3-((λ³-Oxidanylidene)(propylamino)methyl)-2-ethoxybenzo[e]-[1,2]oxaphosphinine-2-oxide

Abstract

A method for the simple preparation of 2-ethoxy-N-propylbenzo[e][1,2]oxaphosphinine-3-carboxamide 2-oxide via an ultrasound technique using catalytic amounts of CuI is reported. The formation of the amide could indicate the isomerization of the formed E-alkene intermediate to its Z-form, assisted by the sonication irradiation, and such transformation under the presented conditions has not been previously reported in the literature.

1. Introduction

Phosphorus compounds like the naturally occurring carboxylic acid derivatives and coumarin derivatives 3, presented in Scheme 1, are subjects of prolonged research interest, and they have garnered great attention in the fields of pharmacology, synthetic organic chemistry, and agriculture. The reason why considerable attention has been given to these compounds is related to their application as important synthetic precursors with reliable biological properties. The presence of pharmacophore moieties in their structures indicates that they have anti-inflammatory, anticonvulsant, anti-arthritic, and anti-cancer activity [1,2,3,4,5,6,7,8,9,10].

The formation of alkyl 1,2-benzoxaphosphorin-3-carboxylates 3b where the α-pyronyl carbon atom was replaced with a P-atom was reported for the first time by Chen et al. [11] Later on, more representatives were published based on the application of various CH-acidic components under Knoevenagel reaction conditions [12,13]. A comprehensive study on the possible mechanism of the reaction with different CH-acids and the regioselectivity during catalyst application was also conducted [12]. Perkin, Pechmann, and Knoevenagel condensations with hydroxy-substituted phenols or benzaldehydes proceeded with intermolecular pre-esterification on the presented functional groups. Reactions with triethylphosphonoacetate 2, as a CH-component, facilitate the formation of alkene intermediates with E- and Z-configurations, as illustrated in Scheme 2. The pre-esterification step, in this case, resulted in ring closure for the 3-diethylphosphonocoumarines 3a or 1,2-benzoxaphosphorines 3b. The preferred E-configuration of the intermediate E-I-2 directed the predominant isolation of 3a over 3b.

Another example of a study demonstrating the importance of reagents in the formation of E- or Z-olefin as an intermediate during the synthesis of coumarins or 1,2-benzoxaphosphorines under Horner–Wadsworth–Emmons conditions using salicylaldehyde and phosphonoacetate in the presence of DBU as base and salts (NaI, LiCl, KI, MgBr₂) can be found in [14]. The 1,2-benzoxaphosphorine compound was isolated in a 61% yield.

2. Results

The conversion of 3-substituted phosphonocoumarins 3a to 1,2-benzoxaphosphorines 3b has not been observed until now. A reaction of coumarin 3a with excess n-propylamine (3 eqv.) was carried out in the presence of CuI under ultrasound irradiation (U.S.) in benzene media, see Scheme 3. Product 3-((λ³-oxidanylidene)(propylamino)methyl)-2-ethoxybenzo[e]-[1,2]oxaphosphinine-2-Oxide 4 was isolated in a yield of 41% after column chromatography purification. The structure of the amide of 1,2-benzoxaphosphorines has not been published in the literature until now. It is interesting to note that compound 4 has a garlic-like odor.

The characterization of compound 4 was achieved based on standard spectroscopic methods. IR, ¹H, ¹³C, ³¹P NMR, and HRMS spectra were obtained, but more data were obtained from 2D NMR spectra (COSY, {¹H,¹³C} HSQC, {¹H,¹³C} HMBC). The average chemical shift of 120.9 ppm for the nitrogen atom from the amide group was derived from a {¹H,¹⁵N} HMBC spectrum. The date could be seen in the Supplementary Materials.

The ¹H and ¹³C NMR spectra correlate with the structure of compound 4. In the ¹H NMR, the two spin systems were well assigned. The protons from the 1,2-benzoxaphosphorin part are characterized with high frequency for the H-4 proton at 8.268 ppm. The signal appeared as a doublet with ³J_HP = 36.1 Hz from the spin–spin coupling with phosphorus nucleus from the heterocyclic ring. The presence of NMR-active phosphorus spin influences the signal of the CH₂ group from POCH₂CH₃, appearing as a doublet of quartets. The second characteristic fragment is the n-propyl group with three signals at 3.388, 1.626, and 0.981 ppm for two CH₂ groups and one CH₃ group with expected multiplicity. The ¹³C NMR shows the expected 14 resonance signals. The carbon atoms close to the phosphorus nucleus appeared as doublets with characteristic spin–spin constants. For example, the directly attached C-3 atom is influenced with a constant of ¹J_CP = 162.3 Hz. In the ³¹P NMR, only one resonance characteristic of the 1,2-oxaphosphorin spin systems at 8.922 ppm could be seen.

