Abstract
An atom- and step-economical strategy for the synthesis of bisphosphinoylaminomethanes is reported. This metal-free bisphosphinylation reaction proceeded smoothly through a base-mediated direct 1,1-bisphosphonation of phosphine oxides and isocyanides under mild conditions. The present method offers a facile, efficient, and general approach to a broad range of bisphosphinoylaminomethane derivatives in moderate to good yields.
Introduction
Organic phosphorus compounds have shown great diversity and wide applications in organic chemistry, which are applied to many fields ranging from the pharmaceutical industry to organometallic catalysis.1−4 In particular, bisphosphorous aminomethane derivatives have attracted considerable attention owing to their unique biological and medicinal activities. As shown in Scheme 1, several bisphosphorous aminomethane-based pharmaceuticals are used as clinical drugs to treat osteoporosis, hypercalcemia, and Paget’s disease.5 Also, some of them exhibit various intriguing biological activities such as herbicidal, antibacterial, and antiparasitic properties.6 Therefore, the remarkable activities of these compounds have stimulated a great effort to develop efficient synthetic methodologies. However, efficient synthetic methods for these bisphosphorus compounds, especially for bisphosphinoylaminomethane derivatives, are limited.7 As shown in Scheme 2a, in 2006, Han and Hirai8 reported a rhodium-catalyzed direct insertion of isocyanides to P(O)–H bonds for the synthesis of bisphosphinoylaminomethane. In 2017, Schmidt and Basiouny9 developed a double hydrophosphinylation reaction of primary alkyl nitriles by using an α-metalated N,N-dimethylbenzylamine supported homoleptic lanthanum(III) complex La(Dmba)3 as a catalyst (Scheme 2b). Very recently, Li and co-workers10 constructed the bisphosphinoylaminomethane fragment via a cascade double nucleophilic addition, H2S elimination, and in situ imine reduction of phosphine oxides and isocyanides (Scheme 2c). It was found that, in the previous reports, a noble or complexed metal catalyst should be used, high temperature and long reaction time were always necessary, and the substrate scope was sometimes limited. From economic or environmental friendly perspective, developing a general and green approach for the construction of bisphosphinoylaminomethanes would be highly desirable.
Scheme 1. Representative Bisphosphorous Aminomethane Derivatives.
Scheme 2. (a–d) Synthesis of Bisphosphonaminomethane Derivatives.
Isocyanides are important building blocks in modern organic synthesis, which have been widely employed in the construction of various nitrogen-containing compounds because they are easy to handle and exhibit high reactivity.11,12 Given our continuing interest in isocyanide chemistry,13 herein, we reported a highly efficient and straightforward isocyanide-based formal multicomponent reactions,14 which provide an atom- and step-economical strategy for preparing bisphosphinoylaminomethane derivatives under mild conditions(Scheme 2d).
Results and Discussion
Initially, we investigated the reaction of 2-isocyanoacetophenone 1a with phosphine oxide 2a in 2 mL of DMSO at room temperature in the presence of DBU. To our delight, the desired product 3a was formed in 83% yield (Table 1, entry 1). Encouraged by this promising result, we further tried the reactions by screening different bases. The desired product was obtained in moderate to good yields when some other organic bases were employed (Table 1, entries 2–6). The direct 1,1-bisphosphonation reaction proceeded smoothly in the presence of strong inorganic base (Table 1, entries 7–11). However, a trace amount of product was observed when weak inorganic bases (such as Cs2CO3 and K2CO3) were used (Table 1, entries 12–13). Next, a brief solvent-screening was carried out (Table 1, entries 14–20). It was found that the reaction showing a broad solvent tolerance and MeCN gave the best result (entry 17).
Table 1. Optimization of the Basea,b.
| entry | base | solvent | yield (%)b |
|---|---|---|---|
| 1 | DBU | DMSO | 83 |
| 2 | Et3N | DMSO | 60 |
| 3 | pyridine | DMSO | 72 |
| 4 | piperidine | DMSO | 35 |
| 5 | DIPEA | DMSO | 58 |
| 6 | DABCO | DMSO | 41 |
| 7 | NaOH | DMSO | 50 |
| 8 | KOH | DMSO | 61 |
| 9 | t-BuOK | DMSO | 62 |
| 10 | t-BuONa | DMSO | 55 |
| 11 | C2H5ONa | DMSO | 67 |
| 12 | Cs2CO3 | DMSO | trace |
| 13 | K2CO3 | DMSO | trace |
| 14 | DBU | DMF | 72 |
| 15 | DBU | DMA | 70 |
| 16 | DBU | MeCN | 87 |
| 17 | DBU | DCM | 85 |
| 18 | DBU | THF | 81 |
| 19 | DBU | toluene | 77 |
| 20 | DBU | EtOH | 77 |
Conditions: 1b (0.5 mmol), 2a (1.5 mmol), base (1.0 mmol), solvent (2 mL), at room temperature for 12 h.
Isolated yield.
With the optimized conditions in hand, we explored the substrate scope of isocyanides first. A broad range of isocyanides was examined in this double hydrophosphinylation reaction (Table 2). In general, ortho-, meta-, and para-substituted aromatic isocyanides are tolerated in the reaction and afforded the desired bisphosphorous aminomethane products in moderate to excellent yields. When halogen-substituted aromatic isocyanides were subjected with phosphine oxide 2a under the standard reaction conditions, the desired products were obtained in 85–92% yields (Table 2; 3e, 3f, 3h, and 3i). It should be noticed that aromatic isocyanide bearing a NO2 group has impaired the reactivity and decreased the yield (Table 2, 3d). Unfortunately, only a trace amount of the desired product was observed when other alkyl isocyanide such as n-butyl isocyanide 1k was used.
Table 2. Scope of Isocyanidesa,b.
Reaction conditions: isocyanide 1 (0.5 mmol), 2a (1.5 mmol), DBU (1.0 mmol), MeCN (2 mL), at room temperature, 12 h.
Isolated yield.
Next, we expanded the substrates with different diphenylphosphine oxides (Table 3). When the diphenylphosphine oxide substituted with a fluorine or phenyl group at the para position was employed under standard conditions, the desired bisphosphorous aminomethane products 4b and 4c were isolated in 85 and 81% yield, respectively. The reactions with the meta-substituted groups on P-reagents 1d–1f furnished the corresponding products 4d–4f in 90, 84, and 47% yields, respectively. Unfortunately, no desired product 4g was observed when the ortho-methyl substituted P-reagent was used.
