New Unsaturated Azamacrocyclic Enediynes: Synthesis, Structural Analysis and Thermal Behavior

Abstract

The reaction of a bispropargyl bromide enediyne with several bis-NH-sulfonamide nucleophiles permits the easy synthesis of 14- and 19-membered macrocyclic enediynes. The new nitrogen-containing unsaturated macrocycles are fully characterized. The thermal reactivity of the new cyclic enediyne derivatives is investigated by means of differential scanning calorimetry (DSC).

macrocyclic enediynes - unsaturated azamacrocycles - macrocyclization - differential scanning calorimetry

References and Notes

<A NAME="RS05806ST-1A">1a</A> Nicolaou KC. Smith AL. Modern Acetylenic Chemistry   Stang PJ. Diederich F. VCH; Weinheim: 1995.  p.203-283  

<A NAME="RS05806ST-1B">1b</A> Nicolaou KC. Dai W.-M. Angew. Chem., Int. Ed. Engl.  1991,  30:  1387 

<A NAME="RS05806ST-1C">1c</A> Nicolaou KC. Smith AL. Acc. Chem. Res.  1992,  25:  497 

<A NAME="RS05806ST-1D">1d</A> Maier ME. Synlett  1995,  13 

<A NAME="RS05806ST-1E">1e</A> Galm U. Hager MH. Van Lanen SG. Ju J. Thorson JS. Shen B. Chem. Rev.  2005,  105:  739 

<A NAME="RS05806ST-2A">2a</A> Jones RR. Bergman RG. J. Am. Chem. Soc.  1972,  94:  660 

<A NAME="RS05806ST-2B">2b</A> Bergman RG. Acc. Chem. Res.  1973,  6:  25 

<A NAME="RS05806ST-2C">2c</A> Lockhart TP. Comita PB. Bergman RG. J. Am. Chem. Soc.  1981,  103:  4082 

<A NAME="RS05806ST-2D">2d</A> Lockhart TP. Bergman RG. J. Am. Chem. Soc.  1981,  103:  4091 

<A NAME="RS05806ST-3A">3a</A> König B. Pitsch W. J. Org. Chem.  1996,  61:  4258 

<A NAME="RS05806ST-3B">3b</A> Braña MF. Morán M. Pérez de la Vega MJ. Pita-Romero I. J. Org. Chem.  1996,  61:  1369 

<A NAME="RS05806ST-3C">3c</A> Basak A. Bdour HM. Shain JC. Mandal S. Rudra KR. Nag S. Bioorg. Med. Chem. Lett.  2000,  10:  1321 

<A NAME="RS05806ST-3D">3d</A> Chandra T. Pink M. Zaleski JM. Inorg. Chem.  2001,  40:  5878 

<A NAME="RS05806ST-3E">3e</A> Basak A. Mandal S. Das AK. Bertolasi V. Bioorg. Med. Chem. Lett.  2002,  12:  873 

<A NAME="RS05806ST-3F">3f</A> Bhattacharyya S. Clark AE. Pink M. Zaleski JM. Chem. Commun.  2003,  1156 

<A NAME="RS05806ST-3G">3g</A> Basak A. Roy SK. Mandal S. Angew. Chem. Int. Ed.  2005,  44:  132 

<A NAME="RS05806ST-3H">3h</A> Du Y. Creighton CJ. Yan Z. Gauthier DA. Dahl JP. Zhao B. Belkowski SM. Reitz AB. Bioorg. Med. Chem.  2005,  13:  5936 

<A NAME="RS05806ST-3I">3i</A> Kar M. Basak A. Bhattacharjee M. Tetrahedron Lett.  2006,  47:  117 

For related intermolecular N-dialkylation reactions in the synthesis of azamacrocyclic enediynes, see:

<A NAME="RS05806ST-4A">4a</A> König B. Fricke T. Dix I. Jones PG. J. Chem. Res., Synop.  1997,  68 ; J. Chem. Res., Miniprint 1997, 385

<A NAME="RS05806ST-4B">4b</A>

Ref. 3f.

<A NAME="RS05806ST-4C">4c</A>

Ref. 3i.

