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

Abstract

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 S_N2 intramolecular cyclization of vicinal haloamines have been modeled.

1. Introduction

The aziridine motif frequently appears in biologically active compounds [1,2,3,4,5,6,7]. Therefore, this heterocyclic three-membered ring motif also serves as an attractive building block for organic transformations owing to the strained ring system and its ability to undergo highly regio- and stereospecific ring-opening reactions [8,9,10,11,12,13,14,15,16,17,18].

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 N-substituted 2,2-difluorinated aziridines with aqueous HCl or MeONa in methanol led to α-chloroacetamides [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 propargyl amines through α-formation 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).

2. Results and Discussion

2.1. Synthesis of α,α-Halofluoro-β-aminophosphonates via Reduction of α,α-Halofluoro-β-iminophosphonates

We initiated the sequence by the condensation of diethyl ß-ketophosphonate 1 with a series of primary amines, respectively, (S)- and (R)-α-methylbenzylamine (MBn-NH₂), p-methoxybenzylamine (PMB-NH₂), and p-methoxyphenylamine (PMP-NH₂). These reactions resulted in a tautomeric mixture of major β-enaminophosphonates (2–5) and minor β-iminophosphonates (6–9) [54,55]. When p-methoxyphenylamine was used, the ratio of enamine (Z)/imine (E:Z) 5a/9a,b was 1/0.53 (1:0.1), as determined by ³¹P NMR. The Z geometry of β-enamines was confirmed by the chemical shifts and coupling constants J_CP values of C(β) and C(α) signals (δ: 161.6, ²J_CP 6 Hz and δ: 82.2, ¹J_CP 188 Hz, respectively) in ¹³C NMR spectra. The signals of C=N and an ipso carbon atom (attached to the double bond) appeared at δ: 160.1, ²J_CP equals to 8 Hz and δ: 144.0, ³J_CP 2 Hz, respectively, matching the main E isomer of the imine 9a (

Table 1. Synthesis of gem-halofluorinated ß-iminophosphonates (10–11,14a,b and rac-12–13,15).

Entry	PG	Enamine/Imine	Yield [%]	Imine	X	Yield [%]
1	(S)-MBn	2a,b/6a,b	93 a	10a,b	Br	92 c
2	(R)-MBn	3a,b/7a,b	91 a	11a,b	Br	95 c
3	PMB	4a,b/8a,b	85 a	rac-12	Br	94
4	PMP	5a/9a,b	93 b	rac-13	Br	87
5	(S)-MBn	2a,b/6a,b	93 a	14a,b	Cl	94 c
6	PMB	4a,b/8a,b	85 a	rac-15	Cl	91

Reaction conditions: i. 1 (0.5 mmol), PG-NH₂ (0.5 mmol), MgSO₄, toluene, reflux, 24 h, Dean-Stark; ii. NBS (0.5 mmol), Selectfluor (0.9 mmol), CH₃CN, rt, 15 min or iii. NCS (0.5 mmol), Selectfluor (0.67 mmol), CH₃CN, rt, 15 min. ^a see Ref. [54], ^b enamine (Z)/imine (E:Z) 1/0.53 (1:0.1) ^c dr 1:1.

). In a second step, a mild and efficient one-pot gem-bromo- or gem-chlorofluorination of 2–9 led to the formation of imines (10–11,14a,b and rac-12–13,15) possessing chiral (S)- or (R)-MBn or non-optically active PMB or PMP protecting groups (PG).

The one-pot gem-bromofluorination or gem-chlorofluorination of crude E/Z enamine/imine (2–5/6–9) mixture was accomplished using Selectfluor and N-bromosuccinimide (NBS) or N-chlorosuccinimide (NCS) yielding α,α-bromofluoro or α,α-chlorofluoro-β-iminophosphonates (10–11,14a,b and rac-12–13,15). The reactions, monitored by ³¹P NMR, proceeded in yields ranging from 87% for rac-13 to 95% for 11a,b (dr 1:1). The formation of β-iminophosphonates was established based on NMR experiments and IR spectra. Analysis of the ¹⁹F NMR spectra of 10a and 10b (dr 1:1) presented two doublets corresponding to the diastereomers at δ: −129.1 and −128.7 (²J_FP 82 Hz). The ³¹P NMR spectra also showed two doublets at δ: 7.4 and 7.9 with the same coupling constants. Similar signals for the chlorofluorinated derivative (14a,b dr 1:1) were observed at δ: −125.6 and −125.4 (d, ²J_FP 86/87 Hz) in the ¹⁹F NMR and at δ: 8.0 and 7.5 in the ³¹P NMR, respectively. This trend is in good agreement with differences in chemical shifts observed in brominated or chlorinated fluoro-organic compounds. [56] Moreover, the C=N bond gave a distinctive doublet of doublets in the ¹³C NMR spectra of 10a,b at δ: 164.4/164.6 as a (²J_CF 27/28 Hz, ²J_CP 6 Hz). The stretching band at 1648 cm⁻¹ in the IR spectra also confirmed the presence of the C=N bond. [57] The halogenated β-iminophosphonates (10–11,14a,b and rac-12–13,15) were formed as a single isomer. Due to steric hindrance between the protecting group (PG), phosphonate moiety, and bromine/chlorine atom, the resulting geometry of the imine bond was attributed to the E-isomer and was confirmed by HSQC, HMBC, and 2D NOESY experiments. For instance, the 2D ¹H-¹H 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,α-difluorinated β-iminophosphonate analogs, the through-space interactions of PG (benzylic) protons and one of the fluorine atoms indicated the major formation of the Z-stereoisomer [54]. Long-range F-H intramolecular nonbonding interactions have also been observed in the case of (Z)-N-tetrafluoropropenyl-uracil/thymine derivatives and α-fluorinated 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.

The obtained α,α-halofluorinated ß-iminophosphonates 10–15 were subsequently used as precursors for the synthesis of ß-aminophosphonates 16–21 (Scheme 1). Thus, the imine bond reduction using NaBH₃CN in glacial acetic acid resulted in the formation of amines (16–17, 20a–d and rac-18–19, 21a,b) as a mixture of diastereomers in yields ranging from 91 to 97%. Furthermore, the reduction of 10a,b using LiAlH₄ (LAH) led to the formation of a monofluorinated tautomeric mixture of enamine 22a,b/imine 23a,b [59] in 83% yield (E-22a/Z-22b ratio 1:0.3; 22a,b/23a,b ratio 1:0.05). This was attributed to the substitution of the bromine atom in the imine 10a,b by the hydrogen and subsequent tautomerization to form the enamine 22a,b/imine 23a,b tautomers (Scheme 1). In contrast, De Kimpe et al. reported that the application of LAH in the reduction of halogenated imines led to reductive cyclization and the formation of an aziridine ring [60,61].

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-2-carbon 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.

To optimize the reduction of imines 10–11,14a,b and rac-12–13,15, various activations were tested, including organic acid (glacial acetic acid), Lewis acid (anhydrous CeCl₃), and chiral organic acid [(1S)-(+)-camphorsulfonic acid (CSA)]. The yields and diastereomer ratios of amines 16–17,20a–d, rac-18–19,21a,b, based on ¹⁹F and ³¹P NMR analysis of the crude reaction mixture are summarized in

Table 2. Reduction of imines (10,11,14a,b and rac-12–13,15).

Entry	X	PG	Imine	Reductor	Yield [%]	Amine	dr
1	Br	(S)-MBn	10a,b  a	NaBH3CN/HOAc	97	16a–d	1:1:0.1:0.07
2	Br	(S)-MBn	10a,b  a	NaBH3CN/CeCl3	89	16a–d	1:0.98:0.1:0.06
3	Br	(S)-MBn	10a,b  a	NaBH3CN/(1S)-(+)CSA	86	16a–d	1:1.06:0.1:0.06
4	Br	(S)-MBn	10a,b  a	BH3.THF	91	16a–d	1:0.25:0:0
5	Br	(S)-MBn	10a,b  a	BH3.S(CH3)2	47	16a–d	1:0.20:0:0
6	Br	(S)-MBn	10a,b  a	NaBH3CN	0	16a–d	-
7	Br	(R)-MBn	11a,b  a	NaBH3CN/HOAc	95	17a–d	1:1:0.1:0.07
8	Br	PMB	12	NaBH3CN/HOAc	97	rac–18a,b	1:0.70
9	Br	PMB	12	NaBH3CN/CeCl3	85	rac–18a,b	1:0.50
10	Br	PMB	12	NaBH3CN/(1S)-(+)CSA	83	rac–18a,b	1:0.74
11	Br	PMP	13	NaBH3CN/HOAc	91	rac–19a,b	1:0.88
12	Cl	(S)-MBn	14a,b a	NaBH3CN/HOAc	95	20a–d	1:1:0.1:0.07
13	Cl	PMB	15	NaBH3CN/HOAc	96	rac–21a,b	1:0.70

^a dr 1:1.

. 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 = 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 ³J_FH coupling constants, which depend on the Karplus equation [56,68]. The β-aminophosphonates 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 (³J_FH ~20 Hz, Figure 4B), while the minor one is a gauche-conformation (³J_FH ~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.

2.2. 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.

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: ³J_HF ~10 Hz and ³J_H-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 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 (Figure 5 and Figure 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.

2.3. Aziridine Synthesis by Ring Closure Reaction

Our approach to aziridine synthesis involved the intramolecular S_N2 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 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. Optimization of the intramolecular cyclization–solvent effect.

Entry	Substrate	Solvent	Time [h]	Aziridine	Yield [%] a	cis/trans a
1	16a–d b	DMF	4	24a–d	82	0.78 f: 1 g
2	16a–d b	CH3CN	12	24a–d	70	0.68 f: 1 g
3	16a–d b	PhCH3	24	24a–d	Traces	-
4	16a–d b	CH2Cl2	24	24a–d	Traces	-
5	16a–d b	THF	24	24a–d	15	ca. 0: 1
6	16a–d b	DMC	8	24a–d	32	ca. 0: 1
7	rac-18a,b c	DMF	4	rac-25a,b	79	0.68: 1
8	rac-19a,b d	DMF	4	rac-26a,b	48	0.09: 1
9	20a–d e	DMF	18	24a,b	Traces	-

Reaction conditions: amine (0.2 mmol), TEA (0.3 mmol), solvent, 70 °C, 4–24 h, Schlenk flask, inert gas. ^a determined by ¹⁹F and/or ³¹P NMR spectra from crude mixture; ^b dr 1:1:0.1:0.07; ^c dr 1:0.72; ^d dr 1:0.88; ^e dr 1:1:0.1:0.07; ^f dr 1:0.13; ^g dr 1:0.08.

.

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 (¹⁹F, ³¹P 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. Optimization of the intramolecular cyclization–base effect.

Entry	Substrate	Base	Yield [%] a	Aziridine	cis/trans a
1	16a–d b	TEA	82	24a–d	0.78 e: 1 f
2	16a–d b	Quinine	84	24a–d	0.86 e: 1 f
3	16a–d b	L-Proline	77	24a–d	0.69 e: 1 f
4	16a–d b	DBU	21 d	24a–d	0.18 e: 1 f
5	16a–d b	DIPEA	70	24a–d	0.67 e: 1 f
6	16a–d b	NaH	<10	24a–d	-
7	16a–d b	w/o base	38	24a–d	0.38 g: 1 h
8	rac-18a,b c	TEA	79	rac-25a,b	0.68: 1
9	rac-18a,b c	Quinine	87	rac-25a,b	0.92: 1
10	rac-18a,b c	L-Proline	69	rac-25a,b	0.61: 1

Reaction conditions: amine (0.2 mmol), base (0.3 mmol), DMF, 70 °C, 4 h, Schlenk flask, inert gas ^a determined by ¹⁹F and/or ³¹P NMR spectra from crude mixture; ^b dr 1:1:0.1:0.07; ^c dr 1:0.72; ^d 22–23a,b were mainly formed (E-22a/Z-22b ratio 1:0.3; 22a,b/23a,b ratio 1:0.05); ^e dr 1:0.13; ^f dr 1:0.08;^g dr 1:0.06; ^h dr 1:0.03.

). 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 ¹⁹F 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 ³¹P 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].

2.4. Spectroscopic Studies Concerning Cis- and Trans-Aziridines

The structure determination of cis- and trans-aziridines was based on the NMR experiments performed on rac-25a,b. In the ¹⁹F NMR spectrum, the major trans-isomer rac-25b showed a signal at δ −171, appearing as a doublet of quartets with a ²J_FP equal to 112 Hz. The aziridine proton (³J_FH 4 Hz, -CH(Ph)CF), and long-range coupling with two benzyl protons (⁴J_FH 5 Hz). The analysis of ³¹P{¹H} 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, ²J_PF 117 Hz). A distinct signal difference was also observed in the ¹⁹F NMR spectrum of rac-25a, where the signal was located at δ: −180 (dd, ²J_FP 117 Hz, ³J_FH 8 Hz). Additionally, there was no coupling between the fluorine and the benzyl proton for the cis-isomer. The ¹H 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, ²J_HH 14 Hz; rac-25b: dd at δ: 4.1, ²J_HH 14, ⁴J_HF 5 Hz, and 4.5, ²J_HH 14, ⁴J_HF 3 Hz). In the ¹H NMR spectrum, the key signal from the aziridine proton was observed at δ: 3.45 (t, ³J_HF and ³J_HP 4 Hz) for the trans-isomer (rac-25b), and at δ: 3.26 (d, ³J_HF 8 Hz) for the cis-isomer rac-25a. Performing ¹H{/¹⁹F} NMR simplified both signals to a broad doublet at δ: 3.45 (³J_HP 3.6 Hz) and a broad singlet at δ: 3.25, respectively. However, the decoupling of the ¹H{/³¹P} NMR spectrum simplified only the signal from rac-25b (d, ³J_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 ³J_HF 8.4 Hz for H-F in the cis-relationship of rac-25a, and a lower ³J_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 ³J_HP around 0–1 Hz. This observation was also noticed in our case for rac-25a with a ³J_HP value of 0 Hz. Similar observations were reported for trifluoromethylcyclopropylphosphonates (³J_HP ca. 1 Hz) [75]. The above-described data were further confirmed by characteristic signals in the ¹³C NMR spectra, with a typical couplings constant for α-substituted aziridinylphosphonates, localized C-2 at δ 83.9 (dd, ²J_CF/P 260, 232 Hz) or 86.7 (dd, ²J_CF/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. Characteristic NMR values for rac-25a,b.

	rac-cis-25a	rac-trans-25b
19F NMR	−180.27 (dd, 2JFP 116.7, 3JFH 8.4 Hz)	−170.98 (dq, 2JFP 111.7, 3JFH 4.3 Hz)
31P{/1H} NMR	9.97 (d, 2JPF 116.9 Hz)	10.95 (d, 2JPF 111.6 Hz)
NCHCFP	3.26 (d, 3JHF 8.5 Hz)	3.45 (t, 3JHF/P 4.1 Hz)
CFP	86.67 (dd, 1JCF/P 274.0, 272.5 Hz)	83.95 (dd, 1JCF/P 259.6, 231.6 Hz)
CH(Ph)CFP	49.08 (dd, 2JCF/P 19.2, 1.3 Hz)	48.43 (dd, 2JCF/P 12.9, 6.0 Hz)
Cipso	133.86 (s)	133.58 (br d, 3JCF 5.2 Hz)

.

