E. Vanotti et al. / Tetrahedron 65 (2009) 10418–10423
10421
4.2.1.3. Step 3. To a suspension of the acid (4 g, 14.3 mmol) in
anhydrous THF (80 mL), DIPEA (5.5 g, 42.9 mmol) and anhydrous
DMF (8 mL), cooled in ice bath and under stirring, hydroxy-
benzotriazole ammonium salt (HOBT$NH3, 3.26 g, 21.4 mmol)
and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochlo-
ride (EDCI, 4.1 g, 21.4 mmol) were added. The reaction mixture
was stirred at room temperature overnight then it was poured
into a stirred 1:1 mixture of water and EtOAc. The organic phase
was washed with water, the aqueous layer was extracted with
EtOAc and the combined organic layers were washed with water,
dried over anhydrous Na2SO4 and concentrated, affording the
title compound as a precipitate that was filtered and washed
with little cold MeOH. The mother liquor was purified by flash
chromatography (DCM/MeOH/acetone 9:1:1), affording the de-
sired amide. The two product batches were combined, yielding
the title compound (1.71 g, 43%) as an orange powder, mp
225–228 ꢀC.
The title compound was obtained (27 mg, 64%) as a yellowish solid,
mp 136 ꢀC.
1H NMR (500 MHz, DMSO-d6)
d
ppm 1.07 (t, J¼7.1 Hz, 3H) 4.10
(q, J¼7.1 Hz, 2H) 6.56 (br s, 2H) 7.30 (d, J¼5.2 Hz, 1H) 7.37–7.49 (m,
5H) 8.32 (d, J¼5.2 Hz, 1H) 12.13 (br s, 1H); 13C NMR (125 MHz,
DMSO-d6): 13.6, 59.5, 67.0, 107.0, 127.7 (2C), 125.9, 128.0, 128.7 (2C),
130.8, 131.1, 138.6, 157.1, 158.3, 163.4, 164.0; IR 1430, 1456, 1563,
1636, 1698, 3141, 3293 nmax cmꢁ1; LCMS (ESI) m/z 435 (MþH)þ;
HRMS (ESI) calcd for C17H15IN4O2þHþ 435.0312, found 435.0308.
With similar procedures and starting from amide 1b, the fol-
lowing compounds were obtained.
4.2.5. 5-(2-Amino-5-chloro-pyrimidin-4-yl)-2-phenyl-1H-pyrrole-3-
carboxamide 3b. 100 ꢀC, 18 h, 72% yield, off white powder, mp 257–
260 ꢀC. 1H NMR (400 MHz, DMSO-d6): 6.62 (br s, 2H), 6.88 (br s,
1H), 7.40 (br s, 1H), 7.33–7.39 (m, 1H), 7.39–7.47 (m, 2H), 7.58 (d,
J¼2.6 Hz, 1H), 7.63–7.69 (m, 2H), 8.27 (s, 1H), 11.27 (br s, 1H); 13C
NMR (125 MHz, DMSO-d6): 112.5, 116.1, 118.5, 126.2, 127.8 (2C),
128.1, 129.2 (2C), 131.4, 136.5, 152.2, 158.5, 161.5, 166.2; IR 1442,
1H NMR (400 MHz, DMSO-d6)
d ppm 6.36 (s, 2H) 6.82 (br s, 1H)
7.02 (d, J¼5.2 Hz, 1H) 7.27 (d, J¼2.6 Hz, 1H) 7.32 (br s, 1H) 7.32–7.37
(m, 1H) 7.37–7.44 (m, 2H) 7.64 (dd, J¼8.3, 1.3 Hz, 2H) 8.20 (d,
J¼5.2 Hz, 1H) 11.63 (br s, 1H); 13C NMR (125 MHz, DMSO-d6): 106.2,
116.1, 118.4, 126.2, 126.7 (2C), 127.5, 128.2 (2C), 130.7, 136.5, 157.8,
1452, 1538, 1557, 1585, 1620,1646, 3166, 3362, 3481 nmax cmꢁ1
;
LCMS (ESI) m/z 314 (MþH)þ; HRMS (ESI) calcd for C15H12ClN5OþHþ
314.0803, found 314.0802.