<A NAME="RS05806ST-5A">5a</A> König B. Hollnagel H. Ahrens B. Jones PG. Angew. Chem., Int. Ed. Engl.  1995,  34:  2538 

<A NAME="RS05806ST-5B">5b</A> König B. Pitsch W. Dix I. Jones PG. Synthesis  1996,  446 

<A NAME="RS05806ST-5C">5c</A> König B. Pitsch W. Dix I. Jones PG. New J. Chem.  2001,  25:  912 

<A NAME="RS05806ST-6A">6a</A> Cerezo S. Cortes J. Galvan D. Lago E. Marchi C. Molins E. Moreno-Mañas M. Pleixats R. Torrejón J. Vallribera A. Eur. J. Org. Chem.  2001,  329 

<A NAME="RS05806ST-6B">6b</A> Moreno-Mañas M. Pleixats R. Sebastián RM. Vallribera A. Roglans A. J. Organomet. Chem.  2004,  689:  3669 

<A NAME="RS05806ST-7">7</A> Pla-Quintana A. Roglans A. Torrent A. Moreno-Mañas M. Benet-Buchholz J. Organometallics  2004,  23:  2762 

<A NAME="RS05806ST-8">8</A>

Synthesis of (15 Z )-1,6,11-tris[(4-methylphenyl)sulfonyl]-1,6,11-triazacyclononadeca-15-ene-3,8,13,17-tetrayne (2) - General Method for Enediyne Macrocycles.
A solution of 1,8-dibromo-4-octene-2,6-diyne (6, 0.05 g, 0.189 mmol) in MeCN (3 mL) was added dropwise to a stirred mixture of derivative 8 (0.10 g, 0.160 mmol) and K₂CO₃ (0.11 g, 0.810 mmol) in MeCN (10 mL) at r.t. The mixture was stirred for 8 h (TLC monitoring). The salts were filtered off and the solvent was evaporated under vacuum. The residue was purified by column chromatography on silica gel (n-hexane-EtOAc, 8:2) to afford 2 (0.092 g, 79%). Colorless solid; mp 162-163 °C (dec.). IR (ATR): ν = 2924, 2164, 1346, 1157 cm^-1. ¹H NMR (200 MHz, CDCl₃): δ = 2.44 (s, 6 H), 2.46 (s, 3 H), 3.81 (s, 4 H), 3.99 (s, 4 H), 4.04 (s, 4 H), 5.55 (s, 2 H), 7.27-7.37 (m, 6 H), 7.65 (d, J = 7.8 Hz, 6 H). ¹³C NMR (50 MHz, CDCl₃): δ = 22.2, 22.3, 36.9, 37.6, 37.9, 79.0, 79.1, 83.6, 89.6, 120.8, 128.5, 128.6, 130.3, 130.4, 135.3, 145.0, 145.2. ESI-MS: m/z = 714 [M + H]⁺, 731 [M + NH₄]⁺, 736 [M + Na]⁺, 752 [M + K]⁺ Anal. Calcd for C₃₇H₃₅N₃O₆S₃ (713.90): C, 62.25; H, 4.94; N, 5.89; S, 13.48. Found: C, 62.19 and 61.76; H, 5.27 and 5.37; N, 5.82 and 5.84; S, 12.97 and 13.43.
Analytical Data for (3 E ,8 E ,15 Z )-1,6,11-tris[(4-methyl-phenyl)sulfonyl]-1,6,11-triazacyclononadeca-3,8,15-triene-13,17-diyne (1).
Colorless solid; mp 157-158 °C. IR (ATR): ν = 2923, 1335, 1157 cm^-1. ¹H NMR (200 MHz, CDCl₃): δ = 2.43 (s, 9 H), 3.65 (d, J = 6.0 Hz, 4 H), 3.75 (d, J = 6.8 Hz, 4 H), 4.14 (s, 4 H), 5.40 (s, 2 H), 5.42-5.60 (m, 2 H), 5.60-5.78 (m, 2 H), 7.26-7.36 (m, 6 H), 7.63 (d, J = 8.6 Hz, 2 H), 7.68 (d, J = 8.6 Hz, 4 H). ¹³C NMR (50 MHz, CDCl₃): δ = 22.2, 37.3, 48.1, 51.7, 84.2, 89.6, 119.8, 127.7, 128.4, 130.1, 130.5, 133.5, 136.0, 136.6, 144.3, 144.4. ESI-MS: m/z = 718 [M + H]⁺, 740 [M + Na]⁺, 756 [M + K]⁺. Anal. Calcd for C₃₇H₃₉N₃O₆S₃·0.57H₂O (728.20): C, 61.03; H, 5.56; N, 5.77; S, 13.21. Found: C, 60.58 and 60.69; H, 5.74 and 5.76; N, 5.79 and 5.78; S, 13.20 and 12.88.

