Synthesis of Polycyclic Lactams and Sultams by a Cascade Ring-Closure Metathesis/Isomerization and Subsequent Radical Cyclization

Cyril Bressy; Christine Menant; Olivier Piva

doi:10.1055/s-2005-862386

LETTER

Synthesis of Polycyclic Lactams and Sultams by a Cascade Ring-Closure Metathesis/Isomerization and Subsequent Radical Cyclization

Cyril Bressy, Christine Menant, Olivier Piva*
Université Claude Bernard LYON I, UMR 5181 CNRS, Laboratoire de Chimie Organique-Photochimie et Synthèse, Bat Raulin, 43, Bd du 11 Novembre 1918, 69622 Villeurbanne Cedex, France
Fax: +33(4)72448136; e-Mail: piva@univ-lyon1.fr;

Abstract

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Abstract

Starting from readily available substrates, a new one-pot procedure has been devised to prepare polycyclic lactams and sultams. 2-Pyrrolines obtained from N,N-bisallylamides by ring-closure metathesis and subsequent isomerization promoted by ruthenium hydride complexes can undergo radical cyclization to furnish polycyclic lactams in good yields. The process was successfully conducted on bisallylsulfonamides to give the corresponding sultams.

Key words

polycyclic lactams - 2-pyrrolines - ring-closure metathesis

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References

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Preparation of the N , N -Bisallylamides 2.
To a solution of acid (2 mmol) in CH₂Cl₂ (4 mL) were successively added DMAP (0.073 g, 0.6 mmol) and bisallylamine (0.195 g, 2 mmol). The reaction was next cooled to 0 °C and a solution of dicyclohexylcarbodiimide (0.412 g, 2 mmol) in the same solvent (1 mL) was added dropwise. After stirring 10 min at 0 °C, the ice-water bath was removed and the mixture stirred overnight at r.t. Urea was filtered off and the solvent removed by concentration under vacuo. Amide 2 was obtained pure by flash chromatography (eluent: EtOAc-hexanes 10:90).
Compound 2a (95%): ¹H NMR (CDCl₃): δ = 3.65 (d, J = 4.5 Hz, 2 H), 3.75 (dd, J = 15.2, 6.8 Hz, 1 H), 4.48 (dd, J = 15.2, 3.7 Hz, 1 H), 5.03 (dd, J = 1.3, 16.9 Hz, 1 H), 5.10 (dd, J = 11.5, 1.3 Hz, 1 H), 5.18 (dd, J = 10.1, 1.3 Hz, 1 H), 5.23 (dd, J = 17.9, 1.3 Hz, 1 H), 5.59 (ddt, J = 16.9, 10.1, 5.8 Hz, 1 H), 5.83 (ddt, J = 16.9, 10.1, 5.4 Hz, 1 H), 7.13-7.31 (m, 3 H), 7.50 (d, J = 7.9 Hz, 1 H). ¹³C NMR (CDCl₃): δ = 46.70, 50.60, 118.50, 118.51, 119.50, 127.90, 128.00, 130.60, 132.80, 133.00, 133.20, 138.50, 169.40. IR (film): 3080, 2923, 1637, 1415, 1285, 1115, 995, 925, 770 cm^-1.
Compound 2d (63%): ¹H NMR (CDCl₃): δ = 3.74 (d, J = 5.6 Hz, 2 H), 3.80 (m, 1 H), 4.35-4.55 (m, 1 H), 5.11 (ddt, J = 17.0, 1.5, 1.5 Hz, 1 H), 5.18 (ddt, J = 10.2, 1.5, 1.5 Hz, 1 H), 5.23 (ddt, J = 10.4, 1.5, 1.5 Hz, 1 H), 5.27 (ddt, J = 15.6, 1.5, 1.5 Hz, 1 H), 5.67 (ddt, J = 17.0, 10.4, 5.6 Hz, 1 H), 5.87 (ddt, J = 16.4, 10.2, 6.0 Hz, 1 H), 6.00 (s, 2 H), 6.71 (s, 1 H), 6.98 (s, 1 H). ¹³C NMR (CDCl₃): δ = 46.7, 50.5, 102.4, 107.8, 110.4, 113.1, 118.4, 131.3, 132.6, 133.0, 147.7, 149.1, 168.9. HRMS: m/z calcd [MH⁺]: 324.02353; found: 324.02315.
To a solution of N-allyl-2-bromobenzene sulphonamide (5a, 276 mg, 1 mmol) in MeCN (4 mL) was added 4-bromo-butene (148 mg, 1.1 mmol) and K₂CO₃ (553 mg, 4 mmol). The resulting suspension was heated for 16 h. After filtration and concentration, the product was purified by flash chromatography (eluent: EtOAc-hexanes 10:90).
Compound 5c (86%): ¹H NMR (CDCl₃): δ = 2.27 (t, J = 7.4 Hz, 2 H), 3.36 (t, J = 7.4 Hz, 2 H), 3.99 (d, J = 6.4 Hz, 2 H), 4.95-5.15 (m, 2 H), 5.15-5.35 (m, 2 H), 5.59-5.85 (m, 2 H), 7.37 (dt, J = 1.8, 7.5 Hz, 1 H), 7.45 (dt, J = 1.8, 7.5 Hz, 1 H), 7.75 (dd, J = 7.5, 1.3 Hz, 1 H), 8.18 (dd, J = 8.7, 2.1 Hz, 1 H). ¹³C NMR (CDCl₃): δ = 32.7, 46.6, 50.3, 117.5, 119.3, 120.7, 127.9, 132.5, 133.4, 133.9, 134.8, 136.0, 139.8. IR (film): 3070, 2985, 1640, 1575, 1445, 1340, 1155, 915, 755 cm^-1.

