Palladium-Catalyzed Cyclization Reactions of Acetylene-Containing ...

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Palladium-Catalyzed Cyclization Reactions of Acetylene-Containing Amino AcidsFULL PAPERS(m, 2H), 2.39 (s, 3H), 1.23 (t, J ˆ 7.1 Hz, 1H); 13 C NMR (100 MHz, CDCl 3 ):d ˆ 173.8, 143.9, 136.5, 129.6, 127.0, 80.0, 72.5, 53.7, 23.5, 21.4; IR (film): n ˆ3500 ± 2750, 3288, 2125, 1732, 1598, 1335, 1161, 1092 cm 1 ; HRMS (FAB):calcd. for C 12 H 14 NO 4 S (MH ‡ ) 268.0644, found 268.0654.17: 1 H NMR (400 MHz, CD 3 OD): d ˆ 7.90 ± 7.81 (m, 4H), 4.98 ± 4.94 (m,1H), 2.46 ± 2.40 (m, 2H), 2.32 ± 2.22 (m, 2H), 2.10 (t, J ˆ 2.6 Hz, 1H);13C NMR (100 MHz, CD 3 OD): d ˆ 169.4, 135.5, 133.2, 132.0, 131.7, 124.3,83.5, 70.4, 53.0, 28.8, 16.6; IR (film): n ˆ 3288 ± 2750, 1715, 1393 cm 1 ; HRMS(EI): calcd. for C 14 H 11 NO 4 257.0688, found 257.0671.(S)-2-(Toluene-4-sulfonylamino)hex-5-ynoic Acid (14)To a solution of (S)-12 (100 mg, 0.79 mmol) in H 2 O (2.0 mL), 1 M NaOH(0.90 mL, 0.90 mmol) and p-toluenesulfonyl chloride (180 mg, 0.95 mmol)were added and the reaction mixture was stirred for 16 h at ambienttemperature. The reaction mixture was kept basic during the reaction time.The reaction mixture was washed with ether (3 50 mL), acidified with 1 MHCl and extracted with EtOAc (3 50 mL). The combined EtOAc layerswere dried (MgSO 4 ) and concentrated. After purification of the crudeproduct by flash chromatography (ether, 5% AcOH), (S)-14 was obtained asan amorphous solid; yield: 162 mg (0.58 mmol, 73%). (R)-14: 1 H NMR(400 MHz, CDCl 3 ): d ˆ 7.74 (d, J ˆ 8.3 Hz, 2H), 7.29 (d, J ˆ 7.7 Hz, 2H), 5.35(d, J ˆ 8.8 Hz, 1H), 4.07 ± 4.02 (m, 1H), 2.41 (s, 3H), 2.30 ± 2.26 (m, 2H),2.09 ± 2.00 (m, 1H), 1.94 (t, J ˆ 2.6 Hz, 1H), 1.87 ± 1.81 (m, 1H); 13 C NMR(100 MHz, CDCl 3 ); d ˆ 175.6, 143.9, 136.2, 129.6, 127.1, 81.8, 69.8, 54.2, 31.6,21.4, 14.5; IR (film): n ˆ 3292, 3250-2750, 1750, 1410, 1334 cm 1 ; HRMS (EI):calcd. for C 13 H 15 NO 4 S 281.0722, found 281.0707.(R)-2-tert-Butoxycarbonylaminopent-4-ynoic Acid (15)To a solution of (R)-11 (100 mg, 0.88 mmol) in dioxane/water (2.0 mL/2.0 mL), sodium bicarbonate (148 mg, 1.76 mmol) and di-tert-butyl dicarbonate(203 mg, 0.92 mmol) were added. After refluxing for 4 h, the dioxanewas evaporated and aqueous saturated sodium bicarbonate (5 mL) wasadded to the reaction mixture. The reaction mixture was washed with ether(3 10 mL), acidified with 1 M HCl and extracted with EtOAc (3 10 mL).The combined EtOAc layers were dried (MgSO 4 ) and concentrated.Purification of the crude product by flash chromatography (ether, 5%AcOH) afforded (R)-15 as a colorless oil; yield: 114 mg (0.73 mmol, 83%).