Access to 2-Fluorinated Aziridine-2-phosphonates from α,α-Halofluorinated β-Iminophosphonates—Spectroscopic and Theoretical Studies

The efficient one-pot halofluorination of a β-enaminophosphonate/β-iminophosphonate tautomeric mixture resulting in α,α-halofluorinated β-iminophosphonates is reported. Subsequent imine reduction gave the corresponding β-aminophosphonates as a racemic mixture or with high diastereoselectivity. The proposed protocol is the first example of a synthesis of N-inactivated aziridines substituted by a fluorine and phosphonate moiety on the same carbon atom. Based on spectroscopic and theoretical studies, we determined the cis/trans geometry of the resulting fluorinated aziridine-2-phosphonate. Our procedure, involving the reduction of cis/trans-fluoroaziridine mixture 24, allows us to isolate chiral trans-aziridines 24 as well as cis-aziridines 27 that do not contain a fluorine atom. We also investigated the influence of the fluorine atom on the reactivity of aziridine through an acid-catalyzed regioselective ring-opening reaction. The results of DFT calculations, at the PCM/ωB97x-D/def2-TZVPD level of theory, are in good agreement with the experiments. The transition states of the SN2 intramolecular cyclization of vicinal haloamines have been modeled.

Among the commonly encountered substituents in aziridine systems, heteroatoms or heteroatom-based groups, such as fluorine or phosphonates are of special interest [8,14,[19][20][21][22][23][24][25]. Incorporating electronegative fluorine atoms in organic molecules often dramatically influences the physical and biological properties of the parent compounds [26][27][28][29][30][31][32][33]. Furthermore, the presence of fluorine has been reported to have profound effects on the reactivity of aziridines and the regioselectivity of ring-opening reactions. For instance, the reaction of Nsubstituted 2,2-difluorinated aziridines with aqueous HCl or MeONa in methanol led to αchloroacetamides [34,35] or α-methoxyacetamide [34], respectively. The nucleophilic attack occurs preferentially from the less-hindered side. It is important to note that exposure of 2,2-difluorinated aziridines to moist air results in the formation of α-fluoroacetamides [35]. In contrast, when 2-monofluoro aziridines are subjected to gaseous HCl or sodium methoxide, they provides access to 2-chloro-2-fluoroamines or 2,2-dimethoxyethylamine [34]. This reaction occurs from the ring opening at the more hindered position of aziridine ring. As a comparison, Konev et al. reported the transformation of 2-fluoro aziridine to fluorinated at the more hindered position of aziridine ring. As a comparison, Konev et al. reported the transformation of 2-fluoro aziridine to fluorinated propargyl amines through αformation of a fluoro imine intermediate [36]. These findings suggest that fluorinated aziridines, owing to the ring strain and the presence of fluorine atom, can be regarded as valuable reagents for the synthesis of nitrogen-containing compounds. On the other hand, the presence of a phosphonate function on aziridine also induces interesting behaviors. 2-Phosphonoaziridine derivatives have been recognized for their biological properties ( Figure 1). The cyanoaziridinylphosphonate A has exhibited antiproliferative activity (in vitro) against human cancer cell lines derived from human lung adenocarcinoma (A549 strain, IC50 = 1.5 ± 0.84 µM) [37]. Additionally, N-functionalized 2-phosphonoaziridines B and C displayed moderate activity against the bacteria E. coli, and Kocuria spp. (Fs24) [38], as well as moderate antifungal activity against C. albicans ATCC 10,231 (MIC 12.5 µg/mL), respectively [39]. In comparison, the aziridynyl 2-phosphonic acid monoester D is less active than the diester counterparts, and exhibited moderate or low antibacterial activity against E. coli, K. pneumoniae, A. baumanii, and P. aeruginosa [40]. Moreover, racemic series of 1-alkoxycarbonyl-2-phosphonoaziridine E have also been found to possess antibacterial activity [41]. Furthermore, the presence of a phosphonate group attached to the aziridine ring offers a promising pathway for the synthesis of aminophosphonic acids and their derivatives [22][23][24][42][43][44][45]. Aminophosphonates structurally and functionally mimic the amino acids. The tetrahedral phosphonic acid is an effective surrogate of the planar carboxylic group, making them attractive targets for the development of biologically active compounds [32,33,[46][47][48][49][50][51][52].
In a recent study, we successfully achieved the diastereoselective synthesis of fluorinated piperidine phosphonates from N-substituted hydroxyphosphonates derived from proline [53]. The fluorination occurred through an aziridinium intermediate F, and subsequent ring opening, resulting in ring expansion G ( Figure 2). The diastereoselectivity of the deoxyfluorination process appeared to depend on the combination of neighboring group and bulky phosphonate influences, among other factors. Motivated by these findings, we decided to apply our protocol [54] to the synthesis of a series of N-substituted α-halofluorinated aminophosphonates 16-21. Both achiral and optically active aziridinylphosphonates 24-26 could be potentially obtained. Additionally, we will form optically enriched aminophosphonates H through the selective aziridine ring opening ( Figure 2).  Furthermore, the presence of a phosphonate group attached to the aziridine ring offers a promising pathway for the synthesis of aminophosphonic acids and their derivatives [22][23][24][42][43][44][45]. Aminophosphonates structurally and functionally mimic the amino acids. The tetrahedral phosphonic acid is an effective surrogate of the planar carboxylic group, making them attractive targets for the development of biologically active compounds [32,33,[46][47][48][49][50][51][52].
