Synthesis of Dimethyl (Z)-((3-oxoindolin-2-ylidene) (aryl)methyl)phosphonates Through Tandem Cadogan and Arbuzov Reactions

Abstract

A novel method employing a tandem Cadogan and Arbuzov reaction sequence has been developed, providing access to a series of previously unreported dimethyl (Z)-((3-oxoindolin-2-ylidene)(aryl)methyl)phosphonates. Restricted rotation of the aryl substituent, particularly in the presence of ortho substituents, gives axial chirality to these compounds.

1. Introduction

The indole moiety is prevalent in natural products and contributes to a significant number of biologically active compounds [1]. For instance, the plant family Cryptolepis sanguinolenta contains numerous secondary indole metabolites and has been historically employed in the treatment of malaria and cancer [2,3,4]. Consequently, the development of novel methods for assembling the indole core with specific characteristics and substitution patterns remains a crucial challenge for research groups worldwide. One of the prominent approaches to indole synthesis is the Cadogan–Sundberg reaction [5,6,7] (Scheme 1a). This reaction, based on the deoxygenation of the nitro group in 2-vinylnitrobenzenes 1, enables the formation of indoles 2 in good yields and with high substituent diversity without use of transition metals. However, in these transformations, phosphorus acts solely as a reducing agent and is not incorporated into the final molecule. The only exception is the cyclization of β-nitrostyrenes 3 to indoles 4, which cannot be regarded as a typical precedent for the Cadogan–Sundberg reaction [8] (Scheme 1b). We became interested in the possibility of synthesizing organophosphorus indoles and turned our attention to chalcones 5. The Arbuzov reaction involving chalcones 5 is well-documented in the literature [9,10,11,12] (Scheme 1c). At the same time, 2′-nitrochalcones have not been previously utilized in such transformations, which serves as the basis for this study.

Herein, we wish to report the first tandem of Arbuzov and Cadogan–Sundberg reactions of 2′-nitrochalcones and P(OMe)₃, providing access to a series of dimethyl (Z)-((3-oxoindolin-2-ylidene)(aryl)methyl)phosphonates possessing axial chirality.

2. Results and Discussion

As a model reaction, we have investigated the interaction of 4-methyl-2′-nitrochalcone 5a with P(OMe)₃ under reflux in methanol, employing various bases as catalysts (

Table 1. Optimization of reaction of 4-methyl-2′-nitrochalcone 5a with P(OMe)₃.

Entry	Base, 2 Equiv.	Yield, %
1	KOH	0
2	DBU	0
3	Et3N	0
4	MeONa	14
5	K2CO3	31

). An initial attempt with KOH yielded unsatisfactory results (entry 1). Similarly, other bases, including Et₃N and DBU, failed to produce the desired product (entries 2 and 3). However, the use of sodium methoxide resulted in the formation of the target compound 7, albeit in a modest 14% yield (entry 4). Ultimately, conducting the reaction in methanol with K₂CO₃ as the base led to the desired product 7 in a 31% yield (entry 5). This result is not entirely unexpected, as K₂CO₃ has been previously reported as a catalyst for both the Cadogan–Sundberg [5] and Arbuzov [9] reactions. Despite our best efforts, a good yield remained elusive. The primary cause of this yield reduction appears to be the formation of a red polymeric material, which can be isolated via column chromatography using methanol as the eluent. In experiment 5, the isolated mass of this polymer was 238 mg.

The ¹H NMR spectrum indicates the formation of compound 7a as a single geometric isomer. To definitively establish the stereochemistry of the reaction, X-ray analysis was conducted, confirming the (Z)-configuration of the product (Figure 1).

Next, a small library of dimethyl (Z)-((3-oxoindolin-2-ylidene)(aryl)methyl)phosphonates 7 was synthesized under optimized conditions. Notably, the protons at positions 2/6 and 3/5 in the para-substituted products 7a–d exhibited non-equivalence. This observation suggests restricted rotation of the aryl substituent, likely due to steric hindrance induced by the phosphonate moiety. In support of this, the X-ray data show a 60-degree rotation of the 4-tolyl fragment and an elongation of the C2-C3 bond of the pyrrole ring to 1.53 Å. It is worth noting that related indoxyls containing a cyano group had free rotation even of the ortho-substituted aryl substituents and typical bond lengths for 3-oxoindoles [13,14]. Consequently, ortho-substituted analog 7e was also prepared. The presence of axial chirality in this molecule rendered the methyl groups on the phosphorus atom diastereotopic and, therefore, non-equivalent in the NMR spectra (Scheme 2).