To support the stereochemical assessments, 1D ¹H-¹H nuclear Overhauser effect (NOE) experiments as well as 1D ¹⁹F-¹H 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).

2.5. 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 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.

2.6. 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 ³J_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].

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 ¹⁹F NMR. Finally, we were able to isolate of the trans-aziridine (24b,d) in 65% yield and very high diastereoselectivity (dr 1:0.06).

2.7. 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.

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 ³¹P 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 ¹³C NMR spectrum, the doublet of C-α was located at δ 104.5 and 103.9 with large coupling constants of ¹J_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, ²J_CP 15 Hz) and 63.1 (d, ²J_C-P 7 Hz) (see the Supporting Information for details).

3. Experimental Section

3.1. General Methods

All NMR experiments were performed with a Varian Mercury 300 MHz, Varian VNMR-S 400 MHz, Bruker Ascend™ 400 MHz NANOBA and Bruker Avance 600 MHz spectrometers. Full assignment of all NMR signals and determination of the stereochemistry were possible with the use of various NMR techniques, including ¹H, ¹H{/¹⁹F}, ¹H{/³¹P}, ¹H-¹H COSY, ¹H-¹H NOE, ¹H-¹⁹F HOE, ¹H-¹³C HSQC, ¹H-¹³C HMBC, ¹³C, ¹⁹F, and ³¹P{/¹H} experiments. The NMR shifts were determined in relation to the residual solvent proton signal (for CDCl₃: 7.26 ppm–¹H NMR, 77.16 ppm–¹³C NMR) and are expressed in parts per million (ppm) in CDCl₃. Coupling constants (J) were reported in hertz (Hz). The following abbreviations were used to express the multiplicities: s–singlet, d–doublet, t–triplet, 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. ¹⁹F NMR spectra were measured with trichlorofluoromethane (CFCl₃) as the internal standard, while for ³¹P NMR spectroscopy, 85% H₃PO₄ 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.

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-F₂₅₄ 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 (NaH₂) and acetonitrile was distilled over calcium hydride (CaH₂) 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.

3.2. 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.

3.3. General Procedure for Synthesis of β-Enaminophosphonates (2–5a,b)/β-Iminophosphonates (6–9a,b)

Compounds 2–5 and 6–9 were synthesized according to a previously reported methodology from diethyl 2-oxo-2-phenylethylphosphonate 1 (151 µL, 0.5 mmol) and primary amine (0.5 mmol) [54]. The reaction mixture was refluxed using a Dean–Stark apparatus. The obtained NMR data based on ¹H and ³¹P{/¹H} NMR for 2–4a,b and 6–8a,b are identical with those reported in the literature [54].

3.4. The Synthesis of β-Enaminophosphonates/β-Iminophosphonates (5a/9a,b)

Compounds 5a/9a,b are prepared as described in the general procedure.

The ratio of enamine 5a and imines 9a,b was determined with the use of ¹H and ³¹P{/¹H} NMR from the crude mixture, and was 1:0.53; the ratio of enamine (Z) 5a equaled 1, and imines (E/Z) 9a,b equaled 1:0.1, respectively. For tautomeric mixture 5a/9a,b after column chromatography (silica gel, AcOEt/hexane: 5% → 60%), only the NMR spectra of the main products was given (Z-5a/E-9a 1:0.53). Yellow oil, 157 mg, yield 87%.

(Z)-Diethyl (2-((4-methoxyphenyl)amino)-2-phenylvinyl)phosphonate (Z-5a).

¹H NMR (401 MHz): δ = 9.12 (br s, 1H, NH), 7.34–7.30 (m, 2H, H_ar), 7.29–7.23 (m, 3H, H_ar), 6.88–6.87 (m, 2H, H_ar), 6.57–6.56 (m, 2H, H_ar), 4.23 (d, J = 12.4 Hz, 1H, CHP), 4.13–4.05 (m, 4H, 2x OCH₂CH₃), 3.64 (s, 3H, Ph(4-OCH₃)), 1.32 (td, J = 7.1, 0.5 Hz, 6H, OCH₂CH₃). ¹³C NMR (101 MHz): δ = 161.63 (d, J = 6.0 Hz, C=CHP), 155.36 (s, C_ar(OCH₃)), 137.48 (d, J = 19.7 Hz, C_ipso), 134.68 (s, C_ipso), 130.63, 129.30, 128.30, 123.69 (4x s, CH_ar), 113.92 (s, CH_arC_ar(OCH₃)), 82.17 (d, J = 188.1 CHP), 61.45 (d, J = 6.0 Hz, OCH₂CH₃), 55.39 (s, Ph(4-OCH₃)), 16.20 (d, J = 6.7 Hz, OCH₂CH₃). ³¹P{/¹H} NMR (122 MHz): δ = 24.73 (s, 1P). MS (EI) m/z = 361.2 [M]⁺.

(E)-Diethyl (2-((4-methoxyphenyl)imino)-2-phenylethyl)phosphonate (E-9a).

¹H NMR (401 MHz): δ = 7.43–7.39 (m, 3H, H_ar), 7.25–7.19 (m, 2H, H_ar), 6.88–6.87 (m, 2H, H_ar), 6.57–6.56 (m, 2H, H_ar), 4.05–4.00 (m, 2H, OCH₂CH₃), 3.92–3.84 (m, 2H, OCH₂CH₃), 3.78 (s, 3H, Ph(4-OCH₃)), 3.39 (d, J = 23.3 Hz, 2H, CH₂P), 1.10 (td, J = 7.1, 0.5 Hz, 6H, OCH₂CH₃). ¹³C NMR (101 MHz): δ = 160.07 (d, J = 7.8 Hz, C=N), 156.39 (s, C_ar(OCH₃)), 143.97 (d, J = 2.3 Hz, C_ipso), 138.76 (s, C_ipso), 128.32, 128.29, 128.06, 120.83 (4x s, CH_ar), 114.40 (s, CH_arC_ar(OCH₃)), 62.22 (d, J = 6.6 Hz, OCH₂CH₃), 55.55 (s, Ph(4-OCH₃)), 29.51 (d, J = 134.3 Hz, CH₂P), 16.46 (d, J = 6.3 Hz, OCH₂CH₃). ³¹P{/¹H} NMR (122 MHz): δ = 22.12 (s, 1P).

(Z)-Diethyl (2-((4-methoxyphenyl)imino)-2-phenylethyl)phosphonate (Z-9b).

Diagnostic signals: ³¹P{/¹H} NMR (122 MHz): δ = 24.00 (s).

3.5. General Procedure for Synthesis of α,α-Bromofluorinated ß-Iminophosphonates (10–11a,b, rac-12–13)

The solution of Selectfluor (319 mg, 0.9 mmol) in dry, freshly distilled acetonitrile (10 mL) was gently heated to 50 °C and vigorously stirred until the compound was completely dissolved. After, the solution was cooled to ambient temperature and added together with NBS (89 mg, 0.5 mmol) to the mixture of the appropriate β-enaminophosphonate/β-iminophosphonate 2–5/6–9 (0.5 mmol). After 15 min of stirring at room temperature, the solvent was removed under reduced pressure. Next, the residue was dissolved in CHCl₃ (2 mL), water (10 mL) was added, and it was extracted (3 × 10 mL CHCl₃). The organic layers were combined, dried over Na₂SO₄, and evaporated to give products as a pale-yellow oil. The crude products were purified by column chromatography (AcOEt/petroleum ether: 5% → 50%).

(E)-Diethyl ((1R)-1-bromo-1-fluoro-2-phenyl-2-(((S)-1-phenylethyl)imino)ethyl) phosphonate (10a) and (E)-diethyl ((1S)-1-bromo-1-fluoro-2-phenyl-2-(((S)-1-phenylethyl)imino)ethyl) phosphonate (10b).

Pale-yellow oil, 210 mg, yield 92%. Isolated as a mixture of diastereomers 10a,b (dr 1:0.54) (153 mg) and single diastereomer 10b (57mg).

10a: ¹H NMR (400 MHz): δ = 7.44–7.40 (m, 1H, H_ar), 7.39–7.36 (m, 2H, H_ar), 7.33–7.30 (m, 2H, H_ar), 7.29–7.26 (m, 3H, H_ar), 7.25–7.20 (m, 2H, H_ar), 4.47–4.35 (m, 3H, OCH₂CH₃, CHCH₃), 4.34–4.23 (m, 2H, OCH₂CH₃), 1.38 (d, J = 6.6 Hz, 3H, CHCH₃), 1.35 (td, J = 7.0, 0.8 Hz, 3H, OCH₂CH₃), 1.32 (td, J = 7.1, 0.9 Hz, 3H, OCH₂CH₃). ¹³C NMR (101 MHz): δ = 164.44 (dd, J = 27.0, 6.0 Hz, C=N), 144.57 (s, C_ipso), 131.52 (d, J = 5.0 Hz, C_ipso), 128.60, 128.58, 127.87, 126.97, 126.62, 126.47 (6x s, CH_ar), 100.05 (dd, J = 269.8, 187.5 Hz, CBrF), 65.52 (d, J = 6.2 Hz, OCH₂CH₃), 65.20 (d, J = 6.7 Hz, OCH₂CH₃), 61.19 (s, CHCH₃), 24.54 (s, CHCH₃), 16.64 (d, J = 6.1 Hz, OCH₂CH₃), 16.61 (d, J = 6.1 Hz, OCH₂CH₃). ¹⁹F NMR (283 MHz): δ = −129.08 (d, J = 82.2 Hz, 1F). ³¹P{/¹H} NMR (122 MHz): δ = 7.37 (d, J = 82.1 Hz, 1P). IR (neat): 1648, 1261, 1012, 972, 649 [cm⁻¹]. MS (EI) m/z = 457.3 [M+H]⁺.

10b: ¹H NMR (400 MHz): δ = 7.42–7.37 (m, 3H, H_ar), 7.31–7.28 (m, 2H, H_ar), 7.30–7.24 (m, 4H, H_ar), 7.20–7.16 (m, 1H, H_ar), 4.42 (q, J = 6.5 Hz, 1H, CHCH₃), 4.39–4.26 (m, 2H, OCH₂CH₃), 4.25–4.05 (m, 2H, OCH₂CH₃), 1.40 (d, J = 6.5 Hz, 3H, CHCH₃), 1.30 (td, J = 7.1, 0.9 Hz, 3H, OCH₂CH₃), 1.22 (td, J = 7.1, 0.8 Hz, 3H, OCH₂CH₃). ¹³C NMR (101 MHz): δ = 164.64 (dd, J = 28.3, 5.9 Hz, C=N), 144.15 (s, C_ipso), 131.70 (d, J = 5.1 Hz, C_ipso), 128.50, 128.43, 128.41, 128.33, 126.99, 126.72 (6x s, CH_ar), 99.78 (dd, J = 269.3, 187.2 Hz, CBrF), 65.51 (d, J = 6.3 Hz, OCH₂CH₃), 65.05 (d, J = 6.6 Hz, OCH₂CH₃), 61.40 (s, CHCH₃), 23.97 (s, CHCH₃), 16.56 (d, J = 6.1 Hz, OCH₂CH₃), 16.44 (d, J = 6.1 Hz, OCH₂CH₃). ¹⁹F NMR (283 MHz): δ = −128.65 (d, J = 82.3 Hz, 1F). ³¹P{/¹H} NMR (122 MHz): δ = 7.93 (d, J = 82.3 Hz, 1P).

(E)-Diethyl ((1S)-1-bromo-1-fluoro-2-phenyl-2-(((R)-1-phenylethyl)imino)ethyl) phosphonate (11a) and (E)-Diethyl ((1R)-1-bromo-1-fluoro-2-phenyl-2-(((R)-1-phenylethyl)imino)ethyl)phosphonate (11b).

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.

