2-{(E)-{{(R)-1-[(1R,5S,6R)-3,3-Dimethyl-2,4,7-trioxabicyclo[3.3.0]octan-6-yl]ethyl}imino}methyl}-6-{[(diphenylphosphino)oxy] phenyl}palladium(II) chloride

Abstract

An unsymmetrical PCN palladium pincer complex 2-{(E)-{{(R)-1-[(1R,5S,6R)-3,3-dimethyl-2,4,7-trioxabicyclo[3.3.0]octan-6-yl]ethyl}imino}methyl}-6-{[(diphenylphosphino)oxy] phenyl}palladium(II) chloride based on an iminophosphinite ligand bearing two fused five-membered cycles, one of which containing a THF ring, was prepared in an eight-reaction sequence from a sustainable and enantiopure starting material, isosorbide, in a 20% overall yield.

1. Introduction

Since the first Shaw [1] and van Kolten [2] reports on the symmetric PCP and NCN pincer complex of metal transition, these type of complexes have attracted increasing attention due to their particular properties [3] and their use in wide-ranging reactions such as Kharasch and aldol Michael additions, Heck and Suzuki couplings, dehydrogenation, hydrogen transfer, etc. [4,5,6,7,8,9,10,11,12,13,14,15].

For C-C coupling reactions, as palladium complexes are considered to be the catalysts of choice, a large number of symmetrical [4,5,7,10,11], unsymmetrical [6,8], and chiral [11,13] palladium pincer complexes have been investigated. From all of them, only a few unsymmetric PCN pincer palladium (II) complexes with iminophosphinite ligands have been described thus far. Some of them have been synthesized by Xia for Suzuki or Kumada type couplings [16,17,18]. As isohexide derivatives have shown their efficiency as ligands in organometallic catalysis or as organocatalysts [19,20], we report herein the synthesis of an optical active non-symmetrical iminophosphinite PCN pincer palladium (II) complex derived from isosorbide, which is a sustainable material.

2. Results and Discussion

Starting from commercially available isosorbide, the synthesis of the targeted chiral PCN pincer palladium(II) Complex 6 was carried out in eight steps. The first three steps involved the preparation of the bicyclic Alcohol 1 according to our previous reports [21,22,23]. Next, mesylation of (S)-alcohol 1 yielded (S)-mesylate 2, which, after treatment with an excess sodium azide, afforded the corresponding (R)-azide 3 as a single stereoisomer. Slight hydrogenation of the latter led to the desired (R)-amine 4 (Scheme 1).

The targeted NPC palladium(II) Complex 6 (Scheme 1) was obtained in a one-pot (d, e, f, 56% global yield) strategy. The condensation of Amine 4 with 3-hydroxybenzaldehyde led to the Schiff-base 5 (Step d), which was involved in a phosphorylation (Step e) and a final metalation (Step f). Complex 6 was isolated as a yellow powder after purification over silica gel.

3. Materials and Methods

3.1. General

Commercially available reagents were used as received. Dichloromethane and tetrahydrofuran were dried with an activated alumina column (Glass Technology GTS 100). Dry triethylamine and toluene were distillated on CaH₂. Thin Layer Chromatography (TLC) was performed on precoated aluminum (200 μm) Merck silica gel (DC Kieselgel 60 F₂₅₄), and it was visualized using UV irradiation or via staining with a ready-to-use Aldrich phosphomolybdic acid (PMA) solution reagent. Column chromatography was carried out with Merck silica gel (Kiesegel 60, 0.063–0.200 mm). Optical rotations [α]_D²⁵ were carried out on a JASCO P-2000 Polarimeter. Melting points were carried out on a Barnstead Electrothermal IA9300 instrument and were not corrected. The NMR spectra were acquired on a Bruker AVANCE 400 spectroscope operating at 400, 162, and 100 MHz for ¹H, ³¹P, and ¹³C nuclei, respectively. All chemical shifts (δ values) are given in parts per million (ppm) and all homo-heterocoupling patterns (ⁿJ_H,H, ⁿJ_H,P and ⁿJ_C,P values) are given in hertz (Hz). Multiplicity is indicated as singlet (s), broad singlet (bs), doublet (d), triplet (t), quadruplet (q), and multiplet (m). The ¹H and ¹³C NMR spectra were referenced against TMS and ³¹P NMR against triphenylphosphate as the external reference. ATR-FTIR spectra were recorded with an Agilent Technologies apparatus. Only the relevant absorption maxima, ν_max (cm⁻¹), are listed throughout as “s” (strong), “m” (medium), or “w” (weak). High resolution mass spectroscopy (HRMS) was carried out with a Waters Micromass GCT Premier Device apparatus.

