Cycloaddition of Pyrrolo[1,2-c]pyrimidinium Ylides
J . Org. Chem., Vol. 64, No. 21, 1999 7799
(d, 2H, J ) 7.3 Hz), 7.98 (d, 1H, J ) 7.7 Hz), 7.81-7.76 (m,
1H), 7.67-7.62 (m, 2H), 7.59 (d, 1H, J ) 7.7 Hz), 7.42 (dd,
1H, H6, J ) 3.7, 2.5 Hz), 7.05 (d, 1H, J ) 3.7 Hz), 6.21 (s, 2H);
13C NMR (50 MHz, DMSO-d6) δ 190.9, 145.7, 134.7, 133.5,
129.0, 128.3, 128.1, 124.5, 122.6, 118.1, 114.3, 105.8, 62.0.
Anal. Calcd for C15H13BrN2O: C, 56.80; H, 4.13; N, 8.83.
Found: C, 56.49; H, 4.65; N, 8.60.
2-[(E t h oxyca r b on yl)m et h yl]p yr r olo[1,2-c]p yr im id in -
iu m Br om id e (21). Ethyl bromoacetate (1.5 g, 9.0 mmol) was
added to a solution of 1a (1.0 g, 8.47 mmol) in CH3CN (20 mL),
and the mixture was refluxed for 5 h. The resulting precipitate
was filtered off, washed with Et2O, and recrystallized from
EtOH to give 1.35 g (56%) of the title salt as a brown powder:
mp 165-167 °C; IR (KBr) 1742, 1647, 1231; 1H NMR (300
MHz, DMSO-d6) 10.41 (s, 1H), 8.14 (d, 1H, H7, J ) 2.9 Hz),
7.94 (d, 1H, J ) 7.6 Hz), 7.61 (d, 1H, J ) 7.6 Hz), 7.40 (dd,
1H, J ) 3.7, 2.9 Hz), 7.01 (d, 1H, J ) 3.7 Hz), 5.39 (s, 2H),
4.22 (q, 2H, J ) 7.2 Hz), 1.24 (t, 3H, J ) 7.2 Hz); 13C NMR (50
MHz, DMSO-d6) 166.4, 145.9, 128.0, 124.2, 122.8, 118.3, 114.2,
106.0, 62.2, 56.3, 14.1. Anal. Calcd for C11H13BrN2O2: C, 46.34;
H, 4.60; N, 9.82. Found: C, 46.21; H, 4.79; N, 9.72.
2-[(Tr im e t h ylsilyl)m e t h yl]p yr r olo[1,2-c]p yr im id in -
iu m Tr iflu or om eth a n esu lfon a te (22). A mixture of 1a (0.2
g, 1.70 mmol) and (trimethylsilyl)methyl trifluoromethane-
sulfonate (0.44 g, 1.86 mmol) in 10 mL of dry CH2Cl2 was
stirred at room temperature under argon for 3 h. The solvent
was removed under reduced pressure, and the residue was
treated with Et2O. The solid was filtered off, washed with Et2O,
and recrystallized from EtOH to give 373 mg (62%) of 22 as a
brown solid: mp 135-136 °C (EtOH); IR (KBr) 1647, 1278,
1029 cm-1; 1H NMR (300 MHz, DMSO-d6) δ 10.20 (s, 1H), 8.04
(d, 1H, J ) 2.7 Hz), 7.92 (d, 1H, J ) 7.3 Hz), 7.46 (d, 1H, J )
7.3 Hz), 7.33 (dd, 1H, J ) 4.1, 2.7 Hz), 6.97 (d, 1H, J ) 4.1
Hz), 4.08 (s, 2H), 0.16 (s, 9H); 13C NMR (50 MHz, DMSO-d6)
δ 142.3, 127.9, 123.9, 121.5, 117.7, 115.3, 107.6, 105.3, 48.9,
-2.9. Anal. Calcd for C12H17F3N2O3SSi: C, 40.67; H, 4.83; N,
7.90. Found: C, 40.93; H, 4.76; N, 7.77.
δ 197.8, 171.8, 163.8, 134.9, 134.7, 129.2, 129.2, 127.9, 117.8,
116.9, 112.8, 110.9, 106.7, 104.3, 102.0, 53.4, 53.1, 51.3.
3-Ben zoyl-1,2-d im eth oxyca r bon yld ip yr r olo[1,2-a ;1′,2′-
c]p yr im id in e (27): mp 171-173 °C (EtOH); IR (KBr) 1727,
1638, 1519, 1214; 1H NMR (300 MHz, CDCl3) 8.65 (d, 1H, J )
2.5 Hz), 8.29 (d, 1H, J ) 8.0 Hz), 7.72 (d, 2H, J ) 7.0 Hz),
7.58-7.53 (m, 1H), 7.46-7.41 (m, 2H), 6.94 (d, 1H, J ) 8.0
Hz), 6.75 (dd, 1H, J ) 4.0, 2.5 Hz), 6.56 (dd, 1H, J ) 4.0, 1.1
Hz), 3.85 (s, 3H), 3.23 (s, 3H); MS m/z (rel int) 376 (M+, 100),
313 (15). Anal. Calcd for C21H16N2O5: C, 67.02; H, 4.28; N,
7.44. Found: C, 67.42; H, 4.19; N, 7.35.
Rea ction w ith Meth yl P r op iola te. A mixture of 20 (0.4
g, 1.26 mmol) and methyl propiolate (0.26 g, 3.15 mmol) in
CH2Cl2 (25 mL) and 50% aqueous K2CO3 (15 mL) was stirred
at room temperature for 8 h. The organic phase was then
separated, and the organic layer was extracted with CH2Cl2.
