Ruthenium-Catalysed Isomerisation of Allylhydrazines: A New Entry to the Fischer Indole Synthesis

Abstract

The synthesis of non-symmetrically substituted allyl phenylhydrazines and their isomerisation to the corresponding enehydrazines is reported. The isomerisation is triggered by a combination of Grubbs’ first-generation catalyst and LiBEt₃H. Indoles are formed directly from the enehydrazines by the Fischer indole synthesis under the reaction conditions.

indoles - reduction - regioselectivity - hydrazines - transition metals

References and Notes

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28

General.
All reactions were carried out in oven-dried glassware under argon or nitrogen atmosphere. Chemicals and solvents were obtained from commercial suppliers and used as received unless otherwise noted. Toluene and THF were dried with sodium. DMF was dried over molecular sieves (4 Å) prior to use. ¹H NMR and ¹H-decoupled/¹³C NMR spectra were recorded at 500.13 MHz and 125.67 MHz, respectively, on a Bruker Avance DRX 500 instrument using deuterated CHCl₃ (99.8%). Chemical shifts for ¹H NMR are reported in ppm with TMS as internal reference. Chemical shifts for ¹³C NMR are reported in ppm relative to chemical shifts of CHCl₃. Elemental analyses were performed at the University of Vienna, Department of Physical Chemistry (Vienna, Austria), with a Perkin-Elmer 2.400 CHN elemental analyzer and at the University of Copenhagen with a CE Elantech-Thermoquest Flash EA 1112. HRMS were performed on a Jeol JMS-HX/HX110A MS instrument at the University of Copenhagen.
N , N ′-(Dialkyl)arylhydrazines (5) - General Procedure. To a solution of acylated hydrazone^28,29 (4a-d, 23 mmol) in THF (40 mL) at 0 °C was added dropwise BH₃·THF, 1 M in THF, (50 mL, 50 mmol) over 15 min. The reaction mixture was left at 5 °C overnight and subsequently treated carefully with 2 M aq KOH (130 mL). CAUTION: Hydrogen generation. After the gas evolution has ended the reaction mixture was extracted with EtOAc (4 × 50 mL) and the combined organic phases were dried over MgSO₄, concentrated in vacuo and purified by flash chromatography (2% Et₂O in heptane).
N,N′-(Diethyl)phenylhydrazine (5a):²⁹ yield 72% from 4a; yellow oil. ¹H NMR: δ = 6.70-7.20 (m, 5 H), 3.46 (q, 2 H, J = 7.1 Hz), 3.40 (1 H, s), 2.90 (q, 2 H, J = 7.2 Hz), 1.13 (t, 3 H, J = 7.1 Hz), 1.10 (t, 3 H, J = 7.2 Hz). ¹³C NMR: δ = 150.3, 129.5, 117.9, 113.5, 45.9, 43.0, 13.5, 11.2.
N ′-Allyl- N , N ′-(dialkyl)arylhydrazines (6) - General Procedure. To a mixture of a N,N′-(dialkyl)arylhydrazine (5a-d, 11 mmol) and K₂CO₃ (5.3 g, 38 mmol) in DMF (15 mL) was added allyl bromide (2.8 mL, 33 mmol). The mixture was stirred overnight at 50 °C. Then, H₂O (40 mL) was added and the reaction mixture was extracted with EtOAc (4 × 50 mL). The combined organic phases were washed with brine (2 × 30 mL), dried over MgSO₄, concentrated in vacuo and purified by flash chromatography (heptane).
N′-Allyl-N,N′-(diethyl)phenylhydrazine (6a): yield 84% from 5a; yellow oil. ¹H NMR: δ = 7.19 (dd, 2 H, J ₁ = 8.8 Hz, J ₂ = 7.2 Hz), 6.99 (d, 2 H, J = 8.8 Hz), 6.65 (t, 1 H, J = 7.2 Hz), 5.80-5.90 (ddt, 1 H, J ₁ = 17.2 Hz, J ₂ = 10.3 Hz, J ₃ = 6.3 Hz), 5.15 (dd, 1 H, J ₁ = 17.2 Hz, J ₂ = 1.8 Hz), 5.02 (dd, 1 H, J ₁ = 10.3 Hz, J ₂ = 1.3 Hz), 3.32 (d, 2 H, J = 6.3 Hz), 3.30 (q, 2 H, J = 7.1 Hz), 2.73 (q, 2 H, J = 7.1 Hz), 1.22 (t, 3 H, J = 7.1 Hz), 1.01 (t, 3 H, J = 7.1 Hz). ¹³C NMR: δ = 149.1, 134.7, 127.7, 115.7, 115.2, 110.9, 56.5, 45.9, 35.1, 13.2, 11.7. HRMS: m/z calcd for C₁₃H₂₀N₂: 204.1626; found: 204.1631.
