The Journal of Organic Chemistry
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isomer a), 2.09 (s, 3H, isomer b), 2.02 (s, 3H, isomer a), 1.98 (s, 3H,
isomer a), 1.96 (s, 3H, isomer b), 1.95 (m, 1H, isomer a), 1.73−1.65 (m,
1H, isomer b), 1.03 (d, J = 1.5 Hz, 3H, isomer a), 1.02 (d, J = 1.4 Hz, 3H,
isomer a), 0.99 (d, J = 6.7 Hz, 3H, isomer b), 0.93 (d, J = 6.7 Hz, 3H,
isomer b) ppm. 13C NMR (125 MHz, CDCl3) δ 163.74 (isomer a),
163.66 (isomer b), 151.6 (isomer b), 151.2 (isomer a), 139.0 (isomer
b), 138.0 (isomer a), 111.2 (isomer b), 110.8 (isomer a), 89.8 (isomer
a), 77.4 (isomer b), 65.3 (isomer a), 63.2 (isomer b), 62.4 (isomer b),
61.7 (isomer a), 32.2 (isomer a), 31.7 (isomer b), 19.2 (isomer b), 19.1
(isomer a), 18.8 (isomer a), 18.6 (isomer b), 14.12 (isomer a), 14.08
(isomer b), 12.9 (isomer b), 12.7 (isomer a) ppm. HRMS calcd for
C12H20N2O3SNa [M + Na+], 295.1087; found, 295.1087 (0.06 ppm).
( )-1-(1-(Isopropylthio)-2-methoxy-3-methylbutyl)-5-methylpyri-
midine-2,4(1H,3H)-dione (17a and 17b). Following general procedure
D, silylated thymine (0.75 mL, 0.60 mmol, 3.0 equiv of a 0.80 M solution
in DCM) and Me2S(SMe)BF4 (80 mg, 0.41 mmol, 2.05 equiv) were
added to a solution of 16 (50 mg, 0.20 mmol) in anhydrous DCM
7.71 (s, 1H, isomer b), 7.71 (s, 1H, isomer a), 7.42−7.17 (m, 10H,
isomer a and b), 5.91 (d, J = 4.1 Hz, 1H, isomer b), 5.78 (d, J = 3.7 Hz,
1H, isomer a), 4.56 (d, J = 4.5 Hz, 1H, isomer b), 4.46 (d, J = 3.7 Hz, 1H,
isomer a), 3.29 (s, 3H, isomer a), 3.28 (s, 3H, isomer b), 2.04 (s, 3H,
isomer b), 1.98 (s, 3H, isomer b), 1.95 (s, 3H, isomer a), 1.92 (s, 3H,
isomer a) ppm. 13C NMR (100.6 MHz, CDCl3) δ 164.3 (isomer a),
164.2 (isomer b), 151.5 (isomer a), 151.4 (isomer b), 138.0 (isomer a),
137.7 (isomer a), 136.6 (isomer b), 136.5 (isomer b), 128.7 (isomer b),
128.63 (isomer a), 128.59 (isomer b), 128.5 (isomer a), 127.1 (isomer
a), 126.8 (isomer b), 110.7 (isomer b), 110.6 (isomer a), 85.5 (isomer
a), 84.9 (isomer b), 67.1 (isomer a), 65.3 (isomer b), 57.8 (isomer b),
57.7 (isomer a), 14.16 (isomer a or b), 14.14 (isomer a or b), 12.7
(isomer b), 12.6 (isomer a) ppm. HRMS calcd for C15H19N2O3S
[M + H+], 307.1111; found, 307.1113 (−1.0 ppm).