<A NAME="RS05806ST-9">9</A>

Analytical Data for (3 Z ,10 Z )-1,6-bis[(4-methyl-phenyl)sulfonyl]-1,6-diazacyclotetradeca-3,10-diene-8,12-diyne (3). Colorless solid; mp 148-149 °C (dec.). IR (ATR): ν = 2900, 1329, 1157 cm^-1. ¹H NMR (200 MHz, CDCl₃): δ = 2.41 (s, 6 H), 3.96 (d, J = 4.0 Hz, 4 H), 4.23 (s, 4 H), 5.53 (s, 2 H), 5.57 (t, J = 4.0 Hz, 2 H), 7.27 (d, J = 8.2 Hz, 4 H), 7.68 (d, J = 8.2 Hz, 4 H). ¹³C NMR (50 MHz, CDCl₃): δ = 22.2, 37.5, 43.3, 84.1, 90.1, 122.0, 128.3, 130.0, 130.2, 136.3, 144.4. ESI-MS: m/z = 495 [M + H]⁺, 512 [M + NH₄]⁺, 517 [M + Na]⁺, 533 [M + K]⁺. Anal. Calcd for C₂₆H₂₆N₂O₄S₂ (494.63): C, 63.13; H, 5.30; N, 5.66; S, 12.97. Found: C, 62.74 and 62.91; H, 5.65 and 5.60; N, 5.64 and 5.70; S, 13.03 and 13.03.
(3 E ,10 Z )-1,6-Bis[(4-methylphenyl)sulfonyl]-1,6-diaza-cyclotetradeca-3,10-diene-8,12-diyne (4). Colorless solid; mp 177-178 °C (dec.). IR (ATR): ν = 2927, 1328, 1158 cm^-1. ¹H NMR (200 MHz, CDCl₃): δ = 2.42 (s, 6 H), 3.79-3.83 (m, 4 H), 4.14 (s, 4 H), 5.63 (s, 2 H), 5.80-5.87 (m, 2 H), 7.28 (d, J = 8.0 Hz, 4 H), 7.69 (d, J = 8.0 Hz, 4 H). ¹³C NMR (50 MHz, CDCl₃): δ = 22.2, 39.1, 50.8, 83.2, 91.3, 120.9, 128.3, 129.8, 130.2, 136.6, 144.3. ESI-MS: m/z = 495 [M + H]⁺, 512 [M + NH₄]⁺, 517 [M + Na]⁺, 533 [M + K]⁺. Anal. Calcd for C₂₆H₂₆N₂O₄S₂ (494.63): C, 63.13; H, 5.30; N, 5.66; S, 12.97. Found: C, 62.71; H, 5.50; N, 5.68; S, 13.05.
(10 Z )-1,6-Bis[(4-methylphenyl)sulfonyl]-1,6-diaza-cyclotetradeca-10-ene-3,8,12-triyne (5). Colorless solid; mp 173-174 °C (dec.). IR (ATR): ν = 2925, 1343, 1154 cm^-1. ¹H NMR (200 MHz, CDCl₃): δ = 2.43 (s, 6 H), 4.02 (s, 4 H), 4.10 (s, 4 H), 5.68 (s, 2 H), 7.27 (d. J = 8.1 Hz, 4 H), 7.67 (d, J = 8.1 Hz, 4 H). ¹³C NMR (50 MHz, CDCl₃): δ = 22.2, 38.5, 39.0, 79.5, 83.8, 90.4, 121.1, 128.6, 130.1, 135.8, 144.6. ESI-MS: m/z = 493 [M + H]⁺, 510 [M + NH₄]⁺, 515 [M + Na]⁺, 531 [M + K]⁺. Anal. Calcd for C₂₆H₂₄N₂O₄S₂ (492.61): C, 63.39; H, 4.91; N, 5.69; S, 13.02. Found: C, 63.79 and 63.49; H, 5.08 and 5.08; N, 5.62 and 5.58; S, 12.78 and 12.74.

