Diastereoselective ZnCl2-Mediated Joullié–Ugi Three-Component Reaction for the Preparation of Phosphorylated N-Acylaziridines from 2H-Azirines

Abstract

We disclose a direct approach to the diastereoselective synthesis of phosphorus substituted N-acylaziridines based on a one-pot ZnCl₂-catalyzed Joullié–Ugi three-component reaction of phosphorylated 2H-azirines, carboxylic acids and isocyanides. Hence, this robust protocol offers rapid access to an array of N-acylaziridines in moderate-to-good yields and up to 98:2 dr for substrates over a wide scope. The relevance of this synthetic methodology was achieved via a gram-scale reaction and the further derivatization of the nitrogen-containing three-membered heterocycle. The diastereo- and regioselective ring expansion of the obtained N-acylaziridines to oxazole derivatives was accomplished in the presence of BF₃·OEt₂ as an efficient Lewid acid catalyst.

1. Introduction

Multicomponent reactions (MCRs) are highly convergent processes that can be used to create new potent bioactive molecules. On the basis of green chemistry [1], MCRs benefit from efficiency, energy, time and atom economies, use environmentally favorable conditions and decrease the amount of byproducts and/or waste [2,3,4,5,6,7,8]. In addition, MCRs provide one of the most attractive prospects concerning complexity and diversity for the preparation of chemical libraries compared with other traditional synthetic organic methods. A large number of MCRs have been developed and are currently in a promising place in the chemist’s toolbox of sustainable synthetic methodologies.

Among them, the more versatile isocyanide-based MCRs form the backbone of today’s MCRs, such as the Ugi four-component reaction (U-4CR), which comprises the condensation of primary amines, carbonyl compounds, carboxylic acids and isocyanides to furnish dipeptide-like structures [9,10,11,12,13]. As the U-4CR mechanism occurred via the in situ formation of an imine intermediate, the employment of a cyclic imine instead of the amine and the carbonyl components in the Ugi protocol is a simple concept that supplies the robust Joullié–Ugi three-component reaction (JU-3CR). The Ugi variant was first reported by Joullié et al. [14,15] in 1982, and it is an appealing synthetic methodology not only because nitrogen-containing heterocycles can be directly attained in a single step, but also because of its greater stereochemical control [16]. The ring strain and the impossibility of imine E/Z isomerization contribute to a greater diastereoselectivity. Likewise, Joullié–Ugi adducts are privileged structures of interest in medicinal chemistry due to the synergistic effect of peptidic moieties linked to the nitrogen heterocycles leading to products with unique pharmaceutical activities [17,18,19,20].

Due to a better understanding of the benefits of covalent binding mechanisms and to the FDA support of effective and innocuous covalent drugs, there is great interest in covalent binding therapeutics [21,22,23]. Targeted covalent inhibitors are designed by incorporating an electrophile into a ligand that would bind the target protein. The integrated electrophile, acting as “warheads” [24], including ketone, α,β-unsaturated carbonyl, nitrile, ester, epoxide or aziridine, binds irreversibly to endogenous nucleophilic functionalities, including lysine, tyrosine, serine, cysteine and threonine, among others, on the target protein, introducing a covalent interaction. In this regard, aziridines, well known for their robust alkylating properties, possess the potential to function as potent covalent drugs by virtue of their ability to serve as DNA cross-linking agents. This is achieved through the nucleophilic ring opening of the three-membered nitrogen-containing heterocycle [25]. Aziridines are an important class of synthetic targets because they often exhibit a broad range of biological activities; for example, aziridine-containing mitomycin C (I) [26], azinomycin A (II) [27] and imexon (III) [28] show antitumor activity (Figure 1). Other natural aziridines, also known as aziridine alkaloids, display antibacterial and antimicrobial activity against selected microorganisms. For instance, aziridine-2-phosphonates IV have been claimed to show antibacterial properties [29] (Figure 1). We have recently reported the synthesis of phosphorus-substituted N-acylaziridines V [30] and VI [31], which exhibited a very good cytotoxic effect inhibiting the growth of human tumor cell line A549 (adenocarcinomic human alveolar basal epithelial cells). Recently, oxazoles have been emerged as the critical pharmacophore for various biological and medicinal applications. They serve as the key structural motif in numerous naturally occurring compounds and exhibit a broad spectrum of pharmacological properties, such as anti-cancer, anti-tubercular, anti-bacterial, anti-fungal, anti-parasitic and anti-viral properties, among others [32]. Hence, they can be utilized as primary building blocks in the pharmaceutical sector for the synthesis of several drugs. Likewise, from a biological perspective, organophosphorus compounds are very interesting due to their ability to modify the reactivity of heterocycles and regulate essential biological functions [33]. Thus, the anticancer agents 1,3-oxazol-4-ylphosphonium perchlorates VII [34], or the oxazole-phosphine oxide derivative VIII [31], and the oxazol-4-yl-phosphonate derivative IX displaying interesting anti-human cytomegalovirus (HCMV) properties [35], are only some examples of phosphorus-substituted oxazole derivatives with high potential for medical applications.

Many of the reported JU-3CR examples in the literature primarily employ 5, 6 or 7-membered cyclic imines for the preparation of pyrrolidine [36,37], thiazolidine [38], indolines [39,40] (Scheme 1, Equation (1)), piperidine [36,41] or oxazepine [42] peptidomimetics (Scheme 1, Equation (2)). However, only two examples have been reported in relation to the use of 2H-azirines as cyclic imines in the three-component Joullié–Ugi reaction for the synthesis of N-acylaziridines. Kanizsai et al. [43] first described the Lewis acid-promoted version of the Joullié–Ugi reaction using 2H-azirine-2-carboxylates for the diastereoselective synthesis of N-acylaziridines-2-carboxamide derivatives (Scheme 1, Equation (3)). Furthermore, a domino JU-3CR/diastereoselective ring expansion reaction was applied in the preparation of oxazolines from 2-phenyl-2H-azirines [44] (Scheme 1, Equation (4)).

We have been previously involved in the chemistry of phosphorus-substituted 2H-azirines for the synthesis of phosphorylated cyanoaziridines [30] and their ring expansion [31], hybrid molecules such as azirino[2,1-b]benzo[e][1,3]oxazines [45] or α-aminophosphonic acid derivatives [46]. In continuation of our previous research works, as depicted in (Scheme 1, Equation (5)), here, we describe a diastereoselective approach to phosphorylated N-acylaziridine 2-carboxamide derivatives through the JU-3CR using phosphorus-substituted 2H-azirines such as 3-membered cyclic imines, carboxylic acids and isocyanides (Figure 2).

2. Results

As outlined in Table 1, we started our investigation with the optimization of the three-component reaction conditions of 2H-azirine phosphine oxide 1a, benzoic acid (2a) and cyclohexyl isocyanide (3a) in THF at 60 °C. The Joullié–Ugi reaction without a catalyst led to the obtention of only a 10% yield of N-acylaziridine phosphine oxide 4a (entry 1). It is well known that the activation of 2H-azirines by Lewis acids may significantly enhance their reactivity [47,48]. Thus, we next explored the Lewis or Brønsted acid-mediated JU-3CR. Only a 14% yield of 4a could be achieved when PTSA was used as the Brønsted acid catalyst in this process (entry 2). Trifluoromethanesulfonic acid (TfOH, entry 3) showed moderate catalytic activity since the reaction proceeded smoothly in THF at 60 °C to give the product 4a in a 35% yield. Increasing the amount of TfOH from 10 mol% to 25 mol% did not improve the yield of compound 4a. The JU-3CR was carried out in the presence of different Lewis acids. For instance, Ti(OⁱPr)₄, Sc(OTf)₃, InCl₃, BF₃·OEt₂, MgBr₂ and ZnCl₂·H₂O were not suitable for the current reaction since compound 4a could not be detected, and only the starting 2H-azirine 1a or decomposition products were recovered instead (entries 4–9). In general, the most active catalyst for the JU-3CR of 1a with carboxylic acid 2a and isocyanide 3a was found to be ZnCl₂ (Table 1, entry 10), which is consistent with literature reports of other JU-3CRs involving 2H-azirine-2-carboxylates [43] Therefore, the use of ZnCl₂ (25 mol%, entry 10) resulted in the formation of N-acylaziridine 4a in a 60% chemical yield, together with a small amount of the pyrazine that proceed from the thermal treatment of the corresponding 2H-azirine phosphine oxide 1a [49]. This process yielded product 4a in a diastereomeric ratio of 96:4.

The effect of the solvent on the JU-3CR was also tested. The ZnCl₂ catalyst in this process was incompatible with some solvents such as MeOH or MeCN (entries 11 and 12), and in both cases, no reaction product was observed. The degree of consumption of the starting 2H-azirine 1a was found to depend on reaction temperature. In the reaction conducted at –10 °C (entry 13), a significant amount of unreacted 2H-azirine 1a was recovered and the expected product 4a was obtained in a low yield. The JU-3CR was found to work better when the reaction was carried out at room temperature, and the almost complete conversion of the 2H-azirine 1a was then observed (entry 14). Finally, different amounts of ZnCl₂ were examined, which showed that decreasing the amount of ZnCl₂ (10 mol%, entry 15) led to the desired product 4a in a low yield together with α-ketamide derived from the nucleophilic addition of the carboxylic acid to 2H-azirine 1a [50]. Increasing the amount of ZnCl₂ up to 30 mol% (entry 16) did not affect the yield of compound 4a.

Given that the results of this preliminary investigation seemed to define ZnCl₂ as the best catalyst in the JU-3CR in THF and room temperature as the best reaction condition, we adopted these conditions for further studies. Then, a range of N-acylaziridine phosphine oxides 4 with diverse substitution patterns (Figure 2) on the aziridine ring were prepared. A considerable selection of aromatic carboxylic acid partners 2 were well tolerated in the JU-3CR with 1a and 3 as coupling partners (Scheme 2). Both electron-donating (OMe) and electron-withdrawing groups (F, NO₂) at the para-phenyl position of aromatic carboxylic acid 2 yielded desired products 4c, 4d, 4e, 4j and 4k in 20–74% yields and very good diastereoselectivities. Among them, 4-fluor derivatives 4d and 4j were achieved with the best yields (74%).

The electron-donating group (Me) at the meta-phenyl position of aromatic carboxylic acid also furnished N-acylaziridine 4b in a 63% yield (Scheme 2). Other aromatic carboxylic acids such as 2-naphthoic acid 2g or 4-benzoylbenzoic acid 2i were selected as suitable candidates for this transformation, providing products 4 in moderate-to-good yields. Even heteroaromatic carboxylic acids were well tolerated in the Joullié–Ugi three-component reaction. For instance, nicotinic acid 2f, 2-furoic acid 2h and or quinoline-6-carboxylic acid 2j gave desired products 4h, 4m, 4t and 4u in 43–85% yields. Phenylacetic acid 2m yielded N-acylaziridines 4f and 4q in a 68 and 71% yield, respectively. However, worse yields of N-acylaziridines 4o, 4p and 4r, derived, respectively, from acetic acid 2k, trifluoroacetic acid 2l and 4-biphenylacetic acid 2n were attained (Scheme 2). Moreover, propargylic acids, such as propiolic acid 2p, can also be subjected to the JU-3CR to give compound 4g in a low yield but with high diastereoselectivity (96:4 trans:cis dr). This confirms the strength of the carboxylic acid scope in the JU-3CR.

In order to assess the applicability of the JU-3CR, we next investigated the scope of this process with regard to the isocyanide partner. Besides the cyclohexyl isocyanide (3a), other aliphatic isocyanides such as tert-butyl isocyanide (3b) or cyclopropyl isocyanide (3c) have been tested in the JU-3CR. All the isocyanides studied are well tolerated, giving the N-azylaziridines 4 in a moderate-to-good yield (see Scheme 2). The isocyanide partner does not affect the outcome of this protocol. For instance, compare the chemical yields of 4a, 4i and 4s (60–80% yields), 4d and 4j (74% yield) or 4m and 4u, which proceeded smoothly in 85 and 75% yields (Scheme 2).

A careful examination of the spectroscopic data of the crude reaction mixture of N-acylaziridine 4a, showed two well-resolved doublets in the ¹H NMR spectrum corresponding to the H3 methine proton of the aziridine ring, which is consistent with the presence of two diastereoisomers. The major diastereoisomer appears at δ_H ~ 3.81 ppm with the coupling constant ²J_PH = 24.0 Hz, and the minor one at δ_H ~ 3.35 ppm with a lower coupling constant of ²J_PH = 21.7 Hz in a ratio of 96:4. Substrates 4 were extensively characterized on the basis of their ¹H, ¹³C, ³¹P, ¹⁹F NMR and 2D NMR spectra and HRMS (see the Supporting Information). The most characteristic signals for N-acylaziridine 4a (major diastereoisomer) in the ¹H NMR spectrum are the two well-resolved doublets at δ_H ~ 5.76 ppm (³J_HH = 8.1 Hz) and δ_H ~ 3.81 ppm with a coupling constant of ²J_PH = 24.0 Hz, corresponding to the NH of amide group and the H3 methine proton of the aziridine ring, respectively. A singlet at δ_H ~ 1.96 ppm was attributed to the methyl group. In the ¹³C NMR spectrum, the formation of compound 4a is evident from the presence of two carbonyl groups at δ_C ~ 176.2 (³J_PC = 3.3 Hz) and 165.6 ppm, while the quaternary carbon C2 appears as a doublet at δ_C ~ 49.6 ppm (²J_PC = 3.0 Hz) and the methine carbon C3 shows a chemical shift at δ_C ~ 42.0 ppm with a large coupling constant (¹J_PC = 100.4 Hz).

Since it was not possible to assign the stereochemistry of N-acylaziridines 4 via ¹H and ¹³C NMR, their structure has been unambiguously determined via X-ray diffraction analysis [51,52,53], establishing the trans-relationship between the amide group at the C2 position and the phosphorus moiety at the C3 position of the major diastereoisomer 4i. The CIF data are presented in the Supporting Information, and the ORTEP drawing of 4i is shown in Figure 3.

The ZnCl₂-catalyzed Joullié–Ugi three-component reaction was extended to the use of 2H-azirine phosphonate 1b. Then, 2H-azirine 1b reacted with a series of carboxylic acids 2 and isocyanides 3 in THF at room temperature in the presence of ZnCl₂ (25 mol%). As outlined in Scheme 3, aromatic (2a and 2d), heteroaromatic (2h and 2j), aliphatic (2m and 2n), propargylic (2o) and acrylic (2q) acids are allowable in the JU-3CR, yielding the desired N-acylaziridine phosphonates 5 in chemical yields ranging from 35 to 76%.

