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4-Chloro-6,7-dimethoxy-2-methylquinazoline (4a): General proce-
dure 2 was performed using 3a to afford 4a as a red solid:
1H NMR (300 MHz, CDCl3): d=2.94 (s, 3H, C-CH3), 4.08 (s, 3H, O-
CH3), 4.12 (s, 3H, O-CH3), 7.40 (s, 1H, CH), 7.69 ppm (s, 1H, CH); IR
1499 cmꢀ1 (C=N); HRMS-ESI(+): m/z calcd [M+H]+: 438.13274, de-
tected: 438.13234. m/z calcd [MNa]+: 460.11469, detected:
460.11478. m/z calcd [2M+Na]+: 897.24016, detected: 897.23952.
(KBr): n=2964 (CH3), 1504 cmꢀ1 (N=C).
7-(Benzyloxy)-4-chloro-6-methoxyquinazoline (13): General pro-
cedure 2 was performed using 12[25] to yield compound 13 as
pale-yellow crystals (yield: 199 mg, 0.66 mmol, 94%): mp: >1408C
~
4-Chloro-2-(fluoromethyl)-6,7-dimethoxyquinazoline (4b): Gener-
al procedure 2 was performed using 3b to afford 4b as an orange
1
(under decomposition); H NMR (300 MHz, CDCl3): d=4.12 (s, 3H),
1
5.47 (s, 2H), 7.35–7.45 (m, 6H), 8.11 (s, 1H), 9.02 ppm (s, 1H).
solid: H NMR (300 MHz, CDCl3): d=3.85 (s, 3H, O-CH3), 3.87 (s, 3H,
O-CH3), 5.57 (d, JH,F =46.7 Hz, CH2F), 7.37 (s, 1H, CH), 7.37 ppm (s,
1H, CH). 13C NMR (75 MHz, CDCl3): d=56.6 (O-CH3), 56.8 (O-CH3),
83.4 (d, JH,F =175.0 Hz, 1C, CH2F), 102.9 (CH), 107.1 (CH), 118.5 (C),
149.3 (C), 151.7 (C-OCH3), 157.3 (C-OCH3), 158.7 (d, JH,F =18.2 Hz,
1C, C-CH2F), 159.6 ppm (C-Cl); 19F NMR (282 MHz, CDCl3): d=
ꢀ222.5 ppm (t, JH,F =46.7 Hz, 1F); LRMS-ESI(+):m/z calcd: 257.0
[M+H]+: detected: 256.9; m/z calcd: 257.0 [M+Na]+: 279.0, de-
tected: 278.9.
(R)-7-(Benzyloxy)-6-methoxy-4-(3-(quinoxaline-2-yloxy)-pyrroli-
dine-1-yl)-quinazoline (14): General procedure 3 was performed
using 6 (270 mg, 1.25 mmol, 1 equiv) and 13 (358 mg, 1.19 mmol,
0.95 equiv) in 12 mL dioxane/water (5:1, v/v) and potassium car-
bonate (866 mg, 6.27 mmol, 5.0 equiv). The foamy yellow crude
product was recrystallized from 20 mL MeOH/EtOAc (95:5) to yield
14 as colorless crystals (yield: 305 mg, 0.64 mmol, 57%): Rf =0.56
(EtOAc/MeOH, 9:1, v/v), 0.59 (CHCl3/MeOH, 95:5, v/v); mp: 86–908C
1
(MeOH/EtOAc); [a]D23 = +157.98 (c 1.06, CHCl3); H NMR (300 MHz,
General procedure 3 for the coupling of 4-chloroquinazolines
with 2-(pyrrolidin-3-yloxy)quinoxalines to quinoxaline-2-yloxy)-
pyrrolidine-1-yl)-quinazolines (7a–f, 14, 17 f): 4-Chloroquinazoline
4a–e in excess was added to a solution of 6 (215 mg, 0.69 mmol,
1 equiv) in dioxane/water (12 mL, 5:1 v/v) (min 1.1 equiv with
regard to the quinazoline-4-3(H)-one derivative) and K2CO3
(5 equiv). The suspension was stirred at 808C for 16 h. After remov-
ing the solvent under reduced pressure, the residue was re-dis-
solved in CH2Cl2 (20 mL) and the organic layer was washed in
water, 5% citric acid, and brine. After drying the organic layer over
Na2SO4, the solvent was removed under reduced pressure.