The proposed reaction mechanism initiates with a nucleophilic attack by P(OMe)₃ on the double bond, resulting in the formation of phosphonium salt 8. The demethylation of this intermediate produces phosphonate 6. Subsequent deprotonation, resulting in the formation of benzyl anion 9, triggers a Cadogan-type cyclization. This cyclization starts from a nucleophilic attack on the nitro group, forming a six-membered ring intermediate 10, which then undergoes dehydration to yield the 1-oxo-4-quinolone anion 12. A second nucleophilic attack on the nitrogen atom generates an aziridine 13. This strained ring is readily cleaved under the reaction conditions to form intermediate 14, which is subsequently reduced by P(OMe)₃ to furnish the desired product 7 (Scheme 3). Cadogan-type cyclizations involving a nitro group are relatively uncommon in the literature. But, based on existing research [13,14,15,16], it appears that the enolate anion lacks sufficient nucleophilicity to effectively participate in such a reaction. Moreover, our recent work demonstrated that the interaction of nitrochalcones with methylene-active compounds, including 1,3-diketones, nitroalkanes, and benzyl cyanide, failed to facilitate this transformation, which is further suggesting the necessity of forming a three-membered ring intermediate [17].

To elucidate the reaction mechanism, we conducted a series of control experiments (Scheme 4). Initially, we lowered the reaction temperature to 40 °C, enabling the isolation of intermediate compound 6e in an 8% yield (Scheme 4a). Subsequently, compound 6e was subjected to standard reaction conditions, yielding product 7e (Scheme 4b). To determine whether the (Z) product was kinetically or thermodynamically favored, we performed isomerization of (Z)-7c in the presence of H₂SO₄-H₃PO₄ with subsequent treatment with NaHCO₃ (Scheme 4c). Upon concentrating the solution, the resulting product (E)-7c completely converted into the primary isomer (Z)-7c within half an hour. For this reason, we could only acquire a ¹H NMR spectrum of an approximately 1:1 mixture of isomers (Figures S35 and S36). This observation confirms that the (Z) isomer represents the thermodynamically favored product of the reaction. Furthermore, we performed photoisomerization using two-dimensional thin-layer chromatography (TLC), which produced a product spot consistent with the previously observed (E) isomer (Figure S37). This outcome suggests a distortion of the double bond in compound (E)-7e, attributable to the repulsion between the phosphonate fragment and the lone pairs of electrons on the indoxyl oxygen. We also attempted to introduce triethylamine as a scavenger for the methyl group liberated during the conversion of 9 to 10. However, the addition of triethylamine did not result in a yield of the target product that was significantly higher than the statistical error (Scheme 4d).

3. Materials and Methods

3.1. General Information

NMR spectra, ¹H, ¹³C, ¹⁹F, and ³¹P, were measured in solutions of CDCl₃ on Bruker AVANCE-III HD instrument (at 400, 101, 376, and 162 MHz, respectively). Residual solvent signals were used as internal standards (7.26 ppm for ¹H, and 77.16 ppm for ¹³C nuclei). HRMS spectra was measured on Bruker maXis impact (electrospray ionization, in MeCN solutions, employing HCO₂Na–HCO₂H for calibration). IR spectra was measured on FT-IR spectrometer Shimadzu IRAffinity-1S equipped with an ATR sampling module. Reaction progress, purity of isolated compounds, and R_f values were monitored with TLC on Silufol UV-254 plates. A two-dimensional thin-layer chromatography (2D TLC) experiment was performed using Convoy S2+ 365 nm UV flashlight. Column chromatography was performed on silica gel (32–63 μm, 60 Å pore size). Melting points were measured with Stuart SMP30 apparatus. 2′-Nitrochalcones 5a–e were synthesized according to the previously reported procedure and were identical to those described [14]. All reagents and solvents were purchased from commercial vendors and used as received.