11a: ¹H NMR (400 MHz): δ = 7.43–7.37 (m, 5H, H_ar), 7.26–7.21 (m, 5H, H_ar), 4.42–4.35 (m, 3H, OCH₂CH₃, CHCH₃), 4.34–4.25 (m, 2H, OCH₂CH₃), 1.39 (d, J = 6.5 Hz, 3H, CHCH₃), 1.36 (td, J = 7.1, 0.8 Hz, 3H, OCH₂CH₃), 1.33 (td, J = 7.1, 0.9 Hz, 3H, OCH₂CH₃). ¹³C NMR (101 MHz): δ = 164.45 (dd, J = 27.1, 6.1 Hz, C=N), 144.53 (s, C_ipso), 131.52 (d, J = 5.1 Hz, C_ipso), 129.52, 128.60, 128.45, 126.96, 126.69, 126.43 (6x s, CH_ar), 100.99 (dd, J = 269.7, 187.4 Hz, CBrF), 65.45 (d, J = 6.1 Hz, OCH₂CH₃), 65.14 (d, J = 6.7 Hz, OCH₂CH₃), 61.17 (s, CHCH₃), 24.49 (s, CHCH₃), 16.56 (d, J = 6.0 Hz, OCH₂CH₃), 16.45 (d, J = 6.1 Hz, OCH₂CH₃). ¹⁹F NMR (283 MHz): δ = −128.52 (d, J = 82.1 Hz, 1F). ³¹P{/¹H} NMR (122 MHz): δ = 7.38 (d, J = 82.1 Hz, 1P). IR (neat): 1644, 1262, 1017, 970, 647 [cm⁻¹]. MS (EI) m/z = 457.3 [M+H]⁺.

11b: ¹H NMR (400 MHz): δ = 7.32–7.27 (m, 5H, H_ar), 7.23–7.16 (m, 5H, H_ar), 4.43 (q, J = 6.5 Hz, 1H, CHCH₃), 4.27–4.17 (m, 2H, OCH₂CH₃), 4.16–4.08 (m, 2H, OCH₂CH₃), 1.41 (d, J = 6.5 Hz, 3H, CHCH₃), 1.31 (td, J = 7.1, 0.8 Hz, 3H, OCH₂CH₃), 1.23 (td, J = 7.1 0.8 Hz, 3H, OCH₂CH₃). ¹³C NMR (101 MHz): δ = 164.63 (dd, J = 28.4, 5.9 Hz, C=N), 144.12 (s, C_ipso), 131.69 (d, J = 5.1 Hz, C_ipso), 128.55, 128.41, 128.36, 128.29, 127.01, 126.93 (6x s, CH_ar), 99.14 (dd, J = 269.1, 187.0 Hz, CBrF), 65.42 (d, J = 6.2 Hz, OCH₂CH₃), 65.00 (d, J = 6.6 Hz, OCH₂CH₃), 61.37 (s, CHCH₃), 23.92 (s, CHCH₃), 16.53 (d, J = 6.1 Hz, OCH₂CH₃), 16.41 (d, J = 6.0 Hz, OCH₂CH₃). ¹⁹F NMR (283 MHz): δ = −128.13 (d, J = 82.3 Hz, 1F). ³¹P{/¹H} NMR (122 MHz): δ = 7.42 (d, J = 82.4 Hz, 1P).

rac-(E)-Diethyl ((1R/1S)-1-bromo-1-fluoro-2-((4-methoxybenzyl)imino)-2-phenylethyl)phosphonate (rac-12).

Pale-yellow oil, 222 mg, yield 94%.

¹H NMR (400 MHz): δ = 7.45–7.42 (m, 3H, H_ar), 7.34–7.30 (m, 2H, H_ar), 7.22–7.15 (m, 2H, H_ar), 6.85–6.80 (m, 2H, H_ar), 4.46 (br s, CH₂N, 2H), 4.33–4.24 (m, 2H, OCH₂CH₃), 4.23–4.10 (m, 2H, OCH₂CH₃), 3.76 (s, 3H, Ph(4-OCH₃)), 1.26 (td, J = 7.1, 0.9 Hz, 3H, OCH₂CH₃), 1.25 (td, J = 7.1, 0.8 Hz, 3H, OCH₂CH₃). ¹³C NMR (101 MHz): δ = 166.67 (dd, J = 27.7, 6.1 Hz, C=N), 158.67 (s, C_ar(OCH₃)), 131.44 (d, J = 5.2 Hz, C_ipso), 130.90 (s, C_ipso), 129.70, 128.93 (2x s, CH_ar), 128.60 (d, J = 1.5 Hz, CH_ar), 128.50 (s, CH_ar), 113.93 (s, CH_arC_ar(OCH₃)), 99.97 (dd, J = 269.7, 187.6 Hz, CBrF), 65.54 (d, J = 6.3 Hz, OCH₂CH₃), 65.15 (d, J = 6.7 Hz, OCH₂CH₃), 56.42 (br s, CH₂N), 55.39 (s, Ph(4-OCH₃)), 16.49 (d, J = 6.1 Hz, OCH₂CH₃), 16.48 (d, J = 6.0 Hz, OCH₂CH₃). ¹⁹F NMR (283 MHz): δ = −129.07 (d, J = 81.2 Hz, 1F). ³¹P{/¹H} NMR (122 MHz): δ = 7.98 (d, J = 81.4 Hz, 1P). IR (neat): 1645, 1261, 1247, 1013, 970, 647 [cm⁻¹]. MS (EI) m/z = 392.2 [M-Br]⁺.

rac-(E)-Diethyl ((1R/1S)-1-bromo-1-fluoro-2-((4-methoxyphenyl)imino)-2-phenylethyl)phosphonate (rac-13).

Brown oil, 200 mg, yield 87%.

¹H NMR (400 MHz): δ = 7.31–7.26 (m, 5H, H_ar), 6.68–6.64 (m, 4H, H_ar), 4.41–4.30 (m, 4H, 2x OCH₂CH₃), 3.68 (s, 3H, Ph(4-OCH₃)), 1.36 (td, J = 7.1, 0.9 Hz, 3H, OCH₂CH₃), 1.35 (td, J = 7.1, 0.9 Hz, 3H, OCH₂CH₃). ¹³C NMR (101 MHz): δ = 164.12 (dd, J = 28.4, 5.9 Hz, C=N), 157.44 (s, C_ar(OCH₃)), 140.26 (s, C_ipso), 131.94 (d, J = 5.0 Hz C_ipso), 129.56, 129.43, 123.19, 118.90 (4x s, CH_ar), 113.90 (s, CH_arC_ar(OCH₃)), 100.17 (dd, J = 270.1, 187.2 Hz, CBrF), 65.58 (d, J = 6.4 Hz, OCH₂CH₃), 65.29 (d, J = 6.6 Hz, OCH₂CH₃), 55.35 (s, Ph(4-OCH₃)), 16.56 (d, J = 5.9 Hz, OCH₂CH₃), 16.55 (d, J = 6.0 Hz, OCH₂CH₃). ¹⁹F NMR (283 MHz): δ = −128.49 (d, J = 81.7 Hz, 1F). ³¹P{/¹H} NMR (122 MHz): δ = 7.30 (d, J = 81.5 Hz, 1P). IR (neat): 1645, 1262, 1246, 1012, 972, 645 [cm⁻¹]. MS (EI) m/z = 459.3 [M+H]⁺.

3.6. General Procedure for Synthesis of α,α-Chlorofluorinated ß-Iminophosphonates (14a,b, rac-15)

Compounds 14a,b and rac-15 were obtained according to the above-described procedure for bromofluorinated iminophosphonates (10–11a,b, rac-12–13). Selectfluor and N-chlorosuccinimide (NCS) were used as halogenation reagents with appropriate molar equivalents equaled 1.35 and 1.0, respectively.

(E)-Diethyl ((1R)-1-chloro-1-fluoro-2-phenyl-2-(((S)-1-phenylethyl)imino)ethyl)phosphonate (14a) and (E)-diethyl ((1S)-1-chloro-1-fluoro-2-phenyl-2-(((S)-1-phenylethyl)imino)ethyl)phosphonate (14b)

Pale-yellow oil, 128 mg, yield 62%. Isolated as a mixture of diastereomers 14a,b (dr 0.2:1). The rest of diastereomer 14a (65 mg) was contaminated with difluoro- and dichloroiminophosphonate derivatives.

14a: ¹H NMR (400 MHz): δ = 7.45–7.41 (m, 3H, H_ar), 7.32–7.27 (m, 4H, H_ar), 7.25–7.21 (m, 3H, H_ar), 4.49 (q, J = 6.5 Hz, 1H, CHCH₃), 4.38–4.32 (m, 2H, OCH₂CH₃), 4.29–4.25 (m, 2H, OCH₂CH₃), 1.42 (d, J = 6.5 Hz, 3H, CHCH₃), 1.34 (td, J = 7.1, 0.8 Hz, 3H, OCH₂CH₃), 1.32 (td, J = 7.1, 0.8 Hz, 3H, OCH₂CH₃). ¹³C NMR (101 MHz): δ = 163.55 (dd, J = 28.1, 6.5 Hz, C=N), 144.46 (s, C_ipso), 131.51 (d, J = 4.7 Hz, C_ipso), 128.58, 128.55, 128.43, 128.02, 127.08, 126.58 (6x s, CH_ar), 105.89 (dd, J = 260.7, 189.9 Hz, CClF), 65.11 (d, J = 6.5 Hz, OCH₂CH₃), 64.78 (d, J = 6.5 Hz, OCH₂CH₃), 61.33 (s, CHCH₃), 24.51 (s, CHCH₃), 16.52 (d, J = 6.1 Hz, OCH₂CH₃), 16.48 (d, J = 6.0 Hz, OCH₂CH₃). ¹⁹F NMR (283 MHz): δ = −125.59 (d, J = 86.2 Hz, 1F). ³¹P{/¹H} NMR (122 MHz): δ = 8.02 (d, J = 86.0 Hz, 1P). IR (neat): 1657, 1262, 1011, 969, 666 [cm⁻¹]. MS (EI) m/z = 376.2 [M-Cl]⁺.

14b: ¹H NMR (400 MHz): δ = 7.43–7.37 (m, 3H, H_ar), 7.31–7.26 (m, 4H, H_ar), 7.25–7.22 (m, 3H, H_ar), 4.46 (q, J = 6.5 Hz, 1H, CHCH₃), 4.39–4.23 (m, 3H, OCH₂CH₃, OCHHCH₃), 4.22–4.12 (m, 1H, OCHHCH₃), 1.44 (d, J = 6.5 Hz, 3H, CHCH₃), 1.31 (td, J = 7.1, 0.9 Hz, 3H, OCH₂CH₃), 1.24 (td, J = 7.1, 0.8 Hz, 3H, OCH₂CH₃). ¹³C NMR (101 MHz): δ = 163.75 (dd, J = 28.6, 6.8 Hz, C=N), 144.16 (s, C_ipso), 131.64 (d, J = 4.8 Hz, C_ipso), 129.56, 129.53, 128.50, 128.39, 126.99, 126.68 (6x s, CH_ar), 105.77 (dd, J = 259.9, 193.0 Hz, CClF), 65.35 (d, J = 6.5 Hz, OCH₂CH₃), 64.96 (d, J = 6.5 Hz, OCH₂CH₃), 61.45 (br s, CHCH₃), 24.16 (s, CHCH₃), 16.53 (d, J = 6.0 Hz, OCH₂CH₃), 16.42 (d, J = 5.9 Hz, OCH₂CH₃). ¹⁹F NMR (283 MHz): δ = −125.39 (d, J = 87.0 Hz, 1F). ³¹P{/¹H} NMR (122 MHz): δ = 7.54 (d, J = 87.0 Hz, 1P).

rac- (E)-Diethyl (1R/1S)-1-chloro-1-fluoro-2-((4-methoxybenzyl)imino)-2-phenylethyl)phosphonate (rac-15).

Pale-yellow oil, 195 mg, yield 91%.

¹H NMR (400 MHz): δ = 7.43–7.39 (m, 3H, H_ar), 7.33–7.27 (m, 2H, H_ar), 7.19–7.14 (m, 2H, H_ar), 6.84–6.78 (m, 2H, H_ar), 4.46 (br s, 2H, CH₂N), 4.32–4.23 (m, 2H, OCH₂CH₃), 4.21–4.15 (m, 2H, OCH₂CH₃), 3.75 (s, 3H, Ph(4-OCH₃)), 1.26 (td, J = 7.1, 0.9 Hz, 3H, OCH₂CH₃), 1.24 (td, J = 7.1, 0.8 Hz, 3H, OCH₂CH₃). ¹³C NMR (101 MHz): δ = 165.78 (dd, J = 27.9, 6.7 Hz, C=N), 158.68 (s, C_ar(OCH₃)), 131.35 (d, J = 4.9 Hz C_ipso), 129.18, 129.15, 128.93, 128.51 (4x s, CH_ar), 128.43 (d, J = 1.3 Hz, CH_ar), 128.25 (s, CH_ar), 113.91 (s, CH_arC_ar(OCH₃)), 105.94 (dd, J = 260.5, 193.5 Hz, CClF), 65.55 (d, J = 6.9 Hz, OCH₂CH₃), 65.10 (d, J = 6.6 Hz, OCH₂CH₃), 56.46 (br s, CH₂N), 55.36 (s, Ph(4-OCH₃)), 16.48 (d, J = 6.0 Hz, OCH₂CH₃), 16.45 (d, J = 5.8 Hz, OCH₂CH₃). ¹⁹F NMR (283 MHz): δ = −125.57 (d, J = 85.6 Hz, 1F). ³¹P{/¹H} NMR (122 MHz): δ = 8.09 (d, J = 86.0 Hz, 1P). IR (neat): 1648, 1260, 1014, 970, 668 [cm⁻¹]. MS (EI) m/z = 428.8 [M+H]⁺.

3.7. General Procedure for Synthesis of α,α-Halofluorinated ß-Aminophosphonates (16–17,20a–d, rac-18–19,21a,b)

To the stirred solution of β-iminophosphonate (10–11,14a,b, rac-12–13,15) (0.5 mmol) in MeOH (3 mL), NaBH₃CN (188 mg, 3 mmol) and glacial CH₃COOH (171 µL, 180 mg, 3 mmol) at room temperature were added. Stirring was continued for 40 min and then the solvent was evaporated. Next, the residue was dissolved in CHCl₃ (2 mL), water (10 mL) was added, and the inorganic layer was extracted (3 × 10 mL CHCl₃). The organic layers were combined, dried over Na₂SO₄, and evaporated to give the product as a pale-yellow oil. The crude products were purified by column chromatography (AcOEt/hexane: 5% → 60%).

