PAPER
Stereoselective Syntheses of Spirane Bridged Semi-titanocenes
967
1H NMR (300 MHz, CDCl3): d = 1.5–1.9 (m, 4 H, H3, H4), 2.1–2.8
(m, 6 H, H2, CH2CH=CH2), 3.4–3.5 (m, 1 H, H9) 4.8–5.1 (m, 4 H,
CH=CH2), 5.2–5.4 (m, 1 H, 9-allyl-CH=CH2), 5.5–5.7 (m, 1 H, 1-
allyl-CH=CH2), 7.1–7.4 (m, 4 H, H5–H8), 9.64 (s, 1 H, CHO).
13C NMR (75 MHz, CDCl3): d = 18.7 (C3), 22.2 (C2), 30.1 (C4),
34.0 (9-allyl-CH2), 38.9 (1-allyl-CH2), 48.2 (C9), 51.4 (C1), 117.3
(CH=CH2), 118.4 (CH=CH2), 118.4 (CH-Ar), 123.1 (CH-Ar),
125.0 (CH-Ar), 126.5 (CH-Ar), 133.7 (9-allyl-CH=CH2), 139.4,
142.3, 143.5, 146.6, 202.7 (CHO).
mixture of the alcohol epimers 2,3,4,4a,9,9a-hexahydro-1H-fluo-
ren-1-ol (10) (51 mg).
IR (film): 3333 (s), 3040 (w), 2995 (w), 2904 (s), 2830 (s), 1420 (m)
cm–1.
1H NMR (200 MHz, CDCl3): d = 1.2–1.5 (m, 4 H), 1.6–1.9 (m, 7
H), 2.0–2.2 (m, 2 H), 2.33 (s, 2 H, OH), 2.7–3.1 (m, 6 H), 3.2–3.3
(m, 1 H, H9), 3.3–3.4 (m, 0.5 H, CHOH), 4.0–4.1 (m, 0.5 H,
CHOH), 7.1–7.4 (m, 8 H, H-Ar).
13C NMR (50 MHz, CDCl3): d = 20.1, 23.2, 25.4, 29.6, 29.9, 29.9,
33.8, 35.2, 44.0, 44.9, 46.1, 48.8, 70.4 (C-OH), 70.8 (C-OH), 122.1
(CH-Ar), 122.9 (CH-Ar), 125.1 (CH-Ar), 125.9 (CH-Ar), 126.2
(CH-Ar), 141.7 (C-Ar), 143.2 (C-Ar), 145.5 (C-Ar), 148.6 (C-Ar);
MS (EI, 70 eV): m/z (%) = 278 (38) [M]+, 249 (50), 237 (91), 208
(52), 179 (48), 165 (100).
HRMS (EI, 70 eV): m/z [M]+ calcd for C20H22O: 278.1671; found:
278.1666.
MS (EI, 70 eV): m/z (%) = 188 (76) [M]+, 170 (100), 155 (9), 145
(18), 142 (65), 129 (49), 116 (70).
HRMS (EI, 70 eV): m/z [M]+ calcd for C13H16O: 188.1201; found:
188.1210.
(4aR*,9aR*)-2,3,4,4a,9,9a-Hexahydro-1H-fluoren-1-one (9)
Et3N (21.0 g, 0.21 mol), HCO2H (8.28 g, 0.18 mol), and 10% Pd/C
(2.65 g, 2.5 mmol Pd) were added to a soln of 3 (18.4 g, 0.1 mol) in
DMF (60 mL). The mixture was stirred at 60 °C for 1 h, filtered
through a bed of Celite, and the filtrate poured into H2O (500 mL).
The cold mixture was extracted with Et2O (4 × 150 mL) and the
combined extracts were washed with H2O (2 × 150 ml), dried
(MgSO4), and evaporated to dryness. The residual material was fur-
ther dried under vacuum overnight to give 17.5 g of a 1:1 mixture
9/10. The mixture was subjected to Swern oxidation using oxalyl
chloride (6.35 g, 50 mmol) in anhyd CH2Cl2 (120 mL) at –60 °C un-
der N2 with addition of DMSO (7.81 g, 0.1 mol) in CH2Cl2 (30 mL)
over 5 min. Stirring was continued for 10 min, the crude intermedi-
ate (~45 mmol alcohol) was transferred by a syringe into CH2Cl2
(40 mL). The cooling bath was removed after 15 min, the mixture
left to stand for 5 min, cooled to –60 °C and Et3N (25 g, 0.25 mol)
added over 5 min, the cooling bath removed, and H2O (150 mL)
added. The mixture was stirred for 10 min and the two layers sepa-
rated and the aqueous layer extracted with Et2O (3 × 50 mL). The
combined ether extracts were dried (MgSO4), evaporated to dry-
ness, and the residual material crystallized (MeOH, 2.5 mL/g) to
give a solid product; yield: 12.8 g (69%). The mother liquor from
the crystallization was evaporated to dryness and the residual mate-
rial subjected to flash chromatography (silica gel 60, EtOAc–hex-
ane, 1:10); yellow solid; combined yield: 16.0 g (86%); mp 82–83
°C.