3.2. Preparation of Dimethyl (Z)-((3-oxoindolin-2-ylidene)(aryl)methyl)phosphonates 7 (General Procedure)

A 10 mL round-bottomed flask was charged with 2′-nitrochalcone 5 (2.00 mmol), MeOH (1 mL), P(OMe)₃ (471 µL, 496 mg, 4.0 mmol), and K₂CO₃ (280 mg, 2 mmol) and heated at reflux temperature upon vigorous stirring for 1 h. After consumption of starting material (TLC control) the reaction mixture was concentrated in vacuo and obtained residue was purified by column chromatography (EtOAc/hexane, 1:2, v/v). Alternatively, products can be recrystallized from benzene/hexane 1:5.

Dimethyl (Z)-((3-oxoindolin-2-ylidene)(p-tolyl)methyl)phosphonate (7a): red solid, m.p. 159.9–161.1 °C, R_f 0.4 (EtOAc/hexane, 1:2, v/v). Yield 199 mg (0.58 mmol, 29%). ¹H NMR (400 MHz, CDCl₃) δ 9.42 (br. s, 1H), 7.49 (d, J = 7.6 Hz, 1H), 7.44 (ddd, J = 8.1, 7.3, 1.3 Hz, 1H), 7.23–7.18 (m, 2H), 7.14 (dd, J = 8.1, 1.9 Hz, 2H), 6.92–6.82 (m, 2H), 3.74 (s, 3H), 3.72 (s, 3H), 2.39 (s, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 185.3 (d, J = 17.9 Hz), 152.2, 143.8 (d, J = 7.1 Hz), 137.9 (d, J = 2.6 Hz), 137.2, 129.6, 129.5, 129.5, 129.5, 125.3, 120.7 (d, J = 3.6 Hz), 120.6, 111.5, 105.8 (d, J = 174.6 Hz), 53.1, 53.0, 21.5; ³¹P NMR (162 MHz, CDCl₃) δ 21.29; FTIR, v_max: 3257, 2949, 1705, 1514, 1578, 1463, 1239 cm⁻¹; HRMS (ESI TOF) m/z calc’d. for C₁₈H₁₈NNaO₄P [M + Na]⁺: 366.0866, found: 366.0875 (−2.6 ppm).

Dimethyl (Z)-((4-methoxyphenyl)(3-oxoindolin-2-ylidene)methyl)phosphonate (7b): red solid, m.p. 166.4–167.2 °C, R_f 0.34 (EtOAc/hexane, 1:2, v/v). Yield 244 mg (0.68 mmol, 34%). ¹H NMR (400 MHz, CDCl₃) δ 9.43 (s, 1H), 7.52–7.47 (m, 1H), 7.43 (ddd, J = 8.5, 7.3, 1.4 Hz, 1H), 7.19 (dd, J = 8.7, 2.0 Hz, 2H), 6.93 (d, J = 8.5 Hz, 2H), 6.89–6.82 (m, 2H), 3.83 (s, 3H), 3.74 (s, 3H), 3.71 (s, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 185.3 (d, J = 17.7 Hz), 159.5 (d, J = 2.4 Hz), 152.1, 143.8 (d, J = 7.4 Hz), 137.2, 131.0, 131.0, 125.3, 124.5 (d, J = 3.3 Hz), 120.7 (d, J = 3.7 Hz), 120.6, 114.1, 114.1, 111.5, 105.6 (d, J = 174.6 Hz), 55.3, 53.1, 53.0; ³¹P NMR (162 MHz, CDCl₃) δ 21.38; FTIR, v_max: 3268, 2926, 2851, 1701, 1624, 1590, 1510, 1471, 1289, 1236, 1175, 1020 cm⁻¹; HRMS (ESI TOF) m/z calc’d. for C₁₈H₁₈NNaO₅P [M + Na]⁺: 382.0815, found: 382.0819 (−1.0 ppm).

