19], gave This reaction, as other reactions of PIII-compounds with sulfenyl chlorides [19], gave the desired product 6(Cl) in a stereospecific way with retention of configuration at phos- the desired product 6(Cl) in a stereospecific way with retention of configuration at phosphorus via the phorusintermediate via the quasi-phosphonium intermediate quasi-phosphonium chloride (A). Hence, chloride the (isomerA). Hence, of 6( theCl) isomer of 6(Cl) obtained has the same trans-relation between the C4-methyl group and the chlorine atom obtained has the same trans-relation between the C4-methyl group and the chlorine atom as in the startingas phosphorochloridite in the starting phosphorochloridite (7). (7). To gain more detailedTo gain insight more detailedinto the ring insight stereochemistry into the ring and stereochemistry conformation andthe 270 conformation the 1 MHz H-NMR spectrum270 MHz 1ofH-NMR trans-6( spectrumCl) was recorded. of trans-6 It(Cl showed) was recorded. that all the It showedresonance that sig- all the resonance nals of the ring signalsprotons of were the ring well protons separated were from well each separated other, fromthus allowing each other, the thus first allowing order the first order analysis of the analysisspectrum of without the spectrum use of withoutspin decoupling. use of spin In decoupling.Table 1, all of In the Table chemical1, all of the chemical shifts and couplingshifts constants, and coupling derived constants, from the derived spectrum, from are the summarized. spectrum, are summarized.

1 Table 1. 1H-NMRTable 1. data H-NMR for trans-2-chloro-4-methyl-1,3,2-dioxaphosphorinan-2-thione data for trans-2-chloro-4-methyl-1,3,2-dioxaphosphorinan-2-thione6(Cl) in carbon 6(Cl) tetrachloride in car- solution at 270 MHz;bon atom tetrachloride numbering solution in the ring at 270 shown MHz; below. atom numbering in the ring shown below.

ChemicalChemical Shift Shift Coupling CouplingConstants Constants (Hz) to: (Hz) to: Proton Proton δ (δ, ppm) CH3 5eq 5ax 6eq 6ax 4ax P ( , ppm) CH3 5eq 5ax 6eq 6ax 4ax P CH3 1.26 n/a - - - - 6.2 2.6 CH 1.26 n/a - - - - 6.2 2.6 3 5eq 1.59 - n/a 14.8 1.85 2.6 2.6 1.25 5eq 1.59 - n/a 14.8 1.85 2.6 2.6 1.25 5ax5ax 1.851.85 - -14.8 14.8n/a n/a4.8 4.811.5 11.5 11.5 - 11.5 - 6eq6eq 4.174.17 - -1.85 1.854.8 4.8n/a n/a11.5 11.5- 29.3 - 29.3 6ax6ax 4.304.30 - -2.6 2.611.5 11.511.5 11.5n/a n/a- 4.4 - 4.4 4ax4ax 4.544.54 6.2 6.22.6 2.611.5 11.5- - - n/a - 3.3 n/a 3.3

31 These values andThese particularly values and very particularly distinct differences very distinct between differences the betweenlong-range the long-rangeP- 31P-1H 1 H couplings observedcouplings for observed axial and for equatorial axial and protons equatorial indicated protons that indicated the dioxaphosphori- that the dioxaphosphorinan nan ring in trans-6(Cl) adopts the chair conformation with the equatorial C4-methyl group ring in trans-6(Cl) adopts the chair conformation with the equatorial C4-methyl group and and thiophosphorylthiophosphoryl sulfur. Thus, sulfur. the methyl Thus, protons the methyl appeared protons in appearedthe spectrum in the as spectruma dou- as a double ble doublet with coupling constants with the axial methine proton, 3JCH3-CH = 6.2 3Hz, and doublet with coupling constants with the axial methine proton, JCH3-CH = 6.2 Hz, and with phosphorus, 4JCH3-P = 2.6 Hz. These4 values are diagnostic for equatorial position of the with phosphorus, JCH3-P = 2.6 Hz. These values are diagnostic for equatorial position methyl group ofin thethe methyldioxaphosphorinan group in the dioxaphosphorinanring. The 31P-NMR ring.spectrum The 31ofP-NMR trans-6( spectrumCl) of trans- showed the resonance signal shaped like a double multiplet at δP = 59.0 ppm (see Figure 6(Cl) showed the resonance signal shaped like a double multiplet at δP = 59.0 ppm (see 4, which is characteristicFigure4, which and typical is characteristic for the 1,3,2-dioxaphosphorinan and typical for the 1,3,2-dioxaphosphorinan ring with the methyl ring with the group and thiophosphorylmethyl group sulfur and in thiophosphoryl equatorial positions.) sulfur in Interestingly, equatorial positions.) almost the Interestingly,same almost shape of the 31P-spectrumthe same shape was observed of the 31 P-spectrumfor the phos wasphoryl observed analogues for of the our phosphoryl compounds analogues of our [12,20]. compounds [12,20]. The second, convenient approach to the same isomer trans-6(Cl) consists in chlorination of an equimolar mixture of cis- and trans-2-hydrogen-4-methyl-1,3,2-dioxaphosphorinan- 2-thiones 8 [21] by means of sulfuryl chloride. The chlorination reaction was performed in benzene at 0 ◦C and afforded, rather unexpectedly, a diastereomerically pure trans-6(Cl) in 80% yield. However, when the reaction was carried out at −40 ◦C, a mixture of trans-6(Cl) (85%) and cis-6(Cl) (15%) was formed as revealed by 31P-NMR spectra. MoleculesMolecules 20212021, 26, 26, x, 3655FOR PEER REVIEW 7 of7 of30 30

31 FigureFigure 4. 4.31P-NMRP-NMR spectra spectra of diastereomeric of diastereomeric 2-haloge 2-halogeno-4-methyl-1,3,2-dioxaphosphorinan-no-4-methyl-1,3,2-dioxaphosphorinan- 2- 2- thionesthiones 66 obtainedobtained with with a a Jeol-C60H-NMR Jeol-C60H-NMR spectrometer; ((aa)) transtrans--66((ClCl)() (bb))trans trans-6-6(Br(Br)) and and ( c()c)cis cis-6-(F). 6(F). The results of the chlorination reaction of diastereomeric thiophosphites 8 summarized in SchemeThe second,4 indicated convenient that the approach diastereomer to the sametrans- 6isomer(Cl) is trans thermodynamically-6(Cl) consists in more chlorina- stable tionthan ofcis an- 6equimolar(Cl) and that mixture epimerization of cis- and at trans phosphorus-2-hydrogen-4-methyl-1,3,2-dioxaphosphori- was occurring in the reaction course. → nan-2-thionesA possibility of8 epimerization[21] by means of of the sulfuryl starting chloride. thiophosphites The chlorination8 (trans-8 reactioncis-8) was was excluded per- formedsince treatment in benzene of at a 1:10 °C mixture and afforded, of isomeric rath8erwith unexpectedly, gaseous hydrogen a diastereomerically chloride under pure the reaction conditions comparable to the chlorination reaction did not affect the isomeric trans-6(Cl) in 80% yield. However, when the reaction was carried out at −40 °C, a mixture ratio of 8. Most probably, cis-6(Cl), when formed from trans-8, undergoes conversion to Molecules 2021, 26, x FOR PEER REVIEWof trans -6(Cl) (85%) and cis-6(Cl) (15%) was formed as revealed by 31P-NMR spectra. 8 of 30 the more stable trans-6(Cl) via the chloride–chloride exchange reaction at phosphorus as The results of the chlorination reaction of diastereomeric thiophosphites 8 summa- shown below (Scheme5). rized in Scheme 4 indicated that the diastereomer trans-6(Cl) is thermodynamically more stable than cis-6(Cl) and that epimerization at phosphorus was occurring in the reaction course. A possibility of epimerization of the starting thiophosphites 8 (trans-8→cis-8) was excluded since treatment of a 1:1 mixture of isomeric 8 with gaseous hydrogen chloride under the reaction conditions comparable to the chlorination reaction did not affect the isomeric ratio of 8. Most probably, cis-6(Cl), when formed from trans-8, undergoes conversion to the more stable trans-6(Cl) via the chloride–chloride exchange reaction at phosphorus as shown below (Scheme 5).

SchemeScheme 4. StereospeciﬁcStereospecific synthesis synthesis of trans of trans-2-chloro-4-methyl-1,3,2-dioxaphosphorinan-2-thione-2-chloro-4-methyl-1,3,2-dioxaphosphorinan-2-thione6(Cl) 6from(Cl) from diastereomeric diastereomer thiophosphitesic thiophosphites8. 8.

Scheme 5. Proposed pathway of conversion of thiophosphite trans-8 into thiophosphoryl chloride trans-6(Cl).

The observation of a fully stereospecific formation of trans-6(Cl) upon chlorination of a mixture of isomeric thiophosphites 8 prompted us to investigate their bromination (Scheme 6). It was found that the reaction of thiophosphite 8 consisting of 73% trans-8 and 27% cis-8 with elemental bromine carried out at 30 °C in benzene gave only one crystalline isomer of phosphorobromidate trans-6(Br) in 85% yield. As in the case of trans-6(Cl), the C4-methyl protons of the crystalline isomer appeared in 1H-NMR spectrum as a double doublet with characteristic coupling constants, 3JCH3-H = 6.9 Hz and 4JCH3-P = 2.9 Hz, indicating that it exists in a chair conformation with both the C4-methyl and P=S groups in equatorial position. Moreover, Figure 4 shows that the shape of the resonance signal in the 31P- NMR spectrum of the more stable crystalline thiophosphoryl bromide trans-6(Br) is almost the same as that of the corresponding chloride trans-6(Cl). When the same mixture of isomeric thiophosphites 8 was reacted with bromine at −15°C, a mixture of both isomeric phosphorobromidates was formed, i.e., trans-6(Br) (64%) and cis-6(Br) (36%).

Molecules 2021, 26, x FOR PEER REVIEW 8 of 30

Molecules 2021, 26, 3655 8 of 30 Scheme 4. Stereospecific synthesis of trans-2-chloro-4-methyl-1,3,2-dioxaphosphorinan-2-thione 6(Cl) from diastereomeric thiophosphites 8.

Scheme 5. ProposedProposed pathway pathway of of conversion conversion of of thiophosphite thiophosphite transtrans-8-8 intointo thiophosphoryl thiophosphoryl chloride chloride transtrans--6((Cl).).

The observation of a fully stereospeciﬁcstereospecific formation of trans-6(Cl) uponupon chlorinationchlorination of a mixture of isomeric thiophosphites 8 prompted us to investigateinvestigate their bromination (Scheme6 6).). ItIt waswas foundfound thatthat thethe reactionreaction ofof thiophosphitethiophosphite 8 consisting of 73% trans-8 and ◦ 27% cis-8 with elemental bromine carried out at 30 °CC in benzene benzene gave only one crystalline isomerisomer of of phosphorobromidate trans- 6(Br) in 85% yield. As in the case of trans-6(Cl), the 1 C44-methyl-methyl protons protons of of the the crystalline isomer appeared in 1H-NMR spectrum as a double 3 4 doublet with with characteristic characteristic coupling coupling constants, constants, 3JCH3-HJCH3-H = 6.9= Hz 6.9 and Hz 4J andCH3-P =J CH3-P2.9 Hz,= indicat- 2.9 Hz, ingindicating that it exists that it in exists a chair in aconformation chair conformation with both with the both C4-methyl the C4-methyl and P=S and groups P=S groups in equa- in torialequatorial position. position. Moreover, Moreover, Figure Figure 4 shows4 shows that that the shape the shape of the of resonance the resonance signal signal in the in the31P- 31 NMRP-NMR spectrum spectrum of the of themore more stable stable crystalline crystalline thiophosphoryl thiophosphoryl bromide bromide transtrans-6(Br-6)( Bris )al- is mostalmost the the same same as as that that of of the the corresponding corresponding chloride chloride transtrans--66((ClCl).). When When the the same same mixture Molecules 2021, 26, x FOR PEER REVIEW ◦ 9 of 30 of isomeric thiophosphitesthiophosphites8 8was was reacted reacted with with bromine bromine at − at15 −15°C,C, a mixture a mixture of both of both isomeric iso- mericphosphorobromidates phosphorobromidates was formed, was formed, i.e., trans i.e.,-6 trans(Br) (64%)-6(Br) and(64%)cis and-6(Br cis) (36%).-6(Br) (36%).

Scheme 6. StereospecificStereospeciﬁc synthesis synthesis of of transtrans-2-bromo-4-methyl-1,3,2-dioxaphosphorinan-2-thione-2-bromo-4-methyl-1,3,2-dioxaphosphorinan-2-thione 6(Br).

In search search of of a a stereospecific stereospeciﬁc synthesis synthesis of of th thee less less stable stable cyclic cyclic thiophosphoryl thiophosphoryl chloride chlo- cisride-6(cisCl-),6 (weCl), turned we turned our attention our attention on the on reaction the reaction of monothiophosphoric of monothiophosphoric acids with acids phos- with phorusphosphorus pentachloride. pentachloride. This reaction This reaction with withthe enantiomers the enantiomers of thiophosphonic of thiophosphonic acid 1 acid afforded exclusively enantiomerically pure thiophosphonyl chlorides 2 with inversion of configuration [2,4,22].In the hope that cyclic monothiophosphoric acids will react with phosphorus pentachloride in a similar way, the reaction of easily available cis- and trans- 2-hydroxy-4-methyl-1,3,2-dioxaphosphorinan-2-thiones 9 [23]withthis reagent was investigated. However, we were surprised to find that in addition to the expected isomeric chlorides 6(Cl), two other products were formed. Their structures were dependent on the configuration at phosphorus in starting cyclic thioacids 9. Thus, treatment of trans-9 with PCl5 suspended in benzene at 0–5 °C resulted in formation of three products as revealed by 31P-NMR spectra: thiophosphoryl chloride (trans-6(Cl), phosphoryl chloride trans-5(Cl) and unsymmetrical trans-cis-dithiopyrophosphate 10 (see Scheme 7).

Scheme 7. Structure of products formed in reaction between phosphorus pentachloride and thiophosphoric acid trans-9.

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Scheme 6. Stereospecific synthesis of trans-2-bromo-4-methyl-1,3,2-dioxaphosphorinan-2-thione 6(Br).