The combined organic phases were washed with H2O and
brine. The organic phase was dried over Na2SO4 and concen-
trated under reduced pressure to yield a dark oil. Chroma-
tography (hexane/EtOAc 8:2) allowed the separation of the
dihydro derivative 28a (64 mg, 16%) as a yellow oil and 29a
(85 mg, 21%) as a yellow solid.
3-Ben zoyl-1-m eth oxycar bon yl-3,10a-dih ydr odipyr r olo-
[1,2-a ;1′,2′-c]p yr im id in e (28a ): IR (KBr) 1722, 1702, 1640,
1260, 1236 cm-1; 1H NMR (300 MHz, CDCl3) δ 8.11-8.07 (m,
1H), 7.84 (d, 2H, J ) 8.0 Hz), 7.68 (d, 1H, J ) 1.7 Hz), 7.58-
7.44 (m, 3H), 7.30 (d, 1H, J ) 1.7 Hz), 6.81 (d, 1H, J ) 8.5
Hz), 6.68 (dd, 1H, J ) 4.1, 2.7 Hz), 6.38 (d, 1H, J ) 8.5 Hz),
6.12 (dd, 1H, J ) 6.1, 2.6 Hz), 5.93 (dd, 1H, J ) 4.1, 1.5 Hz),
3.83 (s, 3H); 13C NMR (50 MHz, CDCl3) δ 185.5, 163.9, 138.1,
133.2, 132.4, 129.3, 128.4, 125.2, 122.1, 120.6, 119.9, 118.1,
116.9, 111.5, 109.8, 51.5; MS m/z (rel int) 320 (M+, 39), 215
(49), 105 (100). Anal. Calcd for C19H16N2O3: C, 71.24; H, 5.03;
N, 8.74. Found: C, 70.82; H, 4.93; N, 9.13.
3-Ben zoyl-1-m et h oxyca r b on yld ip yr r olo[1,2-a ;1′,2′-c]-
p yr im id in e (29a ): mp 153-155 °C (EtOH); IR (KBr) 1715,
1
1620, 1211, 1178 cm-1; H NMR (300 MHz, CDCl3) δ 9.18 (d,
2-Am in op yr r olo[1,2-c]p yr im id in iu m Mesit ylen esu l-
fon a te (23). 1a (0.25 g, 2.10 mmol) in 3 mL of dry CH2Cl2
was added to a solution of MSH (0.45 g, 2.10 mmol) in 5 mL
of dry CH2Cl2 at 0 °C, and the reaction mixture was stirred
for 1 h at that temperature. The precipitate that formed was
filtered off and washed with Et2O to give 290 mg (41%) of 23:
mp 151-153 °C (brown powder, EtOH); IR (KBr) 3240, 1610,
1220 cm-1; 1H NMR (300 MHz, DMSO-d6) δ 10.27 (s, 1H), 8.00
(d, 1H, J ) 2.5 Hz), 7.84 (d, 1H, J ) 7.4 Hz), 7.49 (d, 1H, J )
7.4 Hz), 7.30 (dd, 1H, J ) 3.7, 2.5 Hz), 6.95 (d, 1H, J ) 3.7
Hz), 6.72 (s, 2H), 2.48 (s, 6H), 2.15 (s, 3H). Anal. Calcd for
1H, J ) 2.8 Hz), 8.91 (d, 1H, J ) 7.9 Hz), 7.82 (d, 2H, J ) 7.7
Hz), 7.60-7.53 (m,3H), 7.52 (s, 1H), 6.99 (d, 1H, J ) 7.9 Hz),
6.80 (dd, 1H, J ) 3.7, 2.8 Hz), 6.59 (dd, 1H, J ) 3.7, 1.1 Hz),
3.88 (s, 3H); 13C NMR (50 MHz, CDCl3) δ 185.8, 163.8, 139.5,
131.9, 129.2, 128.5, 127.8, 127.6, 119.6, 118.1, 114.2, 113.0,
106.9, 104.2, 100.0, 51.9; MS m/z (rel int) 318 (M+, 57), 105
(52), 77 (100). Anal. Calcd for C19H14N2O3: C, 71.69; H, 4.43;
N, 8.80. Found: C, 71.56; H, 4.56; N, 8.97.
Rea ction w ith Eth yl P r op iola te. Ethyl propiolate (0.27
g; 2.84 mmol) was added to a suspension of 20 (0.3 g, 0.95
mmol) in CH2Cl2 (20 mL) and 50% K2CO3 (10 mL). The
reaction mixture was stirred for 15 h, and then the organic
phase was separated, washed with water and brine, and dried
over Na2SO4. The solvent was removed under reduced pres-
sure, and the crude extract was purified by chromatography.
