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Article

Synthesis of α-Aminophosphonic Acid Derivatives Through the Addition of O- and S-Nucleophiles to 2H-Azirines and Their Antiproliferative Effect on A549 Human Lung Adenocarcinoma Cells

by
Victor Carramiñana
,
Ana M. Ochoa de Retana
,
Francisco Palacios
* and
Jesús M. de los Santos
*
Department of Organic Chemistry I, Faculty of Pharmacy and Lascaray Research Center, University of the Basque Country (UPV/EHU), 01006 Vitoria, Spain
*
Authors to whom correspondence should be addressed.
Molecules 2020, 25(15), 3332; https://doi.org/10.3390/molecules25153332
Submission received: 16 June 2020 / Revised: 8 July 2020 / Accepted: 20 July 2020 / Published: 22 July 2020

Abstract

:
This work reports a straightforward regioselective synthetic methodology to prepare α-aminophosphine oxides and phosphonates through the addition of oxygen and sulfur nucleophiles to the C–N double bond of 2H-azirine derivatives. Determined by the nature of the nucleophile, different α-aminophosphorus compounds may be obtained. For instance, aliphatic alcohols such as methanol or ethanol afford α-aminophosphine oxide and phosphonate acetals after N–C3 ring opening of the intermediate aziridine. However, addition of 2,2,2-trifluoroethanol, phenols, substituted benzenthiols or ethanethiol to 2H-azirine phosphine oxides or phosphonates yields allylic α-aminophosphine oxides and phosphonates in good to high general yields. In some cases, the intermediate aziridine attained by the nucleophilic addition of O- or S-nucleophiles to the starting 2H-azirine may be isolated and characterized before ring opening. Additionally, the cytotoxic effect on cell lines derived from human lung adenocarcinoma (A549) and non-malignant cells (MCR-5) was also screened. Some α-aminophosphorus derivatives exhibited very good activity against the A549 cell line in vitro. Furthermore, selectivity towards cancer cell (A549) over non-malignant cells (MCR-5) has been detected in almost all compounds tested.

Graphical Abstract

1. Introduction

α-Aminophosphonic acids are structural bioisosteres of amino acids displaying a wide range of biological properties and applications in many areas ranging from agrochemistry to medicine [1,2,3,4]. Some of their varied applications include antitumor agents [5,6,7], potent antibiotics [8,9], as antibacterial agents [10,11], antiviral [12], and enzyme inhibitors [13,14,15] such as renin [14,16], or HIV protease [17,18], among others. Joined with their structural similarity to natural carboxylic acids, the intriguing properties of α-aminophosphonic acids also stem from the fact that the tetrahedral geometry of phosphonic acid functionality resembles in a stable manner the high-energy transition state of peptide bond hydrolysis [19]. The last-mentioned feature is directly responsible for the biological activity of α-amino-phosphonic acids, mostly as enzyme inhibitors involved in peptide metabolism.
Moreover, it is well-known that allylic amines [20,21,22] are key structural features in variety of natural products and pharmaceuticals, such as the calcium channel blocker flunarizine (I) [23], effective in the prophylaxis of migraine, and the antifungal drugs naftifine (II) [24,25] and terbinafine (III) [24,26], and have been recognized as an important class of organic compounds owing to their use as valuable intermediates vital for molecular complexity buildup [27] (Figure 1).
To overcome the drastic side effects related to a single drug, hybrid molecules modulate several targets of multifactorial diseases, and have been established as a popular approach for multidrug therapy [28,29]. Within this class of drugs, hybrids molecules introducing two potentially pharmacophores, including allylic amine moieties and α-aminophosphonic acid functional groups, such as allylic α-aminophosphonic acid derivatives (IV and V), have attracted scarce attention since only a few examples have been reported in the literature. For instance, (1-amino-2-propenyl)phosphonic acid (IV) inhibit alanine racemase and D-alanine:D-alanine ligase [30,31], while α-aminophosphonic acid analogue (V) of the natural phenylalanine bearing a methylidene at the β-position acts as an inhibitor of phenylalanine ammonia-lyases (PAL) [32] (Figure 1).
There is a new renewal of the interest in covalent binding therapeutics due to the FDA support of efficient and innocuous covalent drugs and a better understanding of the benefits of the covalent binding mechanism [33,34]. Numerous new drugs contain electrophilic moieties acting as “warheads”, and many molecules with a variety of electrophilic warheads, including epoxide, ketone, nitrile, ester, α,β-unsaturated carbonyl, or aziridine functionalities have been recognized as covalent inhibitors [35]. Aziridines as powerful alkylating agents, may act as covalent drugs by means of their ability to act as DNA cross-linking agents througH-Nucleophilic ring opening of the three-membered nitrogen heterocycle [36].
In this sense, we have been previously involved in the synthesis of phosphorus-substituted aziridines via nucleophilic addition to 2H-azirines [37,38,39,40] Moreover, these aziridines are valuable building blocks for the preparation of more complex products, such as 1H-benzo[d]azepines [37], pyrroles [37,41], oxazoles [42], and α- or β-aminophosphorus acid derivatives [43,44], among others. More recently, we have disclosed a diastereoselective approach to cyanoaziridines [45] and hybrid molecules, such as azirino [2,1-b]benzo[e][1,3]oxazines [46], througH-Nucleophilic addition of cyanide anion or functionalized phenols, respectively, to the C–N double bond of phosphorus substituted 2H-azirines. We were intrigued about the possibility of accessing other saturated aziridines containing phosphorus substituents by means of the addition of oxygen and sulfur nucleophilic reagents to 2H-azirines. For this aim, here we wish to account the results of the incorporation of aliphatic alcohols, phenols, thiols and benzenethiols into the three-membered nitrogen heterocycle, since these nucleophilic additions to 2H-azirines may be a new approach for the construction of substituted aziridines containing phosphorus substituents or even, more complex ring opening compounds. Furthermore, all these new functionalized acyclic and heterocyclic compounds were proved for antiproliferative activity against human cancer cell lines. This strategy entails a stimulating challenge due to the inherent interest of these new molecules, both in synthetic and medicinal chemistry.

2. Results

2.1. Chemistry

First, we studied the addition of aliphatic alcohols 2ab to 2H-azirine phosphine oxides and phosphonates 1. Initially, we tested the reaction of 2H-azirine phosphine oxide 1a with two equivalents of methanol (2a) in the presence of triethylamine as the base and using methylene chloride as the solvent. Since no reaction was observed using these conditions, the reaction of 2H-azirines 1 with aliphatic alcohol 2 as nucleophilic reagent and as the solvent, all at once, was assessed. Therefore, as outlined in Scheme 1, in an initial experiment the nucleophilic addition of methanol (2a) to 2H-azirine-phosphine oxide 1a (R = Ph, R1 = Me) was readily achieved using Et3N at 25 °C and MeOH as the nucleophile and solvent. Under these reaction conditions, we anticipated to obtain the desired aziridine 3a, as previously observed in the reaction of fluoroalkylated 2H-azirines with methanol [38]. Conversely, rather than aziridine 3a, functionalized α-aminophosphine oxide dimethyl acetal (4a, R = Ph, R1 = R2 = Me, Table 1, entry 1) in 74% yield was attained, as evidenced by the two sets of signals for the methoxy group which appeared as singlets in 1H-NMR (see the Supplementary Data). Starting from 2H-azirine-phosphine oxide 1b, α-aminophosphine oxide dimethyl acetal (4b, R = Ph, R1 = Et, R2 = Me) was isolated in 92% yield (Scheme 1, Table 1, entry 2), while the addition of methanol (2a) to functionalized 2H-azirine-phosphine oxide 1c furnished 81% of α-aminophosphine oxide dimethyl acetal (4c, R = R1 = Ph, R2 = Me) (Scheme 1, Table 1, entry 3).
A rational mechanism for the formation of α-aminophosphine oxide acetals 4 can be explained via initial nucleophilic addition of methanol (2a) at the carbon-nitrogen double bond of 2H-azirine 1 to give aziridine intermediate 3. As reported previously [37,38,39,40,41,42,43,44], this nucleophilic addition is likely to arise in a diastereoselective way through the less hindered face. Subsequent ring opening to form α-aminophosphine oxide acetals 4 occurs with complete site selectivity at N–C3 bond, after nucleophilic attack of a second molecule of methanol. This behavior has been previously observed in the addition of methanol to methylene-2H-azirines [47], or more recently to an aryl substituted 2H-azirine [48].
This synthetic procedure could be broadened to the nucleophilic addition of methanol (2a) to 2H-azirine-phosphonates 1d (R = OiPr) and 1e (R = OEt) under the same reaction conditions (Scheme 1). α-Aminophosphonate dimethyl acetals 4e (R = OiPr, R1 = R2 = Me, Table 1, entry 5) and 4f (R = OEt, R1 = R2 = Me, Table 1, entry 6) were attained in moderate yields. Next, we tested other aliphatic alcohols in the nucleophilic addition to 2H-azirines 1, under the optimal reaction conditions. For instance, 2H-azirine 1a (R = Ph) reacted with ethanol (2b) in the presence of Et3N, producing the corresponding α-aminophosphine oxide diethyl acetal 4d (see Table 1, entry 4).
We also explored the N-functionalization of α-aminophosphine oxide and phosphonate acetals 4 using the tosyl group as protecting group. Hence, sulfonylation of compounds 4 were achieved by treatment with p-toluenesulfonyl chloride (TsCl) in the presence of pyridine, in methylene chloride (CH2Cl2) at 25 °C. The corresponding N-tosylates 5 were obtained in moderate to good yields (Table 1, entries 7–9). This process might be performed in a one-pot operation from 2H-azirines 1 that would be appealing from an atom-economic alternative for carbon-heteroatom bond construction. Therefore, addition of ethanol (2b) to 2H-azirine 1e in the presence of triethylamine afforded compound 4, which, without isolation, was subjected to sulfonylation conditions to yield α-aminophosphonate diethyl acetal 5d (Table 1, entry 10).
In addition, we studied deacetalization reaction of compounds 5 under acidic conditions in order to get β-keto-α-aminophosphonates 6 (Scheme 1). Treatment of α-aminophosphonate dimethyl acetal 5b with a solution of 37% HCl in chloroform gave ketone 6 in 68% yield (Table 1, entry 11).
Reaction of other aliphatic alcohols with 2H-azirines 1 was also studied to check if these nucleophiles could provide a new entry to functionalized α-aminophosphorus derivatives. For this purpose we explored the reaction of 2H-azirine phosphine oxide 1a with 2,2,2-trifluoroethanol (2c). However, unlike the α-aminophosphine oxide acetals 4 observed in the reaction of azirines 1 with methanol or ethanol, when 2H-azirine 1a was treated, even under the standard conditions (see Scheme 1) or with two equivalents of trifluoroethanol (2c) in the presence of a base such as Et3N and CH2Cl2 as the solvent, aziridine 7 was obtained in very good yield (Scheme 2).
However, if the addition of trifluoroethanol (2c) to 1a was performed in refluxing chloroform, [1-amino-2-(2,2,2-trifloroethoxy)allyl]diphenyl phosphine oxide 8 was exclusively obtained instead of aziridine 7 (Scheme 2). The spectroscopic data were in agreement with the assigned structure for compound 8 (see characterization data for compound 8). The outcome of this conversion may be due to the initial formation of the corresponding aziridine 7, resulting from the addition of trifluoroethanol (2c) to the imine bond of 2H-azirine 1a. Subsequent C–C double bond formation and ring opening througH-N–C3 bond of aziridine afforded allylic α-aminophosphine oxide 8. The former compound turned out to be unstable and therefore it was converted into the sulfonamide derivative 9 in 90% chemical yield by treatment with p-toluenesulfonyl chloride in the presence of pyridine (Scheme 2).
In order to limit the scope of the addition of O-nucleophilic reagents to 2H-azirines 1 and increase the diversity of substituents in our substrates, this methodology was extended to include the reactivity of phenols 2de toward phosphorus substituted 2H-azirines 1. For this purpose, the nucleophilic addition of phenol (2d) to 2H-azirine phosphine oxide 1a was performed using Et3N as the base in CH2Cl2 to yield aziridine 10a in moderate yield (Scheme 3, Table 2, entry 1).
Conversely, the addition of 2-naphtol (2d) to 2H-azirine 1a, in the same reaction conditions, yielded a mixture of aziridine 10b and allylic α-aminophosphine oxide 11b (Scheme 3, Table 2, entry 2). Aziridine 10b seemed to be very unstable and cleavage of the C3–N bond in the three-membered ring of 10b promptly occurs to give allylic α-aminophosphine oxide 11b. This observation was further confirmed when aziridine 10a, or a mixture of aziridine 10b and derivative 11b was heated at refluxing chloroform. Under these reaction conditions, allylic α-aminophosphine oxide 11a or 11b, respectively, was obtained in good yields (Scheme 3, Table 2, entry 3 and 4). We then extended the scope of the nucleophilic addition of phenols (2de) to 2H-azirine phosphonate 1e. In this case, only allylic α-aminophosphonates 11 were directly observed in the crude NMR, but owing to their instability, they could not be isolated. Hence, intermediates 11 derived from phosphonates were submitted to sulfonylation reaction in a one-pot procedure giving to the formation of allylic N-tosyl α-aminophosphonates 12ab (Scheme 3, Table 2, entries 5 and 6).
As far as we know, this regioselective process represents the first example of the synthesis of an allylic α-aminophosphorus derivative through the addition of oxygen nucleophiles to the carbon-nitrogen double bond of a phosphorus substituted 2H-azirines.
Finally, in order to verify the potential of our synthetic methodology, we investigated the nucleophilic addition of sulfur nucleophiles to our phosphorus substituted 2H-azirines 1. We anticipated that nucleophilic addition of thiophenols and thiols to 2H-azirines 1, would supply a useful approach to the synthesis of aziridine derivatives 14 or even allylic α-aminophosphorus compounds 15. Thus, as outlined in Scheme 4, in an initial experiment the nucleophilic addition of benzenethiol (13a) (R2 = Ph) to 2H-azirine phosphine oxide 1a (R = Ph, R1 = Me) was readily attained using Et3N in dichloromethane at 25 °C (method A). Under these reaction conditions, aziridine derivative 14a was achieved in 92% yield (Table 3, entry 1). This aziridine 14a was very unstable since after crystallization the 1H-NMR spectrum showed different signals corresponding to aziridine 14a and minor ones matching to the allylic α-aminophosphine oxide 15a, formed through C3–N bond cleavage of aziridine ring. After a brief heating of the 14a and 15a compounds mixture in refluxing chloroform, only allylic α-aminophosphine oxide 15a was observed by NMR (Table 3, entry 4). In our previous results [43], both trapping of aziridine intermediate nor detection in crude NMR could be accomplished, and only the allylic α-aminophosphine oxide 15a was observed instead. Similarly, starting from 2H-azirine 1a and 4-methylbenzenethiol (13b) (R2 = p-MeC6H4), a mixture of aziridine 14b (Scheme 4, method A, Table 3, entry 2) and allylic α-aminophosphine oxide 15b was isolated, which afforded 15b after heating in refluxing chloroform.
Next, we carried out the addition of benzenethiol (13a) to 2H-azirine phosphine oxide 1c (R = R1 = Ph) avoiding the C–C double bond formation and confirming the reaction mechanism. Thus, reaction of 2H-azirine 1c with benzenethiol (13a) in the standard reaction conditions (method A) allowed us to get E-aziridine derivative 14c stereoselectively (Scheme 4, Table 3, entry 2).
Optimization of the reaction conditions allowed us to achieve the successful regioselective formation of allylic α-aminophosphorus derivatives 15. Therefore, when 2H-azirine 1a reacted with 4-methylbenzenethiol (13b) (R2 = p-MeC6H4) without base at 0 °C for 48h (method B), only the formation of derivative 15b was observed in 89% chemical yield (Scheme 4, Table 3, entry 5). Further scrutiny of the synthetic approach revealed that this process is also suitable to other substituted benzenethiols 13. For instance, as outlined in Scheme 3, 2H-azirine phosphine oxide 1a (R = Ph, R1 = Me) reacted with 4-fluorobenzenethiol (13c) (R2 = p-FC6H4) or 4-methoxybenzenethiol (13d) (R2 = p-MeOC6H4) for 48h at 0 °C, giving the corresponding allylic α-aminophosphine oxides 15cd (see Table 3, entries 6–7). This method also accommodates other 2H-azirines with phosphonate substitution, given that addition reaction of benzenethiol (13a) to 2H-azirine 1e (R = OEt, R1 = Me) afforded allylic α-aminophosphonate 15e in moderate yield (Table 3, entry 8). Likewise, aliphatic thiols such as ethanothiol (13e) satisfactorily reacted with 2H-azirine 1a giving to the formation of derivative 15f in a regioselective fashion (Table 3, entry 9).
Finally, we also examined the N-protection of allylic α-aminophosphine oxides and phosphonates 15. As before, for this aim we used the tosyl group as N-protecting group. Then, compounds 15 were subjected to sulfonylation reaction using the standard conditions already used formerly (TsCl in the presence of pyridine, CH2Cl2 as the solvent, and at 25 °C), and allylic N-tosyl α-aminophosphine oxides and phosphonates 16ac were attained in good yields (Scheme 3, Table 3, entries 10–12). The process might be performed in a one-pot procedure from 2H-azirine 1e when it reacts with p-substituted benzenethiols 13 at 0 °C for 48 h and subsequent treatment with p-toluenesulfonyl chloride in the presence of pyridine, yielding allylic N-tosyl α-aminophosphonates 16d–e (Table 3, entries 13–14).
This approach represents a practical short regioselective route to allylic α-aminophosphine oxides and phophonates 15 via addition reaction of sulfur nucleophiles to phosphorus substituted 2H-azirines 1. Moreover, N-functionalization by adding electron-withdrawing groups can be performed by N-tosylation of the corresponding derivatives 15.

