I. Samb et al. / Tetrahedron 65 (2009) 896–902
901
(KBr) nmax 2921, 1693 cmꢁ1
;
1H NMR (250 MHz, CDCl3)
d
3.62 (s,
Rf¼0.66 (CH2Cl2/MeOH, 99:1); [
a
]
D ꢁ40.7 (c 1.0, CHCl3); IR (KBr) nmax
3H), 3.98 (app t, 1H, J¼9.8 Hz), 4.22 (app td, 1H, J¼9.8, 4.7 Hz),
4.48 (dd, 1H, J¼9.8, 4.7 Hz), 4.72 (d, 1H, J¼9.8 Hz), 5.59 (s, 1H),
5.80 (s, 1H), 6.56 (dd, 1H, J¼3.6, 1.8 Hz), 7.35–7.45 (m, 4H), 7.55–
2916, 1580 cmꢁ1; 1H NMR (250 MHz, CDCl3)
d 3.60 (s, 3H), 3.98 (app
t, 1H, J¼9.8 Hz), 4.19 (app td, 1H, J¼9.8, 4.7 Hz), 4.47 (dd, 1H, J¼9.8,
4.7 Hz), 4.70 (d, 1H, J¼9.8 Hz), 5.58 (s, 1H), 5.81 (s,1H), 7.13 (dd, 1H,
J¼5.1, 3.6 Hz), 7.38–7.45 (m, 3H), 7.49 (dd, 1H, J¼5.1, 1.1 Hz), 7.60–7.65
(m, 2H), 8.06 (dd, 1H, J¼3.6, 1.1 Hz), 8.59 (s, 1H); 13C NMR (62.9 MHz,
7.65 (m, 3H), 8.65 (s, 1H); 13C NMR (62.9 MHz, CDCl3)
d 56.4, 63.2,
69.4, 76.0, 96.6, 102.8, 112.5, 114.8, 124.5, 126.7, 128.4, 129.4, 137.1,
145.6, 151.8, 156.9, 157.8, 161.5; MS (CI) m/z 367 (50, [MþH]þ), 367
(54), 355 (25), 289 (15), 217 (34), 149 (100); HRMS (ESIþ) calcu-
lated for C20H18N2NaO5 [MþNa]þ: 389.1108, found: 389.1126.
CDCl3)
d 56.3, 63.1, 69.4, 76.0, 96.7, 102.5, 124.3, 126.6, 128.4, 129.3,
130.2, 130.6, 137.2, 142.8, 156.8, 161.3, 161.7; MS (CI) m/z 382 (46,
[M]þ), 351 (22), 233 (25), 149 (100); HRMS (ESIþ) calculated for
C20H19N2O4S [MþH]þ: 383.1060, found: 383.1075.
4.6.2.7. (2R,4aR,6S,10bS)-4,4a,6,10b-Tetrahydro-6-methoxy-2-phenyl-
9-(4-(methoxycarbonyl)phenyl)-1,3-dioxino[40,50:5,6]pyrano[4,3-d]-
pyrimidine (6g). Yield: 63% (method C) as white crystals; mp
4.7.2.3. E-(2R,4aR,6S,10bS)-4,4a,6,10b-Tetrahydro-6-methoxy-2-phen-
yl-9-(styryl)-1,3-dioxino[40,50:5,6]pyrano[4,3-d]pyrimidine (6j). Yield:
65% (method A), 71% (method B) as white crystals; mp 209–210 ꢀC;
224–225 ꢀC; Rf¼0.40 (CH2Cl2/MeOH, 98:2); [
a
]
D
ꢁ13.6 (c 1.0,
CHCl3); IR (KBr) nmax 2921, 1720 cmꢁ1
;
1H NMR (250 MHz, CDCl3)
Rf¼0.45 (hexane/EtOAc, 50:50); [
a]
D
ꢁ13.0 (c 1.0, CHCl3); IR (KBr)
d
3.63 (s, 3H), 3.94 (s, 3H), 4.01 (app t, 1H, J¼9.8 Hz), 4.25 (app td,
nmax 2916, 1580 cmꢁ1; 1H NMR (250 MHz, CDCl3)
d 3.62 (s, 3H), 3.99
1H, J¼9.8, 4.7 Hz), 4.49 (dd,1H, J¼9.8, 4.7 Hz), 4.76 (d, 1H, J¼9.8 Hz),
5.63 (s, 1H), 5.83 (s, 1H), 7.40–7.50 (m, 2H), 7.60–7.65 (m, 2H), 8.13
(d, 2H, J¼8.4 Hz), 8.54 (d, 2H, J¼8.5 Hz), 8.73 (s, 1H); 13C NMR
(app t, 1H, J¼9.8 Hz), 4.23 (app td, 1H, J¼9.8, 4.7 Hz), 4.47 (dd, 1H,
J¼9.8, 4.7 Hz), 4.72 (d, 1H, J¼9.8 Hz), 5.59 (s, 1H), 5.81 (s, 1H), 7.27–
7.45 (m, 7H), 7.55–7.65 (m, 4H), 8.02 (d, 1H, J¼15.7 Hz), 8.63 (s, 1H);
(62.9 MHz, CDCl3)
d
52.4, 56.5, 63.2, 69.4, 76.1, 96.6, 102.6, 125.6,
13C NMR (62.9 MHz, CDCl3)
d 56.4, 63.1, 69.4, 76.1, 96.6, 103.0, 124.3,
126.6, 128.5, 128.7, 129.4, 129.9, 132.3, 137.1, 141.2, 156.9, 161.4,
164.0, 167.0; HRMS (ESIþ) calculated for C24H22N2O6Na [MþNa]þ:
457.1370, found: 457.1382.