Encouraged by the abovementioned obtained results of the Joullié–Ugi three-component reaction between phosphorylated 2H-azirines 1, carboxylic acids 2 and isocyanides 3, we further investigated the substrate scope using N-Fmoc-protected amino acids as carboxylic acid partners for the preparation of phosphorylated aziridine peptidomimetics. To our delight, it was found that the reaction proceeded smoothly when 2H-azirine phosphonate 1b reacted with tert-butyl isocyanide (3b) and Fmoc-Leu (2r, R¹ = ⁱBu) in the standard conditions to yield derivative 6a in a 65% isolated yield (Scheme 4). The ¹H NMR spectrum of the crude reaction mixture confirmed the presence of two well-resolved doublets at δ_H = 3.03 and 2.90 ppm with a coupling constant of ²J_PH = 18.6 and 18.4 Hz, respectively, for the H3 methine proton of the aziridine ring of both trans-diastereoisomers, in a ratio of 1:1: Conversely, another doublet appeared at δ_H = 2.71 ppm with a lower coupling constant of ²J_PH = 14.7 Hz corresponding to H3 of the cis-diastereoisomer, while the fourth doublet corresponding to the other cis-diastereoisomer appeared overlapped in the range of δ_H = 2.83–2.75 ppm. The diastereomeric ratio between trans- and cis-diastereoisomers is approximately 92:8. After purification via flash-chromatography, it was possible to identity both trans-diastereoisomers of 6a. The Joullié–Ugi reaction between 2H-azirine 1b, tert-butyl isocyanide (3b) and Fmoc-Ala (2s, R¹ = Me) using 25 mol% of ZnCl₂ in THF and at room temperature led to the formation of derivative 6b in a lower yield (Scheme 4). Via the ¹H NMR of the crude compound, it was possible to determine the 1:1 ratio between both trans-diastereoisomers. Nevertheless, in this case, determining the diastereomeric ratio (trans/cis) was infeasible.

The gram-scale synthesis of phosphorylated N-acylaziridines was accomplished, as shown in Scheme 3. The use of 4.0 mmol of 2H-azirine phosphonate 1b, under the JU standard conditions, gave N-acylaziridine phosphonate 5a in a 70% yield (1.11 g) after recrystallization.

Scheme 5 outlines a plausible mechanism for the JU-3CR. This process carried out in a polar solvent, suggesting the formation of polar intermediates, is compatible with a stepwise mechanism. The addition of Lewis acids (in our case ZnCl₂) increases the electrophilicity of the iminic C–N double bond in 2H-azirine 1. Thus, the electrophilic imine and nucleophilic carboxylic acid 2 add to the carbon atom of isocyanide 3. The amino group of the adduct thus formed promotes the irreversible Mumm rearrangement in the presence of a zinc catalyst and the intramolecular acylation of the amine nitrogen atom, which after subsequent hydroxylimine → amide tautomerization leads to phosphorylated N-acylaziridines 4, 5 or 6.

We performed further derivatization in order to illustrate the utility of the Joullié–Ugi adducts. Thus, we explored the isomerization reaction of N-acylaziridines 4 and 5 to oxazole derivatives. For this purpose, and taking into account that the regio- and stereochemical outcomes of these rearrangements strongly depend on the reaction conditions, as well as the substitution pattern of the N-acylaziridine, we started exploring thermal conditions for the ring opening of compounds 4 and 5. Thus, phosphorus-substituted N-acylaziridine 4a was heated in refluxing CHCl₃. Under these conditions, the corresponding oxazole derivative was not observed, and the unreacted starting substrate was recovered instead. Next, the rearrangement of 4a was also tested under nucleophilic conditions [31,54,55,56,57]. When 4a reacted with 0.2 equivalents of NaI in THF at 60 °C, as in the previous case, no satisfactory results were attained, observing only decomposition products. Likewise, the isomerization of the N-acylaziridine to oxazole derivative under mild acidic conditions was examined. Compound 4a was treated with both Brønsted acids, including p-toluenesulfonic acid (PTSA), and Lewis acids, including BF₃·OEt₂. Only the use of BF₃·OEt₂ gave satisfactory results. Hence, when N-acylaziridine 4a reacted in the presence of 1.2 equivalents of BF₃·OEt₂ in MeCN at 90 °C and under microwave irradiation for 10 min, the formation of 4-diphenylphosphoryl-4,5-dihydrooxazole-5-carboxamide 7a was achieved in a very good yield and in a regio- and diastereoselective fashion (Scheme 6).

Spectroscopic data confirmed the isomerization of N-acylaziridine 4a into oxazole derivative 7a. While the ¹H NMR spectrum of 4a shows a signal for the methyl group at δ_H = 1.96 ppm and the methine hydrogen resonates at δ_H = 3.81 ppm as a well-resolved doublet (²J_PH = 24 Hz, see above), in dihydrooxazole-5-carboxamide 7a, these signals appear at δ_H = 1.63 and 5.32 ppm as a singlet and a well-resolved doublet with a much lower coupling constant (²J_PH = 6.0 Hz), respectively. Similarly, other N-acylaziridines derived from phosphine oxide 4b, 4i and 4l reacted with BF₃·OEt₂ under the same reaction conditions, providing 60, 92 and 91% yields of oxazole derivatives 7b–d (Scheme 6). This synthetic methodology was extended to the use of N-acylaziridines 5 derived from phosphonate. Thus, the ring expansion of 5a and 5b easily occurred via the slight excess of BF₃·OEt₂ (3 equivalents) in CHCl₃ at 71 °C and under microwave irradiation for 15 min, to obtain regio- and diasteroselective 7e and 7f in high yields (Scheme 6).

Since it was not possible to assign the stereochemistry of oxazole derivatives 7 via ¹H and ¹³C NMR, their structure has been unambiguously determined via X-ray diffraction analysis [51,52,53], establishing not only the regioselectivity of the isomerization process, but also the anti-relationship between the amide group at the C5 position and the phosphorus moiety at the C4 position of 7a (Figure 4).

A reasonable mechanism that would explain the formation of 7 is exemplified in Scheme 7. First, BF₃·OEt₂ would activate the carbonyl group of N-acylaziridine 4 or 5, thus assisting the ring-opening reaction, through the N–C2 bond of N-acylaziridine, with the concomitant generation of the most stable carbocation. This intermediate enables the ring expansion of N-acylaziridine 4 or 5 to oxazole derivative 7, as the only regio- and diastereoisomer.

3. Materials and Methods

3.1. General Experimental Information

Solvents for extraction and chromatography were reagent-grade. All solvents used in reactions were freshly distilled and dried over 4 Å molecular sieves before use. Unless otherwise mentioned, all other solvents and chemicals were purchased from commercial vendors and recrystallized or distilled as necessary, or used without further purification. All reactions were performed under an atmosphere of dry nitrogen. The reaction progress was monitored via ³¹P NMR or analytical thin-layer chromatography (TLC) performed on precoated Merck silica gel 60 F₂₅₄ TLC aluminum plates, and spot-visualized with UV light or permanganate stain. Melting points were uncorrected. ¹H (400 MHz), ¹³C (100 MHz), ¹⁹F (376 MHz) and ³¹P NMR (160 MHz) spectra were recorded using a Bruker Avance 400 (400 MHz) spectrometer in CDCl₃ at room temperature. Chemical shifts (δ) are reported in parts per million (ppm) with the internal chloroform signal at 7.26 ppm as a standard for ¹H, the internal chloroform signal at 77.2 ppm as a standard for ¹³C, the external fluorotrichloromethane (CFCl₃) signal at 0.0 ppm for ¹⁹F or the external H₃PO₄ (50%) signal at 0.0 ppm as a standard for ³¹P NMR spectra. All coupling constants (J) values are reported in Hz. ¹⁹F and ¹³C NMR spectra were recorded in a broadband decoupled mode from hydrogen nuclei. Distortionless enhanced polarization transfer (DEPT) supported peak assignments for ¹³C NMR. Data for 1H NMR spectra are reported for the following: chemical shift, multiplicity, coupling constant and integration. Multiplicity abbreviations are reported as s = singlet; d = doublet; t = triplet; q = quartet; m = multiplet; dd = double doublet; bs = broad singlet. IR spectra were measured using a Nicolet iS10 Termo Scientific spectrometer using an attenuated total reflectance technique (ATR). Absorbance frequencies are given at maximum of intensity in cm^–1. High-resolution mass spectra (HRMS) were obtained via the positive-ion electrospray ionization (ESI) method with a time of flight Q-TOF method. Data are reported in the form m/z (intensity relative to base = 100). 2H-Azirine phosphine oxide 1a [58] and phosphonate 1b [59] were prepared according to procedures in the literature and characterized using NMR spectra.

3.2. Experimental Procedure and Characterization Data for N-Acylaziridine Phosphine Oxide 4

In a flame-dried flask, the corresponding carboxylic acid 2 (0.65 mmol, 1.3 eq.), isocyanide 3 (0.65 mmol, 1.3 eq.) and 1M diethyl ether solution of ZnCl₂ (0.12 mL; 0.12 mmol; 0.25 eq.) were added to 0.5 mL of dry THF. Then, 2H-azirine phosphine oxide 1a (0.50 mmol, 1 eq.) was added at room temperature. The reaction mixture was stirred until TLC showed the disappearance of 2H-azirine 1a (1–24 h). The solvent was removed under vacuum, and the residue was dissolved in dichloromethane (5 mL) and washed with water (2 × 5 mL). The organic layer was dried over anhydrous MgSO₄ and filtered, and the solvent was evaporated under reduced pressure. The resulting residue was purified via flash column chromatography (SiO₂, hexanes/AcOEt) to yield compounds 4.

(2S*,3S*)-1-Benzoyl-N-cyclohexyl-3-(diphenylphosphoryl)-2-methylaziridine-2-carboxamide (4a) (182 mg, 75%) was obtained as a white solid from carboxylic acid 2a (79 mg, 0.65 mmol), isocyanide 3a (81 µL mg, 0.65 mmol) and 2H-azirine 1a (127 mg, 0.50 mmol), as described in the general procedure. The crude product was purified via flash column chromatography (SiO₂, AcOEt/hexanes 50:50) to give the title compound 4a. mp 249–251 °C; IR (neat) v_max 3281, 3070, 2923, 2848, 1685, 1651, 1549, 1285, 1193 cm^–1; ¹H NMR (400 MHz, CDCl₃) δ 8.01–7.95 (m, 4H, ArH), 7.84–7.82 (m, 2H, ArH), 7.62–7.47 (m, 7H, ArH), 7.40–7.37 (m, 2H, ArH), 5.76 (d, ²J_HH = 8.2 Hz, 1H, HC-NH), 3.81 (d, ²J_PH = 24.0 Hz, 1H, CH-P), 3.50–3.40 (m, 1H, HC-NH), 1.96 (s, 3H, CH₃), 1.76–1.73 (m, 1H, ^cHex), 1.63–1.59 (m, 1H, ^cHex), 1.53–1.45 (m, 2H, ^cHex), 1.27–0.98 (m, 5H, ^cHex), 0.73–0.63 (m, 1H, ^cHex) ppm; ¹³C {1H} NMR (100 MHz, CDCl₃) δ 176.9 (d, ³J_PC = 3.1 Hz), 165.6), 134.2, 132.6 (d, ¹J_PC = 103.4 Hz, C_quat), 132.5, 132.4, 132.4, 132.3, 132.3, 131.8, 131.7, 131.2, 131.1, 129.1, 129.0, 128.8, 128.6, 128.5, 49.7 (d, ²J_PC = 2.7 Hz, C_quat), 49.1, 42.2 (d, ¹J_PC = 101.0 Hz), 32.5, 32.4, 25.4, 24.7, 24.6, 15.5 ppm; ³¹P NMR (160 MHz, CDCl₃) δ 24.1 ppm; ESI-HRMS (CI) m/z calculated for C₂₉H₃₂N₂O₃P ([M + H]⁺), 487.2151; found 487.21567.

(2S*,3S*)-N-Cyclohexyl-3-(diphenylphosphoryl)-2-methyl-1-(3-methylbenzoyl)aziridine-2-carboxamide (4b) (158 mg, 63%) was obtained as a white solid from carboxylic acid 2b (88 mg, 0.65 mmol), isocyanide 3a (81 µL, 0.65 mmol) and 2H-azirine 1a (127 mg, 0.50 mmol), as described in the general procedure. The crude product was purified via flash column chromatography (SiO₂, AcOEt/hexane 50:50) to give the title compound 4b. mp 201–203 °C; IR (neat) v_max 3303, 3056, 2939, 1679, 1643, 1538, 1293, 1191 cm^–1; ¹H NMR (400 MHz, CDCl₃) δ 7.90–7.85 (m, 4H, ArH), 7.59 (s, 1H, ArH), 7.59–7.39 (m, 7H, ArH), 7.21–7.13 (m, 2H, ArH), 5.81 (d, ³J_HH = 8.2 Hz, 1H, HC-NH), 3.78 (d, ²J_PC = 24.2 Hz, 1H, CH-P), 3.42–3.33 (m, 1H, HC-NH), 2.26 (s, 3H, CH₃), 1.86 (s, 3H, CH₃), 1.65–1.63 (m, 1H, ^cHex), 1.52–1.49 (m, 1H, ^cHex), 1.43–1.36 (m, 2H, ^cHex), 1.18–0.90 (m, 5H, ^cHex), 0.70–0.61 (m, 1H, ^cHex) ppm; ¹³C {1H} NMR (100 MHz, CDCl₃) δ 176.2 (d, ³J_PC = 3.3 Hz), 165.6, 138.2, 133.9, 133.2, 132.3, 132.2, 132.2, 132.1, 131.7, 131.6 131.1, 131.0, 129.1, 129.0, 128.9, 128.7, 128.6, 128.2, 125.5, 49.6 (d,² J_PC = 3.0 Hz), 49.0, 42.0 (d, ¹J_PC = 100.4 Hz), 32.5, 32.4, 25.3, 24.7, 24.6, 21.4, 15.4 ppm; ³¹P NMR (160 MHz, CDCl₃) δ 23.9 ppm; ESI-HRMS (CI) m/z calculated for C₃₀H₃₄N₂O₃P ([M + H]⁺), 501.2307; found 501.2308.

(2S*,3S*)-N-Cyclohexyl-3-(diphenylphosphoryl)-2-methyl-1-(4-nitrobenzoyl)aziridine-2-carboxamide (4c) (135 mg, 51%) was obtained as a white solid from carboxylic acid 2c (108 mg, 0.65 mmol), isocyanide 3a (81 µL, 0.65 mmol) and 2H-azirine 1a (127 mg, 0.50 mmol), as described in the general procedure. The crude product was purified via flash column chromatography (SiO₂, AcOEt/hexane 50:50) to give the title compound 4c. mp 254–256 °C; IR (neat) v_max 3281, 3078, 2923, 1737, 1687, 1649, 1596, 1554, 1501, 1390, 1285, 1193 cm^–1; ¹H NMR (400 MHz, CDCl₃) δ 8.20 (d, ³J_HH = 8.7 Hz, 2H, ArH), 7.96–7.78 (m, 6H, ArH), 7.59–7.48 (m, 6H, ArH), 5.88 (d, ³J_HH = 7.8 Hz, 1H, HC-NH), 3.68 (d, ²J_PH = 23.5 Hz, 1H, CH-P), 3.49–3.38 (m, 1H, HC-NH), 1.95 (s, 3H, CH₃), 1.73 (d, ³J_HH = 12.2 Hz, 1H, ^cHex), 1.60 (d, ³J_HH = 14.4 Hz, 1H, ^cHex), 1.52–1.45 (m, 2H, ^cHex), 1.34 (d, ³J_HH = 12.4, 1H, ^cHex), 1.23–1.03 (m, 4H, ^cHex), 0.83–0.75, 1H, ^cHex) ppm; ¹³C {1H} NMR (100 MHz, CDCl₃) δ 175.2 (d, ³J_PC = 3.2 Hz), 165.7, 150.0, 139.8, 132.6, 136.6, 132.6, 132.5, 132.2 (d, ¹J_PC = 103.9 Hz), 131.6, 131.5, 131.3 (d, ¹J_PC = 105.2 Hz), 131.1, 131.0, 129.3, 129.2, 129.1, 128.9, 128.8. 123.7, 50.0 (d, ²J_PC = 2.73 Hz), 49.4, 42.7 (d, ¹J_PC = 99.2 Hz), 32.6, 32.5, 25.3, 24.7, 24.6, 15.3 ppm; ³¹P NMR (160 MHz, CDCl₃) δ 23.5 ppm; ESI-HRMS (CI) m/z calculated for C₂₉H₃₁N₃O₅P ([M + H]⁺), 532.2001; found 532.1980.

