The Journal of Organic Chemistry
Article
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dihydro-1,3-dioxepine 5e (80 mg, 0.36 mmol), dichloromethane (1.8
mL), BF3·OEt2 (9 μL, 10 mg, 0.07 mmol), and methanol (1.8 mL)
and NaBH4 (>3 equiv) followed by workup and column
chromatography (30−80% EtOAc/hexanes) afforded 13e as a
brownish oil (41 mg, 0.18 mmol, 50% over 2 steps). 1H NMR
(400 MHz, CDCl3, δ) (diastereomeric ratio = 3:1): 8.22 (dd, J = 8.9,
2.3 Hz, 2H), 7.61−7.50 (m, 2H), 5.14 (d, J = 6.9 Hz, 1H), 4.28 (td, J
= 8.3, 4.8 Hz, 1H), 4.00 (dt, J = 8.5, 7.7 Hz, 1H), 3.33−3.17 (m, 2H),
2.77 (h, J = 6.9 Hz, 1H), 2.24 (dtd, J = 12.5, 7.7, 4.8 Hz, 1H), 2.06−
1.95 (m, 1H), 1.34 (s, 1H); 13C{1H} NMR (100 MHz, CDCl3, δ):
147.7, 147.4, 127.3 (2C), 123.7 (2C), 81.6, 68.1, 62.6, 46.0, 29.1;
LRMS-ESI (m/z): 242.1 [M + H]+, 246.1 [M + Na]+. HRMS (APCI-
Orbitrap) (m/z): calcd for C11H14NO4 [M + H]+, 224.0917; found,
224.0920.
grainy oil (54 mg, 0.34 mmol, 55% over 2 steps). H NMR (400
MHz, CDCl3, δ) (diastereomeric ratio = 2:1): 3.98−3.78 (m), 3.77−
3.52 (m), 2.34−2.14 (m), 2.10−1.92 (m), 1.91−1.61 (m), 1.46 (m),
1.27 (m), 0.99−0.82 (m); 13C{1H} NMR (100 MHz, CDCl3, δ):
79.0, 66.3, 62.5, 43.4, 38.9, 29.0, 25.6, 23.7, 22.1; LRMS-ESI (m/z):
159.1 [M + H]+. HRMS (APCI-Orbitrap) (m/z): calcd for C9H19O2
[M + H]+, 159.1380; found, 159.1379.
(2-((Benzyloxy)methyl)tetrahydrofuran-3-yl)methanol (13j). The
reaction of 2-((benzyloxy)methyl)-4,7-dihydro-1,3-dioxepine 5j (60
mg, 0.27 mmol), dichloromethane (1.4 mL), BF3·OEt2 (7 μL, 11 mg,
0.05 mmol), and methanol (1.4 mL) and NaBH4 (>3 equiv) followed
by workup and column chromatography (20% EtOAc/hexanes−80%
EtOAc/hexanes) afforded 13j as a light-brown oil (26 mg, 0.12 mmol,
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42% over 2 steps). H NMR (400 MHz, CDCl3, δ) (diastereomeric
(2-(Furan-2-yl)tetrahydrofuran-3-yl)methanol (13f). Following
the general procedure, the reaction of 2-(furan-2-yl)-4,5-dihydro-
1,3-dioxepine 5f (111 mg, 0.67 mmol), dichloromethane (3.3 mL),
BF3·OEt2 (16 μL, 19 mg, 0.13 mmol), and methanol (3.3 mL) and
NaBH4 (>3 equiv) followed by workup and column chromatography
(20−80% EtOAc/hexanes) afforded 13f as a light-yellow grainy oil
(61 mg, 0.36 mmol, 54% over 2 steps). 1H NMR (400 MHz, CDCl3,
δ) (diastereomeric ratio = 3:1): 7.39 (dd, J = 1.9, 0.9 Hz, 1H), 6.40−
6.21 (m, 2H), 5.05 (d, J = 7.3 Hz, 1H), 4.18 (td, J = 8.3, 3.7 Hz, 1H),
3.87 (td, J = 8.4, 7.2 Hz, 1H), 3.55−3.31 (m, 2H), 2.77−2.58 (m,
1H), 2.12 (dtd, J = 12.2, 7.4, 3.7 Hz, 1H), 2.00−1.89 (m, 1H), 1.67
(s, 1H, superimposed by peak corresponding to the minor isomer);
13C{1H} NMR(100 MHz, CDCl3, δ): 153.7, 142.4, 110.4, 107.9, 76.1,
68.1, 63.1, 46.1, 28.8; LRMS-ESI (m/z): 169.1 [M + H]+. HRMS
(APCI-Orbitrap) (m/z): calcd for C9H13O3 [M + H]+, 169.0859;
found, 169.0858.