2.2. Biological Results

The cytotoxicity of the new α-aminophosphine oxide and phosphonate acetals 4 and 5, β-keto-α-aminophosphonate 6, aziridines 7, 10 and 14, and allylic α-aminophosphine oxides and phosphonates 8, 9, 11, 12, 15 and 16 was investigated in vitro by checking their antiproliferative activities against the human cancer cell line A549 (carcinomic human alveolar basal epithelial cells). Human colon carcinoma cell line (RKO) was also used to test the antiproliferative activity of some of our compounds. In order to assess growth inhibition, cell counting kit (CCK-8) assay was employed. Cell proliferation inhibitory activities as IC50 values for all synthesized compounds and chemotherapeutic doxorubicin (DOX) are displayed in Table 4 and Table 5. Likewise, healthy lung cells, such as MRC-5 non-malignant lung fibroblasts were tested to study the selectivity of the cytotoxicity [49].
Primary 4 and secondary α-aminophosphine oxides and phosphonate acetals 5 demonstrated cytotoxic effect when evaluated against A549 cell line in vitro (Table 4, entries 2–11). For instance, compounds 4 showed IC50 values between 1.3 ± 0.10 and 21.3 ± 0.22 µM, with the most effective compound being α-aminophosphonate dimethyl acetal 4f (Table 4, entry 7) with an IC50 value of 1.3 ± 0.10 µM. Similar activities was observed for secondary α-aminophosphine oxides and phosphonate acetals 5 with IC50 values between 1.7 ± 0.30 and 8.2 ± 0.23 µM, with the most cytotoxic compound being N-tosyl α-aminophosphonate dimethyl acetal 5b (Table 4, entry 9). The hydrolysis of acetal group seemed not to have any effect since β-keto-α-aminophosphonate 6 do not exhibited any toxicity toward A549 (Table 4, entry 12).
Concerning allylic α-aminophosphorus derivatives obtained from the addition of trifluoroethanol (2c) or phenols (2de), besides allylic α-aminophosphine oxide 8 (Table 4, entry 15) which do not exhibited any toxicity effect toward A549, derivatives 11ab even allylic N-tosyl α-aminophosphine oxide 9 and phosphonates 12ab displayed very good cytotoxicity (Table 4, entries 16–17, 18, 19–20, respectively).
Regarding the new oxygen and sulfur-containing aziridine derivatives 7, 10a, (Table 4) and 14c (Table 5) against A549 cell line in vitro, diphenyl [3-phenyl-3-(phenylthio)aziridin-2-yl]phosphine oxide (14c) was the most cytotoxic compound with an IC50 value of 1.1 ± 0.32 µM (Table 5, entry 2).
We next studied allylic α-aminophosphorus derivatives with sulfur substituents 15 and 16 into their cytotoxicity against A549 cell line (Table 5). All of them showed good cytotoxicity. For instance, IC50 values between 0.1 ± 0.08 and 7.2 ± 0.49 µM was observed, being allylic α-aminophosphine oxide 15c (Table 5, entry 5) the most effective compound for primary allylic α-aminophosphorus derivatives 15. However, for allylic N-tosyl α-aminophosphorus derivatives 16, the most cytotoxic compound with an IC50 value of 0.2 ± 0.07 µM was derivative 16c (Table 5, entry 10).
Some of our synthesized compounds were tested as antiproliferative agents toward the RKO cell line. For instance, α-aminophosphine oxide acetal 4a, allylic α-aminophosphine oxide 11a (Table 4, entries 2, 16), and allylic α-aminophosphine oxides 15a, 15c, and 16c (Table 5, entries 3, 5, and 10) do not exhibited any toxicity toward RKO. However, good cytotoxicity effect was observed for aziridine phosphine oxide 14c, with an IC50 value of 9.7 ± 1.4 µM (Table 5, entry 2). Additionally, MRC-5 non-malignant lung fibroblasts were tested to explore selective toxicity [26]. Except for some allylic α-aminophosphorus derivatives, which displayed moderate cytotoxicity, nearly all the synthesized α-aminophosphorus derivatives, aziridines, and doxorubicin did not exhibit toxicity toward MRC-5 cell line (see Table 4 and Table 5). Additionally, aziridine 14c, (Table 5, entry 2) which showed good cytotoxicity against A549 and RKO cell lines, also exhibited good cytotoxicity toward MRC-5 cell line.

3. Materials and Methods

3.1. Chemistry

3.1.1. General Information

Solvents for extraction and chromatography were of technical grade. All solvents used in reactions were freshly distilled and dried over 4 Å molecular sieves before use. All other solvents and reagents were obtained from commercial sources and recrystallized or distilled as necessary or used without further purification. All reactions were performed under an atmosphere of dry nitrogen. Melting points were determined with an IA9100 Digital Melting Point Apparatus (Electrothermal; Cole-Parmer, Staffordshire, UK) and are uncorrected. IR spectra were measured as neat solids on a Nicolet iS10 spectrometer (Thermo Scientific, Waltham, MA, USA). Absorbance frequencies are given at maximum of intensity in cm−1. High-resolution mass spectra (HRMS) were obtained by positive-ion electrospray ionization (ESI) method with a time of flight Q-TOF system (Agilent 6530, Agilent Technologies, Santa Clara, CA, USA). Data are reported in the form m/z (intensity relative to base = 100). 1H- (300, 400 MHz), 13C- (75, 100 MHz), 19F- (282 MHz), and 31P-NMR (120, 160 MHz) spectra were recorded on a VXR 300 MHz (Varian, Agilent Technologies, Santa Clara, CA, USA) or Avance 400 MHz (Bruker Corporation Billerina, MA, USA) spectrometers, respectively, in CDCl3 or DMSO-d6, as specified below at 25 °C. Chemical shifts (δH) are reported in parts per million (ppm) with the internal chloroform signal at 7.24 ppm as standard for 1H-NMR. Chemical shifts (δC and δP) are reported in parts per million (ppm) with the internal chloroform signal at 77.0 ppm as standard for 13C-NMR; the external fluorotrichloromethane (CFCl3) signal at 0.0 ppm as standard for 19F-NMR; or the external H3PO4 (50%) signal at 0.0 ppm as standard for 31P-NMR. All coupling constants (J) values are given 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. The data is being reported as (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, dd = double doublet, bs = broad singlet). Chromatographic purification was performed as flash chromatography using commercial grades of silica gel finer than 230 mesh with pressure. Analytical thin layer chromatography (TLC) was performed on precoated silica gel 60 F254 TLC aluminium plates (Merck, Darmstad, Germany) and spots visualized with UV light or permanganate stain. 2H-Azirines 1 were prepared according to literature procedures [25,29,30,52].

3.1.2. Experimental Procedure and Characterization Data for Compounds 4, 5 and 6

General Procedure and Spectral Data for the Addition of Aliphatic Alcohols to Functionalized 2H-Azirines 1