Molecules 2021, 26, 3655 9 of 30 In search of a stereospecific synthesis of the less stable cyclic thiophosphoryl chloride cis-6(Cl), we turned our attention on the reaction of monothiophosphoric acids with phosphorus pentachloride. This reaction with the enantiomers of thiophosphonic acid 1 af- forded1 afforded exclusively exclusively enantiomerically enantiomerically pure pure thiophosphonyl thiophosphonyl chlorides chlorides 2 with2 with inversion inversion of configurationof configuration [2,4,22].In [2,4,22]. the In hope the hope that cyclic that cyclic monothiophosphoric monothiophosphoric acids acidswill react will reactwith phosphoruswith phosphorus pentachloride pentachloride in a similar in a similar way, the way, reaction the reaction of easily of easilyavailable available cis- andcis trans- and- 2-hydroxy-4-methyl-1,3,2-diotrans-2-hydroxy-4-methyl-1,3,2-dioxaphosphorinan-2-thionesxaphosphorinan-2-thiones 9 [23]withthis9 [23] withthis reagent reagent was inves- was tigated.investigated. However, However, we were we were surprised surprised to find to find that that in inaddition addition to to the the expected expected isomeric isomeric chlorides 6(Cl), two other products were formed. Their structures were dependent on the configurationconfiguration at phosphorus in starting cyclic thioacids 9. Thus, treatment of trans-9 with ◦ PCl55 suspendedsuspended in in benzene benzene at at 0–5 0–5 °CC resulted resulted in in formation of three products as revealed by 3131P-NMRP-NMR spectra: spectra: thiophosphoryl thiophosphoryl chloride chloride ( (transtrans--66((ClCl),), phosphoryl phosphoryl chloride chloride transtrans--55((ClCl)) and unsymmetrical trans-cis-dithiopyrophosphate 10 (see Scheme7 7).).

Scheme 7. StructureStructure of of products products formed formed in in reaction reaction between between phosphorus phosphorus pe pentachloridentachloride and and thio- thio- phosphoric acid trans-9.

The formation of thiophosphoryl chloride trans-6(Cl) in this reaction was expected as well as the fact that it was formed from thioacid trans-9 with inversion of configuration at phosphorus. However, the appearance of phosphorochloridate trans-5(Cl) among the reaction products was astonishing. Moreover, the replacement of sulfur in trans-9 by chlorine leading to trans-5(Cl) was occurring with retention at phosphorus. The third product was identified as one of the three isomeric bis-(4-methyl-1,3,2-dioxaphosphorinan- 2-thionyl)oxides 10. Their synthesis, configuration and conformation were reported in a separate paper [24]. A somewhat different outcome of the reaction of thioacid cis-9 with PCl5 was observed. To our satisfaction the major product in this case was the desired thermodynamically less stable thiophosphoryl chloride cis-6(Cl) formed in 60% yield. It was accompanied by the more stable isomer trans-6(Cl) (21%). The latter was undoubtedly the product of epimerization at phosphorus in cis-6(Cl) taking place in the presence of chloride anions in a reaction mixture. Interestingly, the same dithiopyrophosphate trans-cis-10 was also formed in this reaction in comparable amounts (19%) (Scheme8). Distillation of a mixture of these three reaction products allowed us to isolate thiophosphoryl chloride cis-6(Cl) containing 5% trans-isomer as the lowest boiling fraction. This almost diastereomerically pure cis-chloride 6 was used in our further experiments. Molecules 2021, 26, x FOR PEER REVIEW 10 of 30

The formation of thiophosphoryl chloride trans-6(Cl) in this reaction was expected as well as the fact that it was formed from thioacid trans-9 with inversion of configuration at phosphorus. However, the appearance of phosphorochloridate trans-5(Cl) among the reaction products was astonishing. Moreover, the replacement of sulfur in trans-9 by chlorine leading to trans-5(Cl) was occurring with retention at phosphorus. The third product was identified as one of the three isomeric bis-(4-methyl-1,3,2-dioxaphosphorinan-2-thionyl)oxides 10. Their synthesis, configuration and conformation were reported in a separate paper [24]. A somewhat different outcome of the reaction of thioacid cis-9 with PCl5 was observed. To our satisfaction the major product in this case was the desired thermodynamically less stable thiophosphoryl chloride cis-6(Cl) formed in 60% yield. It was accompanied by the more stable isomer trans-6(Cl) (21%). The latter was undoubtedly the product of epimerization at phosphorus in cis-6(Cl) taking place in the presence of chloride anions in a reaction mixture. Interestingly, the same dithiopyrophosphate trans-cis-10 was also formed in this reaction in comparable amounts (19%) (Scheme 8). Distillation of a mixture of these three reaction products allowed us to isolate thiophosphoryl chloride cis-6(Cl) Molecules 2021, 26, 3655 10 of 30 containing 5% trans-isomer as the lowest boiling fraction. This almost diastereomerically pure cis-chloride 6 was used in our further experiments.

Scheme 8. StructureStructure of of products products formed formed in in reaction reaction between between phosphorus phosphorus pe pentachloridentachloride and and thio- thio- phosphoric acid cis-9.

Although elucidation of all mechanistic deta detailsils of the reaction under discussion was beyond the scope of the present work, we wish to rationalizerationalize herein itsits multidirectionalmultidirectional course and and stereochemistry stereochemistry of of the the products products formation formation (Scheme (Scheme 9).9 Taking). Taking into into account account the well-knownthe well-known ambident ambident reactivity reactivity of monothiophosphoric of monothiophosphoric acids acidsand their and anions, their anions, it is rea- it sonableis reasonable to assume to assume that cyclic that cyclicthioacids, thioacids, like acyclic like acyclic ones, ones,react reactwith withphosphorus phosphorus pen- tachloridepentachloride at the at theoxygen oxygen atom. atom. This This initial initial reaction, reaction, for forexample example with with transtrans-9, -results9, results in formationin formation of O of-trichlorophosphoniumO-trichlorophosphonium chloride chloride (A) as (A the) as first the reaction ﬁrst reaction intermediate. intermediate. This, inThis, turn, in upon turn, a upon nucleophilic a nucleophilic attack of attack the chloride of the chlorideanion at the anion phosphorinanyl at the phosphorinanyl phospho- phosphorus and the concomitant four-membered ring closure between sulfur and the Molecules 2021, 26, x FOR PEER REVIEWrus and the concomitant four-membered ring closure between sulfur and the trichloro-11 of 30 phosphoniumtrichlorophosphonium phosphorus phosphorus atom, is atom, converted is converted into a intosecond a second intermediate intermediate (B). Its (B ).for- Its mationformation and and relative relative stability stability are due are dueto the to pr theesence presence of two of six- two and six- four-membered and four-membered rings, whichrings, whichare known are known to stabilize to stabilize hypervalent hypervalent phosphorus phosphorus compounds. compounds. Interestingly, Interestingly, almost thealmost same the type same of typestructure of structure was postulated was postulated for the for intermediate the intermediate found found in the in reaction the reaction betweenbetween oxophosphoranesulfenyl oxophosphoranesulfenyl chloride chloridess and and phosphorus phosphorus trichloride trichloride [25]. [25 ].

SchemeScheme 9. 9. ProposedProposed course course of of reaction reaction between between thioacid thioacid transtrans--99 andand phosphorus phosphorus pentachloride. pentachloride.

This trigonal bipyramidal intermediate (B) may undergo decomposition in two ways. The first accompanied by elimination of phosphoryl trichloride affords the expected thiophosphoryl chloride trans-6(Cl) with the experimentally confirmed inversion of configuration. On the other hand, simultaneous elimination of thiophosphoryl trichloride from (B) results in formation of the unexpected phosphoryl chloride trans-5(Cl) with retention of configuration at phosphorus. This stereochemistry of the conversion trans-9→trans- 5(Cl) is also in a full agreement with that experimentally found (see Scheme 9). Finally, the formation of dithiopyrophosphate 10 as a third reaction product is worthy of notice. It is undoubtedly formed in the reaction between starting thioacid trans-9 and the first reaction intermediate (A). The latter, having a good leaving group, undergoes nucleophilic substitution by thioacid trans-9 with inversion of configuration at phosphorus, which affords unsymmetrical trans-cis-diastereomer of dithiopyrophosphate 10. To complete the synthesis of cyclic thiophosphoryl halogenides 6(Cl, Br, F) and having some experience with the preparation of chlorides 6(Cl) and bromides 6(Br), we turned to the synthesis of diastereomeric fluorides 6(F). In general, the synthetic ap- proaches to acyclic and cyclic thiophosphoryl fluorides are sparse and of limited applicability. The most practical method of their synthesis involves the halogen exchange reaction at phosphorus using inorganic fluorides [3,26]. In our first attempt to obtain 6(F), a very simple reaction was tested, namely, the addition of elemental sulfur to cyclic fluorophosphite 11. The latter was prepared according to the modified procedure described by Schmutzler [27] from trans-chlorophosphite 7 and antimony trifluoride (Scheme 10).

Scheme 10. Synthesis of fluorophosphite 11.

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the same type of structure was postulated for the intermediate found in the reaction between oxophosphoranesulfenyl chlorides and phosphorus trichloride [25].

Molecules 2021, 26, 3655 11 of 30 Scheme 9. Proposed course of reaction between thioacid trans-9 and phosphorus pentachloride.

This trigonal bipyramidal intermediate ( B) may may undergo undergo decomposition decomposition in two two ways. ways. The firstfirst accompanied by elimination of phosphoryl trichloride affords the expected thiophosphoryl chloridechloride transtrans--66((ClCl)) withwith thethe experimentally experimentally confirmed confirmed inversion inversion of of configura- configu- ration.tion. On On the the other other hand, hand, simultaneous simultaneous elimination elimination of thiophosphorylof thiophosphoryl trichloride trichloride from from (B) (resultsB) results in formation in formation of the of the unexpected unexpected phosphoryl phosphoryl chloride chloridetrans trans-5(Cl-5()Cl with) with retention retention of ofconfiguration configuration at phosphorus.at phosphorus. This This stereochemistry stereochemistry of the of conversionthe conversiontrans -trans9→trans-9→-trans5(Cl-) 5is(Cl also) is in also a full in a agreement full agreement with with that experimentallythat experimentally found found (see Scheme(see Scheme9). Finally, 9). Finally, the theformation formation of dithiopyrophosphate of dithiopyrophosphate10 as 10 a as third a third reaction reaction product prod isuct worthy is worthy of notice. of notice. It is Itundoubtedly is undoubtedly formed formed in the in reaction the reaction between between starting starting thioacid thioacidtrans-9 andtrans the-9 and first reactionthe first reactionintermediate intermediate (A). The latter,(A). The having latter, a goodhaving leaving a good group, leaving undergoes group, nucleophilicundergoes nucleo- substi- philictution substitution by thioacid transby thioacid-9 with inversiontrans-9 with ofconfiguration inversion of atconfiguration phosphorus, at which phosphorus, affords whichunsymmetrical affords unsymmetricaltrans-cis-diastereomer trans-cis- ofdiastereomer dithiopyrophosphate of dithiopyrophosphate10. 10. To completecomplete thethe synthesissynthesis of of cyclic cyclic thiophosphoryl thiophosphoryl halogenides halogenides6( Cl6(Cl, Br, Br, F,) F and) and having hav- ingsome some experience experience with with the preparation the preparation of chlorides of chlorides6(Cl) and6(Cl bromides) and bromides6(Br), we6(Br turned), we turnedto the synthesis to the synthesis of diastereomeric of diastereomeric fluorides fluorides6(F). In general, 6(F). In the general, synthetic the approachessynthetic ap- to proachesacyclic and to cyclic acyclic thiophosphoryl and cyclic thiophosphoryl fluorides are sparsefluorides and are of limitedsparse and applicability. of limited The applica- most practicalbility. The method most practical of their synthesismethod of involves their synthesis the halogen involves exchange the halogen reaction exchange at phosphorus reac- tionusing at inorganic phosphorus fluorides using [inorganic3,26]. In our fluoride first attempts [3,26]. toIn obtainour first6(F attempt), a very to simple obtain reaction 6(F), a wasvery tested,simple namely, reaction the was addition tested, ofnamely, elemental the sulfuraddition to cyclicof elemental fluorophosphite sulfur to 11cyclic. The fluoro- latter wasphosphite prepared 11. The according latter was tothe prepared modified according procedure to the described modified by procedure Schmutzler described [27] from by Schmutzlertrans-chlorophosphite [27] from trans7 and-chlorophosphite antimony trifluoride 7 and (Scheme antimony 10 trifluoride). (Scheme 10).

Molecules 2021, 26, x FOR PEER REVIEW 12 of 30

Scheme 10. Synthesis of fluorophosphite ﬂuorophosphite 11.

Trans-fluorophosphite 11 as a major and thermodynamically more stable product ob- Trans-ﬂuorophosphite 11 as a major and thermodynamically more stable product tainedobtained in this in thisreaction reaction was contaminated was contaminated with 5% with cis 5%-isomer.cis-isomer. To our To surprise, our surprise, it was found it was thatfound the thataddition the addition of elemental of elemental sulfur to sulfur trans-11 to doestrans -not11 doesoccur not even occur in boiling even in toluene. boiling When,toluene. however, When, however,acetylsulfenyl acetylsulfenyl chloride was chloride used wasinstead used of instead elemental of elemental sulfur, the sulfur, conver- the sionconversion of trans- of11 transto cis--116(Fto) wascis- 6achieved(F) was achieved efficiently efﬁciently under mild under reaction mild conditions reaction conditions (Scheme 11).(Scheme 11).

SchemeScheme 11. 11. SynthesisSynthesis of of thiophosphoryl thiophosphoryl fluoride ﬂuoride 66(F(F).).