In a recent study, we successfully achieved the diastereoselective synthesis of fluorinated piperidine phosphonates from N-substituted hydroxyphosphonates derived from proline [53]. The fluorination occurred through an aziridinium intermediate F, and subsequent ring opening, resulting in ring expansion G ( Figure 2). The diastereoselectivity of the deoxyfluorination process appeared to depend on the combination of neighboring group and bulky phosphonate influences, among other factors. Motivated by these findings, we decided to apply our protocol [54] to the synthesis of a series of N-substituted αhalofluorinated aminophosphonates 16-21. Both achiral and optically active aziridinylphosphonates 24-26 could be potentially obtained. Additionally, we will form optically enriched aminophosphonates H through the selective aziridine ring opening ( Figure 2). at the more hindered position of aziridine ring. As a comparison, Konev et al. reported the transformation of 2-fluoro aziridine to fluorinated propargyl amines through αformation of a fluoro imine intermediate [36]. These findings suggest that fluorinated aziridines, owing to the ring strain and the presence of fluorine atom, can be regarded as valuable reagents for the synthesis of nitrogen-containing compounds. On the other hand, the presence of a phosphonate function on aziridine also induces interesting behaviors. 2-Phosphonoaziridine derivatives have been recognized for their biological properties ( Figure 1). The cyanoaziridinylphosphonate A has exhibited antiproliferative activity (in vitro) against human cancer cell lines derived from human lung adenocarcinoma (A549 strain, IC50 = 1.5 ± 0.84 µM) [37]. Additionally, N-functionalized 2-phosphonoaziridines B and C displayed moderate activity against the bacteria E. coli, and Kocuria spp. (Fs24) [38], as well as moderate antifungal activity against C. albicans ATCC 10,231 (MIC 12.5 µg/mL), respectively [39]. In comparison, the aziridynyl 2-phosphonic acid monoester D is less active than the diester counterparts, and exhibited moderate or low antibacterial activity against E. coli, K. pneumoniae, A. baumanii, and P. aeruginosa [40]. Moreover, racemic series of 1-alkoxycarbonyl-2-phosphonoaziridine E have also been found to possess antibacterial activity [41]. Furthermore, the presence of a phosphonate group attached to the aziridine ring offers a promising pathway for the synthesis of aminophosphonic acids and their derivatives [22][23][24][42][43][44][45]. Aminophosphonates structurally and functionally mimic the amino acids. The tetrahedral phosphonic acid is an effective surrogate of the planar carboxylic group, making them attractive targets for the development of biologically active compounds [32,33,[46][47][48][49][50][51][52].
In a recent study, we successfully achieved the diastereoselective synthesis of fluorinated piperidine phosphonates from N-substituted hydroxyphosphonates derived from proline [53]. The fluorination occurred through an aziridinium intermediate F, and subsequent ring opening, resulting in ring expansion G ( Figure 2). The diastereoselectivity of the deoxyfluorination process appeared to depend on the combination of neighboring group and bulky phosphonate influences, among other factors. Motivated by these findings, we decided to apply our protocol [54] to the synthesis of a series of N-substituted α-halofluorinated aminophosphonates 16-21. Both achiral and optically active aziridinylphosphonates 24-26 could be potentially obtained. Additionally, we will form optically enriched aminophosphonates H through the selective aziridine ring opening ( Figure 2
by HSQC, HMBC, and 2D NOESY experiments. For instance, the 2D H-H NOESY experiment of 14a indicated significant correlations between the proton -CH(CH3)Ph from the (S)-MBn group and the ortho proton from the phenyl ring located at imine carbon -NC(Ph)CFP (see the Supporting Information for details). On the other hand, for α,αdifluorinated β-iminophosphonate analogs, the through-space interactions of PG (benzylic) protons and one of the fluorine atoms indicated the major formation of the Zstereoisomer [54]. Long-range F-H intramolecular nonbonding interactions have also been observed in the case of (Z)-N-tetrafluoropropenyl-uracil/thymine derivatives and αfluorinated imines [35,58]. Moreover, it is worth noting that less than 10% of difluoro, dibromo, or dichloro derivatives were also formed during the reaction. They can be removed by column chromatography. Only in the case of 5a/9a,b tautomers was it necessary to purify the crude reaction mixture due to the formation of impurities in the subsequent step.
We observed that the reduction of 10-11,14a,b substituted by the chiral (S) or (R)-αmethylbenzyl groups resulted in asymmetric induction, yielding aminophosphonates 16-17,20a-d with high diastereoselectivity. The configuration of the new stereogenic C-2carbon center strongly depends on a chiral protecting group (C-1′). The favorable hydride anion attack occurs from the least hindered face of the imine rigidified by an intramolecular hydrogen bond, which according to the Houk model ( Figure 3A), yields 16a-d as a diastereomeric mixture (dr 1:1:0.1:0.07) predominantly containing two major (presumably 1′S, 1R, 2R and 1′S, 1S, 2R) and two minor (1′S, 1S, 2S, and 1′S, 1R, 2S) isomers. The diastereoselection only depends on steric factors between C-H moiety, which eclipses the double bond of imine, and the methyl group and phenyl ring derived from the (S)-MBn protecting group [62]. Transformations of imines containing this particular protecting group frequently led to asymmetric induction in different types of nucleophilic addition to the imine C=N bond [54,[63][64][65]. In comparison, the reduction of rac-12-13,15 which have achiral protecting groups (PMB or PMP) leads to aminophosphonates rac-18-19,21a,b as the mixture of two diastereomers, with a slight preference for one isomer and a dr ratio ranging from 1:0.7 for rac-18,21a,b to 1:0.88 for rac-19a,b. For the major diastereomer, the hydride addition to C=N occurs from the most unhindered side with the most electronegative group (F) perpendicular to the imine bond and the system We observed that the reduction of 10-11,14a,b substituted by the chiral (S) or (R)α-methylbenzyl groups resulted in asymmetric induction, yielding aminophosphonates 16-17,20a-d with high diastereoselectivity. The configuration of the new stereogenic C-2carbon center strongly depends on a chiral protecting group (C-1 ). The favorable hydride anion attack occurs from the least hindered face of the imine rigidified by an intramolecular hydrogen bond, which according to the Houk model ( Figure 3A), yields 16a-d as a diastereomeric mixture (dr 1:1:0.1:0.07) predominantly containing two major (presumably 1 S, 1R, 2R and 1 S, 1S, 2R) and two minor (1 S, 1S, 2S, and 1 S, 1R, 2S) isomers. The diastereoselection only depends on steric factors between C-H moiety, which eclipses the double bond of imine, and the methyl group and phenyl ring derived from the (S)-MBn protecting group [62]. Transformations of imines containing this particular protecting group frequently led to asymmetric induction in different types of nucleophilic addition to the imine C=N bond [54,[63][64][65]. In comparison, the reduction of rac-12-13,15 which have achiral protecting groups (PMB or PMP) leads to aminophosphonates rac-18-19,21a,b as the mixture of two diastereomers, with a slight preference for one isomer and a dr ratio ranging from 1:0.7 for rac-18,21a,b to 1:0.88 for rac-19a,b. For the major diastereomer, the hydride addition to C=N occurs from the most unhindered side with the most electronegative group (F) perpendicular to the imine bond and the system stiffened by an intramolecular H-bond ( Figure 3B) [66,67]. Analogous diastereoselectivity has also been observed during the synthesis of fluorinated epoxy alkylphosphonate from α-fluoro-β-keto alkylphosphonates [53]. Based on these data, we temporarily established the stereochemistry of major 18-19,21a as rac 1R, 2R and the minor isomers 18-19,21b as rac 1R,2S (e.g., 1R,2S/1S,2R). The stereochemical hydride addition to the imine C=N bond, based on the proposed Houk model ( Figure 3A) for 10a,b and the Felkin-Anh model ( Figure 3B) for rac-12,13 leading to major diastereomers is presented on Figure 3.  