To a 0 °C solution of 2H-azirine 1 (5 mmol, 1 eq) in aliphatic alcohol 2ab (25 mL) and 4 Å M.S., Et3N (1.4 mL, 10 mmol, 2 eq) was added dropwise. The reaction mixture was allowed to reach 25 °C and stirred until TLC showed the disappearance of starting 2H-azirine 1 (24 h). 4 Å M.S. was filtered through a sintered glass vacuum filtration funnel with Celite and washed with alcohol. The filtrate was concentrated to dryness in vacuum and the resulting residue was diluted with CH2Cl2 (15 mL). The organic phase was washed with water (3 × 15 mL) and extracted with CH2Cl2. The organic layer was dried over anhydrous MgSO4, filtered and concentrated to dryness in vacuum. The crude products 4 were purified by crystallization or by flash-column chromatography.
(1-Amino-2,2-dimethoxypropyl) diphenylphosphine oxide (4a), (1.18 g, 74%) obtained as a yellow solid from 2H-azirine 1a (1.28 g, 5 mmol) using MeOH as described in the general procedure. The crude product was purified by crystallization from Et2O to afford the title compound 4a. mp 125–127 °C; IR (neat) vmax 3386, 3056, 2990, 2942, 2832, 1442, 1385, 1179, 1116, 1040, 723, 701 cm−1; 1H-NMR (300 MHz, CDCl3) δ 7.80–7.65 (m, 4H, ArH), 7.39–7.21 (m, 6H, ArH), 3.67 (d, 2JPH = 5.5 Hz, 1H, CH–P), 3.03 (s, 3H, OCH3), 2.64 (s, 3H, OCH3), 1.47 (bs, 2H, NH2), 1.32 (s, 3H, CH3) ppm; 13C {1H}-NMR (75 MHz, CDCl3) δ 133.0 (d, 1JPC = 97.6 Hz, Cquat), 133.0 (d, 1JPC = 97.9 Hz, Cquat), 131.4, 131.3, 131.1, 131.0, 130.9, 130.9, 128.4 (d, JPC = 11.3 Hz), 127.6 (d, JPC = 11.8 Hz) (CAr), 102.5 (d, 2JPC = 4.9 Hz, Cquat), 54.0 (d, 1JPC = 75.6 Hz, CH-P), 48.1 (OCH3), 47.6 (OCH3), 18.4 (CH3) ppm; 31P-NMR (120 MHz, CDCl3) δ 30.9 ppm; ESI-HRMS (CI) m/z calcd. for C17H22NNaO3P ([M + Na]+) 342.1235, found 342.1230.
Molecules 25 03332 i011
(1-Amino-2,2-dimethoxybutyl)diphenylphosphine oxide (4b), (1.53 g, 92%) obtained as a yellow solid from 2H-azirine 1b (1.35 g, 5 mmol) using MeOH as described in the general procedure. The crude product was purified by crystallization from Et2O to afford the title compound 4b. mp 96–97 °C; IR (neat) vmax 3322, 3060, 2939, 2822, 1442, 1182, 1159, 1097, 1046 cm−1; 1H-NMR (400 MHz, CDCl3) δ 7.91–7.81 (m, 4H, ArH), 7.45–7.37 (m, 6H, ArH), 3.84 (d, 2JPH = 6.6 Hz, 1H, CH-P), 3.10 (s, 3H, OCH3), 2.97 (s, 3H, OCH3), 2.01–1.81 (m, 2H, CH2), 1.74 (bs, 2H, NH2), 0.98 (t, 3JHH = 7.5 Hz, 3H, CH3) ppm; 13C {1H}-NMR (100 MHz, CDCl3) δ 133.5 (d, 1JPC = 97.0 Hz, Cquat), 133.2 (d, 1JPC = 97.2 Hz, Cquat), 131.4, 131.4, 131.3, 131.0, 131.0, 128.5 (d, JPC = 11.2 Hz), 127.7 (d, JPC = 11.9 Hz) (CAr), 103.2 (d, 2JPC = 3.3 Hz, Cquat), 55.5 (d, 1JPC = 75.4 Hz, CH-P), 49.3 (OCH3), 48.5 (OCH3), 26.1 (CH2), 8.8 (CH3) ppm; 31P-NMR (160 MHz, CDCl3) δ 30.3 ppm; ESI-HRMS (CI) m/z calcd. for C18H24NNaO3P ([M + Na]+) 356.1391, found 356.1386.
Molecules 25 03332 i012
(1-Amino-2,2-dimethoxy-2-phenylethyl)diphenylphosphine oxide (4c), (1.54 g, 81%) obtained as a yellow solid from 2H-azirine 1c (1.59 g, 5 mmol) using MeOH as described in the general procedure. The crude product was purified by flash-column chromatography (SiO2, EtOAc/hexane 50:50) to afford the title compound 4c. mp 113–115 °C; IR (neat) vmax 3462, 3060, 2984, 2939, 1448, 1438, 1372, 1242, 1116, 1097, 1046 cm−1; 1H-NMR (400 MHz, CDCl3) δ 7.91–7.20 (m, 15H, ArH), 4.12 (d, 2JPH = 8.6 Hz, 1H, CH-P), 3.23 (s, 3H, OCH3), 3.15 (s, 3H, OCH3), 1.68 (bs, 2H, NH2) ppm; 13C {1H}-NMR (75 MHz, CDCl3) δ 137.2, 134.6, 133.3, 132.9, 131.6, 131.3, 131.2, 131.0, 130.9, 130.9, 130.8, 128.0, 127.9, 127.9, 127.8, 127.8, 127.6, 127.5 (CAr), 103.7 (d, 2JPC = 3.8 Hz, Cquat), 56.7 (d, 1JPC = 78.2 Hz, CH-P), 49.8 (OCH3), 48.8 (OCH3) ppm; 31P-NMR (120 MHz, CDCl3) δ 27.8 ppm; ESI-HRMS (CI) m/z calcd. for C22H24NNaO3P ([M + Na]+) 404.1391, found 404.1386.
Molecules 25 03332 i013
(1-Amino-2,2-diethoxypropyl)diphenylphosphine oxide (4d), (0.97 g, 56%) obtained as a yellow solid from 2H-azirine 1a (1.28 g, 5 mmol) using EtOH as described in the general procedure. The crude product was purified by flash-column chromatography (SiO2, EtOAc) to afford the title compound 4d. mp 126–128 °C; IR (neat) vmax 3386, 3326, 2974, 2927, 2889, 1438, 1385, 1182, 1120, 1068, 1049, 951, 723, 695 cm−1; 1H-NMR (300 MHz, CDCl3) δ 7.90–7.76 (m, 4H, ArH), 7.44–7.34 (m, 6H, ArH), 3.80 (d, 2JPH = 5.0 Hz, 1H, CH-P), 3.48–3.38 (m, 2H, CH2), 3.24–3.00 (m, 2H, CH2), 1.59 (bs, 2H, NH2), 1.49 (s, 3H, CH3), 1.12 (t, 3JHH = 7.0 Hz, 3H, CH3), 0.51 (t, 3JHH = 7.0 Hz, 3H, CH3) ppm; 13C {1H}-NMR (75 MHz, CDCl3) δ 133.5 (d, 1JPC = 97.8 Hz, Cquat), 133.5 (d, 1JPC = 97.8 Hz, Cquat), 131.4, 131.3, 131.0, 130.9, 130.8, 128.5 (d, JPC = 11.1 Hz), 127.6 (d, JPC = 11.9 Hz) (CAr), 102.4 (d, 2JPC = 4.3 Hz, Cquat), 56.2 (OCH2), 55.1 (OCH2), 54.63 (d, 1JPC = 75.5 Hz, CH-P), 19.5 (CH3), 15.2 (CH3), 14.2 (CH3) ppm; 31P-NMR (120 MHz, CDCl3) δ 31.1 ppm; ESI-HRMS (CI) m/z calcd. for C19H26NNaO3P ([M + Na]+) 370.1548, found 370.1543.
Molecules 25 03332 i014
Diisopropyl (1-amino-2,2-dimethoxypropyl)phosphonate (4e), (0.98 g, 69%) obtained as a yellow oil from 2H-azirine 1d (1.10 g, 5 mmol) using MeOH as described in the general procedure. The crude product was purified by flash-column chromatography (SiO2, AcOEt) to afford the title compound 4e. IR (neat) vmax 3300, 2971, 2933, 1467, 1381, 1239, 983 cm−1; 1H-NMR (400 MHz, CDCl3) δ 4.68–4.58 (m, 2H, OCH), 3.19–3.16 (m, 1H, CH-P), 3.15 (s, 3H, OCH3), 3.08 (s, 3H, OCH3), 1.57 (bs, 2H, NH2), 1.36 (s, 3H, CH3), 1.25–1.21 (m, 12H, CH(CH3)2) ppm; 13C {1H}-NMR (100 MHz, CDCl3) δ 101.8 (d, 2JPC = 7.8 Hz, Cquat), 70.8 (d, 2JPC = 6.8 Hz, OCH), 70.2 (d, 2JPC = 7.2 Hz, OCH), 53.0 (d, 1JPC = 153.4 Hz), 48.4 (OCH3), 47.5 (OCH3), 24.2 (d, 3JPC = 2.7 Hz, CH3), 24.0 (d, 3JPC = 3.4 Hz, CH3), 23.7 (d, 3JPC = 5.2 Hz, CH3), 23.5 (d, 3JPC = 5.8 Hz, CH3), 17.7 (CH3) ppm; 31P-NMR (160 MHz, CDCl3) δ 23.8 ppm; ESI-HRMS (CI) m/z calcd. for C10H23NO4P ([M–OMe]+) 252.1370, found 252.1361.
Molecules 25 03332 i015
Diethyl (1-amino-2,2-dimethoxypropyl)phosphonate (4f), (0.78 g, 61%) obtained as a brown oil from 2H-azirine 1e (0.96 g, 5 mmol) using MeOH as described in the general procedure. The crude product was purified by flash-column chromatography (SiO2, EtOAc/MeOH 99:1) to afford the title compound 4f. IR (neat) vmax 3466, 3319, 2928, 2945, 2905, 1650, 1454, 1236, 1022 cm−1; 1H-NMR (400 MHz, CDCl3) δ 4.18–4.05 (m, 4H, OCH2), 3.32 (d, 2JPH = 17.6 Hz, 1H, CH-P), 3.24 (s, 3H, OCH3), 3.16 (s, 3H, OCH3), 1.61 (bs, 2H, NH2), 1.44 (s, 3H, CH3), 1.31 (dt, 3JHH = 7.0 Hz, 3JPH = 0.5 Hz, 3H, CH3), 1.30 (dt, 3JHH = 7.1 Hz, 3JPH = 0.5 Hz, 3H, CH3) ppm; 13C {1H}-NMR (100 MHz, CDCl3) δ 101.8 (d, 2JPC = 8.1 Hz, Cquat), 62.5 (d, 2JPC = 6.6 Hz, OCH2), 61.8 (d, 2JPC = 6.8 Hz, OCH2), 52.7 (d, 1JPC = 152.0 Hz, CH-P), 48.8 (OCH3), 47.8 (OCH3), 17.9 (CH3), 16.5 (d, 3JPC = 4.9 Hz, CH3), 16.4 (d, 3JPC = 4.9 Hz, CH3) ppm; 31P-NMR (160 MHz, CDCl3) δ 25.9 ppm; ESI-HRMS (CI) m/z calcd. for C8H19NO4P ([M–OMe]+) 224.1057, found 224.1052.
Molecules 25 03332 i016

General Procedure and Spectral Data for the N-Tosyl Functionalization of α-Aminophosphine Oxide and Phosphonate Acetals 4

p-Toluenesulfonyl chloride (1 g, 5.5 mmol, 1.1 eq) and pyridine (2.42 mL, 30 mmol, 6 eq) were added to a 0 °C solution of α-aminophosphine oxide or phosphonate acetal 4 (5 mmol, 1 eq) in CH2Cl2 (25 mL). The reaction mixture was allowed to reach 25 °C and stirred until TLC showed the disappearance of starting compound 4. The crude product was washed twice with a 2M HCl solution (15 mL) and water (15 mL) and extracted with CH2Cl2 (15 mL). The organic layers were dried over anhydrous MgSO4, filtered and concentrated to dryness in vacuum. The crude products 5 were purified by crystallization or by flash-column chromatography.
N-[1-(Diphenylphosphoryl)-2,2-dimethoxypropyl]-4-methylbenzenesulfonamide (5a), (1.89 g, 80%) obtained as a yellow solid from α-aminophosphine oxide 4a (1.60 g, 5 mmol) after 24 h at 25 °C as described in the general procedure. The crude product was purified by crystallization from Et2O/CH2Cl2 50:50 to afford the title compound 5a. mp 205–207 °C; IR (neat) vmax 3440, 2990, 2939, 2885, 1445, 1331, 1182, 1157, 1119, 1097, 1046 cm−1; 1H-NMR (400 MHz, CDCl3) δ 7.92–7.06 (m, 14H, ArH), 4.80 (t, 3JPH = 18.1 Hz, 3JHH = 9.1 Hz, 1H, CH-P), 2.92 (s, 3H, OCH3), 2.60 (s, 3H, OCH3), 2.31 (s, 3H, CH3), 1.40 (s, 3H, CH3), ppm; 13C {1H}-NMR (100 MHz, CDCl3) δ 142.2, 139.7, 133.8, 132.8, 132.0, 131.6, 131.3, 131.2, 131.2, 131.1, 131.1, 131.0, 130.9, 128.8, 128.5, 128.4, 127.8, 127.7, 126.5 (CAr), 102.4 (d, 2JPC = 7.1 Hz, Cquat), 55.6 (d, 2JPC = 74.1 Hz, CH-P), 48.3 (OCH3), 48.0 (OCH3), 21.4 (CH3), 19.0 (CH3) ppm; 31P-NMR (120 MHz, CDCl3) δ 31.5 ppm; ESI-HRMS (CI) m/z calcd. for C24H28NNaO5PS ([M+Na]+) 496.1323, found 496.1318.
Molecules 25 03332 i017
Diisopropyl [2,2-dimethoxy-1-((4-methylphenyl)sulfonamido)propyl]phosphonate (5b), (1.36 g, 62%) obtained as a white solid from α-aminophosphonate 4e (1.42 g, 5 mmol) after 24 h at 25 °C as described in the general procedure. The crude product was purified by flash-column chromatography (SiO2, EtOAc/hexane 16:84) and crystallization from Et2O to afford the title compound 5b. mp 137–139 °C; IR (neat) vmax 3161, 2923, 1590, 1378, 1328, 1176, 989 cm−1; 1H-NMR (400 MHz, CDCl3) δ 7.73 (d, 3JHH = 8.3 Hz, 2H, ArH), 7.24 (d, 3JHH = 8.0 Hz, 2H, ArH), 5.04 (dd, 3JHH = 9.1 Hz, 3JPH = 6.7 Hz, 1H, NH), 4.76–4.64 (m, 2H, OCH), 4.10 (dd, 3JHH = 9.1 Hz, 2JPH = 21.4 Hz, 1H, CH-P), 3.14 (s, 3H, OCH3), 2.88 (s, 3H, OCH3), 2.38 (s, 3H, CH3), 1.36 (s, 3H, CH3), 1.32–1.29 (m, 12H, CH(CH3)2) ppm; 13C {1H}-NMR (75 MHz, CDCl3) δ 142.6, 139.5, 129.0, 126.9 (CAr), 101.3 (d, 2JPC = 12.0 Hz, Cquat), 71.9 (d, 2JPC = 7.0 Hz, OCH), 71.8 (d, 2JPC = 7.2 Hz, OCH), 55.0 (d, 1JPC = 154.1 Hz, CH-P), 49.1 (OCH3), 48.1 (OCH3), 23.8 (CH3), 23.7 (CH3), 23.6 (CH3), 23.5 (CH3), 21.5 (CH3), 18.4 (CH3) ppm; 31P-NMR (120 MHz, CDCl3) δ 18.3 ppm; ESI-HRMS (CI) m/z calcd. for C17H29NO6PS ([M–OMe]+) 406.1459, found 406.1450.
Molecules 25 03332 i018
Diethyl [2,2-dimethoxy-1-((4-methylphenyl)sulfonamido)propyl]phosphonate (5c), (1.31 g, 64%) obtained as a pale yellow oil from α-aminophosphonate 4f (1.28 g, 5 mmol) after 3 h at 25 °C as described in the general procedure. The crude product was purified by flash-column chromatography (SiO2, EtOAct/hexane 20:80) to afford the title compound 5c. IR (neat) vmax 3174, 2987, 1331, 1239, 1220, 1157, 995 cm−1; 1H-NMR (400 MHz, CDCl3) δ 7.74 (d, 3JHH = 8.4 Hz, 2H, ArH), 7.21 (d, 3JHH = 8.0 Hz, 2H, ArH), 5.98 (dd, 3JHH = 9.4 Hz, 3JPH = 5.2 Hz, 1H, NH), 4.15–4.00 (m, 5H, CH-P and OCH2), 3.14 (s, 3H, OCH3), 2.86 (s, 3H, OCH3), 2.36 (s, 3H, CH3), 1.36 (s, 3H, CH3), 1.26 (t, 3JHH = 7.1 Hz, 3H, CH3), 1.24 (t, 3JHH = 7.1 Hz, 3H, CH3) ppm; 13C {1H}-NMR (75 MHz, CDCl3) δ 142.3, 139.7, 128.8, 126.7 (CAr), 101.3 (d, 2JPC = 12.7 Hz, Cquat), 62.9 (d, 2JPC = 6.6 Hz, OCH2), 62.9 (d, 2JPC = 7.1 Hz, OCH2), 54.2 (d, 1JPC = 153.6 Hz, CH-P), 49.0 (OCH3), 48.0 (OCH3), 21.4 (CH3), 18.4 (CH3), 16.2 (CH3), 16.2 (CH3) ppm; 31P-NMR (120 MHz, CDCl3) δ 20.3 ppm; ESI-HRMS (CI) m/z calcd. for C15H25NO6PS ([M–OMe]+) 378.1146, found 378.1133.
Molecules 25 03332 i019