AsAs expected, expected, the the sulfurization sulfurization of oftranstrans-fluorophosphite-fluorophosphite 11 occurred11 occurred with with a full a fullreten- re- tiontention of configuration of configuration at phosphorus at phosphorus and andafforded afforded the crude the crude thiophosphoryl thiophosphoryl fluoride fluoride cis- 6cis(F)- 6containing(F) containing 5% of 5% trans of -trans6(F). -The6(F). diastereomerically The diastereomerically pure solid pure cis solid-isomercis-isomer (m.p. 33–34 (m.p. ◦ °C)33–34 was C)isolated was isolated from this from mixture this mixture by distillation by distillation and crystallization. and crystallization. The NMR The NMR (1H, 31 (1P)H, data31P) of data cis-fluoride of cis-fluoride 6(F) were6(F) wereconsistent consistent with witha rigid a rigidchair chairconformation conformation in which in which the thi- the ophosphorylthiophosphoryl sulfur sulfur and and the themethyl methyl group group on on C4 C are4 are in inequatorial equatorial positions positions on on the the 1,3,2- 1,3,2- dioxaphosphorinandioxaphosphorinan ring. ring. For For instance, instance, the the resona resonancence signal signal (double (double doublet) doublet) of of the the methyl methyl 3 4 protonsprotons with with characteristic characteristic coupling coupling constants, constants, 3JCH3-HJCH3-H = 6.2 =Hz 6.2 and Hz 4JCH3-P and = J2.6CH3-P Hz,= shows 2.6 Hz , 31 thatshows the that methyl the methylgroup groupis equatorial. is equatorial. The 31 TheP-NMRP-NMR spectrum spectrum of cis of-6cis(F)- 6shows(F) shows a typical a typi- 1 doubletcal doublet with with the thecoupling coupling constant constant 1JP-FJ=P-F 1086= 1086 Hz Hzdue due to tothe the presence presence of of fluorine fluorine directly directly bonded to phosphorus. The shape of each arm of this doublet is almost identical with the 31P-NMR resonance signals of trans-6(Cl) and trans-6(Br) (see Figure 1). This observation may be taken as additional evidence that all the thiophosphoryl halogenides mentioned above exist in the same chair conformation with the equatorial C4-methyl and thiophosphoryl group. Finally, a single-crystal X-ray analysis of cis-6(F) revealed [28] that the 1,3,2- dioxaphosphorinan ring also adopts a chair conformation in the solid state and confirmed our configurational assignments based on NMR measurements (see Figures 2 and 5).

Figure 5. 31P-NMR spectra of trans-6(F) (85%) and cis-6(F) (15%) mixture: upper spectrum with a proton decoupling, bottom spectrum without proton decoupling.

Molecules 2021, 26, x FOR PEER REVIEW 12 of 30

Trans-fluorophosphite 11 as a major and thermodynamically more stable product obtained in this reaction was contaminated with 5% cis-isomer. To our surprise, it was found that the addition of elemental sulfur to trans-11 does not occur even in boiling toluene. When, however, acetylsulfenyl chloride was used instead of elemental sulfur, the conversion of trans-11 to cis-6(F) was achieved efficiently under mild reaction conditions (Scheme 11).

Scheme 11. Synthesis of thiophosphoryl fluoride 6(F).

As expected, the sulfurization of trans-fluorophosphite 11 occurred with a full retention of configuration at phosphorus and afforded the crude thiophosphoryl fluoride cis- 6(F) containing 5% of trans-6(F). The diastereomerically pure solid cis-isomer (m.p. 33–34 °C) was isolated from this mixture by distillation and crystallization. The NMR (1H, 31P) data of cis-fluoride 6(F) were consistent with a rigid chair conformation in which the thiophosphoryl sulfur and the methyl group on C4 are in equatorial positions on the 1,3,2- dioxaphosphorinan ring. For instance, the resonance signal (double doublet) of the methyl Molecules 2021, 26, 3655 12 of 30 protons with characteristic coupling constants, 3JCH3-H = 6.2 Hz and 4JCH3-P = 2.6 Hz, shows that the methyl group is equatorial. The 31P-NMR spectrum of cis-6(F) shows a typical doublet with the coupling constant 1JP-F= 1086 Hz due to the presence of fluorine directly bondedbonded to to phosphorus. phosphorus. The The shape shape of of each each arm arm of of this this doublet doublet is is almost almost identical identical with the 3131P-NMRP-NMR resonance resonance signals signals of of transtrans--66((ClCl)) and and transtrans--66((BrBr)) (see (see FigureFigure 11).). This observation maymay be be taken taken as additional evidence that all the thiophosphoryl halogenides mentioned aboveabove exist exist in in the the same chair conformation with with the equatorial C 44-methyl-methyl and and thiophos- thiophos- phorylphoryl group. group. Finally, Finally, a a single-crystal single-crystal X-ray X-ray analysis analysis of of ciscis--66((FF)) revealed revealed [28] [28] that that the the 1,3,2- 1,3,2- dioxaphosphorinandioxaphosphorinan ring also also adopts adopts a a chair chair co conformationnformation in the the solid solid state state and and confirmed conﬁrmed ourour configurational conﬁgurational assignments assignments based on NMR measurements (see Figures 2 2 and and5 ).5).

Molecules 2021, 26, x FOR PEER REVIEW 13 of 30 31 FigureFigure 5. 5. 31P-NMRP-NMR spectra spectra of of transtrans-6-(6F()F (85%)) (85%) and and ciscis-6(-F6)( F(15%)) (15%) mixture: mixture: upper upper spectrum spectrum with with a a protonproton decoupling, decoupling, bottom spectr spectrumum without proton decoupling.

The transtrans-isomer-isomer of of 66(F(F) )was was obtained obtained from from transtrans-bromide-bromide 6(Br6()Br and) and ammonium ammonium flu- fluoride.oride. The The bromide bromide → fluoride→ fluoride exchange exchange reaction reaction carried carried out in out acetonitrile in acetonitrile solution solution at 40 at°C 40afforded◦C afforded after after8 h a8 mixture h a mixture of trans of trans- and- andcis-fluoridescis-fluorides at a atratio a ratio of 84:16. of 84:16. When When the thereaction reaction was was conducted conducted for 24 for h 24 at hthe at thesame same temperature, temperature, the desired the desired transtrans-fluoride-fluoride 6(F) 6was(F) wasformed formed with inversion with inversion of configuration of configuration and with and 94% with diastereomeric 94% diastereomeric purity. The purity. di- Theastereomerically diastereomerically pure trans pure-6trans(F) was-6(F obtained) was obtained by preparative by preparative gas chromatography. gas chromatography. How- However,ever, prolongation prolongation of the of thereaction reaction time time to to50 50h hresulted resulted in in the the isomerization isomerization of of trans-6(F) (inversion(inversion ofof configurationconfiguration atat P)P) toto thethe thermodynamicallythermodynamically moremore stablestable ciscis--66((FF)) andand thethe latterlatter waswas formedformed withwith 83%83% diastereomericdiastereomeric puritypurity (Scheme(Scheme 1212).).

Br S F P NH4F P NH4F P O S MeCN O F O S O O MeCN O 40 oC, 50 h 40 oC, 50 h trans-6(Br) trans-6(F) (94% dp) cis-6(F) (83% dp) P=55.0 ppm P=54.0 ppm Scheme 12. Synthesis of thiophosphoryl ﬂuoridefluoride transtrans--66((FF)) andand itsits epimerizationepimerization toto ciscis--66((FF).).

Most probably, the the above above fluoride–fluoride fluoride–fluoride exchange exchange reaction reaction should should lead lead to the to thedi- diastereomericallyastereomerically pure pure ciscis-6(-F6)( Fafter) after longer longer heating. heating. Moreover, Moreover, the thefact fact that that a trace a trace of the of theless lessstable stable transtrans-6(F)- 6was(F) wasnot observed not observed when when the pure the purefluoride fluoride cis-6(cisF) -was6(F) heated was heated with ◦ withNH4F NH (604 Fh, (60 40 h,°C) 40 indicatesC) indicates that this that identity this identity reaction reaction reflects reflects a strong a strong preference preference of fluo- of fluorinerine for an for axial an axial position position versus versus a P=S a P=Sbond bond in the in 1,3,2-dioxapho the 1,3,2-dioxaphosphorinansphorinan ring. ring. DFT DFT cal- calculationsculations show show that that the the transtrans-6-(6F()F )isomer isomer has has a a free free energy energy of ∆ΔG == 2.52.5 kcal/molkcal/mol higherhigher thanthan ciscis--6((F)) isomer,isomer, whichwhich correspondscorresponds roughlyroughly toto anan equilibriumequilibrium concentrationconcentration ratioratio [trans-6(F)] /[cis-6(F)] of ca. 1.5 × 10−2. Taking into account 1H- and 31P-NMR data, as [trans-6(F)]eqeq/[cis-6(F)]eqeq of ca. 1.5 × 10−2. Taking into account 1H- and 31P-NMR data, as well as DFT calculations (see Supplementary Materials), it is reasonable to assume that the trans-6(F) isomer exists in two chair conformations (A and B) and one boat conformation(C) that are in a fast equilibrium as shown below (Scheme 13).

Scheme 13. Conformational equilibrium in trans-6(F).

The conformer (B) with the axial methyl group at C4 should be present in equilibrium in substantial proportions, which is reflected in the different shape of the diagnostic 1H- NMR resonance signal of the C4-Me from that of the cis-isomer 6(F). Thus, the methyl protons of trans-6(F) appeared in the spectrum as a doublet of triplets due to characteristic splitting by the C4-proton (3JCH3-H = 6.5 Hz), then by phosphorus (4JCH3-P = 0.9 Hz) and ad- ditionally by the vicinal axial proton at C5 with the same coupling constant value (0.9 Hz) as with phosphorus. The observation of the last coupling and a small value of the coupling constant with phosphorus is indicative of the presence of the conformer (B) in equilibrium. On the other hand, the 31P-NMR spectrum of trans-6(F) shows a typical doublet due to splitting by fluorine with the coupling constant 1JP-F = 1094 Hz. Both arms of this doublet are dense multiplets, which are characteristic of the dioxaphosphorinan rings, having methyl and thiophosphoryl groups trans situated. The 31P-NMR spectra of a mixture of trans- 6(F) (84%) and cis-6(F) (16%) (shown in Figure 5) in conjunction with Figure 4 best illustrate the relationship between the shape of the 31P-NMR resonance signals and configuration at phosphorus and C4-carbon in the 1,3,2-dioxaphosphorinan systems.

Molecules 2021, 26, x FOR PEER REVIEW 13 of 30

The trans-isomer of 6(F) was obtained from trans-bromide 6(Br) and ammonium fluoride. The bromide → fluoride exchange reaction carried out in acetonitrile solution at 40 °C afforded after 8 h a mixture of trans- and cis-fluorides at a ratio of 84:16. When the reaction was conducted for 24 h at the same temperature, the desired trans-fluoride 6(F) was formed with inversion of configuration and with 94% diastereomeric purity. The diastereomerically pure trans-6(F) was obtained by preparative gas chromatography. How- ever, prolongation of the reaction time to 50 h resulted in the isomerization of trans-6(F) (inversion of configuration at P) to the thermodynamically more stable cis-6(F) and the latter was formed with 83% diastereomeric purity (Scheme 12).

Br S F P NH4F P NH4F P O S MeCN O F O S O O MeCN O 40 oC, 50 h 40 oC, 50 h trans-6(Br) trans-6(F) (94% dp) cis-6(F) (83% dp) P=55.0 ppm P=54.0 ppm Scheme 12. Synthesis of thiophosphoryl fluoride trans-6(F) and its epimerization to cis-6(F).

Most probably, the above fluoride–fluoride exchange reaction should lead to the diastereomerically pure cis-6(F) after longer heating. Moreover, the fact that a trace of the less stable trans-6(F) was not observed when the pure fluoride cis-6(F) was heated with NH4F (60 h, 40 °C) indicates that this identity reaction reflects a strong preference of fluorine for an axial position versus a P=S bond in the 1,3,2-dioxaphosphorinan ring. DFT cal- Molecules 2021, 26, 3655 13 of 30 culations show that the trans-6(F) isomer has a free energy of ΔG = 2.5 kcal/mol higher than cis-6(F) isomer, which corresponds roughly to an equilibrium concentration ratio [trans-6(F)]eq/[cis-6(F)]eq of ca. 1.5 × 10−2. Taking into account 1H- and 31P-NMR data, as well wellas DFT as DFTcalculations calculations (see (see Supplementary Supplementary Materials), Materials), it itis isreasonable reasonable to to assume assume that thethe transtrans--66((FF)) isomerisomer exists exists in in two two chair chair conformations conformations (A and (AB )and and B one) and boat one conformation( boat confor-C) thatmation( areC in) athat fast are equilibrium in a fast equilibriu as shownm below as shown (Scheme below 13 (Scheme). 13).

Scheme 13. Conformational equilibrium in transtrans--66((F).).

The conformer ((BB)) withwith thethe axialaxial methylmethyl groupgroup atat CC44 should be present in equilibrium 1 inin substantialsubstantial proportions,proportions, which is reflectedreflected inin thethe differentdifferent shapeshape ofof thethe diagnosticdiagnostic 1H- NMR resonance signal of thethe CC44-Me from thatthat ofof thethe ciscis-isomer-isomer 66((FF).). Thus,Thus, thethe methylmethyl protonsprotons ofof transtrans--66((FF)) appearedappeared inin thethe spectrumspectrum asas aa doubletdoublet ofof tripletstriplets duedue toto characteristiccharacteristic 3 4 splitting by the C4-proton ( 3JJCH3-HCH3-H = =6.5 6.5 Hz), Hz), then then by by phosphorus phosphorus (4J (CH3-PJCH3-P = 0.9= Hz) 0.9 Hz) and and ad- additionallyditionally by by the the vicinal vicinal axial axial proton proton at at C C5 5withwith the the same same coupling coupling constant constant value value (0.9 Hz) as with phosphorus. The observation ofof thethe lastlast couplingcoupling andand aa smallsmall valuevalue ofof the coupling constant withwith phosphorusphosphorus is is indicative indicative of of the the presence presence of theof the conformer conformer (B) in(B equilibrium.) in equilib- 31 Onrium. the On other the other hand, hand, the theP-NMR 31P-NMR spectrum spectrum of trans of trans-6(F)-6 shows(F) shows a typical a typical doublet doublet due due to splitting by fluorine with the coupling constant 1J = 1094 Hz. Both arms of this doublet to splitting by fluorine with the coupling constantP-F 1JP-F = 1094 Hz. Both arms of this doublet are dense multiplets, multiplets, which which are are characteristic characteristic of ofthe the dioxaphosphorina dioxaphosphorinann rings, rings, having having me- 31 methylthyl and and thiophosphoryl thiophosphoryl groups groups transtrans situated.situated. The 31P-NMR The P-NMR spectra spectraof a mixture of a mixtureof transtrans 6 F cis 6 F of6(F) (84%)- ( and) (84%) cis-6 and(F) (16%)- ( (shown) (16%) in (shown Figure in5) Figurein conjunction5) in conjunction with Figure with 4 best Figure illus-4 best illustrate the relationship between the shape of the 31P-NMR resonance signals and trate the relationship between the shape of the 31P-NMR resonance signals and configura- configuration at phosphorus and C4-carbon in the 1,3,2-dioxaphosphorinan systems. tion at phosphorus and C4-carbon in the 1,3,2-dioxaphosphorinan systems. These observations are supported by our DFT calculations. We performed full conformational analysis of one pair of diastereomers, namely (RP,SC4) and (SP,SC4), as the other pair, (SP,RC4) and (RP,RC4), respectively, are their equivalent enantiomeric forms. For both diastereomers, two stable low energy chair conformations and one boat conformation were identified. The structures and relative free energies of the cis- and trans-conformers of 6(F) in aqueous solution (in kcal/mol) are given in Supplementary Materials, Figure S2 and Ta- ble S2. The calculated geometry of cis-2-fluoro-4-methyl-1,3,2-dioxaphosphorinan-2-thione in the aqueous solution agrees very well with its crystal structure reported [24], which proves the reliability of the theoretical method used (Supplementary Materials, Table S4). The most stable conformer of the two diastereomers (Scheme 11) is the conformer cis-6(F) in which fluorine occupies an axial position and the methyl group on the C4 carbon occupies an equatorial position.