Figure 3B) [66,67]. Analogous diastereoselectivity has also been observed during the synthesis of fluorinated epoxy alkylphosphonate from α-fluoro-β-keto alkylphosphonates [53]. Based on these data, we temporarily established the stereochemistry of major 18-19,21a as rac 1R, 2R and the minor isomers 18-19,21b as rac 1R,2S (e.g., 1R,2S/1S,2R). The stereochemical hydride addition to the imine C=N bond, based on the proposed Houk model ( Figure 3A) for 10a,b and the Felkin-Anh model ( Figure 3B) for rac-12,13 leading to major diastereomers is presented on Figure 3.  Table 2. Among the tested conditions, the combination of sodium cyanoborohydride and acetic acid (entry 1, Table 2) for the imines 10a,b reduction gave the highest yield (97%) of 16a-d, (dr 1:1:0.1:0.07). On the contrary, the use of BH3 . THF furnished the highest diastereoselectivity with a dr of 1:0.25:ca.0:ca.0 and a high yield of 91% (entry 4, Table 2). However, changing borane to BH3 × S(CH3)2 resulted in a drastic decrease in yields to 47% with a dr of 1:0.20:ca.0:ca.0 (entry 5, Table 2). When rac-12 was reacted with NaBH3CN/HOAc, rac-18a,b was obtained with a predominance of one diastereomer (dr 1:0.7) and a yield of 97% (entry 8, Table 2). Chiral organic acid (1S)-(+)-CSA activation gave the amine 83% yield and a dr of 1:0.74 (entry 10, Table 2). Furthermore, the reaction with Lewis acid CeCl3 and NaBH3CN (entry 9, Table 2) led to higher diastereoselectivity, yielding rac-18a,b with a dr of 1:0.5 (85% yield). As previously mentioned, the diastereoselectivity of the E-imine reduction strongly depended on the nature of the nitrogen-substituent. The hydride addition to rac-13 (PG = 4methoxyphenyl) gave a poor selectivity of rac-19a,b with a dr of 1:0.88 (entry 11, Table 2), while higher diastereoselectivity was observed with the 4-methoxybenzyl (PMB) group, leading to rac-18a,b with a dr of 1:0.70) (entry 8, Table 2). Moreover, replacing the bromine atom by a chlorine atom (14a,b, rac-15) did not significantly affect the yields nor diastereomeric ratios (entry 12-13, Table 2).   Table 2. Among the tested conditions, the combination of sodium cyanoborohydride and acetic acid (entry 1, Table 2) for the imines 10a,b reduction gave the highest yield (97%) of 16a-d, (dr 1:1:0.1:0.07). On the contrary, the use of BH 3 . THF furnished the highest diastereoselectivity with a dr of 1:0.25:ca.0:ca.0 and a high yield of 91% (entry 4, Table 2). However, changing borane to BH 3 × S(CH 3 ) 2 resulted in a drastic decrease in yields to 47% with a dr of 1:0.20:ca.0:ca.0 (entry 5, Table 2). When rac-12 was reacted with NaBH 3 CN/HOAc, rac-18a,b was obtained with a predominance of one diastereomer (dr 1:0.7) and a yield of 97% (entry 8, Table 2). Chiral organic acid (1S)-(+)-CSA activation gave the amine 83% yield and a dr of 1:0.74 (entry 10, Table 2). Furthermore, the reaction with Lewis acid CeCl 3 and NaBH 3 CN (entry 9, Table 2) led to higher diastereoselectivity, yielding rac-18a,b with a dr of 1:0.5 (85% yield). As previously mentioned, the diastereoselectivity of the E-imine reduction strongly depended on the nature of the nitrogen-substituent. The hydride addition to rac-13 (PG = 4-methoxyphenyl) gave a poor selectivity of rac-19a,b with a dr of 1:0.88 (entry 11, Table 2), while higher diastereoselectivity was observed with the 4-methoxybenzyl (PMB) group, leading to rac-18a,b with a dr of 1:0.70) (entry 8, Table 2). Moreover, replacing the bromine atom by a chlorine atom (14a,b, rac-15) did not significantly affect the yields nor diastereomeric ratios (entry 12-13, Table 2). The diastereoselectivity of reduction was assessed by spectral analysis of products. The diastereomers of amines 16-17,20a-d, and not chiral (±)-like and (±)-unlike stereoisomers rac-18-19,21a,b were distinguished based on their respective vicinal 3 J FH coupling Molecules 2023, 28, 5579 6 of 31 constants, which depend on the Karplus equation [56,68]. The β-aminophosphonates and their acids can exist in CDCl 3 in major "frozen" chair-like conformation, due to an intramolecular hydrogen bonding between the amino group and the phosphoryl group ( Figure 4) [69]. The (±)-unlike isomer ( Figure 4A) presented two conformations where the more stable one presented an anti-periplanar H-F arrangement ( 3 J FH~2 0 Hz, Figure 4B), while the minor one is a gauche-conformation ( 3 J FH~1 0 Hz, Figure 4C) [54,56]. By contrast, the two conformations of the (±)-like isomer ( Figure 4D) only presented gauche-orientations ( Figure 4E,F). Furthermore, due to the bulkiness of the phenyl and phosphonate groups (both likely in anti-position), we attributed the configuration of 16a as 1 S, 1R, 2R and for 16b as 1 S, 1S, 2R, while the major or minor isomers of rac-18-19, 21 were assigned as rac-1R, 2R or rac-1R, 2S, respectively. The diastereoselectivity of reduction was assessed by spectral analysis of products. The diastereomers of amines 16-17,20a-d, and not chiral (±)-like and (±)-unlike stereoisomers rac-18-19,21a,b were distinguished based on their respective vicinal 3 JFH coupling constants, which depend on the Karplus equation [56,68]. The βaminophosphonates and their acids can exist in CDCl3 in major "frozen" chair-like conformation, due to an intramolecular hydrogen bonding between the amino group and the phosphoryl group ( Figure 4) [69]. The (±)-unlike isomer ( Figure 4A) presented two conformations where the more stable one presented an anti-periplanar H-F arrangement ( 3 JFH ~20 Hz, Figure 4B), while the minor one is a gauche-conformation ( 3 JFH ~10 Hz, Figure  4C) [54,56]. By contrast, the two conformations of the (±)-like isomer ( Figure 4D) only presented gauche-orientations ( Figure 4E,F). Furthermore, due to the bulkiness of the phenyl and phosphonate groups (both likely in anti-position), we attributed the configuration of 16a as 1′S, 1R, 2R and for 16b as 1′S, 1S, 2R, while the major or minor isomers of rac-18-19, 21 were assigned as rac-1R, 2R or rac-1R, 2S, respectively. On the other hand, apart from the vicinal H-F coupling constant values between fluorine and hydrogen nuclei and the [N-H… . O=P(OEt)2] hydrogen bond, it was necessary to take into account the electrostatic interactions between C-F and N-H in relation to the structure of each conformer.