Diethyl ((1S/R, 2S/R)-1-bromo-1-fluoro-2-phenyl-2-(((S)-1-phenylethyl)amino)ethyl)phosphonate (16a-d).

Isolated as a mixture of two major diastereomers 16a,b (dr 1:0.96). Diagnostic signals for traces of diastereomers 16c,d were determined from the crude reaction mixture. Pale-yellow oil, 222 mg, yield 97%.

Diethyl ((1R, 2R)-1-bromo-1-fluoro-2-phenyl-2-(((S)-1-phenylethyl)amino)ethyl)phosphonate (16a).

¹H NMR (400 MHz): δ = 7.36–7.33 (m, 5H, H_ar), 7.28–7.25 (m, 2H, H_ar), 7.21–7.19 (m, 3H, H_ar), 4.58 (dd, J = 10.2, 4.7 Hz, 1H, CH(Ph)CF), 4.40–4.29 (m, 2H, OCH₂CH₃), 4.27–4.23 (m, 2H, OCH₂CH₃), 3.75 (q, J = 6.4 Hz, 1H, CHCH₃), 1.34 (d, J = 6.4 Hz, 3H, CHCH₃), 1.28 (td, J = 7.1, 0.8 Hz, 3H, OCH₂CH₃), 1.27 (td, J = 7.1, 0.8 Hz, 3H, OCH₂CH₃). ¹³C NMR (101 MHz): δ = 145.46 (s, C_ipso), 135.70 (d, J = 8.6 Hz, C_ipso), 128.54, 128.50, 128.41, 128.06, 127.24, 126.91 (6x s, CH_ar), 107.44 (dd, J = 270.1, 184.3 Hz, CBrF), 65.58 (d, J = 7.3 Hz, OCH₂CH₃), 65.16 (d, J = 7.3 Hz, OCH₂CH₃), 64.12 (dd, J = 22.0, 7.5 Hz, CH(Ph)CF), 54.71 (s, CHCH₃), 21.89 (s, CHCH₃), 16.60 (d, J = 6.1 Hz, OCH₂CH₃), 16.44 (d, J = 6.2 Hz, OCH₂CH₃). ¹⁹F NMR (283 MHz): δ = −125.06 (dd, J = 82.3, 10.2 Hz, 1F). ³¹P{/¹H} NMR (122 MHz): δ = 9.77 (d, J = 82.0 Hz, 1P). IR (neat): 1264, 1024, 977, 648 [cm⁻¹]. MS (EI) m/z = 459.4 [M+H]⁺.

Diethyl ((1S, 2R)-1-bromo-1-fluoro-2-phenyl-2-(((S)-1-phenylethyl)amino)ethyl)phosphonate (16b).

¹H NMR (400 MHz): δ = 7.33–7.29 (m, 5H, H_ar), 7.26–7.24 (m, 1H, H_ar), 7.23–7.21 (m, 2H, H_ar), 7.18–7.16 (m, 2H, H_ar), 4.37 (dd, J = 22.0, 3.5 Hz, 1H, CH(Ph)CF), 4.22–4.17 (m, 2H, OCH₂CH₃), 4.17–4.07 (m, 2H, OCH₂CH₃), 3.74 (q, J = 6.5 Hz, 1H, CHCH₃), 1.35 (d, J = 6.4 Hz, 3H, CHCH₃), 1.26 (td, J = 7.1, 0.8 Hz, 3H, OCH₂CH₃), 1.25 (td, J = 7.1, 0.8 Hz, 3H, OCH₂CH₃). ¹³C NMR (101 MHz): δ = 145.67 (s, C_ipso), 137.14 (dd, J = 6.0, 2.5 Hz, C_ipso), 128.44, 128.40, 128.13, 127.64, 127.15, 126.84 (6x s, CH_ar), 107.62 (dd, J = 274.2, 183.1 Hz, CBrF), 66.47 (dd, J = 18.2, 7.9 Hz, CH(Ph)CF), 64.88 (d, J = 7.2 Hz, OCH₂CH₃), 64.74 (d, J = 7.2 Hz, OCH₂CH₃), 55.67 (s, CHCH₃), 22.10 (s, CHCH₃), 16.52 (d, J = 6.1 Hz, OCH₂CH₃), 16.42 (d, J = 6.1 Hz, OCH₂CH₃). ¹⁹F NMR (283 MHz): δ = −135.38 (dd, J = 84.6, 22.1 Hz, 1F). ³¹P{/¹H} NMR (122 MHz): δ = 9.25 (d, J = 84.7 Hz, 1P).

Diethyl ((1S, 2S)-1-bromo-1-fluoro-2-phenyl-2-(((S)-1-phenylethyl)amino)ethyl)phosphonate (16c).

Diagnostic signals: ¹⁹F NMR (283 MHz): δ = −128.26 (dd, J = 78.0, 10.2 Hz). ³¹P{/¹H} NMR (122 MHz): δ = 9.06 (d, J = 77.9 Hz).

Diethyl ((1R, 2S)-1-bromo-1-fluoro-2-phenyl-2-(((S)-1-phenylethyl)amino)ethyl)phosphonate (16d).

Diagnostic signals: ¹⁹F NMR (283 MHz): δ = −135.49 (dd, J = 88.4, 20.9 Hz). ³¹P{/¹H} NMR (122 MHz): signal masked by other diastereomers signals.

Diethyl ((1S/1R, 2S/2R)-1-bromo-1-fluoro-2-phenyl-2-(((R)-1-phenylethyl)amino)ethyl)phosphonate (17a-d).

Isolated as a mixture of two major diastereomers 17a,b (dr 1:0.8). Diagnostic signals for traces of diastereomers 17c,d were determined from the crude reaction mixture. Pale-yellow oil, 217 mg, yield 95%.

Diethyl ((1S, 2S)-1-bromo-1-fluoro-2-phenyl-2-(((R)-1-phenylethyl)amino)ethyl)phosphonate (17a).

¹H NMR (400 MHz): δ = 7.35–7.33 (m, 5H, H_ar), 7.28–7.26 (m, 2H, H_ar), 7.22–7.19 (m, 3H, H_ar), 4.58 (dd, J = 10.2, 4.7 Hz, 1H, CH(Ph)CF), 4.36–4.32 (m, 2H, OCH₂CH₃), 4.26–4.23 (m, 2H, OCH₂CH₃), 3.75 (q, J = 6.4 Hz, 1H, CHCH₃), 1.35 (td, J = 7.1, 0.8 Hz, 3H, OCH₂CH₃), 1.32 (d, J = 6.4 Hz, 3H, CHCH₃), 1.31 (td, J = 7.1, 0.8 Hz, 3H, OCH₂CH₃). ¹³C NMR (101 MHz): δ = 145.41 (s, C_ipso), 135.63 (d, J = 8.6 Hz, C_ipso), 128.52, 128.49, 128.42, 128.04, 127.22, 126.81 (6x s, CH_ar), 107.39 (dd, J = 270.1, 184.4 Hz, CBrF), 65.56 (d, J = 7.0 Hz, OCH₂CH₃), 65.15 (d, J = 7.3 Hz, OCH₂CH₃), 64.05 (dd, J = 21.9, 7.5 Hz, CH(Ph)CF), 54.65 (s, CHCH₃), 21.85 (s, CHCH₃), 16.59 (d, J = 6.0 Hz, OCH₂CH₃), 16.43 (d, J = 6.1 Hz, OCH₂CH₃). ¹⁹F NMR (283 MHz): δ = −125.04 (dd, J = 82.1, 10.1 Hz, 1F). ³¹P{/¹H} NMR (122 MHz): δ = 9.25 (d, J = 82.0 Hz, 1P). IR (neat): 1262, 1021, 978, 646 [cm⁻¹]. MS (EI) m/z = 459.4 [M-H]⁺.

Diethyl ((1R, 2S)-1-bromo-1-fluoro-2-phenyl-2-(((R)-1-phenylethyl)amino)ethyl)phosphonate (17b).

¹H NMR (400 MHz): δ = 7.32–7.29 (m, 5H, H_ar), 7.26–7.24 (m, 2H, H_ar), 7.19–7.16 (m, 3H, H_ar), 4.42–4.37 (m, 2H, OCH₂CH₃), 4.34 (dd, J = 22.1, 3.2 Hz, 1H, CH(Ph)CF), 4.23–4.15 (m, 2H, OCH₂CH₃), 3.74 (q, J = 6.5 Hz, 1H, CHCH₃), 1.33 (d, J = 6.4 Hz, 3H, CHCH₃), 1.27 (td, J = 7.1, 0.8 Hz, 3H, OCH₂CH₃), 1.26 (td, J = 7.1, 0.8 Hz, 3H, OCH₂CH₃). ¹³C NMR (101 MHz): δ = 145.62 (s, C_ipso), 137.08 (dd, J = 6.2, 2.7 Hz, C_ipso), 128.45, 128.40, 128.31, 128.11, 127.13, 126.88 (6x s, CH_ar), 107.57 (dd, J = 274.0, 182.8 Hz, CBrF), 66.42 (dd, J = 18.2, 8.0 Hz, CH(Ph)CF), 64.85 (d, J = 7.2 Hz, OCH₂CH₃), 64.72 (d, J = 7.1 Hz, OCH₂CH₃), 55.63 (s, CHCH₃), 22.06 (s, CHCH₃), 16.51 (d, J = 6.1 Hz, OCH₂CH₃), 16.42 (d, J = 6.1 Hz, OCH₂CH₃). ¹⁹F NMR (283 MHz): δ = −135.36 (dd, J = 84.6, 22.0 Hz, 1F). ³¹P{/¹H} NMR (122 MHz): δ = 8.73 (d, J = 84.6 Hz, 1P).

Diethyl((1R, 2R)-1-bromo-1-fluoro-2-phenyl-2-(((R)-1-phenylethyl)amino)ethyl)phosphonate (17c).

Diagnostic signals ¹⁹F NMR (283 MHz): δ = −128.25 (dd, J = 77.9, 10.2 Hz). ³¹P{/¹H} NMR (122 MHz): δ = 8.56 (d, J = 78.0 Hz).

Diethyl((1R, 2S)-1-bromo-1-fluoro-2-phenyl-2-(((R)-1-phenylethyl)amino)ethyl)phosphonate (17d).

¹⁹F NMR (283 MHz): signal masked by other diastereomers signals. Diagnostic signals ³¹P{/¹H} NMR (122 MHz): δ = 8.40 (d, J = 86.9 Hz).

rac-Diethyl ((1R, 2R)-1-bromo-1-fluoro-2-((4-methoxybenzyl)amino)-2-phenylethyl)phosphonate (rac-18a) and rac-diethyl ((1R, 2S)-1-bromo-1-fluoro-2-((4-methoxybenzyl)amino)-2-phenylethyl)phosphonate (rac-18b).

Isolated as a mixture of two diastereomers rac-18a,b (dr 1:0.75), which could not be separated by the chromatography techniques employed in this study. Pale-yellow oil, 230 mg, yield 97%.

rac-18a: ¹H NMR (400 MHz): δ = 7.46–7.44 (m, 3H, H_ar), 7.38–7.36 (m, 2H, H_ar), 7.14–7.10 (m, 2H, H_ar), 6.83–6.81 (m, 2H, H_ar), 4.37–4.26 (m, 3H, OCH₂CH₃, CH(Ph)CFP), 4.20–4.15 (m, 2H, OCH₂CH₃), 3.76 (s, 3H, Ph(4-OCH₃)), 3.72 (br d, J = 12.9 Hz, 1H, CHHN), 3.48 (br d, J = 13.1 Hz, 1H, CHHN), 1.30 (td, J = 7.1, 0.9 Hz, 3H, OCH₂CH₃), 1.22 (td, J = 7.0, 0.8 Hz, 3H, OCH₂CH₃). ¹³C NMR (101 MHz): δ = 158.84 (s, C_ar(OCH₃)), 135.13 (d, J = 8.5 Hz, C_ipso), 131.52 (s, C_ipso), 129.85 (d, J = 1.5 Hz, CH_ar), 129.71, 128.65, 128.12 (3x s, CH_ar), 113.78 (s, CH_arC_ar(OCH₃)), 106.46 (dd, J = 270.2, 183.8 Hz, CBrF), 65.79 (d, J = 7.0 Hz, OCH₂CH₃), 65.24 (dd, J = 21.5, 7.9 Hz, CH(Ph)CF), 65.03 (d, J = 7.1 Hz, OCH₂CH₃), 55.32 (s, Ph(4-OCH₃)), 50.02 (s, CH₂N), 16.48 (d, J = 5.9 Hz, OCH₂CH₃), 16.33 (d, J = 5.9 Hz, OCH₂CH₃). ¹⁹F NMR (283 MHz): δ = −126.81 (dd, J = 79.5, 9.4 Hz, 1F). ³¹P{/¹H} NMR (122 MHz): δ = 9.52 (d, J = 79.5 Hz, 1P). IR (neat): 1261, 1245, 1020, 975, 647 [cm⁻¹]. MS (EI) m/z = 475.3 [M-H]⁺.

rac-18b: ¹H NMR (400 MHz): δ = 7.44–7.41 (m, 3H, H_ar), 7.35–7.32 (m, 2H, H_ar), 7.17–7.14 (m, 2H, H_ar), 6.80–6.78 (m, 2H, H_ar), 4.28–4.22 (m, 3H, OCH₂CH_3, CH(Ph)CFP), 4.13–4.04 (m, 2H, OCH₂CH₃), 3.76 (s, 3H, Ph(4-OCH₃)), 3.65 (br d, J = 13.0 Hz, 1H, CHHN), 3.47 (br d, J = 13.0 Hz, 1H, CHHN), 1.22 (td, J = 7.1, 1.0 Hz, 3H, OCH₂CH₃), 1.21 (td, J = 7.1, 0.8 Hz, 3H, OCH₂CH₃). ¹³C NMR (101 MHz): δ = 158.80 (s, C_ar(OCH₃)), 136.37 (dd, J = 5.9, 2.5 Hz, C_ipso), 131.54 (s, C_ipso), 129.95 (d, J = 1.5 Hz, CH_ar), 129.59, 128.55, 128.14 (3x s, CH_ar), 113.77 (s, CH_arC_ar(OCH₃)), 106.64 (dd, J = 272.9, 184.4 Hz, CBrF), 67.72 (dd, J = 18.4, 8.2 Hz, CH(Ph)CF), 64.99 (d, J = 7.0 Hz, OCH₂CH₃), 64.57 (d, J = 7.3 Hz, OCH₂CH₃), 55.31 (s, Ph(4-OCH₃)), 50.76 (s, CH₂N), 16.47 (d, J = 5.9 Hz, OCH₂CH₃), 16.36 (d, J = 5.9 Hz, OCH₂CH₃). ¹⁹F NMR (283 MHz): δ = −135.34 (dd, J = 85.7, 20.6 Hz, 1F). ³¹P{/¹H} NMR (122 MHz): δ = 8.93 (d, J = 85.7 Hz, 1P).

rac-Diethyl ((1R, 2R)-1-bromo-1-fluoro-2-((4-methoxyphenyl)amino)-2-phenylethyl)phosphonate (rac-19a) and rac-diethyl ((1R, 2S)-1-bromo-1-fluoro-2-((4-methoxyphenyl)amino)-2-phenylethyl)phosphonate (rac-19b).