2.2. Stereochemistry of Nucleophilic Displacement Reactions at Phosphorus in 2-Halogeno-4-methyl-1,3,2-dioxaphosphorinan-2-thiones 6 Having in hand the diastereomeric pairs of thiophosphoryl chloride 6(Cl) and fluoride 6(F), we could start with investigation of the stereochemical course of nucleophilic displacement processes occurring at phosphorus. In the present work, three basic substitution reactions were examined, namely alkaline hydrolysis, methanolysis and aminolysis. The choice of the first two reactions was due to the fact that they produce diastereomeric thioacids 9 [23] and thionophosphates 12 [19], respectively, which were obtained by us in an independent way and the configuration at phosphorus in both diastereomers of 9 and 12 was firmly established. Moreover, the diastereomeric hydrolysis products 9 as well as thiophosphoryl amides 13 formed in the third reaction do not undergo epimerization at phosphorus under the reaction conditions. At first, the stereochemical course of displacement reactions at phosphorus in the trans-isomer of thiophosphoryl chloride 6(Cl) was investigated. The results obtained are summarized in Scheme 14. Molecules 2021, 26, x FOR PEER REVIEW 14 of 30

These observations are supported by our DFT calculations. We performed full conformational analysis of one pair of diastereomers, namely (RP,SC4) and (SP,SC4), as the other pair, (SP,RC4) and (RP,RC4), respectively, are their equivalent enantiomeric forms. For both diastereomers, two stable low energy chair conformations and one boat conformation were identified. The structures and relative free energies of the cis- and trans-conformers of 6(F) in aqueous solution (in kcal/mol) are given in Supplementary Materials, Figure S2 and Table S2. The calculated geometry of cis-2-fluoro-4-methyl-1,3,2-dioxaphosphorinan- 2-thione in the aqueous solution agrees very well with its crystal structure reported [24], which proves the reliability of the theoretical method used (Supplementary Materials, Ta- ble S4). The most stable conformer of the two diastereomers (Scheme 11) is the conformer cis- 6(F) in which fluorine occupies an axial position and the methyl group on the C4 carbon occupies an equatorial position.

2.2. Stereochemistry of Nucleophilic Displacement Reactions at Phosphorus in 2-Halogeno-4- methyl-1,3,2-dioxaphosphorinan-2-thiones 6 Having in hand the diastereomeric pairs of thiophosphoryl chloride 6(Cl) and fluoride 6(F), we could start with investigation of the stereochemical course of nucleophilic displacement processes occurring at phosphorus. In the present work, three basic substitution reactions were examined, namely alkaline hydrolysis, methanolysis and aminolysis. The choice of the first two reactions was due to the fact that they produce diastereomeric thioacids 9 [23] and thionophosphates 12 [19], respectively, which were obtained by us in an independent way and the configuration at phosphorus in both diastereomers of 9 and 12 was firmly established. Moreover, the diastereomeric hydrolysis products 9 as well as thiophosphoryl amides 13 formed in the third reaction do not undergo epimerization at phosphorus under the reaction conditions. Molecules 2021, 26, 3655 At first, the stereochemical course of displacement reactions at phosphorus in the 14 of 30 trans-isomer of thiophosphoryl chloride 6(Cl) was investigated. The results obtained are summarized in Scheme 14.

Molecules 2021, 26, x FOR PEER REVIEW 15 of 30

Scheme 14.SchemeNucleophilic 14. Nucleophilic displacement displacement reactions at reactions phosphorus at phos in cyclicphorus thiophosphoryl in cyclic thiophosphoryl chloride trans chloride-6(Cl), path a, and bromide transtrans-6(-Br6(Cl), path), pathb. a, and bromide trans-6(Br), path b. Alkaline hydrolysis of the diastereomerically pure trans-6(Cl) as well as other Alkaline hydrolysis of the diastereomerically pure trans-6(Cl) as well as other halo- halogenidesgenides 6 was 6 was carried carried out in out a water-dioxanein a water-dioxane solution solution at ca. at 0 ◦ ca.C. The0 °C. crude The crude sodium sodium salt of salt of thioacid 9 isolated from the reaction mixture showed two resonance signals at δP = thioacid 9 isolated from the reaction mixture showed two resonance signals at δP = 50.5 and 31 50.554.0 and ppm 54.0 in theppm31 P-NMRin the P-NMR spectrum, spectrum, corresponding corresponding to the sodium to the sodium salts of salts thioacid of thioacidtrans-9 trans-9 and cis-9, respectively. They were formed in a 92:8 ratio. For further identification and cis-9, respectively. They were formed in a 92:8 ratio. For further identiﬁcation and andcharacterization, characterization, this mixturethis mixture of both of sodiumboth sodium salts was salts converted was converted into the into corresponding the corre- spondingdicyclohexyl dicyclohexyl ammonium ammonium salts of trans salts-9 (92%)of trans and-9 (92%)cis-9 (8%) and displayingcis-9 (8%) displaying chemical shifts chemi- at cal shifts at δP = 50.5 and 53.5 ppm. The fact that thioacid trans-9 was formed as the major δP = 50.5 and 53.5 ppm. The fact that thioacid trans-9 was formed as the major hydrolysis hydrolysisproduct indicates product that indicates the reaction that the under reacti discussionon under occurreddiscussion with occurred inversion with of inversion conﬁgu- ofration configuration at phosphorus. at phosphorus. A very small A very amount small (8%)amount of thioacid (8%) of cisthioacid-9 formed cis-9 in formed this reaction in this reactionmay be explainedmay be explained by a concomitant by a concomitant formation formation of cis-6 (ofCl cis) (via-6(Cl the) (via chloride–chloride the chloride–chlo- ex- ridechange exchange reaction reaction in the starting in the startingtrans-6( Cltrans)) and-6(Cl its)) subsequentand its subsequent hydrolysis hydrolysis to cis-9. Alkalineto cis-9. Alkalinehydrolysis hydrolysis of the thermodynamically of the thermodynamically less stable thiophosphoryl less stable thiophosphoryl chloride cis-6 (Clchloride) with 95%cis- 6diastereomeric(Cl) with 95% puritydiastereomeric afforded purity a mixture afforded of two a sodiummixturesalts of two of thioacidsodium saltscis-9 andof thioacidtrans-9 cisin- a9 77:23and trans ratio-9 as in revealed a 77:23 byratio31P-NMR as revealed spectrum. by 31P-NMR Formation spectrum. of the sodiumFormation salt of cisthe-9 so-as diumthe major salt productof cis-9 as also the demonstrated major product the also prevailing demonstrated stereoinvertive the prevailing course ofstereoinvertive hydrolysis of coursethis stereomer of hydrolysis (Scheme of th15is). stereomer (Scheme 15).

SchemeScheme 15. 15. AlkalineAlkaline hydrolysis hydrolysis of of thiophosphoryl thiophosphoryl chloride ciscis--6((Cl).).

TheThe methanolysis methanolysis reaction reaction of transtrans--6((Cl)) was was carried carried out in in a a mixture mixture of benzene and sodiumsodium methoxide inin methanol methanol at at 0 ◦0C. °C. It affordedIt afforded the the cyclic cyclic thionophosphate thionophosphatetrans -trans12 with-12 with93% diastereomeric93% diastereomeric purity purity (31P-NMR (31P-NMR assay). assay). As in As the in case the ofcase alkaline of alkaline hydrolysis hydrolysis of trans of- trans6(Cl),-6 the(Cl), stereochemical the stereochemical outcome outcome of the of methanolysis the methanolysis was also was inversion also inversion of conﬁguration of config- urationat phosphorus. at phosphorus. However, However, in this case in athis small case decrease a small of decrease diastereoselectivity of diastereoselectivity in this reaction in this reaction may be due to the methoxy–methoxy exchange reaction at phosphorus in trans-12, resulting in formation of cis-12, the more thermodynamically stable isomer. In contrast to alkaline hydrolysis and methanolysis, the reaction of trans-6(Cl) with dimethylamine in ether at 0 °C gave the corresponding thiophosphoryl amide trans-13 with complete inversion of configuration at phosphorus. As the aminolysis product (trans- 13) was not reported in the literature, it was prepared by us in an independent way starting from cis-2-dimethylamino-4-methyl-1,3,2-dioxaphosphorinan 14 (80% dp) [29], which upon treatment with acetylsulfenyl chloride gave thiophosphoryl amide trans-13 with 94% diastereomeric purity. Addition of elemental sulfur to amidophosphite 14 also occurred with retention of configuration at phosphorus and afforded trans-13 with 82% diastereomeric purity (Scheme 16).

Scheme 16. Sulfurization of cyclic amidophosphite cis-14 with MeC(O)SCl (a) and S8 (b).

Molecules 2021, 26, x FOR PEER REVIEW 15 of 30

Alkaline hydrolysis of the diastereomerically pure trans-6(Cl) as well as other halogenides 6 was carried out in a water-dioxane solution at ca. 0 °C. The crude sodium salt of thioacid 9 isolated from the reaction mixture showed two resonance signals at δP = 50.5 and 54.0 ppm in the 31P-NMR spectrum, corresponding to the sodium salts of thioacid trans-9 and cis-9, respectively. They were formed in a 92:8 ratio. For further identification and characterization, this mixture of both sodium salts was converted into the corresponding dicyclohexyl ammonium salts of trans-9 (92%) and cis-9 (8%) displaying chemical shifts at δP = 50.5 and 53.5 ppm. The fact that thioacid trans-9 was formed as the major hydrolysis product indicates that the reaction under discussion occurred with inversion of configuration at phosphorus. A very small amount (8%) of thioacid cis-9 formed in this reaction may be explained by a concomitant formation of cis-6(Cl) (via the chloride–chloride exchange reaction in the starting trans-6(Cl)) and its subsequent hydrolysis to cis-9. Alkaline hydrolysis of the thermodynamically less stable thiophosphoryl chloride cis- 6(Cl) with 95% diastereomeric purity afforded a mixture of two sodium salts of thioacid cis-9 and trans-9 in a 77:23 ratio as revealed by 31P-NMR spectrum. Formation of the sodium salt of cis-9 as the major product also demonstrated the prevailing stereoinvertive course of hydrolysis of this stereomer (Scheme 15).

Scheme 15. Alkaline hydrolysis of thiophosphoryl chloride cis-6(Cl).

The methanolysis reaction of trans-6(Cl) was carried out in a mixture of benzene and sodium methoxide in methanol at 0 °C. It afforded the cyclic thionophosphate trans-12 Molecules 2021, 26, 3655 15 of 30 with 93% diastereomeric purity (31P-NMR assay). As in the case of alkaline hydrolysis of trans-6(Cl), the stereochemical outcome of the methanolysis was also inversion of configuration at phosphorus. However, in this case a small decrease of diastereoselectivity in thismay reaction be due to may the methoxy–methoxybe due to the methoxy–me exchangethoxy reaction exchange at phosphorus reaction in transat phosphorus-12, resulting in transin formation-12, resulting of cis -in12 formation, the more of thermodynamically cis-12, the more thermodynamically stable isomer. stable isomer. In contrast to alkaline hydrolysis and methanolysis, the reaction of trans-6(Cl) with dimethylamine in in ether at 0 ◦°CC gave the correspondingcorresponding thiophosphorylthiophosphoryl amide transtrans-13 with complete inversion of configuration conﬁguration at phosphorus. As the the aminolysis aminolysis product product ( (transtrans-- 13) was was not not reported reported in in the the literature, literature, it was it was prepared prepared by us by in us an in independent an independent way start- way ingstarting from fromcis-2-dimethylamino-4-methyl-cis-2-dimethylamino-4-methyl-1,3,2-dioxaphosphorinan1,3,2-dioxaphosphorinan 14 (80%14 dp)(80% [29], dp) which [29], uponwhich treatment upon treatment with acetylsulfenyl with acetylsulfenyl chloride chloride gave thiophosphoryl gave thiophosphoryl amide amide trans-trans13 with-13 94%with diastereomeric 94% diastereomeric purity. purity. Addition Addition of elemental of elemental sulfur sulfur to amidophosphite to amidophosphite 14 also14 also oc- curredoccurred with with retention retention of configurat of conﬁgurationion at phosphorus at phosphorus and and afforded afforded transtrans-13 -with13 with 82% 82% diastereomericdiastereomeric purity purity (Scheme (Scheme 16). 16 ).