One Pot Procedure for the Synthesis of N-tosyl-α-Aminophosphonate Acetal 5d

To a 0 °C solution of 2H-azirine 1e (0.96 g, 5 mmol) in EtOH (25 mL) and 4 Å M.S., Et3N (1.4 mL, 10 mmol, 2 eq) was added dropwise. The reaction mixture was allowed to reach 25 °C and stirred for 24 h until TLC showed the disappearance of starting 2H-azirine 1e. 4 Å M.S. was filtered through a sintered glass vacuum filtration funnel with celite and washed with EtOH. The filtrate was concentrated to dryness in vacuum and the resulting residue was diluted with CH2Cl2 (15 mL). The organic phase was washed with water (3 × 15 mL) and extracted with CH2Cl2. The organic layer was dried over anhydrous MgSO4, filtered and concentrated to dryness under vacuum. To a 0 °C solution of the crude product 4 in CH2Cl2 (25 mL) was directly added p-toluenesulfonyl chloride (1 g, 5.5 mmol, 1.1 eq) and pyridine (2.42 mL, 30 mmol, 6 eq). The reaction mixture was allowed to reach 25 °C and stirred for 24 h. The crude product was washed twice with a 2M HCl solution (15 mL) and water (15 mL) and extracted with CH2Cl2 (15 mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated to dryness in vacuum. The crude product 5d was purified by crystallization from Et2O.
Diethyl [2,2-diethoxy-1-((4-methylphenyl)sulfonamido)propyl]phosphonate (5d), (1.53 g, 70%) obtained as a white solid. mp 126–128 °C; IR (neat) vmax 3434, 3189, 2979, 2931, 2885, 1560, 1474, 1463, 1391, 1330, 1241, 1158, 1136, 1088, 1052, 1013, 975, 950, 890 cm−1; 1H-NMR (300 MHz, CDCl3) δ 7.76 (d, 3JHH = 7.7 Hz, 2H, ArH), 7.21 (d, 3JHH = 7.9 Hz, 2H, ArH), 5.62 (dd, 3JHH = 9.5 Hz, 3JPH = 5.3 Hz, 1H, NH), 4.18–3.94 (m, 5H, CH-P and OCH2), 3.50–3.20 (m, 4H, OCH2), 2.35 (s, 3H, CH3), 1.43 (s, 3H, CH3), 1.25–1.19 (m, 6H, CH3), 1.10 (t, 3JHH = 7.1 Hz, 3H, CH3), 0.88 (t, 3JHH = 7.1 Hz, 3H, CH3) ppm; 13C {1H}-NMR (75 MHz, CDCl3) δ 142.6, 139.5, 129.0, 126.8, 120.3 (CAr), 100.9 (d, 2JPC = 11.7 Hz, Cquat), 62.7 (d, 2JPC = 7.1 Hz, OCH2), 62.7 (d, 2JPC = 6.6 Hz, OCH2), 56.9 (OCH2), 55.1 (d, 1JPC = 153.6 Hz, CH-P), 56.0 (OCH2), 21.4 (CH3), 19.7 (CH3), 16.3 (d, 3JPC = 3.1 Hz, CH3), 16.2 (d, 3JPC = 3.0 Hz, CH3), 15.1 (CH3), 14.7 (CH3) ppm; 31P-NMR (120 MHz, CDCl3) δ 20.8 ppm; ESI-HRMS (CI) m/z calcd. for C18H32NNaO7PS ([M + Na]+) 460.1535, found 460.1549.
Molecules 25 03332 i020

General Procedure and Spectral Data of β-Keto-α-Aminophosphine Oxide 6

To a stirred solution of α-aminophosphonate acetal 5b (0.87 g, 2 mmol) in CHCl3 (10 mL), a 37% solution of HCl (5 drops) was added dropwise. The mixture was refluxed for 5 h and was allowed to reach 25 °C. The crude product was washed twice with water (5 mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated to dryness in vacuum, and the resulting residue was purified by crystallization from Et2O/hexane 50:50 to afford the title compound 6.
Diisopropyl [1-((4-methylphenyl)sulfonamido)-2-oxopropyl]phosphonate (6), (0.53 g, 68%) as a white solid. mp 121–122 °C; IR (neat) vmax 3136, 2977, 1717, 1328, 1230, 995 cm−1; 1H-NMR (400 MHz, CDCl3) δ 7.67 (d, 3JHH = 8.3 Hz, 2H, ArH), 7.26 (d, 3JHH = 8.0 Hz, 2H, ArH), 5.55 (dd, 3JHH = 9.3 Hz, 3JPH = 2.0 Hz, 1H, NH), 4.79–4.71 (m, 2H, OCH), 4.70–4.62 (m, 2H, OCH), 4.41 (dd, 3JHH = 9.3 Hz, 2JPH = 25.2 Hz, 1H, CH-P), 2.39 (s, 3H, CH3), 2.14 (s, 3H, CH3), 1.34–1.25 (m, 12H, CH(CH3)2) ppm; 13C {1H}-NMR (100 MHz, CDCl3) δ 199.8 (C = O), 144.2, 136.0, 129.8, 127.4 (CAr), 73.4 (d, 2JPC = 7.2 Hz, OCH), 73.3 (d, 2JPC = 7.2 Hz, OCH), 61.5 (d, 1JPC = 143.2 Hz, CH-P), 28.8 (CH3), 24.0 (d, 3JPC = 3.6 Hz, CH3), 23.9 (d, 3JPC = 3.8 Hz, CH3), 23.7 (d, 3JPC = 5.2 Hz, CH3), 23.6 (d, 3JPC = 5.4 Hz, CH3), 21.6 (CH3) ppm; 31P-NMR (120 MHz, CDCl3) δ 11.8 ppm; ESI-HRMS (CI) m/z calcd. for C16H27NO6PS ([M + H]+) 392.1297, found 392.1293.
Molecules 25 03332 i021

3.1.3. Experimental Procedure and Characterization Data for Compounds 7, 8 and 9

General procedure and spectral data for the addition of 2,2,2-trifluoroethanol (2c) to functionalized 2H-azirines 1

To a 0 °C solution of 2H-azirine 1a (1.28 g, 5 mmol, 1 eq) in CH2Cl2 (25 mL) was added dropwise 2,2,2-trifluoroethanol (2c) (0.73 mL, 10 mmol, 2 eq), Et3N (3.15 mL, 22.5 mmol, 4.5 eq), and 4 Å M.S. The reaction mixture was allowed to reach 25 °C and stirred at the same temperature for 24 h. 4 Å M.S. was then filtered through a sintered glass vacuum filtration funnel with celite and washed with CH2Cl2. The reaction mixture was washed with water (3 × 15 mL) and extracted with CH2Cl2 (15 mL). The organic layers were dried over anhydrous MgSO4, filtered and concentrated to dryness in vacuum. The crude product was purified by crystallization in Et2O.
[(2S*,3S*)-3-Methyl-3-(2,2,2-trifluoroethoxy)aziridin-2-yl]diphenylphosphine oxide (7), (1.62 g, 91%) as a yellow solid. mp 98–100 °C; IR (neat) vmax 3439, 3248, 2972, 2941, 1635, 1590, 1438, 1394, 1359, 1280, 1252, 1169, 1122, 1080, 745, 726, 694 cm−1; 1H-NMR (300 MHz, CDCl3) δ 7.78–7.38 (m, 10H, ArH), 3.88 (dq, 2JHH = 1.5 Hz, 3JHF = 8.7 Hz, 2H, CH2), 2.53 (dd, 3JHH = 9.4 Hz, 2JPH = 21.5 Hz, 1H, CH-P), 1.84 (dd, 3JHH = 9.7 Hz, 3JPH = 18.0 Hz, 1H, NH), 1.69 (s, 3H, CH3) ppm; 13C {1H}-NMR (75 MHz, CDCl3) δ 132.5, 132.4, 132.3, 132.2, 131.2, 130.9, 130.9, 130.8, 130.7, 129.0, 128.8, 128.7 (CAr), 125.4 (d, 1JCF = 277.8 Hz, CF3), 71.6 (Cquat), 61.8 (q, 2JCF = 33.8 Hz, CH2), 38.0 (d, 1JPC = 89.9 Hz), 17.0 (CH3) ppm; 31P-NMR (120 MHz, CDCl3) δ 25.2 ppm; 19F NMR (282 MHz, CDCl3) δ –74.6, –74.7, –74.7 ppm; ESI-HRMS (CI) m/z calcd. for C17H18F3NO2P ([M + H]+) 356.1027, found 356.1014.
Molecules 25 03332 i022

General Procedure and Spectral Data of Allylic α-Aminophosphine Oxide 8

A solution of aziridine 7 (1.78 g, 5 mmol, 1 eq) was stirred in refluxing CHCl3 (11mL) for 15 h until TLC showed the disappearance of aziridine 7. The crude product was purified by flash-column chromatography (SiO2, AcOEt/hexane 50:50) to afford the title compound 8.
[1-Amino-2-(2,2,2-trifluoroethoxy)allyl]diphenylphosphine oxide (8), (1.30 g, 73%) as a yellow oil. IR (neat) vmax 3387, 3314, 3059, 2940, 1638, 1591, 1438, 1288, 1169, 1119, 1102, 975, 910, 827, 730, 694 cm−1; 1H-NMR (300 MHz, CDCl3) δ 7.90–7.37 (m, 10H, ArH), 4.45 (t, 2JHH = 3.5 Hz, 1H, = CH2), 4.20 (d, 2JPH = 8.7 Hz, 1H, CH-P), 4.10 (t, 2JHH = 3.2 Hz, 1H, = CH2), 3.92–3.80 (m, 1H, CH2), 3.64–3.52 (m, 1H, CH2), 1.95 (bs, 2H, NH2) ppm; 13C {1H}-NMR (75 MHz, CDCl3) δ 158.6 (d, 2JPC = 1.9 Hz, = C-O), 132.0, 132.0, 131.9, 131.9, 131.6, 131.5, 131.5, 131.4 (CAr), 122.7 (q, 1JCF = 277.6 Hz, CF3), 86.8 (d, 3JPC = 6.2 Hz, = CH2), 64.5 (q, 2JCF = 36.2 Hz, CH2), 55.4 (d, 1JPC = 71.9 Hz) ppm; 31P-NMR (120 MHz, CDCl3) δ 30.2 ppm; 19F NMR (282 MHz, CDCl3) δ –73.9, –74.0, –74.0 ppm; ESI-HRMS (CI) m/z calcd. for C17H17F3NNaO2P ([M + Na]+) 378.0847, found 378.0851.
Molecules 25 03332 i023

