Enantiopure Oxygen-Functionalized Bipyridine Derivatives: Synthesis and Characterization

Abstract

A new class of chiral pinene 2,2′-bipyridine compounds containing carboxylic or alcoholic groups have been synthesized using the Kröhnke procedure followed by haloform or lithium mediated substitution reactions.

Key words

pyridine - chiral ligands - carboxylic acids - alcohols - diastereoselectivity

References

• 1 von Zelewsky A. Mamula O. J. Chem. Soc., Dalton Trans.  2000,  219 
• 2 Mamula O. von Zelewsky A. Coord. Chem. Rev.  2003,  242:  87 
• 3 Mamula O. von Zelewsky A. Bark T. Stoeckli-Evans H. Chem.-Eur. J.  2000,  6:  3575 
• 4 Mamula O. von Zelewsky A. Bernadinelli G. Angew. Chem. Int. Ed.  1998,  37:  289 
• 5 Mamula O. Bark T. von Zelewsky A. Bernadinelli G. Angew. Chem. Int. Ed.  1999,  38:  2945 
• 6 Bark T. Düggeli M. Stoeckli-Evans H. von Zelewsky A. Angew. Chem. Int. Ed.  2001,  40:  2848 
• 7 Ziessel R. Charbonnière L. Cesario M. Prangé T. Guardigli M. Roda A. van Dorsselaer A. Nierengarten H. Supramol. Chem.  2003,  15:  277 
• 8 Charbonnière L. Ziessel R. Guardigli M. Roda A. Sabbatini N. Cesario M. J. Am. Chem. Soc.  2001,  123:  2436 
• 9 Hayoz P. von Zelewsky A. Tetrahedron Lett.  1992,  33:  5165 
• 10 Kröhnke F. Synthesis  1976,  1 
• 11 Mihelich ED. Eickoff DJ. J. Org. Chem.  1983,  48:  4135 
• 14 Perret-Aebi L.-E. von Zelewsky A. Synlett  2002,  773 
• 16a The protonation constants were determined by pH-potentiometry at constant ionic strength (0.1 M KCl). The titrations of acidic solutions of compounds 5 and 7 (concentrations ca. 2 mM, the exact concentrations being calculated from the titration curves) were carried out in a thermostatic vessel (25.0 ± 0.2 °C) using a dosed NaOH solution. The pH values were measured using a combined glass electrode (C14/02-SC, reference electrode Ag/AgCl in 3 M KCl, Moeller Scientific Instruments, CH) connected to a pH/ion-meter (Metrohm 692). The hydronium concentration was calculated from the measured pH values using the Irving method. See: Irving H. Miles MG. Pettit L. Anal. Chim. Acta  1967,  38:  475 
• 16b The results were computed using the PSE-QUAD program. See: Zékány L. Nagypál I. In Computational Methods for Determination of Formation Constants   Legett DJ. Plenum Press; New York: 1985.  p.291 
• 17 Fan J. Wang J. Ye C. Talanta  1998,  46:  1285 
• 18 Hayoz P. von Zelewsky A. Stoeckli-Evans H. J. Am. Chem. Soc.  1993,  115:  5111 
• 19 Muller G. Bünzli J.-CG. Riehl JP. Suhr D. von Zelewsky A. Mürner H. Chem. Commun.  2002,  1522 