(R)-15: [a] D : 33.6 (c 1, CH 2 Cl 2 ); 1 H NMR (400 MHz, CDCl 3 ): d ˆ 5.34 (d,J ˆ 7.8 Hz, 1H), 4.52 ± 4.51 (m, 1H), 2.80 ± 2.74 (m, 2H), 2.08 (t, J ˆ 2.6 Hz,1H), 1.46 (s, 9H); 13 C NMR (100 MHz, CDCl 3 ): d ˆ 174.5, 155.2, 80.4, 78.1,71.6, 51.5, 28.0, 22.3; IR (film): n ˆ 3500 ± 2800, 3298, 2980, 1716, 1668, 1514,1161 cm 1 ; HRMS (EI): calcd. for C 10 H 15 NO 4 213.1001, found 213.0994.(S)-2-(1,3-Dioxo-1,3-dihydroisoindol-2-yl)pent-4-ynoic Acid(16)To a solution of (S)-11 (500 mg, 3.76 mmol) in H 2 O (10 mL) phthalicanhydride (560 mg, 3.76 mmol) was added. The reaction mixture wasirradiated in a microwave until the water was evaporated. Then, again H 2 O(10 mL) was added and this procedure was repeated three times. Afterpurification of the crude product by flash chromatography (ether, 5%AcOH), (S)-16 was obtained as a colorless oil; yield: 830 mg (3.42 mmol,91%). (S)-16:[a] D : 40.4 (c 0.5, MeOH); 1 H NMR (400 MHz, CDCl 3 ): d ˆ9.20 ± 8.80 (bs, 1H), 7.92 ± 7.85 (m, 2H), 7.78 ± 7.72 (m, 2H), 5.14 (dd, J ˆ4.8 Hz, 11.3 Hz), 3.30 ± 3.22 (m, 1H), 3.12 ± 3.06 (m, 1H), 1.90 (t, J ˆ 2.6 Hz,1H); 13 C NMR (100 MHz, CDCl 3 ): d ˆ 171.3, 168.8, 135.7, 134.1, 132.9,132.0, 130.0, 124.4, 80.3, 71.7, 51.9, 20.04; IR (film): n ˆ 3290, 1775, 1713,1393 cm 1 ; HRMS (EI): calcd. for C 13 H 9 NO 4 243.0532, found 243.0537.2-(1,3-Dioxo-1,3-dihydroisoindol-2-yl)hex-5-ynoic Acid (17)To a solution of rac-12 (200 mg, 1.57 mmol) in H 2 O (10 mL) phthalicanhydride (233 mg, 1.57 mmol) was added. The reaction mixture wasirradiated in a microwave until the water was evaporated. Then, again H 2 O(10 mL) was added and the procedure was repeated three times. Afterpurification of the crude product by flash chromatography (ether, 5%AcOH), 17 was obtained as a colorless oil; yield: 369 mg (1.44 mmol, 91%).(S)-2-(4-Toluenesulfonylamino)pent-4-ynoic Acid MethylEster (18)To a solution of (S)-11 (3.00 g, 0.020 mol) in MeOH (100 mL) thionylchloride (2.9 mL, 0.040 mol) was added. After refluxing at 708C for 3 h, thereaction mixture was concentrated under vacuum. The crude reactionmixture was dissolved in pyridine (50 mL), p-toluenesulfonyl chloride(4.60 g, 0.020 mol) was added and the reaction mixture was stirred for 16 h atambient temperature. The pyridine was evaporated and aqueous saturatedCuSO 4 (50 mL) was added. The mixture was extracted with CH 2 Cl 2 (3 50 mL) and the combined organic layers were washed