N ′-Ethyl- N -phenylacetohydrazide (7). To a solution of acetaldehyde N-acetylphenylhydrazone (4a, 3.0 g, 17 mmol) and BH₃·NMe₃ (1.6 g, 26 mmol) in toluene (40 mL), was slowly added a solution of HCl in Et₂O (approximately 4.5 M, 3 mL) and the reaction was stirred overnight at 50 °C. To the reaction was added Na₂CO₃ (aq sat., 50 mL) and phases were separated. The aqueous phase was extracted with EtOAc (3 × 30 mL). The combined organic phased were washed with brine, dried over MgSO₄, and concentrated in vacuo. Purification by flash chromatography (heptane-Et₂O, 3:1) yielded 2.67 g (91%) of 7 as a colourless solid, mp 65-68 °C. The ¹H NMR spectrum shows double signals due to the existence of two conformers. ¹H NMR: δ = 7.30-7.40 (m, 5 H), 5.81 (br s, 1 H) [4.18 (br s, 1 H)], 2.86 (br q, 2 H, J = 7.1 Hz) [2.74 (br s, 2 H)], 1.96 (s, 3 H) [2.37 (br s, 3 H)], 1.06 (t, 3 H, J = 7.1 Hz). ¹³C NMR: δ = 168.4, 141.6, 129.3, 127.8, 127.3, 44.3, 21.8, 12.8. Anal. Calcd for C₁₀H₁₄N₂O: C, 67.39; H, 7.92; N, 15.72. Found: C, 67.60; H, 7.92; N, 15.70. N ′-Allyl- N ′-ethyl- N -phenylacetohydrazide (8). To a mixture of N′-ethyl-N-phenylacetohydrazide (7, 2.10 g, 11.8 mmol) and Cs₂CO₃ (16 g, 50 mmol) in DMF (20 mL) was added allyl bromide (4.1 mL, 47 mmol) at r.t., the reaction was then stirred overnight at 50 °C. Then, H₂O (30 mL) was added and the mixture was extracted with EtOAc (4 × 50 mL). The combined organic phases were dried over MgSO₄, concentrated in vacuo and purified by flash chromatography (heptane-Et₂O, 4:1) to yield 2.15 g (84%) of 8 as a colorless oil. ¹H NMR: δ = 7.10-7.40 (m, 5 H), 5.93 (m, 1 H), 5.21 (br d, 2 H, J = 14.1 Hz), 3.38 (dd, 1 H, J ₁ = 14.1 Hz, J ₂ = 5.9 Hz), 3.20 (dd, 1 H, J ₁ = 14.1 Hz, J ₂ = 6.2 Hz), 2.72 (m, 1 H), 2.57 (m, 1 H), 2.36 (s, 3 H) [1.84 (s, 3 H)], 1.21 (br t, 3 H, J = 7.0 Hz). ¹³C NMR: δ = 176.0, 135.8, 135.7, 131.2, 130.3, 129.6, 119.8, 60.25, 55.3, 49.0, 23.1, 13.9. HRMS: m/z calcd for C₁₃H₁₈N₂O: 218.1419; found: 218.1417.
General Procedure for the Conversion of Allyl Arylhydrazines 6 into Indoles 9. To a solution of N′-allyl-N,N′-dialkylarylhydrazine (6a-d, 1.0 mmol) and bis(tricyclohexylphosphine) benzylidine ruthenium(IV) dichloride (42 mg, 49 µmol) in toluene (4 mL) was added LiBHEt₃ 1 M in THF (100 µL, 100 µmol). The reaction was stirred for 16 h at 100 °C. Then, H₂O (20 mL) and EtOAc (20 mL) were added to the reaction, phases were separated and the aqueous phase was extracted with EtOAc (3 × 30 mL). The combined organic phases were washed with brine (30 mL), dried over MgSO₄, concentrated in vacuo and the purified by flash chromatography (heptane-toluene, 4:1).
N-Ethyl-3-methylindole (9a):³⁰ yield 56% from 6a; colorless oil. ¹H NMR: δ = 7.10-7.60 (m, 4 H), 6.86 (s, 1 H), 4.08 (q, 2 H, J = 7.3 Hz), 2.32 (s, 3 H), 1.40 (t, 3 H, J = 7.3 Hz). ¹³C NMR: δ = 136.4, 129.2, 125.1, 121.7, 119.4, 118.8, 110.6, 109.4, 41.0, 15.9, 10.0.

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