( )-1-(2-Methoxy-1-(methylthio)-3-phenylpropyl)-5-methylpyri-
midine-2,4(1H,3H)-dione (23a and 23b). Following general procedure
D, silylated thymine (1.6 mL, 1.2 mmol, 3.0 equiv of a 0.80 M solution in
DCM) and I2 (0.21 g, 0.83 mmol, 2.0 equiv) were added to a solution of
22 (0.10 g, 0.41 mmol) in anhydrous THF (2.6 mL, 0.16 M). 1H NMR
spectroscopic analysis of the unpurified product indicated the formation
of a 2:1 mixture of 1,2-syn and anti diastereomers. Purification by
flash chromatography (hexanes/EtOAc, 70:30) provided 23a and 23b
(0.11 g, 83%) as a white foam.
1
(1.3 mL, 0.20 M). H NMR spectroscopic analysis of the unpurified
product indicated the formation of a 9:1 mixture of 1,2-syn and anti
diastereomers. Purification by flash chromatography (hexanes/EtOAc,
40:60) provided a mixture of 17a (47 mg) and 17b (4 mg) for a total
yield of (51 mg) 84%.
17a: Rf = 0.35 (hexanes/EtOAc, 60:40). Formula: C14H24N2O3S.
MW: 300.4170 g/mol. 1H NMR (400 MHz, CDCl3) δ 9.52 (s, 1H), 7.85
(s, 1H), 5.87 (d, J = 2.7 Hz, 1H), 3.32 (s, 3H), 2.97 (dd, J = 8.7, 2.8 Hz,
1H), 2.87−2.74 (m, 1H), 1.97 (s, 3H), 2.00−1.93 (m, 1H), 1.28 (d, J =
6.6 Hz, 3H), 1.20 (d, J = 6.8 Hz, 3H), 1.01 (d, J = 6.7 Hz, 3H), 1.00 (d,
J = 6.7 Hz, 3H) ppm. 13C NMR (100.6 MHz, CDCl3) δ 164.4, 151.0,
138.7, 110.4, 90.6, 62.0, 61.8, 34.9, 32.2, 23.5, 23.2, 19.0, 18.9, 12.7 ppm.
HRMS calcd for C14H25N2O3S [M + H+], 301.1580; found, 301.1581
(−1.7 ppm).
23a (isolated with 10% of 23b): Rf = 0.10 (hexanes/EtOAc, 60:40).
1
Formula: C16H20N2O3S. MW: 320.4066 g/mol. H NMR (400 MHz,
CDCl3) δ 8.38 (s, 1H), 7.76 (s, 1H), 7.36−7.18 (m, 5H), 5.55 (d, J =
2.9 Hz, 1H), 3.64 (apptd, J = 7.1, 2.9 Hz, 1H), 3.25 (s, 3H), 3.10 (dd, J =
13.7, 6.7 Hz, 1H), 2.88 (dd, J = 13.7, 7.4 Hz, 1H), 2.00 (s, 3H), 1.93 (s,
3H) ppm. 13C NMR (100.6 MHz, CDCl3) δ 164.3, 151.4, 138.0, 136.9,
129.2, 128.8, 126.9, 110.5, 85.1, 65.2, 58.9, 38.5, 14.1, 12.7 ppm. HRMS
calcd for C16H20N2O3SNa: [M + Na+], 343.1087; found, 343.1088
(−1.3 ppm).
17b: Rf = 0.40 (hexanes/EtOAc, 60:40). 1H NMR (400 MHz,
CDCl3) δ 8.21 (s, 1H), 7.73 (s, 1H), 5.97 (d, J = 3.7 Hz, 1H), 3.51 (s,
3H), 3.15 (dd, J = 7.6, 3.7 Hz, 1H), 2.96−2.85 (m, 1H), 1.95 (s, 3H),
1.76−1.65 (m, 1H), 1.36 (d, J = 6.6 Hz, 3H), 1.21 (d, J = 6.8 Hz, 3H),
0.99 (d, J = 6.7 Hz, 3H), 0.95 (d, J = 6.8 Hz, 3H) ppm.