Molecules 2021, 26, x FOR PEER REVIEW 16 of 30

Scheme 16. Sulfurization of cyclic amidophosphite cis-14 with MeC(O)SCl (a) and S8 ((bb)).. Similar results were obtained with the thiophosphoryl bromide trans-6(Br), which Similar results were obtained with the thiophosphoryl bromide trans-6(Br), which was was used as a substrate in the three substitution reactions investigated herein (see Scheme used as a substrate in the three substitution reactions investigated herein (see Scheme 14). 14).Thus, Thus, alkaline alkaline hydrolysis hydrolysis and and methanolysis methanolysis of thisof this bromide bromide were were found found to to occur occur with with a apredominant predominant inversion inversion of of configuration configuration at at phosphorus phosphorus whilewhile aminolysis,aminolysis, asas in the case of the trans-chloride 6((Cl),), was fully diastereoselective and and gave the pure trans-13 with inversioninversion of of configuration. configuration. In In this this connection, connection, it is it interesting is interesting to mention to mention that that the conden- the con- sationdensation reactions reactions of isomeric of isomeric cis- andcis trans- and-chloridestrans-chlorides and bromides, and bromides, 6(Cl) and6( 6Cl(Br) and) with6( theBr) diastereomericwith the diastereomeric thioacid 9 thioacidanions occurred9 anions almost occurred exclusively almost by exclusively inversionby of P-configura- inversion of tionP-configuration [24]. [24]. Before discussing our present results on displacement reactions in the diastereomeric thiophosphorylthiophosphoryl fluorides fluorides 6(6F(),F ),it itis necessary is necessary to note to note that thatInch Inchand coworkers and coworkers [30] reported [30] re- veryported early very that early the that displacement the displacement of fluorine of fluorine by nucleophilic by nucleophilic reagents reagents in the 1,3,2-dioxa- in the 1,3,2- phosphorinan-2-onesdioxaphosphorinan-2-ones derived derived from from carbohydrate carbohydratess occurs occurs with with preponderant preponderant retention retention at phosphorus.at phosphorus. However, However, the the stereochemical stereochemical cour coursese of of these these reactions reactions was was examined examined with only one, more stable diastereomer with the axial fluorine.fluorine. Therefore, the discussion on thethe stereochemistry-mechanism stereochemistry-mechanism relationship relationship was was rather rather limited limited and and not not conclusive. conclusive. As we As havewe have been been successful successful in pr ineparing preparing and andpurifying purifying both both cis- andcis- andtranstrans-fluorides-fluorides 6(F),6 (weF), de- we cideddecided to concentrate to concentrate our ourattention attention on their on their alkali alkalinene hydrolysis. hydrolysis. In the In first the place, first place, this reac- this tionreaction was wasinvestigated investigated with with the the thermodynami thermodynamicallycally more more stable stable thiophosphoryl thiophosphoryl fluoride fluoride ciscis--66((FF),), and and also also with with the axial fluorine, fluorine, to compare our results with those reported by Inch.Inch. Thus, Thus, hydrolysis hydrolysis was was carried carried out out accord accordinging to to a a general procedure also applied for ◦ other thiophosphoryl halogenides 6 (NaOH, HH22O-dioxane, 0 °C)C) and resulted in a mixture of the two sodium salts of the thioacid cis--9 and trans--9 in a ratio of 66:34 as estimated by 3131P-NMRP-NMR spectra spectra [27] [27] (see (see Scheme Scheme 17).17).

Scheme 17. AlkalineAlkaline hydrolysis hydrolysis of th thiophosphoryliophosphoryl fluoride ﬂuoride cis-6(F).

This result result clearly showed that the the fluoride ﬂuoride ciscis--6((F)) underwent underwent hydrolytic hydrolytic conversion toto cis--9(Na) as the major product with retention of conﬁgurationconfiguration at phosphorus.phosphorus. In this way, the results of Inch were to some extent corroborated. However, the most intriguing was a high content of the sodium salt of trans-9, which was simultaneously formed in this reaction with inversion of configuration, as epimerization of the more stable cis-6(F) to its less stable trans-isomer does not occur in the presence of fluoride anion. Such a stereochemical outcome of alkaline hydrolysis should be due to a different mechanism of hydrolysis of 2-fluorophosphorinanes 6(F) as compared with their chloro- and bromo-analogues. We have also noted a negligible effect of the reaction medium and added inorganic salts on the retention-inversion ratio (see Table 2).

Table 2. Effect of reaction medium on percentage of cis- and trans-isomers of thioacid 9 obtained in hydrolysis of thiophosphoryl fluoride cis-6(F).

Sodium Salt No Reaction Medium cis-9(Na) (%) Retention trans-9(Na) (%) Inversion 1 NaOH, water-dioxane (1:1) 66 34 2 NaOH, water-DMF (1:1) 66 34 3 NaOH, water-DMF (1:1), Et4NBr 54 36 4 NaOH, water-dioxane (1:1), NH4F 70 30 5 KOH, water-dioxane (1:1) 64 36

Molecules 2021, 26, 3655 16 of 30

way, the results of Inch were to some extent corroborated. However, the most intriguing was a high content of the sodium salt of trans-9, which was simultaneously formed in this reaction with inversion of configuration, as epimerization of the more stable cis-6(F) to its less stable trans-isomer does not occur in the presence of fluoride anion. Such a stereochemical outcome of alkaline hydrolysis should be due to a different mechanism of hydrolysis of 2-fluorophosphorinanes 6(F) as compared with their chloro- and bromo- analogues. We have also noted a negligible effect of the reaction medium and added inorganic salts on the retention-inversion ratio (see Table2).

Table 2. Effect of reaction medium on percentage of cis- and trans-isomers of thioacid 9 obtained in hydrolysis of thiophosphoryl ﬂuoride cis-6(F).

Sodium Salt No Reaction Medium cis-9(Na) (%) trans-9(Na) (%) Retention Inversion 1 NaOH, water-dioxane (1:1) 66 34 2 NaOH, water-DMF (1:1) 66 34 3 NaOH, water-DMF (1:1), Et4NBr 54 36 Molecules 2021, 26, x FOR PEER REVIEW 4 NaOH, water-dioxane (1:1), NH4F 70 30 17 of 30

5 KOH, water-dioxane (1:1) 64 36

TheThe results results of of alkaline alkaline hydrolysis hydrolysis of ofthe the less less stable stable fluoride fluoride transtrans-6(F-)6 (equatorial(F) (equatorial fluorine)fluorine) were were even even more more interesting. interesting. In Inthis this case, case, two two sodium sodium salts salts of of the the thioacid thioacid 99 were obtainedobtained in a 73:2773:27 ratio;ratio; however,however, the the major major product, product,cis cis-9(-Na9(Na), was), was formed formed with with inversion inver- sionof configuration of configuration (see Scheme(see Scheme 18). 18).

SchemeScheme 18. 18. AlkalineAlkaline hydrolysis hydrolysis of of th thiophosphoryliophosphoryl fluoride ﬂuoride transtrans--6((F).).

InIn additional additional experiments, experiments, it itwas was found found that that diastereomeric diastereomeric purity purity of the of starting the starting thiophosphorylthiophosphoryl fluoride ﬂuoride transtrans-6(-F6)( Fhas) has practically practically no no effect effect on on the the product product ratio, ratio, which which is is in thisthis case case equivalent equivalent to to the the inversion-retention inversion-retention ratio (see Table 3 3).).

TableTable 3. EffectEffect of of diastereomeric diastereomeric purity purity of of thiophosphoryl thiophosphoryl fluoride ﬂuoride transtrans-6-(6F()F on) on percentage percentage of of ciscis- - andand transtrans-isomers-isomers of of thioacid thioacid 9 sodiumsodium salt.

Diastereomeric Purity Sodium SaltSodium Salt No Diastereomeric Purity No of trans-6(F), dp (%) cis-9(Na)(%) Inversion trans-9(Na) (%) Retention of trans-6(F), dp (%) cis-9(Na) (%) trans-9(Na) (%) 1 71 78 Inversion 22Retention 2 89 77 25 1 71 78 22 3 90 74 26 2 89 77 25 4 394 90 73 74 27 26 4 94 73 27 To estimate the effect of epimerization of the starting trans-fluoride 6(F) to cis-isomer by fluoride ion, alkaline hydrolysis was performed with an insufficient molar amount of To estimate the effect of epimerization of the starting trans-fluoride 6(F) to cis-isomer sodium hydroxide. The results obtained are shown in Scheme 19. It turned out that the by fluoride ion, alkaline hydrolysis was performed with an insufficient molar amount unreacted fluoride trans-6(F) was only slightly epimerized and recovered with 84% dia- of sodium hydroxide. The results obtained are shown in Scheme 19. It turned out that stereomeric purity. Therefore, this side process considered here cannot essentially change the unreacted fluoride trans-6(F) was only slightly epimerized and recovered with 84% the main stereochemical outcome of hydrolysis. diastereomeric purity. Therefore, this side process considered here cannot essentially change the main stereochemical outcome of hydrolysis.

Scheme 19. Partial alkaline hydrolysis of thiophosphoryl fluoride trans-6(F).

Finally, for comparison purposes, the reaction of the more stable thiophosphoryl fluoride cis-6(F) with sodium methoxide was briefly investigated. In accord with the results of alkaline hydrolysis of this thiofluoridate, its methanolysis afforded both isomeric thion- ophosphatescis-12 and trans-12, the former being the major product was formed with retention of configuration as shown in Scheme 20.

Molecules 2021, 26, x FOR PEER REVIEW 17 of 30

The results of alkaline hydrolysis of the less stable fluoride trans-6(F) (equatorial fluorine) were even more interesting. In this case, two sodium salts of the thioacid 9 were obtained in a 73:27 ratio; however, the major product, cis-9(Na), was formed with inversion of configuration (see Scheme 18).

Scheme 18. Alkaline hydrolysis of thiophosphoryl fluoride trans-6(F).

In additional experiments, it was found that diastereomeric purity of the starting thiophosphoryl fluoride trans-6(F) has practically no effect on the product ratio, which is in this case equivalent to the inversion-retention ratio (see Table 3).

Table 3. Effect of diastereomeric purity of thiophosphoryl fluoride trans-6(F) on percentage of cis- and trans-isomers of thioacid 9 sodium salt.

Diastereomeric Purity Sodium Salt No of trans-6(F), dp (%) cis-9(Na)(%) Inversion trans-9(Na) (%) Retention 1 71 78 22 2 89 77 25 3 90 74 26 4 94 73 27

To estimate the effect of epimerization of the starting trans-fluoride 6(F) to cis-isomer by fluoride ion, alkaline hydrolysis was performed with an insufficient molar amount of sodium hydroxide. The results obtained are shown in Scheme 19. It turned out that the Molecules 2021, 26, 3655 unreacted fluoride trans-6(F) was only slightly epimerized and recovered with 84%17 ofdia- 30 stereomeric purity. Therefore, this side process considered here cannot essentially change the main stereochemical outcome of hydrolysis.

Scheme 19. Partial alkaline hydrolysis of thiophosphoryl ﬂuoridefluoride transtrans--6((F).).

Finally, for for comparison comparison purposes, purposes, the the reacti reactionon of ofthe the more more stable stable thiophosphoryl thiophosphoryl flu- oridefluoride cis-cis6(F-)6 (withF) with sodium sodium methoxide methoxide was wasbriefly briefly investigated. investigated. In accord In accord with the with results the results of alkaline hydrolysis of this thiofluoridate, its methanolysis afforded both isomeric Molecules 2021, 26, x FOR PEER REVIEWof alkaline hydrolysis of this thiofluoridate, its methanolysis afforded both isomeric18 thion- of 30 ophosphatesthionophosphatescis-12cis and-12 transand trans-12, the-12 ,former the former being being the major the major product product was was formed formed with with re- tentionretention of ofconfiguration configuration as as shown shown in inScheme Scheme 20. 20 .

SchemeScheme 20. 20. MethanolysisMethanolysis of of thiophosphoryl thiophosphoryl fluoride ﬂuoride transtrans--6((F).).

ItIt was was also also found found that that the the product product isomer isomer ratios ratios are arepractically practically not notinfluenced inﬂuenced by sol- by vents,solvents, both both protic protic and andaprotic, aprotic, indicating indicating that they that reflect they reﬂect the mode the modeof substitution of substitution (Table 4).(Table 4).

Table 4. Effects of solvents on percentage of cis- and trans-thiophosphates 12 obtained in meth- Table 4. Effects of solvents on percentage of cis- and trans-thiophosphates 12 obtained in methanolysis anolysisof thiophosphoryl of thiophosphoryl ﬂuoride fluoridecis-6(F). cis-6(F).

ThionophosphateThionophosphate 12 12 No. No. SolventSolvent ciscis--1212 transtrans-12-12 1 C6H6 84 16 1 C6H6 84 16 2 2DMF DMF 87 87 13 13 3 3MeCN MeCN 88.5 88.5 11.5 11.5 4 4MeOH MeOH 88 88 12 12

DissectingDissecting the the results results of of our our studies studies on on the the stereochemistry stereochemistry of of displacement displacement reactions reactions atat phosphorus in 2-halogeno-4-methyl-1,3,2-dioxaphosphorinan-2-thiones2-halogeno-4-methyl-1,3,2-dioxaphosphorinan-2-thiones 66 presented aboveabove several several important important observations observations and and interpre interpretationstations cancan be inferred. be inferred. First of First all, ofthere all, isthere a sharp is a sharpdifference difference in the in stereochemical the stereochemical course course of substitution of substitution reactions reactions between between diastereomericdiastereomeric thiophosphoryl thiophosphoryl chlorides chlorides and andbromides bromides 6(Cl,6 Br(Cl) ,onBr the) on one the side one and side fluo- and ridesfluorides 6(F) 6on(F )the on other the other side. side.Both Bothdiastereomeric diastereomeric chlorides chlorides 6(Cl) 6and(Cl )bromides and bromides 6(Br) react6(Br) withreact nucleophilic with nucleophilic reagents reagents as a rule as a rulewith with full inversion full inversion of configuration of configuration at phosphorus. at phosphorus. A smallA small decrease decrease of ofdiastereoselectivity diastereoselectivity observed observed in inalkaline alkaline hydrolysis hydrolysis and and methanolysis methanolysis is dueis due to toconcomitant concomitant side side epimerization epimerization reacti reactionsons of a of substrate a substrate and/or and/or a product a product of the of displacementthe displacement reaction reaction investigated. investigated. In the In case the caseof thiophosphoryl of thiophosphoryl chlorides chlorides 6(Cl)6 and(Cl) bro- and midesbromides 6(Br6),(Br the), thesubstitutions substitutions are are kinetically kinetically cont controlled,rolled, which which implies implies that that inversion inversion at phosphorusphosphorus may be a cons consequenceequence of a direct S N2-P2-P type type displacement. displacement. InIn contrast toto thethe diastereomericdiastereomeric chlorides chlorides6( 6Cl(Cl), both), both diastereomeric diastereomeric fluorides fluorides (cis -(6cis(F-) 6and(F) andtrans trans-6(F))-6 undergo(F)) undergo alkaline alkaline hydrolysis, hydrolysis, affording affording the same the same mixture mixture of the of correspond- the corre- spondinging thioacids thioacids9 with 9 the with thermodynamically the thermodynamically more stable more thioacid stable thioacidcis-9 being cis- a9 majorbeing producta major productin both cases.in both It cases. means It thatmeans hydrolysis that hydrolysis of cis-6 (ofF) cis affords-6(F) affordscis-9 with cis- retention9 with retention of config- of configuration,uration, while whiletrans- trans6(F)- upon6(F) upon hydrolysis hydrolysis gives gives the samethe sa majorme major product product with with inversion inver- sionof configuration. of configuration. Such Such a stereochemical a stereochemical outcome outcome of alkaline of alkaline hydrolysis hydrolysis of both of both isomeric iso- mericfluorides fluorides6(F) and 6(F other) and observationsother observations presented presented above indicateabove indicate that this that reaction this reaction as well as wellmethanolysis as methanolysis are controlled are controlled by thermodynamic by thermodynamic factors. factors. Taking Taking into account into account well known well known facts that (a) fluorine forms a very strong bond with phosphorus, (b) the fluoride anion is a poor leaving group, and (c) fluorine as a substituent stabilizes pentacoordinate phosphorus and is strongly apicophilic, it is believed that nucleophilic substitution at phosphorus in thiophosphoryl fluorides 6(F) occurs according to the addition–elimination (A–E) mechanism.