CDCl3): d=2.45 (m, 2H, 4-CH2), 3.97 (s, 3H, 6-OCH3), 4.17 (m, 2H, 5-
CH2), 4.29 (m, 1H, 2-CH2), 4.41 (dd, JH,H =1.32 Hz, JH,H =8.20 Hz, 1H,
2-CH2), 5.27 (s, 2H, CH2, benzyl), 5.94 (m, 1H, 3-CH), 7.28 (s, 1H, 8-
CH, quinazoline), 7.30–7.40 (m, 3H, 3,4,5-CH, benzyl), 7.47 (m, 2H,
2,5-CH, benzyl), 7.49 (s, 1H, 5-CH, quinazoline), 7.58 (ddd, JH,H
1.5 Hz, 7.1 Hz, 8.4 Hz, 1H, 6-CH, quinoxaline), 7.68 (ddd, JH,H
=
=
1.5 Hz, 7.1 Hz, 8.4 Hz, 1H, 7-CH, quinoxaline), 7.84 (dd, JH,H =1.1 Hz,
8.3 Hz, 1H, 8-CH, quinoxaline), 8.02 (dd, JH,H =1.3 Hz, 8.2 Hz, 1H, 5-
CH, quinoxaline), 8.48 (s, 1H, 3-CH, quinoxaline), 8.50 ppm (s, 1H,
2-CH, quinazoline); 13C NMR (75 MHz, CDCl3): d=31.7 (4-CH2), 49.0
(5-CH2), 56.0 (2-CH2), 56.5 (6-OCH3), 70.9 (CH2, benzyl), 74.7 (3-CH),
105.1 (5-CH, quinazoline), 109.0 (8-CH, quinazoline), 110.5 (4a-C,
quinazoline), 127.1 (6-CH, quinoxaline), 127.5 (8-CH, quinoxaline),
127.7 (2,6-CH, benzyl), 128.4 (4-CH, benzyl), 128.9 (3,5-CH, benzyl),
129.3 (5-CH, quinoxaline), 130.6 (7-CH, quinoxaline), 136.1 (1-CH,
benzyl), 139.3 (4a-C, quinoxaline), 139.8 (3-CH, quinoxaline), 140.3
(8a-C, quinoxaline), 147.9 (8a-C, quinazoline), 148.1 (6-C, quinazo-
line), 153.2 (2-CH, quinazoline), 153.3 (7-C, quinazoline), 156.5 (2-C,
(R)-6,7-Dimethoxy-2-methyl-4-(3-(quinoxaline-2-yloxy)-pyrroli-
dine-1-yl)-quinazoline (7a): General procedure 3 was performed
using 4a to afford a crude product, which was purified by recrys-
tallization from MeOH to produce 7a as colorless crystals (yield:
180 mg, 0.43 mmol, 62%): mp: 118–1208C; [a]D23 = +1928 (0.43,
CHCl3); 1H NMR (300 MHz, CDCl3): d=2.57–2.30 (m, 2H), 2.58 (s,
3H), 3.95 (s, 3H), 3.98 (s, 3H), 4.44–4.07 (m, 4H), 5.97–5.89 (m, 1H),
7.45 (s, 1H), 7.18 (s, 1H), 7.58 (ddd, JH,H =8.4, 7.0, 1.5 Hz, 1H), 7.69
(ddd, JH,H =8.4, 7.0, 1.5 Hz, 1H), 7.84 (dd, JH,H =8.3, 1.0 Hz, 1H), 8.01
(dd, JH,H =8.2, 1.4 Hz, 1H), 8.47 ppm (s, 1H); 13C NMR (75 MHz,
CDCl3): d=26.1, 31.7, 48.8, 55.8, 56.2, 56.2, 74.6, 104.6, 106.9, 108.1,
127.0, 127.4, 129.1, 130.4, 139.1, 139.8, 140.2, 146.9, 149.3, 154.0,
~
quinoxaline), 159.4 ppm (4-C, quinazoline); IR (KBr): n=2914 (-CH2-,
-CH-), 1664, 1643, 1500 (conj. -C=N-), 1570, 1501 cmꢀ1 (arom. C=C);
UV/VIS (CH3CN): l (loge)=220 (4.63), 246 (4.66), 324 nm (4.21); MS
(EI): m/z (%)=479 (M+, 4), 333 (M+ꢀC8H6N2O, 99), 266 (M+
ꢀC12H12N3O, 13), 214 (M+ꢀC16H13N2O2, 14); HRMS-ESI(+): m/z calcd:
C28H26N5O3 [M+H]+: 480.20302, detected: 480.20276.
+
~
156.5, 159.5, 162.1 ppm; IR (KBr): n=2957 CH, 1571 (C=N),
1511 cmꢀ1 (C=N); HRMS-ESI(+) m/z calcd: [M+H]+: 418.18737, de-
tected: 418.18690, m/z calcd: [M+Na]+: 440.16931, detected:
440.16920., m/z calcd [2M+Na]+: 857.34940, detected: 857.34843.