Conformational Analysis of α,α-Halofluorinated ß-Aminophosphonates by DFT Calculations
To explain the differences in H-F coupling constants, and to confirm the relative configuration of stereogenic centers for both β-aminophosphonate diastereomers 16a and 16b, a conformational analysis was conducted using the PCM/ωB97x-D/def2-TZVPD level of theory. To simplify the calculations, the ethoxy groups were substituted with methoxy groups, and the PG group was replaced with a methyl group ( Figure 5 A-F 1-2). The potential conformations for both diastereomers (16a' or 16b') were clustered into three groups corresponding to three distinct arrangements of the C(β)H-C(α)F single bond: A, B, and C for 16a', or D, E, and F for 16b'. ( Figure 5) All structures were drawn in the chair-

Conformational Analysis of α,α-Halofluorinated ß-Aminophosphonates by DFT Calculations
To explain the differences in H-F coupling constants, and to confirm the relative configuration of stereogenic centers for both β-aminophosphonate diastereomers 16a and 16b, a conformational analysis was conducted using the PCM/ωB97x-D/def2-TZVPD level of theory. To simplify the calculations, the ethoxy groups were substituted with methoxy groups, and the PG group was replaced with a methyl group ( Figure 5 A-F 1-2). The potential conformations for both diastereomers (16a' or 16b') were clustered into three groups corresponding to three distinct arrangements of the C(β)H-C(α)F single bond: A, B, and C for 16a', or D, E, and F for 16b'. ( Figure 5) All structures were drawn in the chair-like representation to show the conformations of all relevant bonds. The most thermodynamically stable conformations within each group were labeled with the number 1 (A1-F1), while geometries labeled with the number 2 (A2-F2) were selected for comparative purposes. All energies presented were calculated in reference to the most stable conformer B1, which possessed the lowest energy.
like representation to show the conformations of all relevant bonds. The most thermodynamically stable conformations within each group were labeled with the number 1 (A1-F1), while geometries labeled with the number 2 (A2-F2) were selected for comparative purposes. All energies presented were calculated in reference to the most stable conformer B1, which possessed the lowest energy. The B1 geometry with the H-F atoms of the C(β)H-C(α)F bond in the gauche position was determined to be the most favorable conformation for 16a'. Moreover, the most stable conformation for 16b' was the E1 conformation (+ 0.6 kcal/mol), where the vicinal H-F atoms were anti. These results are in good agreement with the experimental NMR coupling constants: 3 JHF ~10 Hz and 3 JH-F ~22 Hz for 16a' and 16b', respectively. Analyzing the relative energies of the conformers depicted in Figure 5, it becomes evident that the electrostatic interaction between N-H and C-Br or C-F (present in the A1, A2, B1, C2, D1, D2, E1, F2) likely plays a more significant role than the stabilization via the P=O…H-N hydrogen bonding (present in the B2, C1, E2, F1). However, in the case of C and F conformations, the preference is reversed: the geometries with the P=O…H-N hydrogen bond (C1 and F1) are more stable. This phenomenon is likely due to the phosphonate−aromatic (P=O…π) repulsive interaction [70], which destabilizes conformers C2 and F2. The same interaction explains why the most stable geometries of conformers A (A1 and A2) are the anti-arrangement of P=O/C-F, while the most stable geometries for conformers D (D1 and D2) have the anti-arrangement of P=O/C-Br ( Figure  5). As shown in Figure 6, the anti-arrangement of P=O/C-Br (conformer A1′) leads to a phosphonate−aromatic (P=O…π) repulsive interaction, resulting in an energy increase up to +3.3 kcal/mol. A similar effect can be observed for D conformations, which have the anti-arrangement of P=O/C-F (D1′). Conformations A1′' and D1′', both having the antiarrangement of P=O/C-C, are not preferred due to the unfavorable dipole-dipole interactions between P=O and C-F/C-Br occupying the gauche position ( Figure 6). The B1 geometry with the H-F atoms of the C(β)H-C(α)F bond in the gauche position was determined to be the most favorable conformation for 16a'. Moreover, the most stable conformation for 16b' was the E1 conformation (+ 0.6 kcal/mol), where the vicinal H-F atoms were anti. These results are in good agreement with the experimental NMR coupling constants: 3 J HF~1 0 Hz and 3 J H-F~2 2 Hz for 16a' and 16b', respectively. Analyzing the relative energies of the conformers depicted in Figure 5, it becomes evident that the electrostatic interaction between N-H and C-Br or C-F (present in the A1, A2, B1, C2, D1, D2, E1, F2) likely plays a more significant role than the stabilization via the P=O. . .H-N hydrogen bonding (present in the B2, C1, E2, F1). However, in the case of C and F conformations, the preference is reversed: the geometries with the P=O. . .H-N hydrogen bond (C1 and F1) are more stable. This phenomenon is likely due to the phosphonate−aromatic (P=O. . .π) repulsive interaction [70], which destabilizes conformers C2 and F2. The same interaction explains why the most stable geometries of conformers A (A1 and A2) are the anti-arrangement of P=O/C-F, while the most stable geometries for conformers D (D1 and D2) have the anti-arrangement of P=O/C-Br ( Figure 5). As shown in Figure 6, the antiarrangement of P=O/C-Br (conformer A1 ) leads to a phosphonate−aromatic (P=O. . .π) repulsive interaction, resulting in an energy increase up to +3.3 kcal/mol. A similar effect can be observed for D conformations, which have the anti-arrangement of P=O/C-F (D1 ). Conformations A1 and D1 , both having the anti-arrangement of P=O/C-C, are not preferred due to the unfavorable dipole-dipole interactions between P=O and C-F/C-Br occupying the gauche position ( Figure 6).
Furthermore, comparing the energy of A1 and A2 (or D1 and D2) reveals an equivalence in the electrostatic interaction between N-H and C-F vs. N-H and C-Br. This conclusion is also supported by comparison of geometries that differ only in the position of the -F and -Br substituents. These pairs of geometries include A1 and D1; A1 and D1 ; A1 and D1 ; A2 and D2; B1 and E1; B2 and E2; C1 and F1; and C2 and F2 (Figures 5 and 6). The small differences in stability between these structures (maximum of 0.6 kcal/mol) indicate similar effects caused by C-Br and C-F bonds on the overall energy of the molecule.
In summary, the conformational analysis described above allows us to conclude that the stability of P=O--H-N hydrogen bonding can be outweighed by the electrostatic interaction between C-F (C-Br) and N-H, unless it leads to phosphonate−aromatic (P=O. . .π) repulsive interactions. Furthermore, comparing the energy of A1 and A2 (or D1 and D2) reveals an equivalence in the electrostatic interaction between N-H and C-F vs. N-H and C-Br. This conclusion is also supported by comparison of geometries that differ only in the position of the -F and -Br substituents. These pairs of geometries include A1 and D1; A1′ and D1′; A1′' and D1′'; A2 and D2; B1 and E1; B2 and E2; C1 and F1; and C2 and F2 (Figures 5 and  6). The small differences in stability between these structures (maximum of 0.6 kcal/mol) indicate similar effects caused by C-Br and C-F bonds on the overall energy of the molecule.
In summary, the conformational analysis described above allows us to conclude that the stability of P=O--H-N hydrogen bonding can be outweighed by the electrostatic interaction between C-F (C-Br) and N-H, unless it leads to phosphonate−aromatic (P=O…π) repulsive interactions.

Aziridine Synthesis by Ring Closure Reaction
Our approach to aziridine synthesis involved the intramolecular SN2 nucleophilic substitution of a halogen atom by a vicinal amine leading to the formation 2-fluoroaziridinyl-2-phosphonates 24-26. We observed that bromofluorinated aminophosphonates 16a-d, rac- 18-19a,b, when left at room temperature, undergo spontaneous transformation into aziridines, with 50% of conversion over the course of one month. This process depends on the nature of the diastereomers. For amine 16a-d, only a pair of isomers 16b,d cyclized to form the aziridines trans-24b,d. To expedite this reaction, treatment of the ß-aminophosphonates 16a-d, rac-18-19a,b with TEA in DMF for 4 h gave a mixture of diastereomers of fluoro-aziridinylphosphonates 24a-d, rac-25-26a,b in yields ranging from 48% to 82% (Scheme 2).

Aziridine Synthesis by Ring Closure Reaction
Our approach to aziridine synthesis involved the intramolecular S N 2 nucleophilic substitution of a halogen atom by a vicinal amine leading to the formation 2-fluoro-aziridinyl-2-phosphonates 24-26. We observed that bromofluorinated aminophosphonates 16a-d, rac- 18-19a,b, when left at room temperature, undergo spontaneous transformation into aziridines, with 50% of conversion over the course of one month. This process depends on the nature of the diastereomers. For amine 16a-d, only a pair of isomers 16b,d cyclized to form the aziridines trans-24b,d. To expedite this reaction, treatment of the ßaminophosphonates 16a-d, rac-18-19a,b with TEA in DMF for 4 h gave a mixture of diastereomers of fluoro-aziridinylphosphonates 24a-d, rac-25-26a,b in yields ranging from 48% to 82% (Scheme 2). Furthermore, comparing the energy of A1 and A2 (or D1 and D2) reveals an equivalence in the electrostatic interaction between N-H and C-F vs. N-H and C-Br. This conclusion is also supported by comparison of geometries that differ only in the position of the -F and -Br substituents. These pairs of geometries include A1 and D1; A1′ and D1′; A1′' and D1′'; A2 and D2; B1 and E1; B2 and E2; C1 and F1; and C2 and F2 (Figures 5 and  6). The small differences in stability between these structures (maximum of 0.6 kcal/mol) indicate similar effects caused by C-Br and C-F bonds on the overall energy of the molecule.
In summary, the conformational analysis described above allows us to conclude that the stability of P=O--H-N hydrogen bonding can be outweighed by the electrostatic interaction between C-F (C-Br) and N-H, unless it leads to phosphonate−aromatic (P=O…π) repulsive interactions.