All the correlations of the coupling signals for the protons from the two fragments of the molecule were mapped by applying the homonuclear decoupling (COSY) method. Heteronuclear correlation techniques, HSQC and HMBC, had clearly shown the cross-peaks for one H- bond C and two or multiple H bond -C connectivities within the characterized structure. The date could be seen in the Supplementary Materials.

3. Discussion

The described reaction—the ring opening of 3-diethylphosphonocoumarin 3a and the subsequent pre-esterification of the phosphonic group—was studied by using several amines (propan-2-amine, piperidine, aniline, propan-1-ol). The reaction was carried out in the presence of catalysts such as KOH, DBU, triethylamine, and I₂, where different salts, such as ZnCl₂ and CuI, were chosen without the same outcome as for the combination of primary amine with copper salt. The amines easily react with lactones in appropriate solvents [15,16]. Under the studied reaction conditions, CuI was useful for the suitable chelation of the forming functional groups with a predominant Z-configuration of the olefins I-3, which allowed us to isolate 1,2-oxaphosphorine 4. It is also clear that the formed amide group in the intermediate is not appropriate for further ring closure, and the next possible step is esterification by the phosphonic group. Such a ring closure is not frequently observable. Most probably, the energy from the sonication promotes the reaction, though this cannot be fully proven due to the absence of literature data on ring opening in nonpolar solvents. The reaction was carried out in solvent media comprising acetonitrile, ethanol, and chloroform without a tendency of ring rearrangement.

A synthetic path for the formation of compound 4 was proposed, as shown in Scheme 4. It included the nucleophilic attack of the lactone carbonyl atom by the used propylamine, meaning a 1,2-product could be formed; later, we could facilitate E → Z isomerization by the applied ultrasound irradiation energy, similar to isomerization described in the literature for cases when a photochemical approach for the synthesis of alkenes has been applied [17,18,19,20]. Several authors discuss the importance of Cu-salts as part of a photocatalytic system [21,22]; however, no data have been published for the combination ultrasound/CuI for isomerization of alkenes. The Z-isomer formed after lactonization could form the amide 4. The mechanism of the isomerization via sonication is still not clearly understood.

Classic protocols [23,24] for amide formation with or without using a catalyst (para-toluenesulphonic acid, p-TsOH) were applied to obtain compound 3b as an alternative procedure to obtaining product 4 in a better yield (n-propylamine, catalytic amount of p-TsOH, and reflux for 5 days). Unfortunately, the desired product was not formed, and the starting compound did not react under the classic conditions. Therefore, the only suitable synthetic protocol for obtaining 2-ethoxy-N-propylbenzo[e][1,2]oxaphosphinine-3-carboxamide-2-oxide 4 is by applying CuI by ultrasound-assisted domino reaction.

4. Materials and Methods

The IR spectra were recorded with a Specord IR 75 spectrophotometer. ¹H, ¹³C, and ³¹P NMR spectra were recorded on a Bruker Avance III 500 spectrometer (at 500 MHz for ¹H, 125.7 MHz for ¹³C, and 202.4 MHz for ³¹P, respectively). Chemical shifts are given in ppm from tetramethylsilane as an internal standard with CDCl₃ as the solvent. The chemical shifts in ³¹P NMR spectra were extracted from an external standard (85% H₃PO₄, and for ¹⁵N NMR, a reference amount of liquid ammonia was used). Liquid chromatography–mass spectrometry analysis (LC-HRAM) was carried out on a Q Exactive Plus^® hybrid quadrupole-Orbitrap^® mass spectrometer (ThermoScientific Co., Waltham, MA, USA) equipped with a HESI^® (heated electrospray ionization) module, a TurboFlow^® Ultra-High Performance Liquid Chromatography (UHPLC) system (ThermoScientific Co., USA), and an HTC PAL^® autosampler (CTC Analytics, Zwingen, Switzerland). The chromatographic separation of the analyzed compounds was achieved on an Accucore™ C18 (50 × 2.1 mm, 1.7 µm) analytical column (Thermo Fisher Scientific™, Dreieich, Germany) using gradient elution at a 300 µL/min flow rate. The used eluent systems were as follows: A—0.1% formic acid in water; B—0.1% formic acid in CH₃CN. Full-scan mass spectra over the m/z range 80–1200 were acquired in positive-ion mode at resolution settings of 70,000. The used mass spectrometer operating parameters were as follows: spray voltage—3.8 kV; capillary temperature—320 °C; probe heater temperature—350 °C; sheath gas flow rate 30 units; auxiliary gas flow 6 units; sweep gas 0 units (units refer to arbitrary values set by the Q Exactive Tune Software 2.11 QF1Build 3006); and S-Lens RF level of 50.00. Nitrogen was used for sample nebulization and as a collision gas in the HCD cell. Data acquisition and processing were carried out with the XCalibur^® version 2.4 software package (ThermoScientific Co., USA). Ultrasonic irradiation was performed in an ultrasonic cleaner with a frequency of 20 kHz and power of 250 W. The reactions were monitored by TLC on silica gel 60 F₂₅₄. Column chromatography was carried out on silica gel (Merck 0.063–0.200 mm) using, as an eluent, an n-hexane/EtOAc mixture with increasing polarity. The date could be seen in the Supplementary Materials.