Table 3. Scope of Phosphine Oxidesa,b.
Reaction conditions: isocyanide 1a (0.5 mmol), diphenylphosphine oxides (1.5 mmol), DBU (1.0 mmol), MeCN (2 mL), at room temperature, 12 h.
Isolated yield.
Furthermore, we tried to scale up the reaction to a gram scale. The reaction was well adapted for a gram scale and gave 2.20 g of bisphosphinoylaminomethane derivative 3a in 87% yield (Scheme 3), which proves a simple and efficient approach for the synthesis of bisphosphinoylaminomethane derivatives.
Scheme 3. Scale-Up Synthesis.
Some control experiments were carried out to gain some insights into the reaction. No desired product 3a was observed when the double hydrophosphinylation reaction was treated in the absence of base (Scheme 4, eq 1). The bisphosphorous aminomethane product was isolated in 83 and 84% yield, respectively, when an excessive amount of free radical scavenger TEMPO or BHT was added under standard conditions (Scheme 4, eq 2). The results indicate that the reaction may not proceed with a free radical pathway, although our group13g and others15 have reported the radical cascade addition reaction of phosphine oxides with aryl isonitriles before.
Scheme 4. Control Experiments.
Based on the experiment results, a base-promoted double nucleophilic addition pathway was proposed for the 1,1-bisphosphonation reaction (Scheme 5). First, phosphite 2′ generated via tautomerization of phosphine oxide 2 was deprotonated by DBU. Then, the nucleophilic addition of isocyanide led to the imine intermediate A. The intermediate A would be attacked by another phosphite anion to generate intermediate B, which captured a hydrogen to give the final product.
Scheme 5. Plausible Mechanism.
Conclusions
In summary, we have developed an atom- and step-economical strategy for the synthesis of bisphosphinoylaminomethane derivatives in moderate to excellent yields by a base-mediated direct 1,1-bisphosphonation of phosphine oxides and isocyanides. The reaction proceeds under mild conditions and avoids using a noble and complexed metal catalyst. The simple and mild reaction conditions make the present method very practical and useful, offering a facile and efficient approach for the construction of bisphosphoryl derivatives.
Experimental Section
General Experimental Information
All the solvents for routine isolation of products and chromatography were reagent grade. Flash chromatography was performed using a silica gel (200–300 mesh) with the indicated solvents. IR spectra were recorded on a spectrophotometer using a KBr optics. 1H NMR and 13C NMR spectra were recorded on a 400 MHz (1H NMR) and 100 MHz (13C NMR) spectrometer using CDCl3 as a solvent and TMS as an internal standard. The 1H NMR data are reported as the chemical shift in parts per million, multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet), coupling constant in hertz, and number of protons. High-resolution mass spectra were obtained using a high-resolution ESI-TOF mass spectrometer and high-resolution CI-TOF mass spectrometer.
General Procedure for the Synthesis of Arylisonitrile,13g13o
Step 1: Formylation
A total of 1.5 mL of formic acid and 3 mL of acetic anhydride were added to a 25 mL round-bottom flask, and then the flask was stirred in an oil bath at 55 °C for 2 h to give formic acetic anhydride. Aniline (10 mmol) and THF (20 mL) were added to a 100 mL round-bottom flask, and then the prepared formic acetic anhydride was added slowly. Afterward, the TCL thin layer chromatography plate was used for tracking and detection until the reaction was complete. Next, the reaction solution was placed in an ice-water bath, and a saturated sodium bicarbonate solution was slowly added until no bubbles were generated followed by extraction with ethyl acetate three times and drying with anhydrous magnesium sulfate and then concentrated under reduced pressure to give formamide for use.
Step 2: Dehydration
The prepared formamide was added into a 100 mL round-bottom flask, and the flask was evacuated and backfilled with argon three times followed by addition of dichloromethane (20 mL) and triethylamine (5 mL). The flask was cooled with an ice-water bath for 10 min, and then phosphorus oxychloride (1.5 mL) was added slowly. After the addition was complete, the reaction was stirred in the ice-water bath for 20 min. After that, the saturated carbon bicarbonate was added until no bubbles were generated. Then, the mixture was extracted with dichloromethane three times and dried over anhydrous magnesium sulfate. The product was isolated by silica gel column chromatography (petroleum ether/ethyl acetate V/V = 100:1–10:1).
General Procedure for the Synthesis of Diphenylphosphine10
A 100 mL three-neck round-bottom flask equipped with a reflux condenser was added 30.5 mmol of crushed magnesium scraps, and then a small amount of anhydrous tetrahydrofuran was added to immerse the magnesium scraps. A small amount of iodine was added into the flask and then the flask was heated to 65 °C in an oil bath until the iodine was completely dissolved, after which the diluted substituted bromobenzene was added slowly to keep the liquid in it slightly boiling status and continuously refluxed for 0.5–1.5 h after the dropwise addition of bromobenzene. After the reflux was completed, the flask was cooled to 0 °C in an ice-water bath, then 10 mmol of diethyl phosphate was slowly added thereto, and then the ice-water bath was reacted for half an hour. The ice-water bath was removed and stirred warmly, and the reaction was detected using a TCL plate. After quenching with dilute hydrochloric acid, the reaction solution was filtered with a Buchner funnel. The filtrate was extracted three times with ethyl acetate and dried over anhydrous magnesium sulfate. The product was isolated by silica gel column chromatography (petroleum ether/ethyl acetate V/V = 30:1–1:1).
General Procedure for Generation of 3 (3a as an Example)
An over-dried reaction tube equipped with a magnetic stir bar was charged with 1a (0.5 mmol, 1 equiv), 2a (1.5 mmol, 3 equiv), and DBU (1.0 mmol, 2.0 equiv), and then MeCN (2.0 mL) was added into the mixture. Later, the reaction system was kept stirring at room temperature (25 °C) for 12 h. After that, the mixture was purified by column chromatography on a silica gel to afford the corresponding product 3a as a green solid in 87% yield.