126.8, 127.2, 127.9, 128.4, 128.9, 129.4, 129.5, 136.0, 137.1, 139.3, 156.5,
161.0, 165.1; MS (ES) m/z 425 (30, [MþNa]þ), 403 (68), 280 (100);
HRMS (ESIþ) calculated for C24H23N2O4 [MþHþ]: 403.1652, found:
403.1647.
4.7. General procedure for Stille cross-coupling (6h–l)
4.7.2.4. (2R,4aR,6S,10bS)-4,4a,6,10b-Tetrahydro-6-methoxy-2-phenyl-
9-(2-E-(methoxycarbonyl)ethenyl)-1,3-dioxino[40,50:5,6]pyrano[4,3-d]-
pyrimidine (6k). Yield: 46% (method A), 78% (method B) as white
4.7.1. Conventional heating
In a dry round-bottomed flask equipped with a condenser
flushed with argon, 5 mL of dry DME, compound 4 (300 mg,
0.87 mmol), Pd(PPh3)4 (5 mol %), CuBr$Me2S (392 mg,1.9 mmol), n-
tributylstannane (1.9 mmol) were stirred and heated at 80 ꢀC until
reaction completion. The mixture was diluted with an aqueous so-
lution of KF (20%) (20 mL) and extracted with CH2Cl2 (3ꢂ20 mL). The
dried organic layer was evaporated under reduced pressure and the
residue was purified by column chromatography on silica gel.
crystals; mp 225–226 ꢀC; Rf¼0.35 (hexane/EtOAc, 50:50); [
D ꢁ7.3
a
]
(c 1.0, CHCl3); IR (KBr) nmax 2916, 1723 cmꢁ1 1H NMR (250 MHz,
;
CDCl3)
d
3.62 (s, 3H), 3.82 (s, 3H), 3.98 (app t, 1H, J¼9.9 Hz), 4.21
(app td, 1H, J¼9.9, 4.7 Hz), 4.48 (dd, 1H, J¼9.9, 4.7 Hz), 4.72 (d, 1H,
J¼9.9 Hz), 5.60 (s, 1H), 5.80 (s, 1H), 7.22 (d, 1H, J¼15.7 Hz), 7.38–7.45
(m, 3H), 7.54–7.65 (m, 2H), 7.75 (d, 1H, J¼15.7 Hz), 8.68 (s, 1H); 13C
NMR (62.9 MHz, CDCl3)
d 52.1, 56.5, 63.1, 69.3, 75.9, 96.4, 102.8,
126.2, 126.6, 128.0, 128.5, 129.5, 136.9, 142.6, 156.8, 161.3, 163.0,
166.7; MS (ES) m/z 407 (100, [MþNa]þ), 385 (45); HRMS (ESIþ)
calculated for C20H20N2NaO6 [MþNa]þ: 407.1214, found: 407.1244.
4.7.2. Microwave irradiation
In a dry round-bottomed flask equipped with a condenser
flushed with argon, 5 mL of dry DMF, compound 4 (300 mg,
0.87 mmol), Pd(PPh3)4 (5 mol %), CuBr$Me2S (392 mg, 1.9 mmol),
n-tributylstannane (1.9 mmol) were stirred and heated by micro-
wave irradiation at constant temperature (80 ꢀC controlled by
a standard external IR-sensor). All reactions were completed within
5–8 min. The reaction was then allowed to cool to room tempera-
ture and was evaporated to dryness under reduced pressure. The
residue was diluted with aqueous solution of KF (20%) (20 mL) and
extracted with CH2Cl2 (3ꢂ20 mL). The dried organic layer was
evaporated under reduced pressure and the residue was purified by
column chromatography on silica gel.
