Reaction of 1-Amino Bisphosphinic
Acids with Acid Chlorides: Synthesis of Novel Cyclic 1-Hydroxy-1′-amino-1,1-bisphosphinic
Acids

Babak Kaboudin; Fariba Saadati; Tsutomu Yokomatsu

doi:10.1055/s-0030-1258115

LETTER

Reaction of 1-Amino Bisphosphinic Acids with Acid Chlorides: Synthesis of Novel Cyclic 1-Hydroxy-1′-amino-1,1-bisphosphinic Acids

Babak Kaboudin*^a, Fariba Saadati^a, Tsutomu Yokomatsu^b
^a Department of Chemistry, Institute for Advanced Studies in Basic Sciences (IASBS), Gava Zang, Zanjan 45137-66731, Iran
Fax: +98(241)4249023; e-Mail: kaboudin@iasbs.ac.ir;
^b School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horonouchi, Hachioji, Tokyo 192-0392, Japan

Abstract

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Abstract

Treatment of 1-amino bisphosphinic acids with HMDS followed by reaction with acid chlorides gives 1-hydroxy-1′-amino-1,1-bisphosphinic acid in good yields. The reaction gave a mixture of the racemate and meso form of 1-hydroxy-1′-amino-1,1-bisphosphinic acid. The stereochemistry of the readily separable diastereomer was confirmed after converting to the corresponding novel cyclic 1-hydroxy-1′-amino-1,1-bisphosphinic acid.

Key words

bisphosphinic acids - aminophosphinic acids - acid chlorides - hydroxyphosphinic acids