(2S*,3S*)-N-Cyclohexyl-3-(diphenylphosphoryl)-1-(4-fluorobenzoyl)-2-methylaziridine-2-carboxamide (4d) (186 mg, 74%) was obtained as a white solid from carboxylic acid 2d (91 mg, 0.65 mmol), isocyanide 3a (81 µL, 0.65 mmol) and 2H-azirine 1a (127 mg, 0.50 mmol), as described in the general procedure. The crude product was purified via flash column chromatography (SiO₂, AcOEt/hexane 50:50) to give the title compound 4d. mp 255–257 °C; IR (neat) v_max 3284, 3018, 2939, 1688, 1650, 1590, 1286, 1102 cm^–1; ¹H NMR (400 MHz, CDCl₃) δ 7.96–7.91 (m, 4H, ArH), 7.82 (dd, ³J_HH = 8.8, ⁴J_HH = 5.4 Hz, 2H), 7.60–7.46 (m, 6H, ArH), 7.04 (t, ³J_HH = 8.6 Hz, ³J_HF = 8.6 Hz, 2H, ArH), 5.77 (d, ³J_HH = 8.2 Hz, 1H, HC-NH), 3.75 (d, ²J_PH = 24.0 Hz, 1H, CH-P), 3.48 (m, 1H, HC-NH), 1.93 (s, 3H, CH₃), 1.75–1.72 (m, 1H, ^cHex), 1.62–1.59 (m, 1H, ^cHex), 1.53–1.48 (m, 2H, ^cHex), 1.22–1.17 (m, 2H, ^cHex), 1.12–1.00 (m, 3H, ^cHex), 0.79–0.70 (m, 1H, ^cHex) ppm; ¹³C {1H}NMR (100 MHz, CDCl₃) δ 175.7 (d, ³J_PC = 3.2 Hz), 165.6, 165.4 (d, ¹J_CF = 253.3 Hz), 132.5 (d, ¹J_PC = 103.6 Hz, C_quat), 132.4, 132.4, 132.4, 132.3, 132.2, 131.7, 131.1, 131.0, 130.9, 130.8, 130.6 (d, ⁴J_CF = 3.0 Hz), 129.1, 129.0, 128.8, 115.7, 115.5, 49.7 (d, ²J_PC = 3.0 Hz), 49.0, 42.2 (d, ¹J_PC = 100.4 Hz), 32.5, 32.5, 25.4, 24.7, 24.6, 15.4 ppm; ³¹P NMR (160 MHz, CDCl₃) δ 24.4 ppm; ¹⁹F NMR (376 MHz, CDCl₃) δ –106.5 ppm; ESI-HRMS (CI) m/z calculated for C₂₉H₃₁FN₂O₃P ([M + H]⁺), 505.2056; found 505.2043.

(2S*,3S*)-N-Cyclohexyl-3-(diphenylphosphoryl)-1-(4-methoxybenzoyl)-2-methylaziridine-2-carboxamide (4e) was (51 mg, 20%) obtained as a white solid from carboxylic acid 2e (100 mg, 0.65 mmol), isocyanide 3a (81 µL, 0.65 mmol) and 2H-azirine 1a (127 mg, 0.50 mmol), as described in the general procedure. The crude product was purified via flash column chromatography (SiO₂, AcOEt/hexane 50:50) to give the title compound 4e. mp 251–252 °C; IR (neat) v_max 3278, 3075, 2923, 1685, 1651, 1596, 1549, 1282, 1196, 1121 cm^–1; ¹H NMR (400 MHz, CDCl₃) δ 7.96–7.92 (m, 4H, ArH), 7.77 (d, ³J_HH = 8.9 Hz, 2H, ArH), 7.57–7.44 (m, 6H, ArH), 6.84 (d, ³J_HH = 8.9 Hz, 2H, ArH), 5.82 (d, ³J_HH = 7.9 Hz, 1H, HC-NH), 3.80 (s, 3H, OCH₃), 3.76 (d, ¹J_PC = 24.2 Hz, 1H, CH-P), 3.51–3.40 (m, 1H, HC-NH), 1.92 (s, 3H, CH₃), 1.73–1.69 (m, 1H, ^cHex), 1.59–1.56 (m, 1H, ^cHex), 1.59–1.47 (m, 2H, ^cHex), 1.31–0.96 (m, 5H, ^cHex), 0.77–0.68 (m, 1H, ^cHex) ppm; ¹³C {1H} NMR (100 MHz, CDCl₃) δ 176.0 (d, ³J_PC = 3.3 Hz), 165.6, 163.1, 133.2, 132.3, 132.3, 132.2, 132.2, 131.8, 131.7, 131.3, 131.1, 131.0, 130.5, 129.0, 128.9, 128.7, 128.6, 126.7, 113.7, 55.5, 49.7 (d, ²J_PC = 2.9 Hz, C_quat), 49.0, 41.9 (d, ¹J_PC = 101.0 Hz), 32.5, 32.4, 25.4, 24.7, 24.6, 15.5 ppm; ³¹P NMR (160 MHz, CDCl₃) δ 24.0 ppm; ESI-HRMS (CI) m/z calculated for C₃₀H₃₄N₂O₄P ([M + H]⁺), 517.2256; found 517.2257.

(2S*,3S*)-N-Cyclohexyl-3-(diphenylphosphoryl)-2-methyl-1-(2-phenylacetyl)aziridine-2-carboxamide (4f) (170 mg, 68%) was obtained as a white solid from carboxylic acid 2m (88 mg, 0.65 mmol), isocyanide 3a (81 µL, 0.65 mmol) and 2H-azirine 1a (127 mg, 0.50 mmol), as described in the general procedure. The crude product was purified via flash column chromatography (SiO₂, AcOEt/hexane 60:40) to give the title compound 4f. mp 245–247 °C; IR (neat) v_max 3311, 3056, 2978, 1691, 1653, 1524, 1254, 1182 cm^–1; ¹H NMR (400 MHz, CDCl₃) δ 7.97–7.91 (m, 2H, ArH), 7.85–7.80 (m, 2H, ArH), 7.54–7.41 (m, 6H, ArH), 7.22–7.18 (m, 3H, ArH), 7.12 (dd, ³J_HH = 7.6, ⁴J_HH = 1.8, 2H, ArH), 5.99 (bs, 1H, HC-NH), 3.74–3.63 (m, 1H, HC-NH), 3.68 (d, ²J_HH = 16.4 Hz, 1H, CH₂), 3.57 (d, ²J_HH = 16.5 Hz, 1H, CH₂), 3.40 (d, ²J_PH = 23.7 Hz, 1H, CH-P), 1.91–1.87 (m, 1H, ^cHex), 1.83–1.79 (m, 1H, ^cHex), 1.70–1.57 (m, 3H, ^cHex), 1.39–1.25 (m, 2H, ^cHex), 1.31 (s, 3H, CH₃), 1.19–1.09 (m, 3H, ^cHex); ¹³C {1H} NMR (100 MHz, CDCl₃) δ 180.8 (d, ³J_PC = 2.1 Hz), 166.8, 134.2, 133.2, 132.3, 132.3, 132.2, 132.1, 131.7, 131.6, 131.2 (d, ¹J_PC = 103.5 Hz) 131.0, 130.7, 130.1, 129.0, 128.9, 128.6, 128.5, 128.4, 126.9, 49.5, 49.1 (d, ²J_PC = 2.9 Hz), 44.4, 42.2 (d, ¹J_PC = 101.3 Hz), 32.9, 32.7, 25.3, 24.9, 24.8, 24.7, 14.8 ppm; ³¹P NMR (160 MHz, CDCl₃) δ 24.4 ppm; ESI-HRMS (CI) m/z calculated for C₃₀H₃₄N₂O₃P ([M + H]⁺), 501.2307; found 501.2290.

(2S*,3S*)-N-Cyclohexyl-3-(diphenylphosphoryl)-2-methyl-1-propioloylaziridine-2-carboxamide (4g) (33 mg, 15%) was obtained as a pale orange solid from carboxylic acid 2p (40 µL, 0.65 mmol), isocyanide 3a (81 µL, 0.65 mmol) and 2H-azirine 1a (127 mg, 0.50 mmol), as described in the general procedure. The crude product was purified via flash column chromatography (SiO₂, AcOEt/hexane 50:50) to give the title compound 4g. mp 152–153 °C; IR (neat) v_max 3270, 3059, 2923, 2098, 1674, 1658, 1587, 1371, 1188 cm^–1; ¹H NMR (400 MHz, CDCl₃) δ 7.91–7.86 (m, 4H, ArH), 7.57–7.51 (m, 6H, ArH), 6.06 (d, ³J_HH = 8.1 Hz, 1H, HC-NH), 3.81–3.75 (m, 1H, HC-NH), 3.67 (d, ²J_PH = 23.9 Hz, 1H, CH-P), 2.80 (s, 1H, C≡CH), 1.93–1.92 (m, 2H, ^cHex), 1.85 (s, 3H, CH₃), 1.77–1.73 (m, 2H, ^cHex), 1.68–1.58 (m, 1H, ^cHex), 1.41–1.26 (m, 2H, ^cHex), 1.25–1.11 (m, 3H, ^cHex) ppm; ¹³C {1H} NMR (100 MHz, CDCl₃) δ 165.5, 160.3, 132.7, 132.6, 132.5, 132.5, 131.9 (d, ¹J_PC = 103.4 Hz), 131.8, 131.7, 131.2 (d, ¹J_PC = 105.3 Hz), 131.1, 131.0, 129.2, 129.0, 128.8, 128.7, 76.7, 49.8, 49.3 (d, ²J_PC = 2.2 Hz), 43.9 (d, ¹J_PC = 98.0 Hz), 33.2, 32.8, 25.5, 24.9, 24.9, 14.7 ppm; ³¹P NMR (160 MHz, CDCl₃) δ 22.8 ppm; ESI-HRMS (CI) m/z calculated for C₂₅H₂₈N₂O₃P ([M + H]⁺), 435.1838; found 435.1838.

(2S*,3S*)-N-Cyclohexyl-3-(diphenylphosphoryl)-2-methyl-1-nicotinoylaziridine-2-carboxamide (4h) (104 mg, 43%) was obtained as a white solid from carboxylic acid 2f (80 mg, 0.65 mmol), isocyanide 3a (81 µL, 0.65 mmol) and 2H-azirine 1a (127 mg, 0.50 mmol), as described in the general procedure. The crude product was purified via flash column chromatography (SiO₂, AcOEt/hexane 50:50) to give the title compound 4h. mp 234–236 °C; IR (neat) v_max 3275, 3078, 3053, 2925, 1690, 1651, 1543, 1318, 1199, 1127 cm^–1; ¹H NMR (400 MHz, CDCl₃) δ 8.95 (s, 1H, ArH), 8.68 (d, ³J_HH = 4.60 Hz, 1H, ArH), 8.14 (d, ³J_HH = 8.0 Hz, 1H, ArH), 7.96–7.90 (m, 4H, ArH), 7.57–7.48 (m, 6H, ArH), 7.34 (dd, ³J_HH = 7.7 Hz, ³J_HH = 4.60 Hz, 1H, ArH), 5.86 (bs, 1H, HC-NH), 3.76 (d, ²J_PH = 23.5 Hz, 1H, CH-P), 3.45–3.37 (m, 1H, HC-NH), 1.95 (s, 3H, CH₃), 1.72 (d, ³J_HH = 11.7 Hz, 1H, ^cHex), 1.61–1.57 (m, 1H, ^cHex), 1.51–1.45 (m, 2H, ^cHex), 1.27–0.99 (m, 5H, ^cHex), 0.78–0.69 (m, 1H, ^cHex) ppm; ¹³C {1H} NMR (100 MHz, CDCl₃) δ 175.4 (d, ³J_PC = 3.4 Hz), 165.5, 152.9, 149.4, 132.5, 132.5, 132.5, 132.4, 132.4 (d, ¹J_PC = 103.8 Hz), 131.7, 131.4 (d, ¹J_PC = 105.4 Hz), 131.6, 131.1, 131.0, 130.0), 129.1, 129.0, 128.8, 128.7, 123.6, 50.0, 49.4, 42.5 (d, ¹J_PC = 100.1 Hz), 32.5, 32.5, 25.3, 24.7, 24.6, 15.3 ppm; ³¹P NMR (160 MHz, CDCl₃) δ 23.7 ppm; ESI-HRMS (CI) m/z calculated for C₂₈H₃₁N₃O₃P ([M + H]⁺), 488.2103; found 488.2102.

(2S*,3S*)-1-Benzoyl-N-(tert-butyl)-3-(diphenylphosphoryl)-2-methylaziridine-2-carboxamide (4i) (184 mg, 80%) was obtained as a white solid from carboxylic acid 2a (79 mg, 0.65 mmol), isocyanide 3b (79 µL, 0.65 mmol) and 2H-azirine 1a (127 mg, 0.50 mmol), as described in the general procedure. The crude product was purified via flash column chromatography (SiO₂, AcOEt/hexane 50:50) to give the title compound 4i. mp 177–179 °C; IR (neat) v_max 3319, 3050, 2967, 2923, 1699, 1682, 1699, 1601, 1535, 1232, 1190 cm^–1; ¹H NMR (400 MHz, CDCl₃) δ 8.03–7.93 (m, 4H, ArH), 7.80–7.78 (m, 2H, ArH), 7.59–7.45 (m, 7H, ArH), 7.36 (t, ³J_HH = 7.6 Hz, 2H, ArH), 5.66 (s, 1H, NH), 3.80 (d, ²J_PH = 23.6 Hz, 1H, CH-P), 1.89 (s, 3H, CH₃), 0.98 (s, 9H, ^tBu) ppm; ¹³C {1H} NMR (100 MHz, CDCl₃) δ 177.1 (d, ³J_PC = 3.1 Hz), 165.3, 134.3, 132.9 (d, ¹J_PC = 103.5 Hz), 132.5, 132.3, 132.3, 132.2, 132.2, 131.8, 131.7, 131.6 (d, ¹J_PC = 105.3 Hz) 131.2, 131.1, 129.0, 128.9, 128.7, 128.6, 128.5, 128.4, 52.1, 50.0 (d, ²J_PC = 3.0 Hz, C_quart), 42.3 (d, ¹J_PC = 101.3 Hz), 28.1, 15.8 ppm; ³¹P NMR (160 MHz, CDCl₃) 23.9 ppm; δ ESI-HRMS (CI) m/z calculated for C₂₇H₃₀N₂O₃P ([M + H]⁺), 461.1994; found 461.1995.