(2-(Naphthalen-1-yl)tetrahydrofuran-3-yl)methanol (13g). Fol-
lowing the general procedure, the reaction of 2-(naphthalen-1-yl)-4,5-
dihydro-1,3-dioxepine 5g (114 mg, 0.50 mmol) in dichloromethane
(2.5 mL), BF3·OEt2 (12 μL, 14 mg, 0.10 mmol), and methanol (2.5
mL) and NaBH4 (>3 equiv) followed by workup and column
chromatography (20% EtOAc/hexanes−50% EtOAc/hexanes) af-
forded 13g as a colorless syrup (64 mg, 0.28 mmol, 55% over 2 steps),
1H NMR (400 MHz, CDCl3, δ) (diastereomeric ratio= 14:1): 7.97−
7.84 (m, 2H), 7.76 (ddt, J = 19.2, 7.2, 1.0 Hz, 2H), 7.57−7.40 (m,
3H), 5.61 (d, J = 6.3 Hz, 1H), 4.27 (td, J = 8.3, 5.6 Hz, 1H), 3.98 (td,
J = 8.5, 6.8 Hz, 1H), 3.15−3.00 (m, 2H), 2.93 (dddd, J = 12.7, 7.9,
6.4, 3.9 Hz, 1H), 2.34 (dtd, J = 12.6, 8.2, 5.6 Hz, 1H), 2.09 (dddd, J =
12.6, 8.0, 6.8, 3.9 Hz, 1H), 1.01 (br s, 1H); 13C{1H} NMR (100
MHz, CDCl3, δ): 134.9, 133.5, 130.3, 129.1, 127.9, 126.3, 125.8,
125.6, 122.9, 122.8, 79.4, 67.0, 63.0, 44.4, 29.7; LRMS-ESI (m/z):
229.1 [M + H]+. HRMS (APCI-Orbitrap) (m/z): calcd for C15H17O2
[M + H]+, 229.1223; found, 223.1225.
(2-([1,1′-Biphenyl]-4-yl)tetrahydrofuran-3-yl)methanol (13h).
Following the general procedure, the reaction of 2-([1,1′-biphenyl]-
4-yl)-4,5-dihydro-1,3-dioxepine 5h (46 mg, 0.18 mmol) in toluene
(0.90 mL), BF3·OEt2 (5 μL, 6 mg, 0.04 mmol), and methanol (0.90
mL) and NaBH4 (>3 equiv) followed by workup and column
chromatography (20% EtOAc/hexanes−50% EtOAc/hexanes) af-
forded 13h as a colorless syrup (29 mg, 0.11 mmol, 63% over 2 steps).
1H NMR (400 MHz, CDCl3, δ) (diastereomeric ratio = 11:1): 7.59
(dd, J = 7.9, 3.0 Hz, 4H), 7.47−7.38 (m, 4H), 7.37−7.31 (m, 1H),
5.07 (d, J = 6.8 Hz, 1H), 4.25 (td, J = 8.3, 4.6 Hz, 1H), 3.94 (q, J =
8.0 Hz, 1H), 3.34 (ddd, J = 35.3, 11.1, 6.5 Hz, 2H), 2.69 (h, J = 6.6
Hz, 1H), 2.21 (dtd, J = 12.5, 7.8, 4.6 Hz, 1H), 2.04−1.88 (m, 1H),
1.04 (s, 1H); 13C{1H} NMR (100 MHz, CDCl3, δ): 140.7, 140.3,
138.6, 128.8 (2C), 127.3, 127.1 (2C), 127.0 (2C), 126.4 (2C), 81.9,
67.6, 62.9, 45.6, 29.1; LRMS-ESI (m/z): 255.1 [M + H]+, 277.1 [M +
Na]+. HRMS (APCI-Orbitrap) (m/z): calcd for C17H17O2 [M − H]−,
253.1223; found, 253.1228.
ratio = 5:1): 7.33 (qd, J = 7.1, 3.4 Hz, 5H, superimposed by peak
corresponding to the minor isomer), 4.58 (s, 2H), 4.15 (td, J = 7.2,
4.2 Hz, 1H), 3.95 (td, J = 8.3, 3.7 Hz, 1H), 3.76−3.53 (m, 3H,
superimposed by peak corresponding to the minor isomer), 2.98 (t, J
= 6.4 Hz, 1H), 2.56 (pd, J = 7.8, 5.6 Hz, 1H), 1.98 (dtd, J = 12.3, 7.6,
3.7 Hz, 1H), 1.67 (dq, J = 12.4, 8.4 Hz, 2H); 13C{1H} NMR (100
MHz, CDCl3, δ): 137.3, 128.7 (2C), 128.1 (2C), 128.0, 78.5, 74.1,
69.5, 67.4, 62.3, 44.0, 28.5; LRMS-ESI (m/z): 223.1 [M + H]+, 245.1
[M + Na]+. HRMS (APCI-Orbitrap) (m/z): calcd for C13H19O2 [M
+ H]+, 223.1329; found, 223.1328.