Elution with hexane/EtOAc (8:2) allowed the separation of the
dihydro derivative 28b (60 mg, 19%) as an oil and the product
29b as a white solid (104 mg, 33%).
C
16H19N3O3S: C, 57.64; H, 5.74; N, 12.60. Found: C, 57.78;
H, 5.98; N, 12.44.
Dip ola r Cycloa d d ition Rea ction s of 20. Rea ction w ith
DMAD. DMAD (0.45 g, 3.15 mmol) and 50% aqueous K2CO3
(13 mL) were added to a suspension of 0.4 g (1.26 mmol) of 20
in CH2Cl2 (25 mL). The mixture was stirred at room temper-
ature for 12 h, and then the organic phase was separated,
washed with water and brine, and dried over Na2SO4. After
the solvent was removed under reduced pressure, the oily
residue was chromatographed. Elution with hexane/EtOAc 9:1
and 8:2 allowed the separation of the dihydro derivative 26
(130 mg, 28%) as a yellowish oil and the fully aromatized 27
(66 mg, 14%) as a white solid.
Compound 27 was also obtained by treatment of the mixture
of 26 and 27 (185 mg) with DDQ (120 mg, 0.51 mmol) in
CH2Cl2 (10 mL) by stirring the mixture for 2 h at room
temperature. Compound 27 (185 mg, 40% from 20) was
purified using silica gel chromatography with CH2Cl2 as
eluent.
3-Ben zoyl-1-eth oxyca r bon yl-3,10a -d ih yd r od ip yr r olo-
[1,2-a ;1′,2′-c]p yr im id in e (28b): IR (KBr) 1728, 1700, 1272,
1
1230 cm-1; H NMR (300 MHz, CDCl3) δ 8.07-8.03 (m, 1H),
7.83 (d, 2H, J ) 7.3 Hz), 7.67 (d, 1H, J ) 1.4 Hz), 7.60-7.54
(m, 1H), 7.50-7.45 (m, 2H), 7.29 (d, 1H, J ) 1.4 Hz), 6.80 (d,
1H, J ) 8.4 Hz), 6.68-6.65 (m, 1H), 6.38 (d, 1H, J ) 8.4 Hz),
6.12 (app t, 1H, J ) 2.8 Hz), 5.94-5.92 (m, 1H), 4.29 (c, 2H, J
) 7.2 Hz), 1.33 (t, 3H, J ) 7.2 Hz); 13C NMR (50 MHz, CDCl3)
δ 185.5,163.6, 138.2, 133.1, 132.4, 129.3, 128.4, 125.3, 122.1,
120.6, 120.0, 118.2, 117.4, 111.7, 109.9, 60.5, 14.4. Anal. Calcd
for C20H18N2O3: C, 71.84; H, 5.43; N, 8.38. Found: C, 71.98;
H, 5.49; N, 8.09.
(2R,3S)- a n d (2S,3R)-3-ben zoyl-1,2-d im eth oxyca r bon yl-
2,3-dih ydr odipyr r olo[1,2-a ;1′,2′-c]pyr im idin e (26): IR (KBr)
3-Be n zoyl-1-e t h oxyca r b on yld ip yr r olo[1,2-a ;1′,2′-c]-
p yr im id in e (29b): mp 140-142 °C; IR (KBr) 1706, 1621,
1
1732, 1680, 1633, 1217 cm-1
;
1H NMR (300 MHz, CDCl3) δ
1213, 1186 cm-1; H NMR (300 MHz, CDCl3) δ 9.17 (d, 1H, J
8.01 (d, 2H, J ) 7.1 Hz), 7.66-7.63 (m, 1H), 7.56-7.49 (m,
2H), 6.86 (d, 1H, J ) 2.7 Hz), 6.28 (dd, 1H, J ) 3.5, 2.7 Hz),
6.18 (d, 1H, J ) 8.7 Hz), 6.05 (dd, 1H, J ) 3.5, 1.3 Hz), 5.99
(d, 1H, J ) 7.4 Hz), 5.83 (d, 1H, J ) 7.4 Hz), 4.76 (d, 1H, J )
8.7 Hz), 3.90 (s, 3H), 3.45 (s, 3H); 13C NMR (50 MHz, CDCl3)
) 2.1 Hz), 8.89 (d, 1H, J ) 7.7 Hz), 7.83 (d, 2H, J ) 7.5 Hz),
7.60-7.52 (m, 3H), 7.51 (s, 1H), 6.96 (d, 1H, J ) 7.7 Hz), 6.78
(dd, 1H, J ) 3.8, 2.1 Hz), 6.56 (d, 1H, J ) 3.8 Hz), 4.33 (q, 2H,
13
J ) 7.1 Hz), 1.35 (t, 3H, J ) 7.1 Hz);
C NMR (50 MHz,
CDCl3) δ 185.7, 163.1, 139.4,131.9, 129.1, 128.4, 127.6, 121.3,