HETEROCYCLES

Short Paper | Regular issue | Vol. 85, No. 10, 2012, pp. 2543-2550
Received, 31st July, 2012, Accepted, 23rd August, 2012, Published online, 27th August, 2012.
DOI: 10.3987/COM-12-12560

■ Stereospecific Synthesis of trans-1,4-Diphosphacyclohexanes

Yasuhiro Morisaki,* Hiroaki Imoto, Ryosuke Kato, Yuko Ouchi, and Yoshiki Chujo*

Department of Polymer Chemistr, Graduate School of Engineering, Kyoto University, Katsura, Nishikyo-ku, Kyoto 615-8510, Japan

Abstract

Stereospecific synthesis of trans-1,4-diphosphacyclohexanes via intramolecular oxidative coupling of P-stereogenic bisphosphine borane complexes is reported. Regardless of the enantiopurity of the starting materials, only trans-isomers were formed. The synthesis and characterization of the obtained products are described in detail herein.

Phosphines (trivalent organophosphorus compounds; PR3; R = organic moiety), similar to tertiary amines (NR3), have a trigonal pyramidal structure with the phosphorus atom at the apex; however, the inversion energy of PR3 is much higher because of the increased s character resulting from the unshared electron pair on phosphorus.1 Therefore, the phosphorus atom behaves as a chiral center in the same manner as a chiral carbon atom, and optically active phosphines are conformationally stable. From this structural viewpoint, a large number of optically active P-stereogenic phosphines have been synthesized;2 in particular, optically active P-stereogenic bisphosphines have been widely used as chiral ligands for transition-metal-catalyzed asymmetric reactions.3 One such bisphosphine with a methyl substituent at each phosphorus atom, BisP* (Figure 1), was synthesized with relatively high enantiomeric excess (ee%) by Evans4 and Imamoto.5 In this study, we investigated the reactivity of BisP*–borane complexes and the feasibility of using BisP* as chiral building blocks for a variety of P-stereogenic compounds.
Lithiation of the methyl group of BisP* by alkyllithium reagents proceeds smoothly because of the strong electron-withdrawing character of the coordinated borane. Actually, the BisP*–boranes can also be prepared by the lithiation of methylphosphine boranes or methylphosphine sulfides.4,5 Lithiation of BisP*–boranes and successive oxidative coupling affords various optically active P-stereogenic oligomers6 and polymers.7

We found that intramolecular oxidative coupling of the lithiated BisP*–boranes afforded trans-diphosphacyclohexanes in a stereospecific manner,8 which is the rare example of the stereo-controlled synthesis of cis- or trans-diphosphacycloalkanes. Alder and coworkers succeeded in the stereoselective synthesis of a series of cis-diphosphacycloalkanes by the ring-opening reaction of the corresponding bicyclic compounds.9 Recently, Strohmann and coworkers reported the synthesis of trans-1,4-diphenyl-1,4-diphosphacyclohexane by the direct dilithiation of prochiral dimethylphenylphosphine borane and its one-pot oxidative cou pling reaction.10 Our synthetic route is attractive in that the only trans-isomer can be obtained from BisP*–borane, regardless of the enantiopurity of the starting material. For the purpose of establishing the synthetic method for the stereospecific synthesis of trans-1,4-diphosphacyclohexanes, we carried out the synthesis of trans-1,4-diphosphacyclohexanes from several optically active BisP*–boranes and characterized the products in detail.
The synthesis of trans-1,4-diphosphacyclohexanes commenced with optically active BisP*–boranes (S,S)-1a-f–BH3, as shown in Scheme 1. Treatment of (S,S)-1a-f–BH3 with sec-BuLi and amine ligands such as N,N,N´,N´-tetramethylethylenediamine (TMEDA) and (–)-sparteine afforded a dilithiated intermediate. Transmetallation from Li to Cu using CuCl2 and successive reductive elimination with aqueous NH3 caused intramolecular oxidative coupling to provide the corresponding 1,4-diphosphacyclohexanes trans-2a-f–BH3. The crude products were purified by SiO2 column chromatography and recrystallized from hot toluene and hexane to give the desired products in moderate-to-good isolated yields. In this reaction, cyclization proceeded dominantly without polymeric compounds even in dilute solution, and the main by-product was the starting material.