General Procedure and Spectral Data of Allylic N-Tosyl α-Aminophosphine Oxide 9

p-Toluenesulfonyl chloride (1 g, 5.5 mmol, 1.1 eq) and pyridine (2.4 mL, 30 mmol, 6 eq) were added to a 0 °C solution of 8 (1.78 g, 5 mmol, 1 eq) in CH2Cl2 (25 mL). The reaction mixture was allowed to reach 25 °C and stirred for 24 h. The crude product was washed twice with a 2M HCl solution (15 mL) and water (15 mL) and extracted with CH2Cl2 (15 mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated to dryness in vacuum. The crude product was purified by crystallization from Et2O to afford the title compound 9.
N-[1-(Diphenylphosphoryl)-2-(2,2,2-trifluoroethoxy)allyl]-4-methylbenzenesulfonamide (9), (2.29 g, 90%) obtained as a pale yellow solid. mp 201–203 °C; IR (neat) vmax 3412, 3062, 2942, 2879, 1652, 1596, 1444, 1338, 1285, 1160, 910, 733 cm−1; 1H-NMR (400 MHz, CDCl3) δ 7.85–7.72 (m, 4H, ArH), 7.67 (d, 3JHH = 8.3 Hz, 2H, ArH), 7.56–7.38 (m, 6H, ArH), 7.11 (d, 3JHH = 8.4 Hz, 2H, ArH), 7.07 (d, 3JHH = 9.8 Hz, 1H, NH), 4.80 (t, 2JPH = 11.1 Hz, 1H, CH-P), 4.48 (t, 2JHH = 3.8 Hz, 1H, = CH2), 3.67 (t, 2JHH = 3.6 Hz, 1H, = CH2), 3.42–3.33 (m, 1H, CH2), 3.00–2.91 (m, 1H, CH2), 2.34 (s, 3H, CH3) ppm; 13C {1H}-NMR (100 MHz, CDCl3) δ 153.4, 143.2, 137.5, 132.4, 132.3, 131.6, 131.5, 130.0, 129.8, 129.0, 128.8, 128.7, 128.4, 128.2, 127.6 (CAr), 122.5 (q, 1JCF = 277.5 Hz, CF3), 89.0 (d, 3JPC = 6.1 Hz, = CH2), 64.2 (q, 2JCF = 35.6 Hz, CH2), 55.5 (d, 1JPC = 73.5 Hz, CH-P), 21.5 (CH3) ppm; 31P-NMR (120 MHz, CDCl3) δ 29.6 ppm; 19F NMR (282 MHz, CDCl3) δ –73.9, –73.9, –73.9 ppm; ESI-HRMS (CI) m/z calcd. for C24H24F3NO4PS ([M + H]+) 510.1116, found 510.1117.
Molecules 25 03332 i024

3.1.4. Experimental Procedure and Characterization Data for Compounds 10, 11 and 12

General Procedure and Spectral Data for the Addition of Phenols (2de) to Functionalized 2H-Azirines 1

To a 0 °C solution of 2H-azirine 1 (5 mmol, 1 eq) in CH2Cl2 (25 mL), the corresponding phenols (2d–e) (10 mmol, 2 eq) and Et3N (1.4 mL, 10 mmol, 2 eq) was added dropwise. The reaction mixture was allowed to reach 25 °C and stirred at the same temperature for 24 h. The reaction mixture was washed with water (3 × 15 mL) and extracted with CH2Cl2 (15 mL). The organic layers was dried over anhydrous MgSO4, filtered and concentrated to dryness in vacuum. The crude products were purified by crystallization or by flash-column chromatography.
[(2S*,3S*)-3-Methyl-3-phenoxyaziridin-2-yl]diphenylphosphine oxide (10a), (1.22 g, 70%) obtained as a pale yellow solid from 2H-azirine 1a (1.28 g, 5 mmol) and phenol (2d) (0.88 g, 10 mmol) as described in the general procedure. The crude product was purified by crystallization from Et2O to afford the title compound 10a. mp 124–126 °C; IR (neat) vmax 3203, 3059, 2990, 1593, 1488, 1438, 1391, 1349, 1224, 1191, 1122, 733, 691 cm−1; 1H-NMR (300 MHz, CDCl3) δ 7.85–7.42 (m, 10H, ArH), 7.07–6.63 (m, 5H, ArH), 2.62 (dd, 3JHH = 10.0 Hz, 2JPH = 22.0 Hz, 1H, CH-P), 2.06 (dd, 3JHH = 10.2 Hz, 3JPH = 18.2 Hz, 1H, NH), 1.87 (s, 3H, CH3) ppm; 13C {1H}-NMR (75 MHz, CDCl3) δ 154.9 (OCAr), 132.5, 132.4, 132.2, 131.2, 131.1, 131.0, 130.9, 129.2, 129.0, 128.8, 128.7, 121.7, 116.7 (CAr), 70.3 (Cquat), 37.9 (d, 1JPC = 88.7 Hz, CH-P), 16.9 (CH3) ppm; 31P-NMR (120 MHz, CDCl3) δ 25.1 ppm; ESI-HRMS (CI) m/z calcd. for C21H21NO2P ([M + H]+) 350.1310, found 350.1302.
Molecules 25 03332 i025
[(2S*,3S*)-3-Methyl-3-(naphthalen-2-yloxy)aziridin-2-yl]diphenyl-phosphine oxide (10b), Obtained as a pale yellow solid from 2H-azirine 1a (1.28 g, 5 mmol) and 2-naphthol (2e) (1.44 g, 10 mmol) as described in the general procedure. The crude product was purified by crystallization from Et2O to afford title compound 10b. This product was identified only by 1H-NMR, since cleavage of C3–N bond in the three-membered ring of 10b promptly occurs to give a mixture of aziridine 10b and allyl α-aminophosphine oxide 11b. 1H-NMR (300 MHz, CDCl3) δ 7.92–6.83 (m, 17H, ArH), 2.77 (d, 2JPH = 20.0 Hz, 1H, CH-P), 2.23 (bs, 1H, NH), 2.02 (s, 3H, CH3) ppm.
Molecules 25 03332 i026

General Procedure for the Preparation of Allylic α-Aminophosphine Oxides 11

A solution of aziridine 10 (5 mmol, 1 eq) was stirred in refluxing CHCl3 (11mL) for 8 h until TLC showed the disappearance of aziridine 10. The crude product was concentrated to dryness in vacuum to afford the title compound 11.
(1-Amino-2-phenoxyallyl)diphenylphosphine oxide (11a), (1.62 g, 93%) obtained as an orange oil from aziridine 10a (1.75 g, 5 mmol) as described in the general procedure. IR (neat) vmax 3389, 3060, 2933, 2860, 1638, 1587, 1489, 1442, 1264, 1220, 1182, 1122, 910, 742 cm−1; 1H-NMR (300 MHz, CDCl3) δ 7.91–6.55 (m, 15H, ArH), 4.36 (t, J = 2.8 Hz, 1H, = CH2), 4.30 (d, 2JPH = 8.6 Hz, 1H, CH-P), 3.94 (t, J = 2.3 Hz, 1H, = CH2), 2.21 (bs, 2H, NH2) ppm; 13C {1H}-NMR (75 MHz, CDCl3) δ 159.8 (d, 2JPC = 2.6 Hz, = Cquat), 153.8 (OCAr), 131.5, 131.5, 131.4, 131.4, 131.3, 131.2, 130.3, 130.0, 129.1, 128.2, 128.0, 128.0, 127.8, 124.1, 120.5, 116.2, 115.4 (CAr), 90.5 (d, 3JPC = 6.6 Hz, = CH2), 55.1 (d, 1JPC = 73.1 Hz, CH-P) ppm; 31P-NMR (120 MHz, CDCl3) δ 30.2 ppm; ESI-HRMS (CI) m/z calcd. for C21H20NNaO2P ([M + Na]+) 372.1129, found 372.1134.
Molecules 25 03332 i027
[1-Amino-2-(naphyhalen-2-yloxy)allyl]diphenylphosphine oxide (11b), (1.48 g, 74%) obtained as an orange oil from aziridine 10b (2.00 gr, 5mmol) as described in the general procedure. IR (neat) vmax 3382, 3069, 2923, 1635, 1597, 1508, 1438, 1249, 1211, 1179, 1125, 907, 745, 698 cm−1; 1H-NMR (300 MHz, CDCl3) δ 8.04–6.53 (m, 17H, ArH), 4.55 (t, J = 2.9 Hz, 1H, = CH2), 4.46 (d, 2JPH = 8.4 Hz, 1H, CH-P), 4.14 (t, J = 2.5 Hz, 1H, = CH2), 2.11 (bs, 2H, NH2) ppm; 13C {1H}-NMR (75 MHz, CDCl3) δ 160.0 (d, 2JPC = 2.6 Hz, = Cquat), 151.7 (OCAr), 133.9, 131.9, 131.8, 131.7, 131.6, 130.6, 129.4, 128.5, 128.4, 128.3, 128.2, 127.5, 127.1, 126.2, 125.1, 120.9, 117.1, 111.6, 109.4 (CAr), 91.5 (d, 3JPC = 6.6 Hz, = CH2), 55.5 (d, 1JPC = 72.3 Hz, CH-P) ppm; 31P-NMR (120 MHz, CDCl3) δ 30.5 ppm; ESI-HRMS (CI) m/z calcd. for C25H22NNaO2P ([M + Na]+) 422.1286, found 422.1291.
Molecules 25 03332 i028

One Pot Procedure for the Synthesis of N-Tosyl Allyl Amines 12 Derived From Phosphonate

To a 0 °C solution of 2H-azirine 1e (0.96 g, 5 mmol) in CH2Cl2 (25 mL), the corresponding alcohol (2de) (10 mmol, 2 eq) and Et3N (1.4 mL, 10 mmol, 2 eq) was added dropwise. The reaction mixture was allowed to reach 25 °C and stirred for 24 h until TLC showed the disappearance of starting 2H-azirine 1e. The reaction mixture was washed with water (3 × 15 mL) and extracted with CH2Cl2. The organic layer was dried over anhydrous MgSO4, filtered and concentrated to dryness in vacuum. Without any further purification step, to a 0 °C solution of crude products 11 in CH2Cl2 (25 mL) was directly added p-toluenesulfonyl chloride (1 g, 5.5 mmol, 1.1 eq) and pyridine (2.42 mL, 30 mmol, 6 eq). The reaction mixture was allowed to reach 25 °C and stirred for 24 h. The crude product was washed twice with a 2M HCl solution (15 mL) and water (15 mL) and extracted with CH2Cl2 (15 mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated to dryness in vacuum. The crude products 12 were purified by crystallization from Et2O.
Diethyl [1-((4-methylphenyl)sulfonamido)-2-phenoxyallyl]phosphonate (12a), (1.93 g, 88%) obtained as a white solid from phenol (2d) (0.88 g, 10 mmol) following the general procedure described above. mp 117–119 °C; IR (neat) vmax 3270, 3123, 2984, 2934, 2915, 2881, 1643, 1593, 1494, 1452, 1391, 1344, 1241, 1091, 1044, 1013, 972 cm−1; 1H-NMR (400 MHz, CDCl3) δ 7.79 (d, 3JHH = 8.3 Hz, 2H, ArH), 7.25–7.04 (m, 5H, ArH), 6.61 (d, 3JHH = 8.5 Hz, 2H, ArH), 6.09 (dd, 3JHH = 10.1 Hz, 3JPH = 3.1 Hz, 1H, NH), 4.44 (dd, 3JHH = 10.1 Hz, 2JPH = 23.9 Hz, 1H, CH-P), 4.31 (t, J = 3.2 Hz, 1H, = CH2), 4.24–4.09 (m, 4H, OCH2), 3.83 (t, J = 2.5 Hz, 1H, = CH2), 2.40 (s, 3H, CH3), 1.29 (q, 3JHH = 7.0 Hz, 3H, CH3), 1.28 (q, 3JHH = 7.0 Hz, 3H, CH3) ppm; 13C {1H}-NMR (100 MHz, CDCl3) δ 155.1 (d, 2JPC = 2.7 Hz, = Cquat), 154.0 (OCAr), 143.4 (CquatAr), 137.9 (d, 4JPC = 1.6 Hz, CquatAr), 129.4, 129.4, 127.5, 124.7, 121.0 (CAr), 91.6 (d, 3JPC = 8.8 Hz, = CH2), 63.8 (d, 2JPC = 6.7 Hz, OCH2), 63.7 (d, 2JPC = 6.9 Hz, OCH2), 54.1 (d, 1JPC = 157.4 Hz, CH-P), 21.4 (CH3), 16.3 (d, 3JPC = 6.1 Hz, CH3), 16.3 (d, 3JPC = 6.2 Hz, CH3) ppm; 31P-NMR (120 MHz, CDCl3) δ 18.0 ppm; ESI-HRMS (CI) m/z calcd. for C20H26NO6PS ([M + H]+) 440.1297, found 440.1304.
Molecules 25 03332 i029
Diethyl [1-((4-methylphenyl)sulfonamido)-2-(naphthalen-2-yloxy)allyl]-phosphonate (12b), (1.64 g, 67%) obtained as a grey solid from 2-naphthol (2e) (1.44 g, 10 mmol) following the general procedure described above. mp 147–149 °C; IR (neat) vmax 3425, 3065, 2981, 2926, 1599, 1380, 1191, 1177, 816, 714, 664 cm−1; 1H-NMR (300 MHz, CDCl3) δ 7.87 (d, 3JHH = 8.1 Hz, 2H, ArH), 7.81–7.39 (m, 5H, ArH), 7.31 (d, 3JHH = 8.2 Hz, 2H, ArH), 7.07 (d, J = 1.8 Hz, 1H, ArH), 6.85 (dd, J = 2.2 Hz, J = 8.9 Hz, 1H, ArH), 6.17 (dd, 3JHH = 10.0 Hz, 3JPH = 3.3 Hz, 1H, NH), 4.54 (dd, 3JHH = 10.1 Hz, 2JPH = 23.8 Hz, 1H, CH-P), 4.41 (t, J = 3.1 Hz, 1H, = CH2), 4.33–4.16 (m, 4H, OCH2), 3.93 (t, J = 2.6 Hz, 1H, = CH2), 2.46 (s, 3H, CH3), 1.35 (q, 3JHH = 7.2 Hz, 6H, CH3) ppm; 13C {1H}-NMR (75 MHz, CDCl3) δ 155.1 (d, 2JPC = 2.9 Hz, = Cquat), 151.5 (OCAr), 143.5 (CquatAr), 138.0 (CquatAr), 133.9 (CquatAr), 130.9 (CquatAr), 129.5, 129.4, 127.7, 127.6, 127.2, 126.4, 125.3, 120.9, 117.6 (CAr), 92.1 (d, 3JPC = 9.1 Hz, = CH2), 63.9 (d, 2JPC = 6.7 Hz, OCH2), 63.8 (d, 2JPC = 7.1 Hz, OCH2), 54.2 (d, 1JPC = 157.5 Hz, CH-P), 21.5 (CH3), 16.4 (d, 3JPC = 5.6 Hz, CH3) ppm; 31P-NMR (120 MHz, CDCl3) δ 18.1 ppm; ESI-HRMS (CI) m/z calcd. for C24H29NO6PS ([M + H]+) 490.1453, found 490.1469.
Molecules 25 03332 i030