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Spectroscopic Data for Compounds 3-5. Compound 3: ¹H NMR (400 MHz, DMSO-d ₆): δ = 9.02 [d, 2 H, H(10), H(14), ³ J _10,11 = 7.5 Hz], 8.73 [m, 1 H, H(12)], 8.26 [dd, 2 H, H(11), H(13), ³ J _4,3 = 7.8 Hz, ³ J _4,5 = 7.8 Hz], 8.18 [dd, 1 H, H(4), ³ J _4,3 = 7.8 Hz, ³ J _4,5 = 7.8 Hz], 8.02 [d, 1 H, H(3), ³ J _3,4 = 7.8 Hz], 7.91 [d, 1 H, H(5), ³ J _5,4 = 7.8 Hz], 6.50 [s, 2 H, CH_{2 (}8)], 3.55 [AB, 4 H, H(17), H(19), ² J = 10.3 Hz], 1.60 (s, 3 H, Me), 1.48 (s, 3 H, Me), 0.71 (s, 3 H, Me) ppm.
Compound 4: ¹H NMR (400 MHz, CDCl₃): δ = 8.61 [dd, 1 H, H(2), ³ J _2,3 = 7.8 Hz, ⁴ J _2,4 = 1.2 Hz], 8.22 [d, 1 H, H(7), ³ J _7,8 = 7.7 Hz], 8.02 [dd, 1 H, H(4), ³ J _4,3 = 7.6 Hz, ⁴ J _4,2 = 1.1 Hz], 7.93 [dd, 1 H, H(3), ³ J _3,4 = 7.5 Hz, ³ J _3,2 = 7.5 Hz], 7.38 [d, 1 H, H(8), ³ J _8,7 = 7.8 Hz], 3.21 [d, 2 H, H(13a), H(13b), ³ J _13b,12 = 2.7 Hz], 2.86 [dd, 1 H, H(10), ³ J _10,15a = 5.6 Hz, ³ J _10,15b = 5.6 Hz], 2.84 [s, 3 H, Me(18)], 2.74 [ddd, 1 H, H(15b), ² J _15b,15a = 9.6 Hz, ³ J _15b,10 = 5.81 Hz, ³ J _15b,12 = 5.81 Hz], 2.44 [ddt, 1 H, H(12), ³ J _12,15b = 5.8 Hz, ⁴ J _12,10 = 5.8 Hz, ³ J _12,15b = 2.8 Hz], 1.45 [s, 3 H, Me(17)], 1.34 [d, 1 H, H(15a), ² J _15a,15b = 9.6 Hz], 0.71 [s, 3 H, Me(16)] ppm. MS (CI): m/z (%) = 293 (46) [M + H]⁺, 278 (29), 264 (25), 250 (100) [M - C₂H₃O]⁺. IR: ν = 2929 (m), 1695 (s), 1575 (m), 1440 (m), 1355 (s), 810 (s) cm^-1.
Compound 5: ¹H NMR (400 MHz, DMSO-d ₆): δ = 8.57 [dd, 1 H, H(2), ³ J _2,3 = 7.8 Hz, ⁴ J _2,4 = 1.2 Hz], 8.36 [d, 1 H, H(7), ³ J _7,8 = 7.7 Hz], 8.18 [dd, 1 H, H(3), ³ J _3,4 = 7.6 Hz, ³ J _3,2 = 7.6 Hz], 8.12 [d, 1 H, H(4), ³ J _4,3 = 7.6 Hz], 7.80 [d, 1 H, H(8), ³ J _8,7 = 7.8 Hz], 3.23 [AB, 2 H, H(13a), H(13b), ² J _13a,13b = 17.7 Hz], 2.98 [dd, 1 H, H(10), ³ J _10,15a = 5.6 Hz, ³ J _10,15b = 5.6 Hz], 2.75 [ddd, 1 H, H(15b), ² J _15b,15a = 9.6 Hz, ³ J _15b,10 = 5.81 Hz, ³ J _15b,12 = 5.81 Hz], 2.41 [ddt, 1 H, H(12), ³ J _12,15b = 5.8 Hz, ⁴ J _12,10 = 5.8 Hz, ³ J _12,15b = 2.8 Hz], 1.43 [s, 3 H, Me(17)], 1.28 [d, 1 H, H(15a), ² J _15a,15b = 9.6 Hz], 0.64 [s, 3 H, Me(16)] ppm. ¹³C NMR (100 MHz, DMSO-d ₆): δ = 167.8, 157.1, 156.7, 153.3, 152.1, 141.8, 137.6, 133.9, 123.0, 120.3, 118.1, 45.4, 40.2, 38.3, 35.9, 32.2, 25.6, 21.0 ppm. HRMS: m/z calcd for C₁₈H₁₉N₂O₂: 295.1442; found: 295.1441. IR: ν = 3414 (m), 3306 (m), 2934 (m), 2741 (b), 2567 (m), 2083 (b), 1709 (s), 1609 (m), 1373 (s), 1210 (s) cm^-1. [α]_D = -90 deg·mL·g^-1·dm^-1 (MeCN, 20 °C).

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Crystal data for 5·H₂O·HCl: C₁₈H₂₁ClN₂O₃ were deposited at the Cambridge Crystallography Data Centre, CCDC 235123.

