9232
S. Bugge et al. / Tetrahedron 68 (2012) 9226e9233
was dissolved in CH2Cl2 (30 mL) and washed with water
(3ꢁ20 mL), and saturated aq NaCl solution (20 mL). The organic
phase was dried over Na2SO4, and filtered. To the CH2Cl2 phase was
added HCl in diethyl ether (3 mL) and the mixture was kept at
ꢂ18 ꢀC for 18 h. The precipitated product was isolated by filtration
and washed with diethyl ether (3ꢁ15 mL). Drying gave 160 mg
(0.366 mmol, 68%) of 10c$HCl as a white solid, mp. 280 ꢀC (dec);
116.3, 116.2, 48.9, 22.5; IR (neat, cmꢂ1): 3068 (br), 2978 (br), 1603,
1453, 1104, 751, 700; HRMS (EI, 70 eV, m/z): 347.1087 (calcd
C20H17N3OS, 347.1087, Mþ).
4.3.21. (R)-6-Mesityl-N-(1-phenylethyl)thieno[2,3-d]pyrimidin-4-
amine (10g). The reaction and extractive work-up were performed
as described in Section 4.3.14 starting with mesitylboronic acid
(5 g) (136 mg, 0.827 mmol). The reaction time was 3 h. The crude
product was absorbed onto silica and purified by silica gel column
chromatography (n-pentane/EtOAc, 3/1). The purified product was
dissolved in diethyl ether (50 mL), and HCl in diethyl ether (1 mL)
was added. The solution was then cooled to ꢂ18 ꢀC for 93 h, and the
resulting solid material was isolated by filtration, and washed with
diethyl ether (3ꢁ15 mL). Drying gave 164 mg (0.401 mmol, 74%) of
½
a 2D0
ꢃ
ꢂ281.4 (c 1.05, DMSO); HPLC purity (method A): 99%,
tR¼26.7 min; 1H NMR (400 MHz, DMSO-d6)
: 8.44 (d, J¼7.8, 1H),
d
8.39 (s, 1H), 8.32 (s, 1H), 7.88e7.80 (m, 4H), 7.47e7.42 (m, 2H),
7.35e7.29 (m, 2H), 7.24e7.19 (m, 1H), 5.56e5.47 (m, 1H), 1.58 (d,
J¼7.1, 3H); 13C NMR (100 MHz, DMSO-d6)
d: 165.3, 156.0, 154.2,
144.4, 137.1e137.0 (m), 136.1, 128.3 (q, J¼32.1), 128.3 (2C), 127.1 (q,
J¼282.8), 126.8, 126.3 (q, J¼3.7, 2C), 126.10 (2C), 126.09 (2C), 117.9,
117.4, 49.2, 22.4; 19F NMR (564 MHz, DMSO-d6)
d: ꢂ60.6 (s); IR
10g$HCl as a pale white solid, mp. 217e221 ꢀC; ½a D20
ꢂ171.3 (c 1.03,
ꢃ
(neat, cmꢂ1): 2495, 1601, 1318, 1114, 1068, 697; HRMS (ESI, m/z):
DMSO); Rf (n-pentane/EtOAc, 3/1)¼0.36. HPLC purity (method A):
400.1082 (calcd C21H17F3N3S, 400.1090, MþHþ).
99%, tR¼43.1 min; 1H NMR (400 MHz, DMSO-d6)
d: 8.31 (s, 1H), 8.12
(d, J¼7.9, 1H), 7.51 (s, 1H), 7.45e7.41 (m, 2H), 7.35e7.29 (m, 2H),
4.3.18. (R)-4-(4-(1-Phenylethylamino)thieno[2,3-d]pyrimidin-6-yl)
phenol (10d). Compound 10d was made as described in Section
4.3.14 starting with (4-hydroxyphenyl)boronic acid (5d) (112 mg,
0.812 mmol). The reaction time was 2.5 h. This gave 165 mg
(0.430 mmol, 80%) of 10d$HCl as a white solid, mp. 185e187 ꢀC;
7.24e7.19 (m, 1H), 7.00 (s, 2H), 5.56e5.47 (m, 1H), 2.29 (s, 3H), 2.13
(s, 6H), 1.55 (d, J¼7.0, 3H); 13C NMR (100 MHz, DMSO-d6)
d: 166.1,
155.7, 153.4, 144.6, 138.0 (2C), 137.1, 136.4, 129.8, 128.3 (2C), 128.2
(2C), 126.7, 126.1 (2C), 118.9, 116.7, 49.0, 22.4, 20.7, 20.3 (2C); IR
(neat, cmꢂ1): 1606, 1495, 850, 762, 699; HRMS (EI, 70 eV, m/z):
373.1607 (calcd C23H23N3S, 373.1607, Mþ).
