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Synlett 2002(11): 1860-1864
DOI: 10.1055/s-2002-34875
LETTER
© Georg Thieme Verlag Stuttgart · New York

Palladium-Catalyzed Cyclization of N-n-Butyl, N-(o-Iodobenzyl)-3-butenamides: Six- versus Seven- and Eight-membered Ring Formation

Raffaella Ferraccioli*a, Davide Carenzia, Marta Catellanib
a CNR-Istituto di Scienze e Tecnologie Molecolari (ISTM), Via C. Golgi 19, 20133 Milano, Italy
Fax: +39(2)50314139; e-Mail: rferra@icil64.cilea.it;
b Dipartimento di Chimica Organica e Industriale, Parco Area delle Scienze 17/A, 43100 Parma, Italy
Further Information

Publication History

Received 1 August 2002
Publication Date:
21 October 2002 (online)

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Abstract

The regiochemistry of the palladium-catalyzed annulation of N-n-butyl, N-(o-iodobenzyl)-3-butenamides 1 can be dramatically varied by addition of water to the reaction mixture. In anhydrous DMF 1 lead to 6-membered ring formation, while in aqueous DMF 7/8-membered rings were formed. The water effect was also observed in MeCN and THF.

Key words

palladium catalysis - cyclization - medium-sized rings - regioselectivity - water

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Palladium-catalyzed Cyclization of 1 in Dry DMF: Synthesis of 1,4-Dihydro-2 H -isoquinolin-3-ones (3): n-Bu4NOAc (173 mg, 0.575 mmol) was placed in a Schlenk-type flask and stirred under vacuo at 110 °C for 2 h in order to remove water. After cooling to r.t. 1 (0.23 mmol), Pd(OAc)2 (5.2 mg, 0.023 mmol), Ph3P (12 mg, 0.046 mmol) and dry and degassed DMF (the content of water was ≤0.005%) (4.6 mL, 0.05 M) were added under nitrogen. The mixture was heated at 85 °C under stirring until the conversion was complete (monitored by TLC). The reaction mixture was cooled, diluted with water (10 mL) and extracted with diethyl ether (3 × 5 mL). After drying (Na2SO4) and removal of the solvent the residue was purified by flash chromatography on silica gel (eluent: EtOAc/petroleum ether) leading to (E), (Z)- 2 (R1 = H, 1/1, 60% yield), (R1 = Me, 1/1, 49% yield), (E), (Z)- 2 and (E)-2a (R1 = Ph, 1/1/1, 50% yield), respectively (Table [1] , entries 1, 3, 5; the configuration of 2 was determined by NOESY experiments). Due to their instability 2 and 2a, were submitted to catalytic reduction with 10% Pd/C (25-30% mol) under 1 atm of hydrogen in EtOAc for 24 h. After usual work-up and purification of the crude by flash chromatography on silica gel (EtOAc/petroleum ether) compounds 3 were obtained. 3 (R1 = H): Oil, yield: 72%; IR (neat): 2961, 2931, 2872, 1651 cm-1; 1H NMR (300 MHz, CDCl3): δ = 0.82 (t, 3 H, J = 7.53 Hz), 0.87 (t, 3 H, J = 7.6 Hz), 1.22-1.34 (m, 2 H), 1.47-1.57 (m, 2 H), 1.71-1.86 (m, 2 H), 3.24-3.34 (m, 1 H), 3.39 (t, 1 H, J = 6.86 Hz), 3.55-3.65 (m, 1 H), 4.17 (d, 1 H, J = 15.8 Hz), 4.59 (d, 1 H, J = 15.8 Hz), 7.05-7.20 (m, 4 H); 13C NMR (75 MHz, CDCl3): δ = 11.1, 13.8 (Me), 20.1, 27.1, 29.4, 46.9 (CH2), 49.0 (CH), 50.4 (CH2), 125.1, 126.4, 127.3, 127.6 (CH), 131.2, 136.6, 171.6 (Cquat); Ms (EI): m/z (%) = 231(12) [M+], 202(100), 160(50), 146(25), 132(60), 117(55), 91(20). Anal. Calcd for C15H21NO: C, 77.88; H, 9.15; N 6.05. Found: C, 78.02; H, 9.14; N, 6.12.
3 (R1 = Me): Oil, yield 68%; IR(neat): 2959, 2929, 2871, 1647 cm-1; 1H NMR (300 MHz, DMSO-d 6): δ = 0.76 (t, 3 H, J = 7.3 Hz), 0.80 (t, 3 H, J = 7.3 Hz), 1.13-1.2 (m, 4 H), 1.40-1.6 (m, 4 H), 3.17-3.20 (m, 1 H), 3.30 (t, 1 H, J = 7.0 Hz), 3.43-3.52 (m, 1 H), 4.26 (d, 1 H, J = 16.1 Hz), 4.56 (d, 1 H, J = 16.1 Hz), 7.10-7.20 (m, 4 H); 13C NMR (75 MHz, DMSO-d 6): δ = 14.0 (2 C), 19.8 (2 C), 29.2, 35.2, 45.9, 47.3, 49.5, 125.7, 126.6, 127.4 (2 C), 132.3, 137.1, 170.6; Ms (EI): m/z (%) = 245(15) [M+], 203 (100), 174 (30), 146 (15), 131 (30), 117 (15), 91 (10). Anal Calcd for C16H23NO: C, 78.32; H, 9.45; N 5.71. Found: C, 78.14; H, 9.59; N, 5.78.
3 (R1 = Ph): Oil, yield: 70%; IR(neat): 2957, 2928, 2860, 1651 cm-1; 1H NMR (300 MHz, CDCl3): δ = 0.94 (t, 3 H, J = 7.3 Hz), 1.35 (sextet, 2 H, J = 7.4 Hz), 1.59 (quintet, 2 H, J = 7.5 Hz), 1.96-2.20 (m, 2 H), 2.65 (t, 2 H, J = 8.3 Hz), 3.32-3.42 (m, 1 H), 3.60-3.72 (m, 2 H), 4.26 (d, 1 H, J = 15.8 Hz), 4.67 (d, 1 H, J = 15.8 Hz), 7.14-7.31 (m, 9 H);13C NMR (75 MHz, CDCl3): δ = 13.9 (Me), 20.1, 28.9, 32.9, 35.3, 46.9 (CH2), 47.5 (CH), 50.4 (CH2), 125.3, 125.9, 126.5, 127.4, 127.5, 128.3, 128.4 (CH), 131.3, 136.7, 141.4, 171.3 (Cquat); MS (EI): m/z (%) = 306(75) [M - 1], 214(90), 203(100), 158(25), 91(90). Anal. Calcd for C21H25NO: C, 82.04; H, 8.20; N, 4.56. Found: C, 82.32; H, 8.19; N, 4.61.