The stereochemistry of the obtained 1,4-diphosphacyclohexanes was completely “trans”; the reaction afforded only trans-isomers, because the reaction proceeded stereospecifically due to the use of enantiopure (S,S)-BisP*–boranes. In this stereospecific reaction, we do not need take care of the enantiopurity of the starting BisP*–boranes; in other words, BisP*–boranes with poor ee% as well as even racemi-BisP*–boranes provide only the trans-1,4-diphosphacyclohexanes, as shown in Scheme 2. (S,S)-BisP*–boranes could be readily obtained with high ee% by the intermolecular oxidative dimerization of RMe2P–BH3 using sec-BuLi and a chiral amine ligand such as (–)-sparteine; however, meso-BisP*–boranes formed in the reaction had to be removed from the reaction mixture since they would stereospecifically yield cis-1,4-diphosphacyclohexanes. Oxidative coupling of the mixture of rac- and meso-BisP*–boranes afforded equimolar amounts of trans- and cis-1,4-diphosphacyclohexane boranes, which could be separated by column chromatography, as shown in Scheme S1 (Supporting Information).

All the trans-2a-f–BH3 compounds prepared were purified by recrystallization from hot toluene and hexane. Their structures were confirmed by 1H, 13C, and 31P NMR, high-resonance mass analysis, elemental analysis, and X-ray crystallography. The ORTEP drawings of trans-2a-f–BH3 are shown in Figure 2, and the crystallographic data are listed in Tables S1–S6 (Supporting Information). X-Ray crystallographic analysis revealed that trans-2a-f–BH3 adopted a chair conformation with equatorial alkyl (and aryl) substituents and axial boranes in the crystal state.
We confirmed that the coordinated boranes could be removed from the trans-1,4-diphosphacyclohexane-borane complexes to obtain trans-1,4-diphosphacyclohexanes. Scheme 3 shows the removal of boranes of trans-2a– and 2d–BH3 as representative examples of aryl- and alkyl-substituted compounds, respectively. Generally, the removal of boranes of trialkylphosphine requires a relatively severe reaction conditions because of the strong phosphorus–boron coordination bond. Treatment of trans-2d–BH3 with excess CF3SO3H and then with KOH afforded trans-2d in 91% isolated yield.11 On the other hand, boranes of trans-2a–BH3 were readily removed by the reaction with an organic base such as 1,4-diazabicyclo[2.2.2]octane (DABCO) to afford the corresponding bisphosphine trans-2a in 94% isolated yield.

In conclusion, we demonstrated that trans-1,4-diphosphacyclohexanes can be stereospecifically prepared via the intramolecular oxidative coupling of optically active bisphosphine BisP*–boranes. Only trans-1,4-diphosphacyclohexane skeletons were formed, regardless of the enantiopurity of the BisP*–boranes. We showed the generality of our original synthetic method for the formation of trans-1,4-diphosphacyclohexanes with various substituents. Enantiopure BisP*s have been employed only as chiral ligands for transition metal-catalyzed asymmetric reactions; the results of this study reveal an entirely new set of applications of BisP* as chiral building blocks for a variety of P-stereogenic phosphorus compounds.