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Spectroscopic Data for Compounds 7 and 8. Compound 7: ¹H NMR (400 MHz, DMSO-d ₆): δ = 13.6 (br s, 1 H, COOH), 8.71 [m, 2 H, H(2), H(7)], 8.56 [s, 1 H, H(8)], 8.31 [dd, H(3), ³ J _3,4 = 7.8 Hz, ³ J _3,2 = 7.8 Hz], 8.23 [d, 1 H, H(4), ³ J _4,3 = 7.8 Hz], 3.26 [ABq, 2 H, H(13), ² J _13a,13b = 19.3 Hz], 3.17 [dd, 1 H, H(10), ³ J _10,15b = 5.5 Hz, ⁴ J _10,12 = 5.5 Hz], 2.78 [ddd, 1 H, H(15b), ² J _15a,15b = 10.3 Hz, ³ J _15b,10 = 5.5 Hz, ³ J _15b,12 = 5.5 Hz], 2.36 [ddt, 1 H, H(12), ³ J _{12 ,15b} = 5.5 Hz, ⁴ J _12,10 = 5.5 Hz, ³ J _12,13 = 2.6 Hz], 1.42 [s, 3 H, H(17)], 1.21 [d, 1 H, H(15a), ² J _15a,15b = 10.3 Hz], 0.63 [s, 3 H, H(16)] ppm. ¹³C NMR (100 MHz, DMSO-d ₆): δ = 165.0, 154.7, 148.9, 147.7, 146.8, 146.1, 140.0, 139.1, 126.0, 125.0, 123.1, 43.5, 40.1, 38.3, 33.5, 30.5, 25.3, 21.1 ppm. HRMS: m/z calcd for C₁₈H₁₉N₂O₂: 295.1441; found: 295.1441. IR: ν = 2931 (m), 1694 (s), 1583 (s), 1245 (s), 1233 (s). [α]_D = -94 deg·mL·g^-1·dm^-1 (MeCN, 20 °C).
Compound 8: ¹H NMR (400 MHz, CDCl₃): δ = 8.20 [d, 1 H, H(2), ³ J _2,3 = 7.8 Hz], 8.17 [s, 1 H, H(8)], 8.06 [s, 1 H, H(7)], 7.70 [dd, 1 H, H(3), ³ J _3,2 = 7.8 Hz, ³ J _3,4 = 7.8 Hz], 7.12 [d, 1 H, H(4), ³ J _4,3 = 7.6 Hz], 4.70 (br, 1 H, OH), 4.09 [t, 2 H, H(β), ³ J _{α , β} = 5.5 Hz], 3.07 [t, 2 H, H(α), ³ J _{β , α} = 5.5 Hz], 3.02 [d, 2 H, H(13), ³ J _13,12 = 2.8 Hz], 2.83 [dd, 1 H, H(10), ³ J _10,15b = 5.6 Hz, ⁴ J _10,12 = 5.6 Hz], 2.68 [ddd, 1 H, H(15b), ³ J _15b,15a = 9.6 Hz, ³ J _15b,10 = 5.6 Hz, ³ J _15b,12 = 5.6 Hz, ² J _15b,15a = 9.6 Hz], 2.29 [ddt, 1 H, H(12), ³ J _12,15b = 5.6 Hz, ⁴ J _12,10 = 5.6 Hz, ³ J _12,13 = 2.8 Hz], 1.39 [s, 3 H, H(17)], 1.21 [d, 1 H, H(15a), ² J _15a,15b = 9.6 Hz], 0.63 [s, 3 H, H(16)]. ¹³C NMR (100 MHz, CDCl₃): δ = 159.9, 156.0, 154.2, 145.7, 145.6, 143.2, 137.7, 123.0, 120.3, 118.9, 61.9, 44.6, 40.2, 39.3, 38.9, 33.1, 31.9, 26.1, 21.5 ppm. HRMS: m/z calcd for C₁₉H₂₃N₂O: 295.1805; found: 295.1805. MS (CI): m/z (%) = 294 (20)[M⁺], 265 (100) [M - CH₂OH]⁺. IR: ν = 3337 (b), 2922 (s), 1588 (m), 1573 (m), 1553 (m), 1456 (s), 1049 (s) cm^-1. [α]_D = -91 deg·mL·g^-1·dm^-1 (MeCN, 20 °C).