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Palladium-catalyzed Cyclization of 1 in Aqueous DMF: Synthesis of 2,3-Dihydro-1 H -2-benzazepin-3-ones (4a) and 1,4-Dihydro-2 H -2-benzazocin-3-ones (5a). In a Schlenk-type flask nBu4NOAc (173 mg, 0.575 mmol), Pd(OAc)2 (5.2 mg, 0.023 mmol), Ph3P (12.1 mg, 0.046 mmol), a solution of 1 (0.23 mmol) in degassed DMF (4.2 mL), degassed water (0.42 mL) were added under nitrogen. The mixture was heated at 85 °C under stirring until the conversion was complete (TLC), then worked-up as described in ref. [3] The crude obtained was dissolved in dry DMF (3.0 mL) and added with t-BuOK (28 mg, 0.25 mmol). The resulting mixture was heated under stirring at 80 °C for 18 h. After cooling it was poured into water (7 mL) and extracted with ether (3 × 4 mL). The combined organic layer was dried (Na2SO4) and evaporated under vacuo. The crude was purified by flash chromatography on silica gel (EtOAc/petroleum ether) to give in order of elution 5a (R1 = H, Me) and 4a (R1 = H, Me, Ph).
5a (R1 = H): Mp 41-42 °C (n-hexane/EtOAc); IR (nujol): 1737, 1646 cm-1; 1H NMR (300 MHz, CDCl3): δ = 0.92 (t, 3 H, J = 7.3 Hz), 1.3 (sextet, 2 H, J = 7.4 Hz), 1.49-1.59 (m, 2 H), 3.33-3.40 (m, 4 H), 4.45 (s, 2 H), 5.8 (ddd, 1 H, J = 12.6, 6.4, 6.4 Hz), 6.55 (d, 1 H, J = 12.6 Hz), 7.16-7.32 (m, 4 H); 13C NMR (75 MHz, CDCl3): δ = 13.9 (Me), 20.1, 29.5, 38.9, 45.1, 51.9 (CH2), 125.7, 127.6, 128.4, 130.1, 131.6, 131.8 (CH), 135.0, 136.5, 168.7 (Cquat); MS (EI): m/z (%) = 229(60) [M+], 186(30), 129(100), 115(40). Anal. Calcd for C15H19NO: C, 78.56; H, 8.35; N, 6.11. Found: C, 78.48; H, 8.41; N, 6.15.
4a (R1 = H): Oil; IR (neat): 2931, 2872, 1737, 1636, 1595 cm-1; 1H NMR (300 MHz, CDCl3): δ = 0.85 (t, 3 H, J = 7.3 Hz), 1.20-1.27 (m, 2 H), 1.47-1.57 (m, 2 H), 2.29 (s, 3 H), 3.44-3.49 (m, 2 H), 3.7-4.5 (br s, 2 H), 6.4 (s, 1 H), 7.25-7.48 (m, 4 H); 13C NMR (75 MHz, CDCl3): δ = 13.7 (Me), 19.9 (CH2), 23.9 (Me), 30.5, 47.1, 51.6 (CH2), 125.5, 126.9, 127.2, 128.2, 128.8 (CH), 137.1, 137.7, 143.0, 166.4 (Cquat); MS (EI): m/z (%) = 229(80) [M+], 187(90), 173(100), 159(60), 129(85), 115(55). Anal. Calcd for C15H19NO: C, 78.56; H, 8.35; N, 6.11. Found: C, 78.75; H, 8.15; N, 5.99.
