The Journal of Organic Chemistry
Note
114.6, 113.2, 111.2, 104.7, 97.8, 94.3, 86.5, 82.2, 81.9 (1C overlap),
63.7, 63.6, 55.9, 28.2, 27.9, 14.7, 14.6, 13.5, 12.8; HRMS (ESI) m/z
[M + H]+ calcd for C18H23O4 303.1591, found 303.1586.
119.7, 111.9, 96.5, 92.5, 86.7, 82.9, 82.0, 81.9, 63.5, 28.2, 27.9, 21.7,
21.6, 14.2, 11.7; HRMS (ESI) m/z [M + H]+ calcd for C17H21O3
273.1485, found 273.1481.
tert-Butyl 2-Methyl-5-(3-methylphenyl)-3-oxopent-4-ynoate
(1g). The title compound was prepared according to the general
procedure as described above. The crude material was purified by
column chromatography on silica gel (eluting with hexane/ethyl
acetate = 60/1) to give the title compound as a pale yellow solid (0.41
tert-Butyl 2-Benzyl-3-oxo-5-phenylpent-4-ynoate (1l). The title
compound was prepared according to the general procedure as
described above. The crude material was purified by column
chromatography on silica gel treated Et3N (eluting with hexane/
ethyl acetate = 80/1) to give the title compound as a white solid (0.45
1
1
g, 67% yield): H NMR (500 MHz, CDCl3) [keto form, 44%] δ
g, 54% yield): H NMR (500 MHz, CDCl3) [enol form, 100%] δ
7.39−7.18 (4H, m), 3.58 (1H, q, J = 7.1 Hz), 2.33 (3H, s), 1.48 (9H,
s), 1.45 (3H, d, J = 7.2 Hz); [enol form, 56%] δ 12.34 (1H, s), 7.39−
7.18 (4H, m), 2.35 (3H, s), 1.94 (3H, s), 1.53 (9H, s); 13C{1H} NMR
(100 MHz, CDCl3) [keto and enol form] δ 183.3, 172.7, 168.7, 151.5,
138.5, 138.2, 133.6, 132.4, 131.9, 130.4, 130.2, 129.0, 128.5, 128.3,
121.2, 119.4, 105.4, 97.4, 93.1, 86.2, 82.8, 81.95, 81.93, 55.9, 28.2,
27.8, 21.12, 21.09, 13.5, 12.7; HRMS (ESI) m/z [M + H]+ calcd for
C17H21O3 273.1485, found 273.1477; mp 52−54 °C.
tert-Butyl 2-Methyl-3-oxo-5-(2,4,6-trimethylphenyl)pent-4-
ynoate (1h). The title compound was prepared according to the
general procedure as described above. The crude material was purified
by column chromatography on silica gel (eluting with hexane/ethyl
acetate = 60/1) to give the title compound as a pale yellow solid (0.40
g, 58% yield): 1H NMR (500 MHz, CDCl3) [keto form, 50%] δ 6.89
(2H, s), 3.60 (1H, q, J = 7.1 Hz), 2.44 (6H, s), 2.29 (3H, s), 1.48
(3H, d, J = 7.1 Hz), 1.45 (9H, s); [enol form, 50%] δ 12.35 (1H, s),
6.90 (2H, s), 2.44 (6H, s), 2.30 (3H, s), 1.96 (3H, s), 1.53 (9H, s);
13C{1H} NMR (100 MHz, CDCl3) [keto and enol form] δ 183.3,
12.55 (1H, s), 7.52−7.18 (5H, m), 3.74 (2H, s), 1.39 (9H, s);
13C{1H} NMR (100 MHz, CDCl3) [enol form, 100%] δ 172.3, 152.8,
140.9, 132.1, 129.7, 128.5, 128.3, 128.1, 125.9, 121.2, 109.7, 96.9,
83.4, 82.4, 34.1, 28.1; HRMS (ESI) m/z [M + H]+ calcd for
C22H23O3 335.1642, found 335.1633; mp 67−69 °C.