<A NAME="RS05806ST-10A">10a</A> Cortes J. Moreno-Mañas M. Pleixats R. Tetrahedron Lett.  2001,  42:  4337 

<A NAME="RS05806ST-10B">10b</A> Feigenbaum A. Lehn J.-M. Bull. Soc. Chim. Fr.  1973,  198 

<A NAME="RS05806ST-11">11</A> Torrent A. González I. Pla-Quintana A. Roglans A. Moreno-Mañas M. Parella T. Benet-Buchholz J. J. Org. Chem.  2005,  70:  2033 

<A NAME="RS05806ST-12">12</A>

Crystal Data of 2.
C₃₇H₃₅N₃O₆S₃, MW: 713.86, monoclinic, P2₁/c, a = 14.4270 (6) Å, b = 8.5483 (3) Å, c = 28.3007 (13) Å, α = 97.5210 (10)°, V = 3460.2 (2) ų, Z = 4, D _x = 1.370 mg/m³, µ (MoK_α) = 0.266 mm^-1, T = 100 (2) K. R ₁ = 0.0442 (0.716), wR ₂ = 0.1172 (0.1815), for 12270 reflections with I > 2σ(I) (for 17267 reflections [R _int: 0.0393] with a total of 57110 reflections measured), goodness-of-fit on F ² = 1.038, largest diff. peak(hole) = 1.320 (-0.504) e Å^-3. Data collection Apex2 V. 1.0-22 (Bruker-Nonius 2004), data reduction Saint + Version 6.22 (Bruker-Nonius 2001) and absorption correction SADABS Version 2.10 (2003). Crystal structure solution was achieved using direct methods as implemented in SHELXTL Version 6.10 [Sheldrick, Universität Göttingen (Germany), 2000] and visualized using XP program. Missing atoms were subsequently located from different Fourier syntheses and added to the atom list. Least-squares refinement on F ² using all measured intensities was carried out using the program SHELXTL Version 6.10 [Sheldrick, Universtität Göttingen (Germany), 2000]. All non-hydrogen atoms were refined including anisotropic displacement parameters.
Crystal Data of 1.
C₃₇H₃₉N₃O_6.57S₃, MW: 721.01, triclinic, P-1, a = 11.7195 (12) Å, b = 13.1586 (13) Å, c = 13.7583 (13) Å, α = 70.603 (2)°, β = 86.018 (2)°, γ = 68.282 (2)°, V = 1855.8 (3) ų, Z = 2, D _x = 1.301 mg/m³, µ (MoK_α) = 0.250 mm^-1, T = 300 (2) K, R ₁ = 0.0606 (0.1575), wR ₂ = 0.1229 (0.1597). For 8880 reflections [R _int = 0.0704] with a total of 29015 reflections measured, goodness-of-fit on F ² = 0.949, largest diff. peak(hole) = 0.299 (-0.504) e Å^-3. Data collection Smart version 5.625 (Bruker AXS 1997-01), data reduction Saint + Version 6.32A (Bruker AXS 2001) and absorption collection SADABS Version 2.05 (Bruker AXS 2001). Crystal structure solution and refinement was performed using SHELXL Version 6.12 (Bruker AXS 2001). The non-hydrogen atoms were refined including anisotropic displacement parameters. All the H-atoms were placed in geometrically optimized positions and forced to ride on the atom to which they are attached. The hydrogen atoms of the solvent (H₂O) could not be placed on the different Fourier map. The asymmetric unit contains one molecule of the macrocycle and partially a molecule of water.
Crystal Data of 3.
C₂₆H₂₆N₂O₄S₂, MW: 494.61, triclinic, P-1, a = 10.368 (5) Å, b = 11.995 (5) Å, c = 11.998 (5) Å, α = 119.912 (7)°, β = 91.482 (8)°, γ = 105.676 (8)°, V = 1221.9 (9) ų, Z = 2, D _x = 1.344 mg/m³, µ (MoK_α) = 0.253 mm^-1, T = 100 (2) K, R ₁ = 0.0454 (0.0672), wR ₂ = 0.1161 (0.1236). For 5845 reflections [R _int = 0.0530] with a total of 18749 reflections measured, goodness-of-fit on F ² = 1.039, largest diff. peak(hole) = 0.354 (-0.407) e Å^-3. Data collection Smart Version 5.631 (Bruker AXS 1997-02), data reduction Saint + Version 6.32A (Bruker AXS 2001) and absorption collection SADABS Version 2.10 (Bruker AXS 2001). Crystal structure solution and refinement was performed using SHELXL Version 6.14 (Bruker AXS 2000-2003). The non-hydrogen atoms were refined including anisotropic displacement parameters. The H-atoms were placed in geometrically optimized positions and refined without constraints.
Crystal Data of 4.
C₂₆H₂₆N₂O₄S₂, MW: 494.61, monoclinic, P2₁/n, a = 6.098 (4) Å, b = 38.47 (2) Å, c = 10.457 (6) Å, α = 101.769°, V = 2402 (3) ų, Z = 4, D _x = 1.368 mg/m³, µ (Mo K_α) = 0.258 mm^-1, T = 100 (2) K, R ₁ = 0.0995 (0.1736), wR ₂ = 0.2383 (0.2720). For 5935 reflections [R _int = 0.1912] with a total of 34600 reflections measured, goodness-of-fit on F ² = 0.987, largest diff. peak(hole) = 0.963 (-1.075)
e Å^-3. Data collection Smart version 5.631 (Bruker AXS 1997-02), data reduction Saint + Version 6.36A (Bruker AXS 2001) and absorption collection SADABS Version 2.10 (Bruker AXS 2001). Crystal structure solution and refinement was performed using SHELXL Version 6.14 (Bruker AXS 2000-2003). The non-hydrogen atoms were refined including anisotropic displacement parameters. All the H-atoms were placed in geometrically optimized positions and forced to ride on the atom to which they are attached.
Crystal Data of 5.
C₂₆H₂₄N₂O₄S₂, MW: 492.59, triclinic, P-1, a = 8.545 (4) Å, b = 14.333 (6) Å, c = 20.383 (8) Å, α = 76.470 (7)°, β = 81.169 (7)°, γ = 86.531°, V = 2397.6 (17) ų, Z = 4, D _x = 1.365 mg/m³, µ (MoK_α) = 0.258 mm^-1, T = 100 (2) K, R ₁ = 0.0592 (0.1196), wR ₂ = 0.1426 (0.1651). For 11618 reflections [R _int = 0.0706] with a total of 36894 reflections measured, goodness-of-fit on F ² = 1.042, largest diff. peak(hole) = 1.683 (-0.491) e Å^-3. Data collection Smart Version 5.631 (Bruker AXS 1997-02), data reduction Saint + Version 6.36A (Bruker AXS 2001) and absorption collection SADABS Version 2.10 (Bruker AXS 2001). Crystal structure solution and refinement was performed using SHELXL Version 6.14 (Bruker AXS 2000-2003). The non-hydrogen atoms were refined including anisotropic displacement parameters. All the H-atoms were placed in geometrically optimized positions and forced to ride on the atom to which they are attached. Crystallographic data (excluding structure factors) for the five structures in this paper have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication number CCDC 603826 (2), CCDC 606863 (1), CCDC 606864 (3), CCDC 606866 (4), CCDC 606865 (5). Copies of the data can be obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge, CB2 1EZ, UK [fax: [phone]; or e-mail: [e-mail]].