3.2. Synthesis and Characterization

Alcohol 1 was synthetized and exhibited analytical data in full agreement with the Ejjiyar procedure [21,22]. For the NMR assignment and for a better understanding, adapted numbering based on IUPAC nomenclature was chosen. Copies of NMR spectra (S1–S11) and HRMS of the complex 6 (S12) are available in the Supplementary Material.

3.2.1. (S)-1-{[(1R,5S,6R)-3,3-Dimethyl-2,4,7-trioxabicyclo[3.3.0]octan-6-yl]ethyl}methanesulfonate (2)

At 0 °C, under argon and stirring, methanesulfonyl chloride (1.12 g, 0.76 mL, 9.82 mmol, 1.05 equiv) and triethylamine (0.90 mg, 1.40 mL, 10.00 mmol, 1.10 equiv) were successively added to a solution of Alcohol 1 (1.75 g, 9.31 mmol) in anhydrous dichloromethane (40 mL). After stirring overnight, TLC monitoring (cyclohexane/AcOEt, 6:4 v/v) indicated completion of the reaction. The reaction mixture was washed with water (20 mL), with HCl aq (1N, 10 mL), and then with water (20 mL) and brine (20 mL). Finally, the organic phase was dried over MgSO₄, which was filtered off and concentrated in a vacuum to afford Mesylate 2 (2.22 g, 8.29 mmol, 89% yield) as a pure analytical sample. Compound 2 was used without further purification.

White solid m.p. 128 °C (DCM). Rf = 0.41 (cyclohexane/AcOEt, 6:4 v/v, PMA). [α]_D²⁵ = −15.6 (c 0.5, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃) 1.30 (3H, s, Me_a); 1.47 (3H, s, Me_b); 1.51 (3H, d, ³J_H2H1 = 6.5 Hz, H-2); 3.06 (3H, s, H-1″); 3.48 (1H, dd, ³J_H6′H2 = 6.6 Hz, ³J_H6′H5′ = 3.6 Hz, H-6′); 3.50 (1H, dd, ²J_H8′aH8′b = 10.8 Hz, ³J _{H8′a H1′} = 3.7 Hz, H-8′a); 4.04 (1H, d, ²J_H8′bH8′a = 10.8 Hz, H-8′b), 4.63 (1H, dd, ³J_H5′H1′ = 6.1 Hz, ³J_H5′6′ = 3.6 Hz, H-5′); 4.80 (1H, dd, ³J_H1′H5′ = 6.1 Hz, ³J_H1′H8′a = 3.7 Hz, H-1′); 4.90 (1H, dq, ³J_H1H6′ = 6.6 Hz, ³J_H1H2 = 6.5 Hz, H-1). ¹³C NMR (100 MHz, CDCl₃) 18.0 (Me_a); 24.0 (Me_b); 26.0 (C-2); 38.3 (C-1”); 73.0 (C-8′); 79.7 (C-1); 80.2 (C-5′); 81.1 (C-1′); 84.1 (C-6′); and 112.4 (C-3′). HRMS (FDI) m/z [M-CH₃]⁺ 251.0609; Calcd. for C₉H₁₅O₆S 251.0589).

3.2.2. (R)-1-{[(1R,5S,6R)-3,3-Dimethyl-2,4,7-trioxabicyclo[3.3.0]octan-6-yl]ethyl}azide (3)

A solution of Mesylate 2 (1.72 g, 6.42 mmol) and sodium azide (2.1 g, 32.1 mmol, 5 equiv) in a DMF/water mixture (5:2 v/v, 20 mL) was heated at 140 °C for 48 h. The mixture was cooled to room temperature before adding water. The solution was extracted four times with diethyl ether. The combined organic phases were dried over MgSO₄ and concentrated in a vacuum. The crude azide was purified by column chromatography (cyclohexane/AcOEt, 95:5 then 60:40 v/v) to give Azide 3 (0.75 g, 3.52 mmol, 56%) as a colorless oil.