3.1.5. Experimental Procedure and Characterization Data for Compounds 14, 15 and 16

General Procedure and Spectral Data for the Addition of Thiophenols and Thiols to 2H-Azirines 1

Method A: To a 0 °C solution of 2H-azirine 1 (5 mmol, 1 eq) in CH2Cl2 (25 mL) was added dropwise thiophenol or thiol (5.5 mmol, 1.1 eq), Et3N (1.40 mL, 10 mmol, 2 eq), and 4 Å M.S. The reaction mixture was allowed to reach 25 °C and stirred at the same temperature for 24 h. 4 Å M.S. was then filtered through a sintered glass vacuum filtration funnel with celite and washed with CH2Cl2. The reaction mixture was washed with water (3 × 15 mL) and extracted with CH2Cl2 (15 mL). The organic layers were dried over anhydrous MgSO4, filtered and concentrated to dryness in vacuum to give aziridine 14. In the case of R1 = Me, aziridines 14, allylic α-aminophosphine oxides or phosphonates 15, or a mixture of both compounds can be obtained. When aziridines 14 or the mixture is obtained in the reaction crude, stirring of this crude in refluxing CHCl3 afford allylic α-aminophosphine oxides or phosphonates 15. The crude products 14 or 15 were purified by crystallization or by flash-column chromatography.
Method B: To a 0 °C solution of 2H-azirine 1 (5 mmol, 1 eq) in CH2Cl2 (25 mL) was added dropwise the corresponding p-substituted benzenethiol (5.5 mmol, 1.1 eq). The reaction mixture was stirred at 0 °C for 48 h until TLC showed the disappearance of starting compound 1. The reaction mixture was concentrated to dryness in vacuum to afford allylic α-aminophosphine oxides or phosphonates 15.
[(2S*,3S*)-3-Methyl-3-(phenylthio)aziridin-2-yl]diphenylphosphine oxide (14a), (1.68 g, 92%) as a white solid from 2H-azirine 1a (1.28 g, 5 mmol) and benzenethiol (13a) (0.56 mL, 5.5 mmol) as described in the general procedure (method A). The crude product was purified by crystallization from Et2O to afford the title compound 14a. This product was identified only by 1H- and 31P-NMR, since cleavage of C3–N bond in three-membered ring of 14a promptly occurs to give allylic α-aminophosphine oxide 15a. 1H-NMR (400 MHz, CDCl3) δ 7.68–7.21 (m, 15H, ArH), 2.60 (dd, 3JHH = 8.4 Hz, 2JPH = 23.2 Hz, 1H, CH-P), 1.95 (dd, 3JHH = 8.8 Hz, 3JPH = 15.0 Hz, 1H, NH), 1.76 (s, 3H, CH3) ppm; 31P-NMR (120 MHz, CDCl3) δ 26.8 ppm.
Molecules 25 03332 i031
Diphenyl [(2S*,3S*)-3-methyl-3-(p-tolylthio)aziridin-2-yl]phosphine oxide (14b), From 2H-azirine 1a (1.28 g, 5 mmol) and 4-methylbenzenethiol (13b) (0.68 g, 5.5 mmol) as described in the general procedure (method B). This product was identified only by 1H and 31P-NMR in a mixture of aziridine 14b and allylic α-aminophosphine oxide 15b, since cleavage of C3–N bond in three-membered ring of 14b promptly occurs to give allylic α-aminophosphine oxide 15b. 1H-NMR (300 MHz, CDCl3) δ 8.08–7.43 (m, 28H, ArH)mixture, 2.78 (d, 2JPH = 23.4 Hz, 1H, CH-P), 2.48 (s, 3H, CH3), 1.90 (s, 3H, CH3) ppm; 31P-NMR (120 MHz, CDCl3) δ 26.8 ppm.
Molecules 25 03332 i032
Diphenyl [(2S*,3S*)-3-phenyl-3-(phenylthio)aziridin-2-yl]phosphine oxide (14c), (1.29 g, 60%) as a white solid from 2H-azirine 1c (1.59 g, 5 mmol) and benzenethiol (13a) (0.56 mL, 5.5 mmol) as described in the general procedure (method A). The crude product was purified by crystallization from Et2O/CH2Cl2 50:50 to afford the title compound 14c, whose data are in agreement with those reported previously [43].
Molecules 25 03332 i033
[1-Amino-2-(phenylthio)allyl]diphenylphosphine oxide (15a), Following the general procedure described above (method A), aziridine intermediate 14a was stirred in refluxing CHCl3 (11mL) for 8 h. The crude product was concentrated to dryness in vacuum to afford the title compound 15a, whose data are in agreement with those reported previously [43].
Molecules 25 03332 i034
[1-Amino-2-(p-tolylthio)allyl]diphenylphosphine oxide (15b), (1.69 g, 89%) as a yellow oil from 2H-azirine 1a (1.28 g, 5 mmol) and 4-methylbenzenethiol (13b) (0.68 g, 5.5 mmol) as described in the general procedure (method B). IR (neat) vmax 3389, 3060, 3022, 2987, 2930, 1676, 1635, 1590, 1489, 1442, 1242, 1185, 1119, 1106, 910, 729, 694 cm−1; 1H-NMR (400 MHz, CDCl3) δ 7.96–7.06 (m, 14H, ArH), 5.56 (d, 2JHH = 3.3 Hz, 1H, = CH2), 4.88 (d, 2JHH = 3.2 Hz, 1H, = CH2), 4.13 (d, 2JPH = 6.0 Hz, 1H, CH-P), 2.29 (s, 3H, CH3), 2.21 (bs, 2H, NH2) ppm; 13C {1H}-NMR (100 MHz, CDCl3) δ 144.2 ( = Cquat), 138.4, 133.6, 131.8, 131.6, 131.5, 131.5, 131.4, 129.9, 129.6, 128.5, 128.4, 128.1, 127.9 (CAr), 115.1 (d, 3JPC = 6.6 Hz, = CH2), 55.8 (d, 1JPC = 72.8 Hz, CH-P), 21.0 (CH3) ppm; 31P-NMR (120 MHz, CDCl3) δ 30.9 ppm; ESI-HRMS (CI) m/z calcd. for C22H23NOPS ([M + H]+) 380.1238, found 380.1225.
Molecules 25 03332 i035
[1-Amino-2-((4-fluorophenyl)thio)allyl]diphenylphosphine oxide (15c), (1.46 g, 76%) as an orange oil from 2H-azirine 1a (1.28 g, 5 mmol) and 4-fluorobenzenethiol (13c) (0.59 mL, 5.5 mmol) as described in the general procedure (method B). Rf = 0.15 (AcOEt); IR (neat) vmax 3381, 3301, 3065, 2914, 1593, 1495, 1437, 1226, 1185, 1157, 1122, 834, 726, 694 cm−1; 1H-NMR (300 MHz, CDCl3) δ 7.86–6.86 (m, 14H, ArH), 5.50 (d, 2JHH = 3.3 Hz, 1H, = CH2), 4.76 (d, 2JHH = 3.1 Hz, 1H, = CH2), 4.11 (d, 2JPH = 6.3 Hz, 1H, CH-P), 2.13 (bs, 2H, NH2) ppm; 13C {1H}-NMR (75 MHz, CDCl3) δ 164.2 (CAr-F), 160.9 (Cquat), 144.1 ( = Cquat), 135.7, 135.6, 131.8, 131.7, 131.7, 131.6, 131.6, 131.5, 131.4, 131.4, 131.3, 130.2, 128.4, 128.3, 128.0, 127.9, 126.8, 126.7 (CAr), 116.4, 116.1, 115.0 (d, 3JPC = 6.8 Hz, = CH2), 55.9 (d, 1JPC = 72.5 Hz, CH-P) ppm; 31P-NMR (120 MHz, CDCl3) δ 30.6 ppm; 19F NMR (282 MHz, CDCl3) δ –112.6 ppm; ESI-HRMS (CI) m/z calcd. for C21H20FNOPS ([M + H]+) 384.0987, found 384.0988.
Molecules 25 03332 i036
[1-Amino-2-((4-methoxyphenyl)thio)allyl]diphenylphosphine oxide (15d), (1.37 g, 70%) as a yellow oil from 2H-azirine 1a (1.28 g, 5 mmol) and 4-methoxy-benzenethiol (13d) (0.77 g, 5.5 mmol) as described in the general procedure (method B). IR (neat) vmax 3381, 3053, 2965, 2940, 2837, 1596, 1574, 1491, 1463, 1438, 1288, 1247, 1180, 1113, 1102, 1030, 830, 725, 694 cm−1; 1H-NMR (400 MHz, CDCl3) δ 7.90–7.34 (m, 10H, ArH), 7.09 (d, 3JHH = 8.9 Hz, 2H, ArH), 6.79 (d, 3JHH = 8.8 Hz, 2H, ArH), 5.48 (d, 2JHH = 3.3 Hz, 1H, = CH2), 4.71 (d, 2JHH = 2.9 Hz, 1H, = CH2), 4.11 (d, 2JPH = 5.9 Hz, 1H, CH-P), 3.75 (s, 3H, OCH3), 1.95 (bs, 2H, NH2) ppm; 13C {1H}-NMR (100 MHz, CDCl3) δ 160.1 (CAr-O), 145.3 ( = Cquat), 136.0, 132.6, 131.9, 131.9, 131.7, 131.7, 131.6, 131.6, 131.5, 128.6, 128.5, 128.1, 128.0, 121.7, 114.8 (CAr), 113.3 (d, 3JPC = 6.7 Hz, = CH2), 55.8 (d, 1JPC = 72.8 Hz, CH-P), 55.3 (OCH3)ppm; 31P-NMR (120 MHz, CDCl3) δ 30.9 ppm; ESI-HRMS (CI) m/z calcd. for C22H23NO2PS ([M + H]+) 396.1187, found 396.1183.
Molecules 25 03332 i037
Diethyl [1-amino-2-(phenylthio)allyl]phosphonate (15e), (0.62 g, 41%) as a yellow oil from 2H-azirine 1e (0.96 g, 5 mmol) and benzenethiol (13a) (0.56 mL, 5.5 mmol) as described in the general procedure (method B). The crude product was purified by flash-column chromatography (SiO2, AcOEt) to afford the title compound 15e, whose data are in agreement with those reported previously [43].
Molecules 25 03332 i038
[1-Amino-2-(ethylthio)allyl]diphenylphosphine oxide (15f), (1.02 g, 64%) as a pale yellow oil from 2H-azirine 1a (1.28 g, 5 mmol) and ethanethiol (13e) (0.40 mL, 5.5 mmol) as described in the general procedure (method A). The crude product was purified by flash-column chromatography (SiO2, AcOEt/methanol 95:5) to afford the title compound 15f. IR (neat) vmax 3414, 3060, 2977, 1682, 1631, 1590, 1435, 1246, 1188, 1122, 739, 698 cm−1; 1H-NMR (300 MHz, CDCl3) δ 7.91–7.383 (m, 10H, ArH), 5.46 (d, 2JHH = 3.3 Hz, 1H, = CH2), 4.84 (d, 2JHH = 2.4 Hz, 1H, = CH2), 4.07 (d, 2JPH = 6.1 Hz, 1H, CH-P), 2.57 (q, 3JHH = 7.4 Hz, 2H, CH2), 2.26 (bs, 2H, NH2), 1.09 (q, 3JHH = 7.4 Hz, 3H, CH3) ppm; 13C {1H}-NMR (75 MHz, CDCl3) δ 143.5 ( = Cquat), 131.8, 131.7, 131.6, 131.6, 131.5, 131.5, 128.6, 128.5, 128.4, 128.3, 128.2, 128.1, 127.9, 127.8 (CAr), 109.7 (d, 3JPC = 7.2 Hz, = CH2), 57.3 (d, 1JPC = 73.2 Hz, CH-P), 25.8 (CH2), 12.7 (CH3) ppm; 31P-NMR (120 MHz, CDCl3) δ 30.9 ppm; ESI-HRMS (CI) m/z calcd. for C17H21NOPS ([M + H]+) 318.1081, found 318.1071.
Molecules 25 03332 i039