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References

References and Notes

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The aldehyde (3 mmol) was added to ammonium hydroxide (30%, 15 mL), and the solution was stirred for 5 h at reflux. During this time, a white precipitate formed. The precipitate was removed by filtration and dried. The solid was dissolved in 5 mL of EtOH, H₃PO₂ (5 mmol, anhyd) was added to this mixture, and the resulting solution was stirred for 2-12 h at reflux. The solvent was evaporated and the mixture resolved in acetone by heating. Dropwise addition of H₂O gave the crude product as a white solid. The crude product was washed with EtOH and dried in air at r.t. to give product 2 in 40-71% yield.^¹² The solid product was washed with EtOH-H₂O (50 mL, 9:1) and dried in air at r.t. to give a single diastereomer. A mixture of phosphinic acid 2 (one diastereomer, 1 mmol) and 1,1,1,3,3,3-hexamethyl-disilazane (5 mmol, 1 mL) was heated at 110 ˚C for 2 h under Ar. The mixture was then cooled to r.t. Acid chloride (1 mmol) was added dropwise, and the resulting mixture was stirred at r.t. for 12 h. The mixture was cooled in an ice bath, absolute EtOH (10 mL) was added, and the reaction mixture was stirred for 2 h at r.t. The removal of the solvent gave a residue, out of which a white solid precipitated after adding absolute EtOH (10 mL). The solid was washed with EtOAC (50 mL) and EtOH (50 mL), and gave pure novel cyclic amino bisphosphinic acid dl-5 as a white solid. All products gave satisfactory spectroscopic data in accordance with the assigned structures.
Analytical and Spectral Data for Compounds dl -5
Compound 5a: mp 234-236 ˚C. ^¹H NMR (250 MHz, D₂O): δ = 2.21 (6 H, s), 5.02 (1 H, d, J = 10.3 Hz), 5.27 (1 H, d, J = 10.5 Hz), 7.10-7.85 (13 H, m). ^³¹P NMR (101.2 MHz, D₂O-NaOD-H₃PO₄): δ = 21.58 (d, J _pp = 9.1 Hz), 22.29 (d, J _pp = 9.1 Hz). ^¹³C NMR (62.9 MHz, D₂O): δ = 20.1, 56.2 (d, J _PC = 89.3 Hz), 59.3 (d, J _PC = 86.7 Hz), 78.5 (dd, J _PC = 87.4, 71.4 Hz), 126.5-130.2 (m, Ar), 132.6, 133.7, 135.7, 137.5, 132.7. HRMS: m/z calcd for C₂₃H₂₅NO₅P₂ [MH⁺]: 458.1286; found: 458.1291.
Compound 5b: mp 238-240 ˚C. ^¹H NMR (250 MHz, D₂O): δ = 4.61 (1 H, d, J = 11.5 Hz), 4.73 (1 H, d, J = 11.5 Hz), 7.10-7.38 (13 H, m), 7.64 (2 H, d, J = 7.5 Hz). ^³¹P NMR (101.2 MHz, D₂O-H₃PO₄): δ = 21.03 (d, J _pp = 9.1 Hz), 22.08 (d, J _pp = 9.1 Hz). ^¹³C NMR (62.9 MHz, D₂O): δ = 56.8 (d, J _PC = 87.2 Hz), 59.2 (d, J _PC = 86.2 Hz), 78.5 (dd, J _PC = 86.4, 69.3 Hz,), 126.5-127.8 (m, Ar), 128.3, 135.9, 136.5, 137.8. HRMS: m/z calcd for C₂₁H₂₁NO₅P₂ [MH⁺]: 430.0973; found: 430.0966.
Compound 5c: mp 220-222 ˚C. ^¹H NMR (250 MHz, D₂O): δ = 4.75 (1 H, d, J = 15.0 Hz), 5.02 (1 H, d, J = 8.5 Hz), 7.05-7.40 (13 H, m), 8.20-8.32 (1 H, br). ^³¹P NMR (101.2 MHz, D₂O-H₃PO₄): δ = 19.60 (d, J _pp = 10.1 Hz), 22.93 (d, J _pp = 10.1 Hz). ^¹³C NMR (62.9 MHz, D₂O): δ = 56.9 (d, J _PC = 90.6 Hz), 58.8 (dd, J _PC = 87.4, 5.0 Hz), 80.0 (dd, J _PC = 87.4, 64.2 Hz), 126.0, 127.2, 127.5, 127.9 (d, J _PC = 5.0 Hz), 128.3, 128.4, 128.5, 130.5, 132.0, 133.1, 134.2 (d, J _PC = 3.8 Hz), 136.2 (d, J _PC = 3.8 Hz), 137.5. HRMS: m/z calcd for C₂₁H₂₀ClNO₅P₂ [MH⁺]: 464.0584; found: 464.0587.