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Metathesis and Isomerization of Amides 2, Typical Procedure.
To a solution of amide 2a (140 mg, 0.5 mmol) in toluene was added first generation Grubbs’ catalyst (11 mg, 2.5% mol). After stirring at r.t. for 1 h and complete disappearance of the starting material, NaH (7 mg, 1.5 mmol) was added at once and the mixture was heated to reflux. A new addition of both Grubbs’ catalyst (11 mg, 2.5% mol) and NaH (7 mg, 1.5 mmol) was performed after 12 h of heating and this sequence was repeated three times more. After cooling to r.t., the solvent was removed by concentration and the resulting crude mixture was purified by flash chromatography on silica (eluent: hexanes-EtOAc 7:3).
Compound 7a (72%): ¹H NMR (CDCl₃) 2 rotamers (ratio 4.2:1): δ (major rotamer) = 2.76 (dt, J = 8.6, 2.4 Hz, 2 H), 4.07 (t, J = 9.0 Hz, 2 H), 5.23 (dt, J = 4.3, 2.4 Hz, 1 H), 6.02 (dt, J = 6.4, 1.2 Hz, 1 H), 7.35 (m, 3 H), 7.60 (d, J = 7.5 Hz, 1 H); δ (minor rotamer) = 2.76 (dt, J = 8.6, 2.4 Hz, 2 H), 3.58 (t, J = 9.0 Hz, 2 H), 5.42 (dt, J = 4.3, 2.4 Hz, 1 H), 7.11 (dt, J = 6.4, 2.1 Hz, 1 H), 7.35 (m, 3 H), 7.60 (d, J = 7.5 Hz, 1 H). ¹³C NMR (CDCl₃): δ (major rotamer) = 27.6, 43.8, 111.8, 118.4, 126.7, 127.4, 128.6, 129.7, 131.9, 136.9, 173.4;
δ (minor rotamer) = 28.8, 45.7, 111.8, 117.7, 126.7, 127.4, 128.6, 129.7, 131.9, 137.6, 173.4. IR (film): 3065, 2955, 1645, 1420, 1045, 1025, 830 cm^-1. HRMS: m/z calcd [MH⁺]: 252.00240; found: 252.00229.
Compound 7d (71%): yellow oil. ¹H NMR (CDCl₃): δ = 2.73 (dt, J = 6.0, 0.8 Hz, 2 H), 4.01 (t, J = 8.3 Hz, 2 H), 5.22 (dt, J = 5.3, 2.6 Hz, 1 H), 6.02 (s, 2 H), 6.06 (dt, J = 4.3, 2.1 Hz, 1 H), 6.80 (s, 1 H), 7.01 (s, 1 H). ¹³C NMR (CDCl₃): δ = 28.9, 45.1, 102.4, 108.2, 108.5, 110.9, 113.0, 113.1, 130.0, 147.7, 149.4, 164.5. HRMS: m/z calcd [MH⁺]: 294.98441; found: 294.98497.

