I
C. L. Sutherell, S. V. Ley
Paper
Synthesis
and solvent removed in vacuo. Purification by FCC (2% MeOH/CH2Cl2
to 5% MeOH/CH2Cl2) gave the title compound 52 (28.9 mg, 0.103
mmol, 32%) as a tan amorphous solid; Rf = 0.30 (5% MeOH/CH2Cl2).
(E)-3-[(4-Methyl-1,4-diazepan-1-yl)methylene]-2,3-dihydropyrro-
lo[1,2-a]quinazolin-5(1H)-one (55)
To a solution of 51 (21.0 mg, 0.0870 mmol) in EtOH (0.5 mL) was add-
ed 1-methylhomopiperazine (32 μL, 0.257 mmol, 3.4 equiv), and N,N-
dimethylaminopyridine (1.1 mg, 0.0087 mmol, 0.1 equiv), and heated
at reflux for 96 h. The solvent was removed in vacuo and purification
by FCC (5% MeOH/CH2Cl2) gave the product 55 (13.2 mg, 0.0425
mmol, 49%) as a pale brown amorphous solid; mp 92–94 °C; Rf = 0.32
(10% MeOH/CH2Cl2 + 1% NH4OH).
IR (neat): 2934, 2853, 1643, 1600, 1587, 1510, 1486, 1439, 1402 cm–1
.
1H NMR (600 MHz, DMSO-d6): δ = 7.93 (dd, J = 7.8, 1.2 Hz, 1 H), 7.64
(ddd, J = 8.4, 7.8, 1.2 Hz, 1 H), 7.40 (s, 1 H), 7.27 (dt, J = 7.8, 0.6 Hz, 1
H), 7.24 (d, J = 8.4 Hz, 1 H), 4.11 (app t, J = 7.8 Hz, 2 H), 3.47–3.45 (m, 4
H), 3.11 (app t, J = 7.8 Hz, 2 H), 1.63–1.57 (m, 6 H).
13C NMR (100 MHz, CDCl3): δ = 168.1, 164.1, 142.4, 139.5, 132.9,
127.2, 123.4, 118.8, 114.2, 93.9, 50.9, 45.5, 26.1, 23.6, 23.2.
IR (neat): 2939, 2913, 2857, 2810, 1641, 1602, 1587, 1506, 1496 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 8.27 (dd, J = 7.9, 1.4 Hz, 1 H), 7.74 (t, J =
1.5 Hz, 1 H), 7.57 (ddd, J = 8.3, 7.3, 1.5 Hz, 1 H), 7.29 (ddd, J = 8.1, 7.5,
1.0 Hz, 1 H), 7.00 (d, J = 8.0 Hz, 1 H), 4.11–4.07 (m, 2 H), 3.62 (t, J = 6.3
Hz, 2 H), 3.59–3.57 (m, 2 H), 3.21 (m, 2 H), 2.67–2.65 (m, 2 H), 2.61–
2.59 (m, 2 H), 2.39 (s, 3 H), 1.95–1.91 (m, 2 H).
13C NMR (125 MHz, CDCl3): δ = 170.4, 164.6, 144.5, 139.7, 133.0,
128.8, 124.1, 119.5, 113.1, 94.1, 59.1, 57.0, 54.1, 51.7, 46.9, 45.8, 28.5,
23.9.
HRMS (ESI+): m/z [M + H]+ calcd for C17H20N3O: 282.1606; found:
282.1615.
(E)-3-(Morpholinomethylene)-2,3-dihydropyrrolo[1,2-
a]quinazolin-5(1H)-one (53)
To a solution of 4 (50.0 mg, 0.269 mmol, 1.0 equiv) in CH2Cl2 (1.35 mL)
was added morpholine-4-carbaldehyde (310 mg, 2.69 mmol, 10.0
equiv) and POCl3 (50.1 μL, 0.538 mmol, 2.0 equiv). The reaction mix-
ture was refluxed for 3 h, diluted with CH2Cl2 (10 mL), cooled to r.t.,
and quenched with aq NaHCO3 (15 mL). The aqueous layer was ex-
tracted with CH2Cl2 (5 × 15 mL), the combined organic layers dried
(Na2SO4), and solvent removed in vacuo. Purification by FCC (5%
MeOH/CH2Cl2 to 10% MeOH/CH2Cl2) gave the title compound 53 (26.7
mg, 0.0942 mmol, 35%) as a tan amorphous solid; mp 275 °C (dec.);
Rf = 0.25 (5% MeOH/CH2Cl2).
HRMS (ESI+): m/z [M + H]+ calcd for C18H23N4O: 311.1872; found:
311.1884.
tert-Butyl (E)-4-[(5-Oxo-1,2-dihydropyrrolo[1,2-a]quinazolin-
3(5H)-ylidene)methyl]piperazine-1-carboxylate (56)
To a solution of 51 (21.0 mg, 0.0870 mmol) in EtOH (0.5 mL) was add-
ed with 1-Boc-piperazine (49.0 mg, 0.263 mmol, 3.0 equiv) and N,N-
dimethylaminopyridine (1.1 mg, 0.0087 mmol, 0.1 equiv), and heated
at reflux for 96 h. The solvent was removed in vacuo and purification
by FCC (5% MeOH/CH2Cl2) gave the product 56 (20.0 mg, 0.0522
mmol, 60%) as a pale brown amorphous solid; mp 140 °C (dec.); Rf =
0.25 (5% MeOH/CH2Cl2).
IR (neat): 2961, 2925, 2887, 1634, 1600, 1594, 1525, 1510, 1110, 760
cm–1
.