EXPERIMENTAL
1H (400 MHz) and 13C (100 MHz) NMR spectra were recorded on a JEOL EX400 or AL400 instrument. Samples were analyzed in CDCl3, and the chemical shift values were expressed relative to Me4Si as an internal standard. 31P NMR spectra were recorded on a JEOL EX400 spectrometer at 161.9 MHz, and samples were analyzed in CDCl3 using H3PO4 as an external standard. Mass analysis was performed at technical support office at Department of Synthetic Chemistry and Biological Chemistry, Kyoto University; high-resolution mass spectra (HRMS) were obtained on a JEOL JMS-SX102A spectrometer for EI, JEOL JMS-HX110A for FAB, and Thermo Scientific EXACTIVE for ESI. Analytical thin layer chromatography (TLC) was performed with silica gel 60 Merck F254 plates. Column chromatography was performed with Wakogel C-300 SiO2. Elemental analysis was performed at the Microanalytical Center of Kyoto University.
Materials. THF was purchased and purified by passage through purification column under Ar pressure.12 Dehydrated grade solvents of toluene and CHCl3 were purchased and used without further purification. N,N,N´,N´-Tetramethylethylenediamine (TMEDA) and (–)-sparteine were purchased and distilled from KOH under Ar atmosphere. sec-BuLi (1.0 M in cyclohexane and n-hexane solution), 1,4-diazabicyclo[2.2.2]octane (DABCO), CuCl2, aqueous NH3 (28%) were purchased and used without purification. All (S,S)-BisP* borane complexes — (S,S)-1a–BH3,4 (S,S)-1b–BH3,4 (S,S)-1c–BH3,13 (S,S)-1d–BH3,5 (S,S)-1e–BH3,5 and (S,S)-1f–BH35 — were prepared by the literature’s procedures. Reactions were performed under Ar atmosphere using standard Schlenk techniques.
Synthesis. Typical procedure is as follows. A solution of (–)-sparteine (0.55 mL, 2.5 mmol) as a ligand in THF (10 mL) was cooled to –78 °C. To this solution, sec-BuLi (1.0 M in cyclohexane and n-hexane solution, 2.5 mL, 2.5 mmol) was added by a syringe. After 15 min, a solution of (S,S)-1a–BH3 (0.302 g, 1.0 mmol) in THF (10 mL) was added dropwise, and the mixture was stirred at –78 °C for 3 h. CuCl2 (0.270 g, 2.0 mmol) was added in one portion with vigorous stirring, and the mixture was allowed to slowly warm to room temperature. After 15 h, aqueous NH3 (10 mL) was added, and the organic species were extracted with CH2Cl2 (3 × 10 mL). The combined extracts were washed with 5% aqueous NH3, 2 N HCl, and brine, and then dried over MgSO4. After evaporation of the solvent, the residue was purified by column chromatography on SiO2 with hexane-CH2Cl2 (v/v = 1:1) and recrystallization from hot toluene-hexane to obtain trans-2a–BH3 (167 mg, 0.56 mmol) as a colorless solid.
trans-2a–BH3: CCDC # 888064; 56% isolated yield; Rf = 0.83 (CH2Cl2 100%, SiO2); 1H NMR (CDCl3, 400 MHz δ 0.87 (br q, JHB = 108.4Hz, -BH3, 6H), 2.19 (dd, J = 10.5 Hz, JHP = 21.4 Hz, -PCH2-, 4H), 2.81 (m, -PCH2-, 4H), 7.56 (m, -Ar, 6H) 7.88 (m, -Ar, 4H) ppm; 13C NMR (CDCl3, 100 MHz) δ 19.7 (d, JCP = 33.7 Hz, -PCH2-), 127.3-132.2 (m, -Ar) ppm; 31P{1H}NMR (CDCl3, 161.9 MHz) δ +6.3 ppm. HRMS (EI). Calcd for C16H24B2P2 [M]+: 300.1539. Found 300.1532. Anal. Calcd for C16H24B2P2: C, 64.07; H, 8.07. Found: C, 63.85; H, 7.97.
