PAPER
Regioselective Methylenation and in situ Methanolation of Ketones
237
13C NMR (50 MHz, CDCl3): d = 22.7 (CH2), 23.5 (CH2), 31.5
(CH2), 36.2 (CH2), 106.9 (=CH2), 118.7 (CH-Ar), 123.5 (CH-Ar),
123.6 (CH-Ar), 125.1 (CH-Ar), 130.3, 140.3, 141.4, 141.7, 142.7.
MS (EI, 70 eV): m/z (%) = 182 (100) [M+], 167 (49), 153 (24), 141
(25), 128 (27), 115 (13).
tion and subsequent in situ hydroboration of easily
enolisable ketones. The in situ hydroboration is particular-
ly advantageous when the methylene compound first
formed is susceptible to double-bond isomerisation.
HRMS (EI): m/z calcd for C14H14: 182.1095; found: 182.1093.
1H (200 MHz) and 13C (50 MHz) NMR spectra were recorded of
samples in CDCl3 on a Bruker DPX 200 spectrometer. Chemical
shifts are reported relative to residual CHCl3 (d = 7.24) and CDCl3
(d = 77). The mass spectra were recorded at 70-eV ionising potential
on a VG Prospect Sector mass spectrometer from Fissions Instru-
ments. IR spectra were measured on a Nicolet Magma 550 spec-
trometer using attenuated total reflection (ATR). THF was dried by
distillation from sodium–benzophenone under N2. CH2Cl2 was
dried by distillation from CaH2. Anhyd ZnCl2 was heated to 200 °C
under 0.01 mm Hg for 20 h shortly before use. Reactions requiring
dry and/or oxygen-free conditions were run under a slight positive
pressure of argon gas.
Compounds 15, 16, 17, and 18 by Methylenation–Hydrobora-
tion–Oxidation of Ketones; General Procedure
A 0.5 M soln of 9-BBN in THF (13.2 mL, 6.6 mmol) was added to
the reaction mixture from the ketone methylenation reaction, then
stirring continued for 5 min, and the turbid mixture was filtered
through Celite. The filtrate was washed with an aq sat. brine–sat.
NaHCO3 mixture (1:1, 20 mL), and then with sat. brine until addi-
tion of H2O2 to some of the brine showed no formation of I2. NaOH
(2.4 g, 60 mmol) in H2O (10 mL) and 30% H2O2 (6.8 g, 60 mmol)
were subsequently added and the mixture was stirred vigorously at
50 °C for 2 h. Sat. aq brine (20 mL) was added and the phases were
separated. The organic soln was washed with sat. aq NH4Cl (20 mL)
and sat. aq NaCl (20 mL), and then dried (MgSO4) and evaporated.
The residual product consisted mainly of the desired alcohol and
cis-1,5-cyclooctadiol.
Compounds 4, 9, 11, and 13 by Methylenation of Ketones; Gen-
eral Procedure
Li wire (0.292 g, 42 mmol) was cut in a glovebox under an argon
atmosphere and placed together with naphthalene (0.538 g, 4.2
mmol) in a 100-mL round-bottomed flask. The flask was sealed
with a rubber septum, THF (50 mL) was added, and the mixture was
stirred at r.t. under argon for 15 min. Dry ZnCl2 (3.00 g, 22 mmol)
in THF (50 mL) was introduced by syringe over 3 h under vigorous
stirring. The mixture was stirred for 30 min. The precipitated Rieke
Zn was washed with THF and suspended in THF (50 mL), the
stirred suspension was cooled to –20 °C, and CH2I2 (2.68 g, 10
mmol) was added over 20 min. The mixture was stirred for 30 min
before neat PbCl2 (97 mg, 0.20 mmol) was introduced. The cooling
bath was removed after the mixture had stirred for 1 h, and then the
mixture was left to stir at r.t. for 30 min. The mixture was cooled to
–20 °C and TiCl4 (1.27 g, 6.67 mmol) in CH2Cl2 (3 mL) was added
dropwise before the cooling bath was removed and the mixture was
left at r.t. for 45 min. The ketone (6.0 mmol) in THF (5 mL) was in-
troduced over 5 min, and the mixture was stirred at r.t. for 1 h before
hexane (50 mL) was added. The soln was washed with a sat. brine–
sat. NaHCO3 mixture (1:1, 30 mL), and subsequently with sat. brine
(30 mL). The brine was extracted with hexane (2 × 20 mL), the
combined extracts were dried (MgSO4), the solvents were evaporat-
ed, and the residue was washed out with hexane; this furnished the
crude alkene on evaporation of the solvents.