Isolated as a mixture of two diastereomers rac-19a,b (dr 1:0.86), which could not be separated by the chromatography techniques employed in this study. Pale yellow oil, 209 mg, yield 91%.

rac-19a: ¹H NMR (400 MHz): δ = 7.34–7.26 (m, 5H, H_ar), 6.66–6.64 (m, 2H, H_ar), 6.59–6.57 (m, 2H, H_ar), 4.37–4.26 (m, 3H, OCH₂CH₃, CH(Ph)CFP), 4.17–4.10 (m, 2H, OCH₂CH₃), 3.65 (s, 3H, Ph(4-OCH₃)), 1.35 (td, J = 7.1, 0.8 Hz, 3H, OCH₂CH₃), 1.25 (td, J = 7.1, 0.7 Hz, 3H, OCH₂CH₃). ¹³C NMR (101 MHz): δ = 152.95 (s, C_ar(OCH₃)), 139.48 (s, C_ipso), 135.71 (d, J = 8.8 Hz, C_ipso), 129.17 (d, J = 2.1 Hz, CH_ar), 128.66, 128.51, 128.19 (3x s, CH_ar), 114.84 (s, CH_arC_ar(OCH₃)), 105.61 (dd, J = 271.6, 183.6 Hz, CBrF), 65.87 (d, J = 6.9 Hz, OCH₂CH₃), 65.65 (d, J = 7.4 Hz, OCH₂CH₃), 63.30 (dd, J = 23.4, 6.9 Hz, CH(Ph)CF), 55.68 (s, Ph(4-OCH₃)), 16.57 (d, J = 5.7 Hz, OCH₂CH₃), 16.43 (d, J = 5.6 Hz, OCH₂CH₃). ¹⁹F NMR (283 MHz): δ = −126.36 (dd, J = 78.1, 9.7 Hz, 1F). ³¹P{/¹H} NMR (122 MHz): δ = 9.22 (d, J = 77.9 Hz, 1P). IR (neat): 1260, 1249, 1023, 974, 646 [cm⁻¹]. MS (EI) m/z = 459.2 [M-H]⁺.

rac-19b: ¹H NMR (400 MHz): δ = 7.51–7.43 (m, 5H, H_ar), 6.70–6.67 (m, 2H, H_ar), 6.57–6.53 (m, 2H, H_ar), 4.24–4.17 (m, 3H, OCH₂CH_3, CH(Ph)CFP), 4.10–4.00 (m, 2H, OCH₂CH₃), 3.66 (s, 3H, Ph(4-OCH₃)), 1.27 (td, J = 7.1, 0.8 Hz, 3H, OCH₂CH₃), 1.16 (td, J = 7.1, 0.8 Hz, 3H, OCH₂CH₃). ¹³C NMR (101 MHz): δ = 152.82 (s, C_ar(OCH₃)), 140.04 (s, C_ipso), 136.51 (d, J = 4.8 Hz, C_ipso), 129.36 (d, J = 1.7 Hz, CH_ar), 128.85, 128.61, 128.49 (3x s, CH_ar), 115.68 (s, CH_arC_ar(OCH₃)), 105.37 (dd, J = 274.0, 181.3 Hz, CBrF), 66.49 (dd, J = 19.7, 7.6 Hz, CH(Ph)CF), 65.06 (d, J = 6.6 Hz, OCH₂CH₃), 64.79 (d, J = 6.7 Hz, OCH₂CH₃), 55.69 (s, Ph(4-OCH₃)), 16.36 (d, J = 5.7 Hz, OCH₂CH₃), 16.24 (d, J = 5.9 Hz, OCH₂CH₃). ¹⁹F NMR (283 MHz): δ = −135.34 (dd, J = 82.1, 18.6 Hz, 1F). ³¹P{/¹H} NMR (122 MHz): δ = 8.17 (d, J = 82.1 Hz, 1P).

Diethyl ((1S/1R, 2S/2R)-1-chloro-1-fluoro-2-phenyl-2-(((S)-1-phenylethyl)amino)ethyl)phosphonate (20a-d).

Isolated as a mixture of four diastereomers 20a–d (dr 1:0.83:0.07:0.11). Pale-yellow oil, 196 mg, yield 95%.

Diethyl ((1R, 2R)-1-chloro-1-fluoro-2-phenyl-2-(((S)-1-phenylethyl)amino)ethyl)phosphonate (20a).

¹H NMR (400 MHz): δ = 7.35–7.32 (m, 5H, H_ar), 7.27–7.25 (m, 2H, H_ar), 7.21–7.19 (m, 3H, H_ar), 4.71 (dd, J = 8.9, 4.6 Hz, 1H, CH(Ph)CF), 4.38–4.31 (m, 2H, OCH₂CH₃), 4.29–4.26 (m, 2H, OCH₂CH₃), 3.74 (q, J = 6.4 Hz, CHCH₃), 1.36 (td, J = 7.1, 0.8 Hz, 3H, OCH₂CH₃), 1.34 (d, J = 6.4 Hz, 3H, CHCH₃), 1.33 (td, J = 7.1, 0.8 Hz, 3H, OCH₂CH₃). ¹³C NMR (101 MHz): δ = 145.40 (s, C_ipso), 135.16 (d, J = 8.2 Hz, C_ipso), 128.49, 128.45, 128.40, 128.09, 127.21, 126.76 (6x s, CH_ar), 110.45 (dd, J = 260.4, 191.5 Hz, CClF), 65.32 (d, J = 6.9 Hz, OCH₂CH₃), 64.97 (d, J = 7.2 Hz, OCH₂CH₃), 63.80 (dd, J = 23.3, 8.1 Hz, CH(Ph)CF), 54.76 (s, CHCH₃), 21.68 (s, CHCH₃), 16.54 (d, J = 6.0 Hz, OCH₂CH₃), 16.42 (d, J = 6.3 Hz, OCH₂CH₃). ¹⁹F NMR (283 MHz): δ = −123.06 (dd, J = 87.4, 8.8 Hz, 1F). ³¹P{/¹H} NMR (122 MHz): δ = 9.61 (d, J = 87.4 Hz, 1P). IR (neat): 1264, 1025, 984, 673 [cm⁻¹]. MS (EI) m/z = 413.2 [M]⁺.

Diethyl ((1S, 2R)-1-chloro-1-fluoro-2-phenyl-2-(((S)-1-phenylethyl)amino)ethyl)phosphonate (20b).

¹H NMR (400 MHz): δ = 7.32–7.29 (m, 5H, H_ar), 7.25–7.24 (m, 2H, H_ar), 7.23–7.21 (m, 2H, H_ar), 7.19–7.18 (m, 1H, H_ar), 4.41 (dd, J = 21.3, 3.3 Hz, 1H, CH(Ph)CF), 4.24–4.19 (m, 2H, OCH₂CH₃), 4.18–4.04 (m, 2H, OCH₂CH₃), 3.73 (q, J = 6.6 Hz, 1H, CHCH₃), 1.33 (d, J = 6.3 Hz, 3H, CHCH₃), 1.29 (td, J = 7.1, 0.8 Hz, 3H, OCH₂CH₃), 1.26 (td, J = 7.1, 0.8 Hz, 3H, OCH₂CH₃). ¹³C NMR (101 MHz): δ = 145.55 (s, C_ipso), 136.48 (dd, J = 6.1, 2.7 Hz, C_ipso), 128.45, 128.35, 128.30, 128.15, 127.12, 126.84 (6x s, CH_ar), 111.08 (dd, J = 265.2, 190.1 Hz, CClF), 65.83 (dd, J = 18.6, 8.7 Hz, CH(Ph)CF), 64.80 (d, J = 7.2 Hz, OCH₂CH₃), 64.68 (d, J = 7.4 Hz, OCH₂CH₃), 55.52 (s, CHCH₃), 21.96 (s, CHCH₃), 16.48 (d, J = 6.1 Hz, OCH₂CH₃), 16.43 (d, J = 6.2 Hz, OCH₂CH₃). ¹⁹F NMR (283 MHz): δ = −134.74 (dd, J = 89.0, 21.5 Hz, 1F). ³¹P{/¹H} NMR (122 MHz): δ = 9.02 (d, J = 89.2 Hz, 1P).

Diethyl ((1S, 2S)-1-chloro-1-fluoro-2-phenyl-2-(((S)-1-phenylethyl)amino)ethyl)phosphonate (20c).

Diagnostic signals ¹⁹F NMR (283 MHz): δ = −125.91 (dd, J = 83.2, 9.2 Hz). ³¹P{/¹H} NMR (122 MHz): δ = 8.89 (d, J = 83.3 Hz).

Diethyl ((1R, 2S)-1-chloro-1-fluoro-2-phenyl-2-(((S)-1-phenylethyl)amino)ethyl)phosphonate (20d).

Diagnostic signals ¹⁹F NMR (283 MHz): δ = −134.88 (dd, J = 91.3, 21.0 Hz). ³¹P{/¹H} NMR (122 MHz): δ = 8.66 (d, J = 91.5 Hz).

rac-Diethyl ((1R, 2R)-1-chloro-1-fluoro-2-((4-methoxybenzyl)amino)-2-phenylethyl)phosphonate (rac-21a) and rac-diethyl ((1R, 2S)-1-chloro-1-fluoro-2-((4-methoxybenzyl)amino)-2-phenylethyl)phosphonate (rac-21b).

Isolated as a mixture of two diastereomers rac-21a,b (dr 1:0.92), which could not be separated by the chromatography techniques employed in this study. Pale-yellow oil, 206 mg, yield 96%.

rac-21a: ¹H NMR (400 MHz): δ = 7.45–7.42 (m, 3H, H_ar), 7.39–7.36 (m, 2H, H_ar), 7.14–7.11 (m, 2H, H_ar), 6.83–6.81 (m, 2H, H_ar), 4.45 (dd, J = 8.4, 4.4 Hz, 1H, CH(Ph)CFP), 4.36–4.25 (m, 2H, OCH₂CH₃), 4.16–4.08 (m, 2H, OCH₂CH₃), 3.75 (s, 3H, Ph(4-OCH₃)), 3.70 (br d, J = 12.9 Hz, 1H, CHHN), 3.47 (d, J = 12.9 Hz, 1H, CHHN), 1.28 (td, J = 7.1, 0.8 Hz, 3H, OCH₂CH₃), 1.23 (td, J = 7.1, 0.8 Hz, 3H, OCH₂CH₃). ¹³C NMR (101 MHz): δ = 158.86 (s, C_ar(OCH₃)), 134.75 (d, J = 8.3 Hz, C_ipso), 131.48 (s, C_ipso), 129.83 (d, J = 1.3 Hz, CH_ar), 129.71, 128.64, 128.18 (3x s, CH_ar), 113.82 (s, CH_arC_ar(OCH₃)), 109.70 (dd, J = 260.8, 191.2 Hz, CClF), 65.57 (d, J = 6.9 Hz, OCH₂CH₃), 65.07 (dd, J = 22.1, 8.6 Hz, CH(Ph)CF), 64.92 (d, J = 7.1 Hz, OCH₂CH₃), 55.31 (s, Ph(4-OCH₃)), 50.18 (s, CH₂N), 16.45 (d, J = 5.9 Hz, OCH₂CH₃), 16.32 (d, J = 5.9 Hz, OCH₂CH₃). ¹⁹F NMR (283 MHz): δ = −124.54 (dd, J = 84.8, 8.3 Hz, 1F). ³¹P{/¹H} NMR (122 MHz): δ = 9.37 (d, J = 84.7 Hz, 1P). IR (neat): 1263, 1253, 1024, 981, 672 [cm⁻¹]. MS (EI) m/z = 430.8 [M-H]⁺.

rac-21b: ¹H NMR (400 MHz): δ = 7.43–7.40 (m, 3H, H_ar), 7.36–7.33 (m, 2H, H_ar), 7.18–7.14 (m, 2H, H_ar), 6.80–6.78 (m, 2H, H_ar), 4.23–4.17 (m, 3H, OCH₂CH_3, CH(Ph)CFP), 4.10–3.98 (m, 2H, OCH₂CH₃), 3.76 (s, 3H, Ph(4-OCH₃)), 3.65 (br d, J = 12.9 Hz, 1H, CHHN), 3.46 (d, J = 12.9 Hz, 1H, CHHN), 1.25 (td, J = 7.1, 0.9 Hz, 3H, OCH₂CH₃), 1.22 (td, J = 7.0, 0.8 Hz, 3H, OCH₂CH₃). ¹³C NMR (101 MHz): δ = 158.83 (s, C_ar(OCH₃)), 135.85 (dd, J = 6.0, 2.4 Hz, C_ipso), 131.52 (s, C_ipso), 129.90 (d, J = 1.3 Hz, CH_ar), 129.60, 128.55, 128.21 (3x s, CH_ar), 113.81 (s, CH_arC_ar(OCH₃)), 110.35 (dd, J = 264.0, 191.1 Hz, CClF), 67.24 (dd, J = 18.8, 8.9 Hz, CH(Ph)CF), 64.99 (d, J = 7.1 Hz, OCH₂CH₃), 64.61 (d, J = 7.2 Hz, OCH₂CH₃), 55.30 (s, Ph(4-OCH₃)), 50.70 (s, CH₂N), 16.42 (d, J = 5.9 Hz, OCH₂CH₃), 16.35 (d, J = 5.9 Hz, OCH₂CH₃). ¹⁹F NMR (283 MHz): δ = −134.91 (dd, J = 90.6, 20.5 Hz, 1F). ³¹P{/¹H} NMR (122 MHz): δ = 8.76 (d, J = 90.8 Hz, 1P).