All chemical reagents were purchased from Merck and Sigma Aldrich. The starting diethyl (2-oxo-2H-chromen-3-yl)phosphonate 3a was prepared according to a procedure previously reported by us [12].

4.1. General Procedure for the Preparation of 2-Ethoxy-N-propylbenzo[e][1,2]oxaphosphinine-3-carboxamide-2-oxide 4

A mixture of 3a (0.282 g, 0.001 mol) and CuI (0.0282 g, 10 wt%) was sonicated in benzene (4 mL) for 30 min. n-propylamine (0.246 mL, 0.003 mol) was added, and the sonication of the mixture continued until the coumarin 3a was consumed (TLC monitoring; 5 h). The reaction mixture was diluted with chloroform (20 mL) and filtered through Celite 545. After the evaporation of the solvent, the residue was purified by column chromatography using n-hexane/EtOAc as an eluent system with increasing polarity. The product had the following properties: 0.120 g, 41%, yellow oil, garlic-like odor.

4.2. 2-Ethoxy-N-propylbenzo[e][1,2]oxaphosphinine-3-carboxamide-2-oxide, 4

IR (nujol): ν = 3330, 1620, 1520, 1260, 1040, 1030 cm⁻¹.

¹H NMR (500 MHz, CDCl₃) δ = 8.268 (d, ³J_HP = 36.1 Hz, 1H, H-4), 7.588 (bs, 1H, CONH), 7.499 (dd, ³J_HH = 7.8 Hz, 1.4 Hz, 1H, H-5), 7.464 (m as tt, 1H, H-7), 7.245 (dd as t, ³J_HH = 7.5 Hz, 1H, H-6), 7.203 (d, ³J_HH = 8.2 Hz, 1H, H-8), 4.167 (dq, ³J_HP = 9.2 Hz, ³J_HH = 7.1 Hz, 2H, CH₃CH₂OP), 3.388 (dddd, 2H, NHCH₂CH₂CH₃), 1.626 (ddq, 2H, NHCH₂CH₂CH₃), 1.305 (t, ³J_HH = 7.1 Hz, 3H, CH₃CH₂OP), 0.981 (t, ³J_HH = 7.4 Hz, 3H, NHCH₂CH₂CH₃);

¹³C NMR (125.7 MHz, CDCl₃) δ = 162.11 (d, ²J_CP = 15.4 Hz, CONH), 152.08 (d, ²J_CP = 9.3 Hz, C-8a), 148.04 (d, ²J_CP = 2.5 Hz, C-4), 132.86 (s, C-7), 131.75 (d, ⁴J_CP = 1.3 Hz, C-5), 124.69 (s, C-6), 120.73 (d, ³J_CP = 16.6 Hz, C-4a), 119.07 (d, ¹J_CP = 162.3 Hz, C-3), 118.53 (d, ³J_CP = 7.5 Hz, C-8), 63.66 (d, ²J_CP = 6.7 Hz, CH₃CH₂OP), 41.82 (s, NHCH₂CH₂CH₃), 22.68 (s, NHCH₂CH₂CH₃), 16.31 (d, ³J_CP = 6.0 Hz, CH₃CH₂OP), 11.40 (s, NHCH₂CH₂CH₃);

³¹P NMR (202.4 MHz, CDCl₃) δ = 8.922.

HRMS (FTMS-p ESI) m/z calculated for C₁₄H₁₈NO₄P [M+H]⁺ 296.1052 found 296.1044 (ppm: 0.8).

5. Conclusions

2-Ethoxy-N-propylbenzo[e][1,2]oxaphosphinine-3-carboxamide-2-oxide was synthesized via an ultrasound technique using catalytic amounts of CuI. The formation of the products could indicate isomerization of the formed E-alkene intermediate to its Z-form before lactonization.