2S*,3S*-N-(tert-Butyl)-3-(diphenylphosphoryl)-1-(4-fluorobenzoyl)-2-methylaziridine-2-carboxamide (4j) (177mg, 74%) was obtained as a white solid from carboxylic acid 2d (91 mg, 0.65 mmol), isocyanide 3b (76 µL, 0.65 mmol) and 2H-azirine 1a (127 mg, 0.50 mmol), as described in the general procedure. The crude product was purified via flash column chromatography (SiO₂, AcOEt/hexane 50:50) to give the title compound 4j. mp 221–223 °C; IR (neat) v_max 3297, 3053, 2964, 1685, 1665, 1524, 1282, 1196 cm^–1; ¹H NMR (400 MHz, CDCl₃) δ 8.01–7.91 (m, 4H, ArH), 7.83–7.79 (m, 2H, ArH), 7.59–7.44 (m, 6H, ArH), 7.04 (t, ³J_HH = 8.6 Hz, ³J_HF = 8.6 Hz, 2H, ArH), 5.69 (s, 1H, NH), 3.77 (d, ²J_PH = 23.5 Hz, 1H, CH-P), 1.89 (s, 3H, CH₃), 1.03 (s, 9H, ^tBu) ppm; ¹³C {1H} NMR (100 MHz, CDCl₃) δ 176.0 (d, ³J_PC = 2.8 Hz), 165.4 (d, ¹J_CF = 253.3 Hz), 165.3, 133.3, 132.4, 132.3, 132.3, 132.1, 131.8, 131.7, 131.2, 131.1, 131.0, 130.9, 130.8 (d, ⁴J_CF = 3.0 Hz), 129.1, 129.0, 128.8, 128.7, 115.6 (d, ²J_CF = 21.9 Hz, ArC), 52.3, 50.1, 42.2 (d, ¹J_PC = 101.0 Hz, 28.2, 15.7 ppm; ³¹P NMR (160 MHz, CDCl₃) 24.0 ppm; ¹⁹F NMR (376 MHz, CDCl₃) δ –106.5 ppm; ESI-HRMS (CI) m/z calculated for C₂₇H₂₉FN₂O₃P ([M + H]⁺), 479.1900; found, 479.1904.

(2S*,3S*)-N-(tert-Butyl)-3-(diphenylphosphoryl)-1-(4-methoxybenzoyl)-2-methylaziridine-2-carboxamide(4k) (123 mg, 50%) was obtained as a white solid from carboxylic acid 2e (100 mg, 0.65 mmol), isocyanide 3b (76 µL, 0.65 mmol) and 2H-azirine 1a (127 mg, 0.50 mmol), as described in the general procedure. The crude product was purified via flash column chromatography (SiO₂, AcOEt/hexane 45:55) to give the title compound 4k. mp > 275 °C; IR (neat) v_max 3250, 2961, 1671, 1660, 1601, 1066 cm^–1; ¹H NMR (400 MHz, CDCl₃) δ 8.01–7.92 (m, 4H, ArH), 7.77 (d, ³J_HH = 8.9 Hz, 2H, ArH), 7.54–7.45 (m, 6H, ArH), 6.85 (d, ³J_HH = 8.9 Hz, 2H, ArH), 5.67 (s, 1H, NH), 3.82 (s, 3H, CH₃), 3.79 (d, ²J_PH = 23.8 Hz, 1H, CH-P), 1.89 (s, 3H, CH₃), 1.01 (s, 9H, ^tBu) ppm; ¹³C {1H} NMR (100 MHz, CDCl₃) δ 176.2 (d, ³J_PC = 3.3 Hz), 165.3, 163.1 (C_quat), 133.0 (d, ¹J_PC = 103.3 Hz), 132.3, 132.2, 132.2, 131.8, 131.7 (ArC), 131.2 (C_quat), 131.2, 131.1, 130.6, 129.0, 128.9, 128.7, 128.6, 126.9, 113.7, 55.6, 52.1, 50.1 (d, ²J_PC = 3.1 Hz, C_quat), 42.0 (d, ¹J_PC = 101.5 Hz), 28.2, 15.8 ppm; ³¹P NMR (160 MHz, CDCl₃) δ 24.1 ppm ESI-HRMS (CI) m/z calculated for C₂₈H₃₂N₂O₄P ([M + H]⁺), 491.2100; found 491.2101.

(2S*,3S*)-1-(2-Naphthoyl)-N-(tert-butyl)-3-(diphenylphosphoryl)-2-methylaziridine-2-carboxamide (4l) (178 mg, 70%) was obtained as a white solid from carboxylic acid 2g (112 mg, 0.65 mmol), isocyanide 3b (76µL, 0.65 mmol) and 2H-azirine 1a (127 mg, 0.50 mmol), as described in the general procedure. The crude product was purified via flash column chromatography (SiO₂, AcOEt/hexane 50:50) to give the title compound 4l. mp 265–267 °C; IR (neat) v_max 3381, 3061, 2970, 1682, 1662, 1529, 1293, 1196 cm^–1; 1H NMR (400 MHz, CDCl₃) δ 8.33 (s, 1H, ArH), 8.04–7.93 (m, 4H, ArH), 7.88–7.81 (m, 4H, ArH), 7.58–7.43 (m, 8H, ArH) 5.66 (s, 1H, NH), 3.84 (d, ²J_PH = 23.6 Hz, 1H, CH-P), 1.98 (s, 3H, CH₃), 0.88 (s, 9H, ^tBu) ppm; ¹³C {1H} NMR (100 MHz, CDCl₃) δ 177.2 (d, ³J_PC = 3.3 Hz), 165.4, 135.4, 133.0 (d, ¹J_PC = 103.6 Hz), 132.5, 132.4, 132.3, 132.3, 132.2, 131.8, 131.7, 131.2, 131.1, 129.6, 129.3, 129.1, 129.0, 128.7, 128.6, 128.3, 128.2, 127.9, 126.8, 124.7, 51.1, 50.2 (d, ²J_PC = 2.9 Hz), 42.4 (d, ¹J_PC = 100.5 Hz), 28.1, 15.7 ppm; ³¹P NMR (160 MHz, CDCl₃) δ 23.9 ppm; ESI-HRMS (CI) m/z calculated for C₃₁H₃₂N₂O₃P [M + H]⁺), 511.2151; found 511.2152.

(2S*,3S*)-N-(tert-Butyl)-3-(diphenylphosphoryl)-1-(furan-2-carbonyl)-2-methylaziridine-2-carboxamide (4m) (191 mg, 85%) was obtained as a white solid from carboxylic acid 2h (73 mg, 0.65 mmol), isocyanide 3b (76 µL, 0.65 mmol) and 2H-azirine 1a (127 mg, 0.50 mmol), as described in the general procedure. The crude product was purified via flash column chromatography (SiO₂, AcOEt/hexane 45:55) and recrystallized from diethyl ether to give the title compound 4m. mp 222–224 °C; IR (neat) v_max 3317, 3056, 2959, 1674, 1576, 1296, 1118 cm^–1; ¹H NMR (400 MHz, CDCl₃) δ 8.02–7.91 (m, 4H, ArH), 7.59–7.45 (m, 6H), 7.31 (dd, ³J_HH = 1.7 Hz, ⁴J_HH = 0.8 Hz, 1H), 7.14 (dd, ³J_HH = 3.5, ⁴J_HH = 0.9 Hz, 1H), 6.44 (dd, ³J_HH = 3.5 Hz, ³J_HH = 1.7 Hz, 1H), 5.85 (s, 1H, NH), 3.69 (d, ²J_PH = 23.3 Hz, 1H, CH-P), 1.86 (s, 3H, CH₃), 1.18 (s, 9H, ^tBu) ppm; ¹³C {1H} NMR (100 MHz, CDCl₃) δ 166.4 (d, ³J_PC = 3.5 Hz), 166.0, 148.7, 145.0, 133.0 (d, ¹J_PC = 103.5 Hz), 132.3, 132.2, 132.1, 131.8, 131.7, 131.1, 131.0, 129.0, 128.9, 128.7, 128.6, 116.5, 112.3, 52.0, 49.8 (d, ²J_PC = 3.2 Hz, C_quat), 42.3 (d, ¹J_PC = 101.0 Hz), 28.3, 15.6 ppm; ³¹P NMR (160 MHz, CDCl₃) δ 23.6 ppm; ESI-HRMS (CI) m/z calculated for C₂₅H₂₈N₂O₄P ([M + H]⁺), 451.1787; found 451.1789.

(2S*,3S*)-1-(4-Benzoylbenzoyl)-N-(tert-butyl)-3-(diphenylphosphoryl)-2-methylaziridine-2-carboxamide (4n) (57 mg, 20%) was obtained as a white solid from carboxylic acid 2i (147 mg, 0.65 mmol), isocyanide 3b (76 µL, 0.65 mmol) and 2H-azirine 1b (127 mg, 0.50 mmol), as described in the general procedure. The crude product was purified via flash column chromatography (SiO₂, AcOEt/hexane 50:50) to give the title compound 4n. mp 103–105 °C; IR (neat) v_max 3385, 3062, 2974, 1694, 1656, 1524, 1273, 1188 cm^–1; ¹H NMR (400 MHz, CDCl₃) δ 8.02–7.88 (m, 6H, ArH), 7.78–7.74 (m, 4H, ArH), 7.63–7.46 (m, 9H, ArH), 5.71 (s, 1H, NH), 3.78 (d, ²J_PH = 23.3 Hz, 1H, CH-P), 1.91 (s, 3H, CH₃), 1.04 (s, 9H, ^tBu) ppm; ¹³C {1H} NMR (100 MHz, CDCl₃) δ 196.0, 176.5 (d, ³J_PC = 3.3 Hz), 165.5, 140.8, 137.5, 137.1, 133.0, 132.7 (d, ¹J_PC = 103.7 Hz), 132.5, 132.4, 132.4, 132.3, 131.7, 131.6, 131.5 (d, ¹J_PC = 105.4 Hz), 131.1, 131.0, 130.2, 129.9, 129.1, 129.0, 128.8, 128.7, 128.6, 128.3, 52.3, 50.1 (d, ³J_PC = 2.8 Hz), 42.7 (d, ¹J_PC = 100.2 Hz), 28.2, 15.6 ppm; ³¹P NMR (160 MHz, CDCl₃) δ 25.7 ppm; ESI-HRMS (CI) m/z calculated for C₃₄H₃₄N₂O₄P ([M + H]⁺), 565.2256; found 565.2252.

(2S*,3S*)-1-Acetyl-N-(tert-butyl)-3-(diphenylphosphoryl)-2-methylaziridine-2-carboxamide (4o) (89 mg, 45%) was obtained as a white solid from carboxylic acid 2k (38 µL, 0.65 mmol), isocyanide 3b (76 µL, 0.65 mmol) and 2H-azirine 1a (127 mg, 0.50 mmol), as described in the general procedure. The crude product was purified via flash column chromatography (SiO₂, AcOEt/hexane 50:50) and recrystallized from diethyl ether to give the title compound 4o. mp 195–197 °C; IR (neat) v_max 3358, 3056, 2984, 1699, 1665, 1540, 1274, 1116 cm^–1; ¹H NMR (400 MHz, CDCl₃) δ 8.06–7.76 (m, 4H, ArH), 7.69–7.35 (m, 6H, ArH), 5.90 (s, 1H, NH), 3.46 (d, ²J_PH = 24.8 Hz, 1H, CH-P), 1.94 (s, 3H, CH₃), 1.76 (s, 3H, CH₃), 1.33 (s, 9H, ^tBu) ppm; ¹³C {1H} NMR (100 MHz, CDCl₃) δ 179.8 (d, ³J_PC = 2.9 Hz), 166.5, 132.5 (d, ¹J_PC = 103.5 Hz), 132.4, 132.3 131.7, 131.7 (d, ¹J_PC = 104.3 Hz), 131.6, 131.1, 130.0, 129.1, 129.0, 128.8, 128.7, 52.4, 48.4 (d, ²J_PC = 3.3 Hz), 42.9 (d, ¹J_PC = 100.4 Hz), 28.6, 24.3, 15.4 ppm; ³¹P NMR (160 MHz, CDCl₃) δ 23.8 ppm; ESI-HRMS (CI) m/z calculated for C₂₂H₂₈N₂O₃P ([M + H]⁺), 399.1838; found 399.1837.

(2S*,3S*)-N-(tert-Butyl)-3-(diphenylphosphoryl)-2-methyl-1-(2,2,2-trifluoroacetyl)aziridine-2-carboxamide (4p) (61 mg, 27%,) was obtained as a white solid from carboxylic acid 2l (50 µL, 0.65 mmol), isocyanide 3b (76 µL, 0.65 mmol) and 2H-azirine 1a (127 mg, 0.50 mmol), as described in the general procedure. The crude product was purified via flash column chromatography (SiO₂, AcOEt/hexane 75:25) to give the title compound 4p. mp 172–174 °C; IR (neat) v_max 3346, 3059, 2921, 1732, 1664, 1538, 1399, 1204, 1138 cm^–1; ¹H NMR (400 MHz, CDCl₃) δ 7.95–7.90 (m, 2H, ArH), 7.85–7.79 (m, 2H, ArH), 7.58–7.45 (m, 6H, ArH), 5.91 (s, 1H, NH), 3.42 (d, ²J_PH = 21.0 Hz, 1H, CH-P), 1.75 (s, 3H, CH₃), 1.29 (s, 9H, ^tBu) ppm; ¹³C {1H} NMR (100 MHz, CDCl₃) δ 167.3 (qd, ²J_CF = 38.2 Hz, ³J_PC = 3.4 Hz), 166.1, 132.7, 132.7, 132.7, 132.6, 132.1 (d, ¹J_PC = 104.7 Hz), 131.4, 130.9, 130.8, 129.9, 129.2, 129.1, 128.9, 128.8, 115.37 (q, ¹J_CF = 287.7 Hz), 55.9, 52.6 (d, ²J_PC = 3.5 Hz, C_quat), 41.8 (d, ¹J_PC = 98.3 Hz), 28.3, 14.8 ppm; ¹⁹F NMR (376 MHz, CDCl₃) δ –75.5 ppm; ³¹P NMR (160 MHz, CDCl₃) δ 23.4 ppm; ESI-HRMS (CI) m/z calculated for C₂₂H₂₅F₃N₂O₃P ([M + H]⁺), 453.1555; found 453.1543.

(2S*,3S*)-N-(tert-Butyl)-3-(diphenylphosphoryl)-2-methyl-1-(2-phenylacetyl)aziridine-2-carboxamide (4q) (158 mg, 71%) was obtained as a white solid from carboxylic acid 2m (88 mg, 0.65 mmol), isocyanide 3b (76 µL mg, 0.65 mmol) and 2H-azirine 1a (127 mg, 0.50 mmol), as described in the general procedure. The crude product was purified via flash column chromatography (SiO₂, AcOEt/hexane 50:50) to give the title compound 4q. mp: 236–238 °C; IR (neat) v_max 3286, 3056, 2956, 1693, 1657, 1549, 1293, 1188 cm^–1; ¹H NMR (400 MHz, CDCl₃) δ 8.01 (m, 2H, ArH), 7.91–7.77 (m, 2H, ArH), 7.59–7.41 (m, 6H, ArH), 7.27–7.21 (m, 3H, ArH), 7.16 (d, ³J_HH = 7.5, 2H, ArH), 5.68 (s, 1H, NH), 3.71 (d, ²J_HH = 16.5 Hz, 1H, CH₂), 3.61 (d, ²J_HH = 16.5 Hz, 1H, CH₂), 3.41 (d, ²J_PH = 23.5 Hz, 1H, CH-P), 1.35 (s, 9H, ^tBu), 1.32 (s, 3H, CH₃) ppm; ¹³C {1H} NMR (100 MHz, CDCl₃) δ 180.8 (d, ³J_PC = 2.7 Hz), 166.6, 134.2, 133.3, 132.8 (d, ¹J_PC = 103.5 Hz), 132.2, 132.2, 132.0, 132.0, 131.6, 131.5, 131.3 (d, ¹J_PC = 104.8 Hz), 130.9, 130.9, 130.1, 128.9, 128.8, 128.5, 128.4, 128.4, 126.9, 52.3, 49.3 (d, ²J_PC = 3.5 Hz, C_quat), 44.4, 42.2 (d, ¹J_PC = 101.4 Hz), 28.5, 15.0 ppm; ³¹P NMR (160 MHz, CDCl₃) δ 23.9 ppm; ESI-HRMS (CI) m/z calculated for C₂₈H₃₂N₂O₃P ([M + H]⁺), 475.2151; found 475.21341.

