Phosphonium-Mediated SNAr Reactions
NMR (100 MHz, CDCl3) δ 164.6, 163.5, 153.5, 151.9, 140.8, 136.9,
134.9, 129.7, 124.6, 121.0, 114.6; HRMS (ESI) m/z calcd for
C11H7N6OS (M + H+) 271.0397, found 271.0390.
1H), 8.50-8.48 (m, 2H), 7.49 (dd, J ) 4.4, 8.8 Hz, 1H), 7.35 (d,
J ) 1.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 169.9, 163.1,
158.3, 152.0, 141.1, 134.9, 129.7, 121.1, 106.7; HRMS (ESI) m/z
calcd for C9H6ClN6O (M + H+) 249.0286, found 249.0282.
4,6-Bis(1H-benzo[d][1,2,3]triazol-1-yloxy)pyrimidine (34a).
Synthesized according to General Method A (reaction mixture
stirred for 8 h at rt) from 6-chloro-3H-pyrimidin-4-one 27 and
purified by flash chromatography as a white solid (110 mg, 31%):
1H NMR (400 MHz, DMSO-d6) δ 8.45 (d, J ) 0.8 Hz, 1H), 8.20
(d, J ) 8.4 Hz, 2H), 7.87-7.86 (m, 2H), 7.84 (s, 1H), 7.71-7.67
(m, 2H), 7.58-7.56 (m, 2H); 13C NMR (100 MHz, DMSO-d6) δ
171.3, 158.7, 143.0, 129.8, 128.5, 125.8, 120.3, 109.7, 90.7; HRMS
(ESI) m/z calcd for C16H11N8O2 (M + H+) 347.0999, found
347.1005.
4-(Benzotriazol-1-yloxy)-5-methylthieno[2,3-d]pyrimidine-6-
carboxylic Acid Methyl Ester (29a). Synthesized according to
General Method A (reaction mixture stirred for 12 h at rt) from
5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylic acid
methyl ester 23 and purified by flash chromatography as a yellow
solid (260 mg, 76%): 1H NMR (400 MHz, DMSO-d6) δ 8.71 (s,
1H), 8.21 (dd, J ) 0.8, 7.6 Hz, 1H), 7.92-7.90 (m, 1H), 7.67-
7.56 (m, 2H), 3.96 (s, 3H), 3.10 (s, 3H); 13C NMR (100 MHz,
DMSO-d6) δ 169.0, 164.7, 162.3, 155.0, 143.0, 138.7, 129.6, 128.7,
126.5, 125.8, 120.2, 118.3, 110.1, 53.2, 16.0; HRMS (ESI) m/z calcd
for C15H12N5O3S (M + H+) 342.0655, found 342.0659.
5-Methyl-4-(1,2,3-triazolo[4,5-b]pyridin-3-yloxy)thieno[2,3-d]-
pyrimidine-6-carboxylic Acid Methyl Ester (29b). Synthesized
according to General Method B (reaction mixture stirred for 12 h
at rt) from 5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-
carboxylic acid methyl ester 23 and purified by flash chromatog-
raphy as a yellow solid (1.25 g, 91%): 1H NMR (400 MHz, CDCl3)
δ 8.72 (dd, J ) 0.8, 4.0 Hz, 1H), 8.52 (dd, J ) 1.2, 8.0 Hz. 1H),
8.49 (s, 1H), 7.50 (dd, J ) 4.0, 8.1 Hz, 1H), 4.00 (s, 3H), 3.19 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 170.0, 164.6, 162.5, 154.1,
151.9, 140.8, 138.3, 135.0, 129.7, 127.5, 121.0, 118.1, 52.7, 15.9;
HRMS (ESI) m/z calcd for C14H11N6O3S (M + H+) 343.0608, found
343.0600.
1-(4-Methylpyrimidin-2-yloxy)-1H-benzotriazole (30). Syn-
thesized according to General Method A (reaction mixture stirred
for 12 h at rt) from 4-methylpyrimidin-2(1H)-one 24 and purified
by flash chromatography as a white solid (160 mg, 70%): 1H NMR
(400 MHz, DMSO-d6) δ 8.53 (dd, J ) 4.8 Hz, 1H), 8.17 (dd, J )
8.4 Hz, 1H), 7.75 (dd, J ) 8.4 Hz, 1H), 7.64-7.53 (m, 2H), 7.42
(dd, J ) 5.2 Hz, 1H), 3.3 (s, 3H); 13C NMR (100 MHz, DMSO-
d6) δ 171.9, 164.1, 159.8, 142.7, 129.0, 128.0, 125.0, 119.7, 119.2,
109.2, 23.4; HRMS (ESI) m/z calcd for C11H10N5O (M + H+)
228.0880, found 228.0877.