For recent reviews based on geometric and electronic effects of the Bergman cyclisation, see:

<A NAME="RS05806ST-13A">13a</A> Grissom JW. Gunawardena GU. Klingberg D. Huang D. Tetrahedron  1996,  52:  6453 

<A NAME="RS05806ST-13B">13b</A> König B. Eur. J. Org. Chem.  2000,  381 

<A NAME="RS05806ST-13C">13c</A> Basak A. Mandal S. Bag SS. Chem. Rev.  2003,  103:  4077 

<A NAME="RS05806ST-13D">13d</A> Rawat DS. Zaleski JM. Synlett  2004,  393 

<A NAME="RS05806ST-13E">13e</A> Klein M. Walenzyk T. König B. Collect. Czech. Chem. Commun.  2004,  69:  945 

<A NAME="RS05806ST-13F">13f</A> Schreiner PR. Navarro-Vazquez A. Prall M. Acc. Chem. Res.  2005,  38:  29 

<A NAME="RS05806ST-14A">14a</A> König B. Rütters H. Tetrahedron Lett.  1994,  35:  3501 

<A NAME="RS05806ST-14B">14b</A> Warner BP. Millar SP. Broene RD. Buchwald SL. Science  1995,  269:  814 

For a description of the technique, see:

<A NAME="RS05806ST-14C">14c</A> Höhne GWH. Hemminger WF. Flammersheim H.-J. Differential Scanning Calorimetry   2nd ed.:  Springer; Berlin: 2003. 

<A NAME="RS05806ST-14D">14d</A> Clas S.-D. Dalton CR. Hancock BC. Pharm. Sci. Technol. Today  1999,  2:  311 

<A NAME="RS05806ST-14E">14e</A> Giron D. Thermochim. Acta  1995,  248:  1