23b: Rf = 0.14 (hexanes/EtOAc, 60:40). 1H NMR (400 MHz,
CDCl3) δ 9.09 (s, 1H), 7.69 (s, 1H), 7.31−7.17 (m, 5H), 5.79 (d, J = 3.8
Hz, 1H), 3.77 (ddd, J = 7.6, 4.6, 4.0 Hz, 1H), 3.26 (s, 3H), 2.83 (dd, J =
14.1, 4.7 Hz, 1H), 2.68 (dd, J = 14.1, 7.5 Hz, 1H), 2.06 (s, 3H), 1.95 (s, 3H)
ppm. 13C NMR (100.6 MHz, CDCl3) δ 163.9, 151.8, 138.6, 137.1, 129.5,
128.6, 126.8, 111.2, 85.1, 64.5, 60.4, 38.4, 14.2, 12.9 ppm. HRMS calcd for
C16H20N2O3SNa: [M + Na+], 343.1087; found, 343.1094 (0.5 ppm).
( )-1-(2-Methoxy-3,3-dimethyl-1-(methylthio)butyl)-5-methyl-
pyrimidine-2,4(1H,3H)-dione (25a and 25b). Following general pro-
cedure D, silylated thymine (1.8 mL, 1.4 mmol, 3.0 equiv of a 0.80 M
solution in DCM) and I2 (0.24 g, 0.96 mmol, 2.0 equiv) were added to a
solution of 24 (0.10 g, 0.48 mmol) in anhydrous THF (3.0 mL, 0.16 M).
1H NMR spectroscopic analysis of the unpurified product indicated the
( )-1-(1-(tert-Butylthio)-2-methoxy-3-methylbutyl)-5-methylpyri-
midine-2,4(1H,3H)-dione (19a and 19b). Following general procedure
D, silylated thymine (0.45 mL, 0.36 mmol, 2.0 equiv of a 0.80 M solution
in DCM) and I2 (91 mg, 0.36 mmol, 2.0 equiv) were added to a solution
of 18 (50 mg, 0.18 mmol) in anhydrous THF (2.0 mL, 0.10 M).
1H NMR spectroscopic analysis of the unpurified product indicated the
formation of a 9:1 mixture of 1,2-syn and anti diastereomers. Purification
by flash chromatography (hexanes/EtOAc, 50:50) provided 19a (50 mg)
and 19b (2.3 mg) for a total yield of (52 mg) 92%.
19a: Rf = 0.39 (hexanes/EtOAc, 50:50). Formula: C15H26N2O3S.
MW: 314.4435 g/mol. IR (neat) νmax 3183, 2961, 1689 cm−1. 1H NMR
(400 MHz, CDCl3) δ 9.88 (s, 1H), 7.87 (s, 1H), 5.89 (s, 1H), 3.29 (s,
3H), 2.91 (ad, J = 9.0 Hz, 1H), 2.06−1.97 (m, 1H), 1.96 (s, 3H), 1.26 (s,
9H), 1.00 (d, J = 6.7 Hz, 6H) ppm. 13C NMR (100.6 MHz, CDCl3) δ
164.8, 150.8, 139.2, 109.9, 91.8, 61.8, 61.0, 44.2, 32.3, 31.2, 19.1, 18.8,
12.6 ppm. HRMS calcd for C15H26N2O3S: 314.1664; found, 314.1675
(−3.5 ppm).
19b: Rf = 0.44 (hexanes/EtOAc, 50:50). IR (neat) νmax 3158, 2963,
1692, 1679 cm−1. 1H NMR (400 MHz, CDCl3) δ 8.15 (s, 1H), 7.68 (s,
1H), 5.98 (d, J = 4.0 Hz, 1H), 3.50 (s, 3H), 3.13 (dd, J = 7.2, 4.0 Hz, 1H),
1.95 (s, 3H), 1.80−1.66 (m, 1H), 1.32 (s, 9H), 0.99 (d, J = 6.1 Hz, 3H),
0.97 (d, J = 6.2 Hz, 3H) ppm. HRMS calcd for C15H26N2O3S: 314.1664;
found, 314.1651 (4.1 ppm).