General Procedure for the Gram-Scale Synthesis of 3b
An over-dried round-bottom reaction flask (100 mL) equipped with a magnetic stir bar was charged with 1b (5.0 mmol, 1.0 equiv), 2a (15.0 mmol, 3 equiv), and DBU (10.0 mmol, 2 equiv), and then MeCN (20.0 mL) was added into the mixture. Later, the reaction system was kept stirring at room temperature (25 °C) for 12 h. After that, the mixture was purified by column chromatography on a silica gel to afford the corresponding product 3b as a white solid in 87% yield.
1-(2-((Bis(diphenylphosphoryl)methyl)amino)phenyl)ethan-1-one (3a)
Green solid (238 mg, yield 87%). m.p.: 188 °C–190 °C. 1H NMR (400 MHz, chloroform-d) δ 9.61 (d, J = 10.8 Hz, 1H), 7.84 (m, 8H), 7.42 (m, 3H), 7.27 (m, 10H), 7.11 (m, 1H), 6.67 (m, 1H), 6.50 (m, 1H), 5.48 (br, 1H), 2.38 (s, 3H). 13C NMR (100 MHz, chloroform-d) δ 200.6, 149.2, 134.6, 132.2, 131.9 (t, J = 4.8 Hz), 131.7 (t, J = 4.8 Hz), 131.2, 130.2, 128.3 (t, J = 6.0 Hz), 128.1 (t, J = 5.9 Hz), 119.4, 116.2, 112.5, 57.2, 27.7. HRMS (ESI) m/z: calcd for C33H29NO3P2 [M + H]+: 549.1623, found: 549.1623.
((Phenylamino)methylene)bis(diphenylphosphine oxide) (3b)
White solid (228 mg, yield 90%). m.p.:183 °C–185 °C. 1H NMR (400 MHz, chloroform-d) δ 7.81 (d, J = 26.7 Hz, 8H), 7.63–7.04 (m, 12H), 6.87 (t, J = 6.3 Hz, 2H), 6.56 (t, J = 6.4 Hz, 1H), 6.29 (d, J = 7.2 Hz, 2H), 5.16 (q, J = 12.6 Hz, 1H), 4.66 (s, 1H). 13C NMR (100 MHz, chloroform-d) δ 146.0, 131.9, 131.8 (t, J = 4.7 Hz), 131.6 (t, J = 4.9 Hz), 128.8, 128.2 (m), 57.1. HRMS (ESI) m/z: calcd for C31H27NO2P2 [M + H]+: 507.1517, found: 507.1516.
((o-Tolylamino)methylene)bis(diphenylphosphine oxide) (3c)
White solid (195 mg, yield 75%). m.p.:182 °C–184 °C. 1H NMR (400 MHz, chloroform-d) δ 7.81 (dd, J = 22.0, 14.0 Hz, 8H), 7.47–7.27 (m, 12H), 6.70 (d, J = 7.8 Hz, 2H), 6.21 (d, J = 8.0 Hz, 2H), 5.13 (q, J = 12.9 Hz, 1H), 4.57 (s, 1H), 2.13 (s, 3H). 13C NMR (100 MHz, chloroform-d) δ 143.7, 132.0, 131.7 (t, J = 4.8 Hz), 131.6 (t, J = 4.8 Hz), 131.0, 128.3 (t, J = 5.9 Hz), 128.2 (t, J = 6.0 Hz), 126.6, 123.1, 118.5, 110.8, 56.6 (t, J = 64.1), 17.1. HRMS (ESI) m/z: calcd for C32H29NO2P2 [M + H]+: 521.1674, found: 521.1674.
(((2-Nitrophenyl)amino)methylene)bis(diphenylphosphine oxide) (3d)
Yellow solid (55 mg, yield 20%). m.p.:190 °C–192 °C. 1H NMR (400 MHz, chloroform-d) δ 8.57 (d, J = 10.4 Hz, 1H), 7.96–7.73 (m, 8H), 7.62–7.11 (m, 13H), 6.83 (d, J = 8.5 Hz, 1H), 6.55 (t, J = 7.7 Hz, 1H), 5.46 (q, J = 9.6, 8.7 Hz, 1H). 13C NMR (100 MHz, chloroform-d) δ 145.1, 132.0, 131.7 (t, J = 4.6 Hz), 131.5–131.3 (m), 128.3–128.2 (m), 115.4, 110.7, 57.1. HRMS (ESI) m/z: calcd for C31H26N2O4P2 [M + H]+: 552.1368, found: 552.1365.
(((2-Chlorophenyl)amino)methylene)bis(diphenylphosphine oxide) (3e)
White solid (230 mg, yield 85%). m.p.:185 °C–187 °C. 1H NMR (400 MHz, chloroform-d) δ 7.83 (dd, J = 27.8, 8.5 Hz, 8H), 7.46–7.25 (m, 12H), 7.00 (d, J = 7.8 Hz, 1H), 6.81 (t, J = 7.8 Hz, 1H), 6.48 (t, J = 7.4 Hz, 1H), 6.35 (d, J = 8.0 Hz, 1H), 5.25 (d, J = 39.1 Hz, 2H). 13C NMR (100 MHz, chloroform-d) δ 145.2, 132.1, 131.8 (t, J = 4.6 Hz), 131.6–131.5 (m), 128.5–128.3 (m), 115.6, 110.8, 57.2. HRMS (ESI) m/z: calcd for C31H26ClNO2P2 [M + H]+: 541.1127, found: 541.1127.
(((3-Chlorophenyl)amino)methylene)bis(diphenylphosphine oxide) (3f)
White solid (241 mg, yield 89%). m.p.:186 °C–188 °C. 1H NMR (400 MHz, chloroform-d) δ 7.82 (dd, J = 17.1, 9.0 Hz, 8H), 7.58–7.11 (m, 12H), 6.81 (t, J = 8.2 Hz, 1H), 6.53 (d, J = 7.9 Hz, 1H), 6.23 (d, J = 6.5 Hz, 2H), 5.16–4.99 (m, 1H), 4.97–4.78 (m, 1H). 13C NMR (100 MHz, chloroform-d) δ 147.2, 134.5, 132.1, 131.8 (t, J = 4.7 Hz), 131.5 (t, J = 4.6 Hz), 129.8, 128.4–128.3 (m), 118.9, 113.8, 112.1, 56.8 (t, J = 63.8). HRMS (ESI) m/z: calcd for C31H26ClNO2P2 [M + H]+: 541.1127, found: 541.1127.