(2S*,3S*)-1-(2-([1,1’-Biphenyl]-4-yl)acetyl)-N-(tert-butyl)-3-(diphenylphosphoryl)-2-methylaziridine-2-carboxamide (4r) (96 mg, 35%) was obtained as a white solid from carboxylic acid 2n (137 mg, 0.65 mmol), isocyanide 3b (76 µL, 0.65 mmol) and 2H-azirine 1a (127 mg, 0.50 mmol), as described in the general procedure. The crude product was purified via flash column chromatography (SiO₂, AcOEt/hexane 50:50) to give the title compound 4r. mp 256–258 °C; IR (neat) v_max 3363, 3056, 2977, 1698, 1675, 1533, 1197 cm^–1; ¹H NMR (400 MHz, CDCl₃) δ 8.02–7.97 (m, 2H, ArH), 7.88–7.83 (m, 2H, ArH), 7.56–7.41 (m, 12H, ArH), 7.34 (t, ³J_HH = 7.3 Hz, 1H, ArH), 7.22 (d, ³J_HH = 7.9 Hz, 2H, ArH), 5.74 (s, 1H, NH), 3.71 (d, ²J_HH = 16.6 Hz, 1H, CH₂) 3.64 (d, ²J_HH = 16.6 Hz, 1H, CH₂), 3.41 (d, ²J_PC = 21.9 Hz, 1H, CH-P), 1.40 (s, 3H, CH₃), 1.38 (s, 9H, ^tBu) ppm; ¹³C {1H} NMR (100 MHz, CDCl₃) δ 181.0 (d, ³J_PC = 2.9 Hz), 166.8, 141.0, 140.0, 133.4, 132.4, 132.4, 132.2, 132.2, 131.8, 131.7, 131.3 (d, ¹J_PC = 104.9 Hz), 131.1, 131.0, 130.6, 129.0, 128.9, 128.9, 128.7, 128.6, 127.4, 127.2, 127.2, 52.5, 49.6 (d, ²J_PC = 3.6 Hz), 44.2, 42.3 (d, ¹J_PC = 101.3 Hz), 28.7, 15.2 ppm; ³¹P NMR (160 MHz, CDCl₃) δ 24.2 ppm; ESI-HRMS (CI) m/z calculated for C₃₄H₃₆N₂O₃P ([M + H]⁺), 551.2464; found 551.2459.

(2S*,3S*)-1-Benzoyl-N-cyclopropyl-3-(diphenylphosphoryl)-2-methylaziridine-2-carboxamide (4s) (133 mg, 60%) was obtained as a white solid from carboxylic acid 2a (79 mg, 0.65 mmol), isocyanide 3c (43 µL, 0.65 mmol) and 2H-azirine 1a (127 mg, 0.50 mmol), as described in the general procedure. The crude product was purified via flash column chromatography (SiO₂, AcOEt/hexane 20:80) to give the title compound 4s. mp 203–205 °C; IR (neat) v_max 3256, 3059, 2923, 1674, 1579, 1299, 1182 cm^–1; ¹H NMR (400 MHz, CDCl₃) δ 8.04–7.88 (m, 4H, ArH), 7.81 (d, ³J_HH = 7.5 Hz, 2H, ArH), 7.64–7.44 (m, 7H, ArH), 7.38 (t, ³J_HH = 7.6 Hz, 2H, ArH), 6.30 (s, 1H, HC-NH) 3.80 (d, ²J_PC = 23.8 Hz, 1H, CH-P), 2.46–2.29 (m, 1H, HC-NH), 1.93 (s, 3H, CH₃), 0.68–0.43 (m, 2H, CH₂), 0.40–0.21 (m, 1H, CH₂), 0.00 to –0.17 (m, 1H, CH₂) ppm; ¹³C {1H} NMR (100 MHz, CDCl₃) δ 176.7 (d, ³J_PC = 3.2 Hz), 168.0, 134.1, 132.6 (d, ¹J_PC = 103.5 Hz), 132.6, 132.4, 132.4, 132.3, 132.3, 132.1, 131.7, 131.6, 131.1, 131.1, 129.1, 129.0, 128.8, 128.6, 128.5, 128.5, 49.5 (d, ²J_PC = 3.0 Hz, C_quat), 42.4 (d, ¹J_PC = 100.5 Hz), 23.1, 15.4, 6.5, 6.4 ppm; ³¹P NMR (160 MHz, CDCl₃) δ 26.4 ppm; ESI-HRMS (CI) m/z calculated for C₂₆H₂₆N₂O₃P ([M + H]⁺), 445.1681; found 445.1682.

(2S*,3S*)-N-Cyclopropyl-3-(diphenylphosphoryl)-2-methyl-1-(quinoline-6-carbonyl)aziridine-2-carboxamide (4t) (136 mg, 55%) obtained as a white solid from carboxylic acid 2j (112 mg, 0.65 mmol), isocyanide 3c (43 µL, 0.65 mmol) and 2H-azirine 1a (127 mg, 0.50 mmol), as described in the general procedure. The crude product was purified via flash column chromatography (SiO₂, AcOEt/hexane 20:80) to give the title compound 4t. mp 212–214 °C; IR (neat) v_max 3195, 3045, 2953, 1674, 1660, 1551, 1290, 1177 cm^–1; ¹H NMR (400 MHz, CDCl₃) δ 8.98 (d, ⁴J_HH = 3.0 Hz, 1H, ArH), 8.37 (s, 1H, ArH), 8.16 (d, ³J_HH = 9.5 Hz, 1H, ArH), 8.08–8.03 (m, 2H, ArH), 7.98–7.86 (m, 4H, ArH), 7.60–7.48 (m, 4H, ArH), 7.46–7.41 (m, 3H, ArH), 6.20 (d, ²J_HH = 22.1 Hz, 1H, HC-NH), 3.78 (d, ²J_PC = 23.7 Hz, 1H, CH-P), 2.41–2.34 (m, 1H, HC-NH), 0.62–0.44 (m, 2H, CH₂), 0.29–0.23 (m, 1H, CH₂), 0.04 to –0.10 (m, 1H, CH₂); ¹³C {1H} NMR (100 MHz, CDCl₃) δ 176.1 (d, ³J_PC = 3.1 Hz), 168.3, 152.5, 149.9, 137.5, 132.5 (d, ¹J_PC = 103.5 Hz), 132.5, 132.5, 132.4, 132.4, 132.2, 131.5 (d, ¹J_PC = 105.3 Hz), 129.9, 129.7, 129.2, 129.0, 128.8, 128.7, 128.1, 127.6, 122.0, 49.7 (d, ³J_PC = 2.8 Hz, C_quat), 42.5 (d, ¹J_PC = 99.9 Hz), 23.2, 15.3, 6.6, 6.6 ppm; ³¹P NMR (160 MHz, CDCl₃) δ 23.8 ppm; ESI-HRMS (CI) m/z calculated for C₂₉H₂₇N₃O₃P ([M + H]⁺), 496.1790; found 496.1788.

(2S*,3S*)-N-Cyclopropyl-3-(diphenylphosphoryl)-1-(furan-2-carbonyl)-2-methylaziridine-2-carboxamide (4u) (162 mg, 75%) was obtained as a white solid from carboxylic acid 2h (73 mg, 0.65 mmol), isocyanide 3c (43 µL, 0.65 mmol) and 2H-azirine 1a (127 mg, 0.50 mmol), as described in the general procedure. The crude product was purified via flash column chromatography (SiO₂, AcOEt/hexane 80:20) to give the title compound 4u. mp 127–129 °C; IR (neat) v_max 3236, 3114, 2961, 1674, 1579, 1290, 1171 cm^–1; ¹H NMR (400 MHz, CDCl₃) δ 7.98–7.91 (m, 4H, ArH), 7.59–7.46 (m, 6H, ArH), 7.27 (d, ⁴J_HH = 1.0 Hz, 1H, ArH), 7.15 (dd, ³J_HH = 3.5 Hz, ⁴J_HH = 0.8 Hz, 1H, ArH), 6.46 (dd, ³J_HH = 3.6 Hz, ³J_HH = 1.7 Hz, 1H, ArH), 6.24 (s, 1H, HC-NH), 3.70 (d, ²J_PH = 23.6 Hz, 1H, CH-P), 2.60–2.54 (m, 1H, HC-NH), 1.90 (s, 3H, CH₃), 0.76–0.64 (m, 2H, CH₂), 0.49–0.42 (m, 1H, CH₂), 0.32–0.26 (m, 1H, CH₂) ppm; ¹³C {1H} NMR (100 MHz, CDCl₃) δ 168.6, 165.8 (d, ³J_PC = 3.4 Hz), 148.3, 145.0, 132.5 (d, ¹J_PC = 103.5 Hz), 132.3, 132.3, 132.2, 132.1, 131.7, 131.6, 131.0, 130.9, 129.0, 128.8, 128.6, 128.5, 116.7, 112.3, 48.9, 42.5 (d, ¹J_PC = 99.9 Hz), 29.7, 23.2, 15.1, 6.6, 6.6 ppm; ³¹P NMR (160 MHz, CDCl₃) δ 24.6 ppm; ESI-HRMS (CI) m/z calculated for C₂₄H₂₄N₂O₄P ([M + H]⁺), 435.1474; found 434.1463.

3.3. Experimental Procedure and Characterization Data for N-Acylaziridine Phosphonates 5

In a flame-dried flask, the corresponding carboxylic acid 2 (0.65 mmol, 1.3 eq.), isocyanide 3 (0.65 mmol, 1.3 eq.) and a 1M diethyl ether solution of ZnCl₂ (0.12 mL, 0.12 mmol, 0.25 eq.) were added to 0.5 mL of dry THF. Then, 2H-azirine phosphonate 1b (0.50 mmol, 1 eq.) was added at room temperature. The reaction mixture was stirred until TLC showed the disappearance of 2H-azirine 1b (1–24 h). The solvent was removed under vacuum, and the residue was dissolved in dichloromethane (5 mL) and washed with water (2 × 5 mL). The organic layer was dried over anhydrous MgSO₄ and filtered, and the solvent was evaporated under reduced pressure. The resulting residue was purified via flash column chromatography (SiO₂, hexanes/AcOEt) to yield compounds 5.

Diethyl ((2S*,3S*)-1-benzoyl-3-(tert-butylcarbamoyl)-3-methylaziridin-2-yl)phosphonate (5a) (118 mg, 60%) was obtained as a white solid from carboxylic acid 2a (79 mg, 0.65 mmol), isocyanide 3b (76 µL, 0.65 mmol) and 2H-azirine 1b (96 mg, 0.50 mmol), as described in the general procedure. The crude product was purified via flash column chromatography (SiO₂, AcOEt/hexane 45:55) to give the title compound 5a. mp 140–141 °C; IR (neat) v_max 3306, 3071, 2966, 1688, 1665, 1633, 1236 cm^–1; ¹H NMR (400 MHz, CDCl₃) δ 7.83 (d, ³J_HH = 7.3 Hz, 2H, ArH), 7.48 (d, ³J_HH = 7.3 Hz, 1H, ArH), 7.39 (t, ³J_HH = 7.5 Hz, 2H, ArH), 5.75 (s, 1H, NH), 4.33–4.10 (m, 4H, OCH₂CH₃), 3.25 (d, ²J_PC = 17.2 Hz, 1H, CH-P), 1.94 (s, 3H, CH₃), 1.39–1.35 (m, 6H, OCH₂CH₃), 1.01 (s, 9H, ^tBu) ppm; ¹³C {1H} NMR (100 MHz, CDCl₃) δ 176.3 (d, ³J_PC = 4.7 Hz), 165.2, 134.1, 132.5, 128.5, 128.4, 63.6 (d, ²J_PC = 6.9 Hz), 62.6 (d, ²J_PC = 6.9 Hz), 52.1, 48.4 (d, ²J_PC = 2.8 Hz), 38.8 (d, ¹J_PC = 202.0 Hz), 28.1, 16.5 (d, ³J_PC = 6.5 Hz), 16.4 (t, ³J_PC = 6.5 Hz), 15.4 ppm; ³¹P NMR (160 MHz, CDCl₃) δ 17.3 ppm; ESI-HRMS (CI m/z calcd. For C₁₉H₃₀N₂O₅P ([M + H]⁺), 397.1892; found 397.1891.

Diethyl ((2S*,3S*)-3-(tert-butylcarbamoyl)-1-(4-fluorobenzoyl)-3-methylaziridin-2-yl)phosphonate (5b) (158 mg, 76%) was obtained as a needle-shaped crystal from carboxylic acid 2d (91 mg, 0.65 mmol), isocyanide 3b (76 µL, 0.65 mmol) and 2H-azirine 1b (96 mg, 0.50 mmol), as described in the general procedure. The crude product was purified via flash column chromatography (SiO₂, AcOEt/hexane 50:50) to give the title compound 5b. mp 99–101 °C; IR (neat) v_max 3391, 2982, 1686, 1602, 1525, 1288, 1240 cm^–1; ¹H NMR (400 MHz, CDCl₃) δ 7.85 (dd, ²J_HH = 8.8 Hz, ³J_HF = 5.4 Hz, 2H, ArH), 7.08 (t, ²J_HF = 8.6 Hz, ²J_HH = 8.6 Hz, 2H, ArH), 5.76 (s, 1H, NH), 4.42–4.05 (m, 4H, OCH₂CH₃), 3.24 (d, ²J_PC = 17.1 Hz, 1H, CH-P), 1.94 (s, 3H, CH₃), 1.55–1.20 (m, 6H, OCH₂CH₃), 1.06 (s, 9H, ^tBu) ppm; ¹³C {1H} NMR (100 MHz, CDCl₃) δ 175.2 (d, ³J_PC = 4.7 Hz), 165.4 (d, ¹J_CF = 253.4 Hz), 165.2, 130.9 (d, ³J_CF = 9.1 Hz, 130.5 (d, ⁴J_CF = 3.0 Hz), 115.5 (d, ²J_CF = 21.8 Hz), 63.6 (d, ²J_PC = 6.1 Hz), 62.7 (d, ²J_PC = 6.6 Hz), 52.2, 48.4 (d, ²J_PC = 2.8 Hz), 38.7 (d, ¹J_PC = 202.4 Hz), 28.2, 16.5 (d, ²J_PC = 6.6 Hz), 16.5 (d, ²J_PC = 6.6 Hz) 15.4 ppm; ³¹P NMR (160 MHz, CDCl₃) δ 17.1 ppm; ¹⁹F NMR (376 CDCl₃) δ –106.4 ppm; ESI-HRMS (CI) m/z calcd. For C₁₉H₂₉FN₂O₅P ([M + H]⁺), 415.1798; found 415.1806.