½
a 2D0
ꢃ
ꢂ304.1 (c 0.98, DMSO); HPLC purity (method A): 99%,
tR¼16.8 min; 1H NMR (400 MHz, DMSO-d6)
d: 9.84 (s, 1H), 8.24 (s,
1H), 8.13 (d, J¼7.9,1H), 7.97 (s,1H), 7.54e7.49 (m, 2H), 7.45e7.40 (m,
2H), 7.35e7.29 (m, 2H), 7.24e7.19 (m, 1H), 6.91e6.86 (m, 2H),
5.55e5.46 (m, 1H), 1.56 (d, J¼7.0, 3H); 13C NMR (100 MHz, DMSO-
4.3.22. (R)-N-(1-Phenylethyl)-6-(2,4,6-tri-isopropylphenyl)thieno
[2,3-d]pyrimidin-4-amine (10h). The reaction was performed as
described in Section 4.3.14 starting with (2,4,6-triisopropylphenyl)
boronic acid (5h) (203 mg, 0.818 mmol). The reaction time was
22 h. Work-up was done by extraction using diethyl ether (20 mL),
followed by washing with water (3ꢁ15 mL), and a saturated aq
NaCl solution (20 mL). The concentrated crude product was
absorbed onto silica and purified by flash chromatography
(n-pentane/EtOAc, 1/1). Then the free amine was precipitated as it
HCl salt by dissolving in diethyl ether (2 mL) followed by slow
addition of n-pentane (30 mL) and HCl in diethyl ether (2 mL). The
material isolated after 23 h at ꢂ18 ꢀC, was washed with n-pentane
(3ꢁ15 mL). Drying gave 228 mg (0.364 mmol, 67%) of 10h$HCl as
d6) d: 164.5, 158.0, 155.5, 153.4, 144.7, 138.8, 128.3 (2C), 127.1 (2C),
126.7, 126.1 (2C), 124.3, 117.6, 116.1 (2C), 113.2, 49.0, 22.5; IR (neat,
cmꢂ1): 3057 (br), 2978 (br), 1606, 1492, 832, 765, 698; HRMS (ESI,
m/z): 348.1164 (calcd C20H18N3OS, 348.1165, MþHþ).
4.3.19. (R)-3-(4-(1-Phenylethylamino)thieno-[2,3-d]pyrimidin-6-yl)
phenol (10e). Compound 10e was made as described in Section
4.3.14 starting with (3-hydroxyphenyl)boronic acid (5e) (113 mg,
0.817 mmol), and reacting for 2.5 h. This gave 188 mg (0.488 mmol,
91%) of 10e$HCl as a white solid, mp. 175e178 ꢀC; ½a D20
ꢂ303.7
ꢃ
(c 0.99, DMSO); HPLC purity (method A): 99%, tR¼17.6 min; 1H NMR
a pale white solid, mp. 215e219 ꢀC; ½a D20
ꢂ127.2 (c 1.08, DMSO); Rf
ꢃ
(400 MHz, DMSO-d6)
d
: 9.73 (s, 1H), 8.28 (s, 1H), 8.23 (d, J¼7.9, 1H),
(n-pentane/EtOAc, 1/1)¼0.90; HPLC purity (method A): 99%,
1
8.14 (s,1H), 7.46e7.41 (m, 2H), 7.36e7.27 (m, 3H), 7.25e7.19 (m,1H),
7.15e7.11 (m, 1H), 7.10e7.07 (m, 1H), 5.56e5.47 (m, 1H), 1.57 (d,
tR¼52.3 min; H NMR (400 MHz, DMSO-d6)
d: 8.32 (s, 1H), 8.13 (d,
J¼7.9, 1H), 7.54 (s, 1H), 7.45e7.41 (m, 2H), 7.35e7.30 (m, 2H),
7.24e7.19 (m, 1H), 7.13 (s, 2H), 5.58e5.48 (m, 1H), 2.93 (sept, J¼6.8,
1H), 2.83e2.70 (m, 2H), 1.56 (d, J¼7.1, 3H), 1.24 (d, J¼6.8, 6H),
J¼7.0, 3H); 13C NMR (100 MHz, DMSO-d6)
d: 165.0, 158.0, 155.8,
153.9, 144.6, 138.3, 134.4, 130.4, 128.3 (2C), 126.7, 126.1 (2C), 117.4,
116.5, 115.7, 115.4, 112.3, 49.0, 22.5; IR (neat, cmꢂ1): 3059 (br), 2929
(br), 1600, 1583, 764, 698; HRMS (ESI, m/z): 348.1164 (calcd
C20H18N3OS, 348.1165, MþHþ).