((p-Tolylamino)methylene)bis(diphenylphosphine oxide) (3g)
White solid (182 mg, yield 70%). m.p.:181 °C–183 °C. 1H NMR (400 MHz, chloroform-d) δ 7.81 (dd, J = 22.0, 14.0 Hz, 8H), 7.47–7.27 (m, 12H), 6.70 (d, J = 7.8 Hz, 2H), 6.21 (d, J = 8.0 Hz, 2H), 5.13 (q, J = 12.9 Hz, 1H), 4.57 (s, 1H), 2.13 (s, 3H). 13C NMR (100 MHz, chloroform-d) δ 143.7, 131.9 (t, J = 4.3 Hz), 131.6 (t, J = 4.8 Hz), 129.3, 128.3, 128.3–128.2 (m), 114.3, 57.6, 20.3. HRMS (ESI) m/z: calcd for C32H29NO2P2 [M + H]+: 521.1674, found: 521.1677.
(((4-Chlorophenyl)amino)methylene)bis(diphenylphosphine oxide) (3h)
White solid (238 mg, yield 88%). m.p.:182 °C–184 °C. 1H NMR (400 MHz, chloroform-d) δ 7.79 (dd, J = 15.6, 7.1 Hz, 8H), 7.45–7.29 (m, 12H), 6.84 (d, J = 8.3 Hz, 2H), 6.24 (d, J = 8.3 Hz, 2H), 5.06 (q, J = 12.8 Hz, 1H), 4.76 (d, J = 4.3 Hz, 1H). 13C NMR (100 MHz, chloroform-d) δ 144.8, 132.1, 131.8 (t, J = 4.7 Hz), 131.5 (t, J = 4.8 Hz), 130.6 (t, J = 44.5 Hz), 128.7, 128.4–128.3 (m), 123.6, 115.1, 57.4 (t, J = 63.0 Hz). HRMS (ESI) m/z: calcd for C31H26ClNO2P2 [M + H]+: 541.1127, found: 541.1125.
(((4-Bromophenyl)amino)methylene)bis(diphenylphosphine oxide) (3i)
White solid (269 mg, yield 92%). m.p.:186 °C–188 °C. 1H NMR (400 MHz, chloroform-d) δ 7.79 (dd, J = 19.8, 8.2 Hz, 8H), 7.44–7.27 (m, 12H), 6.96 (d, J = 8.3 Hz, 2H), 6.18 (d, J = 8.2 Hz, 2H), 5.05 (q, J = 12.6 Hz, 1H), 4.80 (d, J = 8.5 Hz, 1H). 13C NMR (100 MHz, chloroform-d) δ 145.2, 132.1, 131.8 (t, J = 4.6 Hz), 131.6–131.4 (m), 130.6 (t, J = 46.8 Hz), 128.4–128.3 (m), 115.5, 110.8, 57.2. HRMS (ESI) m/z: calcd for C31H26BrNO2P2 [M + H]+: 585.0622, found: 585.0620.
(((4-(tert-Butyl)phenyl)amino)methylene)bis(diphenylphosphine oxide) (3j)
White solid (217 mg, yield 77%). m.p.:180 °C–182 °C. 1H NMR (400 MHz, chloroform-d) δ 7.84 (dd, J = 37.0, 9.0 Hz, 8H), 7.49–7.26 (m, 12H), 6.89 (d, J = 8.5 Hz, 2H), 6.24 (d, J = 8.5 Hz, 2H), 5.17 (q, J = 12.8 Hz, 1H), 4.49 (d, J = 9.9 Hz, 1H), 1.19 (s, 9H). 13C NMR (100 MHz, chloroform-d) δ 141.9, 131.9–131.6 (m), 130.8, 128.3–128.1 (m), 125.6, 114.4, 57.8, 33.8, 31.4. HRMS (ESI) m/z: calcd for C35H35NO2P2 [M + H]+: 563.2143, found: 563.2140.
1-(2-((Bis(bis(4-fluorophenyl)phosphoryl)methyl)amino)phenyl)ethan-1-one (4a)
Green solid (264 mg, yield 85%). m.p.:175 °C–177 °C. 1H NMR (400 MHz, chloroform-d) δ 9.63 (d, J = 10.4 Hz, 1H), 7.88–7.74 (m, 8H), 7.54 (dd, J = 8.0, 1.5 Hz, 1H), 7.19–7.12 (2H), 7.04 (t, J = 8.4 Hz, 4H), 6.96 (t, J = 8.4 Hz, 4H), 6.60–6.56 (m, 1H), 5.34 (br, 1H), 2.44 (s, 3H). 13C NMR (100 MHz, chloroform-d) δ 201.1, 165.3 (d, J = 253.4 Hz), 148.9, 134.9, 134.7–134.2 (m), 132.6, 125.8, 119.5, 116.9, 116.1 (t, J = 6.4 Hz), 116.0–115.8 (m), 115.6 (t, J = 6.4 Hz), 112.3, 27.9. HRMS (ESI) m/z: calcd for C33H25F4NO3P2 [M + H]+: 621.1246, found: 621.1245.
1-(2-((Bis(di([1,1′-biphenyl]-4-yl)phosphoryl)methyl)amino)phenyl)ethan-1-one (4b)
Green solid (350 mg, yield 81%). m.p.:173 °C–175 °C. 1H NMR (400 MHz, chloroform-d) δ 9.76 (d, J = 10.8 Hz, 1H), 8.09 (s, 4H), 7.94 (s, 4H), 7.55–7.53 (m, 4H), 7.42–7.36 (m, 24H), 7.19 (t, J = 7.7 Hz, 2H), 7.04 (br, 1H), 6.50 (t, J = 7.6 Hz, 1H), 5.79 (br, 1H), 2.30 (s, 3H). 13C NMR (100 MHz, chloroform-d) δ 200.8, 149.5, 144.6, 144.5, 139.6, 134.8, 132.4–132.1 (m), 128.9, 128.1, 127.1, 126.7 (t, J = 6.0 Hz), 119.5, 116.5, 113.4, 27.7. HRMS (ESI) m/z: calcd for C57H45NO3P2 [M + H]+: 863.2875, found: 863.2872.