4.7.2.5. (2R,4aR,6S,10bS)-4,4a,6,10b-Tetrahydro-6-methoxy-2-phenyl-
9-(2-Z-(methoxycarbonyl)ethenyl)-1,3-dioxino[40,50:5,6]pyrano[4,3-d]-
pyrimidine (6k). Yield: 9% (method A), 35% (method B) as white
crystals; mp 141–142 ꢀC; Rf¼0.25 (hexane/EtOAc, 50:50); [
D ꢁ1.2
a
]
(c 1.0, CHCl3); IR (KBr) nmax 2932, 1728 cmꢁ1 1H NMR (250 MHz,
;
CDCl3)
d
3.47 (s, 3H), 3.60 (s, 3H), 3.95 (app t, 1H, J¼9.8 Hz), 4.19
(app td, 1H, J¼9.8, 4.8 Hz), 4.45 (dd, 1H, J¼9.8, 4.8 Hz), 4.68 (d, 1H,
J¼9.8 Hz), 5.56 (s, 1H), 5.75 (s, 1H), 6.34 (d, 1H, J¼12.0 Hz), 6.87 (d,
1H, J¼12.0 Hz), 7.35–7.45 (m, 3H), 7.55–7.62 (m, 2H), 8.61 (s, 1H);
13C NMR (62.9 MHz, CDCl3)
d 52.0, 56.5, 63.1, 69.5, 76.0, 96.5, 103.1,
125.5, 126.9, 128.4, 128.9, 129.6, 133.9, 137.0, 156.5, 161.0, 162.9,
168.0; MS (CI) m/z 423 (18, [MþK]þ), 407 (100), 193 (30); HRMS
(ESIþ) calculated for C20H20N2NaO6 [MþNa]þ: 407.1214, found:
407.1245.
4.7.2.1. (2R,4aR,6S,10bS)-4,4a,6,10b-Tetrahydro-6-methoxy-2-phenyl-
9-vinyl-1,3-dioxino[40,50:5,6]pyrano[4,3-d]pyrimidine (6h). Yield:
45% (method A) as white crystals; mp 284–285 ꢀC; Rf¼0.55 (CH2Cl2/
MeOH, 99:1); [
a]
þ7.3 (c 1.05, CHCl3); IR (KBr) nmax 2916, 1583,
D
1543 cmꢁ1; 1H NMR (250 MHz, CDCl3)
d
3.61 (s, 3H), 3.97 (app t, 1H,
4.7.2.6. (2R,4aR,6S,10bS)-4,4a,6,10b-Tetrahydro-6-methoxy-2-phenyl-
9-(1-(3-E-(tert-butoxycarbonylamino)propenyl))-1,3-dioxino[40,50:5,6]-
pyrano[4,3-d]pyrimidine (6l). Yield: 45% (method A), 58% (method
B) as white crystals; mp 295–296 ꢀC; Rf¼0.48 (hexane/EtOAc,
J¼9.8 Hz), 4.20 (app td, 1H, J¼9.8, 4.7 Hz), 4.46 (dd, 1H, J¼4.7,
9.8 Hz), 4.70 (d, 1H, J¼9.8 Hz), 5.58 (s, 1H), 5.75 (dd, 1H, J¼10.6,
1.8 Hz), 5.79 (s, 1H), 6.67 (dd, 1H, J¼1.8, 17.5 Hz), 6.93 (dd, 2H,
J¼10.6, 17.5 Hz), 7.35–7.45 (m, 3H), 7.55–7.65 (m, 2H), 8.61 (s, 1H);
50:50); [
a
]
þ4.7 (c 1.0, CHCl3); IR (KBr) nmax 3320, 2921,
D
13C NMR (62.9 MHz, CDCl3)
d
56.5, 63.2, 69.5, 76.1, 96.7, 102.9, 125.2,
1677 cmꢁ1 1H NMR (250 MHz, CDCl3)
; d 1.45 (s, 9H), 3.60 (s, 3H),
126.8, 128.4, 129.5, 136.4, 137.1, 156.7, 161.0, 164.7; HRMS (ESIþ)
3.96 (app t, 1H, J¼9.8 Hz), 3.98–4.05 (m, 2H), 4.20 (app td, 1H, J¼9.8,
4.7 Hz), 4.46 (dd, 1H, J¼9.8, 4.7 Hz), 4.68 (d, 1H, J¼9.8 Hz), 5.57 (s,
1H), 5.78 (s, 1H), 6.74 (d, 1H, J¼15.7 Hz), 7.18 (dt, 1H, J¼15.7, 4.7 Hz),
7.35–7.45 (m, 3H), 7.55–7.65 (m, 2H), 8.58 (s, 1H); 13C NMR
calculated for C18H19N2O4 [MþH]þ: 327.1339, found: 327.1337.
4.7.2.2. (2R,4aR,6S,10bS)-4,4a,6,10b-Tetrahydro-6-methoxy-2-phenyl-
9-(2-thienyl)-1,3-dioxino[40,50:5,6]pyrano[4,3-d]pyrimidine (6i). Yield:
55% (method A), 85% (method B) as white crystals; mp 260–271 ꢀC;
(62.9 MHz, CDCl3)
d 28.5, 42.0, 56.4, 63.1, 69.4, 76.0, 79.7, 96.6,
102.9, 124.7, 126.7, 128.4, 129.4, 129.5, 137.0, 138.8, 155.7, 156.6,