( )-1-(2-Methoxy-1-(methylthio)-2-phenylethyl)-5-methylpyrimidine-
2,4(1H,3H)-dione (21a and 21b). Following general procedure D,
silylated thymine (2.4 mL, 2.0 mmol, 3.0 equiv of a 0.82 M solution in
DCM) and I2 (0.30 g, 1.3 mmol, 2.0 equiv) were added to a solution of
20 (0.150 g, 0.66 mmol) in anhydrous THF (4.1 mL, 0.16 M). 1H NMR
spectroscopic analysis of the unpurified product indicated the formation
of a 3:1 mixture of 1,2-syn and anti diastereomers. Purification by flash
chromatography (hexanes/EtOAc, 60:40) provided a mixture of 21a
and 21b (0.18 g, 90%) as a white foam: Rf = 0.17 (hexanes/EtOAc,
60:40). Formula: C15H18N2O3S. MW: 306.3800 g/mol. 1H NMR
(400 MHz, CDCl3) δ 8.95 (s, 1H, isomer a), 8.54 (s, 1H, isomer b),
formation of a single diastereomer (>20:1). Purification by flash chromato-
graphy (hexanes/EtOAc, 60:40) provided 25a (0.11 g, 81%) as a colorless
oil: Rf = 0.30 (hexanes/EtOAc, 60:40). Formula: C13H22N2O3S. MW:
286.3904 g/mol. 1H NMR(400 MHz, CDCl3) δ 8.47 (s, 1H), 7.80 (s, 1H),
5.79 (d, J = 2.6 Hz, 1H), 3.46 (s, 3H), 3.03 (d, J = 2.8 Hz, 1H), 1.99 (s, 3H),
1.96 (s, 3H), 1.04 (s, 9H) ppm. 13C NMR (100.6 MHz, CDCl3) δ 164.1,
151.2, 137.7, 111.4, 92.7, 65.1, 63.1, 36.7, 26.9, 13.8, 12.8 ppm. HRMS calcd
for C13H23N2O3S: [M + H+], 287.1424; found, 287.1426 (−1.3 ppm).
( )-1-(2-Methoxy-3,3-dimethyl-1-(methylthio)butyl)-5-methyl-
pyrimidine-2,4(1H,3H)-dione (27a and 27b). Thioaminals 27a and
27b have previously been reported in the literature by our laboratory.4
Preparation and Coupling on Thioacetate 28 (Table 2). ( )-2-
Methoxy-3-methyl-1-(methylthio)butyl Acetate (28). To a solution
of 14 (0.52 g, 2.7 mmol, 1.0 equiv) in anhydrous acetonitrile (26 mL,
0.10 M) at 0 °C was added Hg(OAc)2 (1.0 g, 3.2 mmol, 1.2 equiv). The
reaction mixture was stirred at room temperature for 2 h, filtered on a
pad of Celite, rinsed with diethyl ether, and concentrated in vacuo.
1H NMR spectroscopic analysis of the unpurified product indicated the
formation of a single diastereomer. Purification by flash chromatography
(hexanes/EtOAc, 90:10) provided 28 (0.45 g, 82%) as a colorless oil:
Rf = 0.37 (hexanes/EtOAc, 90:10). Formula: C9H18O3S. MW: 206.3024
g/mol. IR (neat) νmax 2963, 1743 cm−1. 1H NMR (500 MHz, CDCl3) δ
6.07 (d, J = 3.5 Hz, 1H), 3.51 (s, 3H), 3.06 (dd, J = 6.7, 3.6 Hz, 1H), 2.20
(s, 3H), 2.13 (s, 3H), 1.95−1.84 (m, 1H), 0.97 (at, J = 6.5 Hz, 6H) ppm.
13C NMR (125 MHz, CDCl3) δ 170.6, 88.3, 83.3, 61.0, 31.0, 21.4, 19.8,
10515
dx.doi.org/10.1021/jo502181a | J. Org. Chem. 2014, 79, 10504−10525