trans-2b–BH3: CCDC # 888063; 30% isolated yield; Rf = 0.5 (hexane/EtOAc: v/v = 4:1, SiO2); 1H NMR (CDCl3, 400 MHz) δ 0.91 (br q, JHB = 123.0 Hz, -BH3, 6H), 2.04 (m, P-CH2-, 4H), 3.43 (m, P-CH2, 4H), 4.05 (s, -CH3, 6H), 6.99 (d, J = 8.6 Hz, -Ar, 2H), 7.10 (t, J = 7.3 Hz, -Ar, 2H), 7.56 (t, J = 7.3 Hz, -Ar, 2H), 8.00 (q, J = 4.8 Hz, -Ar, 2H) ppm; 13C NMR (CDCl3, 100 MHz) δ 17.0 (d, JCP = 34.6 Hz, -PCH2-), 55.6 (s, -OCH3), 110.7, 120.9, 134.1, 136.4, 136.5 and 162.0 (-Ar) ppm; 31P{1H}NMR (CDCl3, 161.9 MHz) δ +6.6 (JPB = 60.5 Hz) ppm. HRMS (ESI). Calcd for C18H28B2O2P2 [M+Na]+: 383.1643. Found 383.1638. Anal. Calcd for C18H28B2O2P2: C, 60.06; H, 7.84. Found: C, 59.89; H, 8.11.
trans-2c–BH3: CCDC # 888062; 44% isolated yield; 1H NMR (CDCl3, 400 MHz) δ 0.39 (br q, JHB = 100.6 Hz, -BH3, 6H), 1.19 (q, J = 8.3 Hz, -(CH3)2, 12H), 1.88-2.03 (m, -PCH2- and -CH(CH3)2, 6H), 2.24 (m, -PCH2-, 4H) ppm; 13C NMR (CDCl3, 100 MHz) δ 14.8 (d, JCP = 29.7 Hz, -PCH2-), 16.1 (s, -CH(CH3)2), 24.2 (d, JCP = 35.5 Hz, -PCH-) ppm; 31P{1H}NMR (CDCl3, 161.9 MHz) δ +18.1 (JPB = 65.9 Hz) ppm. HRMS (ESI). Calcd for C10H28B2P2 [M+H]+: 233.1925. Found 233.1926.
trans-2d–BH3: CCDC # 888065; 73% isolated yield; Rf = 0.78 (CH2Cl2 100%, SiO2); 1H NMR (CDCl3, 400 MHz) δ 0.40 (br q, JHB = 98.8Hz, -BH3, 6H), 1.19 (d, JHP = 14.0 Hz, -But, 18H), 1.88 (dd, J = 9.7 Hz, JHP =20.8Hz, -PCH2-, 4H), 2.36 (t, J = 10.0Hz, -PCH2-, 4H) ppm; 13C NMR (CDCl3, 100 MHz) δ 12.9 (d, JCP = 29.2 Hz, -PCH2-), 24.8 (s, -PC(CH3)3), 27.2 (d, -PC(CH3)3, JCP = 32.9 Hz) ppm; 31P{1H}NMR (CDCl3, 161.9 MHz) δ +26.6 ppm. HRMS (FAB). Calcd for C12H32B2P2 [M-H]+: 259.2087. Found 259.2086. Anal. Calcd for C12H32B2P2: C, 55.44; H, 12.41. Found: C, 55.45; H, 12.63.
trans-2e–BH3: CCDC # 888061; 36% isolated yield; Rf = 0.6 (hexane/EtOAc: v/v = 4:1, SiO2); 1H NMR (CDCl3, 400 MHz) δ 0.39 (br q, JHB = 101.0 Hz, -BH3, 6H), 1.29 (m, -C6H­11, 12H), 1.61-2.02 (m, -PCH2- and -C6H­11, 14H), 2.24 (m, -PCH2-, 4H), ppm; 13C NMR (CDCl3, 100 MHz) δ 14.7 (d, JCP = 23.1 Hz, -PCH2-), 25.7, 25.8, 26.3, 26.4, 33.9 and 34.2 (-C6H12) ppm; 31P{1H}NMR (CDCl3, 161.9 MHz) δ +14.1 (JPB = 60.5 Hz) ppm. HRMS (ESI). Calcd for C16H36B2P2 [M+Na]+: 335.2371. Found 335.2364. Anal. Calcd for C16H36B2P2: C, 61.59; H, 11.63. Found: C, 61.30; H, 11.63.
trans-2f–BH3: CCDC # 888060; 39% isolated yield; Rf = 0.30 (CHCl3/hexane: v/v = 1:1, SiO2); 1H NMR (CDCl3, 400 MHz δ 0.36 (br q, JHB = 106.4 Hz, -BH3, 6H), 1.69-1.84 (m, C-CH2-C and P-CH2, 28H), 2.04 (s, -CH-, 6H), 2.35 (m, -PCH2-, 4H) ppm; 13C NMR (CDCl3, 100 MHz) δ 11.3 (d, JCP = 29.7 Hz, -PCH2-), 27.6 (d, JCP = 9.1 Hz, -P-C-), 30.2 (d, JCP = 34.6 Hz, -PCH2-), 35.7 and 36.5 (s, adamantyl) ppm; 31P{1H}NMR (CDCl3, 161.9 MHz) δ +19.6 (JPB = 76.8 Hz) ppm. Anal. Calcd for C24H44B2P2: C, 69.26; H, 10.66. Found: C, 68.99; H, 10.74.
Synthetic details, spectral data, NMR spectra, and X-ray crystallographic data are shown in Supporting Information.

ACKNOWLEDGMENT
This work was partially supported by Grant-in-Aid for the Scientific Research on Innovative Areas of “Fusion Materials: Creative Development of Materials and Exploration of Their Function through Molecular Control” (No. 2206) from the Ministry of Education, Culture, Sports, Science and Technology, Japan. H.I. and Y.O. appreciate Research Fellowships from the Japan Society for the Promotion of Science for Young Scientists.

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