Dimethyl (Z)-((4-chlorophenyl)(3-oxoindolin-2-ylidene)methyl)phosphonate (7c): red solid, m.p. 131.1–132.3°C, R_f 0.3 (EtOAc/hexane, 1:2, v/v). Yield 225 mg (0.62 mmol, 31%). ¹H NMR (400 MHz, CDCl₃) δ 9.41 (s, 1H), 7.51–7.48 (m, 1H), 7.45 (td, J = 7.8, 1.3 Hz, 1H), 7.39–7.32 (m, 2H), 7.21–7.15 (m, 2H), 6.92–6.84 (m, 2H), 3.74 (s, 3H), 3.72 (s, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 185.3 (d, J = 17.6 Hz), 152.2, 143.9 (d, J = 6.6 Hz), 137.4, 134.1 (d, J = 3.2 Hz), 131.3, 131.2, 128.9, 128.9, 125.4, 120.9, 120.5 (d, J = 3.7 Hz), 111.6, 104.1 (d, J = 176.7 Hz), 53.1, 53.1; ³¹P NMR (162 MHz, CDCl₃) δ 20.64; FTIR, v_max: 3314, 1697, 1588, 1463, 1317, 1299, 1243 cm⁻¹; HRMS (ESI TOF) m/z calc’d. for C₁₇H₁₅ClNNaO₄P [M + Na]⁺: 386.0319, found: 386.0310 (2.5 ppm).

Dimethyl (Z)-((4-fluorophenyl)(3-oxoindolin-2-ylidene)methyl)phosphonate (7d): red solid, m.p. 171.8–173.2°C, R_f 0.29 (EtOAc/hexane, 1:2, v/v). Yield 159 mg (0.46 mmol, 23%). ¹H NMR (400 MHz, CDCl₃) δ 9.41 (s, 1H), 7.49 (d, J = 7.6 Hz, 1H), 7.45 (ddd, J = 8.4, 7.4, 1.3 Hz, 1H), 7.21 (ddd, J = 8.8, 5.4, 2.1 Hz, 2H), 7.12–7.03 (m, 2H), 6.91–6.84 (m, 2H), 3.75 (s, 3H), 3.72 (s, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 185.4 (d, J = 17.6 Hz), 162.7 (dd, J = 247.2, 2.8 Hz), 152.2, 144.0 (d, J = 6.9 Hz), 137.4, 131.6 (d, J = 5.6 Hz), 131.6 (d, J = 5.8 Hz), 128.4 (t, J = 3.4 Hz), 125.4, 120.8, 120.5 (d, J = 3.7 Hz), 115.8 (d, J = 2.0 Hz), 115.6 (d, J = 2.0 Hz), 111.6, 104.3 (d, J = 176.5 Hz), 53.1, 53.0; ¹⁹F NMR (376 MHz, CDCl₃) δ -113.97; ³¹P NMR (162 MHz, CDCl₃) δ 20.81; FTIR, v_max: 3321, 1703, 1591, 1505, 1474, 1329, 1214 cm⁻¹; HRMS (ESI TOF) m/z calc’d. for C₁₇H₁₅FNNaO₄P [M + Na]⁺: 370.0615, found: 370.0609 (1.6 ppm).

