E
P. Malová Križková et al.
Paper
Synthesis
1H NMR (400.27 MHz, CDCl3): δ = 7.35–7.19 (m, 5 H), 6.10 (br d, J = 7.1
Hz, 1 H), 5.76–5.65 (m, 1 H), 5.13–5.02 (m, 3 H), 3.65–3.49 (m, 2 H),
2.97 (br s, 1 H), 2.69 (sext, J = 6.5 Hz, 1 H), 2.32 (AB-part of ABX-sys-
tem, J = 14.3, 7.2, 6.2 Hz, 2 H), 1.45 (d, J = 6.9 Hz, 3 H).
13C NMR (100.61 MHz, CDCl3): δ = 171.2, 142.9, 138.0, 128.6 (2 C),
127.4, 126.1 (2 C), 116.7, 65.3, 48.8, 42.7, 38.8, 21.6.
min, the amount had increased (7.582 g, 165 mmol). Then, the tem-
perature was increased to 170 °C and reached that temperature with-
in 15 min and was kept there for 15 min. A total of 10.122 g (220
mmol) of EtOH had formed. Further formation of EtOH was very slow.
Fractional distillation (58 °C/3 mbar) yielded 4,7-dihydro-1,3-diox-
epine (8)2 (13.578 g, 82%) as a colorless liquid.
IR (ATR): 2977, 2941, 1379, 1158, 1072, 1035, 950 cm–1
1H NMR (400.27 MHz, CDCl3): δ = 5.63 (AB-part of ABX-system, JAB
.
Anal. Calcd for C14H19NO2: C, 72.07; H, 8.21; N, 6.00. Found: C, 72.06;
H, 7.71; N, 5.98.
=
11.4 Hz, J = 1.6 Hz, 2 H), 4.26 (br AB-system, J = 15.7 Hz, 4 H), 3.56 (q,
J = 7.1 Hz, 2 H), 1.51 (s, 3 H), 1.22 (t, J = 7.1 Hz, 3 H).
13C NMR (100.65 MHz, CDCl3): δ = 128.9 (2 C), 116.0, 61.4 (2 C), 58.8,
Conversion of Amides (R,S)-6 and (S,S)-6 into Taniguchi Lactones
(R)-4 and (S)-4
19.0, 15.4.
Amide (R,S)-6 (13.57 g, 58.15 mmol), H2O (43 mL), concd H2SO4 (8.76
mL), and 1,4-dioxane (22 mL) were stirred for 19 h at 80 °C (moni-
tored by TLC). H2O (20 mL) was added and the mixture was extracted
with CH2Cl2 (3 × 60 mL). The combined organic phases were washed
with brine (60 mL), dried (Na2SO4), and concentrated in vacuo. The
residue was purified by bulb-to-bulb distillation [90–110 °C/20
mmHg; Lit.1 bp 170 °C (bath)/2666 Pa] to yield Taniguchi lactone (R)-4
HRMS-EI: m/z calcd for C8H14O3+: 158.0943; found: 158.0935 ± 5
ppm.
Anal. Calcd for C8H14O3: C, 60.74; H, 8.92. Found: C, 60.56; H, 9.54.
Conversion of 4,7-Dihydro-1,3-dioxepine (8) into Taniguchi Lac-
tone (±)-4
22
(5.13 g, 79%) as a colorless oil; [α]D20 –3.6 (c 1.05, CHCl3) {Lit.1 [α]D
–5.2 (c 2.3, EtOH); Lit.3 [α]D19 –5.6 (c 1.60, EtOH)}; ee >99%. The spec-
troscopic data were identical to those of (±)-4.
A mixture of 4,7-dihydro-1,3-dioxepine (8; 11.697 g, 73.9 mmol) and
p-hydroquinone (0.813 g, 7.39 mmol, 10 mol%) was heated at 170 °C
for 30 h. EtOH (2.762 g, 60 mmol) was collected. The reaction mixture
contained Taniguchi lactone and 4,7-dihydro-1,3-dioxepine in a mo-
lar ratio of 10:1 admixed with impurities. The mixture was chemical-
ly purified and subjected to bulb-to-bulb distillation (90–100 °C/
5 mmHg) to give lactone (±)-4 (4.324 g, 52%) as a colorless liquid,
which was homogeneous as determined by NMR spectroscopy.
Similarly, amide (S,S)-6 (15.65 g, 67.08 mmol) was converted into the
colorless Taniguchi lactone (S)-4 (6.024 g, 80%); ee 99%; [α]D20 +4.3 (c
25
19
0.94, CHCl3) {Lit.5 [α]D +7.1 (c 1.0, CHCl3); Lit.1 [α]D +4.9 (c 4.3,
EtOH); Lit.3 [α]D19 +6.0 (c 1.68, EtOH)}.
Conversion of cis-2-Butene-1,4-diol into Taniguchi Lactone (±)-4,
Using p-Hydroquinone as Catalyst
(±)-, (4R,1′R/S)- and (4S,1′R/S)-4-(1,2-Dibromoethyl)dihydrofuran-
2(3H)-one [(±)-12, (4R,1′R/S)-12 and (4S,1′R/S)-12]
A mixture of cis-2-butene-1,4-diol (6.70 g, 76 mmol), triethyl ortho-
acetate (13.56 g, 83.6 mmol, 1.1 equiv), and p-hydroquinone (0.937 g,
7.6 mmol, 10 mol%) was heated for 1 h at 120 °C (4.6 g of EtOH was
collected) and 24 h at 170 °C (after heating for 15 min the tempera-
ture of 170 °C was reached and a total of 6.77 g EtOH was obtained;
after 24 h, 10.56 g). A few percentage (1H NMR) of 4,7-dihydro-1,3-
dioxepine might have been present in the crude reaction mixture.