(R)-6-Methoxy-4-(3-(quinoxaline-2-yloxy)-pyrrolidine-1-yl)-quina-
zoline-7-ol (15): Compound 14 (441 mg, 0.92 mmol, 1 equiv) was
held at reflux in TFA (5 mL) for 3 h. After co-distillation of the
excess TFA with toluene, the residue was suspended in a solution
of Na2SO4 (20 mL, 100 gLꢀ1) for 12 h. Compound 15 was collected
by filtration and washed in water (20 mL) and MeOH (20 mL) to
yield a colorless solid (yield: 350 mg, 0.90 mmol, 98%): mp: 260–
(R)-2-Chloro-6,7-dimethoxy-4-(3-(quinoxaline-2-yloxy)-pyrroli-
dine-1-yl)-quinazoline (7 f): A suspension of 2,4-dichloro-6,7-dime-
thoxyquinazoline (1.03 g, 3.8 mmol, 1 equiv), potassium carbonate
(2.7 g, 19.5 mmol, 5.14 equiv) and 6 (1.19 g, 3.8 mmol, 1 equiv) in
dioxane/water (30 mL, 5:1, v/v) was stirred for 24 h at 808C, yield-
ing a colorless solid precipitate. After removing the solvent under
reduced pressure, water (40 mL) was poured into the reaction mix-
ture. The precipitate was filtered and washed in water and MeOH
to produce 7 f as a colorless solid (yield: 1.50 g, 3.42 mmol, 88%:
mp: 213–2148C (MeOH); [a]D23 = +2138 (0.81, CHCl3); 1H NMR
(300 MHz, CDCl3): d=2.61–2.32 (m, 2H), 3.96 (s, 2H), 3.97 (s, 2H),
4.44–4.13 (m, 4H), 6.00–5.87 (m, 1H), 7.15 (s, 1H), 7.45 (s, 1H), 7.59
(ddd, JH,H =8.4, 7.0, 1.5 Hz, 1H), 7.69 (ddd, JH,H =8.4, 7.0, 1.5 Hz, 1H),
7.84 (dd, JH,H =8.3, 1.1 Hz, 1H), 8.02 (dd, JH,H =8.2, 1.4 Hz, 1H),
8.47 ppm (s, 1H); 13C NMR (75 MHz, CDCl3): d=31.6, 49.1, 56.2,
56.3, 56.3, 74.3, 107.2, 127.1, 129.2, 140.1, 108.5, 139.2, 104.6, 127.4,
130.5, 139.6, 147.7, 154.6, 155.3, 156.3, 160.4 ppm, one quaternary
1
2658C; H NMR (300 MHz, [D6]DMSO): d=2.68 (m, 2H, 4-CH2), 4.16
(s, 3H, 6-OCH3), 4.51 (m, 4H, 2-CH2, 5-CH2), 6.12 (m, 1H, 3-CH), 7.31
(s, 1H, 8-CH, quinazoline), 7.46 (s, 1H, 5-CH quinazoline), 7.64 (ddd,
J
H,H =1.5 Hz, 7.0 Hz, 8.3 Hz, 1H, 6-CH quinoxaline), 8.0 (ddd, JH,H =
1.5 Hz, 7.0 Hz, 8.4 Hz, 1H, 7-CH, quinoxaline), 8.07 (dd, JH,H =1.4 Hz,
8.3 Hz, 1H, 8-CH, quinoxaline), 8.21 (dd, JH,H =1.3 Hz, 8.2 Hz, 1H, 5-
CH, quinoxaline), 8.52 (s, 1H, 3-CH, quinoxaline), 8.74 ppm (s, 1H,
2-CH, quinazoline); 13C NMR (75 MHz, [D6]DMSO): d=30.8 (4-CH2),
48.1 (5-CH2), 55.3 (2-CH2), 55.4 (6-OCH3), 74.9 (3-CH), 104.5 (5-CH,
quinazoline), 109.9 (8-CH, quinazoline), 107.4 (4a-C, quinazoline)
126.9 (6-CH, quinoxaline), 127.0 (8-CH, quinoxaline), 128.7 (5-CH,
quinoxaline), 130.5 (7-CH, quinoxaline), 138.4 (4a-C, quinoxaline),
139.58 (3-CH, quinoxaline), 140.1 (8a-C, quinoxaline), 148.0 (6-C,
quinazoline), 148.9 (8a-C, quinazoline), 152.2 (2-CH, quinazoline),
~
C signal was not detectable; IR (KBr): n=2877 (CH), 1575 (C=N),
ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ChemMedChem 2014, 9, 1476 – 1487 1484