3-(5-Bromopyrimidin-2-yloxy)-3H-1,2,3-triazolo[4,5-b]pyri-
dine (31). Synthesized according to General Method B (reaction
mixture stirred for 2 h at rt) from 5-bromo-1H-pyrimidin-2-one 25
and purified by flash chromatography as a white solid (820 mg,
70%): 1H NMR (400 MHz, DMSO-d6) δ 8.96 (s, 2H), 8.81 (dd, J
) 1.2, 4.4 Hz, 1H), 8.75 (dd, J ) 0.8, 8.0 Hz, 1H), 7.66 (dd, J )
4.8, 8.4 Hz, 1H); 13C NMR (100 MHz, DMSO-d6) δ 162.9, 161.3,
152.5, 139.4, 134.4, 129.7, 121.6, 116.6; HRMS (ESI) m/z calcd
for C9H6BrN6O (M + H+) 292.9781, found 292.9783.
1-Methyl-4-(1,2,3-triazolo[4,5-b]pyridin-3-yloxy)-1H-pyrimi-
din-2-one (32). Synthesized according to General Method B
(reaction mixture stirred for 12 h at rt) from 1-methyl-1H-
pyrimidine-2,4-dione 26 and purified by flash chromatography as
a white solid (400 mg, 77%): 1H NMR (400 MHz, DMSO-d6) δ
8.83 (dd, J ) 1.2, 4.8 Hz, 1H), 8.75 (dd, J ) 1.6, 8.4 Hz, 1H),
8.47 (d, J ) 6.8 Hz, 1H), 7.66 (dd, J ) 4.4, 8.4 Hz, 1H), 6.71 (d,
J ) 7.2 Hz, 1H); 13C NMR (100 MHz, DMSO-d6) δ 169.9, 154.6,
152.9, 140.1, 134.6, 130.1, 122.0, 89.9, 38.1; HRMS (ESI) m/z calcd
for C10H9N6O2 (M + H+) 245.0781, found 245.0785.
4,6-Bis(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)pyrimidine
(34b). Synthesized according to General Method B (reaction
mixture stirred for 8 h at rt) from 6-chloro-3H-pyrimidin-4-one 27
and purified by flash chromatography as a white solid (89 mg,
26%): 1H NMR (400 MHz, CDCl3) δ 8.73 (dd, J ) 1.2, 4.4 Hz,
2H), 8.48 (dd, J ) 1.2, 8.4 Hz, 2H), 8.17 (d, J ) 0.8 Hz, 1H), 7.48
(dd, J ) 4.0, 8.0 Hz, 1H), 7.15 (d, J ) 0.8 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ 171.2, 158.1, 152.0, 134.9, 129.7, 121.1, 89.5;
HRMS (ESI) m/z calcd for C14H9N10O2 (M + H+) 349.0904, found
349.0900.
4-(3-Oxybenzotriazol-1-yl)quinazoline (35). To a solution of
4-hydroxyquinazoline (5, 100 mg, 0.684 mmol) and BOP (393 mg,
0.889 mmol, 1.3 equiv) in MeCN (6.8 mL) was added DBU (156
µL, 1.03 mmol, 1.5 equiv) dropwise at 0 °C. The mixture was stirred
while warming to room temperature. The mixture was diluted with
EtOAc (250 mL); this solution was washed with 1:1 brine/1 M aq
HCl (∼200 mL). The EtOAc layer was dried over MgSO4 and
concentrated under vacuum. The mixture was purified by chroma-
tography on silica (gradient elution from hexanes (0.25% TEA) to
EtOAc (0.25% TEA)); fractions containing the desired product were
pooled and concentrated. Residual solvent was removed overnight,
affording 35 (72.2 mg, 40%) as a white solid: mp 187 °C dec; 1H
NMR (400 MHz, DMSO-d6) δ 7.70 (t, J ) 7.8 Hz, 1H), 7.85-
7.99 (m, 2H), 8.07-8.19 (m, 3H), 8.75 (d, J ) 8.6 Hz, 1H), 8.99
(d, J ) 8.6 Hz, 1H), 9.29 (s, 1H); 13C NMR (100 MHz, DMSO-
d6) δ 153.2, 153.1, 152.5, 134.9, 133.6, 132.5, 131.2, 129.0, 128.5,
126.7, 126.4, 117.0, 115.8, 115.0; ESI-MS m/z (relative intensity,
ion) 264 (100%, [M + H+]); HRMS (ESI) m/z calcd for C14H10N5O
(M + H+) 264.0880, found 264.0878.