with aqueoussaturated sodium bicarbonate (25 mL), then with brine, dried (MgSO 4 )and concentrated. After purification by flash chromatography (70% ether/petroleum ether) and crystallization (EtOAc/petroleum ether), (S)-18 wasobtained as a white solid; 5.30 g (18.0 mmol, 94%). (S)-18:mp82±848C; [a] D :‡ 19.4 (c 1, CH 2 Cl 2 ); 1 H NMR (400 MHz, CDCl 3 ) d ˆ 7.73 (d, J ˆ 1.5 Hz,2H), 7.71 (d, J ˆ 7.7 Hz, 2H), 5.71 (d, J ˆ 8.8 Hz, 1H), 4.12 ± 4.07 (m, 1H),3.59 (s, 3H), 2.67 ± 2.63 (m, 2H), 2..39 (s, 3H), 2.01 (t, J ˆ 2.6 Hz, 1H);13C NMR (100 MHz, CDCl 3 ): d ˆ 169.9, 143.7, 136.7, 126.6, 127.1, 77.4, 72.2,53.9, 52.7, 23.9, 21.4; IR (film): n ˆ 3273, 2953, 1712 cm 1 ; HRMS: (FAB)calcd. for C 13 H 16 NO 4 S (MH ‡ ) 282.0800, found 282.0791.(R)-2-(4-Toluenesulfonylamino)hex-5-ynoic Acid MethylEster (19)To a solution of (R)-12 (1.00 g, 7.87 mmol) in MeOH (250 mL) thionylchloride (1.12 mL, 15.7 mmol) was added. After refluxing at 708C for 5 h thereaction mixture was concentrated under vacuum. The crude reactionmixture was dissolved in CH 2 Cl 2 (50 mL), Et 3 N (5.46 mL, 29.4 mmol) and p-toluenesulfonyl chloride (3.0 g, 15.7 mmol) were added and the reactionmixture was stirred for 16 h at ambient temperature. An aqueous solution ofNH 4 Cl (50 mL) was added to the reaction mixture. After separation, theaqueous layer was extracted with CH 2 Cl 2 (3 50 mL). The combinedorganic layers were stirred with aqueous saturated sodium bicarbonate(25 mL) for 1 h. After separation the organic layer was dried (MgSO 4 ) andconcentrated. Purification of the crude product by flash chromatography(70% ether/petroleum ether) and crystallization (EtOAc/petroleum ether)afforded (R)-19 as a white solid; yield: 1.68 g (5.69 mmol, 72%). (R)-19:mp75 ± 778C; [a] D : 35.7 (c 1, CH 2 Cl 2 ); 1 H NMR (400 MHz, CDCl 3 ) d ˆ 7.73(dd, J ˆ 1.6 Hz, 6.6 Hz, 2H), 7.29 (d, J ˆ 7.9 Hz, 2H), 5.22 (d, J ˆ 8.9 Hz, 1H),4.02 ± 3.99 (m, 1H), 3.52 (s, 3H), 2.41 (s, 3H) 2.32 ± 2.27 (m, 2H), 1.98 ± 1.94(m, 2H), 1.86 ± 1.81 (m, 1H); 13 C NMR (100 MHz, CDCl 3 ): d ˆ 171.6, 143.6,136.4, 129.5, 127.1, 82.1, 69.4, 54.6, 52.4, 31.9, 21.3, 14.4; IR (film): n ˆ 3280,2954, 2119, 1922, 1732, 1598 cm 1 ; HRMS (EI): calcd. for C 14 H 17 NO 4 S295.0878, found 295.0858.