Diethyl ((2S*,3S*)-3-(tert-butylcarbamoyl)-1-(furan-2-carbonyl)-3-methylaziridin-2-yl)phosphonate (5c) (135 mg, 70%) was obtained as a white solid from carboxylic acid 2h (73 mg, 0.65 mmol), isocyanide 3b (76 µL, 0.65 mmol) and 2H-azirine 1b (96 mg, 0.50 mmol), as described in the general procedure. The crude product was purified via flash column chromatography (SiO₂, AcOEt/hexane 50:50) to give the title compound 5c. mp 94–96 °C; IR (neat) v_max 3246, 3062, 2986, 1701, 1679, 1652, 1448, 1188, 1121 cm^–1; ¹H NMR (400 MHz, CDCl₃) δ 7.44–7.42 (m, 1H, ArH), 7.13–7.11 (m, 1H, ArH), 6.59–6.11 (m, 1H, ArH), 5.97 (s, 1H, NH), 4.40–3.69 (m, 4H, OCH₂CH₃), 3.12 (d, ²J_PC = 18.2 Hz, 1H, CH-P), 1.89 (s, 3H, CH₃), 1.35 (t, ³J_HH = 7.1 Hz, 6H, OCH₂CH₃), 1.15 (s, 9H, ^tBu) ppm; ¹³C {1H} NMR (100 MHz, CDCl₃) δ 165.7 (d, ³J_PC = 5.1 Hz), 165.7 (d, ³J_PC = 1.1 Hz), 148.4, 145.2, 116.5, 112.2, 63.8 (d, ²J_PC = 6.4 Hz), 63.0 (d, ²J_PC = 6.5 Hz), 52.1, 48.5 (d, ²J_PC = 3.0 Hz), 39.2 (d, ¹J_PC = 203.7 Hz), 28.2, 16.3 (d, ³J_PC = 5.0 Hz), 16.2 (d, ³J_PC = 5.1 Hz), 15.3 ppm; ³¹P NMR (160 MHz, CDCl₃) δ 16.9 ppm; ESI-HRMS (CI) m/z calcd. for C₁₇H₂₈N₂O₆P ([M + H]⁺), 387.1685; found 387.1668.

Diethyl ((2S*,3S*)-3-(tert-butylcarbamoyl)-3-methyl-1-(quinoline-6-carbonyl)aziridin-2-yl)phosphonate (5d) (123 mg, 55%) was obtained as a white solid from carboxylic acid 2j (112 mg, 0.65 mmol), isocyanide 3b (76 µL, 0.65 mmol) and 2H-azirine 1b (96 mg, 0.50 mmol), as described in the general procedure. The crude product was purified via flash column chromatography (SiO₂, CH₂Cl₂/MeOH 99:1) to give the title compound 5d. mp 152–153 °C; IR (neat) v_max 3412, 2922, 1676, 1665, 1528, 1287, 1157 cm^–1; ¹H NMR (400 MHz, CDCl₃) δ 8.99 (dd, ³J_HH = 4.2 Hz, ⁴J_HH = 1.7 Hz, 1H, ArH), 8.42 (dd, ⁴J_HH = 1.8 Hz, ⁴J_HH = 0.9 Hz, 1H), 8.26–8.23 (m, 1H, ArH), 8.13–8.08 (m, 2H, ArH), 7.46 (ddd, ³J_HH = 8.3 Hz, ³J_HH = 4.2 Hz, ⁴J_HH = 1.0 Hz, 1H, ArH), 5.76 (s, 1H, NH), 4.30–4.23 (m, 4H, OCH₂CH₃), 3.32 (d, ²J_PC = 17.0 Hz, 1H, CH-P), 2.02 (s, 3H, CH₃), 1.42–1.38 (m, 6H, OCH₂CH₃), 0.95 (s, 9H, ^tBu) ppm; ¹³C {1H} NMR (100 MHz, CDCl₃) δ 175.9 (d, ³J_PC = 4.7 Hz), 165.3, 152.5, 149.9, 137.4, 132.1, 129.9, 129.7, 128.1, 127.6, 122.0, 63.7 (d, ²J_PC = 6.2 Hz), 62.7 (d, ²J_PC = 6.6 Hz), 52.2, 48.6 (d, ²J_PC = 2.8 Hz), 39.2 (d, ¹J_PC = 201.9 Hz), 28.2, 16.6, (d, ³J_PC = 6.6 Hz), 16.5, (d, ³J_PC = 6.9 Hz), 15.5 ppm; ³¹P NMR (160 MHz, CDCl₃) δ 17.0 ppm; ESI-HRMS (CI) m/z calcd. for C₂₂H₃₁N₃O₅P ([M + H]⁺), 448.2001; found 448.1994.

Diethyl ((2S*,3S*)-3-(tert-butylcarbamoyl)-3-methyl-1-(2-phenylacetyl)aziridin-2-yl)phosphonate (5e) (71 mg, 35%) was obtained as a white crystalline solid from carboxylic acid 2m (88 mg, 0.65 mmol), isocyanide 3b (76 µL, 0.65 mmol) and 2H-azirine 1b (96 mg, 0.50 mmol), as described in the general procedure. The crude product was purified via flash column chromatography (SiO₂, AcOEt/hexane 50:50) to give the title compound 5e. mp 124–126 °C; IR (neat) v_max 3312, 3061, 2985, 1688, 1669, 1565, 1236, 1028 cm^–1; ¹H NMR (400 MHz, CDCl₃) δ 7.43–6.85 (m, 5H, ArH), 5.76 (s, 1H, NH), 4.37–4.09 (m, 4H, OCH₂CH₃), 3.73 (d, ²J_HH = 16.3, 1H, CH₂), 3.66 (d, ²J_HH = 16.4 Hz, 1H, CH₂), 2.89 (d, ²J_PC = 18.3 Hz, 1H, CH-P), 1.49 (s, 3H, CH₃), 1.42–1.22 (m, 15H), 1.32 (s, 9H, ^tBu) ppm; ¹³C {1H} NMR (100 MHz, CDCl₃) δ 180.1 (d, ³J_PC = 4.2 Hz), 166.6, 134.3, 130.2, 128.6, 127.1, 63.5 (d, ² J_PC = 6.3 Hz), 62.7 (d, ²J_PC = 6.5 Hz), 52.3, 48.0 (d, ²J_PC = 3.3 Hz), 44.4, 38.8 (d, ¹J_PC = 201.5 Hz), 28.6, 16.3 (d, ³J_PC = 6.3 Hz), 16.3 (d, ³J_PC = 7.8, Hz), 14.8 (CH₃) ppm; ³¹P NMR (160 MHz, CDCl₃) δ 16.7 ppm; ESI-HRMS (CI) m/z calcd. for C₂₀H₃₂N₂O₅P⁺ ([M + H]⁺), 411.2049; found 411.2046.

Diethyl ((2S*,3S*)-1-(2-([1,1’-biphenyl]-4-yl)acetyl)-3-(tert-butylcarbamoyl)-3-methylaziridin-2-yl)phosphonate (5f) (126 mg, 52%) was obtained as a white solid from carboxylic acid 2n (137 mg, 0.65 mmol), isocyanide 3b (76 µL, 0.65 mmol) and 2H-azirine 1b (96 mg, 0.50 mmol), as described in the general procedure. The crude product was purified via flash column chromatography (SiO₂, AcOEt/hexane 50:50) to give the title compound 5f. mp 150–152 °C; IR (neat) v_max 3361, 3056, 2975, 1699, 1654, 1526, 1252 cm^–1; ¹H NMR (400 MHz, CDCl₃) δ 7.56 (dd, ³J_HH = 10.7 Hz, ³J_HH = 7.8 Hz, 4H, ArH), 7.43 (t, ³J_HH = 7.6 Hz, 2H, ArH), 7.34 (d, ³J_HH = 8.1 Hz, 3H, ArH), 5.77 (s, 1H, NH), 4.25–4.15 (m, 4H, OCH₂CH₃), 3.75 (d, ²J_HH = 16.3 Hz, 1H, CH₂), 3.69 (d, ²J_HH = 16.3 Hz, 1H, CH₂), 2.91 (d, ²J_PC = 18.2 Hz, 1H, CH-P), 1.55 (s, 3H, CH₃), 1.37–1.33 (m, 6H, OCH₂CH₃) 1.36 (s, 9H, ^tBu) ppm; ¹³C {1H} NMR (100 MHz, CDCl₃) δ 180.1 (d, ³J_PC = 4.3 Hz), 166.6, 140.9, 140.1, 133.4, 130.6, 128.9, 127.4, 127.2, 127.0, 63.5 (d, ²J_PC = 6.3 Hz), 62.7 (d, ²J_PC = 6.5 Hz), 52.4, 47.9 (d, ²J_PC = 3.3 Hz), 44.0, 38.9 (d, ¹J_PC = 201.3 Hz), 28.7, 16.5 (d, ³J_PC = 6.2 Hz), 16.5 (d, ³J_PC = 6.3 Hz), 14.9 (CH₃) ppm; ³¹P NMR (160 MHz, CDCl₃) δ 16.6 ppm; ESI-HRMS (CI) m/z calcd. for C₂₆H₃₆N₂O₅P ([M + H]⁺), 487.2362; found 487.2340.

Diethyl ((2S*,3S*)-3-(cyclopropylcarbamoyl)-3-methyl-1-(3-phenylpropioloyl)aziridin-2-yl)phosphonate (5g) (96 mg, 48%) was obtained as a white wax from carboxylic acid 2o (95 mg, 0.65 mmol), isocyanide 3b (76 µL, 0.65 mmol) and 2H-azirine 1b (96 mg, 0.50 mmol), as described in the general procedure. The crude product was purified via flash column chromatography (SiO₂, AcOEt/hexane 60:40) to give the title compound 5g. mp 133–135 °C; IR (neat) v_max 3332, 2987, 2204, 1681, 1672, 1538, 1286, 1187, 1016 cm^–1; ¹H NMR (400 MHz, CDCl₃) δ 7.55–7.53 (m, 2H, ArH), 7.45–7.41 (m, 1H, ArH), 7.38–7.33 (m, 2H, ArH), 6.56 (d, ³J_HH = 2.9 Hz, 1H, HC-NH), 4.29–4.17 (m, 4H, OCH₂CH₃), 3.26 (d, ²J_PC = 17.1 Hz, 1H, CH-P), 2.75–2.69 (m, 1H, HC-NH), 1.86 (s, 3H, CH₃), 1.36–1.32 (m, 6H, OCH₂CH₃), 0.79–0.74 (m, 2H, CH₂), 0.58–0.54 (m, 2H, CH₂) ppm; ¹³C {1H} NMR (100 MHz, CDCl₃) δ 167.9, 161.0 (d, ³J_PC = 5.6 Hz), 133.0, 130.8, 128.7, 119.9, 89.3, 83.1, 63.6 (d, ² J_PC = 6.3 Hz), 62.8 (d, ²J_PC = 6.5 Hz), 48.1 (²J_PC = 2.04 Hz) 40.8 (d, ¹J_PC = 200.6 Hz), 23.6, 16.5 (d, ³J_PC = 6.1 Hz), 14.6, 6.7, 6.6 ppm; ³¹P NMR (160 MHz, CDCl₃) δ 15.9 ppm; ESI-HRMS (CI) m/z calcd. for C₂₀H₂₆N₂O₅P ([M + H]⁺), 405.1579; found 405.1570.

Diethyl ((2S*,3S*)-1-((E)-but-2-enoyl)-3-(tert-butylcarbamoyl)-3-methylaziridin-2-yl)phosphonate (5h) (96 mg, 48%) was obtained as an oil from carboxylic acid 2q (56 mg, 0.65 mmol), isocyanide 3b (76 µL, 0.65 mmol) and 2H-azirine 1b (96 mg, 0.50 mmol), as described in the general procedure. The crude product was purified via flash column chromatography (SiO₂, AcOEt/hexane 50:50) to give the title compound 5h. R_f: 0.50 (AcOEt); IR (neat) v_max 3362, 2977, 1689, 1645, 1523, 1288, 1244, 1192, 1027 cm^–1; ¹H NMR (400 MHz, CDCl₃) δ 6.90 (dq, ³J_HH = 15.5 Hz, ³J_HH = 6.9 Hz, 1H, CH₃CH=CH) 6.00 (s, 1H, NH), 5.95 (dd, ³J_HH = 15.5 Hz, ⁴J_HH = 1.7 Hz, 1H, CH₃CH=CH) 4.38–4.14 (m, 4H, OCH₂CH₃), 3.03 (d, ²J_PC = 17.1 Hz, 1H, CH-P), 1.88 (dd, ³J_HH = 6.9 Hz, ⁴J_HH = 1.7 Hz, 3H, CH₃-CH=), 1.89 (s, 3H, CH₃), 1.43–1.33 (m, 6H, OCH₂CH₃), 1.34 (s, 9H, ^tBu) ppm; ¹³C {1H} NMR (100 MHz, CDCl₃) δ 173.6 (d, ³J_PC = 4.8 Hz), 165.9, 143.4, 125.4, 63.3 (d, ²J_PC = 6.3 Hz), 62.6 (d, ²J_PC = 6.5 Hz), 52.1, 47.3 (d, ²J_PC = 2.8 Hz), 38.7 (d, ¹J_PC = 200.8 Hz), 28.5, 18.1, 16.4 (d, ³J_PC = 6.0 Hz), 16.4 (d, ³J_PC = 6.2, Hz), 14.9 ppm; ³¹P NMR (160 MHz, CDCl₃) δ 17.1 ppm; ESI-HRMS (CI) m/z calcd. for C₁₆H₃₀N₂O₅P ([M + H]⁺), 361.1892; found 361.1878.

3.4. Gram Scale Procedure of N-Acylaziridine 5a

In a flame-dried flask, benzoic acid 2a (635 mg, 5.2 mmol, 1.3 eq.), tert-butyl isocyanide 3b (588 µL, 5.2 mmol, 1.3 eq.) and a 1M diethyl ether solution of ZnCl₂ (1.0 mL, 1 mmol, 0.25 eq.) were added to 4 mL of dry THF. Then, 2H-azirine phosphonate 1b (764 mg, 4 mmol, 1 eq.) was added at room temperature. The reaction mixture was stirred until TLC showed the disappearance of 2H-azirine 1b (4 h). The solvent was removed under vacuum, and the residue was dissolved in dichloromethane (15 mL) and washed with saturated NaHCO₃ solution (15 mL) and water (2 × 15 mL). The organic layer was dried over anhydrous MgSO₄ and filtered, and the solvent was evaporated under reduced pressure. The resulting residue was recrystallized from pentane to yield the desired N-acylaziridine 5a (1.11 g, 70%).