1H NMR (600 MHz, CDCl3): δ = 8.29 (dd, J = 7.9, 1.3 Hz, 1 H), 7.65 (s, 1
H), 7.59 (ddd, J = 8.3, 7.4, 1.6 Hz, 1 H), 7.32 (ddd, J = 8.0, 7.5, 0.9 Hz, 1
H), 7.03 (d, J = 8.2 Hz, 1 H), 4.14–4.11 (m, 2 H), 3.76–3.75 (m, 4 H),
3.51–3.48 (m, 4 H), 3.50 (d, J = 4.8 Hz, 2 H), 3.18 (ddd, J = 8.3, 6.7, 1.7
Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 170.3, 164.4, 143.0, 139.5, 133.2,
128.9, 124.5, 119.4, 113.3, 95.6, 66.7, 50.4, 45.0, 24.0.
IR (neat): 2974, 2918, 1688, 1644, 1605, 1591, 1518, 1494, 1405 cm–1
.
1H NMR (600 MHz, CDCl3): δ = 8.24 (dd, J = 7.4, 1.2 Hz, 1 H), 7.57 (m, 1
H), 7.54 (ddd, J = 8.4, 7.4, 1.4 Hz, 1 H), 7.27 (dt, J = 7.9, 0.6 Hz, 1 H),
6.97 (d, J = 8.1 Hz, 1 H), 4.07 (app t, J = 7.9 Hz, 2 H), 3.48–3.46 (m, 4 H),
3.39 (br, 4 H), 3.10 (dt, J = 7.8, 1.4 Hz, 2 H), 1.46 (s, 9 H).
13C NMR (150 MHz, CDCl3): δ = 170.2, 164.3, 154.5, 142.5, 139.5,
133.0, 128.6, 124.2, 119.4, 113.4, 95.8, 80.8, 46.0, 28.6, 24.0. * C13 and
C14 were weak and very broad in 13C NMR and could not be reliably
assigned.
HRMS (ESI+): m/z [M + H]+ calcd for C16H18N3O2: 284.1399; found:
284.1396.
(E)-3-[(4-Ethylpiperazin-1-yl)methylene]-2,3-dihydropyrrolo[1,2-
a]quinazolin-5(1H)-one (54)
HRMS (ESI+): m/z [M + H]+ calcd for C21H27N4O3: 383.2078; found:
383.2070.
To a solution of 51 (50.0 mg, 0.207 mmol, 1.0 equiv) in EtOH (1 mL)
was added 1-ethylpiperazine (80.0 μL, 0.630 mmol, 0.33 equiv) and
N,N-dimethylaminopyridine (2.5 mg, 0.020 mmol, 0.1 equiv), and
heated at reflux for 32 h. The solvent was removed in vacuo and puri-
fication by FCC (5% MeOH/CH2Cl2) gave the product 54 (39.6 mg,
0.128 mmol, 62%) as a pale brown amorphous solid; mp 165–168 °C;
Rf = 0.30 (5% MeOH/CH2Cl2).
(E)-7-Chloro-4-[(dimethylamino)methylene]-1,2,3,4-tetrahydro-
6H-pyrido[1,2-a]quinazolin-6-one (57)
To a stirred solution of 40 (88.0 mg, 0.37 mmol, 1.0 equiv) in DMF
(740 μL) was added POCl3 (69.9 μL, 0.74 mmol, 2.0 equiv) and the re-
action mixture was heated to 60 °C for 6 h. The mixture was cooled to
r.t., diluted with CH2Cl2 (15 mL), and quenched with aq NaHCO3 (15
mL). The aqueous layer was extracted with CH2Cl2 (5 × 15 mL), the
combined organic layers dried (Na2SO4) and solvent removed in vac-
uo. The residue was co-evaporated with toluene (3 × 5 mL) and purifi-
cation by FCC (6% MeOH/CH2Cl2) gave the product 57 (52.0 mg, 0.18
mmol, 49%) as a yellow amorphous solid; mp 197–200 °C; Rf = 0.43
(6% MeOH/CH2Cl2).
IR (neat): 2970, 2901, 2819, 1645, 1613, 1598, 1588, 1509, 1491 cm–1
.
1H NMR (600 MHz, CDCl3): δ = 8.27 (dd, J = 7.9, 1.3 Hz, 1 H), 7.65 (s, 1
H), 7.57 (dd, J = 8.4, 7.4, 1.5 Hz, 1 H), 7.29 (dt, J = 7.8, 0.6 Hz, 1 H), 7.00
(d, J = 7.8 Hz, 1 H), 4.10 (app t, J = 7.8 Hz, 2 H), 3.52 (app t, J = 5.0 Hz, 4
H), 3.16 (dt, J = 7.8, 1.2 Hz, 2 H), 2.51 (app t, J = 4.8 Hz, 4 H), 2.46 (q, J =
7.2 Hz, 2 H), 1.10 (t, J = 7.2 Hz, 3 H).
13C NMR (150 MHz, CDCl3): δ = 170.3, 164.6, 142.9, 139.6, 133.1,
128.9, 124.3, 119.5, 113.2, 94.7, 52.8, 52.4, 50.3, 45.9, 24.0, 12.0.
IR (neat): 3111, 2944, 2885, 2813, 1607, 1587, 1499, 1481, 1464 cm–1
.
HRMS (ESI+): m/z [M + H]+ calcd for C18H23N4O: 311.1861; found:
311.1866.
1H NMR (600 MHz, CDCl3): δ = 8.27 (s, 1 H), 7.39 (t, J = 8.2 Hz, 1 H),
7.29 (dd, J = 7.9, 0.9 Hz, 1 H), 7.14 (dd, J = 8.5, 0.6 Hz, 1 H), 3.85 (app t,
J = 6.0 Hz, 2 H), 3.12 (s, 6 H), 2.73–2.71 (m, 2 H), 2.09–2.05 (m, 2 H).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J