(R)-2-(4-Nitrobenzenesulfonylamino)hex-5-ynoic AcidMethyl Ester (20)To a solution of (R)-12 (400 mg, 3.15 mmol) in MeOH (250 mL) thionylchloride (0.45 mL, 6.30 mmol) was added. After refluxing at 708C for 5 h thereaction mixture was concentrated under vacuum. The crude residue wasdissolved in CH 2 Cl 2 (25 mL), Et 3 N (2.15 mL, 15.7 mmol) and p-nitrophenylsulfonylchloride (1.05 g, 4.72 mmol) was added and the reactionmixture was stirred for 16 h at ambient temperature. An aqueous solution ofNH 4 Cl (50 mL) was added to the reaction mixture. After separation theaqueous layer was extracted with CH 2 Cl 2 (3 50 mL). The combinedorganic layers were stirred with aqueous saturated sodium bicarbonate(25 mL) for 1 h. After separation the organic layer was dried (MgSO 4 ) andAdv. Synth. Catal. 2002, 344, 70±83 77
FULL PAPERSLarissa B. Wolf et al.concentrated. Purification by flash chromatography (70% ether/petroleumether) and crystallization (EtOAc/petroleum ether) afforded (R)-20 as ayellowsolid; yield: 604 mg (1.85 mmol, 59%). (R)-20: mp87±898C; [a] D :33.9 (c 1, CH 2 Cl 2 ); 1 H NMR (400 MHz, CDCl 3 ): d ˆ 8.35 (d, J ˆ 8.6 Hz,2H), 8.05 (d, J ˆ 8.6 Hz, 2H), 5.40 (d, J ˆ 8.8 Hz, 1H), 4.13 ± 4.11 (m, 1H),3.60 (s, 3H), 2.34 ± 2.29 (m, 2H), 2.05 ± 2.01 (m, 1H), 1.98 (t, J ˆ 2.6 Hz, 1H),1.90 ± 1.84 (m, 1H); 13 C NMR (100 MHz, CDCl 3 ): d ˆ 171.1, 149.9, 145.2,128.2, 124.0, 81.6, 69.7, 54.6, 52.6, 31.6, 14.3; IR (film): n ˆ 3284, 1742, 1532,1351, 1166 cm 1 ; HRMS (EI): calcd. for C 13 H 14 N 2 O 6 S 326.0573, found326.0583.4-Methyl-N-(6-methylene-2-oxotetrahydropyran-3-yl)benzenesulfonamide (24)Following the general procedure A, to a solution of rac-14 (50 mg,0.18 mmol) in MeCN (2.0 mL), Et 3 N (4.0 mL, 0.03 mmol) and PdCl 2(MeCN) 2 (2.3 mg, 0.01 mmol) were added. The reaction mixture was stirredfor 16 h at reflux temperature. Purification afforded 24 as a white amorphoussolid; yield: 16.0 mg (0.06 mmol, 32%). 24: 1 H NMR (400 MHz, CDCl 3 ): d ˆ7.76 (d, J ˆ 8.2 Hz, 2H), 7.32 (d, J ˆ 8.1 Hz, 2H), 5.10 (d, J ˆ 4.1 Hz, 1H), 4.72(s, 1H), 4.41 (d, J ˆ 1.5 Hz, 1H), 3.84 ± 3.78 (m, 1H), 3.05 ± 2.98 (m, 1H),2.73 ± 2.66 (m, 1H), 2.63 ± 2.57 (m, 1H), 2.55-2.44 (m, 1H), 2.43 (s, 3H).General Procedure A for the Oxypalladation ReactionsTo a solution of the cyclization precursor in THF, Et 3 N and the Pd-catalystwere added. The reaction mixture was stirred at ambient temperature or at608C. After the reaction was finished (TLC), the solvent was evaporated andthe product was purified by flash chromatography (gradient: 20 ! 70%ether/petroleum ether, 1% Et 3 N).