3.5. Experimental Procedure and Characterization Data for Phosphorylated Aziridine Peptidomimetics 6

In a flame-dried flask, corresponding amino acid 2r or 2s (1.3 mmol, 1.3 eq.), tert-butyl isocyanide 3b (1.3 mmol, 1.3 eq.) and a 1M diethyl ether solution of ZnCl₂ (0.25 mL, 0.25 mmol, 0.25 eq.) were added to 1 mL of dry THF. Then, 2H-azirine phosphonate 1b (1 mmol, 1 eq.) was added at room temperature. The reaction mixture was stirred until TLC showed the disappearance of 2H-azirine 1b (6 h). The solvent was removed under vacuum, and the residue was dissolved in dichloromethane (5 mL) and washed with water (2 × 5 mL). The organic layer was dried over anhydrous MgSO₄ and filtered, and the solvent was evaporated under reduced pressure. The resulting residue was purified via flash column chromatography (SiO₂, hexanes/AcOEt) to yield the title compounds.

(9H-Fluoren-9-yl)methyl ((S)-1-((2S,3S)-2-(tert-butylcarbamoyl)-3-(diethoxyphosphoryl)-2-methylaziridin-1-yl)-4-methyl-1-oxopentan-2-yl)carbamate and (9H-fluoren-9-yl)methyl ((S)-1-((2R,3R)-2-(tert-butylcarbamoyl)-3-(diethoxyphosphoryl)-2-methylaziridin-1-yl)-4-methyl-1-oxopentan-2-yl)carbamate (6a) (407 mg, 65%) yielded (50/50) of a mixture of two diastereoisomers, 6a_A and 6a_B, obtained as oils from amino acid 2r (459 mg, 1.3 mmol), tert-butyl isocyanide 3b (152 µL, 1.3 mmol) and 2H-azirine 1b (191 mg, 1 mmol), as described in the general procedure. The crude product was purified via flash column chromatography (SiO₂, AcOEt/hexane 40:60) to give the title compound as a mixture of two diastereoisomers (6a_A and 6a_B). R_f: 0.60 (AcOEt); IR (neat) v_max 3444, 3328, 3067, 2961, 1701, 1668, 1521, 1257, 1218, 1016 cm^–1; ¹H NMR (400 MHz, CDCl₃) δ 7.75 (d, ³J_HH = 7.5 Hz, 4H, ArH)_A+B, 7.60–7.58 (m, 1H, 4H, ArH)_A+B, 7.39 (t, ³J_HH = 7.4 Hz, 4H, ArH)_A+B, 7.32–7.28 (m, ³J_HH = 7.4 Hz, 4H, ArH)_A+B, 5.99 (s, 1H, NH)_A, 5.89 (s, 1H, NH)_B, 5.28 (d, ³J_HH = 8.7 Hz, NH_Fmoc)_A, 5.11 (d, ³J_HH = 9.2 Hz, NH_Fmoc)_B, 4.49–4.18 (m, 16H, CH_α + OCH₂CH₃ + CH_2Fmoc + CH_Fmoc)_A+B, 2.99 (d, ²J_PH = 18.1 Hz, 1H, CH-P)_B, 2.85 (d, ²J_PH = 17.7 Hz, 1H, CH-P)_A, 1.80–1.57 (m, 12H, CH₃ + CHCH₂)_A+B, 1.38–1.29 (m, 30H, OCH₂CH_{3 +} ^tBu)_A+B, 0.97–0.93 (m, 12H, CH₃)_A+B ppm; ¹³C {1H} NMR (100 MHz, CDCl₃) δ 181.8 (d, ³J_PC = 4.3 Hz)_A, 181.7 (d, ³J_PC = 4.3 Hz,)_B, 166.7_A, 166.0_B, 155.8_A, 155.7_B, 143.9_B, 143.8_B, 143.8_A, 141.4_B, 141.3_A, 141.3_B, 141.3_A, 127.8_B, 127.7_A, 127.7_B, 127.6_A, 127.1_A, 127.1_A, 127.1_B, 127.0_B, 125.1_A, 125.0_B, 124.9_B, 120.1_B, 120.0_B, 119.9_A, 66.8_B, 66.6A, 63.5 (d, ²J_PC = 6.6 Hz)_A, 63.3 (d, ²J_PC = 6.3 Hz)_B, 62.7 (d, ²J_PC = 6.4 Hz)_A, 62.7 (d, ²J_PC = 6.0 Hz)_B, 54.9_A, 54.2_B, 52.4_A, 52.3_B, 48.8 (d, ²J_PC = 3.3 Hz)_A, 48.4 (d, ²J_PC = 3.2 Hz)_B, 47.2, 47.2, 42.4_A, 42.3_B, 38.62 (d, ¹J_PC = 201.8 Hz)_A, 37.83 (d, ¹J_PC = 201.1, Hz)_B, 28.5_B, 28.4_A, 24.6_A, 24.5_B, 23.4_B, 23.2_A, 21.8_A, 21.6_B, 16.4_A+B, 15.2_A, 15.1_B ppm; ³¹P NMR (160 MHz, CDCl₃) δ 6a_B 16.9, 6a_A 16.2 ppm; ESI-HRMS (CI) m/z calcd. for C₃₃H₄₇N₃O₇P ([M + H]⁺), 628.3152; found 628.3143.

(9H-Fluoren-9-yl)methyl ((S)-1-((2S,3S)-2-(tert-butylcarbamoyl)-3-(diethoxyphosphoryl)-2-methylaziridin-1-yl)-1-oxopropan-2-yl)carbamate and (9H-fluoren-9-yl)methyl ((S)-1-((2R,3R)-2-(tert-butylcarbamoyl)-3-(diethoxyphosphoryl)-2-methylaziridin-1-yl)-1-oxopropan-2-yl)carbamate (6b) (114 mg, 20%) yielded (50/50) of a mixture of two diastereoisomers, 6b_A and 6b_B, obtained as oils from amino acid 2s (405 mg, 1.3 mmol), tert-butyl isocyanide 3b (152 µL, 1.3 mmol) and 2H-azirine 1b (191 mg, 1 mmol), as described in the general procedure. The crude product was purified via flash column chromatography (SiO₂, AcOEt/hexane 40:60) to give the title compound as a mixture of two diastereoisomers (6b_A and 6b_B). R_f: 0.60 (AcOEt); IR (neat) v_max 3450, 3278, 3075, 2925, 1682, 1651, 1288, 1196 cm^–1;¹H NMR (400 MHz, CDCl₃) δ 7.76–7.74 (m, 4H, ArH), 7.59–7.57 (m, 4H, ArH), 7.41–7.37 (m, 4H, ArH), 7.33–7.27 (m, 4H, ArH), 6.01 (s, 1H, NH), 5.90 (s, 1H, NH), 5.47 (d, ³J_HH = 7.7 Hz, 1H, NH_Fmoc), 5.33 (d, ³J_HH = 7.8 Hz, 1H, NH_Fmoc), 4.48–4.32 (m, 16H, CH_α + OCH₂CH₃ + CH_2Fmoc + CH_Fmoc), 2.99 (d, ²J_PC = 18.1 Hz, 1H, CH-P), 2.87 (d, ²J_PC = 17.8 Hz, 1H, CH-P), 1.72 (s, 3H, CH₃), 1.68 (s, 3H, CH₃), 1.46 (d, ³J_HH = 6.9 Hz, 3H, CH₃), 1.41 (d, ³J_HH = 7.0 Hz, 3H, CH₃), 1.37–1.35 (m, 12H, OCH₂CH₃) 1.33 (s, 9H, ^tBu), 1.30 (s, 9H, ^tBu) ppm; ¹³C {1H} NMR (100 MHz, CDCl₃) δ 182.1 (d, ³J_PC = 4.4 Hz), 181.6 (d, ³J_PC = 4.1 Hz), 166.7, 166.0, 155.7, 155.5, 155.5, 144.0, 143.9, 143.9, 141.5, 141.4, 141.3, 127.9, 127.8, 127.8, 127.7, 127.2, 127.1, 127.1, 127.1, 125.1, 125.1, 125.1, 124.9, 120.2, 120.1, 120.0, 120.0, 66.9, 66.8, 63.7 (d, ²J_PC = 6.4 Hz), 63.5 (d, ²J_PC = 6.3 Hz), 52.6, 52.5, 52.3, 51.7, 49.0, 48.3 (d, ²J_PC = 3.1 Hz), 47.2, 38.8 (d, ¹J_PC = 202.7 Hz), 37.9 (d, ¹J_PC = 201.8 Hz), 28.6, 28.4, 19.5, 18.3, 16.5, 16.4, 16.4, 16.4, 16.3, 16.3, 16.3, 15.3, 15.0 ppm; ³¹P NMR (160 MHz, CDCl₃) δ 16.8, 16.1 ppm; ESI-HRMS (CI) m/z calcd. for C₃₀H₄₁N₃O₇P ([M + H]⁺), 586.2682; found 586.2659.

3.6. Experimental Procedure and Characterization Data for Phosphorus Substituted Oxazole Derivatives 7

Method A: Corresponding Joullié–Ugi adduct 4 derived from phosphine oxide (1 eq.) was dissolved in 20 mL/mmol of acetonitrile, and BF₃·OEt₂ (1.2 eq.) was added. The solution was heated under microwave irradiation at 90 °C for 10 min. The solvent was evaporated, and the crude product was diluted with AcOEt, washed with saturated NaHCO₃ (5 mL) and extracted with AcOEt (3 × 5 mL). The organic layer was dried over anhydrous MgSO₄ and filtered, and the solvent was evaporated under reduced pressure. The resulting residue was purified via flash column chromatography (SiO₂, hexanes/AcOEt) or via crystallization to yield the corresponding oxazole derivative. Method B: Corresponding Joullié–Ugi adduct 5 derived from phosphonate (1 eq.) was dissolved in 20 mL/mmol of chloroform, and BF₃·OEt₂ (3 eq.) was added. The solution was heated under microwave irradiation at 71 °C for 15 min. The solvent was evaporated, and the crude product was diluted with AcOEt, washed with saturated NaHCO₃ (5 mL) and extracted with AcOEt (3 × 5 mL). The organic layer was dried over anhydrous MgSO₄ and filtered, and the solvent was evaporated under reduced pressure. The resulting residue was purified via flash column chromatography (SiO₂, hexanes/AcOEt) to yield the corresponding oxazole derivative.

(4S*,5S*)-N-Cyclohexyl-4-(diphenylphosphoryl)-5-methyl-2-phenyl-4,5-dihydrooxazole-5-carboxamide (7a) (105 mg, 94%) was obtained as a white solid from Joullié–Ugi adduct 4a (111 mg, 0.23 mmol) and BF₃·OEt₂ (35 µL, 0.28 mmol), as described in the general procedure in method A. The crude product was purified via flash column chromatography (SiO₂, AcOEt/hexane 50:50) to give title compound 7a. mp 209–211 °C; IR (neat) v_max 3325, 2936, 1659, 1589, 1251, 1218, 1151 cm^–1; ¹H NMR (400 MHz, CDCl₃) δ 8.15–8.10 (m, 2H, ArH), 7.97–7.90 (m, 4H, ArH), 7.56–7.40 (m, 9H, ArH), 6.91 (d, ³J_HH = 7.9 Hz, 1H, HC-NH), 5.32 (d, ²J_PC = 6.0 Hz, 1H, CH-P), 3.77–3.70 (m, 1H, HC-HN), 1.89–1.87 (m, 1H, ^cHex), 1.82–1.79 (m, 1H, ^cHex), 1.69–1.54 (m, 3H, ^cHex), 1.63 (s, 3H, CH₃), 1.36–1.11 (m, 5H, ^cHex) ppm; ¹³C {1H} NMR (100 MHz, CDCl₃) δ 171.8 (d, ³J_PC = 9.4 Hz), 164.1 (d, ³J_PC = 10.7 Hz), 132.9, 132.4, 132.2, 132.2, 132.1, 131.9, 131.9, 131.9, 131.8, 131.4, 131.3, 128.9, 128.8, 128.5, 128.5, 128.4, 128.3, 127.0 (d, ⁴J_PC = 1.6 Hz), 88.7, 71.6 (d, ¹J_PC = 81.0 Hz), 48.3, 32.8, 32.7, 25.5, 24.7, 24.6, 21.4 (d, ³J_PC = 6.9 Hz) ppm; ³¹P NMR (160 MHz, CDCl₃) δ 25.6 ppm; ESI-HRMS (CI) m/z calculated for C₂₉H₃₂N₂O₃P ([M + H]⁺), 487.2151; found 487.2154.

(4S*,5S*)-N-Cyclohexyl-4-(diphenylphosphoryl)-5-methyl-2-(3-methylphenyl)-4,5-dihydrooxazole-5-carboxamide (7b) (36 mg, 60%) was obtained as a white solid from Joullié–Ugi adduct 4b (60 mg, 0.12 mmol) and BF₃·OEt₂ (18 µL, 0.144 mmol), as described in the general procedure in method A. The crude product was purified via flash column chromatography (SiO₂, AcOEt/hexane 70:30) to give title compound 7b. mp 203–205 °C; IR (neat) v_max 3300, 3059, 1660, 1637, 1527, 1194 cm^–1; ¹H NMR (400 MHz, CDCl₃) δ 8.17–8.12 (m, 2H, ArH), 7.96–7.94 (m, 2H, ArH), 7.79 (s, 2H, ArH), 7.58–7.35 (m, 8H, ArH), 6.94 (d, ³J_HH = 8.1 Hz, 1H, HC-NH), 5.33 (d, ²J_PC = 6.2 Hz, 1H CH-P), 3.77–3.75 (m, 1H, HC-NH), 2.39 (s, 3H, CH₃), 1.92–1.81 (m, 2H, ^cHex), 1.73–1.54 (m, 6H, ^cHex + CH₃), 1.37–1.36 (m, 2H ^cHex), 1.27–1.15 (m, 3H, ^cHex) ppm; ¹³C {1H} NMR (100 MHz, CDCl₃) δ 171.7 (d, ³J_PC = 9.5 Hz), 164.2 (d, ³J_PC = 10.5 Hz), 138.3, 132.9, 132.8, 132.3, 132.1, 131.8, 131.8, 131.7, 131.3, 131.2, 128.9, 128.8, 128.7, 128.4, 128.4, 128.3, 126.8 (d, ⁴J_PC = 1.6 Hz), 125.5, 88.5, 71.7 (d, ¹J_PC = 81 Hz), 48.2, 32.7, 32.7, 25.4, 24.6, 24.5, 21.3, 21.3 ppm; ³¹P NMR (160 MHz, CDCl₃) δ 25.5 ppm; ESI-HRMS (CI) m/z calculated for C₃₀H₃₄N₂O₃P ([M + H]⁺), 501.2307; found 501.2303.

(4S*,5S*)-N-(tert-Butyl)-4-(diphenylphosphoryl)-5-methyl-2-phenyl-4,5-dihydrooxazole-5-carboxamide (7c) (63 mg, 92%) was obtained as a white solid from Joullié–Ugi adduct 4i (69 mg 0.15 mmol) and BF₃·OEt₂ (22 µL, 0.18 mmol), as described in the general procedure described in method A. The crude product was recrystallized from the diethyl ether–pentane mixture to give 7c. mp 206–207 °C; IR (neat) v_max 3306, 3075, 2920, 1662, 1629, 1549, 1196, 1118 cm^–1; ¹H NMR (400 MHz, CDCl₃) δ 8.15–8.10 (m, 2H, ArH), 7.97–7.90 (m, 4H, ArH), 7.57–7.39 (m, 9H, ArH), 6.87 (s, 1H, NH), 5.32 (d, ²J_PC = 6.2 Hz, 1H, CH-P), 1.61 (s, 3H, CH₃), 1.33 (s, 9H, ^tBu) ppm; ¹³C {1H} NMR (100 MHz, CDCl₃) δ 171.8 (d, ³J_PC = 9.5 Hz), 164.1 (d, ³J_PC = 10.7 Hz), 132.6 (d, ¹J_PC = 66.6 Hz), 132.9, 132.3, 132.1, 132.1, 132.1, 132.0, 131.8, 131.8, 131.8, 131.7, 131.3, 131.2, 128.9, 128.4, 128.5, 128.4, 128.3, 128.3, 127.0, 88.8, 71.4 (d, ¹J_PC = 80.7 Hz), 51.4, 28.7, 21.3 (d, ³J_PC = 6.9 Hz) ppm; ³¹P NMR (160 MHz, CDCl₃) δ 25.3 ppm; ESI-HRMS (CI) m/z calculated for C₂₇H₃₀N₂O₃P ([M + H]⁺), 461.1994; found 461.1995.