1-(2-((Bis(bis(3-fluorophenyl)phosphoryl)methyl)amino)phenyl)ethan-1-one (4c)
Green solid (280 mg, yield 90%). m.p.:174 °C–176 °C. 1H NMR (400 MHz, chloroform-d) δ 9.69 (d, J = 10.9 Hz, 1H), 7.76–7.72 (m, 2H), 7.67–7.35 (m, 10H), 7.31–7.07 (m, 6H), 6.79–6.40 (m, 2H), 5.44–5.34 (m, 1H), 2.47 (s, 3H). 13C NMR (100 MHz, chloroform-d) δ 201.0, 148.6, 134.8, 132.4, 130.5–130.2 (m), 127.5, 127.3, 119.8–119.5 (m), 119.1–118.5 (m), 117.0, 112.2, 57.4 (t, J = 63.8 Hz), 27.7. HRMS (ESI) m/z: calcd for C33H25F4NO3P2 [M + H]+: 621.1246, found: 621.1245.
1-(2-((Bis(bis(3-chlorophenyl)phosphoryl)methyl)amino)phenyl)ethan-1-one (4d)
Green solid (288 mg, yield 84%). m.p.:171 °C–173 °C. 1H NMR (400 MHz, chloroform-d) δ 9.68 (d, J = 10.9 Hz, 1H), 7.78–7.05 (m, 18H), 6.75–6.49 (m, 2H), 5.45–5.35 (m, 1H), 2.45 (s, 3H). 13C NMR (100 MHz, chloroform-d) δ 201.1, 148.6, 134.8, 132.4, 130.7–130.5, 130.4–130.2 (m), 127.6–127.4 (m), 127.3–127.2 (m), 57.3 (t, J = )130.2, 130.1, 127.5, 127.1, 119.7, 119.6, 119.5, 119.4, 119.0, 118.7, 118.4, 116.9, 112.1, 57.3 (t, J = 65.0 Hz), 27.7. HRMS (ESI) m/z: calcd for C33H25NO3P2 [M + H]+: 685.0064, found: 685.0062.
1-(2-((Bis(di-m-tolylphosphoryl)methyl)amino)phenyl)ethan-1-one (4e)
Green solid (142 mg, yield 47%). m.p.:176 °C–178 °C. 1H NMR (400 MHz, chloroform-d) δ 9.55 (d, J = 10.8, 1H), 7.73–7.66 (m, 2H), 7.61–7.50 (m, 4H), 7.53–7.48 (m, 2H), 7.43 (dd, J = 8.0, 1.6 Hz, 1H), 7.22–7.07 (m, 9H), 6.75 (d, J = 8.6 Hz, 1H), 6.47 (t, J = 7.5 Hz, 1H), 5.50–5.40 (m, 1H), 2.34 (s, 3H), 2.20 (s, 6H), 2.15 (s, 6H). 13C NMR (100 MHz, chloroform-d) δ 200.4, 149.2, 138.0 (t, J = 6.0 Hz), 137.7 (t, J = 5.8 Hz), 134.4, 132.6, 132.3–132.1 (m), 128.9 (t, J = 4.9 Hz), 128.5 (t, J = 5.1 Hz), 128.1 (t, J = 6.5 Hz), 127.9 (t, J = 6.4 Hz), 119.2, 116.0, 112.6, 57.2 (t, J = 59.7 Hz), 27.7, 21.3, 21.2. HRMS (ESI) m/z: calcd for C37H37NO3P2 [M + H]+: 605.2249, found: 605.2249.
Acknowledgments
We gratefully acknowledge the National Natural Science Foundation of China (21672157), PAPD, the Project of Scientific and Technologic Infrastructure of Suzhou (SZS201708), Natural Science Foundation of Jiangsu Province (BK20200874), Natural Science Foundation for Colleges and Universities in Jiangsu Province (20KJD150001), and Soochow University (Q410900620) for financial support. We thank Hai-Feng Yao in this group for repeating the results.
Supporting Information Available
The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.1c00160.
1H and 13C NMR spectra of all products (PDF)
The authors declare no competing financial interest.
Supplementary Material
References
- a Dutartre M.; Bayardon J.; Jugé S. Applications and stereoselective syntheses of P-chirogenic phosphorus compounds. Chem. Soc. Rev. 2016, 45, 5771–5794. 10.1039/C6CS00031B. [DOI] [PubMed] [Google Scholar]; b Nordheider A.; Chivers T.; Schön O.; Karaghiosoff K.; Arachchige K. S. A.; Slawin A. M. Z.; Woollins J. D. Isolatable Organophosphorus(III)–Tellurium Heterocycles. Chem.-Eur. J. 2014, 20, 704–712. 10.1002/chem.201303884. [DOI] [PubMed] [Google Scholar]; c Nordheider A.; Woollins J. D.; Chivers T. Organophosphorus–Tellurium Chemistry: From Fundamentals to Applications. Chem. Rev. 2015, 115, 10378–10406. 10.1021/acs.chemrev.5b00279. [DOI] [PubMed] [Google Scholar]; d Nordheider A.; Chivers T.; Thirumoorthi R.; Arachchige K. S. A.; Slawin A. M. Z.; Woollins J. D.; Vargas-Baca I. A planar dianionic ditelluride and a cyclic tritelluride supported by P2N2 rings. Dalton Trans. 2013, 42, 3291–3294. 10.1039/C2DT32716C. [DOI] [PubMed] [Google Scholar]; e Hinz A.; Kuzora R.; Rosenthal U.; Schulz A.; Villinger A. Activation of Small Molecules by Phosphorus Biradicaloids. Chem.-Eur. J. 2014, 20, 14659–14673. 10.1002/chem.201403964. [DOI] [PubMed] [Google Scholar]; f Cristau H.-J.; Monbrun J.; Schleiss J.; Virieux D.; Pirat J.-L. First synthesis of P-aryl-phosphinosugars, organophosphorus analogues of C-arylglycosides. Tetrahedron Lett. 2005, 46, 3741–3744. 10.1016/j.tetlet.2005.03.148. [DOI] [Google Scholar]; g Filippini D.; Loiseau S.; Bakalara N.; Dziuganowska Z. A.; Van der Lee A.; Volle J.-N.; Virieux D.; Pirat J.-L. Dramatic effect of modified boranes in diastereoselective reduction of chiral cyclic α-ketophosphinates. RSC Adv. 2012, 2, 816–818. 10.1039/C2RA00799A. [DOI] [Google Scholar]; h Clarion L.; Jacquard C.; Sainte-Catherine O.; Loiseau S.; Filippini D.; Hirlemann M.-H.; Volle J.-N.; Virieux D.; Lecouvrey M.; Pirat J.-L.; Bakalara N. Oxaphosphinanes: New Therapeutic Perspectives for Glioblastoma. J. Med. Chem. 2012, 55, 2196–2211. 10.1021/jm201428a. [DOI] [PubMed] [Google Scholar]; i Clarion L.; Jacquard C.; Sainte-Catherine O.; Decoux M.; Loiseau S.; Rolland M.; Lecouvrey M.; Hugnot J.-P.; Volle J.-N.; Virieux D.; Pirat J.-L.; Bakalara N. C-Glycoside Mimetics Inhibit Glioma Stem Cell Proliferation, Migration, and Invasion. J. Med. Chem. 2014, 57, 8293–8306. 10.1021/jm500522y. [DOI] [PubMed] [Google Scholar]