(R)-4-Methyl-N-(5-methylene-2-oxotetrahydrofuran-3-yl)benzenesulfonamide (21)Following the general procedure A, to a solution of (R)-13 (100 mg,0.37 mmol) in THF (3.0 mL), Et 3 N (8.0 mL, 0.06 mmol) and Pd(OAc) 2(8.0 mg, 0.04 mmol) were added. The reaction mixture was stirred for 1 hat ambient temperature. Purification afforded (R)-21 as a colorless oil; yield:66.0 mg (0.25 mmol, 66%). (R)-21: [a] D : 27.2 (c 1, CH 2 Cl 2 ); 1 H NMR(400 MHz, CDCl 3 ): d ˆ 7.78 (d, J ˆ 8.3 Hz, 2H), 7.74 (d, J ˆ 8.1 Hz, 2H), 5.19(d, J ˆ 3.4 Hz, 1H), 4.82 ± 4.81 (m, 1H), 4.46 ± 4.45 (m, 1H), 4.12 ± 4.06 (m,1H), 3.27 (dd, J ˆ 15.9 Hz, 9.1 Hz, 1H), 2.92 ± 2.85 (m, 1H), 2.44 (s, 3H);13C NMR (100 MHz, CDCl 3 ): d ˆ 171.9, 151.6, 144.1, 136.1, 129.8, 127.1, 90.9,51.9, 33.8, 21.4; IR (film): n ˆ 3270, 2922, 2258, 1811, 1681, 1598, 1340 cm 1 ;HRMS (FAB): calcd. for C 12 H 13 NO 4 S (MH ‡ ) 267.0565, found 267.0554.1-(6-Methylene-2-oxotetrahydropyran-3-yl)isosindole-1,3-dione (25)Following the general procedure A, to a solution of 17 (50 mg, 0.19 mmol) inTHF (2.0 mL) Et 3 N (4.0 mL, 0.03 mmol) and Pd(OAc) 2 (4.0 mg, 0.02 mmol)were added. The reaction mixture was refluxed for 6 h. Purification afforded25 as a colorless oil; yield: 12 mg (0.05 mmol, 24%). 25: 1 H NMR (400 MHz,CDCl 3 ): d ˆ 7.90 ± 7.86 (m, 2H), 7.77 ± 7.73 (m, 2H), 5.00 ± 4.95 (m, 1H), 4.79(t, J ˆ 1.5 Hz, 1H), 4.43 (t, J ˆ 1.4 Hz, 1H), 2.86 ± 2.80 (m, 1H) 2.72-2.52 (m,2H), 2.16 ± 2.09 (m, 1H); 13 C NMR (100 MHz, CDCl 3 ): d ˆ 166.8, 164.5,153.8, 134.5, 131.4, 123.7, 95.2, 48.0, 26.5, 23.6; IR (film): n ˆ 2923, 1759, 1716,1666, 1392 cm 1 .General Procedure B for the Oxypalladation ReactionsTo a solution of the cyclization precursor in MeCN, Et 3 N, TBAC, the arylhalide and finally the Pd(0) catalyst were added. The reaction was heated atreflux and monitored with TLC. Upon completion, the reaction mixture waspoured into saturated aqueous ammonium chloride, extracted with EtOAc(3 ), dried (MgSO 4 ) and concentrated. The product was purified by flashchromatography (gradient: 20 ! 70% ether/petroleum ether, 1% Et 3 N).(R)-(5-Methylene-2-oxotetrahydrofuran-3-yl)carbamic Acidtert-Butyl Ester (22)Following the general procedure A, to a solution of (R)-15 (40 mg,0.19 mmol) in THF (2.0 mL) Et 3 N (4.0 mL, 0.03 mmol) and Pd(OAc) 2(4.0 mg, 0.02 mmol) were added. Work-up and purification afforded (R)-22 as an amorphous solid; yield: 25 mg (0.12 mmol, 63%). (R)-22: [a] D :‡ 64.1 (c 1, CH 2 Cl 2 ); 1 H NMR (400 MHz, CDCl 3 ): d ˆ 5.13 (s, 1H), 4.80 (d,J ˆ 1.8 Hz, 1H), 4.41 ± 4.40 (m, 2H), 3.29 ± 3.23 (m, 1H), 2.89-2.83 (m, 1H),1.45 (s, 9H); 13 C NMR (100 MHz, CDCl 3 ): d ˆ 172.0, 152.11, 90.26, 80.1, 50.4,33.3, 28.0 (the quaternary olefinic carbon was not observed); IR (film): n ˆ3360, 2980, 1816, 1682, 1520, 1255, 1138 cm 1 ; HRMS (EI): calcd. for C 10 H 15NO 4 213.1001, found 213.1003.