Compound 5d: mp 241-243 ˚C. ^¹H NMR (250 MHz, D₂O): δ = 4.74 (1 H, d, J = 14.0 Hz), 4.91 (1 H, d, J = 10.8 Hz), 7.12-7.80 (14 H, m). ^³¹P NMR (101.2 MHz, D₂O-H₃PO₄):
δ = 18.78 (d, J _pp = 8.5 Hz), 19.98 (d, J _pp = 8.5 Hz). ^¹³C NMR (62.9 MHz, D₂O): δ = 56.7 (d, J _PC = 88.1 Hz), 59.3 (dd, J _PC = 90.6, 4.0 Hz), 78.2 (dd, J _PC = 87.2, 65.1 Hz), 125.3, 126.7, 126.8, 127.5, 127.7, 128.4, 128.5, 128.6, 128.9, 132.8, 135.2, 136.3, 138.0. HRMS: m/z calcd for C₂₁H₂₀ClNO₅P₂ [MH⁺]: 464.0584; found: 464.0593.
Compound 5e: mp 239-241 ˚C. ^¹H NMR (250 MHz, D₂O): δ = 4.84 (1 H, d, J = 8.0 Hz), 5.18-5.32 (1 H, br), 6.80-7.60 (13 H, m), 7.70-7.90 (1 H, br). ^³¹P NMR (101.2 MHz, D₂O-H₃PO₄): δ = 17.27, 18.05. ^¹³C NMR (62.9 MHz, D₂O): δ = 56.7 (d, J _PC = 86.7 Hz), 58.1 (d, J _PC = 93.7 Hz), 78.3 (dd, J _PC = 84.9, 74.7 Hz), 115.8, 116.2, 123.9, 128.2 (d, J _PC = 7.5 Hz), 128.5-130.5 (m, Ar), 134.2, 134.9, 160.2 (d, J _FC = 245.4 Hz). HRMS: m/z calcd for C₂₁H₂₀FNO₅P₂ [MH⁺]: 448.0879; found: 448.0883.
Compound 5f: mp 254-256 ˚C. ^¹H NMR (250 MHz, D₂O): δ = 4.67 (1 H, d, J = 14.7 Hz), 4.79 (1 H, d, J = 11.2 Hz), 7.00 (2 H, t, J = 8.7 Hz), 7.10-7.35 (8 H, m), 7.41 (2 H, d, J = 7.0 Hz), 7.65-7.80 (2 H, br). ^³¹P NMR (101.2 MHz, D₂O-H₃PO₄): δ = 20.82 (d, J _pp = 9.5 Hz), 21.84 (d, J _pp = 9.9 Hz). ^¹³C NMR (62.9 MHz, D₂O): δ = 56.7 (d, J _PC = 88.1 Hz), 59.5 (d, J _PC = 85.5 Hz), 78.1 (dd, J _PC = 87.4, 71.7 Hz), 114.3 (d, J _FC = 25.2 Hz), 127.4, 127.7, 128.0-129.0 (m, Ar), 131.3, 135.3, 136.4, 161.8 (d, J _FC = 240.3 Hz). HRMS: m/z calcd for C₂₁H₂₀FNO₅P₂ [MH⁺]: 448.0879; found: 448.0868. Compound 5g: mp 254-256 ˚C. ^¹H NMR (250 MHz, D₂O): δ = 4.00-5.00 (2 H, br), 6.50-7.85 (17 H, m). ^³¹P NMR (101.2 MHz, D₂O-H₃PO₄): δ = 19.70. ^¹³C NMR (62.9 MHz, D₂O): δ = 56.1 (d, J _PC = 84.9 Hz), 59.5 (d, J _PC = 86.2 Hz), 79.6 (dd, J _PC = 84.3, 78.0 Hz), 124.3, 126.5, 127.5, 127.7, 128.0-129.7 (m, Ar), 135.3, 136.0, 137.0. HRMS: m/z calcd for C₂₃H₂₃NO₅P₂ [MH⁺]: 456.1130; found: 456.1125. Compound 5h: mp 241-243 ˚C. ^¹H NMR (250 MHz, D₂O): δ = 4.20-4.80 (2 H, br), 6.90-7.50 (11 H, m), 7.55-7.80 (2H, br). ^³¹P NMR (101.2 MHz, D₂O-H₃PO₄): δ = 20.56 (d, J _pp = 8.8 Hz), 21.42 (d, J _pp = 8.9 Hz). ^¹³C NMR (62.9 MHz, D₂O): δ = 56.2 (d, J _PC = 86.8 Hz), 58.7 (d, J _PC = 89.3 Hz), 78.5 (dd, J _PC = 83.0, 70.5 Hz), 126.8, 126.9, 128.2, 129.0 (d, J _PC = 3.8 Hz), 129.5, 129.8 (d, J _PC = 3.8 Hz), 132.1, 132.5, 134.7, 135.1, 135.7, 136.4. HRMS: m/z calcd for C₂₁H₁₉Cl₂NO₅P₂ [MH⁺]: 498.0194; found: 498.0204.