3.8. Synthesis of α-Fluorinated ß-Enaminophosphonate/ß-Iminophosphonate (22a,b/23a,b)

To a solution of the β-iminophosphonate (10a,b) (137 mg, 0.3 mmol) in anhydrous THF (2 mL), LiAlH₄ (17 mg, 0.45 mmol) at 0 °C was added. The reaction was warmed to room temperature, and then stirred for 40 min. After this time, solvent was evaporated and chloroform (5 mL) was added to the residue. The crude mixture was filtered through a syringe filter and purified using column chromatography (AcOEt/hexane: 10% → 50%) to give yellow oil with 83% yield (94 mg), as a mixture of enamine (22a,b) and imine (23a,b): (E-22a/Z-22b ratio 1:0.3; 22a,b/23a,b ratio 1:0.05)

(E)-Diethyl (1-fluoro-2-phenyl-2-(((S)-1-phenylethyl)amino)vinyl)phosphonate (E-22a).

¹H NMR (401 MHz): δ = 7.38–7.35 (m, 2H, H_ar), 7.28–7.25 (m, 2H, H_ar), 7.24–7.20 (m, 2H, H_ar), 7.19–7.14 (m, 2H, H_ar), 7.05–7.02 (m, 2H, H_ar), 6.48 (dd, J = 10.5 Hz, 4.6 Hz, NH), 4.09–3.76 (m, 5H, 2x OCH₂CH₃, CHCH₃), 1.41 (d, J = 6.9 Hz, 3H, CHCH₃), 1.35 (td, J = 7.1, 0.7 Hz, 3H, OCH₂CH₃), 1.26 (td, J = 7.1, 0.6 Hz, 3H, OCH₂CH₃). ¹³C NMR (101 MHz): δ = 151.41 (dd, J = 30.1 Hz, 17.3 Hz, C(Ph) = CF), 144.55 (s, C_ipso), 129.52, 129.30, 128.39, 128.33, 126.49, 125.78, (6x s, CH_ar), 62.77 (d, J = 4.8 Hz, OCH₂CH₃), 62.56 (d, J = 4.6 Hz, OCH₂CH₃), 54.48 (s, CHCH₃), 23.41 (s, CHCH₃), 16.37 (d, J = 6.7 Hz, OCH₂CH₃), 16.20 (d, J = 6.8 Hz, OCH₂CH₃). ¹⁹F NMR (283 MHz): δ = −175.62 (dd, J = 91.7, 4.6 Hz, 1F). ³¹P{/¹H} NMR (162 MHz): δ = 12.10 (d, J = 91.8 Hz, 1P). MS (EI) m/z = 377.1 [M]⁺.

(Z)-Diethyl(1-fluoro-2-phenyl-2-(((S)-1-phenylethyl)amino)vinyl)phosphonate (Z-22b).

Diagnostic signals ¹⁹F NMR (283 MHz): δ = −163.94 (dd, J = 92.6, 6.1 Hz). ³¹P{/¹H} NMR (162 MHz): δ = 9.42 (d, J = 92.5 Hz).

(E/Z)-Diethyl(1-fluoro-2-phenyl-2-(((S)-1-phenylethyl)imino)ethyl)phosphonate (23a,b).

Diagnostic signals ¹⁹F NMR (283 MHz): −205.17 (dd, J = 78.4, 46.2 Hz), −205.73 (dd, J = 79.1, 46.2 Hz) ³¹P{/¹H} NMR (162 MHz): signals masked by other tautomers signals.

3.9. General Procedure for Synthesis of 2-Fluorinated Aziridine-2-phosphonates (24a–d, rac-25–26a,b)

To a solution of the β-aminophosphonate (16a–d, rac-b) (0.5 mmol) in anhydrous DMF (3 mL), triethylamine (84 µL, 61 mg, 0.6 mmol) was added. The reaction mixture was heated at 70 °C for 4 h at inert atmosphere. After completion of the reaction (monitored by ¹⁹F NMR), the solvent was removed under reduced pressure. The mixture was purified by column chromatography (AcOEt/petroleum ether 5% → 50%) with previously deactivated silica gel (short pad 1 cm, 1% triethylamine in hexane, 20 mL).

Diethyl ((2S/2R, 3R/3S)-2-fluoro-3-phenyl-1-((S)-1-phenylethyl)aziridin-2-yl)phosphonate (24a-d).

Crude reaction mixture: 24a–d (dr 0.78:1:0.13:0.08). Isolated as a mixture of four diastereomers 24a–d (dr 0.70:1:0.17:0.04) (97mg) and single diastereomer 24a (32mg). Diagnostic signals for traces of diastereomers 24c–d were determined from the crude reaction mixture. Pale-yellow oil, 129 mg, yield 68%.

Diethyl ((2S,3R)-2-fluoro-3-phenyl-1-((S)-1-phenylethyl)aziridin-2-yl)phosphonate (cis-24a).

¹H NMR (401 MHz): δ = 7.49–7.43 (m, 1H, H_ar), 7.30–7.21 (m, 8H, H_ar), 7.15–7.10 (m, 1H, H_ar), 4.08–3.96 (m, 3H, OCH₂CH₃, OCHHCH₃), 3.92–3.84 (m, 1H, OCHHCH₃), 3.81 (q, J = 6.4 Hz, 1H, CHCH₃), 3.18 (d, J = 8.7 Hz, 1H, CH(Ph)CPF), 1.61 (d, J = 6.5 Hz, 3H, CHCH₃), 1.19 (t, J = 7.3 Hz, 3H, OCH₂CH₃), 1.17 (t, J = 7.2 Hz, 3H, OCH₂CH₃). ¹H{/¹⁹F} NMR (401 MHz): δ = 7.50–7.44 (m, 1H, H_ar), 7.31–7.21 (m, 8H, H_ar), 7.15–7.10 (m, 1H, H_ar), 4.08–3.97 (m, 3H, OCH₂CH₃, OCHHCH₃), 3.92–3.83 (m, 1H, OCHHCH₃), 3.82 (q, J = 6.6 Hz, 1H, CHCH₃), 3.18 (br s, 1H, CH(Ph)CPF), 1.61 (d, J = 6.5 Hz, 3H, CHCH₃), 1.20 (t, J = 7.3 Hz, 3H, OCH₂CH₃), 1.17 (t, J = 7.3 Hz, 3H, OCH₂CH₃). ¹H{/³¹P} NMR (401 MHz): δ = 7.49–7.42 (m, 1H, H_ar), 7.30–7.21 (m, 8H, H_ar), 7.14–7.10 (m, 1H, H_ar), 4.08–3.95 (m, 3H, OCH₂CH₃, OCHHCH₃), 3.91–3.84 (m, 1H, OCHHCH₃), 3.81 (q, J = 6.4 Hz, 1H, CHCH₃), 3.18 (d, J = 8.7 Hz, 1H, CH(Ph)CPF), 1.61 (d, J = 6.5 Hz, 3H, CHCH₃), 1.20 (t, J = 7.3 Hz, 3H, OCH₂CH₃), 1.17 (t, J = 7.2 Hz, 3H, OCH₂CH₃). ¹³C NMR (101 MHz): δ = 143.12 (s, C_ipso), 133.87 (s, C_ipso), 128.53, 128.38, 128.09, 127.74, 127.60, 127.43 (6x s, CH_ar), 87.05 (dd, J = 274.2, 272.1 Hz, CFP), 63.35 (d, J = 6.2 Hz, OCH₂CH₃), 63.35 (d, J = 6.2 Hz OCH₂CH₃), 60.58 (d, J = 13.3 Hz, CHCH₃), 48.96 (dd, J = 19.1, 1.6 Hz, CH(Ph)CFP), 23.30 (s, CHCH₃), 16.31 (d, J = 6.3 Hz, OCH₂CH₃), 16.22 (d, J = 6.2 Hz, OCH₂CH₃). ¹⁹F NMR (283 MHz): δ = −182.45 (dd, J = 118.5, 8.7 Hz, 1F) ³¹P{/¹H} NMR (122 MHz): δ = 9.64 (d, J = 118.8 Hz, 1P).

Diethyl ((2R,3R)-2-fluoro-3-phenyl-1-((S)-1-phenylethyl)aziridin-2-yl)phosphonate (trans-24b).

¹H NMR (401 MHz): δ = 7.38–7.34 (m, 2H, H_ar), 7.29–7.24 (m, 4H, H_ar), 7.23–7.19 (m, 3H, H_ar), 7.17–7.13 (m, 1H, H_ar), 4.35 (quint, J = 7.2 Hz, 2H, OCH₂CH₃), 4.31–4.24 (m, 1H, OCHHCH₃), 4.23–4.13 (m, 2H, OCHHCH₃, CHCH₃), 3.26 (t, J = 4.2 Hz, 1H, CH(Ph)CFP), 1.64 (d, J = 6.5 Hz, 3H, CHCH₃), 1.44 (td, J = 7.1, 0.7 Hz, 3H, OCH₂CH₃), 1.33 (td, J = 7.1, 0.6 Hz, 3H, OCH₂CH₃). ¹H{/¹⁹F} NMR (401 MHz): δ = 7.37–7.33 (m, 2H, H_ar), 7.28–7.24 (m, 4H, H_ar), 7.23–7.19 (m, 3H, H_ar), 7.18–7.13 (m, 1H, H_ar), 4.35 (quint, J = 7.2 Hz, 2H, OCH₂CH₃), 4.32–4.24 (m, 1H, OCHHCH₃), 4.23–4.12 (m, 2H, OCHHCH₃, CHCH₃), 3.26 (br d, J = 4.3 Hz, 1H, CH(Ph)CFP), 1.64 (d, J = 6.5 Hz, 3H, CHCH₃), 1.44 (td, J = 7.0, 0.7 Hz, 3H, OCH₂CH₃), 1.33 (td, J = 7.1, 0.6 Hz, 3H, OCH₂CH₃). ¹H{/³¹P} NMR (401 MHz): δ = 7.37–7.32 (m, 2H, H_ar), 7.29–7.23 (m, 4H, H_ar), 7.22–7.18 (m, 3H, H_ar), 7.17–7.14 (m, 1H, H_ar), 4.35 (q, J = 7.1 Hz, 2H, OCH₂CH₃), 4.32–4.24 (m, 1H, OCHHCH₃), 4.22–4.14 (m, 2H, OCHHCH₃, CHCH₃), 3.26 (d, J = 4.5 Hz, 1H, CH(Ph)CFP), 1.64 (d, J = 6.5 Hz, 3H, CHCH₃), 1.44 (t, J = 7.1 Hz, 3H, OCH₂CH₃), 1.33 (t, J = 7.1 Hz, 3H, OCH₂CH₃). ¹³C NMR (101 MHz): δ = 143.14 (s, C_ipso), 133.62 (dd, J = 5.2, 1.5 Hz, C_ipso), 128.39, 128.10, 127.73 (3x s, CH_ar), 127.61 (t, J = 0.9 Hz, CH_ar), 127.30, 127.02 (2x s, CH_ar), 84.27 (dd, J = 258.7, 233.2 Hz, CFP), 64.15 (dd, J = 7.8, 1.1 Hz, OCH₂CH₃), 63.54 (dd, J = 6.0, 0.5 Hz, OCH₂CH₃), 61.18 (dd, J = 5.0, 3.1 Hz, CHCH₃), 47.46 (dd, J = 12.7, 5.8 Hz, CH(Ph)CFP), 23.64 (s, CHCH₃), 16.39 (d, J = 6.4 Hz, OCH₂CH₃), 16.38 (d, J = 6.5 Hz, OCH₂CH₃). ¹⁹F NMR (283 MHz): δ = −168.76 (dt, J = 113.8, 4.8 Hz, 1F). ³¹P{/¹H} NMR (122 MHz): δ = 10.83 (d, J = 114.0 Hz, 1P). IR (neat): 1259, 1162, 1019, 957, 759 [cm⁻¹]. HRMS (ESI): m/z calcd for C₂₀H₂₆FNO₃P, [M + H]⁺: 378.1634 found: 378.1628.

Diethyl ((2R,3S)-2-fluoro-3-phenyl-1-((S)-1-phenylethyl)aziridin-2-yl)phosphonate (cis-24c).

Diagnostic signals ¹⁹F NMR (283 MHz): δ = −178.36 (dd, J = 114.2, 8.5 Hz). ³¹P{/¹H} NMR (122 MHz): δ = 8.94 (d, J = 114.1 Hz).

Diethyl ((2S,3S)-2-fluoro-3-phenyl-1-((S)-1-phenylethyl)aziridin-2-yl)phosphonate (trans-24d).