Molecules 2021, 26, 3655 18 of 30

facts that (a) fluorine forms a very strong bond with phosphorus, (b) the fluoride anion is a poor leaving group, and (c) fluorine as a substituent stabilizes pentacoordinate phosphorus and is strongly apicophilic, it is believed that nucleophilic substitution at phosphorus in thiophosphoryl fluorides 6(F) occurs according to the addition–elimination (A–E) mechanism.

2.3. DFT Studies on Mechanism-Stereochemistry Relationship inSubstitution of Cyclic 2-halogeno-4-methyl-1,3,2-dioxaphosphorinane-2-thiones 6 The conformation and structure of 1,3,2-dioxaphosphorinanes have been extensively studied by 1H-, 13C- and 31P-NMR, IR, and X-ray spectroscopies [10,31]. Although theoretical studies of various 1,3,2-dioxaphosphorinanes have also been published [32–34], to the best of our knowledge, the hydrolysis reaction of 2-halogeno-4-methyl-1,3,2- dioxaphosphorinan-2-thiones 6 was not investigated by theoretical methods. Therefore, having in mind the results of our stereochemical studies and suggestions concerning the different mechanisms of the alkaline hydrolysis of both cyclic diastereomeric thiophosphoryl chlorides 6(Cl) and fluorides 6(F), we decided to concentrate on elucidation stereochemical and mechanistic details of this reaction. To calculate the energy of this substitution reaction, we first performed conformational analysis of reagents (6(Cl), 6(F)) and the product, 2-hydroxy-4-methyl-1,3,2- dioxaphosphorinan-2-thione 9. In the case discussed here, the presence of the methyl group at C4 in the six-membered ring induces stereoisomerism in the molecule, which may result in a different reactivity of diastereomers towards the nucleophile. Therefore, we calculated chair and boat conformations for both cis- and trans- diastereomers of chlorides 6(Cl) and fluorides 6(F) and compared the Gibbs free energies of all stable minima. The most stable diastereomer of 6(Cl) was found to exist in a chair conformation with chlorine in the axial position and methyl in the equatorial position, denoted in this work as trans-6(Cl). The remaining conformers are ∆Grel = 2.5–5.6 kcal/mol higher in energy than trans-6(Cl). The relative Gibbs free energies of all isomers are collected in Table S1. These data show a strong preference for chlorine to the axial position. All isomers with chlorine occupying the equatorial position have much higher energies. Additional stabilization of trans-6(Cl) is due to the methyl group in equatorial arrangement, which minimizes the steric congestion. These observations support the common knowledge about these ring systems [10]. The stability order of conformers of 6(F) is very similar in terms of relative stereochemistry. One should remember that due to the different priority of substituents, upon replacement of Cl for F, the most stable conformation is again that with axial fluorine and an equatorial methyl group, i.e., cis-6(F) (see Supplementary Materials, Table S2 and Figure S2). Comparison of the calculated structure of this isomer in the aqueous solution agrees very well with the reported crystal structure [28], which proves the reliability of the theoretical method used (Supplementary Materials, Table S4). The most stable conformer of 9 is that with the axial hydroxyl and equatorial C4- methyl group, i.e., cis-9, as in the case of fluorine and chlorine. However, only slightly less stable (by 0.7 kcal/mol) is the isomer trans-9 with both hydroxyl and methyl groups in equatorial positions (Supplementary Materials, Table S3 and Figure S3). DFT calculations of the alkaline hydrolysis of trans-6(Cl) in water showed that indeed the preferred reaction route is the attack of hydroxide ion from the opposite side to chlorine and the ligand exchange occurs with inversion of configuration. It is a one-step reaction that proceeds via a single transition state as was found for acyclic alkoxyphosphoryl chlorides [35,36]. Both trans and cis isomers react according to the same SN2-P mechanism and their free energy profiles are almost identical (Figure6). Molecules 2021, 26, 3655 19 of 30 Molecules 2021, 26, x FOR PEER REVIEW 20 of 30

FigureFigure 6. 6.RelativeRelative free free energy energy profile proﬁle (kcal/mol) (kcal/mol) for the for chloride–hydroxide the chloride–hydroxide exchange exchange in transin trans- (blue(blue line) line) and and cis-cis- (red(red line) line) 6(Cl)6(Cl); (;(ECEC)-early)-early complex complex (complex (complex of of substrates), substrates), (TS (TS)-transition)-transition state, state, (LC)-late complex (complex of products). (LC)-late complex (complex of products).

TheThe analogous analogous hydrolysis ofof6 6(F(F)) seems seems more more complicated complicated in viewin view of the of experimentalthe experi- mentalresults. results. To deeper To understanddeeper understand the mechanistic the mech andanistic stereochemical and stereochemical details of thisdetails process, of this we process,performed we analogousperformed DFTanalogous calculations DFT calculatio of the replacementns of the replacement of fluoride ion of influoridecis- and iontrans in - cis6(-F and) by trans hydroxyl-6(F) anionby hydroxyl in water anion solution. in water Anticipating solution. thatAnticipating the reaction that may the occurreaction stepwise may occuraccording stepwise to the according addition–elimination to the addition–elimi schemenation [35], scheme we considered [35], we atconsidered first the reactionat first thepathways reaction starting pathways from starting the approach from the of approach the nucleophile of the nucleophile to each face to of each the tetrahedronface of the tetrahedronformed by formed S, O(C4 ),by O(C S, O(C6), and4), O(C F (Scheme6), and F 21(Scheme). The 21). stationary The stationary points on points the reactionon the reactionpathway pathway (intermediates (intermediates and transition and transition states) states) were identifiedwere identified by computing by computing potential po- tentialenergy energy scans scans (PES) (PES) of the of reaction. the reaction. The The route route (a) should (a) should lead lead to formation to formation of aof trigonal a trig- onalbipyramidal bipyramidal intermediate intermediate (TBPI) (TBPI) with OHwith and OH F and in apical F in apical positions. positions. The route The ( broute) consists (b) consistsof two directionsof two directions of nucleophilic of nucleophilic attack, fromattack, the from opposite the opposite side relative side relative to each to oxygen each oxygen in the ring. Energetically, both routes (b-1 and b-2) are almost equivalent. The

Molecules 2021, 26, 3655 20 of 30 Molecules 2021, 26, x FOR PEER REVIEW 21 of 30

inroute the ring.(c) involves Energetically, the attack both of routes OH− (onb-1 phosphorusand b-2) are from almost the equivalent. opposite side The to route sulfur (c) Molecules 2021, 26, x FOR PEER REVIEW − 21 of 30 involves(Scheme the21). attack of OH on phosphorus from the opposite side to sulfur (Scheme 21).

route (c) involves the attack of OH− on phosphorusF from the opposite side to sulfur O (Scheme 21). P S c O F OH a O P S F b O c OH OH O a b O P O P OH F b SOH O S F O a b c O P O P OH S OH O c S OF a P F O OHO O = O S O O P F O O O = S Scheme 21. Three directions of the nucleophilic attack of hydroxide ion on phosphorus: (a) oppo- Scheme 21.OThree directionsO of the nucleophilic attack of hydroxide ion on phosphorus: (a) opposite site to F, (b) opposite to oxygen in the ring (two variants possible as due to substitution at C4, the to F, (b) opposite to oxygen in the ring (two variants possible as due to substitution at C4, the oxygens Schemeoxygens 21. are Three slightly directions nonequivalent), of the nucleophilic (c) opposite attack of to hydroxide S. ion on phosphorus: (a) oppo- siteare to slightly F, (b) opposite nonequivalent), to oxygen (inc) the opposite ring (two to vari S. ants possible as due to substitution at C4, the oxygens are slightly nonequivalent), (c) opposite to S. ItIt should be mentioned that that the the frontside frontside attack, attack, although although usually usually associated associated with with a amuch muchIt should higher higher be energy mentioned energy barrier barrier that than the than frontsidethe the backside backside attack, attack although attack [37], [usually 37is ],in isthis inassociated case this casepossible with possible a as it leads as it muchleadsto the higher toTBPI the energywith TBPI electronegativ with barrier electronegative than thee backsideoxygen oxygen attackin the in [37],apical the is apical in position. this position.case Moreover,possible Moreover, as itthe leads ring the in ring such in tosuchTBPI the TBPI TBPIoccupies with occupies electronegativthe apical-equatorial the apical-equatoriale oxygen inposition, the position,apical which position. which is the Moreover, ispreferred the preferred the arrangement ring in arrangement such in terms in TBPItermsof the occupies ofring the strain. ringthe apical-equatorial strain.In contrast In contrast to position,chloride to chloride which substitution, is substitution, the preferred it was itarrangementfound was foundthat all in that reactionterms all reaction routes ofroutesinvolving the ring involving strain. fluoride In fluoride contrast 6(F) proceed 6to(F chloride) proceed via pentacoordinatesubs viatitution, pentacoordinate it was intermediates, found intermediates, that all reaction as suggested asroutes suggested by stere- by involving fluoride 6(F) proceed via pentacoordinate intermediates, as suggested by stere- stereochemicalochemical studies studies (taking (taking into intoaccount account the high the high electronegativity electronegativity and andapicophilicity apicophilicity of flu- of ochemical studies (taking into account the high electronegativity and apicophilicity of flu- fluorine).orine). Below, Below, all allPV PintermediateV intermediate structures structures identi identifiedfied for for reaction reaction pathways pathways (a)–( (a)–(c) ofc) cis of orine). Below, all PV intermediate structures identified for reaction pathways (a)–(c) of cis andcisand andtrans transtrans diastereomers diastereomersdiastereomers of 6(F) of 6(F) ofare6(F) presented areare presented presented in Figures in inFigures 7Figures and 8). 7 and7 and 8).8).

FigureFigure 7. 7.StructuresStructures of the of thePV intermediates PV intermediates resulting resulting from attack from of attack OH− ofon OHcis-6−(Fon); forcis descrip--6(F); for description tion of routes a, b and c see Scheme 21. of routes (a–c) see Scheme 21. Figure 7. Structures of the PV intermediates resulting from attack of OH− on cis-6(F); for description of routes a, b and c see Scheme 21.

MoleculesMolecules 20212021, 26,, 26x ,FOR 3655 PEER REVIEW 21 of 30 22 of 30

FigureFigure 8. 8. Structures of of the the PV PintermediatesV intermediates resulting resulting from attackfrom ofattack OH− ofon OHtrans− -on6(F trans); for- description6(F); for descrip- tionof routes of routes (a–c) a see, b Schemeand c see 21 .Scheme 21.

TheThe lowest freefree energy energy barrier barrier in in the the case case of cis of-6 cis(F)-6 is(F associated) is associated with the with classical the classical a b backsidebackside attack ofof hydroxylhydroxyl relative relative to fluorineto fluorine (path (path). The a). sideThe attackside attack ( ), which (b), which places places the ring in apical-equatorial position, has the barrier by ca. 1 kcal/mol higher (Table5 ). the ring in apical-equatorial position, has the barrier by ca. 1 kcal/mol higher (Table 5). The approach of OH− from the back direction relative to sulfur is associated with the − Thehighest approach free energy of OH barrier from (by the 8kcal/mol back direction higher thanrelative (a)), to so sulfur it is the is least associated likely. However, with the high- estcalculations free energy showed barrier that (by this 8 pathwaykcal/mol leadshigher to than the most (a)), stable so it is TBPI, the whichleast likely. also loses However, calculationsfluoride most showed readily that to give this the pathway thioacid leads9, as canto the be seenmost in stable Supplementary TBPI, which Materials, also loses flu- orideFigure most S7. Thus,readily from to give the kinetic the thioacid point of 9 view,, as can the be formation seen in ofSupplementary intermediate (a Materials,) seems Fig- urepreferable. S7. Thus, Most from probably, the kinetic the pentacoordinate point of view, intermediate the formation formed of intermediate as a result of backside(a) seems pref- erable.attack (Mosta) can probably, undergo a the sequence pentacoordinate of reversible in pseudorotations,termediate formed eventually as a result leading of tobackside attacka major (a) product can undergo with retention a sequence of configuration of reversible on ps P,eudorotations, in accord with eventually thermodynamic leading to a equilibrium [38]. Indeed, we have identified at least one sequence of pseudorotations major product with retention of configuration on P, in accord with thermodynamic equi- linking both intermediates 6(F)-a and 6(F)-c (Scheme 14). librium [38]. Indeed, we have identified at least one sequence of pseudorotations linking both intermediates 6(F)-a and 6(F)-c (Scheme 14).