Compound 5i: mp 231-232 ˚C. ^¹H NMR (250 MHz, D₂O): δ = 4.60-4.80 (1 H, br), 4.90-5.10 (1 H, br), 7.10-7.50 (11 H, m), 7.55-7.80 (1 H, br). ^³¹P NMR (101.2 MHz, D₂O-H₃PO₄): δ = 19.80 (d, J _pp = 5.8 Hz), 22.93 (d, J _pp = 5.8 Hz). ^¹³C NMR (62.9 MHz, D₂O): δ = 56.2 (d, J _PC = 91.2 Hz), 58.17 (d, J _PC = 91.8 Hz), 79.9 (dd, J _PC = 88.7, 66.0 Hz), 126.1, 128.3, 128.5, 129.5 (d, J _PC = 3.8 Hz), 129.9 (d, J _PC = 3.8 Hz), 130.4, 131.9, 132.5, 132.8, 133.1, 133.2, 134.0 (d, J _PC = 3.8 Hz), 134.5 (d, J _PC = 3.8 Hz), 135.9. HRMS: m/z calcd for C₂₁H₁₈Cl₃NO₅P₂ [MH⁺]: 531.9804; found: 531.9803.
Compound 5j: mp 246-248 ˚C. ^¹H NMR (250 MHz, D₂O): δ = 4.60-4.80 (1 H, br), 4.93 (1 H, d, J = 8.2 Hz), 6.90-7.50 (11 H, m), 7.75-7.95 (1 H, br). ^³¹P NMR (101.2 MHz, D₂O-H₃PO₄): δ = 20.26 (d, J _pp = 19.9 Hz), 21.16 (d, J _pp = 19.8 Hz). ^¹³C NMR (62.9 MHz, D₂O): δ = 56.2 (d, J _PC = 87.4 Hz), 57.8 (d, J _PC = 92.5 Hz), 75.5-79.5 (m), 116.1 (d, J _FC = 25.2 Hz), 123.7, 124.3, 128.4, 129.0, 129.8, 130.0, 132.5, 132.7, 135.0, 135.9, 160.5 (d, J _FC = 242.2 Hz). HRMS: m/z calcd for C₂₁H₁₈Cl₂FNO₅P₂ [MH⁺]: 516.0100; found: 516.0097.
Compound 5k: mp 245-247 ˚C. ^¹H NMR (250 MHz, D₂O): δ = 5.07 (1 H, d, J = 10.0 Hz), 5.34 (1 H, d, J = 10.5 Hz), 6.90-7.35 (10 H, m), 7.42 (1 H, t, J = 7.8 Hz), 7.58 (1 H, t, J = 7.8 Hz), 7.70 (1 H, d, J = 7.2 Hz). ^³¹P NMR (101.2 MHz, D₂O-H₃PO₄): δ = 12.10, 13.50. ^¹³C NMR (62.9 MHz, D₂O): δ = 55.4 (d, J _PC = 89.5 Hz), 59.4 (d, J _PC = 85.7 Hz), 78.1 (dd, J _PC = 87.4, 75.5 Hz), 115.5-117.0 (m, Ar), 126.0-132.0 (m, Ar), 134.2, 163.1 (d, J _FC = 246.7 Hz). HRMS: m/z calcd for C₂₁H₁₉F₂NO₅P₂ [MH⁺]: 466.0785; found: 466.0805.
Compound 5l: mp 242-244 ˚C. ^¹H NMR (250 MHz, D₂O): δ = 4.69 (1 H, d, J = 7.5 Hz), 5.15 (1 H, d, J = 7.5 Hz), 6.90-7.50 (11 H, m), 7.81 (1 H, t, J = 7.5 Hz). ^³¹P NMR (101.2 MHz, D₂O-H₃PO₄): δ = 19.83 (d, J _pp = 23.3 Hz), 20.63 (d, J _pp = 23.3 Hz). ^¹³C NMR (62.9 MHz, D₂O): δ = 56.0 (d, J _PC = 86.9 Hz), 57.5 (d, J _PC = 86.4 Hz), 78.1 (dd, J _PC = 83.0, 66.7 Hz), 115.1 (d, J _FC = 21.5 Hz), 116.1 (d, J _FC = 23.6 Hz), 123.7, 124.3, 124.4, 128.8-130.4 (m, Ar), 132.2, 133.0 160.5 (d, J _FC = 244.5 Hz), 161.9 (d, J _FC = 243.0 Hz), 162.1 (d, J _FC = 243.2 Hz). HRMS: m/z calcd for C₂₁H₁₈F₃NO₅P₂ [MH⁺]: 484.0691; found: 484.0723.

The structure was solved by a direct method using SHELXS-97 (Scheldrik,1997) and refined with a full-matrix least-squares method. Molecular formula = C₂₁H₂₇Cl₂NO₉P₂, MW = 570.28, triclinic, space group = P-1, a = 8.9246 (17) Å, b = 11.069 (2) Å, c = 13.181 (3) Å, V = 1280.1 (4) Å^³, T = 296 K, Z = 2, D _x = 1.479 Mg/m^³, (Mo-Kα) = 0.71073 Å, R = 0.0367 over independent reflections(5886). Crystallographic data (excluding structure factors) for the X-ray crystal structure analysis reported in this paper have been deposited with the Cambridge Crystallographic Data Center (CCDC) as supplementary publication No. CCDC 750864, copies of these data can be obtained, free of charge, upon application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax: +44 (1223)336033 or e-mail: deposit@ccdc.cam.ac.uk].