- a Oosterom G. E.; Reek J. N. H.; Kamer P. C. J.; van Leuwen P. W. N. M. Transition Metal Catalysis Using Functionalized Dendrimers. Angew. Chem., Int. Ed. 2001, 40, 1828–1849. . [DOI] [PubMed] [Google Scholar]; b He Y.-M.; Feng Y.; Fan Q.-H. Asymmetric Hydrogenation in the Core of Dendrimers. Acc. Chem. Res. 2014, 47, 2894–2906. 10.1021/ar500146e. [DOI] [PubMed] [Google Scholar]; c El-Faham A.; Albericio F. Peptide Coupling Reagents, More than a Letter Soup. Chem. Rev. 2011, 111, 6557–6602. 10.1021/cr100048w. [DOI] [PubMed] [Google Scholar]; d Mori S.; Aoyama T.; Shioiri T. New methods and reagents in organic synthesis, 40. Amination of aromatic and heteroaromatic organometallics using diphenyl phosphorazidate (DPPA). Tetrahedron Lett. 1984, 25, 429–432. 10.1016/S0040-4039(00)99903-9. [DOI] [Google Scholar]; e Kleineweischede R.; Hackenberger C. P. R. Chemoselective Peptide Cyclization by Traceless Staudinger Ligation. Angew. Chem., Int. Ed. 2008, 47, 5984–5988. 10.1002/anie.200801514. [DOI] [PubMed] [Google Scholar]
- a Nakamura A.; Kageyama T.; Goto H.; Carrow B. P.; Ito S.; Nozaki K. P-Chiral Phosphine–Sulfonate/Palladium-Catalyzed Asymmetric Copolymerization of Vinyl Acetate with Carbon Monoxide. J. Am. Chem. Soc. 2012, 134, 12366–12369. 10.1021/ja3044344. [DOI] [PubMed] [Google Scholar]; b Nakamura A.; Anselment T. M. J.; Claverie J.; Goodall B.; Jordan R. F.; Mecking S.; Rieger B.; Sen A.; Van Leeuwen P. W. N. M.; Nozaki K. Ortho-Phosphinobenzenesulfonate: A Superb Ligand for Palladium-Catalyzed Coordination–Insertion Copolymerization of Polar Vinyl Monomers. Acc. Chem. Res. 2013, 46, 1438–1449. 10.1021/ar300256h. [DOI] [PubMed] [Google Scholar]; c Methot J. L.; Roush W. R. Nucleophilic Phosphine Organocatalysis. Adv. Synth. Catal. 2004, 346, 1035–1050. 10.1002/adsc.200404087. [DOI] [Google Scholar]; d Basavaiah D.; Chandrashekar V.; Das U.; Reddy G. J. A study toward understanding the role of a phosphorus stereogenic center in (5S)-1,3-diaza-2-phospha-2- oxo-3-phenylbicyclo(3.3.0)octane derivatives as catalysts in the borane-mediated asymmetric reduction of prochiral ketones. Tetrahedron 2005, 16, 3955–3962. 10.1016/j.tetasy.2005.10.038. [DOI] [Google Scholar]; e Denmark S. E.; Beutner G. L. Lewis Base Catalysis in Organic Synthesis. Angew. Chem., Int. Ed. 2008, 47, 1560–1638. 10.1002/anie.200604943. [DOI] [PubMed] [Google Scholar]; f Werner T. Phosphonium Salt Organocatalysis. Adv. Synth. Catal. 2009, 351, 1469–1481. 10.1002/adsc.200900211. [DOI] [Google Scholar]; h Ender D.; Nguyen T. V. Chiral quaternary phosphonium salts: a new class of organocatalysts. Org. Biomol. Chem. 2012, 10, 5327–5331. 10.1039/c2ob25823d. [DOI] [PubMed] [Google Scholar]
- a Chodkiewicz W.; Jore D.; Wodzki W. Optically active phosphines: New synthetic approach. Tetrahedron Lett. 1979, 20, 1069–1072. 10.1016/S0040-4039(01)87194-X. [DOI] [Google Scholar]; b Chodkiewicz W.; Jore D.; Pierrat A.; Wodzki W. Separation de complexes cuivreux de phosphinites diastereoisomeres; Synthese de phosphines tertiaires chirales. J. Organomet. Chem. 1979, 174, C21–C23. 10.1016/S0022-328X(00)96175-8. [DOI] [Google Scholar]; c Mikolajczyk M. Optically active trivalent phosphorus acid esters: synthesis, chirality at phosphorus and some transformations. Pure Appl. Chem. 1980, 52, 959–972. 10.1351/pac198052040959. [DOI] [Google Scholar]; d Chodkiewicz W. One-pot synthesis of chiral phosphonous esters, conversion into asymmetric phosphines. J. Organomet. Chem. 1984, 273, C55–C56. 10.1016/0022-328X(84)80557-4. [DOI] [Google Scholar]; e Neuffer J.; Richter W. J. Optisch aktive phosphine durch asymmetrische substitution prochiraler, homochiral substituierter phosphonite. J. Organomet. Chem. 1986, 301, 289–297. 10.1016/0022-328X(86)80033-X. [DOI] [Google Scholar]
