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.

Keywords: DFT calculations; aminophosphonates; aziridine; halofluorination; imines; phosphonates.

Figure 1

Biologically active aziridinyl phosphonates.

Figure 2

α-Aminophosphonates formed through aziridine ring-opening reaction.

Scheme 1

Reduction of α,α-halofluorinated ß-iminophosphonates (10,11,14a,b, rac-12–13,15). Reaction conditions: i. imine (0.5 mmol), NaBH₃CN (3 mmol), glacial CH₃COOH (3 mmol), MeOH, rt, 40 min. ii. 10a,b (0.3 mmol), LiAlH₄ (0.45 mmol), THF, 0 °C 🡪 rt, 60 min.

Figure 3

Diastereoselective approach for imine reduction based on: (A)—rigid Houk model; (B)—Felkin-Anh model for major isomer; PG: PMB or PMP.

Figure 4

Chair-like conformers (B,C and E,F) representation of amine minor (A) and major (D) diastereomers. PG = PMB, PMP.

Figure 5

Potential conformers of β-aminophosphonates 16a’ (A,B and C) and 16b’ (D,E and F) and their relative potential energies [kcal/mol].

Figure 6

Selected conformers and their relative potential energies [kcal/mol] arise from the rotation of the phosphonate moiety for 16a’ (A) and 16b’ (D).

Scheme 2

Ring closure of α,α-bromofluoro-β-aminophosphonate (16a–d, rac-18–19a,b) to 2-fluoroaziridinyl-2-phosphonate (24a–d, rac-25–26a,b). PG = (S) or (R)-MBn, PMB, PMP. Reaction conditions: amine 16a–d, rac-18–19a,b (0.5 mmol), TEA (0.6 mmol), DMF, 70 °C, 4 h, Schlenk flask, inert gas. Note: for simplicity, in the case of 24a–d, only the stereochemistry of the major diastereomers (24a,b) was shown.

Figure 7

F-H correlations and H-F, H-P coupling constant values for rac-25a,b based on ¹H-¹⁹F HOE and ¹H, ¹H{/¹⁹F}, ¹H{/³¹P} NMR.

Figure 8

The proposed mechanism of aziridine 24a,b’ formation from 16a,b’ and relative potential energy barrier values.

Figure 9

Optimized structures of transition states leading to the formation of aziridines presented in Figure 8.

Scheme 3

Reduction of 10a,b at the higher temperature. Reaction conditions: i. 10a,b (0.5 mmol), NaBH₃CN (4 mmol), CH₃COOH (1.5 mmol), MeOH, 70 °C, 3–7 h. Note: For simplicity, only the stereochemistry of the major diastereomers (16a,b and 24a,b) was shown.

Scheme 4

Synthetic approach to separate trans-aziridine 24b,d from the mixture of 16a,c/trans-24b,d. Reaction conditions: i. 16a,c/trans-24b,d (0.3 mmol)*, NaBH₄ (0.6 mmol), Pd/C (10 mol%), MeOH, 20 min, rt. * calculated for 16a,c.

Scheme 5

Aziridine transformation with NaBH₄. Reaction conditions: i. 24a-d (0.3 mmol), NaBH₄ (0.6 mmol.), Pd/C (10 mol%), MeOH, 70 °C, 3 h. Note: For simplicity, only the stereochemistry of the major diastereomers was shown.

Scheme 6

Acid-catalyzed ring-opening reaction of 24a–d through intermediates A–C. Reaction conditions: i. 24a–d (0.5 mmol), H₂SO₄ 98% (~0.5 mmol) MeOH, 70 °C, 2 h. Note: For simplicity, only the stereochemistry of the major diastereomers was shown.