Efficient Synthesis of Medium-Sized Cyclic Amines by Means of 2-Nitrobenzenesulfonamide

Toshiyuki Kan; Hideki Kobayashi; Tohru Fukuyama

doi:10.1055/s-2002-25369

LETTER

Efficient Synthesis of Medium-Sized Cyclic Amines by Means of 2-Nitrobenzenesulfonamide

Toshiyuki Kan, Hideki Kobayashi, Tohru Fukuyama*
Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Fax: +81(3)58028694; e-Mail: fukuyama@mol.f.u-tokyo.ac.jp;

Abstract

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Abstract

Construction of medium-sized cyclic amines using 2-nitrobenzenesulfonamides is described. Under either conventional alkylation or Mitsunobu reaction conditions, the cyclization reaction proceeded efficiently to give eight- to ten-membered rings.

Key words

medium-sized cyclic amines - macrocyclization - 2-nitrobenzenesulfonamide - alkylation - Mitsunobu reaction

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References

For recent syntheses of medium-sized cyclic amines, see: Ring-opening of bicyclic precursors:

<A NAME="RY01102ST-1A">1a</A> Donohoe TJ. Raoof A. Linney ID. Helliwell M. Org. Lett. 2001, 3: 861

<A NAME="RY01102ST-1B">1b</A> Fatima I. Ramon GA. Juan CC. Org. Lett. 2001, 3: 2957

<A NAME="RY01102ST-1C">1c</A> Cyclization of aminoalkenes: Bergmann DJ. Campi EM. Jackson WR. Patti AF. Saylik D. Tetrahedron Lett. 1999, 40: 5597

Ring-enlargement of six-membered rings:

<A NAME="RY01102ST-1D">1d</A> Moris-Varas F. Quian X.-H. Wong C.-H. J. Am. Chem. Soc. 1996, 118: 7647

Others:

<A NAME="RY01102ST-1E">1e</A> Kitano T. Shirai N. Motoi M. Sato Y. J. Chem. Soc., Perkin Trans. 1 1992, 2851

<A NAME="RY01102ST-1F">1f</A> Shaw R. Anderson M. Gallagher T. Synlett 1990, 584

<A NAME="RY01102ST-1G">1g</A> Shaw RW. Gallagher T. J. Chem. Soc. Perkin Trans.1 1994, 3549

For recent synthesis of medium-sized cyclic amines based on ring-closing metathesis, see:

<A NAME="RY01102ST-2A">2a</A> Meyers AI. Downing SV. Weiser MJ. J. Org. Chem. 2001, 66: 1413

<A NAME="RY01102ST-2B">2b</A> Heinrich MR. Steglich W. Tetrahedron Lett. 2001, 42: 3287

<A NAME="RY01102ST-2C">2c</A> Fujiwara T. Kato Y. Takeda T. Heterocycles 2000, 52: 147

<A NAME="RY01102ST-2D">2d</A> Paquette LA. Leit SM. J. Am. Chem. Soc. 1999, 121: 8126

<A NAME="RY01102ST-2E">2e</A> Visser MS. Heron NM. Didiuk MT. Sagal JF. Hoveyda AH. J. Am. Chem. Soc. 1996, 118: 4291

<A NAME="RY01102ST-2F">2f</A> Miller SJ. Kim S.-H. Chen Z.-R. Grubbs RH. J. Am. Chem. Soc. 1995, 117: 2108

<A NAME="RY01102ST-3">3</A> For a review on Ns-chemistry, see: Kan T. Fukuyama T. J. Syn. Org. Chem., Jpn. 2001, 59: 779

<A NAME="RY01102ST-4">4</A> Fukuyama T. Jow C.-K. Cheung M. Tetrahedron Lett. 1995, 36: 6373

Kurosawa, W.; Kan, T.; Fukuyama, T. Org. Synth., in press.