Diagnostic signals ¹⁹F NMR (283 MHz): δ = −169.11 (dt, J = 110.8, 4.7 Hz). ³¹P{/¹H} NMR (122 MHz): δ = 10.22 (d, J = 110.6 Hz).

rac-Diethyl ((2S,3R)-2-fluoro-1-(4-methoxybenzyl)-3-phenylaziridin-2-yl)phosphonate (rac-cis-25a) and rac-diethyl ((2R,3R)-2-fluoro-1-(4-methoxybenzyl)-3-phenylaziridin-2-yl)phosphonate (rac-trans-25b).

Crude reaction mixture: 25a,b (dr 0.68:1). Isolated as a mixture of diastereomers 25a,b (dr 0.52:1) (94mg) and single diastereomer 25b (28mg). Pale yellow oil, 122 mg, yield 62%.

rac-cis-25a: ¹H NMR (401 MHz): δ = 7.45–7.40 (m, 3H, H_ar), 7.36–7.29 (m, 2H, H_ar), 7.23–7.19 (m, 2H, H_ar), 6.92–6.88 (m, 2H, H_ar), 4.15 (br d, J = 13.6, 1H, CHHN), 3.99–3.85 (m, 4H, 2x OCH₂CH₃), 4.01 (br d, J = 13.6, 1H, CHHN), 3.82 (s, 3H, Ph(4-OCH₃)), 3.26 (d, J = 8.5 Hz, 1H, CH(Ph)CFP), 1.11 (td, J = 7.1, 0.8 Hz, 3H, OCH₂CH₃), 1.09 (td, J = 7.1, 0.7 Hz, 3H, OCH₂CH₃). ¹H{/¹⁹F} NMR (401 MHz): δ = 7.45–7.41 (m, 2H, H_ar), 7.36–7.30 (m, 2H, H_ar), 7.24–7.19 (m, 2H, H_ar), 6.91–6.86 (m, 2H, H_ar), 4.15 (br d, J = 13.5, 1H, CHHN), 3.97–3.85 (m, 4H, 2x OCH₂CH₃), 4.02 (br d, J = 13.6, 1H, CHHN), 3.81 (s, 3H, Ph(4-OCH₃)), 3.25 (br s, 1H, CH(Ph)CFP), 1.11 (td, J = 7.1, 0.8 Hz, 3H, OCH₂CH₃), 1.10 (td, J = 7.1, 0.6 Hz, 3H, OCH₂CH₃). ¹H{/³¹P} NMR (401 MHz): δ = 7.45–7.41 (m, 2H, H_ar), 7.36–7.30 (m, 2H, H_ar), 7.24–7.19 (m, 2H, H_ar), 6.91–6.86 (m, 2H, H_ar), 4.15 (d, J = 12.8 Hz, 1H, CHHN), 3.98–3.84 (m, 4H, 2x OCH₂CH₃), 4.02 (d, J = 13.0 Hz, 1H, CHHN), 3.83 (s, 3H, Ph(4-OCH₃)), 3.27 (d, J = 8.4 Hz, 1H, CH(Ph)CFP), 1.11 (t, J = 7.0 Hz, 3H, OCH₂CH₃), 1.09 (t, J = 7.1 Hz, 3H, OCH₂CH₃). ¹³C NMR (101 MHz): δ = 159.00 (s, C_ar(OCH₃)), 133.44–133.38 (m, C_ipso), 131.86 (s, C_ipso), 129.21, 128.17, 127.86, 127.56 (4x s, CH_ar), 113.80 (s, CH_arC_ar(OCH₃)), 86.67 (dd, J = 274.0, 272.5 Hz, CFP), 63.15 (d, J = 6.1 Hz, OCH₂CH₃), 63.03 (d, J = 6.2 Hz, OCH₂CH₃), 55.23 (s, Ph(4-OCH₃)), 53.30 (d, J = 15.1 Hz, CH₂N), 49.08 (dd, J = 19.2, 1.3 Hz, CH(Ph)CFP), 16.12 (d, J = 6.0 Hz, OCH₂CH₃), 16.11 (d, J = 6.1 Hz, OCH₂CH₃). ¹⁹F NMR (283 MHz): δ = −180.27 (dd, J = 116.7, 8.4 Hz, 1F). ³¹P{/¹H} NMR (122 MHz): δ = 9.97 (d, J = 116.9 Hz, 1P).

rac-trans-25b: ¹H NMR (401 MHz): δ = 7.39 (d, J = 7.7 Hz, 4H, H_ar), 7.36–7.30 (m, 3H, H_ar), 6.87 (d, J = 8.6 Hz, 2H, H_ar), 4.46 (dd, J = 13.6, 2.8 Hz, 1H, CHHN), 4.34–4.27 (m, 1H, OCHHCH₃), 4.25–4.18 (m, 3H, OCHHCH₃, OCH₂CH₃), 4.08 (dd, J = 13.6, 5.1 Hz, 1H, CHHN), 3.80 (s, 3H, Ph(4-OCH₃)), 3.45 (t, J = 4.1 Hz, 1H, CH(Ph)CFP), 1.37 (td, J = 7.1, 0.6 Hz, 3H, OCH₂CH₃), 1.34 (td, J = 7.1, 0.7 Hz, 3H, OCH₂CH₃). ¹H{/¹⁹F} NMR (401 MHz): δ = 7.40–7.35 (m, 4H, H_ar), 7.37–7.32 (m, 3H, H_ar), 6.88 (d, J = 8.8 Hz, 2H, H_ar), 4.47 (d, J = 13.6, 1H, CHHN), 4.32–4.26 (m, 1H, OCHHCH₃), 4.25–4.17 (m, 3H, OCHHCH₃, OCH₂CH₃), 4.08 (d, J = 13.5, 1H, CHHN), 3.81 (s, 3H, Ph(4-OCH₃)), 3.45 (d, J = 4.1 Hz, 1H, CH(Ph)CFP), 1.38 (td, J = 7.1, 0.6 Hz, 3H, OCH₂CH₃), 1.35 (td, J = 7.1, 0.7 Hz, 3H, OCH₂CH₃). ¹H{/³¹P} NMR (401 MHz): δ = 7.40–7.36 (m, 4H, H_ar), 7.37–7.32 (m, 3H, H_ar), 6.88 (d, J = 8.7 Hz, 2H, H_ar), 4.47 (dd, J = 13.6, 2.8 Hz, 1H, CHHN), 4.33–4.26 (m, 1H, OCHHCH₃), 4.25–4.18 (m, 3H, OCHHCH₃, OCH₂CH₃), 4.08 (dd, J = 13.6, 5.1 Hz, 1H, CHHN), 3.81 (s, 3H, Ph(4-OCH₃)), 3.45 (d, J = 4.3 Hz, 1H, CH(Ph)CFP), 1.38 (t, J = 7.1, 3H, OCH₂CH₃), 1.35 (t, J = 7.1, 3H, OCH₂CH₃). ¹³C NMR (101 MHz): δ = 158.79 (s, C_ar(OCH₃)), 133.58 (br d, J = 5.2 Hz, C_ipso), 131.93 (s, C_ipso), 129.99, 128.15, 127.84, 127.67 (4x s, CH_ar), 113.71 (s, CH_arC_ar(OCH₃)), 83.95 (dd, J = 259.6, 231.6 Hz, CFP), 63.71 (d, J = 7.0 Hz, OCH₂CH₃), 63.50 (d, J = 6.0 Hz, OCH₂CH₃), 55.53 (dd, J = 5.4, 3.5 Hz, CH₂N), 55.19 (s, Ph(4-OCH₃)), 48.43 (dd, J = 12.9, 6.0 Hz, CH(Ph)CFP), 16.27 (d, J = 5.9 Hz, OCH₂CH₃), 16.25 (d, J = 6.0 Hz, OCH₂CH₃). ¹⁹F NMR (283 MHz): δ = −170.98 (dq, J = 111.7, 4.3 Hz, 1F). ³¹P{/¹H} NMR (122 MHz): δ = 10.95 (d, J = 111.6 Hz, 1P). IR (neat): 1247, 1164, 1097, 1018, 978, 765 [cm⁻¹]. HRMS (ESI): m/z calcd for C₂₀H₂₆FNO₄P, [M + H]⁺: 394.1583 found: 394.1587.

rac-Diethyl ((2S,3R)-2-fluoro-1-(4-methoxyphenyl)-3-phenylaziridin-2-yl)phosphonate (rac-cis-26a) and rac diethyl ((2R,3R)-2-fluoro-1-(4-methoxyphenyl)-3-phenylaziridin-2-yl)phosphonate (rac-trans-26b).

Crude reaction mixture: 26a,b (dr 0.09:1). Isolated as single diastereomer 26b. Diagnostic signals for traces of diastereomers 26a were determined from the crude reaction mixture. Pale-yellow oil, 85 mg, yield 45%.

rac-cis-26a: Diagnostic signals ¹⁹F NMR (283 MHz): δ = −171.22 (dd, J = 117.5, 7.9 Hz). ³¹P{/¹H} NMR (122 MHz): δ = 8.63 (d, J = 117.4 Hz).

rac-trans-26b: ¹H NMR (401 MHz): δ = 7.51–7.48 (m, 2H, H_ar), 7.40–7.34 (m, 3H, H_ar), 7.13–7.06 (m, 2H, H_ar), 6.86–6.82 (m, 2H, H_ar), 4.19–3.98 (m, 4H, 2x OCH₂CH₃), 3.84 (t, J = 4.1 Hz, 1H, CH(Ph)CFP), 3.77 (s, 3H, Ph(4-OCH₃)), 1.31 (td, J = 7.1, 0.6 Hz, 3H, OCH₂CH₃), 1.17 (td, J = 7.1, 0.6 Hz, 3H, OCH₂CH₃). ¹H{/¹⁹F} NMR (401 MHz): δ = 7.52–7.47 (m, 2H, H_ar), 7.42–7.35 (m, 3H, H_ar), 7.11–7.06 (m, 2H, H_ar), 6.85–6.80 (m, 2H, H_ar), 4.19–3.96 (m, 4H, 2x OCH₂CH₃), 3.84 („d”, J = 4.2 Hz, 1H, CH(Ph)CFP), 3.76 (s, 3H, Ph(4-OCH₃)), 1.31 (td, J = 7.1, 0.6 Hz, 3H, OCH₂CH₃), 1.17 (td, J = 7.1, 0.6 Hz, 3H, OCH₂CH₃). ¹H{/³¹P} NMR (401 MHz): δ = 7.50–7.46 (m, 2H, H_ar), 7.41–7.34 (m, 3H, H_ar), 7.11–7.05 (m, 2H, H_ar), 6.85–6.82 (m, 2H, H_ar), 4.20–3.99 (m, 4H, 2x OCH₂CH₃), 3.83 (d, J = 4.5 Hz, 1H, CH(Ph)CFP), 3.77 (s, 3H, Ph(4-OCH₃)), 1.30 (t, J = 7.1 Hz, 3H, OCH₂CH₃), 1.16 (t, J = 7.1 Hz, 3H, OCH₂CH₃). ¹³C NMR (101 MHz): δ = 156.13 (s, C_ar(OCH₃)), 132.83 (dd, J = 5.3, 1.2 Hz, C_ipso), 134.22 (s, C_ipso), 129.30 (d, J = 3.2 Hz, CH_ar), 128.57, 128.38, 127.79 (3x s, CH_ar), 114.24 (s, CH_arC_ar(OCH₃)), 83.91 (dd, J = 260.8, 238.3 Hz, CFP), 63.63 (d, J = 6.9 Hz, OCH₂CH₃), 63.21 (d, J = 6.0 Hz, OCH₂CH₃), 55.49 (s, Ph(4-OCH₃)), 46.12 (dd, J = 13.1 Hz, 5.4 Hz, CH(Ph)CFP), 16.29 (d, J = 6.1 Hz, OCH₂CH₃), 16.17 (d, J = 5.6 Hz, OCH₂CH₃). ¹⁹F NMR (283 MHz): δ = −169.58 (dd, J = 121.4, 4.3 Hz, 1F). ³¹P{/¹H} NMR (122 MHz): δ = 8.82 (d, J = 121.5 Hz, 1P). HRMS (ESI): m/z calcd for C₁₉H₂₄FNO₄P, [M + H]⁺: 380.1427 found: 380.1421.

3.10. Separation Method for Chiral Aziridines and Synthesis of Non-Fluorinated Aziridine-2-phosphonate: Diethyl ((2S,3R)-3-Phenyl-1-((S)-1-phenylethyl)aziridin-2-yl)phosphonate (cis-27)

Method A. Imine 10a-d (dr 1:1, 228 mg, 0.5 mmol) was dissolved in anhydrous methanol (5 mL) and NaBH₃CN (250 mg, 4 mmol), and glacial CH₃COOH (88 µL, 92 mg, 1.5 mmol) was added. The reaction mixture was refluxed for 7h and next the solvent was evaporated. Then, the residue was dissolved in CH₂Cl₂ (3 mL) and extracted with a saturated solution of NaHCO₃ and brine. The organic layers were combined, dried over Na₂SO₄, and evaporated to give a mixture of products 16a,c, trans-24b,d, and cis-27. The product cis-27 was purified by column chromatography (AcOEt/hexane: 5% → 60%) as a pale-yellow oil (58 mg, yield 32%). Amine 16a,c (dr 1:0.1) and aziridine trans-24b,d (dr 1:0.05) were isolated as a mixture (0.3:1, 84 mg).