- a Widler L.; Jaeggi K. A.; Glatt M.; Müller K.; Bachmann R.; Bisping M.; Born A.-R.; Cortesi R.; Guiglia G.; Jeker H.; Klein R.; Ramseier U.; Schmid J.; Schreiber G.; Seltenmeyer Y.; Green J. R. Highly Potent Geminal Bisphosphonates. From Pamidronate Disodium (Aredia) to Zoledronic Acid (Zometa). J. Med. Chem. 2002, 45, 3721–3738. 10.1021/jm020819i. [DOI] [PubMed] [Google Scholar]; b Barbosa J. S.; Braga S. S.; Almeida Paz F. A. Molecules 2020, 25, 2821. 10.3390/molecules25122821. [DOI] [PMC free article] [PubMed] [Google Scholar]; c Zhou S.; Huang G.; Chen G. Eur. J. Med. Chem. 2020, 197, 112313–112341. 10.1016/j.ejmech.2020.112313. [DOI] [PubMed] [Google Scholar]
- a Kotsikorou E.; Song Y.; Chan J. M. W.; Faelens S.; Tovian Z.; Broderick E.; Bakalara N.; Docampo R.; Oldfield E. Bisphosphonate Inhibition of the Exopolyphosphatase Activity of the Trypanosoma brucei Soluble Vacuolar Pyrophosphatase. J. Med. Chem. 2005, 48, 6128–6139. 10.1021/jm058220g. [DOI] [PubMed] [Google Scholar]; b Leon A.; Liu L.; Yang Y.; Hudock M. P.; Hall P.; Yin F.; Studer D.; Puan K.-J.; Morita C. T.; Oldfield E. Isoprenoid Biosynthesis as a Drug Target: Bisphosphonate Inhibition of Escherichia coli K12 Growth and Synergistic Effects of Fosmidomycin. J. Med. Chem. 2006, 49, 7331–7341. 10.1021/jm060492b. [DOI] [PubMed] [Google Scholar]
- a Sanders J. M.; Gómez A. O.; Mao J.; Meints G. A.; Brussel E. M. V.; Burzynska A.; Kafarski P.; González-Pacanowska D.; Oldfield E. 3-D QSAR Investigations of the Inhibition of Leishmania major Farnesyl Pyrophosphate Synthase by Bisphosphonates. J. Med. Chem. 2003, 46, 5171–5183. 10.1021/jm0302344. [DOI] [PubMed] [Google Scholar]; b Wang A.-E.; Chang Z.; Sun W.-T.; Huang P.-Q. General and Chemoselective Bisphosphonylation of Secondary and Tertiary Amides. Org. Lett. 2015, 17, 732–735. 10.1021/acs.orglett.5b00004. [DOI] [PubMed] [Google Scholar]; c Bálint E.; Tajti Á.; Ádám A.; Csontos I.; Karaghiosoff K.; Czugler M.; Ábrányi-Balogh P.; Keglevich G. The synthesis of α-aryl-α-aminophosphonates and α-aryl-α-aminophosphine oxides by the microwave-assisted Pudovik reaction. Beilstein J. Org. Chem. 2017, 13, 76–86. 10.3762/bjoc.13.10. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hirai T.; Han L.-B. Palladium-Catalyzed Insertion of Isocyanides into P(O)–H Bonds: Selective Formation of Phosphinoyl Imines and Bisphosphinoylaminomethanes. J. Am. Chem. Soc. 2006, 128, 7422–7423. 10.1021/ja060984d. [DOI] [PubMed] [Google Scholar]
- Basiouny M. M. I.; Schmidt J. A. R. Lanthanum-Catalyzed Double Hydrophosphinylation of Nitriles. Organometallics 2017, 36, 721–729. 10.1021/acs.organomet.6b00919. [DOI] [Google Scholar]
- Wen L.-R.; Sun Y.-X.; Zhang J.-W.; Guo W.-S.; Li M. Catalyst- and solvent-free bisphosphinylation of isothiocyanates: a practical method for the synthesis of bisphosphinoylaminomethanes. Green Chem. 2018, 20, 125–129. 10.1039/C7GC03101G. [DOI] [Google Scholar]
- For books, see:; a Ugi I.Isonitrile Chemistry; Academic Press: New York, 1971. [Google Scholar]; b Nenajdenko C.Isocyanide Chemistry: Applications in Synthesis and Material Science; Wiley–VCH: Weinheim, Germany, 2012. [Google Scholar]
- For reviews, see:; a Song B.; Xu B. Metal-catalyzed C–H functionalization involving isocyanides. Chem. Soc. Rev. 2017, 46, 1103–1123. 10.1039/C6CS00384B. [DOI] [PubMed] [Google Scholar]; b Boyarskiy V. P.; Bokach N. A.; Luzyanin K. V.; Kukushkin V. Y. Metal-Mediated and Metal-Catalyzed Reactions of Isocyanides. Chem. Rev. 2015, 115, 2698–2779. 10.1021/cr500380d. [DOI] [PubMed] [Google Scholar]; c Qiu G.; Ding Q.; Wu J. Recent advances in isocyanide insertion chemistry. Chem. Soc. Rev. 2013, 42, 5257–5269. 10.1039/c3cs35507a. [DOI] [PubMed] [Google Scholar]; d Lang S. Unravelling the labyrinth of palladium-catalysed reactions involving isocyanides. Chem. Soc. Rev. 2013, 42, 4867–4880. 10.1039/c3cs60022j. [DOI] [PubMed] [Google Scholar]; e Vlaar T.; Ruijter E.; Maes B. U. W.; Orru R. V. A. Palladium-Catalyzed Migratory Insertion of Isocyanides: An Emerging Platform in Cross-Coupling Chemistry. Angew. Chem., Int. Ed. 2013, 52, 7084–7097. 10.1002/anie.201300942. [DOI] [PubMed] [Google Scholar]; f Zhang B.; Studer A. Recent advances in the synthesis of nitrogen heterocycles via radical cascade reactions using isonitriles as radical acceptors. Chem. Soc. Rev. 2015, 44, 3505–3521. 10.1039/C5CS00083A. [DOI] [PubMed] [Google Scholar]