158.2, 163.4, 167.8; IR 1456, 1480, 1557, 1643, 3117, 3317 nmax cmꢁ1
;
LCMS (ESI) m/z 280 (MþH)þ; HRMS (ESI) calcd for C15H13N5OþHþ
4.2.6. 5-(2-Amino-5-bromo-pyrimidin-4-yl)-2-phenyl-1H-pyrrole-3-
carboxamide 4b. Room temperature, 18 h, 75% yield, pale yellow
powder, mp 229–232 ꢀC. 1H NMR (400 MHz, DMSO-d6): 6.65 (br s,
2H) 6.89 (br s, 1H) 7.34–7.39 (m, 1H) 7.36 (br s, 1H) 7.39–7.46 (m,
2H) 7.64 (d, J¼2.7 Hz, 1H) 7.65–7.69 (m, 2H) 8.35 (s, 1H) 11.27 (br s,
1H); 13C NMR (125 MHz, DMSO-d6): 100.5, 115.3, 118.2, 127.0, 127.7
(2C), 128.0, 128.9 (2C), 131.7, 136.1, 153.7, 159.8, 161.8, 166.3; IR 1437,
1455, 1537, 1549, 1600, 1650, 3190, 3309, 3407 nmax cmꢁ1; LCMS
(ESI) m/z 358 (MþH)þ; HRMS (ESI) calcd for C15H12BrN5OþHþ
358.0298, found 358.0302.
280.1193, found 280.1189.
4.2.2. Ethyl 5-(2-amino-5-chloro-pyrimidin-4-yl)-2-phenyl-1H-pyr-
role-3-carboxylate 3a. To ester 1a (31 mg, 0.1 mmol) in dry DMF
(0.5 mL), under argon atmosphere, N-chlorosuccinimide (13 mg,
0.1 mmol) was added and the mixture was stirred at 80 ꢀC for 2 h.
The reaction mixture was poured into stirred water, the pre-
cipitate was filtered, washed thoroughly and dried, yielding the
title compound (20 mg, 58%) as an off white solid, mp
171–172 ꢀC.
1H NMR (400 MHz, DMSO-d6)
d
ppm 1.18 (t, J¼7.1 Hz, 3H) 4.14
4.2.7. 5-(2-Amino-pyrimidin-4-yl)-4-iodo-2-phenyl-1H-pyrrole-3-
carboxamide 5b. Room temperature, 4 h, 72% yield, pale yellow
powder, mp 244 ꢀC. 1H NMR (400 MHz, DMSO-d6): 6.49 (br s, 2H)
7.30 (d, J¼5.2 Hz, 1H) 7.33 (t, J¼7.4 Hz, 1H) 7.37 (br s, 1H) 7.42 (t,
J¼7.6 Hz, 2H) 7.54 (s, 1H) 7.64 (dd, J¼8.4, 1.2 Hz, 2H) 8.30 (d,
J¼5.2 Hz, 1H) 11.70 (s, 1H); 13C NMR (125 MHz, DMSO-d6): 66.3,
106.2, 126.2, 126.8 (2C), 127.5, 128.2 (2C), 129.6, 130.7, 132.2, 157.8,
158.2, 163.4, 167.9; IR 1451, 1556, 1570, 1617, 1658, 3174, 3366, 3415
nmax cmꢁ1; LCMS (ESI) m/z 406 (MþH)þ; HRMS (ESI) calcd for
C15H12IN5OþHþ 406.0159, found 406.0143.
(q, J¼7.1 Hz, 2H) 6.65 (br s, 2H) 7.39–7.48 (m, 3H) 7.55 (d, J¼2.7 Hz,
1H) 7.59–7.66 (m, 2H) 8.30 (s, 1H) 11.70 (br s, 1H); 13C NMR
(125 MHz, DMSO-d6): 13.8, 59.2, 112.5, 113.2, 116.7, 116.9, 126.6,
127.5, 128.4 (2C), 129.7 (2C),139.3, 151.6, 158.5, 161.5, 163.6; IR 1456,
1484, 1543, 1560, 1633, 1646, 1702, 3162, 3297, 3419 nmax cmꢁ1
;
LCMS (ESI) m/z 343 (MþH)þ; HRMS (ESI) calcd for
C17H15ClN4O2þHþ 343.0956, found 343.0968.