Method B. To the mixture of cis- and trans-aziridines (24a-d; 0.64(dr 1:0.07)/1(dr 1:0.09), 113 mg, 0.3 mmol) dissolved in methanol (3 mL), Pd/C (10 mol%, 2 mg) and NaBH₄ (23 mg, 0.6 mmol) were added. The reaction was stirred at 70 °C for 3h. Then, the solvent was evaporated, the residue was dissolved in CHCl₃ (3 mL), water (10 mL) was added, and it was extracted (3 × 10 mL CHCl₃). The organic layers were dried over anhydrous Na₂SO₄ and evaporated to give crude products trans-24b,d/cis-27 (1:0.49) separated using column chromatography with previously deactivated silica gel (short pad 1 cm, 1% triethylamine in hexane, 20 mL). Cis-27 was isolated as a single diastereomer (42 mg, yield 39%) and trans-24b,d was isolated as a mixture of diastereomers (dr 1:0.07, 49 mg).

cis-27: ¹H NMR (401 MHz): δ = 7.44–7.40 (m, 2H, H_ar), 7.31–7.26 (m, 4H, H_ar), 7.23–7.18 (m, 2H, H_ar), 7.17–7.10 (m, 2H, H_ar), 3.99– 3.90 (m, 2H, OCH₂CH₃), 3.85–3.78 (m, 1H, OCHHCH₃), 3.64–3.54 (m, 1H, OCHHCH₃), 2.95 (t, J = 6.7 Hz, 1H, CH(Ph)CHP), 2.74 (q, J = 6.5 Hz, 1H, CHCH₃), 1.99 (dd, J = 17.8, 6.8 Hz, 1H, CHP), 1.56 (d, J = 6.5 Hz, 3H, CHCH₃), 1.17 (td, J = 7.1, 0.6 Hz, 3H, OCH₂CH₃), 1.07 (td, J = 7.1, 0.6 Hz, 3H, OCH₂CH₃). ¹H{/³¹P} NMR (401 MHz): δ = 7.46–7.40 (m, 2H, H_ar), 7.32–7.25 (m, 4H, H_ar), 7.24–7.18 (m, 2H, H_ar), 7.17–7.11 (m, 2H, H_ar), 4.00–3.92 (m, 2H, OCH₂CH₃), 3.86–3.78 (m, 1H, OCHHCH₃), 3.65–3.56 (m, 1H, OCHHCH₃), 2.96 (d, J = 6.7 Hz, 1H, CH(Ph)CHP), 2.75 (q, J = 6.5 Hz, 1H, CHCH₃), 2.00 (d, J = 6.8 Hz, 1H, CHP), 1.57 (d, J = 6.6 Hz, 3H, CHCH₃), 1.18 (t, J = 7.1 Hz, 3H, OCH₂CH₃), 1.08 (t, J = 7.1 Hz, 3H, OCH₂CH₃). ¹³C NMR (101 MHz): δ = 143.56 (s, C_ipso), 135.94 (d, J = 2.0 Hz, C_ipso), 128.54, 128.06, 127.69, 127.51, 127.18, 127.09, (6 x s, CH_ar), 71.85 (d, J = 6.1 Hz, CHCH₃), 62.10 (d, J = 6.4 Hz, OCH₂CH₃), 61.81 (d, J = 6.4 Hz, OCH₂CH₃), 46.27 (d, J = 5.7 Hz, CH(Ph)CHP), 39.86 (s, CHP), 23.12 (s, CHCH₃), 16.39 (d, J = 6.5 Hz, OCH₂CH₃), 16.36 (d, J = 6.0 Hz, OCH₂CH₃). ³¹P{/¹H} NMR (162 MHz): δ = 21.44 (s, 1P). HRMS (ESI): m/z calcd for C₂₀H₂₇NO₃P, [M + H]⁺: 360.1729 found: 360.1723.

3.11. Isolation of Trans-Aziridine 24. Synthesis of α-Fluorinated ß-Aminophosphonate: Diethyl ((1S/R, 2S/R)-1-Fluoro-2-phenyl-2-(((S)-1-phenylethyl)amino)ethyl)phosphonate (28a–d)

To the mixture of amine (16a,c) and aziridine (24b,d) (0.8 (dr 1:0.1): 1(dr 1:0.05), 186 mg) dissolved in methanol (2 mL), NaBH₄ (15 mg, 0.6 mmol) and Pd/C (10 mol%, 2 mg) were added. The reaction was stirred at room temperature for 20 min. Then, the crude mixture was filtrated through Celite with MeOH as a mobile phase and concentrated under vacuum. The residue was dissolved in CH₂Cl₂ (2 mL) and extracted with brine. The organic layers were dried over anhydrous Na₂SO₄ and evaporated to give a mixture of monofluorinated amine 28a–d and aziridine 24b,d (0.8:1, respectively). The crude products 24b,d/28a–d (28a–d: dr 1:0.8:0.19:0.13) were separated using column chromatography with previously deactivated silica gel (1% triethylamine in hexane, 20 mL). Amine was isolated as a mixture of diastereomers 28a–d (dr 1:0.75:0.09:0.05, 70 mg, pale-yellow oil) and aziridine was separated as a mixture of diastereomers 24b,d (dr 1:0.05, 75 mg).

28a: ¹H NMR (401 MHz): δ = 7.43–7.34 (m, 5H, H_ar), 7.33–7.26 (m, 5H, H_ar), 4.85 (ddd, J = 45.2, 5.1, 3.9 Hz, 1H, CHFP), 4.38 (ddd, J = 23.5, 6.2, 5.1 Hz, 1H, CHCFP), 4.02–3.76 (m, 4H, 2x OCH₂CH₃), 3.67 (q, J = 6.4 Hz, 1H, CHCH₃), 1.36 (d, J = 6.5 Hz, 3H, CHCH₃), 1.27 (td, J = 7.1, 0.6 Hz, 3H, OCH₂CH₃), 1.26 (td, J = 7.1, 0.5 Hz, 3H, OCH₂CH₃). ¹³C NMR (101 MHz): δ = 145.61 (s, C_ipso) 138.58 (d, J = 6.6, 1.3 Hz, C_ipso), 128.37, 128.34, 128.25, 127.85, 126.91, 126.58 (6x s, CH_ar), 92.58 (dd, J = 188.3, 167.2 Hz, CFP), 63.01 (d, J = 6.9 Hz, OCH₂CH₃), 62.10 (d, J = 6.9 Hz, OCH₂CH₃), 59.76 (dd, J = 17.9, 3.5 Hz, CHCFP), 54.55 (s, CHCH₃), 22.08 (s, CHCH₃), 16.33 (d, J = 5.9 Hz, OCH₂CH₃), 16.15 (d, J = 6.0 Hz, OCH₂CH₃). ¹⁹F NMR (283 MHz): δ = −213.48 (ddd, J = 72.0, 45.6, 21.2 Hz, 1F). ³¹P{/¹H} NMR (122 MHz): δ = 16.01 (d, J = 72.2 Hz, 1P). IR (neat): 1253, 1019, 969 [cm⁻¹]. MS (EI) m/z = 379.4 [M]⁺.

28b: ¹H NMR (401 MHz): δ = 7.50–7.43 (m, 5H, H_ar), 7.35–7.32 (m, 5H, H_ar), 4.99 (ddd, J = 45.8, 5.8, 3.7 Hz, 1H, CHFP), 4.28–4.06 (m, 5H, 2x OCH₂CH₃, CHCFP), 3.71 (q, J = 6.4 Hz, 1H, CHCH₃), 1.34 (d, J = 6.5 Hz, 3H, CHCH₃), 1.18 (dd, J = 7.1, 0.5 Hz, 3H, OCH₂CH₃), 1.15 (dd, J = 7.1, 0.6 Hz, 3H, OCH₂CH₃). ¹³C NMR (101 MHz): δ = 145.45 (s, C_ipso) 138.43 (dd, J = 8.6, 3.6 Hz, C_ipso), 128.32, 128.29, 128.20, 127.76, 126.82, 126.57 (6x s, CH_ar), 90.89 (dd, J = 187.8, 165.4 Hz, CFP), 63.38 (d, J = 6.4 Hz, OCH₂CH₃), 62.55 (d, J = 6.7 Hz, OCH₂CH₃), 59.66 (dd, J = 19.9, 4.6 Hz, CHCFP), 54.45 (s, CHCH₃), 21.50 (s, CHCH₃), 16.24 (d, J = 5.9 Hz, OCH₂CH₃), 16.21 (d, J = 6.0 Hz, OCH₂CH₃). ¹⁹F NMR (283 MHz): δ = −215.99 (ddd, J = 76.4, 45.3, 23.5 Hz, 1F). ³¹P{/¹H} NMR (122 MHz): δ = 16.16 (d, J = 76.4 Hz, 1P). MS (EI) m/z = 379.4 [M]⁺.

28c: Diagnostic signals ¹⁹F NMR (283 MHz): δ = −212.07 (ddd, J = 70.3, 45.3, 16.4 Hz). ³¹P{/¹H} NMR (122 MHz): δ = 15.99 (d, J = 70.1 Hz).

28d: Diagnostic signals ¹⁹F NMR (283 MHz): δ = −216.77 (ddd, J = 79.8, 45.2, 24.3 Hz). ³¹P{/¹H} NMR (122 MHz): δ = 15.88 (d, J = 79.6 Hz).

3.12. Ring Opening of Fluorinated Aziridine-2-phosphonate: Synthesis of Diethyl ((1R, 2S)-1,2-Dimethoxy-2-phenyl-1-(((S)-1-phenylethyl)amino)ethyl)phosphonate (29a) and Diethyl ((1S, 2S)-1,2-Dimethoxy-2-phenyl-1-(((S)-1-phenylethyl)amino)ethyl)phosphonate (29b)

To the mixture of aziridines 24a–d (cis/trans 1(dr 1:0.45):0.65(dr 1:0.04), 211 mg, 0.5 mmol) dissolved in MeOH (2 mL), H₂SO₄ (98%; 27 µL, 49 mg, 0.5 mmol) was added dropwise. The reaction was stirred at 70 °C for 2h. Next, the solution was concentrated, and the crude mixture was neutralized with aqueous NaHCO₃, extracted with CH₂Cl₂ (3 × 6 mL), and washed with brine (6 mL). The organic layers were combined and dried over anhydrous Na₂SO₄. After evaporation of the solvent, the crude product was purified by column chromatography to give a mixture of diastereomers 29a,b (dr 1:0.5) as a pale-yellow oil, 149 mg, yield 63%.

29a: ¹H NMR (401 MHz): δ = 7.42–7.39 (m, 5H, H_ar), 7.35–7.31 (m, 5H, H_ar), 4.33 (d, J = 11.9 Hz, 1H, CHOCH₃), 4.02–3.89 (m, 4H, 2x OCH₂CH₃), 3.50 (q, J = 6.7 Hz, 1H, CHCH₃), 3.48 (d, J = 0.7 Hz, 3H, C(P)OCH₃), 3.28 (s, 3H, CHOCH₃), 1.25 (d, J = 6.4 Hz, 3H, CHCH₃), 1.18 (t, J = 7.1 Hz, 3H, OCH₂CH₃), 1.11 (t, J = 7.0 Hz, 3H, OCH₂CH₃). ¹H{/³¹P} NMR (401 MHz): δ = 7.43–7.39 (m, 5H, H_ar), 7.37–7.32 (m, 5H, H_ar), 4.32 (s, 1H, CHOCH₃), 4.00–3.89 (m, 4H, 2x OCH₂CH₃), 3.51 (q, J = 6.7 Hz, 1H, CHCH₃), 3.49 (s, 3H, C(P)OCH₃), 3.29 (s, 3H, CHOCH₃), 1.25 (d, J = 6.4 Hz, 3H, CHCH₃), 1.19 (t, J = 7.0 Hz, 3H, OCH₂CH₃), 1.11 (t, J = 7.1 Hz, 3H, OCH₂CH₃). ¹³C NMR (101 MHz): δ = 144.55 (s, C_ipso), 138.47 (d, J = 5.5 Hz, C_ipso), 104.47 (d, J = 196.3 Hz, CP), 63.38 (d, J = 14.7 Hz, CHOCH₃), 63.02 (d, J = 6.7 Hz, OCH₂CH₃), 62.70 (d, J = 6.9 Hz, OCH₂CH₃), 53.73 (s, CHCH₃), 52.79 (d, J = 4.0 Hz, CHOCH₃), 50.49 (d, J = 8.9 Hz, C(P)OCH₃), 20.91 (s, CHCH₃), 16.48 (d, J = 5.9 Hz, OCH₂CH₃), 16.31 (d, J = 6.1 Hz, OCH₂CH₃). ³¹P{/¹H} NMR (122 MHz): δ = 18.20 (s, 1P). HRMS (ESI): m/z calcd for C₂₂H₃₃NO₅P, [M + H]⁺: 422.2096 found: 422.2092.

29b: ¹H NMR (401 MHz): δ = 7.28–7.24 (m, 5H, H_ar), 7.22–7.17 (m, 5H, H_ar), 4.13–4.02 (m, 5H, 2x OCH₂CH₃, CHOCH₃), 3.42 (q, J = 6.5 Hz, 1H, CHCH₃), 3.34 (br s, 3H, C(P)OCH₃), 3.11 (br s, 3H, CHOCH₃), 1.24 (d, J = 6.6 Hz, 3H, CHCH₃), 1.17 (t, J = 7.1 Hz, 3H, OCH₂CH₃), 1.04 (t, J = 7.1 Hz, 3H, OCH₂CH₃). ¹³C NMR (101 MHz): δ = 145.03 (s, C_ipso), 138.21 (d, J = 3.1 Hz, C_ipso), 103.89 (d, J = 196.3 Hz, CP), 63.09 (d, J = 6.9 Hz, OCH₂CH₃), 62.58 (d, J = 6.8 Hz, OCH₂CH₃), 62.24 (d, J = 7.2 Hz, CHOCH₃), 54.16 (s, CHCH₃), 52.27 (d, J = 3.0 Hz, CHOCH₃), 49.65 (d, J = 10.4 Hz, C(P)OCH₃), 21.85 (s, CHCH₃), 16.25 (d, J = 6.1 Hz, OCH₂CH₃), 16.15 (d, J = 6.2 Hz, OCH₂CH₃). ³¹P{/¹H} NMR (122 MHz): δ = 17.32 (s, 1P). IR (neat): 1494, 1452, 1276, 1259, 1233, 1024, 969 [cm⁻¹].

4. 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.