Nitrogen Nucleophiles. 4-Benzotriazol-1-ylquinazoline (16).
4-Hydroxyquinazoline (5, 100 mg, 0.684 mmol, 1 equiv) and BOP
(393 mg, 0.890 mmol, 1.3 equiv) were added to a 40 mL glass
vial containing a magnetic stir bar. MeCN (27 mL) was added to
the vial, then Ph2O (108 µL, 0.684 mmol; HPLC standard) and
DBU (205 µL, 1.37 mmol, 2 equiv). This solution was stirred for
1 min at room temperature. Benzotriazole (245 mg, 2.05 mmol, 3
equiv) was added to the reaction mixture. The slightly cloudy
solution was stirred at room temperature overnight. Yield of 16 in
the mixture was 95% (as determined by HPLC relative to internal
standard). The reaction mixture was concentrated and then purified
by chromatography on silica (gradient elution from hexanes to
EtOAc). Fractions containing the product were pooled and con-
centrated; residual solvent was removed under reduced pressure,
affording 16 (111 mg, 0.449 mmol, 66%) as a white solid: mp
1-(6-Chloropyrimidin-4-yloxy)-1H-benzotriazole (33a). Syn-
thesized according to General Method A (reaction mixture stirred
for 8 h at rt) from 6-chloro-3H-pyrimidin-4-one 27 and purified
by flash chromatography as a white solid (125 mg, 51%): 1H NMR
(400 MHz, DMSO-d6) δ 8.7 (s, 1H), 8.19 (d, J ) 8.4 Hz, 1H),
8.05-8.04 (m, 1H), 7.82 (d, 1H), 7.69-7.66 (m, 1H), 7.57-7.55
(m, 1H); 13C NMR (100 MHz, DMSO-d6) δ 169.8, 162.3, 158.9,
129.8, 143.0, 128.4, 125.8, 120.3, 109.7, 107.0; HRMS (ESI) m/z
calcd for C10H7ClN5O (M + H+) 248.0334, found 248.0333.
3-(6-Chloropyrimidin-4-yloxy)-3H-1,2,3-triazolo[4,5-b]pyri-
dine (33b). Synthesized according to General Method B (reaction
mixture stirred for 8 h at rt) from 6-chloro-3H-pyrimidin-4-one 27
and purified by flash chromatography as a white solid (78 mg,
60%): 1H NMR (400 MHz, CDCl3) δ 8.72 (dd, J ) 1.6, 4.8 Hz,
1
169.5-169.6 °C; H NMR (400 MHz, DMSO-d6) δ 7.65 (ddd, J
) 8.1, 7.1, 1.0 Hz, 1H), 7.81 (ddd, J ) 8.1, 7.1, 1.0 Hz, 1H), 7.93
(ddd, J ) 8.3, 6.6, 1.8 Hz, 1H), 8.15-8.22 (m, 2H), 8.32 (app dt,
J ) 8.6, 0.9 Hz, 1H), 8.48 (app dt, J ) 8.6, 0.9 Hz, 1H), 8.95
(dddd, J ) 8.6, 1.8, 1.2, 0.5 Hz, 1H), 9.41 (s, 1H); 13C NMR (100
MHz, DMSO-d6) δ 154.7, 153.6, 152.6, 145.2, 135.1, 132.1, 129.8,
129.3, 128.4, 126.7, 126.0, 119.7, 116.9, 114.7; ESI-MS m/z
(relative intensity, ion) 248 (12%, [M + H+]), 220 (100%, [M -
N2]); HRMS (ESI) m/z calcd for C14H10N5 (M + H+) 248.0931,
found 248.0931.
J. Org. Chem, Vol. 72, No. 26, 2007 10207