THF (4 mL), H2O (2 mL) and HCl (0.5 mL, 12 M) were added to the
cooled reaction mixture at r.t. After stirring vigorously for 30 min, a
cold solution of KOH (5.415 g) in H2O (40 mL) was added slowly (exo-
thermic!). After 1 h, the mixture was extracted with Et2O (3 × 20 mL).
The combined organic layers were washed with brine, dried (MgSO4),
and concentrated under reduced pressure. The residue was flash
chromatographed (heptanes/CH2Cl2, 2:1, Rf = 0.31) to give 1,4-
diethoxybenzene (0.128 g) as colorless crystals; mp 69–70 °C (hep-
tanes) (Lit.9 mp 71–72 °C). The NMR spectroscopic data were identi-
cal to those reported in the literature.
A solution of Br2 in CH2Cl2 (29.72 mmol, 1.05 equiv, 12.38 mL of a 2.4
M solution in CH2Cl2) was added dropwise to a stirred solution of (±)-
Taniguchi lactone (3.176 g, 28.3 mmol) in anhyd CH2Cl2 (56 mL) at 0
°C. The solvent and excess Br2 were removed under reduced pressure
to give a mixture of dibromides (±)-12 (quantitative yield) as an or-
ange oil. The crude dibromides were pure enough for the next step.
Flash chromatography (heptanes/EtOAc, 3:1, Rf = 0.30) furnished a
mixture of colorless dibromides in 95% yield.
Similarly, lactone (R)-4 (2.243 g, 20 mmol) was converted into (–)-di-
bromides (4R,1′RS)-12. Flash chromatography yielded the mixture of
(–)-dibromides (5.226 g, 96%) as a colorless oil; ratio of diastereomers
1.00:1.08; [α]D18 –6.7 (c 1.0, acetone).
Similarly, lactone (S)-4 (2.70 g, 24.1 mmol) was converted into a mix-
ture of (+)-dibromides (4S,1′RS)-12 in quantitative yield. The analyti-
cal sample was purified by flash chromatography; ratio of colorless
diastereomers 1.0:1.1; [α]D18 +7.5 (c 2.1, acetone).
The alkaline aqueous layer containing the potassium salt of the or-
ganic acid was acidified by slow addition of concd H2SO4 (9.6 mL) at 0
°C. After vigorously stirring for 1 h, a separate organic phase had
formed. The mixture was extracted with Et2O (4 × 20 mL). The com-
bined organic layers were washed with brine and sat. aq NaHCO3,
dried (Na2SO4), and concentrated under reduced pressure. The residue
was purified by bulb-to-bulb distillation (95–100 °C/5 mmHg) to fur-
nish homogeneous racemic Taniguchi lactone (±)-4 (6.004 g, 70%) as a
colorless oil.
IR (ATR): 3527, 2971, 2911, 1766, 1414, 1172, 1025 cm–1
.
1H NMR (400.27 MHz, CDCl3): δ [A (major dibromide):B (minor dibro-
mide) = 52:48] = 4.49 (dd, J = 9.2, 8.4 Hz, 1 H, B), 4.45 (dd, J = 9.3, 8.1
Hz, 1 H, A), 4.31–4.24 (m, 2 H, A and B), 4.18 (dd, J = 9.2, 7.2 Hz, 1 H,
B), 4.17 (dd, J = 9.3, 7.4 Hz, 1 H, A), 3.86 (dd, J = 10.7, 4.5 Hz, 1 H, B),
3.84 (dd, J = 11.1, 4.5 Hz, 1 H, A), 3.59 (dd, J = 11.1, 9.1 Hz, 1 H, A), 3.53
(t, J = 10.6 Hz, 1 H, B), 3.39–3.22 (m, 2 H, A and B), 2.73 (dd, J = 17.6,
9.1 Hz, 1 H, A), 2.58 (AB-part of ABX-system, JAB = 17.6 Hz, J = 8.9, 8.7
Hz, 2 H, B). 2.50 (dd, J = 17.6, 8.9 Hz, 1 H, A).
2-Ethoxy-2-methyl-4,7-dihydro-1,3-dioxepine (8)
13C NMR (100.65 MHz, CDCl3): δ = 175.1, 174.9, 70.9, 69.6, 52.9, 52.7,
38.8, 38.2, 33.8, 33.32, 33.3, 30.0.
A mixture of cis-2-butene-1,4-diol (10.356 g, 118 mmol), triethyl or-
thoacetate (17.034 g, 19.25 mL, 105 mmol), and p-hydroquinone
(1.299 g, 11.8 mmol, 10 mol%) was heated at 120 °C. EtOH (6.978 g,
151 mmol) was collected during the first 30 min. After another 30
Anal. Calcd for C6H8Br2O2: C, 26.50; H, 2.97. Found: C, 26.75; H, 3.07.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–G