Table 5. Free energies relative to the sum of the free energies of free substrates for the reaction of cis-6(F) with OH−.

a b c

ΔH ΔG ΔH ΔG ΔH ΔG complex of substrates −5.3 2.0 −6.7 1.1 −6.7 1.1 transition state 1 1.2 10.7 2.8 12.4 8.6 18.8 intermediate −23.2 −12.4 −19.8 −9.9 −28.2 −17.7 transition state 2 −18.4 −7.9 −14.4 −2.8 −27.4 −16.5 complex of products −25.6 −17.5 −58.1 −49.5 −58.1 −49.5 free products −19.9 −18.6 −42.0 −41.8 −42.0 −41.8

Molecules 2021, 26, 3655 22 of 30

Table 5. Free energies relative to the sum of the free energies of free substrates for the reaction of cis-6(F) with OH−.

a b c ∆H ∆G ∆H ∆G ∆H ∆G complex of substrates −5.3 2.0 −6.7 1.1 −6.7 1.1 transition state 1 1.2 10.7 2.8 12.4 8.6 18.8 intermediate −23.2 −12.4 −19.8 −9.9 −28.2 −17.7 transition state 2 −18.4 −7.9 −14.4 −2.8 −27.4 −16.5 complex of products −25.6 −17.5 −58.1 −49.5 −58.1 −49.5 free products −19.9 −18.6 −42.0 −41.8 −42.0 −41.8

The reactivity of the diastereomer trans-6(F) is somewhat different. The attack of OH− from the opposite side to fluoride (a) has the lowest free energy barrier (by 7 kcal/mol lower than the attack (b)). The attack from the opposite side to sulfur (c) is again the most unfavourable. This suggests that the reaction with inversion of configuration should kinetically dominate, which is in accord with observations. The thermodynamic parameters of hydrolysis of both diastereomers are presented in Tables5 and6 and the free energy profiles for routes (a) and (b) of cis- and trans-6(F) hydrolysis are compared in Figure9. The difference in energies of the free products comes from the fact that in route (a) the free fluoride anion is formally produced as the byproduct while in routes (b) and (c) it is HF and thiophosphate anion. The reaction leading to hydrogen fluoride and thiophosphate anion is much more favourable thermodynamically but in alkaline medium; this of course is meaningless as the fast equilibrium between these species is immediately established.

Table 6. Free energies relative to the sum of the free energies of free substrates for the reaction of trans-6(F) with OH−.

a b c ∆H ∆G ∆H ∆G ∆H ∆G complex of substrates −4.3 2.4 −5.0 2.5 −5.0 2.5 transition state 1 −2.5 7.4 4.7 14.5 4.4 13.7 intermediate −21.4 −11.8 −18.4 −8.3 −29.4 −18.7 transition state 2 −14.3 −4.2 −11.2 0.3 −27.9 −16.9 complex of products −25.3 −17.3 −30.6 −19.4 −58.7 −50.3 free products −23.0 −20.5 −45.8 −44.2 −45.8 −44.2

Route (a): >P(S)F + OH(−) → >P(S)OH + F(−), ∆G = −18.6 (cis); −19.2 kcal/mol (trans). Route (b) and (c): >P(S)F + OH(−) → >P(S)O(−) + HF, ∆G = −41.8 (cis); −44.4 kcal/mol (trans). Molecules 2021, 26, x FOR PEER REVIEW 23 of 30

The reactivity of the diastereomer trans-6(F) is somewhat different. The attack of OH− from the opposite side to fluoride (a) has the lowest free energy barrier (by 7 kcal/mol lower than the attack (b)). The attack from the opposite side to sulfur (c) is again the most unfavourable. This suggests that the reaction with inversion of configuration should kinetically dominate, which is in accord with observations. The thermodynamic parameters of hydrolysis of both diastereomers are presented in Tables 5 and 6 and the free energy profiles for routes (a) and (b) of cis- and trans-6(F) hydrolysis are compared in Figure 9. The difference in energies of the free products comes from the fact that in route (a) the free fluoride anion is formally produced as the byproduct while in routes (b) and (c) it is HF and thiophosphate anion. The reaction leading to hydrogen fluoride and thiophosphate anion is much more favourable thermodynamically but in alkaline medium; this of course is meaningless as the fast equilibrium between these species is immediately established.

Table 6. Free energies relative to the sum of the free energies of free substrates for the reaction of trans-6(F) with OH−.

a b c

ΔH ΔG ΔH ΔG ΔH ΔG complex of substrates −4.3 2.4 −5.0 2.5 −5.0 2.5 transition state 1 −2.5 7.4 4.7 14.5 4.4 13.7 intermediate −21.4 −11.8 −18.4 −8.3 −29.4 −18.7 transition state 2 −14.3 −4.2 −11.2 0.3 −27.9 −16.9 Molecules 2021,complex26, 3655 of products −25.3 −17.3 −30.6 −19.4 −58.7 −50.3 23 of 30 free products −23.0 −20.5 −45.8 −44.2 −45.8 −44.2

20 TS1 cis-back

10 trans-back EC substr TS2 0 cis-side INT trans-side -10 LC(a) prod(a) -20 ΔG

-30

-40 prod(b) LC(b) -50

-60 reaction coordinate

Figure 9.FigureFree energy9. Free profiles energy for profiles the substitution for the substitution of fluorine byof fluorine OH− in cis byand OHtrans⁻ in cisdiastereomers and trans diastereomers of 6(F); attack from the backof to 6(F) the; fluorineattack from (back) the and back from to the the back fluorine to oxygen (back) in and the ringfrom (side); the back EC-complex to oxygen of substratesin the ring (early (side); complex), TS1-1stEC-complex transition state of (approach substrates of OH(early−), INT-Pcomplex)V intermediate,, TS1-1st transition TS2-2nd transition state (approach state (departure of OH− of), INT-P F−), LC-complexV inter- of productsmediate, (late complex) TS2-2nd according transition to route state (a (departure) or (b) and (ofc) F (Scheme−), LC-complex 21), respectively of products (Tables (late5 and complex)6). according to route (a) or (b) and (c) (Scheme 21), respectively (Tables 5 and 6). The DFT calculations presented above provided convincing evidence that alkaline Route (a): >P(S)Fhydrolysis + OH of(−) cyclic→ >P(S)OH thiophosphoryl + F(−), ΔG fluorides = −18.6 (6cis(F)); proceeds −19.2 kcal/mol according (trans to). the addition– Route (b) andelimination (c): >P(S)F mechanism + OH(−) (A–E)→ >P(S)O and allowed(−) + HF us, Δ toG rationalize = −41.8 (cis the); stereochemical−44.4 kcal/mol course and thermodynamic control of this reaction. Taking into account the Westheimer’s rules (apical (trans). attack, apical departure, pseudorotation, microscopic reversibility), we formulated the most The DFT calculationslikely mechanism presente of thed above alkaline provided hydrolysis convincing of fluorophosphorinans, evidence that which alkaline is presented hydrolysis of cyclicin Scheme thiophosphoryl 22. Thus, the fluorides attack of 6 a(F hydroxyl) proceeds anion according on phosphorus to the inaddition–cis-6(F) results in formation of the first trigonal bipyramidal intermediate TBPI-A with apical fluorine and OH group and diequatorial six-membered ring. It decomposes slowly with inversion of configuration to thioacid trans-9, which is the minor product of this reaction. The fast

Berry pseudorotation of TBPI-A leads to TBPI-B, which, in turn, undergoes permutational isomerization to TBPI-C and TBPI-D. Decomposition of the latter by departure of HF is virtually barrierless (see Supplementary Materials, Figure S7) and leads to the thermodynamically more stable thioacid cis-9 with retention of configuration. This thioacid is the major and stable product. In the case of hydrolysis of trans-6(F), the more stable thioacid cis-9 is formed from the first TBPI-A’ with inversion of configuration. The thioacid trans-9 as the minor product of hydrolysis is formed after three consecutive pseudorotations with retention of P-configuration. As the phosphorane intermediate TBPI-B (and TBPI-B’) with the apical S are energetically unstable and could not be localized, it is possible that the transformation of TBPI-A into TBPI-C can take place directly via the tetragonal pyramidal intermediate (which may be a 2nd order saddle point) transiently formed from TBPI-A in the process of pseudorotation. Molecules 2021, 26, x FOR PEER REVIEW 24 of 30

elimination mechanism (A–E) and allowed us to rationalize the stereochemical course and thermodynamic control of this reaction. Taking into account the Westheimer’s rules (apical attack, apical departure, pseudorotation, microscopic reversibility), we formulated the most likely mechanism of the alkaline hydrolysis of fluorophosphorinans, which is presented in Scheme 22. Thus, the attack of a hydroxyl anion on phosphorus in cis-6(F) results in formation of the first trigonal bipyramidal intermediate TBPI-A with apical fluorine and OH group and diequatorial six-membered ring. It decomposes slowly with inversion of configuration to thioacid trans-9, which is the minor product of this reaction. The fast Berry pseudorotation of TBPI-A leads to TBPI-B, which, in turn, undergoes permutational isomerization to TBPI-C and TBPI-D. Decomposition of the latter by departure of HF is virtually barrierless (see Supplementary Materials, Figure S7) and leads to the thermodynamically more stable thioacid cis-9 with retention of configuration. This thioacid is the major and stable product. In the case of hydrolysis of trans-6(F), the more stable thioacid cis-9 is formed from the first TBPI-A’ with inversion of configuration. The thioacid trans- 9 as the minor product of hydrolysis is formed after three consecutive pseudorotations with retention of P-configuration. As the phosphorane intermediate TBPI-B (and TBPI-B’) with the apical S are energetically unstable and could not be localized, it is possible that the transformation of TBPI-A into TBPI-C can take place directly via the tetragonal py- Molecules 2021, 26, 3655 ramidal intermediate (which may be a 2nd order saddle point) transiently24 of 30 formed from TBPI-A in the process of pseudorotation.

SchemeScheme 22. 22.Mechanism Mechanism of alkaline of alkaline hydrolysis hydrolysis of cis-6(F) andof cistrans-6(-F6(F)) and(bold trans arrows-6(F) show (bold formation arrows show for- ofmation major productof majorcis -product9 from cis andcis-9trans fromﬂuorides). cis and trans fluorides). 3. Materials and Methods 3.1.3. Materials General Experimental and Methods Details 3.1. CommercialGeneral Experimental grade reagents Details and solvents were used without further puriﬁcation except as indicated below. THF and diethyl ether were distilled over Na/benzophenone prior to use. Column chromatography was performed using silica gel (70–230 mesh). The routine 1H-NMR spectra were recorded at 60 and 80 MHz unless stated otherwise. Chemical shifts are quoted in parts per million (ppm) and reported relative to TMS as an internal standard. 31P-NMR spectra were obtained with a spectrometer operating at 24.3 MHz using 85% phosphoric acid as external standard. A heteronuclear spin decoupler was used for precise 31P chemical shift determinations. Diastereomeric purities were determined from integrated 1H- and 31P-NMR spectra and GLPC analysis. Boiling and melting points are uncorrected.

3.2. Synthetic Procedures 3.2.1. Trans-2-Chloro-4-methyl-1,3,2-dioxaphosphorinan-2-thione 6(Cl) Procedure A. To a solution of cyclic trans-chlorophosphite 7 (6.95 g, 45 mmol) in ether (30 mL) was added acetylsulfonyl chloride (5 g, 45 mmol) at 0 ◦C. The reaction mixture Molecules 2021, 26, 3655 25 of 30

was stirred at room temperature for 1 h. The solvent was evaporated and the residue was distilled under reduced pressure to give 7.7 g (91.4% yield) of the diastereomerically ◦ 20 1 pure trans-6(Cl): bp. 78–80 C; nD 1.5220; H-NMR (CCl4, 270 MHz) δ 1.26 (dd, 3H, 3 4 31 JCH3-H = 6.2 Hz, JCH3-P = 2.6 Hz, CH3); P-NMR (C6H6) δ 59.0.Anal. Calcd. for C4H8O2PSCl: C, 25.74; H, 4.26; P, 16.59. Found: C, 25.80; H, 4.07; P, 16.55. Procedure B. To a 1:1 mixture of cyclic cis- and trans-thiophosphites 8 (3.04 g, 20 mmol) in benzene (25 mL), sulfuryl chloride (2.7 g, 20 mmol) was added dropwise at 0 ◦C. The reaction mixture was stirred for 1 h at room temperature. After removal of solvent, the crude product was distilled under reduced pressure to afford 2.9 g (80% yield) of trans-6(Cl) ◦ 20 (100% dp, δP 59.0): bp. 67 C (0.01 mmHg); nD 1.5220. Anal. Calcd. for C4H8O2PSCl: C, 25.74; H, 4.26; P, 16.59. Found: C, 25.75; H, 4.52; P, 16.68.

3.2.2. Trans-2-Bromo-4-methyl-1,3,2-dioxaphosphorinan-2-thione 6(Br) To a solution of cyclic thiophosphites 8 (73% cis-8 and 27% trans-8) in benzene (20 mL), bromine (3.2 g, 20 mmol) was added dropwise at 30 ◦C. The reaction mixture was left overnight at room temperature. The reaction solution was washed with a few mL of sodium sulﬁte, then water, and then it was dried. After removal of benzene, the crude reaction product as a single isomer (31P-NMR assay) was distilled giving 3.9 g (85% yield) of pure trans-bromide 6(Br), which after solidiﬁcation was recrystallized from petroleum ◦ 20 ◦ 1 ether: bp. 82 C (0.05 mmHg); nD 1.5562; mp. 41–43 C; H-NMR (CCl4, 60 MHz) δ 1.47 3 4 31 (dd, 3H, JCH3-H = 6.9 Hz, JCH3-P = 2.9 Hz, 4-CH3); P-NMR (C6H6) δ 43.8. Anal. Calcd. for C4H8O2PSBr: C, 20.79; H, 3.49; P, 13.41. Found: C, 20.81; H, 3.43; P, 13.14.

3.2.3. Reaction of Cyclic Phosphorothioic Acid trans-9 with Phosphorus Pentachloride To phosphorus pentachloride (1.04 g, 5 mmol) suspended in benzene (25 mL), thioacid trans-9 (0.84 g, 5 mmol) was added dropwise at 0–5 ◦C. The reaction mixture was stirred for 1 h at this temperature and for the next 1 h at room temperature. After removal of volatile reaction products, the residue was analysed by 31P-NMR spectra. Based on the chemical shift values, intensity and shape of the P resonance signals, three compounds were identiﬁed as being the reaction products:

(1) thiophosphoryl chloride trans-6(Cl), 60%, δP 59.0 ppm; (2) thiophosphoryl chloride trans-5(Cl), 14%, δP 3.5 ppm; (3) unsymmetrical dithiopyrophosphate trans-cis-10, 21%, δP 45.7 and 50.0 ppm. Distillation of the above mixture under reduced pressure gave 0.37g (40% yield) of ◦ 20 trans-6(Cl), bp.78 C (0.05 mmHg), nD 1.5218.