Aziridine Synthesis by Ring Closure Reaction
Our approach to aziridine synthesis involved the intramolecular SN2 nucleophilic substitution of a halogen atom by a vicinal amine leading to the formation 2-fluoroaziridinyl-2-phosphonates 24-26. We observed that bromofluorinated aminophosphonates 16a-d, rac- 18-19a,b, when left at room temperature, undergo spontaneous transformation into aziridines, with 50% of conversion over the course of one month. This process depends on the nature of the diastereomers. For amine 16a-d, only a pair of isomers 16b,d cyclized to form the aziridines trans-24b,d. To expedite this reaction, treatment of the ß-aminophosphonates 16a-d, rac-18-19a,b with TEA in DMF for 4 h gave a mixture of diastereomers of fluoro-aziridinylphosphonates 24a-d, rac-25-26a,b in yields ranging from 48% to 82% (Scheme 2). To enhance the rate of the cyclization reaction, an optimization was performed by testing various solvents, adjusting the base addition, and changing reaction conditions such as time and temperature (from room temperature to 70 • C). The outcomes of this screening are summarized in Table 3.
The optimization results showed that cyclization initiated by triethylamine (TEA) in N,N-dimethylformamide (entry 1, Table 3), as well in acetonitrile (entry 2, Table 3), were the most favorable for obtaining 24a-d in yields of 82% and 70%, respectively. Toluene, dichloromethane, and tetrahydrofuran (entry 3-5, Table 3) were considered as the least favorable solvents. A better pale, but still poor yield was observed, while the reaction was conducted in dimethyl carbonate (DMC) (entry 6, Table 3). When we monitored the same reaction for chlorofluorinated derivatives (20a-d) (entry 9, Table 3), only signals of substrates were detected ( 19 F, 31 P NMR). Moreover, it should be pointed out that no racemization occurred during the aziridine formation. Additionally, we observed that while two out of four amine diastereomers 16b,d and rac-18-19b (unlike-diastereomers) were readily transformed into trans-aziridine 24b,d and rac-25-26b, the conversion was not complete and the like-ones did not cyclize into cis-aziridines 24a,c and rac-25-26a. According to our observations, they underwent degradation leading to several unidentified products, which could explain the different diastereomeric ratios after reaction, with the trans-isomer being dominant. A shorter reaction time resulted in incomplete substrate conversion, while a longer reaction time influenced the formation of by-products. In addition, we noticed a particularly low stability of the cis-isomer for rac-26a (entry 8, Table 3), which can be explained by steric factors.
Moreover, we also studied the influence of a base on aziridine ratio and reaction yield ( Table 4). The reaction of 16a-d (dr 1:1:0.1:0.07), with TEA as a base in DMF at 70 • C, gave 24a-d with a cis/trans ratio of 0.78:1 (entry 1, Table 4). Without a base at 70 • C in DMF (entry 7, Table 4), the result was a low 38% yield of 24a-d, due to partial decomposition of starting material. Under the same conditions using sodium hydride, only traces of 24a-d were detected by 19 F NMR in the crude mixture (<10% yield) (entry 6, Table 4). Using quinine (entry 2, Table 4) gave the best yield of 84% for 24a-d. By contrast, DBU mainly led to the formation of monofluorinated enamine (E-22a/Z-22b ratio 1:0.3) and imine (23a,b) (22a,b/23a,b ratio 1:0.05) in 21% yield (entry 4, Table 4), while DIPEA furnished 24a-d in 70% yield and a cis/trans ratio of 0.67:1 (entry 5, Table 4). Surprisingly, the cyclization of 16a-d performed with L-proline resulted in a 77% yield of 24a-d with a cis/trans ratio of 0.69:1 (entry 3, Table 4). Selected bases (TEA, quinine, and proline) were also tested for the amine rac-18a,b (entries 8-10, Table 4), and no significant differences were observed compared to 16a-d. We have noticed that the aziridines 24a-d and rac-25-26a,b are air-stable and can be stored for several months without any sign of degradation, as confirmed by 31 P NMR analysis. Unlike the difluoroaziridines reported by De Kimpe et al., no spontaneous fluorine migration was observed [34,35]. During the purification of the crude using silica gel column chromatography, we found that prior deactivation with 1% of triethylamine was necessary. This allowed yields to increase from~20-30% to~50-60%, respectively. Similar observations have been reported in the literature for fluorinated aziridines [35].