(2,3-Dihydro-1H-inden-1-yl)methanol (15)
Purification: flash chromatography (silica gel, hexane–EtOAc, 1:4);
yield: 0.734 g (83%).
(2,3-Dihydro-1H-inden-2-yl)methanol (16)
Purification: flash chromatography (silica gel, hexane); yield: 0.676
g (76%)
(2,3,4,9-Tetrahydro-1H-fluoren-1-yl)methanol (17)
The starting material 2,3,4,9-tetrahydro-1H-fluoren-1-one (10) was
prepared according to a literature procedure.9 Purification of 17 was
by flash chromatography (silica gel, hexane–EtOAc, 1:5).
White oil; yield: 0.974 g (81%).
IR (film): 3355 (s), 3065 (m), 3042 (m), 3018 (m), 2927 (s), 2859
(s), 1628 (w), 1606 (w) cm–1.
1H NMR (200 MHz, CDCl3): d = 1.8–2.3 (m, 7 H, H-1–H-4), 2.76
(s, 1 H, OH), 3.28 (dt, J = 22.3, 2.7 Hz, 1 H, H-9a), 3.50 (dt,
J = 22.3, 2.7 Hz, 1 H, H-9b), 3.74 (dd, J = 10.5, 6.8 Hz, 1 H,
CHHOH), 3.82 (dd, J = 10.5, 5.1 Hz, 1 H, CHHOH), 7.2–7.5 (m, 4
H, H5–H8).
1-Methylene-2,3-dihydro-1H-indene (4)7
Flash chromatography (silica gel, hexane) gave compound 4; yield:
86%.
13C NMR (50 MHz, CDCl3): d = 20.7 (CH2), 22.3 (CH2), 26.1
(CH2), 38.8 (C-1), 39.0 (C-9), 65.9 (COH), 117.8 (CH-Ar), 123.3
(CH-Ar), 124.0 (CH-Ar), 126.0 (CH-Ar), 138.1, 140.82, 142.8,
145.5.
MS (EI, 70 eV): m/z (%) = 200 (23) [M+], 169 (100), 141 (23), 128
(15), 115 (11).
2-Methylene-2,3-dihydro-1H-indene (9)8
Flash chromatography (silica gel, hexane) gave compound 9; yield:
90%.
HRMS (EI): m/z calcd for C14H16O: 200.1201; found: 200.1197
1-Methylene-2,3,4,9-tetrahydro-1H-fluorene (11)
Anal. Calcd for C14H16O: C, 83.96; H, 8.05. Found: C, 84.09; H,
8.15.
The starting material 2,3,4,9-tetrahydro-1H-fluoren-1-one (10) was
prepared according to a literature procedure.9 The hexane soln of
crude product 11 was subjected to rapid suction through a plug of
silica gel; removal of the volatiles gave a yellow oil; yield: 0.862 g
(79%). Compound 11 has limited stability because it readily under-
goes double-bond migration.
(2,3,4,9-Tetrahydro-1H-fluoren-4-yl)methanol (18)
The starting material 2,3-dihydro-1H-fluoren-4(9H)-one (12) was
prepared according to a literature procedure.10 Purification of 18
was by flash chromatography (silica gel, hexane–EtOAc, 1:4).
IR (film): 3068 (m), 3046 (m), 3022 (m), 2921 (s), 2831 (m), 1654
(w), 1619 (m) cm–1.
1H NMR (200 MHz, CDCl3): d = 2.1–2.3 (m, 2 H, H-2), 2.6–2.8 (m,
4 H, H-3, H-4), 3.63 (t, J = 2.5 Hz, 2 H, H-9), 5.00 (s, 1 H, =CHH),
5.21 (s, 1 H, =CHH), 7.3–7.7 (m, 4 H, H-5–H-8).
Pale yellow oil; yield: 0.884 g (74%).
IR (film): 3362 (s), 3066 (m), 3042 (m), 3018 (m), 2920 (s), 2864
(s) 1703 (w), 1626 (w), 1595 (w) cm–1.
1H NMR (200 MHz, CDCl3): d = 1.5–2.0 (m, 7 H, H-1–H-4), 2.99
(s, 1 H, OH), 3.30 (t, J = 2.5 Hz, 2 H, H-9), 3.76 (dd, J = 10.8, 8.4
Synthesis 2007, No. 2, 235–238 © Thieme Stuttgart · New York