3.2.4. Reaction of Cyclic Phosphorothioic Acid cis-9 with Phosphorus Pentachloride

According to the procedure described above thioacid cis-9 (0.84 g, 5 mmol) and PCl5 (1.04 g, 5 mmol) gave the crude reaction product, which according to 31P-NMR spectra consisted of three compounds:

1) thiophosphoryl chloride cis-6(Cl), 60%, δP 58.0 ppm; 2) thiophosphoryl chloride trans-6(Cl), 21%, δP 59.0 ppm; 3) unsymmetrical dithiopyrophosphate trans-cis-10, 19%, δP 45.7 and 50.0 ppm. Upon fractional distillation a fraction boiling at 74 ◦C (0.05 mmHg) was collected, which contained cis-6(Cl) (95%) and trans-6(Cl) (5%); 0.30 g (32% yield).

3.2.5. Trans-2-Fluoro-4-methyl-1,3,2-dioxaphosphorinan 11 To chlorophosphite 7 (7.72 g, 50 mmol), antimony triﬂuoride (8.94 g, 50 mmol) was added portion wise at a temperature around 0–5 ◦C. The reaction mixture was then stirred at 45 ◦C for 0.5 h and distilled to give 6g (88% yield) of trans-ﬂuorophosphite 11 containing ◦ 20 1 5% of cis-11; bp. 38 C (11 mmHg); nD 1.4165. H-NMR (CCl4, 80 MHz) δ 1.26 (d, 3H, 3 31 JCH3-H = 6.2 Hz, CH3), 1.9 (m, 2H, CH2 at C5); 4.2 (m, 3H, H at C4, CH2 at C6); P-NMR Molecules 2021, 26, 3655 26 of 30

1 1 (C6H6) δ 118.8 ( JP-F = 1156 Hz, trans-11); 120.0 ( JP-F = 1178 Hz, cis-11) Anal. Calcd. for C4H8PF: C, 34.89; H, 5.84; P, 22.43. Found: C, 34.88; H, 5.78; P, 22.85.

3.2.6. Cis-2-Fluoro-4-methyl-1,3,2-dioxaphosphorinan-2-thione 6(F) To a solution of trans-ﬂuorophosphite 11 (4.14 g, 30 mmol) in ether (20 mL), acetylsulfenyl chloride (3.32 g, 30 mmol) was added dropwise at a temperature around 0 ◦C and for additional 1 h at room temperature. After removal of solvent, the crude reaction product was distilled under reduced pressure to give 5.1 g (80% yield) of cis-6(F) (895% dp), which after solidification was recrystallized from petroleum ether: bp. 61 ◦C 20 ◦ 1 (0.1 mmHg); nD 1.4770; mp. 33–34 C(cis-6(F)); H-NMR (CDCl3, 80 MHz) δ 1.46 (dd, 3H, 3 4 31 1 JCH3-H = 6.2 Hz, JCH3-P = 2.6 Hz, CH3); P-NMR (CH3CN, 24.3 MHz) δ 54.0 ( JP-F = 1086 Hz). Anal. Calcd. for C4H8O2PSF: C, 28.23; H, 4.74; P, 18.20. Found C, 28.17; H, 4.85; P, 17.97.

3.2.7. Trans-2-Fluoro-4-methyl-1,3,2-dioxaphosphorinan-2-thione 6(F) Thiophosphoryl bromide trans-6(Br) (1.14 g, 5 mmol) was dissolved in acetonitrile (10 mL) and stirred with ammonium ﬂuoride (1.48 g, 5 mmol) at 40 ◦C. Progress of the bromide–ﬂuoride exchange was controlled by 31P-N MR spectra. After 24 h and standard isolation procedure, the crude reaction product was distilled under reduced pressure to give 0.40 g (44% yield) of trans-6(F) with 94% diastereomeric purity: bp. 80 ◦C (0.005 mmHg); 20 1 nD 1.4874. Trans-6(F) with 100% dp was obtained by preparative gas chromatography. H- 3 4 4 NMR (CDCl3, 80 MHz) δ 1.48 (dt, 3H, JCH3-H = 6.5 Hz, JP-CH3 = 0.9 Hz, JCH3-H = 0.9 Hz); 31 1 P-NMR (CH3CN, 24.3 MHz) δ 55.0 ( JP-F = 1094 Hz).

3.2.8. General Procedure for Alkaline Hydrolysis of 2-Halogeno-4-methyl-1,3,2-dioxaphosphorinan-2-thiones 6(Cl,Br,F) To sodium hydroxide (0.4 g, 10 mmol) dissolved in water (20 mL) and dioxane (13 mL), cyclic thiophosphoryl halogenide 6 (5 mmol, 0.85, 0.93, 1.16 g for Cl, Br and F, respectively) in dioxane (5 mL) was added dropwise at 0 ◦C. The reaction mixture was stirred for 2 h at room temperature. After removal of water and dioxane, hot acetone was added to the residue. Then, the organic phase was ﬁltered, concentrated and analyzed by 31P-NMR spectra. The sodium salts of diastereomeric thioacids 9 were converted via free thioacids to the corresponding dicyclohexyl ammonium salt. Their ratio was determined from proton decoupled 31P-NMR spectra. The following chemical shifts were recorded for the salts of thioacids 9: cis-9Na, δP = 54.0 ppm; trans-9Na, δP = 50.5 ppm; trans-9DCHAH, δP = 50.5 ppm; cis-9DCHAH, δP = 53.5 ppm, and were in agreement with the literature data [15,19]. Hydrolysis of trans-6(Cl) is exemplifying the above general procedure.

3.2.9. Alkaline Hydrolysis of 2-Chloro-4-methyl-1,3,2-dioxaphosphorinan-2-thione 6(Cl) Thiophosphoryl chloride trans-6(Cl) (0.94 g, 5 mmol) in dioxane (5 mL) was added dropwise to a solution of sodium hydroxide (0.4 g, 10 mmol) in water (25 mL) and dioxane (15 mL) at a temperature of about 2 ◦C. The reaction mixture was stirred for 2 h at room temperature. After evaporation of solvents in vacuo, the solid residue was dissolved in hot acetone. Then, the ﬁltered solution was evaporated to give the sodium salts of trans-9Na and cis-9Na in a ratio of 92:8. The sodium salts obtained were dissolved in water (5 mL) and added to a solution of 25% hydrochloric acid. The water phase was extracted with CHCl3 (4 × 5 mL), dried over MgSO4 and evaporated to give the crude thioacid9. It was dissolved in ether and dicyclohexylamine was added. After removal of ether, the crude dicyclohexylammonium salt, trans-9DCHAH, was obtained (1.35 g, 80% yield) with 92% ◦ 31 diastereomeric purity, mp. 206–210 C; P-NMR (C6H6, 24.3 MHz) δ 50.5 (δP 53.5 for cis-salt). Anal. Calcd. for C16H32O3PSN: C, 54.99; H, 9.23; P, 8.86. Found: C, 55.07; H, 9.38; P, 8.92. Molecules 2021, 26, 3655 27 of 30

3.2.10. General Procedure for Methanolysis of 2-Halogeno-4-methyl-1,3,2-dioxaphosphorinan-2-thiones 6(Cl,Br,F) To a solution of sodium methoxide (0.069 g, 3 mmol Na, in methanol, 7 mL) in benzene (20 mL) (or CH3CN and DMF), cyclic thiophosphoryl halogenide 6 (3 mmol, 0.51, 0.56, 0.69 g for Cl, Br and F, respectively) was added at ca. 0 ◦C. The reaction mixture was stirred for an additional 2 h. Sodium halogenide that precipitated was removed by washing the reaction solution, and it was then dried and evaporated. The residue was analyzed by 31P-NMR to determine the ratio of the diastereomeric methyl esters 12 formed (trans-12, δP = 63.5 ppm, cis-12, δP = 61.5 ppm). The pure esters 12 were obtained by distillation under reduced pressure. Methanolysis of trans-6(Cl) exempliﬁes the above general procedure.

3.2.11. Methanolysis of 2-Chloro-4-methyl-1,3,2-dioxaphosphorinan-2-thione 6(Cl) To a solution of sodium methoxide (0.069 g, 3 mmol in methanol, 1.7 mL), cyclic thiophosphoryl chloride trans-6(Cl) (0.56 g, 3 mmol) in benzene (75 mL) was added dropwise at around 0–5 ◦C. The reaction mixture was stirred for 2 h. The reaction solution was washed with a few mL of water, then dried and evaporated. The 31P-NMR spectrum of the residue revealed the presence of trans-ester 12 and cis-ester 12 in a ratio of 93:7. Distillation of the crude product gave 0.38 g (70% yield) of analytically pure ester 12 (mixture of trans- and ◦ 20 cis- isomers): bp. 78–80 C (0.3 mmHg), nD 1.4923. Anal. Calcd. for C5H11O3PS: C, 32.96; H, 6.08; P, 17.00. Found: C, 32.47; H, 6.00; P, 17.00.

3.2.12. General Procedure for Aminolysis of 2-Halogeno-4-methyl-1,3,2-dioxaphosphorinan-2-thiones 6(Cl,Br,F) To a solution of dimethylamine (1.13 g, 25 mmol) in ether (25 mL), cyclic thiophospho- rylhalogenide 6 (10 mmol, 1.87, 2.31, 1.70 g for Cl, Br and F, respectively, in ether, 15 mL) was added dropwise at ca. 0 ◦C. The reaction mixture was stirred for 1 h. The precipitated dimethylammonium halogenide was filtered off. The filtrate was evaporated and the crude product was analyzed by gas chromatography. Aminolysis of trans-6(Cl) exemplifies the above general procedure.

3.2.13. Aminolysis of 2-Chloro-4-methyl-1,3,2-dioxaphosphorinan-2-thione 6(Cl) To a solution of dimethylamine (1.1 g, 25 mmol) in ether (25 mL), cyclic thiophosphoryl chloride trans-6(Cl) was added dropwise at 0 ◦C. After stirring the reaction mixture for 1 h the precipitated ammonium chloride was ﬁltered off and the ﬁltrate evaporated. Distillation of the crude reaction product gave the pure amide trans-13 (1.6 g, 76% yield): bp. 60◦C 20 ◦ (0.05 mmHg), nD 1.5031, mp. 35–36.5 C, δP = 75.0 ppm. Anal. Calcd. for C6H14O2PSN: C, 36.91; H, 7.25; P, 15.87. Found: C, 37.15; H, 7.00; P, 16.04.

3.2.14. Synthesis of 2-N,N-Dimethylamino-4-methyl-1,3,2-dioxaphosphorinan-2-thione 13 To a solution of cyclic amidophosphite 14 (cis-14, 80% and trans-14, 20%) (5,5 g, 33 mmol) in ether (20 mL), elemental sulfur (1.1 g, 33 mmol) was added at 0 ◦C. After stirring for 1 h, ether was evaporated and the crude product was distilled under reduced pressure to afford 4.9 g (74% yield) of trans-13 82% dp (GC assay): bp. 65 ◦C (0.05 mmHg), 20 nD 1.5030, δP = 75.0 ppm. Anal. Calcd. for C6H14NO2PS: C, 36.91; H, 7.23; P, 15.87. Found: C, 37.20; H, 7.40; P, 15.82.

3.2.15. Theoretical Methods All quantum mechanical calculations were performed using the Gaussian 16 suite of programs [39]. Geometries of the model compounds were optimized using two DFT methods: the hybrid B3LYP density functional [40] corrected for dispersion interactions using Grimme GD3 empirical term [41], with the Def2TZVP basis set [42] in aqueous solution. SCRF calculations in water were performed using CPCM model with UFF atomic radii as implemented in Gaussian 16 [39]. All stationary points were identiﬁed as stable minima by frequency calculations. The vibrational analysis provided thermal enthalpy Molecules 2021, 26, 3655 28 of 30

and entropy corrections at 298 K within the rigid rotor/harmonic oscillator/ideal gas approximation [39]. Thermochemical corrections were scaled by a factor of 0.99.

Supplementary Materials: The following are available online, Figure S1: Geometries of trans and cis isomers of 2-chloro-4-methyl-1,3,2-dioxaphosphorinan-2-thione 6(Cl); green—chlorine, orange— phosphorus, yellow—sulfur, red—oxygen, grey—carbon, white—hydrogen, Table S1: Relative Gibbs free energies (kcal/mol) of the most stable conformers of cis- and trans-2-chloro-4-methyl- 1,3,2-dioxaphosphorinan-2-thione 6(Cl) (for structures see Figure S1), Figure S2: Geometries of cis and trans conformers of 2-fluoro-4-methyl-1,3,2-dioxaphosphorinan-2-thione 6(F); cyan—fluorine, remaining colours as in Figure S1, Table S2: Relative Gibbs free energies (kcal/mol) of all isomers of 2-fluoro-4-methyl-1,3,2-dioxaphosphorinan-2-thione 6(F) (for structures see Figure S2), Figure S3: Structures of cis and trans conformers of 2-hydroxy-4-methyl-1,3,2-dioxaphosphorinan-2-thione 9, Table S3: Relative Gibbs free energies (kcal/mol) of all isomers of 2-hydroxy-4-methyl-1,3,2- dioxaphosphorinan-2-thione 9 (for structures see Figure S3). Figure S4: Crystal (a) and DFT (b) structures of cis-2-fluoro-4-methyl-1,3,2-dioxaphosphorinan-2-thione 6(F), Table S4: Comparison of X-ray [24] and DFT selected structural parameters for cis-2-fluoro-4-methyl-1,3,2-dioxaphosphorinan- 2-thione 6(F) (bond distances in Å, angles in deg), Figure S5 and S6: Stationary points for the backside attack of hydroxyl anion on chlorothiophosphorinan 6(Cl), Table S5: Free energies relative to the sum of the free energies of free substrates for the reaction of trans- and cis-2-chloro-4-methyl-1,3,2- dioxaphosphorinan-2-thione 6(Cl) with OH−, Figure S7: Total free energy profiles(kcal/mol) for the three reaction pathways (a, b, c—see main text) of fluoride substitution in cis-6(F) (path b appears in two variants which differ only slightly, so the plots overlap each other). Author Contributions: Idea for the project and this paper, preparation of the manuscript and final edition M.M. and M.C.; experimental work B.Z.; NMR spectra J.K.; computations B.G. and M.C. All authors have read and agreed to the published version of the manuscript. Funding: This research received no external funding. Institutional Review Board Statement: Not applicable. Informed Consent Statement: Not applicable. Data Availability Statement: The data presented in this study are available on request from the corresponding author. Acknowledgments: This research (DFT calculations) was supported in part by PL-Grid Infrastructure. Conflicts of Interest: The authors declare no conflict of interest. Sample Availability: Samples of compounds are not available from the authors.

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