Spectroscopic Studies Concerning Cis-and Trans-Aziridines
The structure determination of cisand trans-aziridines was based on the NMR experiments performed on rac-25a,b. In the 19 F NMR spectrum, the major trans-isomer rac-25b showed a signal at δ −171, appearing as a doublet of quartets with a 2 J FP equal to 112 Hz. The aziridine proton ( 3 J FH 4 Hz, -CH(Ph)CF), and long-range coupling with two benzyl protons ( 4 J FH 5 Hz). The analysis of 31 P{ 1 H} NMR spectra showed a signal a doublet at δ: 10.9, while the signal derived from the cis-isomer was observed at δ: 9.97 (d, 2 J PF 117 Hz). A distinct signal difference was also observed in the 19 F NMR spectrum of rac-25a, where the signal was located at δ: −180 (dd, 2 J FP 117 Hz, 3 J FH 8 Hz). Additionally, there was no coupling between the fluorine and the benzyl proton for the cis-isomer. The 1 H NMR spectrum indicated the non-equivalence of benzyl protons [71], which resulted in the splitting of the signal into two separate doublets or a doublet of doublets (rac-25a: br d at δ: 4.0 and 4.1, 2 J HH 14 Hz; rac-25b: dd at δ: 4.1, 2 J HH 14, 4 J HF 5 Hz, and 4.5, 2 J HH 14, 4 J HF 3 Hz). In the 1 H NMR spectrum, the key signal from the aziridine proton was observed at δ: 3.45 (t, 3 J HF and 3 J HP 4 Hz) for the trans-isomer (rac-25b), and at δ: 3.26 (d, 3 J HF 8 Hz) for the cis-isomer rac-25a. Performing 1 H{/ 19 F} NMR simplified both signals to a broad doublet at δ: 3.45 ( 3 J HP 3.6 Hz) and a broad singlet at δ: 3.25, respectively. However, the decoupling of the 1 H{/ 31 P} NMR spectrum simplified only the signal from rac-25b (d, 3 J HF 4 Hz). These data clearly indicated the aziridine protons from both isomers interacted with fluorine, while only the proton from trans-aziridine rac-25b was coupled with the phosphorus atom. These NMR results, along with the literature data, enabled the determination of the presumed geometry of aziridines. Furthermore, the electron-withdrawing substituents (P and F) decreased the values of vicinal couplings constants between hydrogen nuclei and heteroatoms [72]. In practice, the range of coupling constants for the substituted fluorinated aziridines can be estimated depending on the vicinal H-F relationship H-F trans : 2-5 Hz, H-F cis : 7-9 Hz [56,73,74]. Accordingly, we assigned a higher value of 3 J HF 8. 4 Hz for H-F in the cis-relationship of rac-25a, and a lower 3 J HF 4.3 Hz, for the trans H-F in rac-25b, which is in good agreement with the literature. In the case of the trans orientation of the H-P bond, the assumed dihedral angle CHCP is approximately 180 • , resulting in a vicinal coupling constant of 3 J HP around 0-1 Hz. This observation was also noticed in our case for rac-25a with a 3 J HP value of 0 Hz. Similar observations were reported for trifluoromethylcyclopropylphosphonates ( 3 J HP ca. 1 Hz) [75]. The above-described data were further confirmed by characteristic signals in the 13 C NMR spectra, with a typical couplings constant for α-substituted aziridinylphosphonates, localized C-2 at δ 83.9 (dd, 2 J CF/P 260, 232 Hz) or 86.7 (dd, 2 J CF/P 274, 272 Hz), for the transand cis-aziridine, respectively. These significant results for rac-25a,b, along with analogous relationships, were also observed in the case of 24a-d and rac-26a,b (see the Supporting Information for details). The summarized NMR data for rac-25a,b can be found in Table 5. To support the stereochemical assessments, 1D 1 H-1 H nuclear Overhauser effect (NOE) experiments as well as 1D 19 F-1 H heteronuclear NOE (HOE) NMR experiments were performed for both isomers of rac-25a,b. In the 1D NOE spectrum, we observed correlations between the aziridine proton NCHCFP and diastereotopic benzyl protons for both isomers. Furthermore, we observed weak correlations between the aziridine proton NCHCFP (t, δ: 3.45 ppm) and the protons of the phosphonate group -P(O)(OCH 2 CH 3 ) 2 , specifically in the trans-isomer (rac-25b), indicating that these substituents are on the same side of the ring. In addition, the HOE spectrum for the trans-isomer rac-25b revealed strong correlations between the fluorine atom and the closely located protons of the phenyl ring NCH(Ph)CFP. A similar correlation was observed for rac-25a, albeit with a noticeably weaker HOE effect. Based on these observations, there is a cis-relationship between the fluorine atom and the phenyl ring for rac-25b. In contrast, the most intensive enhancement in the HOE experiment was detected for correlation between the fluorine atom and the aziridine proton in rac-25a (Figure 7). were further confirmed by characteristic signals in the 13 C NMR spectra, with a typical couplings constant for α-substituted aziridinylphosphonates, localized C-2 at δ 83.9 (dd, 2 JCF/P 260, 232 Hz) or 86.7 (dd, 2 JCF/P 274, 272 Hz), for the trans-and cis-aziridine, respectively. These significant results for rac-25a,b, along with analogous relationships, were also observed in the case of 24a-d and rac-26a,b (see the Supporting Information for details). The summarized NMR data for rac-25a,b can be found in Table 5. To support the stereochemical assessments, 1D 1 H-1 H nuclear Overhauser effect (NOE) experiments as well as 1D 19 F-1 H heteronuclear NOE (HOE) NMR experiments were performed for both isomers of rac-25a,b. In the 1D NOE spectrum, we observed correlations between the aziridine proton NCHCFP and diastereotopic benzyl protons for both isomers. Furthermore, we observed weak correlations between the aziridine proton NCHCFP (t, δ: 3.45 ppm) and the protons of the phosphonate group -P(O)(OCH2CH3)2, specifically in the trans-isomer (rac-25b), indicating that these substituents are on the same side of the ring. In addition, the HOE spectrum for the trans-isomer rac-25b revealed strong correlations between the fluorine atom and the closely located protons of the phenyl ring NCH(Ph)CFP. A similar correlation was observed for rac-25a, albeit with a noticeably weaker HOE effect. Based on these observations, there is a cis-relationship between the fluorine atom and the phenyl ring for rac-25b. In contrast, the most intensive enhancement in the HOE experiment was detected for correlation between the fluorine atom and the aziridine proton in rac-25a (Figure 7).

Study on Aziridine Ring Closure by DFT Calculations
To decipher the differences in the cyclization tendencies, DFT calculations were used to determine the potential energy barriers associated to the reaction pathways for all stereoisomers. Substrates 16a' and 16b' were utilized, resulting in products 24a' and 24b' (Figure 8). The calculated energies revealed that the transition states TSC1 and TSC2 leading to the formation of cis-aziridine 24a' exhibited higher energy barriers (3 kcal/mol)

Study on Aziridine Ring Closure by DFT Calculations
To decipher the differences in the cyclization tendencies, DFT calculations were used to determine the potential energy barriers associated to the reaction pathways for all stereoisomers. Substrates 16a' and 16b' were utilized, resulting in products 24a' and 24b' (Figure 8). The calculated energies revealed that the transition states TS C1 and TS C2 leading to the formation of cis-aziridine 24a' exhibited higher energy barriers (3 kcal/mol) compared to the transition states leading to the trans-aziridine (TS T1 , TS T2 ), which is attributed to the difference of steric interactions between the phenyl and phosphonate groups (Figure 8). The optimized structures of the transition states leading to the formation of both cisand trans-aziridines are presented in Figure 9. These results are in good agreement with the experimental findings where 16b was found to undergo cyclization at a faster rate (approximately 50% over a month). Furthermore, the most stable conformer of 16b' is E1, which exhibits an anti-arrangement of C-N and C-Br groups which promote the cyclization. Therefore, the cis-aziridine is kinetically favored. attributed to the difference of steric interactions between the phenyl and phosphonate groups (Figure 8). The optimized structures of the transition states leading to the formation of both cis-and trans-aziridines are presented in Figure 9. These results are in good agreement with the experimental findings where 16b was found to undergo cyclization at a faster rate (approximately 50% over a month). Furthermore, the most stable conformer of 16b' is E1, which exhibits an anti-arrangement of C-N and C-Br groups which promote the cyclization. Therefore, the cis-aziridine is kinetically favored.

Isolation of Chiral Trans-Aziridine 24b,d and Non-Fluorinated Cis-Aziridine 27
Trans-aziridine trans-24b,d can be obtained with high diastereoselectivity by the sequence involving an imine reduction and a subsequent ring closure reaction. When the reaction was carried out from 10a,b with sodium cyanoborohydride in glacial acetic acid at 70 °C for 3 h (Scheme 3), we observed a diastereoselective reduction. Two of the four amine diastereomers (16b,d) underwent a direct conversion into trans-aziridines trans-24b,d with a dr of 1:0.05. In parallel, small amounts of non-fluorinated aziridine cis-27 attributed to the difference of steric interactions between the phenyl and phosphonate groups (Figure 8). The optimized structures of the transition states leading to the formation of both cis-and trans-aziridines are presented in Figure 9. These results are in good agreement with the experimental findings where 16b was found to undergo cyclization at a faster rate (approximately 50% over a month). Furthermore, the most stable conformer of 16b' is E1, which exhibits an anti-arrangement of C-N and C-Br groups which promote the cyclization. Therefore, the cis-aziridine is kinetically favored.