(4S*,5S*)-N-(tert-Butyl)-4-(diphenylphosphoryl)-5-methyl-2-(naphthalen-2-yl)-4,5-dihydrooxazole-5-carboxamide (7d) (74 mg, 91%) was obtained as a white solid from Joullié–Ugi adduct 4l (81 mg, 0.16 mmol) and BF₃·OEt₂ (25 µL, 0.20 mmol), as described in the general procedure in method A. The crude product was recrystallized from diethyl ether-pentane mixture to give title compound 7d. mp 199–202 °C; IR (neat) v_max 3297, 2929, 1667, 1521, 1193, 1117 cm^–1; ¹H NMR (400 MHz, CDCl₃) δ 8.45 (s, 1H, ArH), 8.18–8.13 (m, 2H, ArH), 8.06–8.04 (m, 1H ArH), 8.01–7.96 (m, 2H, ArH), 7.92–7.86 (m, 3H, ArH), 7.57–7.42 (m, 8H, ArH), 7.02 (s, 1H, NH), 5.38 (d, ²J_PH = 6.7 Hz, 1H, CH-P), 1.66 (s, 3H, CH₃), 1.35 (s, 9H, ^tBu) ppm; ¹³C {1H} NMR (100 MHz, CDCl₃) δ 171.7 (d, ³J_PC = 9.1 Hz), 164.3 (d, ³J_PC = 10.9 Hz), 135.1, 133.0, 132.7, 132.3, 132.3, 132.2, 132.0, 132.0, 131.9, 131.8, 131.4, 131.3, 131.2, 129.1, 129.0, 128.9, 128.5, 128.4, 128.1, 127.9, 126.9, 124.7, 124.3 (d, ⁴J_PC = 1.6 Hz), 89.0, 71.7 (d, ¹J_PC = 80.6 Hz), 51.5, 28.7, 21.4 (d, ³J_PC = 6.8 Hz) ppm; ³¹P NMR (160 MHz, CDCl₃) δ 25.4 ppm; ESI-HRMS (CI) m/z calculated for C₃₁H₃₂N₂O₃P ([M + H]⁺), 511.2151; found 511.2134.

Diethyl ((4S*,5S*)-5-(tert-butylcarbamoyl)-5-methyl-2-phenyl-4,5-dihydrooxazol-5-yl)phosphonate (7e) (285 mg, 90%) was obtained as a white solid from Joullié–Ugi adduct 5a (316 mg, 0.80 mmol) and BF₃·OEt₂ (296 µL, 2.40 mmol), as described in the general procedure, method B. The crude product was purified via flash column chromatography (SiO₂, AcOEt/hexane 65:35) to give title compound 7e. mp 99–102 °C; IR (neat) v_max 3294, 3067, 2975, 1665, 1637, 1538, 1252, 1213, 1074, 1052 cm^–1; ¹H NMR (400 MHz, CDCl₃) δ 7.97–7.95 (m, 2H, ArH), 7.52 (d, ³J_HH = 7.4 Hz, 1H, ArH), 7.44–7.41 (m, 2H, ArH), 6.31 (s, 1H, NH), 4.81 (d, ²J_PC = 17.3 Hz, 1H, CH-P), 4.36–4.18 (m, 4H, OCH₂CH₃), 1.89 (d, ⁴J_PH = 0.6, 3H, CH₃), 1.39–1.34 (m, 6H, OCH₂CH₃), 1.31 (s, 9H, ^tBu) ppm; ¹³C {1H} NMR (100 MHz, CDCl₃) δ 172.2 (d, ³J_PC = 14.9 Hz), 163.7 (d, ³J_PC = 12.0 Hz), 132.1, 128.6, 128.3, 127.1 (d, ⁴J_PC = 2.6 Hz), 87.4, 69.9 (d, ¹J_PC = 160.4 Hz), 63.8 (d, ²J_PC = 6.7 Hz), 62.8 (d, ²J_PC = 7.4 Hz), 51.3, 28.7, 20.9 (d, ³J_PC = 6.2 Hz), 16.5 (t, ³J_PC = 5.6 Hz) ppm; ³¹P NMR (160 MHz, CDCl₃) δ 18.5 ppm; ESI-HRMS (CI) m/z calculated for C₁₉H₃₀N₂O₅P ([M + H]⁺), 397.1892; found 397.1878.

Diethyl ((4S*,5S*)-5-(tert-butylcarbamoyl)-2-(4-fluorophenyl)-5-methyl-4,5-dihydrooxazol-4-yl)phosphonate (7f) (53 mg, 80%) was obtained as a yellowish oil obtained from Joullié–Ugi adduct 5b (66 mg, 0.16 mmol) and BF₃·OEt₂ (57 µL, 0.48 mmol), as described in the general procedure method B. The crude product was purified via flash column chromatography (SiO₂, AcOEt/hexane 65:35) to give title compound 7f. R_f: 0.70 (AcOEt); IR (neat) v_max 3311, 3067, 2978, 1649, 1587, 1252, 1227, 1040 cm^–1; ¹H NMR (400 MHz, CDCl₃) δ 8.00 (dd, ³J_HH = 8.8 Hz, ⁴J_HF = 5.4 Hz, 2H, ArH), 7.14 (t, ³J_HH = 8.7 Hz, ³J_HF = 8.7 Hz, 2H, ArH), 6.31 (s, 1H, NH), 4.82 (d, ²J_PC = 17.3 Hz, 1H, CH-P), 4.40–4.19 (m, 4H, OCH₂CH₃), 1.91 (s, 3H, CH₃), 1.45–1.35 (m, 6H, OCH₂CH₃), 1.34 (s, 9H, ^tBu) ppm; ¹³C {1H} NMR (100 MHz, CDCl₃) δ 171.9 (d, ³J_PC = 14.9 Hz), 165.1 (d, ¹J_CF = 253.2 Hz), 163.5 (d, ³J_PC = 12.0 Hz), 130.6, 130.5, 123.2 (t, ⁴J_CF = 2.9 Hz), 115.9, 115.7, 87.6 (d, ²J_PC = 1.9 Hz), 69.7 (d, ¹J_PC = 160.7 Hz), 63.6 (d, ³J_PC = 6.7 Hz), 62.8 (d, ²J_PC = 7.3 Hz), 51.3, 28.6, 20.8 (d, ³J_PC = 6.1 Hz), 16.5 (t, ³J_PC = 5.6 Hz) ppm; ¹⁹F NMR (376 MHz, CDCl₃) δ –106.8 ppm; ³¹P NMR (160 MHz, CDCl₃) δ 18.4 ppm; ESI-HRMS (CI) m/z calculated for C₁₉H₂₉FN₂O₅P ([M + H]⁺), 415.1798; found 415.1771.

4. Conclusions

In conclusion, we developed a novel strategy to efficiently access to phosphorylated N-acylaziridines through the zinc chloride-catalyzed Joullié–Ugi three-component reaction of phosphorus-substituted 2H-azirines, carboxylic acids and isocyanides. Most of the JU-3CR proceeded smoothly in THF for a few hours, giving exclusive diastereoselectivity and satisfactory yields. This protocol was applicable to a wide range of substrates, including 2H-azirines derived from phosphine oxide and phosphonate, various aromatic and heteroaromatic, aliphatic, acrylic and propargylic acids, and isocyanide with different alkyl substitutions. Even N-Fmoc protected amino acids as carboxylic acid partners are well tolerated and phosphorylated aziridine peptidomimetics are achieved in a simple procedure. This strategy for the preparation of phosphorylated N-acylaziridines represents a valued method owing to the high degree of diastereoselectivity observed, the high atom economy and the reaction stages. The synthetic potential of this JU-3CR was established with the preparative-scale reaction and useful transformations of the JU-3CR adducts. The regio- and stereospecific ring expansion of N-acylaziridines to oxazole derivatives was accomplished in the presence of BF₃·OEt₂ as an efficient Lewis acid catalyst.

Author Contributions

Conceptualization, F.P. and J.M.d.l.S.; methodology, J.A. and I.O.; validation, J.A. and I.O.; formal analysis J.A. and I.O.; investigation, J.A. and I.O.; resources, F.P. and J.M.d.l.S.; data curation, J.A. and A.M.O.d.R.; writing—original draft preparation, J.M.d.l.S.; writing—review and editing, I.O., A.M.O.d.R., F.P. and J.M.d.l.S.; visualization, J.A., I.O., A.M.O.d.R. and J.M.d.l.S.; supervision, A.M.O.d.R. and J.M.d.l.S.; project administration, A.M.O.d.R. and J.M.d.l.S.; funding acquisition, F.P. and J.M.d.l.S. All authors have read and agreed to the published version of the manuscript.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

The data presented in this study are available in the Supplementary Materials file or on request from the corresponding author (¹H, ¹³C, ¹⁹F, ³¹P, 2D-NMR and HRMS spectra).

Acknowledgments

The authors wish to thank the technical and human support provided by SGIker (UPV/EHU/ERDF, EU).

Conflicts of Interest

The authors declare no conflicts of interest.

Footnotes

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Figures, Schemes and Table

Figure 1. Aziridine-containing natural products and selected examples of phosphorus-substituted oxazole derivatives with high potential for medical applications.

Scheme 1. JU-3CR on three, five and seven-membered cyclic imines [39,42,43,44].

Figure 2. The scope of phosphorus-substituted 2H-azirines 1, carboxylic acids 2 and isocyanides 3 tested in the JU-3CR.

Scheme 2. Substrate scope of the N-acylaziridine phosphine oxides 4 in the Joullié–Ugi three-component reaction. See the Supporting Information for experimental details. Reactions were carried out on a 0.5 mmol scale; 2H-azirine 1a (0.5 mmol), carboxylic acid 2 (1.3 eq.), isocyanide 3 (1.3 eq.), ZnCl2 (25 mol%) and solvent (0.5 mL). Diastereomeric ratio (trans/cis) determined from the crude reaction mixture via 1H NMR. It was not possible to determine the diastereomeric ratio of compounds 4c and 4h as the crude reaction NMR spectra were not clean enough.

Figure 3. ORTEP diagram of functionalized N-acylaziridine phosphine oxide 4i (H, white; C, grey; O, red; N, blue; P, orange) (2S,3S enantiomer shown).

Scheme 3. Substrate scope of the N-acylaziridine phosphonates 5 in the Joullié–Ugi three-component reaction. See the Supporting Information for experimental details. Reactions were carried out on a 0.5 mmol scale; 2H-azirine 1b (0.5 mmol), carboxylic acid 2 (1.3 eq.), isocyanide 3 (1.3 eq.), ZnCl2 (25 mol%) and solvent (0.5 mL). a Yield of isolated compound 5a after crystallization, at a 4 mmol scale. The diastereomeric ratio (trans/cis) was determined from the crude reaction mixture via 1H NMR.

Scheme 4. Substrate scope of phosphorylated aziridine peptidomimetics 6 through the Joullié–Ugi three-component reaction using N-Fmoc amino acids. See the Supporting Information for experimental details. Reactions were carried out on a 1 mmol scale; 2H-azirine 1b (1 mmol), Fmoc-protected amino acid 2r or 2s (1.3 eq.), isocyanide 3b (1.3 eq.), ZnCl2 (25 mol%) and solvent (1 mL). a Diastereomeric ratio (trans/trans) determined from the crude reaction mixture via 1H NMR. The diastereomeric ratio between trans- and cis-diastereoisomers is approximately 92:8. b The diastereomeric ratio (trans/trans) determined from the crude reaction mixture via 1H NMR. The diastereomeric ratio between trans and cis-diastereoisomers could not be determined.

Scheme 5. Plausible mechanism for the synthesis of phosphorus substituted N-Acylaziridines 4, 5 and 6 through the Joullié–Ugi three-component reaction.

Scheme 6. Phosphorus-substituted oxazole derivatives 7 through the ring expansion of N-acylaziridines 4 or 5. See the Supporting Information for experimental details. Reactions were carried out on a 0.12–0.80 mmol scale; N-acylaziridine 4 or 5 (0.12–0.80 mmol), BF3·OEt2 (1.2 eq. for N-acylaziridines 4 derived from phosphine oxide and 3 eq. for N-acylaziridines 5 derived from phosphonate) and solvent (20 mL/mmol).

Figure 4. ORTEP diagram of functionalized diphenylphosphoryl oxazole derivative 7a (H, white; C, grey; O, red; N, blue; P, orange) (4S,5S enantiomer shown).

Scheme 7. Rational mechanism for the stereospecific and regioselective ring expansion of N-acylaziridines 4 or 5 to oxazole derivatives 7.

Table 1

Reaction condition optimization ^a.

[Image omitted. Please see PDF.]
Entry	Catalyst (mol%)	Time (h)	T (°C)	Solvent	Yield (%) b
1			60	THF	10
2	PTSA (25)	1.5	60	THF	14
3	TfOH (10)	1.5	60	THF	35
4	Ti(OiPr)4 (25)	1	60	THF	0
5	Sc(OTf)3 (25)	1	60	THF	0
6	InCl3 (30)	1.5	60	THF	0
7	BF3·OEt2 (25)	1	60	THF	0
8	MgBr2 (25)	1.5	60	THF	trace
9	ZnCl2·H2O (25)	1.5	60	THF	0
10	ZnCl2 (25)	1.5	60	THF	60
11	ZnCl2 (25)	1	60	MeOH	0
12	ZnCl2 (25)	24	60	MeCN	0
13	ZnCl2 (25)	24	−10	THF	35
14	ZnCl2 (25)	5	rt	THF	75
15	ZnCl2 (10)	5	rt	THF	35
16	ZnCl2 (30)	5	rt	THF	75

^a Unless otherwise noted, reactions were carried out on a 0.5 mmol scale; 2H-azirine 1a (0.5 mmol), carboxylic acid 2a (1.3 eq.), isocyanide 3a (1.3 eq.), catalyst (25 mol%) and solvent (0.5 mL). ^b Isolated yields.

Supplementary Materials

The following supporting information can be downloaded at https://www.mdpi.com/article/10.3390/molecules29051023/s1: ¹H, ¹³C{1H}, ¹⁹F, ³¹P NMR spectra of synthesized compounds 4, 5, 6 and 7; Figure S1: ORTEP diagram of compound 4i with thermal displacement parameters drawn at a 50% probability; Table S1: Crystal data and structure refinement for 4i; Figure S2: ORTEP diagram of compound 7a with thermal displacement parameters drawn at a 50% probability; Table S2: Crystal data and structure refinement for 7a.

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