4.2.3. Ethyl 5-(2-amino-5-bromo-pyrimidin-4-yl)-2-phenyl-1H-pyr-
role-3-carboxylate 4a. To ester 1a (31 mg, 0.1 mmol) in dry DMF
(0.5 mL), under argon atmosphere, N-bromosuccinimide (18 mg,
0.1 mmol) was added and the mixture was stirred at room tem-
perature for 1 h. The reaction mixture was poured into stirred
water, the precipitate was filtered, washed thoroughly and dried.
The title compound was obtained (25 mg, 65%) as a white solid, mp
169 ꢀC.
4.2.8. Ethyl 5-(2-amino-5-iodo-pyrimidin-4-yl)-2-phenyl-1H-pyr-
role-3-carboxylate 6a. Ester 1a (308 mg, 1 mmol) and iodine
(279 mg, 1.1 mmol) in dry DMF (2 mL), under a nitrogen atmo-
sphere, stirred at –40 ꢀC were treated dropwise with silver tri-
fluoroacetate (243 mg, 1.1 mmol) in DMF (4 mL). The mixture was
stirred at ꢁ40 ꢀC for 6 h and then filtered. The filtrate was diluted
with EtOAc (150 mL), washed with 10% Na2S2O3, dried over sodium
sulfate, evaporated and purified by flash chromatography over sil-
ica gel (DCM/MeOH 95:5) to give the title compound (220 mg, 50%)
as a pale yellow solid, mp 156 ꢀC.
1H NMR (400 MHz, DMSO-d6)
d
ppm 1.18 (t, J¼7.1 Hz, 3H) 4.14
(q, J¼7.1 Hz, 2H) 6.67 (br s, 2H) 7.39–7.48 (m, 3H) 7.59–7.64 (m, 2H)
7.66 (d, J¼2.7 Hz, 1H) 8.38 (s, 1H) 11.69 (br s, 1H); 13C NMR
(125 MHz, DMSO-d6): 13.8, 58.8, 101.0, 113.0, 116.1, 116.3, 127.3 (2C),
127.7, 128.1, 129.3 (2C), 139.4, 153.2, 160.4, 161.9, 163.4; IR 1457,
1481, 1540, 1556, 1635, 1712, 3145, 3293, 3427 nmax cmꢁ1; LCMS
(ESI) m/z 387 (MþH)þ; HRMS (ESI) calcd for C17H15BrN4O2þHþ
387.0451, found 387.0457.
1H NMR (400 MHz, DMSO-d6)
d
ppm 1.18 (t, J¼7.1 Hz, 3H) 4.14
(q, J¼7.1 Hz, 2H) 6.65 (br s, 2H) 7.38–7.48 (m, 3H) 7.60–7.66 (m, 2H)
7.77 (d, 1H) 8.52 (s, 1H) 11.65 (br s, 1H); 13C NMR (125 MHz, DMSO-
d6): 13.9, 60.0, 71.2, 113.1, 118.0, 127.7 (3C), 128.7 (2C), 128.8, 130.9,
135.5, 156.3, 161.9, 163.3, 166.6; IR 1456, 1480, 1532, 1548, 1636,
1670, 1711, 3158, 3288, 3423 nmax cmꢁ1; LCMS (ESI) m/z 435
(MþH)þ; HRMS (ESI) calcd for C17H15IN4O2þHþ 435.0313, found
435.0319.
4.2.4. Ethyl 5-(2-amino-pyrimidin-4-yl)-4-iodo-2-phenyl-1H-pyr-
role-3-carboxylate 5a. To ester 1a (31 mg, 0.1 mmol) in dry DMF
(0.5 mL), under argon atmosphere, N-iodosuccinimide (18 mg,
0.08 mmol) was added and the mixture was stirred at room tem-
perature overnight. The reaction mixture was poured into stirred
water, the precipitate was filtered, washed thoroughly and dried.
4.2.9. 5-(2-Amino-5-iodo-pyrimidin-4-yl)-2-phenyl-1H-pyrrole-3-
carboxamide 6b. Amide 1b (279 mg, 1 mmol) and iodine (267 mg,