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Radical Cyclization of Amides 7, Typical Procedure Described from Amide 7a.
A solution of amide 7a (100 mg, 0.4 mmol) in toluene (40 mL) containing small amounts of AIBN (7 mg, 0.04 mmol) was bubbled by a dried stream of nitrogen for 10 min and heated to reflux. A solution of tristrimethylsilylsilane (140 µL, 0.44 mmol) in toluene (10 mL) was carefully added drop by drop in 15 min. The reaction was heated for additional 6 h. The solvent was removed by concentration and the crude mixture was purified by flash chromatography on silica (eluent: EtOAc-hexanes 50:50) and gave lactam 10a.
Compound 10a (77%): viscous oil. ¹H NMR (CDCl₃): δ = 1.25 (m, 2 H), 2.34 (m, 2 H), 3.43 (m, 1 H), 3.72 (dt, J = 11.3, 8.3 Hz, 1 H), 4.68 (dd, J = 10.3, 5.3 Hz, 1 H), 7.45 (m, 3 H), 7.80 (d, J = 7.2 Hz, 1 H). ¹³C NMR (CDCl₃): δ = 28.2, 28.7, 40.9, 63.7, 114.9, 121.7, 122.9, 127.3, 130.6, 145.4, 170.6. IR: 3075, 2960, 1685, 1385, 1220, 1145, 740 cm^-1. HRMS: m/z calcd [MH⁺]: 174.09189; found: 174.09163.
Compound 12c (62%): white solid; mp 103-109 °C. ¹H NMR (CDCl₃): δ = 1.40-1.85 (m, 4 H), 2.03 (dt, J = 11.3, 3.0 Hz, 1 H), 2.28 (dd, J = 3.0, 11.3 Hz, 1 H), 3.02 (dt, J = 3.2, 11.3 Hz, 1 H), 3.86 (dt, J = 10.2, 2.7 Hz, 1 H), 4.20 (dd, J = 3.2, 11.3 Hz, 1 H), 7.37 (dd, J = 1.1, 7.5 Hz, 1 H), 7.50 (t, J = 7.5 Hz, 1 H), 7.58 (dt, J = 1.1, 7.5 Hz, 1 H), 7.79 (d, J = 7.5 Hz, 1 H). ¹³C NMR (CDCl₃): δ = 23.9, 24.3, 30.5, 40.4, 58.8, 121.4, 123.2, 129.3, 132.8, 135.4, 138.8. IR: 3080, 2955, 2850, 1645, 1450, 1285, 1170, 1130 cm^-1. HRMS: m/z calcd [MH⁺]: 224.07452; found: 224.07453.

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Tandem Process from Amides 2a,d, Typical Procedure.
To a solution of amide 2a (140 mg, 0.5 mmol) in toluene was added first generation Grubbs’ catalyst (11 mg, 2.5% mol). After stirring at r.t. for 1 h and complete disappearance of the starting material, NaH (7 mg, 1.5 mmol) was added at once and the mixture was heated to reflux. A new addition of both Grubbs’ catalyst (11 mg, 2.5% mol) and NaH (7 mg, 1.5 mmol) was performed after 12 h of heating and this sequence was repeated three times more. After cooling to r.t., AIBN (8 mg, 0.05 mmol) was added. The mixture was bubbled with a dried nitrogen stream and next heated. A solution of TTMSS (320 µL, 1 mmol) in toluene (10 mL) containing AIBN (8 mg, 0.05 mmol) was slowly added to the reaction mixture in 10 min. After heating at 130 °C for 6 h, the mixture was cooled to r.t., and the solvent removed by concentration under vacuum. The products were purified after flash chromatography on silica.