Dimethyl (Z)-((2-fluorophenyl)(3-oxoindolin-2-ylidene)methyl)phosphonate (7e): orange solid, m.p. 160.5–162.4 °C, R_f 0.34 (EtOAc/hexane, 1:2, v/v). Yield 174 mg (0.5 mmol, 25%). ¹H NMR (400 MHz, CDCl₃) δ 9.47 (s, 1H), 7.51 (d, J = 7.5 Hz, 1H), 7.45 (t, J = 7.7 Hz, 1H), 7.36 (q, J = 7.7, 6.8 Hz, 1H), 7.20 (p, J = 7.4 Hz, 2H), 7.11 (t, J = 9.0 Hz, 1H), 6.94–6.85 (m, 2H), 3.80 (d, J = 11.2 Hz, 3H), 3.72 (d, J = 11.4 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 185.3 (d, J = 17.6 Hz), 160.9 (dd, J = 245.2, 6.6 Hz), 152.3, 144.7 (d, J = 6.5 Hz), 137.4, 131.5, 131.5, 131.5, 131.4, 131.0, 130.0, 129.9, 129.9, 124.4 (dd, J = 3.6, 2.2 Hz), 125.7, 124.4, 120.3 (td, J = 8.6, 8.2, 3.2 Hz), 115.6 (d, J = 1.8 Hz), 115.4 (d, J = 1.8 Hz), 111.6, 96.9 (d, J = 180.3 Hz), 53.2 (dd, J = 4.7, 2.7 Hz), 53.0 (d, J = 5.8 Hz); ¹⁹F NMR (376 MHz, CDCl₃) δ -114.34; ³¹P NMR (162 MHz, CDCl₃) δ 20.83; FTIR, v_max: 3253, 1708, 1596, 1461, 1242 cm⁻¹; HRMS (ESI TOF) m/z calc’d. for C₁₇H₁₅FNNaO₄P [M + Na]⁺: 370.0615, found: 370.0629 (−3.8 ppm).

3.3. Control Experiments: Preparation of Dimethyl (1-(2-fluorophenyl)-3-(2-nitrophenyl)-3-oxopropyl)phosphonate 6e (Scheme 4a)

A 10 mL round-bottomed flask was charged with 2-fluoro-2′-nitrochalcone 5e (542 mg, 2.00 mmol), MeOH (1 mL), P(OMe)₃ (471 µL, 496 mg, 4.0 mmol), and K₂CO₃ (280 mg, 2 mmol) and heated at 40 °C upon vigorous stirring for 1 h. After consumption of starting material (TLC control) the reaction mixture was concentrated in vacuo and obtained residue was purified by column chromatography (gradient, EtOAc/hexane, from 1:2 to 1:0 v/v). This compound was isolated among with unreacted 2-fluoro-2′-nitrochalcone 5e (227 mg, 42%) and dimethyl (Z)-((2-fluorophenyl)(3-oxoindolin-2-ylidene)methyl)phosphonate 7e (83 mg, 12%).

Colorless liquid, R_f 0.27 (EtOAc). Yield 61 mg (0.16 mmol, 8%). ¹H NMR (400 MHz, CDCl₃) δ 8.11 (d, J = 8.1 Hz, 1H), 7.69 (t, J = 7.4 Hz, 1H), 7.64–7.55 (m, 1H), 7.45 (tt, J = 7.5, 2.2 Hz, 1H), 7.33–7.22 (m, 2H), 7.17 (t, J = 7.6 Hz, 1H), 7.10 (t, J = 9.2 Hz, 1H), 4.35 (ddd, J = 23.0, 9.6, 4.5 Hz, 1H), 3.79 (d, J = 10.8 Hz, 3H), 3.73–3.50 (m, 2H), 3.59 (d, J = 10.7 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 198.6 (d, J = 16.2 Hz), 160.8 (dd, J = 247.2, 7.3 Hz), 145.5, 137.2 (d, J = 1.4 Hz), 134.3, 130.8, 129.8 (dd, J = 5.0, 3.2 Hz), 129.3 (dd, J = 8.4, 3.3 Hz), 127.5, 124.5, 124.4 (t, J = 3.2 Hz), 122.4 (dd, J = 14.4, 7.3 Hz), 115.7 (dd, J = 22.7, 2.6 Hz), 53.6 (d, J = 7.0 Hz), 53.2 (d, J = 7.0 Hz), 42.2 (t, J = 1.7 Hz), 30.8 (dd, J = 142.0, 2.9 Hz); ¹⁹F NMR (376 MHz, CDCl₃) δ -116.08; ³¹P NMR (162 MHz, CDCl₃) δ 28.93, 28.90; FTIR, v_max: 2957, 2850, 1711, 1527, 1492, 1456, 1347, 1249, 1233, 1183, 1025 cm⁻¹; HRMS (ESI TOF) m/z calc’d. for C₁₇H₁₇FNNaO₆P [M + Na]⁺: 370.0670, found: 404.0674 (−1.0 ppm).