Rf = 0.5 (cyclohexane/AcOEt, 8:2 v/v, PMA); [α]_D²⁵ = −118 (c 1.0, CHCl₃). ¹H NMR (400 MHz, CDCl₃) 1.35 (3H, s, Me_a); 1.40 (3H, d, ³J_H2H = 6.6 Hz, H-2); 1.48 (3H, s, H, Me_b); 3.17 (1H, dd, ³J_H6′H1 = 9.2 Hz, ³J_H6′H5′ = 3.5 Hz, H-6′); 3.48 (1H, dd, ²J_H8′aH8′b = 10.8 Hz, ³J_H8′aH1′ = 3.6 Hz, H-8′a); 3.84 (1H, dq, ³J_H1H6′ = 9.2 Hz, ³J_H1H2 = 6.6 Hz, H-1); 4.01 (1H, d, ²J_H8′bH8′a = 10.8 Hz, H-8′b); 4.71 (1H, dd, ³J_H5′H1′ = 6.1 Hz, ³J_H5′H6′ = 3.5 Hz, H-5′); 4.77 (1H, dd, ³J_H1′H5′ = 6.1 Hz, ³J_H1′H8′a = 3.6 Hz, H-1′). ¹³C NMR (100 MHz, CDCl₃) 17.1 (C-2); 24.8 (Me_a); 26.0 (Me_b); 55.3 (C-1); 73.0 (C-8′); 80.2 (C-5′); 80.9 (C-1′); 84.9 (C-6′); and 112.3 (C-3′). IR (neat, ν_max) 2983 (s), 2937 (s), 2853 (s), 2089 (s, N₃), 1458 (w), 1376 (m), 1264 (s), 1165 (w), 1112 (s), and 1073 (m) cm⁻¹. HRMS (ESI) m/z [M+Na]⁺ 236.1003. (Calcd. for C₉H₁₅O₆N₃Na 236.1006.)

3.2.3. (R)-1-[(1R,5S,6R)-3,3-Dimethyl-2,4,7-trioxabicyclo[3.3.0]octan-6-yl]ethylamine (4)

A solution of Azide 3 (666 mg; 3.13 mmol) and Pd/C 10% (71 mg) in ethanol (18 mL) was stirred at room temperature under hydrogen (4 bar) overnight. The mixture was filtered over Celite, and the filtrate was concentrated in a vacuum to give Amine 4 (542 mg, 2.90 mmol, 88%) as a slightly yellow oil, which was used without further purification.

[α]_D²⁰ = 70.1 (c 1.0, CHCl₃).¹H NMR (400 MHz, CDCl₃) 1.23 (3H, d, ³J_H2H1 = 6.5 Hz, H-2); 1.33 (3H, s, Me_a); 1.49 (3H, s, Me_b); 1.75 (2H, bs, NH₂); 3.09 (1H, dd, ³J_H6′H1 = 8.1 Hz, ³J_H6′H5′ = 3.0 Hz, H-6′); 3.22-3.35 (1H, m, H-1); 3.48 (1H, dd, ²J_H8′aH8′b = 10.8 Hz, ³J_H8′H1′ = 3.4 Hz, H-8′a); 4.02 (1H, d, ²J_H8′bH8′a = 10.8 Hz, H-8′b); 4.73 (1H, dd, ³J_H5′H1′ = 6.2 Hz, ³J_H5′H6′ = 3.0 Hz, H-5′); 4.76 (1H, dd, ³J_H1′H5′ = 6.2 Hz, and ³J_H1′H8′a = 3.4 Hz, H-1′). ¹³C NMR (100 MHz, CDCl₃) 21.0 (C-2); 24.7 (Me_a); 26.0 (Me_b); 46.2 (C-1); 72.4 (C-8′); 80.6 (C-5′); 81.0 (C-1′); 88.0 (C-6′); and 112.0 (C-3′). IR (neat,ν_max) 3376 (m, NH₂), 2982 (s), 2937 (s), 2851 (s), 1460 (w), 1374 (m), 1270 (s), 1168 (w), 1100 (s), and 1091 (m) cm⁻¹. HRMS (ESI) m/z [M+H]⁺ 188.1279. (Calcd. for C₉H₁₈NO₃ 188.1281.)