tert-Butyl 2-[(2Z)-3-Phenylprop-2-en-1-yl]-3-oxo-5-phenylpent-
4-ynoate (1m). The title compound was prepared according to the
general procedure as described above. The crude material was purified
by column chromatography on silica gel treated Et3N (eluting with
hexane/ethyl acetate = 80/1) to give the title compound as a yellow
1
oil (0.31 g, 56% yield): H NMR (500 MHz, CDCl3) [keto form,
38%] δ 7.59−7.18 (5H, m), 6.51 (1H, d, J = 15.7 Hz), 6.23−6.15
(1H, m), 3.67 (1H, t, J = 7.3 Hz), 2.92−2.81 (2H, m), 1.47 (9H, s);
[enol form, 62%] δ 12.47 (1H, s), 7.59−7.18 (5H, m), 6.45 (1H, d, J
= 15.7 Hz), 6.23−6.15 (1H, m), 3.29 (2H, d, J = 6.4 Hz), 1.53 (9H,
s); 13C{1H} NMR (100 MHz, CDCl3) [keto and enol form] δ 182.0,
172.3, 167.5, 152.6, 137.7, 137.1, 133.2, 132.8, 132.0, 131.0, 130.5,
129.7 (1C overlap), 128.7, 128.5, 128.0 (1C overlap), 127.3, 127.0,
126.2, 126.0, 125.5, 121.3, 119.6, 108.1, 97.3, 93.1, 86.8, 82.9, 82.3
(1C overlap), 61.8, 31.7, 31.6, 28.2, 27.9; HRMS (ESI) m/z [M +
Na]+ calcd for C24H24NaO3 383.1623, found 383.1637.
General Procedure for Enantioselective Fluorination of α-
Branched β-Ynone Esters. To a solution of α-branched β-ynone
ester 1 (0.1 mmol, 1.0 equiv) in a mixture of 1/1 m-xylene/toluene
(0.1 M) and water (1.0 M) were added PTC C5 (5 mol %) and
Cs2CO3 (5.0 equiv) at room temperature. The reaction mixture was
then cooled at −40 °C. After 20 min, NFSI (1.5 equiv) was added to
the reaction mixture, and the resulting reaction mixture was stirred
until TLC showed that the ester 1 was totally consumed. After Me2S
was added to quench the reaction at −40 °C, the solution was stirred
for 20 min at room temperature. The resulting mixture was mixed
with saturated NaHCO3 and extracted with EtOAc. The combined
organic phase was washed with brine and dried over MgSO4. The
organic layer was filtered and concentrated with the rotary evaporator.
The residue was purified by a silica gel flash chromatography to afford
the desired fluorinated product 2.
172.8, 168.8, 152.2, 142.7, 141.2, 141.0, 139.3, 128.0, 127.8, 118.4,
116.5, 104.6, 95.6, 94.4, 91.4, 90.8, 81.9, 81.8, 56.1, 28.2, 27.9, 21.5,
21.4, 21.0, 20.9, 13.6, 13.0; HRMS (ESI) m/z [M + Na]+ calcd for
C19H24NaO3 323.1623, found 323.1578; mp 73−76 °C.
tert-Butyl 2-Methyl-3-oxo-5-(thiophene-3-yl)pent-4-ynoate (1i).
The title compound was prepared according to the general procedure
as described above. The crude material was purified by column
chromatography on silica gel (eluting with hexane/ethyl acetate = 50/
1
1) to give the title compound as a yellow oil (0.26 g, 40% yield): H
NMR (500 MHz, CDCl3) [keto form, 38%] δ 7.76 (1H, s), 7.35−
7.34 (1H, m), 7.23−7.21 (1H, m), 3.56 (1H, q, J = 7.1 Hz), 1.48 (9H,
s), 1.43 (3H, d, J = 7.2 Hz); [enol form, 62%] δ 12.33 (1H, s), 7.76
(1H, s), 7.32−7.30 (1H, m), 7.20−7.19 (1H, m), 1.92 (3H, s), 1.53
(9H, s); 13C{1H} NMR (100 MHz, CDCl3) [keto and enol form] δ
183.2, 172.7, 168.7, 151.4, 134.2, 130.7, 130.2, 129.7, 126.3, 125.7,
120.6, 119.0, 105.3, 92.4, 88.0, 86.8, 82.9, 82.0 (1C overlap), 55.8,
28.2, 27.9, 13.5, 12.7; HRMS (ESI) m/z [M + H]+ calcd for
C14H17O3S 265.0893, found 265.0885.