<A NAME="RY01102ST-6">6</A> Fukuyama T. Cheung M. Jow C.-K. Hidai Y. Kan T. Tetrahedron Lett. 1997, 38: 5831

<A NAME="RY01102ST-7">7</A> Hidai Y. Kan T. Fukuyama T. Tetrahedron Lett. 1999, 40: 4711

<A NAME="RY01102ST-8">8</A> Hidai Y. Kan T. Fukuyama T. Chem. Pharm. Bull. 2000, 48: 1570

<A NAME="RY01102ST-9">9</A> Fujiwara A. Kan T. Fukuyama T. Synlett 2000, 1667

<A NAME="RY01102ST-10">10</A> Fukuyama T. Cheung M. Kan T. Synlett 1999, 1301

<A NAME="RY01102ST-11">11</A> For a review of the substituent effect on the cyclization, see: Jung ME. Synlett 1999, 843

Experimental procedure for the introduction of Ns-amide and macrocyclization and spectral data for all new compounds are described below.
Representative Experimental Procedures. Synthesis of 3a: To a stirred solution of 2-nitrobenzenesulfonamide (3.20 g, 15.8 mmol), 7-bromo-1-heptanol (2a) (1.00 g, 5.13 mmol), and Ph₃P (1.80 g, 8.91 mmol) in toluene (9 mL) and THF (1.2 mL) was added DEAD (4 mL, 8.80 mmol, 40% in toluene) dropwise at 0 °C under argon atmosphere. The solution was stirred at 0 °C for 5 min, then at room temperature for 2.5 h. After removal of the solvent under reduced pressure, the remaining residue was purified by flash chromatography, (9:1 hexane-EtOAc) on a silica gel column, to give 3a (1.36 g, 70%) as white powder. IR (film, cm^-1): 3346, 3096, 2933, 2857, 1539, 1440, 1414, 1360, 1341, 1166, 1125, 1060, 853, 782. ¹H NMR (400 MHz, CDCl₃) δ: 1.29 (4 H, m), 1.33 (2 H, m), 1.52 (2 H, m), 1.81 (2 H, m), 3.10 (2 H, q, J = 6.8 Hz), 3.37 (2 H, t, J = 6.8 Hz), 5.23 (1 H, m), 7.76 (2 H, m), 7.87 (1 H, m), 8.14 (1 H, m). ¹³C NMR (100 MHz, CDCl₃) δ: 26.2, 27.8, 28.1, 29.4, 32.5, 33.8, 43.7, 125.3, 131.0, 132.8, 133.5, 133.7, 148.0. FAB-MS: m/z 379 (MH⁺); Anal. Calcd. for C₁₃H₂₀BrN₂O₄S: C, 41.17; H, 5.05; N, 7.39. Found: C, 41.24; H, 5.04; N, 7.30.
Spectral data for 3b (white powder): IR (film, cm^-1): 3346, 3099, 2930, 2856, 1592, 1539, 1440, 1414, 1360, 1342, 1165, 1125, 1061. ¹H NMR (400 MHz, CDCl₃) δ: 1.26 (6 H, m), 1.39 (2 H, m), 1.53 (2 H, m), 1.83 (2 H, m), 3.10 (2 H, q, J = 6.8 Hz), 3.39 (2 H, t, J = 6.8 Hz), 5.23 (1 H, m), 7.75 (2 H, m), 7.87 (1 H, m), 8.15 (1 H, m). ¹³C NMR (100 MHz, CDCl₃) δ: 26.4, 28.0, 28.6, 28.9, 29.6, 32.7, 34.0, 43.9, 125.4, 131.2, 132.8, 133.6, 133.8, 148.2. FAB-MS: m/z 393 (MH⁺); HRMS (FAB): Found 393.0411 (MH⁺), Calcd. 393.0413 (C₁₄H₂₂BrN₂O₄S, MH⁺).
Spectral data for 3c (white powder). IR (film, cm^-1): 3346, 3099, 2930, 2856, 1592, 1539, 1440, 1414, 1360, 1342, 1165, 1125, 1061. ¹H NMR (400 MHz, CDCl₃) δ: 1.25 (8 H, m), 1.40 (2 H, m), 1.54 (2 H, m), 1.83 (2 H, t, J = 4.0 Hz), 3.10 (2 H, q, J = 3.4 Hz), 3.40 (2 H, t, J = 3.4 Hz), 5.22 (1 H, m), 7.75 (2 H, m), 7.87 (1 H, m), 8.15 (1 H, m). ¹³C NMR (100 MHz, CDCl₃) δ: 26.4, 28.0, 28.5, 28.8, 29.1, 29.5, 32.7, 34.0, 43.8, 125.3, 131.1, 132.7, 133.5, 133.8, 148.1. FAB-MS : m/z 407 (MH⁺); Anal. Calcd. for C₁₅H₂₄BrN₂O₄S: C, 44.23; H, 5.69; N, 6.88. Found: C, 44.46; H, 5.71; N, 6.64.