3.2.4. 2-{(E)-{{(R)-1-[(1R,5S,6R)-3,3-Dimethyl-2,4,7-trioxabicyclo[3.3.0]octan-6-yl]octan-6-yl]ethyl}imino}methyl}-6-{[(diphenylphosphino)oxy]phenyl}palladium(II) chloride (6)

Under argon, a solution of Amine 4 (102.8 mg, 0.551 mmol) and 3- hydroxybenzaldehyde (67.3 mg, 0.551 mmol) in dry dichloromethane (3 mL) in the presence of MgSO₄ was stirred overnight at room temperature. The mixture was filtered, and the solvent evaporated in a vacuum to give a crude Imine 5, which was immediately dissolved in dry toluene (5 mL) under argon. Chlorodiphenylphosphine (145 µg, 122 µL, 0.660 mmol, 1.2 equiv) and triethylamine (67 µg, 92 µL, 0.660 mmol, 1.2 equiv) were then added, and the solution was heated under reflux for 1 h. The solution was allowed to cool to room temperature and palladium (II) chloride (97.5 mg, 0.550 mmol) was added. The mixture was heated to reflux overnight, cooled to room temperature, and then filtered. The filtrate was concentrated under vacuum and the crude product purified by column chromatography (CH₂Cl₂ then CH₂Cl₂/Et₂O, 97:3 v/v) to give Complex 6 (190.2 mg, 0.309 mmol, 56%) as a yellow powder.

Rf = 0.1 (CH₂Cl₂, UV); mp > 250 °C; ¹H NMR (400 MHz, CDCl₃) 1.24 (3H, s, H-8 or H-9); 1.49 (3H, s, H-9 or H-8); 1.70 (3H, d, ³J_H2H1 = 6.5 Hz, H-2); 3.57 (1H, dd, ²J_H8′aH8′b = 10.7 Hz, ³J_H8′aH1′ = 3.6 Hz, H-8′a); 3.98 (1H, d, ²J_H8′bH8′a = 10.7 Hz, H-8′b); 4.11 (1H, dq, ³J_H1H6′ = 8.5 Hz, ³J_H1H2 = 6.5 Hz, H-1); 4.43 (1H, dd, ³J _H6′H1 = 8.5 Hz, ³J_H6′H5′ = 3.5 Hz, H-6′); 4.70 (dd, 1H, ³J _H5′H1′ = 6.2 Hz, ³J _H5′H6′ = 3.5 Hz, H-5′); 4.75 (1H, dd, ³J_H1′H5′ = 6.2 Hz, ³J_H1′H8′a = 3.6 Hz, H-1′); 6.93-6.96 (1H, m, H_Ar); 7.09-7.44 (1H, m, H_Ar); 7.46- 7.58 (6H, m, H_Ar); 7.97-8.05 (4H, m, H_Ar); and 8.21 (1H, d, J = 4.9 Hz, H10). ³¹P NMR (162 MHz, CDCl₃) 152.24. ¹³C NMR (100 MHz, CDCl₃) 18.7 (C-1); 24.9 (C-8); 26.1 (C-9); 66.6 (C-2); 72.7 (C-6); 80.3 (C-5); 81.5 (C-4); 82.5 (C-3); 111.8 (C-7); 114.8 (d, J_CP = 17.6 Hz); 122.6, 128.8 (d, J_CP = 12.0 Hz), 131.6, 131.8, 132.2, 132.3, 132.7 (d, J_CP = 55.5 Hz); 153.7; 145.7; 162.1 (d, J_CP = 9.6 Hz); and 175.1 (d, J_CP = 3.2 Hz) (18C_Ar, C-10). HRMS (FD+) m/z (100%) [M-Cl]⁺ 579.1213. (Calcd. for C28H28NO4PPd 580.0869.) m/z (42%) [M]⁺ 615.0492. (Calcd. for C28H28NO4ClPPd 615.0557.)

4. Conclusions

We synthesized and characterized iminophosphinite palladium (II) complexes from isosorbide, which is a sustainable material, in an eight-step sequence with an overall yield of 20%.