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

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.

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

References

1 For recent review, see: Beletskaya IP. Cheprakov AV. Chem. Rev.  2000,  100:  3009 ; and references therein

2a Bocelli G. Catellani M. Chiusoli GP. Cugini F. Lasagni B. Neri Mari M. Inorg. Chim. Acta  1998,  270:  123 

2b Tietze LF. Ferraccioli R. Synlett  1998,  145 

2c Bocelli G. Catellani M. Cugini F. Ferraccioli R. Tetrahedron Lett.  1999,  40:  2623 

2d Catellani M. Catucci C. Celentano G. Ferraccioli R. Synlett  2001,  803 

The use of quaternary ammonium salts in the Heck reaction in dry and aqueous solvents was thoroughly studied by Jeffery:

3a Jeffery T. Tetrahedron  1996,  52:  10113 ; and references therein

3b Jeffery T. David M. Tetrahedron Lett.  1998,  39:  5751 

3c

For a recent report on water effect on Heck reaction see ref. [1]

4

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 (C_quat); 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 (C_quat); 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.

5

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 (C_quat); 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 (C_quat); 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 (C_quat); 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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8

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.

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