General Procedure and Spectral Data for the N-Tosyl Functionalization of Allylic α-Amino-phosphine Oxides and Phosphonates 15

p-Toluenesulfonyl chloride (1 g, 5.5 mmol, 1.1 eq) and pyridine (2.4 mL, 30 mmol, 6 eq) were added to a 0 °C solution of derivative 15 (5 mmol, 1 eq) in CH2Cl2 (25 mL). The reaction mixture was allowed to reach 25 °C and stirred for 24 h. The crude product was washed twice with a 2M HCl solution (15 mL) and water (15 mL) and extracted with CH2Cl2 (15 mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated to dryness in vacuum. The crude product was purified by crystallization or by flash-column chromatography to afford N-tosyl allylic α-aminophosphine oxides and phosphonates 16.
N-[1-(Diphenylphosphoryl)-2-(phenylthio)allyl]-4-methylbenzenesulfonamide (16a), (2.26 g, 87%) obtained as a white solid from allylic α-aminophosphine oxide 15a (1.83 g, 5 mmol) as described in the general procedure. The crude product was purified by flash-column chromatography (SiO2, EtOAc/hexane 10:20) to afford the title compound 16a. mp 199–201 °C; IR (neat) vmax 3431, 3356, 3062, 2920, 2876, 2743, 1602, 1460, 1438, 1335, 1191, 1163, 1122, 1094, 1066, 911, 730 cm−1; 1H-NMR (400 MHz, CDCl3) δ 7.93–7.10 (m, 17H, ArH), 6.72 (d, 3JHH = 6.9 Hz, 2H, ArH), 5.54 (d, 2JHH = 2.5 Hz, 1H, = CH2), 4.83 (t, 2JPH = 10.1 Hz, 1H, CH-P), 4.33 (d, 2JHH = 2.7 Hz, 1H, = CH2), 2.37 (s, 3H, CH3) ppm; 13C {1H}-NMR (100 MHz, CDCl3) δ 142.7 ( = Cquat), 139.4, 138.5, 134.4, 132.2, 132.1, 131.5, 131.4, 130.5, 129.1, 129.0, 128.7, 128.7, 128.6, 128.2, 128.1, 127.7 (CAr), 115.2 (d, 3JPC = 6.6 Hz, = CH2), 56.4 (d, 1JPC = 74.1 Hz, CH-P), 21.5 (CH3) ppm; 31P-NMR (120 MHz, CDCl3) δ 30.8 ppm; ESI-HRMS (CI) m/z calcd. for C28H27NO3PS2 ([M + H]+) 520.1170, found 520.1174.
Molecules 25 03332 i040
N-[1-(Diphenylphosphoryl)-2-(p-tolylthio)allyl]-4-methylbenzene-sulfonamide (16b), (2.24 g, 84%) obtained as an orange solid from allylic α-aminophosphine oxide 15b (1.90 g, 5 mmol) as described in the general procedure. The crude product was purified by crystallization from Et2O/CH2Cl2 50:50 to afford the title compound 16b. mp 180–182 °C; IR (neat) vmax 3428, 3059, 2926, 2870, 1599, 1438, 1333, 1191, 1160, 911, 739 cm−1; 1H-NMR (400 MHz, CDCl3) δ 7.86–7.41 (m, 12H, ArH), 7.13 (d, 3JHH = 8.5 Hz, 2H, ArH), 6.99 (d, 3JHH = 7.8 Hz, 2H, ArH), 6.60 (d, 3JPH = 8.0 Hz, 2H, ArH), 5.37 (d, 2JHH = 2.7 Hz, 1H, = CH2), 4.82 (t, 2JPH = 10.0 Hz, 1H, CH-P), 4.26 (d, 2JHH = 2.5 Hz, 1H, = CH2), 2.38 (s, 3H, CH3), 2.28 (s, 3H, CH3) ppm; 13C {1H}-NMR (75 MHz, CDCl3) δ 142.9 ( = Cquat), 140.3 (CquatAr), 139.0 (CquatAr), 138.1 (CquatAr), 134.6, 132.3, 132.2, 132.2, 132.1, 131.5, 131.4, 129.9, 129.1, 128.8, 128.6, 128.2, 128.0, 127.7, 126.6 (CAr), 114.0 (d, 3JPC = 7.0 Hz, = CH2), 56.4 (d, 1JPC = 73.8 Hz, CH-P), 21.5 (CH3), 21.2 (CH3) ppm; 31P-NMR (120 MHz, CDCl3) δ 31.2 ppm; ESI-HRMS (CI) m/z calcd. for C29H29NO3PS2 ([M + H]+) 534.1326, found 534.1329.
Molecules 25 03332 i041
Diethyl [1-((4-methylphenyl)sulfonamido)-2-(phenylthio)allyl]phosphonate (16c), (1.93 g, 85%) obtained as a pale yellow solid from allylic α-aminophosphonate 15e (1.51 g, 5 mmol) as described in the general procedure. The crude product was purified by flash-column chromatography (SiO2, AcOEt/hexane 17:83) to afford the title compound 16c. mp 99–101 °C; IR (neat) vmax 3126, 2990, 2927, 1600, 1480, 1438, 1337, 1242, 1166, 1055, 1027, 910, 726 cm−1; 1H-NMR (300 MHz, CDCl3) δ 7.75 (d, 3JHH = 8.2 Hz, 2H, ArH), 7.29–7.11 (m, 7H, ArH), 6.82 (dd, 3JPH = 4.4 Hz, 3JHH = 9.8 Hz, 1H, NH), 5.45 (d, 2JHH = 3.9 Hz, 1H, = CH2), 4.65 (d, 2JHH = 3.7 Hz, 1H, = CH2), 4.36 (dd, 3JHH = 9.9 Hz, 2JPH = 24.4 Hz, 1H, CH-P), 4.25–4.08 (m, 4H, OCH2), 2.41 (s, 3H, CH3), 1.31 (q, 3JHH = 7.0 Hz, 6H, CH3) ppm; 13C {1H}-NMR (75 MHz, CDCl3) δ 143.1 ( = Cquat), 139.8 (CquatAr), 138.1 (CquatAr), 134.1, 131.0, 129.2, 129.1, 128.6, 127.5 (CAr), 115.4 (d, 3JPC = 9.1 Hz, = CH2), 64.1 (d, 2JPC = 7.0 Hz, OCH2), 63.8 (d, 2JPC = 7.0 Hz, OCH2), 55.0 (d, 1JPC = 157.6 Hz, CH-P), 21.4 (CH3), 16.6 (d, 3JPC = 5.8 Hz, CH3) ppm; 31P-NMR (120 MHz, CDCl3) δ 18.4 ppm; ESI-HRMS (CI) m/z calcd. for C20H27NO5PS2 ([M + H]+) 456.1068, found 456.1071.
Molecules 25 03332 i042

One pot procedure for the synthesis of N-tosyl allylic α-aminophosphonates 16d–e

To a 0 °C solution of 2H-azirine 1e (0.96 g, 5 mmol) in CH2Cl2 (25 mL) was added dropwise the corresponding p-substituted benzenethiol (5.5 mmol, 1.1 eq). The reaction mixture was stirred at 0 °C for 48 h until TLC showed the disappearance of starting compound 1e. The reaction mixture was concentrated to dryness in vacuum to afford derivatives 15. Without any further purification step, to a 0 °C solution of crude products 15 in CH2Cl2 (25 mL) was directly added p-toluenesulfonyl chloride (1 g, 5.5 mmol, 1.1 eq) and pyridine (2.42 mL, 30 mmol, 6 eq). The reaction mixture was allowed to reach 25 °C and stirred for 24 h. The crude product was washed twice with a 2M HCl solution (15 mL) and water (15 mL) and extracted with CH2Cl2 (15 mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated to dryness in vacuum. The crude products 16de were purified by flash-column chromatography.
Diethyl [2-((4-fluorophenyl)thio)-1-((4-methylphenyl)sulfonamido)-allyl]-phosphonate (16d), (2.01 g, 85%) obtained as a pale yellow solid from 2H-azirine 1e (0.96 g, 5 mmol) and 4-fluorobenzenethiol (13c) (0.59 mL, 5.5 mmol) in a one pot reaction as described in the general procedure. The crude product was purified by flash-column chromatography (SiO2, EtOAc/hexane 10:30) to afford the title compound 16d. mp 117–119 °C; IR (neat) vmax 3370, 3161, 2984, 2927, 1594, 1492, 1239, 1166, 1052, 1030, 907, 739 cm−1; 1H-NMR (300 MHz, CDCl3) δ 8.02 (d, 3JHH = 8.0 Hz, 2H, ArH), 7.54–7.21 (m, 4H, ArH), 7.52 (d, 3JHH = 8.1 Hz, 2H, ArH), 6.99 (dd, 3JHH = 9.8 Hz, 3JPH = 4.5 Hz, 1H, NH), 5.70 (d, 2JHH = 4.3 Hz, 1H, = CH2), 4.87 (d, 2JHH = 3.6 Hz, 1H, = CH2), 4.62 (dd, 3JHH = 9.8 Hz, 2JPH = 24.4 Hz, 1H, CH-P), 4.53–4.31 (m, 4H, OCH2), 2.70 (s, 3H, CH3), 1.61–1.55 (m, 6H, CH3) ppm; 13C {1H}-NMR (75 MHz, CDCl3) δ 164.7 (CAr-F), 161.4 (Cquat), 143.2 ( = Cquat), 140.3, 138.1, 136.6, 136.5, 129.2, 127.5, 116.5, 116.3 (CAr), 115.0 (d, 3JPC = 9.1 Hz, = CH2), 64.2 (d, 2JPC = 7.0 Hz, OCH2), 63.8 (d, 2JPC = 7.0 Hz, OCH2), 54.9 (d, 1JPC = 157.5 Hz, CH-P), 21.4 (CH3), 16.4 (CH3), 16.3 (CH3) ppm; 31P-NMR (120 MHz, CDCl3) δ 18.3 ppm; 19F NMR (282 MHz, CDCl3) δ –112.1 ppm; ESI-HRMS (CI) m/z calcd. for C20H26FNO5PS2 ([M + H]+) 474.0974, found 474.0976.
Molecules 25 03332 i043
Diethyl [1-((4-methylphenyl)sulfonamido)-2-(p-tolylthio)allyl]phos-phonate (16e), (1.71 g, 73%) obtained as a pale yellow solid from 2H-azirine 1e (0.96 g, 5 mmol) and 4-methylbenzenethiol (13b) (0.68 g, 5.5 mmol) in a one pot reaction as described in the general procedure. The crude product was purified by flash-column chromatography (SiO2, EtOAc/hexane 10:20) to afford the title compound 16e. mp 168–170 °C; IR (neat) vmax 3128, 2979, 2934, 2867, 1596, 1491, 1446, 1341, 1247, 1149, 1011, 961, 905, 819 cm−1; 1H-NMR (300 MHz, CDCl3) δ 7.73 (d, 3JHH = 8.3 Hz, 2H, ArH), 7.31–6.98 (m, 6H, ArH), 6.34 (dd, 3JHH = 9.8 Hz, 3JPH = 4.5 Hz, 1H, NH), 5.32 (d, 2JHH = 4.1 Hz, 1H, = CH2), 4.55 (d, 2JHH = 2.7 Hz, 1H, = CH2), 4.35 (dd, 3JHH = 9.9 Hz, 2JPH = 24.2 Hz, 1H, CH-P), 4.24–4.03 (m, 4H, OCH2), 2.41 (s, 3H, CH3), 2.31 (s, 3H, CH3), 1.30 (t, 3JHH = 7.0 Hz, 6H, CH3) ppm; 13C {1H}-NMR (75 MHz, CDCl3) δ 143.2 ( = Cquat), 140.6 (Cquat), 139.0 (Cquat), 138.0 (Cquat), 134.6, 130.0, 129.2, 127.6, 127.1 (Cquat) (CAr), 114.2 (d, 3JPC = 9.2 Hz, = CH2), 64.1 (d, 2JPC = 7.3 Hz, OCH2), 63.9 (d, 2JPC = 6.9 Hz, OCH2), 55.1 (d, 1JPC = 157.4 Hz, CH-P), 21.5 (CH3), 21.2 (CH3), 16.4 (CH3), 16.3 (CH3) ppm; 31P-NMR (120 MHz, CDCl3) δ 18.5 ppm; ESI-HRMS (CI) m/z calcd. for C21H29NO5PS2 ([M + H]+) 470.1225, found 470.1229.
Molecules 25 03332 i044

3.2. Biology

3.2.1. Materials

Reagents and solvents were used as purchased without further purification. All stock solutions of the investigated compounds were prepared by dissolving the powered materials in appropriate amounts of DMSO. The final concentration of DMSO never exceeded 5% (v/v) in reactions. The stock solution was stored at 5 °C until it was used.

3.2.2. Cytotoxicity Assays

Cells were cultured according to the supplier’s instructions. Cells were seeded in 96-well plates at a density of 2–4 × 103 cells per well and incubated overnight in 0.1 mL of media supplied with 10% Fetal Bovine Serum (Lonza) in 5% CO2 incubator at 37 °C. On day 2, compounds were added and samples were incubated for 48 h. After treatment, 10 μL of cell counting kit-8 was added into each well for additional 2 h incubation at 37 °C. The absorbance of each well was determined by an Automatic ELISA Reader System (Multiskan FC, Thermo Fisher Scientific, Waltham, MA, USA) at 450 nm wavelength.