(1R*,4aR*,9aR*)-1-Allyl-2,3,4,4a,9,9a-hexahydro-1H-fluorene-
1-carbaldehyde (14)
Diethyl (benzylideneamino)methylphosphonate (9.79 g, 38.4
mmol) was added over 10 min to a soln of 1.6 M BuLi in hexane (24
mL, 38.4 mmol) in anhyd THF (160 mL) under argon at –78 °C. The
mixture was stirred at this temperature for 1 h before 9 (6.49 g, 34.9
mmol) was added in one portion. The mixture was heated under re-
flux for 2 h, cooled to –78 °C and 1.6 M BuLi in hexane (43.7 mL,
70 mmol) was added over 10 min. The mixture was stirred at –78
°C for 1 h before allyl bromide (16.9 g, 140 mmol) was added over
15 min and the mixture stirred at r.t. for 30 h. 3 M HCl was added
and the mixture stirred vigorously under argon at 60 °C for 3 h. The
two phases of the cold mixture were separated and the aqueous
phase was extracted with Et2O (3 × 75 mL). The combined organic
phases washed with aq sat. NaHCO3, dried (MgSO4), and concen-
trated under vacuum. The residual brown oil was subjected to flash
chromatography (silica gel 60, EtOAc–hexane, 1:5) to give a yellow
oil; yield: 7.30 g (87%).
1H NMR (300 MHz, CDCl3): d = 1.0–1.2 (m, 1 H, H4a), 1.5–2.0 (m,
5 H, H2, H3, H4b), 2.3–2.9 (m, 5 H, H9, H9a, CH2CH=CH2), 3.16
(dt, J = 6.0, 12.1 Hz, 1 H, H4a), 5.1–5.2 (m, 2 H, CH=CH2), 5.6–5.8
(m, 1 H, CH=CH2), 7.2–7.3 (m, 4 H, H5–H8), 9.63 (s, 1 H, CHO).
13C NMR (75 MHz, CDCl3): d = 18.8 (CH2), 23.1 (CH2), 29.5 (C4),
31.5 (C9), 37.8 (CH2CH=CH2), 41.8 (C4a), 44.7 (C9a), 50.5 (C1),
118.2 (CH=CH2), 122.9 (CH-Ar), 124.9 (CH-Ar), 126.3 (CH-Ar),
126.35 (CH-Ar), 132.9 (CH=CH2), 141.2 (C-Ar), 147.9 (C-Ar),
205.7 (CHO).
IR (film): 3041 (m), 3032 (m), 2989 (w), 2905 (s), 2832 (m), 1733
(s) cm–1.
1H NMR (300 MHz, CDCl3): d = 1.6–1.9 (m, 4 H, H3, H4a, H4a),
2.0–2.1 (m, 1 H, H4b), 2.29 (t, J = 7.6 Hz, 2 H, H2), 2.85 (dd,
J = 15.5, 8.1 Hz, 1 H, H9a), 3.0–3.1 (m, 1 H, H9a), 3.35 (dd,
J = 15.5, 10.7 Hz, 1 H, H9b), 7.1–7.3 (m, 4 H, H5–H8).
MS (EI, 70 eV): m/z (%) = 240 (40) [M]+, 222 (42), 211 (17), 199
13C NMR (75 MHz, CDCl3): d = 22.9 (C3), 27.7 (C4), 33.6 (C9),
40.7 (C2), 47.2 (C4a), 52.89 (C9a), 123.2 (CH-Ar), 125.2 (CH-Ar),
127.0 (CH-Ar), 127.2 (CH-Ar), 142.9 (C-Ar), 145.1 (C-Ar), 213.1
(C1).
(22), 169 (56), 143 (95), 130 (100).
HRMS (EI, 70 eV): m/z [M]+ calcd for C17H20O: 240.1514; found:
240.1525.
MS (EI, 70 eV): m/z (%) = 186 (100) [M]+, 158 (49), 142 (23), 130
2,3,4,9-Tetrahydro-1H-fluorene-1-carbaldehyde (15)
Diethyl (benzylideneamino)methylphosphonate (30.6 g, 120 mmol)
was added over 10 min to a soln of 1.6 M BuLi in hexane (75 mL,
120 mmol) in anhyd THF (400 mL) under argon at –78 °C. The mix-
ture was stirred at this temperature for 1 h before 3 (18.4 g, 100
mmol) was added in one portion and the mixture was kept at 50 °C
overnight. 5 M HCl (400 mL) was added and the mixture stirred
vigorously under reflux for 3 h. The two phases of the ice-cold mix-
ture were separated and the aqueous phase extracted with Et2O (3 ×
200 mL). To reduce oxidative reactions, the empty space over the
soln in the separatory funnel was flushed and kept under argon gas.
The combined organic phases were washed with aq sat. NaHCO3
(200 mL), dried (MgSO4), and the filtrate evaporated. The residual
material was dried at 50 °C under vacuum overnight for removal of
benzaldehyde and 1-chlorobutan-4-ol (generated from THF). Flash
(78), 115 (51).
HRMS (EI, 70 eV): m/z [M]+ calcd for C13H14O: 182.1045; found:
186.1036.
Anal. Calcd for C13H14O: C, 83.83; H, 7.58. Found: C, 83.52; H,
7.44.
(1S/R,4aR*,9aR*)-2,3,4,4a,9,9a-Hexahydro-1H-fluoren-1-ol
(10)
The mixture of the ketone 9 from above and its alcohol epimers 10
(129 mg) was subjected to flash chromatography (silica gel 60,
EtOAc–hexane, 1:10) for analytical purposes. Separation yielded
2,3,4,9-tetrahydro-1H-fluoren-1-one (61 mg) and an inseparable
Synthesis 2008, No. 6, 962–970 © Thieme Stuttgart · New York