(R)-(5-Benzylidene-2-oxotetrahydrofuran-3-yl)-carbamicAcid tert-Butyl Ester (27)Following the general procedure B, to a solution of (R)-15 (52 mg,0.27 mmol) in MeCN (2.0 mL), Et 3 N (186 mL, 1.34 mmol), TBAC (148 mg,0.53 mmol), PhI (60 ml, 0.53 mmol), PPh 3 (15 mg, 0.05 mmol) and Pd(OAc) 2(6.0 mg, 0.03 mmol) were added. Work-up and purification afforded (R)-27as a yellowamorphous solid; yield: 34 mg (0.12 mmol, 44%). (R)-27:1H NMR (400 MHz, CDCl 3 ): d ˆ 7.48 ± 7.20 (m, 5H), 6.37 (s, 1H), 5.22 (d,J ˆ 6.2 Hz, 1H), 4.44 (m, 1H), 3.63 ± 3.57 (m, 1H), 3.17 ± 3.12 (m, 1H), 1.46 (s,9H); 13 C NMR (100 MHz, CDCl 3 ): d ˆ 172.0, 147.5, 133.6, 128.5, 127.7,126.8, 108.4, 82.3, 50.2, 33.1, 28.1, (the quaternary olefinic carbon was notobserved); IR (film): n ˆ 2978, 1810, 1681, 1507, 1156 cm 1 .(S)-2-(5-Methylene-2-oxotetrahydrofuran-3-yl)isoindole-1,3-dione (23)Following the general procedure A, to a solution of (S)-16 (50 mg,0.21 mmol) in THF (2.0 mL), Et 3 N (4.0 mL, 0.03 mmol) and Pd(OAc) 2(4.0 mg, 0.02 mmol) were added. The reaction mixture was stirred for 24 hat ambient temperature. Purification afforded (S)-23 as a white amorphoussolid; yield: 21 mg (0.09 mmol, 42%). (S)-23: [a] D : 58.4 (c 0.5, CH 2 Cl 2 );1H NMR (400 MHz, CDCl 3 ): d ˆ 7.91 ± 7.86 (m, 2H), 7.80 ± 7.76 (m, 2H),5.24 (t, J ˆ 10.1 Hz, 1H), 4.91 (d, J ˆ 1.2 Hz, 1H), 4.47 (s, 1H), 3.32 ± 3.18 (m,2H); 13 C NMR (100 MHz, CDCl 3 ): d ˆ 168.0, 166.5, 151.5, 134.5, 131.4,123.7, 90.7, 47.0, 30.3; IR (film): n ˆ 2900, 1809, 1775, 1716, 1676, 1397 cm 1 ;HRMS (EI): calcd. for C 13 H 9 NO 4 243.0532, found 243.0531.2-(5-Benzylidene-2-oxotetrahydrofuran-3-yl)-isoindole-1,3-dione (28)Following the general procedure B, to a solution of (S)-16 (50 mg,0.21 mmol) in MeCN (2.0 mL), Et 3 N (142 mL, 1.03 mmol), TBAC (114 mg,0.41 mmol), PhI (46 mg, 0.41 mmol) and Pd(PPh 3 ) 4 (24 mg, 0.03 mmol) wereadded. Purification afforded 28 as a white amorphous solid; yield: 28 mg(0.09 mmol, 43%). 28: 1 H NMR (400 MHz, CDCl 3 ): d ˆ 7.91 ± 7.88 (m, 2H),7.80 ± 7.76 (m, 2H), 7.36 ± 7.32 (m, 2H), 7.24 ± 7.21 (m, 3H), 6.49 (t, J ˆ2.0 Hz, 1H), 5.28 (t, J ˆ 9.9 Hz, 1H), 3.55 ± 3.52 (m, 2H); 13 C NMR (100MHz, CDCl 3 ): d ˆ 169.3, 166.5, 146.9, 134.5, 133.5, 131.4, 128.5, 127.8, 126.9,123.8, 108.7, 46.8, 30.4; IR (film): n ˆ 2926, 1815, 1778, 1721, 1682, 1397 cm 1 ;HRMS (EI): calcd. for C 19 H 13 NO 4 319.0845, found 319.0840.78 Adv. Synth. Catal. 2002, 344, 70±83
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