4. Conclusions

To sum up, we have develop a very efficient new approach to α-aminophosphine oxide and phosphonate acetals 4, through the nucleophilic addition of methanol or ethanol to the carbon-nitrogen double bond of 2H-azirine and subsequent ring opening through the N–C3 bond. Conversely, addition of O-nucleophiles such as 2,2,2-trifluoroethanol or even phenols to phosphorylated 2H-azirines, gave to the regioselective formation of allylic α-aminophosphorus derivatives 8 and 11. Initially aziridine intermediate formation, following carbon-carbon double bond construction and ring opening by means of the N–C3 aziridine bond occurred to afford compounds 8 and 11. Under these reaction conditions, in some cases, aziridine intermediates 7 and 10 can be isolated and characterized. To the best of our acknowledge, this process exemplifies the first example of a regioselective nucleophilic addition of oxygen nucleophiles to the carbon-nitrogen double bond of a phosphorus substituted 2H-azirine with the formation of allylic α-aminophosphorus derivatives. Furthermore, N-functionalization of α-aminophosphine oxide and phosphonate acetals 4 or allylic α-aminophosphorus derivatives 8 and 11 were assessed by sulfonylation reaction.
As an extension of our previous results, we have broadened this process through the addition of sulfur nucleophiles to phosphorylated 2H-azirines, with the synthesis of novel sulfur-containing allylic α-aminophosphine oxides and phosphonates 15.
Oxygen and sulfur containing α-allylic phosphine oxides and phosphonates, here synthesized, might be regarded as new hybrid molecules introducing two potential pharmacophores, allylic amine and α-aminophosphonic acid moieties. These new hybrid molecules may retain the functional properties of the parent molecules. Moreover, the therapeutic efficiency of all the synthesized α-aminophosphorus derivatives and aziridines was evaluated against the human cancer cell line A549. The best cytotoxic effect was observed for α-aminophosphonate acetal 4f with an IC50 value of 1.3 ± 0.10 µM, allylic α-aminophosphine oxide 11a with a IC50 value of 1.9 ± 0.13 µM, as well as for 15c with an IC50 value of 0.1 ± 0.08 µM. Whereas, colon carcinoma cell line (RKO) is not so sensitive to some of the tested synthesized compounds. In addition, cytotoxic effect of almost all of our compounds in non-malignant lung fibroblasts (MRC-5) seems not to exhibit any effect.

Supplementary Materials

The following are available online, 1H- and 13C-NMR spectra of compounds 4–12, 1416.

Author Contributions

A.M.O.d.R, F.P., and J.M.d.l.S. conceived and designed the molecules and guided the experiments; V.C. performed synthesis and purification of all compounds; V.C. and J.M.d.l.S. performed structural characterization of synthesized compounds; V.C. and J.M.d.l.S. performed cell culture, determination of cell viability, and cytotoxicity assays; J.M.d.l.S. wrote and edited the original manuscript; A.M.O.d.R., F.P., and J.M.d.l.S. reviewed the manuscript; F.P. and J.M.d.l.S. worked in funding acquisition. All authors have read and agreed to the published version of the manuscript.

Funding

Financial support by the Ministerio de Ciencia, Innovación y Universidades (MCIU), Agencia Estatal de Investigación (AEI) y Fondo Europeo de Desarrollo Regional (FEDER) (RTI2018-101818-B-I00, UE), and Gobierno Vasco (GV), (IT 992-16) is gratefully acknowledged.

Acknowledgments

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

Conflicts of Interest

The authors declare no conflict of interest.

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Figure 1. Representative examples of drugs containing allylic amine or allylic α-aminophosphonic acid functionalities.
Figure 1. Representative examples of drugs containing allylic amine or allylic α-aminophosphonic acid functionalities.
Molecules 25 03332 g001
Scheme 1. Synthesis of α-aminophosphine oxides and phosphonates 46. All synthesized compounds are racemic.
Scheme 1. Synthesis of α-aminophosphine oxides and phosphonates 46. All synthesized compounds are racemic.
Molecules 25 03332 sch001
Scheme 2. Addition of 2,2,2-trifluoroethanol to 2H-azirine 1a. All synthesized compounds are racemic. Reagents and Conditions: (i) CF3CH2OH (2c, excess), Et3N, 4 Å M.S. or CF3CH2OH (2c, 2eq), Et3N, 4 Å M.S., CH2Cl2, 0 to 25 °C; (ii) CHCl3, Δ; (iii) TsCl, Py, CH2Cl2, 0 to 25 °C.
Scheme 2. Addition of 2,2,2-trifluoroethanol to 2H-azirine 1a. All synthesized compounds are racemic. Reagents and Conditions: (i) CF3CH2OH (2c, excess), Et3N, 4 Å M.S. or CF3CH2OH (2c, 2eq), Et3N, 4 Å M.S., CH2Cl2, 0 to 25 °C; (ii) CHCl3, Δ; (iii) TsCl, Py, CH2Cl2, 0 to 25 °C.
Molecules 25 03332 sch002
Scheme 3. Synthesis of aziridines 10, allyl α-aminophosphine oxides 11 and phosphonates 12.
Scheme 3. Synthesis of aziridines 10, allyl α-aminophosphine oxides 11 and phosphonates 12.
Molecules 25 03332 sch003
Scheme 4. Synthesis of azidines 14 and allylic α-aminophosphine oxides and phosphonates 15 and 16. All synthesized compounds are racemic. Reagents and Conditions: (i) Method A: R2SH (13), Et3N, 4 Å M.S., CH2Cl2, 0 °C to rt, Method B: R2SH (13), CH2Cl2, 0 °C, 48h; (ii) CHCl3, Δ; (iii) TsCl, Py, CH2Cl2, 0 °C. 13a: R2 = Ph; 13b: R2 = p-MeC6H4; 13c: R2 = p-FC6H4; 13d: R2 = p-MeOC6H4; 13e: R2 = Et.
Scheme 4. Synthesis of azidines 14 and allylic α-aminophosphine oxides and phosphonates 15 and 16. All synthesized compounds are racemic. Reagents and Conditions: (i) Method A: R2SH (13), Et3N, 4 Å M.S., CH2Cl2, 0 °C to rt, Method B: R2SH (13), CH2Cl2, 0 °C, 48h; (ii) CHCl3, Δ; (iii) TsCl, Py, CH2Cl2, 0 °C. 13a: R2 = Ph; 13b: R2 = p-MeC6H4; 13c: R2 = p-FC6H4; 13d: R2 = p-MeOC6H4; 13e: R2 = Et.
Molecules 25 03332 sch004
Table 1. α-Aminophosphine oxides and phosphonates 4, 5 and 6 obtained.
Table 1. α-Aminophosphine oxides and phosphonates 4, 5 and 6 obtained.
EntryCompoundRR1R2Yield (%) 1
14aPhMeMe74
24bPhEtMe92
34cPhPhMe81
44dPhMeEt56
54eOiPrMeMe69
64fOEtMeMe61
75aPhMeMe80
85bOiPrMeMe62
95cOEtMeMe64
105dOEtMeEt70 2
116OiPrMe68
1 Yield of isolated purified compounds 4, 5 and 6. 2 One pot reaction from 2H-azirine 1e.
Table 2. Aziridines 10 and allyl α-aminophosphine oxides and phosphonates 11 and 12 obtained.
Table 2. Aziridines 10 and allyl α-aminophosphine oxides and phosphonates 11 and 12 obtained.
EntryCompound 1RArYield (%) 2
110aPhPh70
210bPh2-Naph3
311aPhPh93
411bPh2-Naph74
512aOEtPh88 4
612bOEt2-Naph67 4
1 All synthesized compounds are racemic. 2 Yield of isolated purified compounds 10, 11, and 12. 3 Identified compound in the crude reaction mixture. 4 One pot reaction from 2H-azirine 1e.
Table 3. Aziridines 14 and allylic α-aminophosphine oxides and phosphonates 15 and 16 obtained.
Table 3. Aziridines 14 and allylic α-aminophosphine oxides and phosphonates 15 and 16 obtained.
EntryCompoundRR1R2Yield (%) 1
114aPhMePh92 2
214bPhMep-MeC6H43,4
314cPhPhPh60 2
415aPhPh91 2
515bPhp-MeC6H489 4
615cPhp-FC6H476 4
715dPhp-MeOC6H470 4
815eOEtPh41 4
915fPhEt64 2
1016aPhPh87
1116bPhp-MeC6H484
1216cOEtPh85
1316dOEtp-FC6H485 5
1416eOEtp-MeC6H473 5
1 Yield of isolated purified compounds 14, 15, and 16. 2 Using method A. 3 Identified compound in the crude reaction mixture. 4 Using method B. 5 One pot reaction from 2H-azirine 1e.
Table 4. Antiproliferative activity of synthesized compounds obtained from the addition of alcohols and phenols to 2H-azirines 1.
Table 4. Antiproliferative activity of synthesized compounds obtained from the addition of alcohols and phenols to 2H-azirines 1.
EntryComp.RR1R2Cytotoxicity IC50 (µM) 1
Lung A549MRC-5
1 Molecules 25 03332 i0010.48 ± 0.017 [50]>50 [51]
Molecules 25 03332 i002
2 24aPhMeMe4.4 ± 0.72>50
34bPhEtMe21.3 ± 0.22>50
44cPhPhMe16.1 ± 2.03>50
54dPhMeEt9.6 ± 1.13>50
64eOiPrMeMe4.6 ± 0.31>50
74fOEtMeMe1.3 ± 0.10>50
Molecules 25 03332 i003
85aPhMeMe8.2 ± 0.23>50
95bOiPrMeMe1.7 ± 0.30>50
105cOEtMeMe4.5 ± 0.45>50
115dOEtMeEt3.7 ± 0.49>50
Molecules 25 03332 i004
126OiPrMe>503
Molecules 25 03332 i005
137PhCH2CF33.6 ± 0.70>50
1410aPhPh13.3 ± 1.69>50
Molecules 25 03332 i006
158PhCH2CF3>50>50
16 211aPhPh1.9 ± 0.13>50
1711bPh2-Naph2.7 ± 0.4433.6 ± 3.73
Molecules 25 03332 i007
189PhCH2CF33.5 ± 0.77>50
1912aOEtPh4.8 ± 0.90>50
2012bOEt2-Naph2.1 ± 0.2217.5 ± 1.47
1 The cytotoxicity IC50 values listed are the concentrations corresponding to 50% growth inhibition. 2 The cytotoxicity value against human colon carcinoma cell line (RKO) is >50 µM. 3 Not determined.
Table 5. Antiproliferative activity of synthesized compounds obtained from the addition of thiophenols to 2H-azirines 1.
Table 5. Antiproliferative activity of synthesized compounds obtained from the addition of thiophenols to 2H-azirines 1.
EntryComp.RR1R2Cytotoxicity IC50 (µM) 1
Lung A549MRC-5
1DOX0.48 ± 0.017 [27]>50 [28]
Molecules 25 03332 i008
2 214cPhPhPh1.1 ± 0.324.9 ± 0.49
Molecules 25 03332 i009
3 315aPhPh2.6 ± 0.6815.9 ± 2.79
415bPhp-MeC6H45.1 ± 0.7714.9 ± 1.61
5 315cPhp-FC6H40.1 ± 0.08>50
615dPhp-MeOC6H42.6 ± 0.42>50
715eOEtPh7.2 ± 0.49>50
Molecules 25 03332 i010
816aPhPh1.2 ± 0.09>50
916bPhp-MeC6H42.1 ± 0.15>50
10 316cOEtPh0.2 ± 0.0724.1 ± 3.55
1116dOEtp-FC6H43.0 ± 0.98>50
1216eOEtp-MeC6H43.9 ± 0.63>50
1 The cytotoxicity IC50 values listed are the concentrations corresponding to 50% growth inhibition. 2 The cytotoxicity value against human colon carcinoma cell line (RKO) is 9.7 ± 1.4 µM. 3 The cytotoxicity value against human colon carcinoma cell line (RKO) is >50 µM.

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Carramiñana, V.; Ochoa de Retana, A.M.; Palacios, F.; de los Santos, J.M. Synthesis of α-Aminophosphonic Acid Derivatives Through the Addition of O- and S-Nucleophiles to 2H-Azirines and Their Antiproliferative Effect on A549 Human Lung Adenocarcinoma Cells. Molecules 2020, 25, 3332. https://doi.org/10.3390/molecules25153332

AMA Style

Carramiñana V, Ochoa de Retana AM, Palacios F, de los Santos JM. Synthesis of α-Aminophosphonic Acid Derivatives Through the Addition of O- and S-Nucleophiles to 2H-Azirines and Their Antiproliferative Effect on A549 Human Lung Adenocarcinoma Cells. Molecules. 2020; 25(15):3332. https://doi.org/10.3390/molecules25153332

Chicago/Turabian Style

Carramiñana, Victor, Ana M. Ochoa de Retana, Francisco Palacios, and Jesús M. de los Santos. 2020. "Synthesis of α-Aminophosphonic Acid Derivatives Through the Addition of O- and S-Nucleophiles to 2H-Azirines and Their Antiproliferative Effect on A549 Human Lung Adenocarcinoma Cells" Molecules 25, no. 15: 3332. https://doi.org/10.3390/molecules25153332

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