- a Wang X.; Xu X.-P.; Wang S.-Y.; Zhou W.; Ji S.-J. Highly Efficient Chemoselective Synthesis of Polysubstituted Pyrroles via Isocyanide-Based Multicomponent Domino Reaction. Org. Lett. 2013, 15, 4246–4249. 10.1021/ol401976w. [DOI] [PubMed] [Google Scholar]; b Wang X.; Wang S.-Y.; Ji S.-J. Isocyanide-Based Multicomponent Reactions: Catalyst-Free Stereoselective Construction of Polycyclic Spiroindolines. Org. Lett. 2013, 15, 1954–1957. 10.1021/ol400606c. [DOI] [PubMed] [Google Scholar]; c Zhu T.-H.; Wang S.-Y.; Wang G.-N.; Ji S.-J. Cobalt-Catalyzed Oxidative Isocyanide Insertion to Amine-Based Bisnucleophiles: Diverse Synthesis of Substituted 2-Aminobenzimidazoles, 2-Aminobenzothiazoles, and 2-Aminobenzoxazoles. Chem.-Eur. J. 2013, 19, 5850–5853. 10.1002/chem.201300239. [DOI] [PubMed] [Google Scholar]; d Zhao L.-L.; Wang S.-Y.; Xu X.-P.; Ji S.-J. Dual 1,3-dipolar cycloaddition of carbon dioxide: two C=O bonds of CO2 react in one reaction. Chem. Commun. 2013, 49, 2569–2571. 10.1039/c3cc38526d. [DOI] [PubMed] [Google Scholar]; e Wang R.; Xu X.-P.; Meng H.; Wang S.-Y.; Ji S.-J. 3-Phenacylideneoxindoles with tosylmethyl isocyanide and MeOH through CeC bond cleavage: facile synthesis of pyrrole and 2H-pyrrolo[3,4-c]quinoline derivatives. Tetrahedron 2013, 69, 1761–1766. 10.1016/j.tet.2012.11.088. [DOI] [Google Scholar]; f Wang R.; Wang S.-Y.; Ji S.-J. Chemoselective synthesis of 3H-pyrrolo[2,3-c]quinolin-4(5H)-one derivatives from 3-phenacylideneoxindoles and substituted tosylmethyl isocyanide (TosMIC). Tetrahedron 2013, 69, 10836–10841. 10.1016/j.tet.2013.10.084. [DOI] [Google Scholar]; g Cao J.-J.; Zhu T.-H.; Gu Z.-Y.; Hao W.-J.; Wang S.-Y.; Ji S.-J. Silver-catalyzed 2-isocyanobiaryls insertion/cyclization with phosphine oxides: synthesis of 6-phosphorylated phenanthridines. Tetrahedron 2014, 70, 6985–6990. 10.1016/j.tet.2014.07.078. [DOI] [Google Scholar]; h Gu Z.-Y.; Zhu T.-H.; Cao J.-J.; Xu X.-P.; Wang S.-Y.; Ji S.-J. Palladium-Catalyzed Cascade Reactions of Isocyanides with Enaminones: Synthesis of 4-Aminoquinoline Derivatives. ACS Catal. 2014, 4, 49–52. 10.1021/cs400904t. [DOI] [Google Scholar]; i Fang Y.; Wang S. Y.; Shen X. B.; Ji S. J. Base-promoted cascade reaction of isocyanides, selenium and amines: a practical approach to 2-aminobenzo[d][1,3]selenazines under metal-free conditions. Org. Chem. Front. 2015, 2, 1338–1341. 10.1039/C5QO00150A. [DOI] [Google Scholar]; j Fang Y.; Zhu Z.-L.; Xu P.; Wang S. Y.; Ji S. J. Aerobic radical-cascade cycloaddition of isocyanides, selenium and imidamides: facile access to 1,2,4-selenadiazoles under metal-free conditions. Green Chem. 2017, 19, 1613–1618. 10.1039/C6GC03521C. [DOI] [Google Scholar]; k Liu H.; Fang Y.; Wang S.-Y.; Ji S.-J. TEMPO-Catalyzed Aerobic Oxidative Selenium Insertion Reaction: Synthesis of 3-Selenylindole Derivatives by Multicomponent Reaction of Isocyanides, Selenium Powder, Amines, and Indoles under Transition-Metal-Free Conditions. Org. Lett. 2018, 20, 930–933. 10.1021/acs.orglett.7b03783. [DOI] [PubMed] [Google Scholar]; l Gu Z.-Y.; Zhang R.; Wang S.-Y.; Ji S.-J. Cobalt(II)-Catalyzed Bis-isocyanides Insertion Reactions with Boric Acids and Sulfonyl Azides via Nitrene Radical Coupling. Chin. J. Chem. 2018, 36, 1011–1016. 10.1002/cjoc.201800307. [DOI] [Google Scholar]; m Gu Z.; Ji S. Recent Advances in Cobalt Catalyzed Isocyanide Coupling Reactions. Acta Chim. Sin. 2018, 76, 347–356. 10.6023/A18010023. [DOI] [Google Scholar]; n Wang F.; Wei T.-Q.; Xu P.; Wang S.-Y.; Ji S.-J. Mn(III)-mediated radical cascade reaction of boronic acids with isocyanides: Synthesis of diimide derivatives. Chin. Chem. Lett. 2019, 30, 379–382. 10.1016/j.cclet.2018.08.006. [DOI] [Google Scholar]; o Yuan Q.; Rao W.; Wang S.-Y.; Ji S.-J. Copper-Catalyzed Chemoselective Cyclization Reaction of 2-Isocyanoacetophenone: Synthesis of 4-Hydroxyquinoline Compounds. J. Org. Chem. 2020, 85, 1279–1284. 10.1021/acs.joc.9b02903. [DOI] [PubMed] [Google Scholar]
- Zhu J., Bienayme H., Eds.; Multicomponent Reactions; Wiley-VCH: Weinheim, Germany, 2005. [Google Scholar]
- a Zhang B.; Daniliuc C. G.; Studer A. 6-Phosphorylated Phenanthridines from 2-Isocyanobiphenyls via Radical C–P and C–C Bond Formation. Org. Lett. 2014, 16, 250–253. 10.1021/ol403256e. [DOI] [PubMed] [Google Scholar]; b Yang B.; Tian Q.; Yang S. Silver-Promoted P-radical Cyclization Reaction with the Addition to Isonitrile. Chin. J. Org. Chem. 2014, 34, 717–721. 10.6023/cjoc201312023. [DOI] [Google Scholar]; c Li Y.; Qiu G.; Ding Q.; Wu J. Synthesis of phenanthridin-6-yldiphenylphosphine oxides by oxidative cyclization of 2-isocyanobiphenyls with diarylphosphine oxides. Tetrahedron 2014, 70, 4652–4656. 10.1016/j.tet.2014.05.039. [DOI] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.