(2-(Benzo[d][1,3]dioxol-5-yl)tetrahydrofuran-3-yl)methanol
(13k). Following the general procedure, the reaction of 5-(4,5-
dihydro-1,3-dioxepin-2-yl)benzo[d][1,3]dioxole 5k (71 mg, 0.32
mmol), dichloromethane (1.6 mL), BF3·OEt2 (8 μL, 13 mg, 0.06
mmol), and methanol (1.6 mL) and NaBH4 (>3 equiv) followed by
workup and column chromatography (20% EtOAc/hexanes−50%
EtOAc/hexanes) afforded 13k as a yellowish oil (49 mg, 0.22 mmol,
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68% over 2 steps). H NMR (400 MHz, CDCl3, δ) (diastereomeric
ratio = 4:1): 6.84−6.70 (m, 3H), 5.94 (s, 2H), 4.92 (d, J = 6.9 Hz,
1H), 4.17 (td, J = 8.3, 4.5 Hz, 1H), 3.86 (q, J = 7.9 Hz, 1H), 3.28
(ddd, J = 35.4, 11.0, 6.6 Hz, 2H), 2.68−2.53 (m, 1H), 2.14 (dtd, J =
12.3, 7.7, 4.6 Hz, 1H), 1.88 (dtd, J = 12.5, 8.0, 6.2 Hz, 1H), 1.25 (s,
1H); 13C{1H} NMR (100 MHz, CDCl3, δ): 147.9, 146.9, 133.6,
119.2, 108.3, 106.8, 101.1, 81.9, 67.6, 62.9, 45.8, 29.1; LRMS-ESI (m/
z): 223.0 [M + H]+,245.0 [M + Na]+. HRMS (APCI-Orbitrap) (m/
z): calcd for C12H18O4 [M + H]+, 223.0965; found, 223.0967.
Synthesis of Select 2,3-Disubstituted Tetrahydrofurans
under Thermal Conditions: General Procedure. To a solution
of 4,5-dihydro-1,3-dioxepine 5 (1 equiv) in xylenes (0.2 M solution)
was added Zn(OTf)2 (0.2 equiv). The flask was then immediately
immersed into an oil bath and heated at reflux for the time specified in
Table 6. After this time, the reaction was allowed to cool to 23 °C and
then to 0 °C. Then, methanol (0.2 M solution) and NaBH4 (>3
equiv) were added. After reduction of the aldehyde was observed on
TLC (about 1 h), the reaction was quenched with deionized water,
and the aqueous layer was extracted twice with ethyl acetate. The
combined organic layer was dried over sodium sulfate. Column
chromatography using the specified solvent systems provided the 2,3-
trans-disubstituted tetrahydrofuran products 14a−k as major isomers.
The diastereomeric ratios (cis:trans) were determined via integration
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of the H NMR spectra.
(2-Phenyltetrahydrofuran-3-yl)methanol (14a).18 Following the
general procedure, the reaction of 2-phenyl-4,5-dihydro-1,3-dioxepine
5a (56 mg, 0.32 mmol), xylenes (1.6 mL), Zn(OTf)2 (23 mg, 0.07
mmol), and methanol (1.6 mL) and NaBH4 (>3 equiv) followed by
workup and column chromatography (30−50% EtOAc/hexanes)
afforded 14a as a colorless oil (27 mg, 0.15 mmol, 48% over 2 steps).
1H NMR (400 MHz, CDCl3, δ) (diastereomeric ratio = 1:20): 7.43−
7.28 (m, 5H), 4.64 (d, J = 6.7 Hz, 1H), 4.18−4.07 (m, 1H), 3.98 (td,
J = 8.2, 6.0 Hz, 1H), 3.82−3.61 (m, 2H), 2.34 (dt, J = 8.0, 6.4 Hz,
1H), 2.24−2.11 (m, 2H), 1.86 (dq, J = 12.6, 7.1 Hz, 1H); 13C{1H}
NMR (100 MHz, CDCl3, δ):142.7, 128.5 (2C), 127.6, 126.1 (2C),
83.2, 68.2, 64.0, 50.3, 29.7.
(2-Isobutyltetrahydrofuran-3-yl)methanol (13i). Following the
general procedure, the reaction of 2-isobutyl-4,5-dihydro-1,3-
dioxepine 5i (98 mg, 0.63 mmol), dichloromethane (3.1 mL), BF3·
OEt2 (15 μL, 24 mg, 0.13 mmol), and methanol (3.1 mL) and NaBH4
(>3 equiv) followed by workup and column chromatography (20%
EtOAc/hexanes−50% EtOAc/hexanes) afforded 13i as a colorless
(2-(4-Methoxyphenyl)tetrahydrofuran-3-yl)methanol (14c). Fol-
lowing the general procedure, the reaction of 2-(4-methoxyphenyl)-
4,5-dihydro-1,3-dioxepine 5c (170 mg, 0.82 mmol), xylenes (4.1 mL),
K
J. Org. Chem. XXXX, XXX, XXX−XXX