Synthesis of 4a: To a stirred solution of Cs₂CO₃ (2.10 g, 6.45 mmol) and TBAI (980 mg, 2.65 mmol) in CH₃CN (3.00 mL) was added N-2-nitrobenzenesulfonyl-7-bromo-1-aminoheptane (3a) (500 mg, 1.32 mmol) in CH₃CN (24.0 mL) via syringe pump for 2 h at 60 °C, and stirred for additional 2 h at the same temperature. The reaction mixture was poured into water and extracted with EtOAc three times. The combined organic layer was washed with brine, dried over MgSO₄, filtered, and evaporated. The residue was purified by flash chromatography (Et₂O) on a silica gel column to give 4a (245 mg, 62%) as white powder. IR (film, cm^-1): 2929, 2857, 1542, 1456, 1373, 1344, 1164, 993. ¹H NMR (400 MHz, CDCl₃) δ: 1.59 (6 H, m), 1.69 (4 H, m), 3.25 (4 H, t, J = 6.0 Hz), 7.52 (1 H, m), 7.61 (2 H, m), 7.84 (1 H, m). ¹³C NMR (100 MHz, CDCl₃) δ: 24.8, 26.5, 27.7, 49.3, 123.9, 130.4, 131.4, 132.5, 133.3, 148.4. FAB-MS:
m/z 299 (MH⁺); HRMS (FAB): Found 299.0981(MH⁺); Calcd 299.0995 (C₁₃H₁₉N₂O₄S, MH⁺). Anal. Calcd for C₁₃H₁₉N₂O₄S: C, 52.33; H, 6.08; N, 9.39. Found: C, 52.29; H, 5.99; N, 9.35.
Spectral data for 4b (white powder): IR (film, cm^-1): 2931, 2859, 1725, 1546, 1463, 1373, 1347, 1290, 1161, 1125, 851, 777, 742. ¹H NMR (400 MHz, CDCl₃) δ: 1.32 (8 H, m), 1.57 (4 H, m), 3.25 (4 H, t, J = 8.0 Hz), 7.61 (1 H, m), 7.68 (2 H, m), 7.98 (1 H, m). ¹³C NMR (100 MHz, CDCl₃) δ: 25.9, 27.9, 28.1, 47.8, 124.4, 129.0, 130.9, 131.8, 133.6, 148.4. FAB-MS: m/z 313 (MH⁺); Anal. Calcd for C₁₄H₂₁N₂O₄S: C, 53.83; H, 6.45; N, 8.97. Found: C, 53.87; H, 6.29; N, 8.68.
Spectral data for 4c (white powder): IR (film, cm^-1): 2928, 2855, 1542, 1463, 1373, 1346, 1160, 851. ¹H NMR (400 MHz, CDCl₃) δ: 1.32 (10 H, m), 1.57 (4 H, m), 3.29 (4 H, t, J = 8.0 Hz), 7.59 (1 H, m), 7.67 (2 H, m), 7.97 (1 H, m). ¹³C NMR (100 MHz, CDCl₃) δ: 26.2, 27.9, 28.3, 28.5, 48.7, 124.0, 130.6, 131.4, 133.2, 133.3, 148.3. FAB-MS: m/z 327 (MH⁺); HRMS (FAB): Found 327.1311 (MH⁺); Calcd. 327.1308 (C₁₅H₂₃N₂O₄S, MH⁺); Anal. Calcd for C₁₅H₂₃N₂O₄S: C, 54.96; H, 6.74; N, 8.30. Found: C, 55.19; H, 6.79; N, 8.58.
Synthesis of 6a: To a stirred solution of N-Boc-2-nitrobenzenesulfonamide (5) (1.25 g, 4.14 mmol), K₂CO₃ (2.50 g, 18.1 mmol) and tetra-n-butylammonium iodide (40 mg, 0.11 mmol) in DMF (7 mL) was added 7-bromo-1-heptanol (770 mg, 3.98 mmol). The solution was stirred at 60 °C for 10 h and then poured into water. The mixture was extracted with EtOAc three times. The combined organic layer was washed with brine, dried over MgSO₄, filtered, and evaporated. The