Isolation of Chiral Trans-Aziridine 24b,d and Non-Fluorinated Cis-Aziridine 27
Trans-aziridine trans-24b,d can be obtained with high diastereoselectivity by the sequence involving an imine reduction and a subsequent ring closure reaction. When the reaction was carried out from 10a,b with sodium cyanoborohydride in glacial acetic acid at 70 °C for 3 h (Scheme 3), we observed a diastereoselective reduction. Two of the four amine diastereomers (16b,d) underwent a direct conversion into trans-aziridines trans-24b,d with a dr of 1:0.05. In parallel, small amounts of non-fluorinated aziridine cis-27

Isolation of Chiral Trans-Aziridine 24b,d and Non-Fluorinated Cis-Aziridine 27
Trans-aziridine trans-24b,d can be obtained with high diastereoselectivity by the sequence involving an imine reduction and a subsequent ring closure reaction. When the reaction was carried out from 10a,b with sodium cyanoborohydride in glacial acetic acid at 70 • C for 3 h (Scheme 3), we observed a diastereoselective reduction. Two of the four amine diastereomers (16b,d) underwent a direct conversion into trans-aziridines trans-24b,d with a dr of 1:0.05. In parallel, small amounts of non-fluorinated aziridine cis-27 were also isolated. Extended reaction time favored the conversion of 16a,c to cis-27 (after 7h: 16a,c/trans-24b,d/cis-27 0.3:1:0.7), while prolonged reaction time led to the formation of some non-identified side-products. Based on these results, we hypothesized that diastereomers 16a,c slowly cyclized to form cis-aziridines 24a,c (Scheme 3). Then, the formation of an azirine intermediate resulting from the departure of the fluorine atom takes place, followed by the stereoselective addition of a hydride nucleophile at the opposite side of the aryl substituent, resulting in the stereospecific formation of aziridine cis-27. The stereochemistry of cis-27 was deduced based on the observed vicinal coupling constants 3 J HH 7 Hz, which are in good agreement with the literature [76][77][78][79][80]. Similar conclusions were drawn by De Kimpe et al. in their study on the N-substituted cis-2-aryl-3-alkylaziridines [77].
7h: 16a,c/trans-24b,d/cis-27 0.3:1:0.7), while prolonged reaction time led to the formation of some non-identified side-products. Based on these results, we hypothesized that diastereomers 16a,c slowly cyclized to form cis-aziridines 24a,c (Scheme 3). Then, the formation of an azirine intermediate resulting from the departure of the fluorine atom takes place, followed by the stereoselective addition of a hydride nucleophile at the opposite side of the aryl substituent, resulting in the stereospecific formation of aziridine cis-27. The stereochemistry of cis-27 was deduced based on the observed vicinal coupling constants 3 JHH 7 Hz, which are in good agreement with the literature [76][77][78][79][80]. Similar conclusions were drawn by De Kimpe et al. in their study on the N-substituted cis-2-aryl-3-alkylaziridines [77]. The aziridine cis-27 is more polar than the fluorinated analogues and was isolated in 32% yield. To isolate the trans-aziridine 24b,d, we treated a mixture of 16a,c/trans-24b,d with sodium borohydride and a catalytic amount of Pd/C (10 mol%). Unfortunately, after 20 min at room temperature, we only observed the conversion of 16a,c to amine products 28a-d (Scheme 4). Interestingly, the presence of palladium catalyst promoted the diastereomerization of 16a,c, resulting in the formation of the mixture of four diastereomers of the amine (28a-d) (dr 1:0.8:0.19:0.13) from 16a,c (dr 1:0.1) as easily observed by 19 F NMR. Finally, we were able to isolate of the trans-aziridine (24b,d) in 65% yield and very high diastereoselectivity (dr 1:0.06). The aziridine cis-27 is more polar than the fluorinated analogues and was isolated in 32% yield. To isolate the trans-aziridine 24b,d, we treated a mixture of 16a,c/trans-24b,d with sodium borohydride and a catalytic amount of Pd/C (10 mol%). Unfortunately, after 20 min at room temperature, we only observed the conversion of 16a,c to amine products 28a-d (Scheme 4). Interestingly, the presence of palladium catalyst promoted the diastereomerization of 16a,c, resulting in the formation of the mixture of four diastereomers of the amine (28a-d) (dr 1:0.8:0.19:0.13) from 16a,c (dr 1:0.1) as easily observed by 19 F NMR. Finally, we were able to isolate of the trans-aziridine (24b,d) in 65% yield and very high diastereoselectivity (dr 1:0.06). diastereomers 16a,c slowly cyclized to form cis-aziridines 24a,c (Scheme 3). Then, the formation of an azirine intermediate resulting from the departure of the fluorine atom takes place, followed by the stereoselective addition of a hydride nucleophile at the opposite side of the aryl substituent, resulting in the stereospecific formation of aziridine cis-27. The stereochemistry of cis-27 was deduced based on the observed vicinal coupling constants 3 JHH 7 Hz, which are in good agreement with the literature [76][77][78][79][80]. Similar conclusions were drawn by De Kimpe et al. in their study on the N-substituted cis-2-aryl-3-alkylaziridines [77]. The aziridine cis-27 is more polar than the fluorinated analogues and was isolated in 32% yield. To isolate the trans-aziridine 24b,d, we treated a mixture of 16a,c/trans-24b,d with sodium borohydride and a catalytic amount of Pd/C (10 mol%). Unfortunately, after 20 min at room temperature, we only observed the conversion of 16a,c to amine products 28a-d (Scheme 4). Interestingly, the presence of palladium catalyst promoted the diastereomerization of 16a,c, resulting in the formation of the mixture of four diastereomers of the amine (28a-d) (dr 1:0.8:0.19:0.13) from 16a,c (dr 1:0.1) as easily observed by 19 F NMR. Finally, we were able to isolate of the trans-aziridine (24b,d) in 65% yield and very high diastereoselectivity (dr 1:0.06).
As expected, the reaction selectively led to the conversion of one pair of diastereomers (cis-aziridine), while the other one (trans-aziridine) remained unchanged in the reaction mixture. By this sequence, both fluorinated and non-fluorinated aziridines can be isolated.