3.4. Control Experiments: Preparation of Dimethyl (Z)-((2-fluorophenyl)(3-oxoindolin-2-ylidene)methyl)phosphonate 7e from Dimethyl (1-(2-fluorophenyl)-3-(2-nitrophenyl)-3-oxopropyl)phosphonate 6e (Scheme 4b)

A 10 mL round-bottomed flask was charged with dimethyl (1-(2-fluorophenyl)-3-(2-nitrophenyl)-3-oxopropyl)phosphonate 6e (50 mg, 0.13 mmol), MeOH (0.5 mL), P(OMe)₃ (30 µL, 31 mg, 0.25 mmol), and K₂CO₃ (280 mg, 2 mmol) and heated at reflux upon vigorous stirring for 1 h. After consumption of starting material (TLC control) the reaction mixture was concentrated in vacuo and obtained residue was purified by column chromatography (EtOAc/hexane, 1:2, v/v). Yield 12 mg (0.035 mmol, 27%). The analytical data are in agreement with those obtained by the general method.

3.5. Control Experiments: Z/E Isomerisation of Dimethyl (Z)-((4-chlorophenyl)(3-oxoindolin-2-ylidene)methyl)phosphonate (7c) in Acidic Medium (Scheme 4c)

A 10 mL round-bottomed flask was charged with dimethyl (Z)-((4-chlorophenyl)(3-oxoindolin-2-ylidene)methyl)phosphonate 7c (72 mg, 0.2 mmol), CH₂Cl₂ (0.5 mL), H₃PO₄ (0.5 mL), and H₂SO₄ (0.5 mL) and stirred at room temperature for 15 min. After consumption of starting material (TLC control), the reaction mixture was diluted with water, neutralized with NaHCO₃ (10 g), and extracted with CH₂Cl₂ (4 × 20 mL). The organic phase was concentrated in vacuo and obtained residue was purified by column chromatography (EtOAc). Yield, (E)-7c 49 mg (0.13 mmol, 67%). R_f, 0.3 (EtOAc). Due to rapid reverse isomerization, the remaining data for the resulting mixture are given in the Supplementary Materials.

3.6. Control Experiments: 2D TLC Observation of Z/E Isomerisation of Dimethyl (Z)-((4-chlorophenyl)(3-oxoindolin-2-ylidene)methyl)phosphonate (7c)

Dimethyl (Z)-((4-chlorophenyl)(3-oxoindolin-2-ylidene)methyl)phosphonate 7c was applied to the lower left corner of a chromatographic plate (5 × 5 cm). The plate was eluted using a mixture of ethyl acetate and hexane (1:2, v/v) as the eluent. While the solvent was evaporating, the resulting spot was irradiated with ultraviolet light at a wavelength of 365 nm for 2 min. Subsequently, the plate was subjected to perpendicular elution using the same solvent mixture.

3.7. Control Experiments: Preparation of Dimethyl (Z)-((2-fluorophenyl)(3-oxoindolin-2-ylidene)methyl)phosphonate 7e in Presense of Et₃N (Scheme 4d)

A 10 mL round-bottomed flask was charged with 2′-nitrochalcone 5 (2.00 mmol), MeOH (1 mL), P(OMe)₃ (471 µL, 496 mg, 4.0 mmol), K₂CO₃ (280 mg, 2 mmol), and Et₃N (277 µL, 202 mg, 2.0 mmol) and heated at reflux temperature upon vigorous stirring for 1 h. After consumption of starting material (TLC control) the reaction mixture was concentrated in vacuo and obtained residue was purified by column chromatography (EtOAc/hexane, 1:2, v/v). Yield 187 mg (0.54 mmol, 27%). The analytical data are in agreement with those obtained by the general method.

4. Conclusions

A method employing a tandem Cadogan and Arbuzov reaction has been developed, providing access to a series of previously unreported dimethyl (Z)-((3-oxoindolin-2-ylidene)(aryl)methyl)phosphonates. The restricted rotation of the aryl substituent, particularly in the presence of ortho substituents, determines axial chirality in these compounds. The resulting compounds hold potential as polydentate chiral ligands.