residue was dissolved in CH₂Cl₂ (1 mL) and TFA (7 mL). After stirring for 1 h, the reaction mixture was concentrated. To the mixture in MeOH was added K₂CO₃ (1.00 g, 7.23 mmol), and stirred for 10 min. The reaction mixture was poured into water and extracted with CH₂Cl₂ three times. The combined organic layer was washed with brine, dried over MgSO₄, filtered, and evaporated. Recrystallization from ether-hexane afforded 6a (1.00 g, 60%) as white powder. IR (film, cm^-1): 3343, 2933, 2859, 1543, 1413, 1364, 1339, 1165, 1126, 1059, 853, 783, 741. ¹H NMR (400 MHz, CDCl₃) δ: 1.30 (4 H, m), 1.50 (2 H, m), 1.53 (4 H, m), 3.09 (2 H, m), 3.63 (2 H, m), 5.25 (1 H, m), 7.75 (2 H, m), 7.87 (1 H, m), 8.14 (1 H, m). ¹³C NMR (100 MHz, CDCl₃) δ: 25.5, 26.4, 28.8, 29.5, 32.5, 43.8, 62.9, 125.4, 131.1, 132.8, 133.5, 133.8, 149.8. FAB-MS: m/z 317 (MH⁺); HRMS (FAB): Found 317.1180 (MH⁺); Calcd 317.1177 (C₁₃H₂₁O₂N₅S, MH⁺).
Spectral data for 6b (white powder): IR (film, cm^-1): 3289, 2931, 2856, 1540, 1418, 1362, 1338, 1163, 1126, 1058. ¹H NMR (400 MHz, CDCl₃) δ: 1.27 (8 H, m), 1.52 (4 H, m), 3.09 (2 H, m), 3.62 (2 H, m), 5.28 (1 H, m), 7.71 (2 H, m), 7.87 (1 H, m), 8.14 (1 H, m). ¹³C NMR (100 MHz, CDCl₃) δ: 25.5, 26.3, 28.9, 29.1, 29.5, 32.6, 43.8, 62.9, 125.3, 131.1, 132.7, 133.5, 133.8, 148.1. FAB-MS: m/z 331 (MH⁺); HRMS (FAB): Found 331.1327 (MH⁺); Calcd 331.1329 (C₁₄H₂₃O₂N₅S, MH⁺).
Spectral data for 6c (white powder): IR (film, cm^-1): 3287, 2926, 2853, 1541, 1360, 1333, 1163, 1126, 1062, 854, 780, 728. ¹H NMR (400 MHz, CDCl₃) δ: 1.25 (10 H, m), 1.53 (4 H, m), 3.09 (2 H, q, J = 6.8 Hz), 3.63 (2 H, t, J = 6.8 Hz), 5.27 (1 H, m), 7.74 (2 H, m), 7.87 (1 H, m), 8.14 (1 H, m). ¹³C NMR (100 MHz, CDCl₃) δ: 25.6, 26.4, 28.9, 29.2, 29.3, 29.5, 32.7, 43.8, 63.0, 125.3, 131.1, 132.7, 133.5, 133.8, 148.0. FAB-MS: m/z 345 (MH⁺); HR MS (FAB): Found 345.1407 (MH⁺); Calcd 345.1414 (C₁₅H₂₅O₂N₅S, MH⁺).
Representative Experimental Procedure. Synthesis of 4a under Mitsunobu Conditions To a stirred solution of Ph₃P (463 mg, 2.29 mmol) and N-(2-nitrobenzenesulfonyl)-7-hydroxy-1-aminoheptane(6a) (200 mg, 0.63 mmol) in toluene (48 mL)and THF (16 mL) was added DEAD (1.05 mL, 2.31 mmol, 40% in toluene) drop wise and stirred for 3 h. The reaction mixture was concentrated in vacuo, the residue was purified by flash chromatography (1:4, EtOAc-hexane) on a silica gel column to give 4a (112 mg, 59%) as white powder.

Attempted macrocyclization of N-tert-Butoxycarbonyl-7-iodo-1-aminoheptane (7) was failed to the desired reaction as shown in Scheme [2] . Treatment of 7 with sodium hydride in DMF at room temperature, the starting material was completely recovered. Upon heating to 60 °C, the dehydroiodination reaction was proceeded to give 8.

Scheme 2