Aziridine Ring Transformations
Finally, as previously mentioned, treatment of aziridine 24a-d cis/trans 0.64(dr 1:0.07)/1(dr 1:0.09) with sodium borohydride afforded aziridine cis-27 in 39% yield via the formation of the azirine intermediate (Scheme 5). As expected, the reaction selectively led to the conversion of one pair of diastereomers (cis-aziridine), while the other one (trans-aziridine) remained unchanged in the reaction mixture. By this sequence, both fluorinated and non-fluorinated aziridines can be isolated.
The reactivity of fluorinoaziridinyl-2-phosphonates was evaluated in a regioselective ring opening of 24a-d (cis/trans 1(dr 1:0.45)/0.65(dr 1:0.04)). In such reactions, N-activation is required as the (S)-MBn is a poor leaving group [81]. Activation by Yb(OTf)3 and CeCl3 Lewis acids turned out to be ineffective. A similar observation was reported by Beksultanova et al. in their study related to the ring opening of aziridine-2-phosphonate catalyzed by BF3 × OEt2 [82]. This lack of reactivity may be due to the presence of a fluorine atom, which decrease the basicity of the nitrogen atom [83].
For comparison, we tested the reaction on aziridines 24a-d with methanol as a nucleophilic agent and sulfuric acid as an activating reagent. This reaction resulted in the formation of β-methoxy-α-hemiaminal phosphonates 29a,b in 86% yield (dr 1:0.5) according to the mechanism depicted in Scheme 6. The reactivity of fluorinoaziridinyl-2-phosphonates was evaluated in a regioselective ring opening of 24a-d (cis/trans 1(dr 1:0.45)/0.65(dr 1:0.04)). In such reactions, N-activation is required as the (S)-MBn is a poor leaving group [81]. Activation by Yb(OTf) 3 and CeCl 3 Lewis acids turned out to be ineffective. A similar observation was reported by Beksultanova et al. in their study related to the ring opening of aziridine-2-phosphonate catalyzed by BF 3 × OEt 2 [82]. This lack of reactivity may be due to the presence of a fluorine atom, which decrease the basicity of the nitrogen atom [83].
For comparison, we tested the reaction on aziridines 24a-d with methanol as a nucleophilic agent and sulfuric acid as an activating reagent. This reaction resulted in the formation of β-methoxy-α-hemiaminal phosphonates 29a,b in 86% yield (dr 1:0.5) according to the mechanism depicted in Scheme 6.
As expected, the reaction selectively led to the conversion of one pair of diastereomers (cis-aziridine), while the other one (trans-aziridine) remained unchanged in the reaction mixture. By this sequence, both fluorinated and non-fluorinated aziridines can be isolated.
The reactivity of fluorinoaziridinyl-2-phosphonates was evaluated in a regioselective ring opening of 24a-d (cis/trans 1(dr 1:0.45)/0.65(dr 1:0.04)). In such reactions, N-activation is required as the (S)-MBn is a poor leaving group [81]. Activation by Yb(OTf)3 and CeCl3 Lewis acids turned out to be ineffective. A similar observation was reported by Beksultanova et al. in their study related to the ring opening of aziridine-2-phosphonate catalyzed by BF3 × OEt2 [82]. This lack of reactivity may be due to the presence of a fluorine atom, which decrease the basicity of the nitrogen atom [83].
For comparison, we tested the reaction on aziridines 24a-d with methanol as a nucleophilic agent and sulfuric acid as an activating reagent. This reaction resulted in the formation of β-methoxy-α-hemiaminal phosphonates 29a,b in 86% yield (dr 1:0.5) according to the mechanism depicted in Scheme 6. First, MeOH attacked the acid-activated aziridine at the less hindered carbon atom, resulting in the formation of α-fluoro-α-aminophosphonate with inversion of configuration at the C-2-carbon atom. Then, an elimination led to the iminium C, which readily reacted with methanol to form 29a,b with a dr of 1:0.5. Based on the Houk model discussed at the Figure 3, the relative stereochemistry of 29a,b was assumed to be 1'S, 1R, 2S and 1'S, 1S, 2S, respectively. We also examined the reaction of 24a-d in glacial acetic acid according to Wróblewski's protocol [80] and we did not observe substrate conversion.
In the 31 P NMR spectra of 29a,b, two singlets were observed at δ: 18.2 and 17.3, corresponding to the mixture diastereomers (dr 1:0.5). Additionally, in the 13 C NMR spectrum, the doublet of C-α was located at δ 104.5 and 103.9 with large coupling constants of 1 J CP 196 Hz, which is characteristic of α-substituted α-aminophosphonates [84]. In comparison, the C-β signal was observed at δ: 63.4 (d, 2 J CP 15 Hz) and 63.1 (d, 2 J C-P 7 Hz) (see the Supporting Information for details).  13 C NMR) and are expressed in parts per million (ppm) in CDCl 3 . Coupling constants (J) were reported in hertz (Hz). The following abbreviations were used to express the multiplicities: s-singlet, d-doublet, ttriplet, q-quartet, quint-quintet, dd-doublet of doublets, dt-doublet of triplets, dq-doublet of quartets, td-triplet of doublets, ddd-doublet of doublet of doublets, m-multiplet, br d-broad doublet, br s-broad singlet. 19 F NMR spectra were measured with trichlorofluoromethane (CFCl 3 ) as the internal standard, while for 31 P NMR spectroscopy, 85% H 3 PO 4 was used as the external standard. High-resolution mass spectra (HRMS) for the final compounds were performed on an Agilent 6210 ESI using electrospray ionization. Electron ionization mass spectroscopy (EI-MS; low-resolution, direct injection) was performed on a Bruker 320MS/420GC spectrometer.

Experimental Section
The obtained compounds were purified by column chromatography using silica gel Merck Kieselgel 60 (230-400 mesh) as the stationary phase, and ethyl acetate/hexane or ethyl acetate/petroleum ether as developing systems. Thin Layer Chromatography (TLC) was performed on commercially available Merck Kieselgel 60-F 254 with ethyl acetate/hexane as the mobile phase. Visualization of the TLC plates was done using UV light and/or permanganate solution.
Solvents were dried by commonly used methods: toluene was freshly distilled over sodium hydride (NaH 2 ) and acetonitrile was distilled over calcium hydride (CaH 2 ) prior to use. Anhydrous MeOH and DMF were stored over 4Å molecular sieves. All of the reagents were purchased from Fluorochem ® , Acros ® , Alfa Aesar ® or Sigma-Aldrich ® , and used as received.

Theoretical Calculations
Gaussian 16 [85] was used to fully optimize and calculate the frequencies for all the structures at the ωB97x-D/def2-TZVPD level of theory [86][87][88]. The vibrational frequencies were calculated at the same level of theory, and then their positivity was applied to confirm that each of the calculated structures corresponds to a minimum on the potential energy surface. The polarizable continuum model (PCM) [89] was used to simulate solvents: DMF (reaction pathways modelling) and chloroform (conformational analysis of NMR solution). Transition structures were located using the Berny algorithm with the NoEigenTest request. Various combinations of conformations for both invertomers (nitrogen atom) were examined to determine minimum energy pathways for all cyclization reactions.
10a: 1   Pale-yellow oil, 217 mg, yield 95%. Isolated as a mixture of diastereomers 11a,b (dr 1:0.93), which could not be separated by the chromatography techniques employed in this study.

Conclusions
In conclusion, we have successfully developed the first synthesis of N-inactivated aziridines 24-26 bearing both a fluorine and phosphonate group on the same carbon atom. Our synthetic methodology involved the one-pot halofluorination of an enamine-imine tautomeric mixture, resulting in α,α-halofluorinated β-iminophosphonates 10-15, which were subsequently reduced to yield the corresponding β-aminophosphonates 16-21. When starting from (R)-or (S)-α-methylbenzyl imine derivatives 10-11,14, the reduction occurred with high diastereoselectivity (dr 1:1:0.1:0.07). We have also investigated the influence of the solvent and the base on the aziridine ratio and reaction yield. Based on the spectroscopic and theoretical studies, we have determined the cis/trans geometry of aziridines obtained as a racemic mixture or prepared in a diastereoselective manner, through intramolecular cyclization. Our procedure involving the reduction of cis/trans-aziridine mixture 24 allows us to isolate chiral trans-aziridines 24 as well as fluorine-free cis aziridines 27. Moreover, the cis/trans fluoroaziridines 24 can react with sulfuric acid and methanol to give the non-fluorinated α, β-dimethoxy-α-aminophosphonate 29 in high yield.
The conformational analysis of both diastereomers of α,α-bromofluoro β-aminophosphonates conducted through DFT calculations (PCM/ωB97x-D/def2-TZVPD level of theory) allowed us to conclude that the stability of P=O. . .H-N hydrogen bonding can be influenced by the electrostatic interaction between C-F (C-Br) and N-H, except when it leads to a phosphonate−aromatic (P=O. . .π) repulsive interaction. This analysis has also confirmed the configuration at stereogenic centers. To explain the observed differences in the cyclization tendencies of pairs of β-aminophosphonates, the proper transition states of the aziridine ring-closure reaction have been modeled.