tert-Butyl 6-(Benzyloxy)-2-methyl-3-oxohex-4-ynoate (1j). The
title compound was prepared according to the general procedure as
described above. The crude material was purified by column
chromatography on silica gel (eluting with hexane/ethyl acetate =
30/1) to give the title compound as a yellow oil (0.55 g, 55% yield):
1H NMR (400 MHz, CDCl3) [keto form, 15%] δ 7.36−7.29 (5H, m),
4.61 (2H, s), 4.33 (2H, s), 3.50 (1H, q, J = 7.1 Hz), 1.47 (9H, s), 1.40
(3H, d, J = 7.2 Hz); [enol form, 85%] δ 12.25 (1H, s), 7.36−7.29
(5H, m), 4.63 (2H, s), 4.38 (2H, s), 1.88 (3H, s), 1.51 (9H, s);
13C{1H} NMR (100 MHz, CDCl3) [keto and enol form] δ 182.7,
172.6, 168.4, 150.6, 137.0, 136.6, 128.5, 128.4 (1C overlap), 128.1
(1C overlap), 128.0, 105.8, 93.4, 89.6, 84.0, 82.14, 82.10, 80.3, 72.0,
71.8, 57.4, 56.8, 55.7, 28.1, 27.8, 13.5, 12.6; HRMS (ESI) m/z [M +
H]+ calcd for C18H23O4 303.1591, found 303.1582.
tert-Butyl 2-Ethyl-3-oxo-5-phenylpent-4-ynoate (1k). The title
compound was prepared according to the general procedure as
described above. The crude material was purified by column
chromatography on silica gel (eluting with hexane/ethyl acetate =
60/1) to give the title compound as a yellow oil (0.19 g, 57% yield):
1H NMR (500 MHz, CDCl3) [keto form, 44%] δ 7.58−7.34 (5H, m),
3.41 (1H, t, J = 7.4 Hz), 2.05−1.95 (2H, m), 1.48 (9H, s), 1.01 (3H,
t, J = 7.5 Hz); [enol form, 56%] δ 12.35 (1H, s), 7.58−7.34 (5H, m),
2.40 (2H, q, J = 7.4 Hz), 1.54 (9H, s), 1.08 (3H, t, J = 7.4 Hz);
13C{1H} NMR (100 MHz, CDCl3) [keto and enol form] δ 182.9,
172.5, 168.0, 151.5, 133.2, 132.0, 130.9, 129.5, 128.6, 128.4, 121.5,
tert-Butyl 2-Fluoro-2-methyl-3-oxo-5-phenylpent-4-ynoate (2a).
The title compound was prepared according to the general procedure
as described above. The crude material was purified by column
chromatography on silica gel (eluting with hexane/ethyl acetate = 60/
1) to give the title compound as a yellow oil (20.4 mg, 83% yield).
Enantiomeric purity was determined by HPLC analysis (Daicel
Chiralpak IC-3, hexane/2-propanol = 20/1, flow rate = 1.0 mL/min,
wavelength = 245 nm, retention time; 7.0 min (minor) and 6.2 min
1
(major): [α]28 = −13.7 (c = 1.0, CHCl3; 83% ee); H NMR (400
D
MHz, CDCl3) δ 7.62−7.60 (2H, m), 7.52−7.48 (1H, m), 7.43−7.39
(2H, m), 1.78 (3H, d, J = 24.6 Hz), 1.50 (9H, s); 13C{1H} NMR (100
MHz, CDCl3) δ 180.0 (d, J = 29.4 Hz), 165.2 (d, J = 25.4 Hz), 133.3,
131.4, 128.7, 119.1, 96.73, 96.68 (d, J = 195.6 Hz), 84.5, 84.0, 27.6,
19.6 (d, J = 23.3 Hz); 19F NMR (376 MHz, CDCl3) δ −155.44 (1F,
q, J = 21.5 Hz); HRMS (ESI) m/z [M + Na]+ calcd for C16H17FNaO3
299.1059, found 299.1045.
Procedure for 1.0 mmol scale reaction of 2a: To a solution of 1a
(259.1 mg, 1.0 mmol, 1.0 equiv) in a mixture of 1/1 m-xylene/toluene
(10 mL, 0.1 M) and water (1.0 mL, 1.0 M) was added PTC C5 (25.1
mg, 5 mol %) and Cs2CO3 (1.632 g, 5.0 equiv) at room temperature.
The reaction mixture was then cooled at −40 °C. After 20 min, NFSI
(0.474 g, 1.5 equiv) was added portionwise to the reaction mixture,
and the resulting reaction mixture was stirred vigorously until TLC
showed that the ester 1a was totally consumed (note that the
efficiency of stirring is very important). After Me2S was added to
E
J. Org. Chem. XXXX, XXX, XXX−XXX