Download PDF
Synlett 2007(3): 0443-0446  
DOI: 10.1055/s-2006-967949
LETTER
© Georg Thieme Verlag Stuttgart · New York

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

Simon D. Nielsena, Thomas Ruhlandb, Lars K. Rasmussen*a,b
a Faculty of Pharmaceutical Sciences, University of Copenhagen, 2 Universitetsparken, 2100 Copenhagen, Denmark
b Department of Medicinal Chemistry, H. Lundbeck A/S, 9 Ottiliavej, 2500 Valby, Denmark
Fax: +45(36)438237; e-Mail: lars@kemiker.dk;
Further Information

Publication History

Received 14 July 2006
Publication Date:
07 February 2007 (online)

    Permissions and Reprints All articles of this category

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.

Key words

indoles - reduction - regioselectivity - hydrazines - transition metals

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 hydrazone28,29 (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.