5a (R1 = Me): Oil; IR(neat): 2958, 2927, 2871, 1728, 1635 cm-1; 1H NMR (300 MHz, CDCl3): δ = 0.91 (t, 3 H, J = 7.3 Hz), 1.25-1.37 (m, 2 H), 1.50-1.63 (m, 2 H), 2.06 (s, 3 H), 2.64 (d, 2 H, J = 8.0 Hz), 3.49 (pst, 2 H, J = 7.49 Hz), 4.16 (s, 2 H), 5.62 (br t, 1 H, J = 8.0 Hz), 7.17-7.30 (m, 4 H); 13C NMR (75 MHz, CDCl3): δ = 13.9, 20.1, 22.1, 30.3, 39.3, 50.5, 52.4, 119.2, 125.6, 128.0, 128.4, 130.3, 133.8, 140.4, 142.3, 168.4; MS (EI): m/z (%) = 243 (15) [M+], 200 (40), 187 (25), 144 (25), 129 (100), 115 (20); HRMS (EI): Calcd for C16H21NO: 243.1623. Found: 243.1654.
4a (R1 = Me): Mp 52-53 °C (n-hexane); IR(nujol): 1733, 1641, 1596 cm-1; 1H NMR (300 MHz, CDCl3): δ = 0.86 (t, 3 H, J = 7.2 Hz), 1.11 (t, 3 H, J = 7.0 Hz), 1.20-1.29 (m, 2 H), 1.45-1.60 (m, 2 H), 2.69-2.73 (br q, 2 H, J = 8.0 Hz), 3.46 (pst, 2 H, J = 7.3 Hz), 4.0 (br s, 1 H), 4.35 (br s, 1 H), 6.26
(br s, 1 H), 7.27-7.50 (m, 4 H);13C NMR (75 MHz, CDCl3): δ = 13.2, 13.7, 19.9, 29.8, 30.5, 46.9, 51.6, 123.9, 126.6, 127.2, 128.1, 128.5, 137.0, 137.6, 148.6, 166.5; MS (EI): m/z (%) = 243 (65) [M+], 201 (72), 187 (100), 173 (45), 144 (30), 128 (43), 115 (20). Anal Calcd for C16H21NO: C, 78.97; H, 8.70; N, 5.76. Found: C, 78.93; H, 8.41; N, 5.71.
4a (R1 = Ph): Mp 92-93 °C (n-hexane); IR(nujol): 1746, 1636, 1597 cm-1; 1H NMR (300 MHz, CDCl3): δ = 0.8 (t, 3 H, J = 7.3 Hz), 1.16 (sextet, 2 H, J = 7.6 Hz), 1.46 (quintet, 2 H, J = 7.5 Hz), 3.40 (t, 2 H, J = 7.3 Hz), 3.90 (br s, 3 H), 4.25 (br s, 1 H), 6.20 (s, 1 H), 7.10-7.30 (m, 8 H), 7.40-7.45 (m, 1 H); 13C NMR (75 MHz, CDCl3): δ = 14.2 (Me), 20.4, 30.9, 43.5, 47.4, 52.1 (CH2), 126.9, 127.4, 127.7, 128.6, 129.0, 129.2, 129.3 (CH), 137.3, 138.0, 138.8, 146.0, 166.7 (Cquat); MS (EI): m/z (%) = 305(100) [M+], 263(87), 249(50), 206(33), 115(25), 91(67) Anal Calcd for C21H23NO: C, 82.59; H, 7.59; N, 4.59. Found: C, 82.76; H, 7.46; N, 4.71.

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Although the water effect is felt even in the presence of traces of water we preferred to carry out experiments with 10% water for reasons of reproducibility.