1.15e1.09 (m, 12H); 13C NMR (100 MHz, DMSO-d6)
d: 166.0, 155.7,
153.5, 149.6, 148.17, 148.16, 144.6, 136.2, 128.3 (2C), 127.3, 126.7,
126.2 (2C), 120.6 (2C), 119.4, 116.5, 49.1, 33.7, 30.2 (2C), 24.5 (2C),
24.0, 23.94, 23.86 (2C), 22.4; IR (neat, cmꢂ1): 2959, 2867, 1605,
1363, 877, 761, 698; HRMS (EI, 70 eV, m/z): 457.2543 (calcd
C29H35N3S, 457.2546, M þ).
4.3.20. (R)-2-(4-(1-Phenylethylamino)thieno[2,3-d]pyrimidin-6-yl)
phenol (10f). The reaction was performed as described in Section
4.3.14 starting with (2-hydroxyphenyl)boronic acid (5f) (113 mg,
0.819 mmol), and reacting for 3 h. Work-up was done by extraction
using diethyl ether (75 mL) followed by washing with water
(3ꢁ15 mL), and a saturated aq NaCl solution (20 mL). The organic
phase was dried over Na2SO4, and filtered. To the diethyl ether
phase was added HCl in diethyl ether (1 mL) and the mixture was
kept at ꢂ18 ꢀC for 12 h. The precipitated product was isolated by
filtration and washed with cold diethyl ether (3ꢁ15 mL). Drying
gave 191 mg (0.497 mmol, 92%) of 10f$HCl as a white solid, mp.
Acknowledgements
The group is thankful to the Anders Jahres foundation for
financial support. Roger Aarvik is thanked for his contributions.
Susana Villa Gonzalez is acknowledged for the HRMS experiments.
References and notes
201e203 ꢀC; ½a 2D0
ꢂ308.1 (c 0.75, DMSO); HPLC purity (method A):
ꢃ
1. Varvounis, G.; Giannopoulos, T. Adv. Heterocycl. Chem. 1996, 66, 193e283.
2. Litvinov, V. P. Adv. Heterocycl. Chem. 2006, 92, 83e143.
3. Aliagas, I.; Gradl, S.; Gunzner, J.; Mathieu, S.; Pulk, R.; Rudolph, J.; Wen, Z.;
Grina, J.; Hansen, J. WO 2011025940, 2011.
4. Baker, S. J.; Goldsmith, P. J.; Hancox, T. C.; Pegg, N. A.; Price, S.; Shuttleworth, S.
J.; Sohal, S. WO 2007122410, 2007.
5. Beckers, T.; Sellmer, A.; Eichhorn, E.; Pongratz, H.; Schaechtele, C.; Totzke, F.;
Kelter, G.; Krumbach, R.; Fiebig, H. H.; Boehmer, F. D.; Mahboobi, S. Bioorg. Med.
Chem. 2012, 20, 125e136.
97%, tR¼17.7 min; 1H NMR (400 MHz, DMSO-d6)
d: 10.42 (s, 1H),
8.62 (s, 1H), 8.24 (s, 1H), 8.22 (d, J¼8.0, 1H), 7.69e7.65 (n, 1H),
7.45e7.41 (m, 2H), 7.35e7.29 (m, 2H), 7.24e7.18 (m, 2H), 7.03e6.99
(m, 1H), 6.97e6.91 (m, 1H), 5.57e5.48 (m, 1H), 1.57 (d, J¼7.1, 3H);
13C NMR (100 MHz, DMSO-d6)
d: 165.4, 155.5, 153.9, 153.4, 144.8,
134.9, 129.3, 128.3 (2C), 127.8, 126.6, 126.1 (2C), 120.1, 119.6, 116.5,