L. Sereni et al. / Tetrahedron 60 (2004) 8561–8577
8575
(400 mg), suspended in pyridine/water 9/1 (v/v) (8 mL),
was added Bu4NHS (1.11 g, 4.02 mmol) the reaction
mixture was shaken for 16 h at 80 8C. The resin was
washed with five alternating washes of water and DMF
(3 mL each) then with five alternating washes of MeOH and
DCM (3 mL each). An aliquot of the resin was subjected to
cleavage with TFA.
2.15.3. 6-[(1,3-Benzodioxol-5-ylcarbonyl)amino]-N-(4-
chlorobenzyl)-1-methyl-4-oxo-1,4-dihydrocinnoline-3-
carboxamide (17c). dH (600 MHz DMSO-D6) 4.26 (3H, s,
Me), 4.56 (2H, d, p-ClC6H4CH2) 5.86 (2H, d, OCH2O), 7.08
(1H, d, JZ8.3 Hz, C7H, 1,3-benzodioxol-5-yl), 7.39 (4H,
m, p-ClC6H4CH2), 7.56 (1H, d, JZ1.5 Hz, C4H 1,3-
benzodioxol-5-yl), 7.63 (1H, dd, JZ8.3, 1.5 Hz, C6H
1,3-benzodioxol-5-yl), 8.01 (1H, d, JZ9.3 Hz, C8H cinno-
line), 8.33 (1H, dd, JZ9.4, 2.3 Hz, C7H cinnoline), 8.75 (d,
JZ2.4 Hz, C5H cinnoline), 10.12 (1H, t, JZ6.0 Hz,
p-ClC6H4CH2NHCO), 10.54 (1H, broad s, CONH 6-[(1,3-
benzodioxol-5-ylcarbonyl)amino]); HRMS (FABS): MHC,
found 491.1102. C25H19ClN4O5 requires 491.1117.
2.14.1. 6-Amino-3-{[(4-chlorobenzyl)amino]carbonyl}-4-
hydroxy-1-methylcinnolin-1-ium trifluoroacetate (14a).
dH (600 MHz DMSO-D6) 4.20 (3H, s, N1Me cinnoline),
4.55–4.54 (2H, d, JZ3 Hz, p-ClC6H4CH2), 6.12 (2H, broad
s, NH2), 7.23 (2H, m, C5H, C7H cinnoline), 7.36 (2H, m,
C2H, C6H 4-chlorobenzyl), 7.38–7.40 (2H, m, C3H, C5H
4-chlorobenzyl), 7.76–7.75 (1H, d, C8H cinnoline), 10.43
(1H, t, JZ3 Hz, CONH), On-bead IR: 1335 cmK1 (N]O),
1350 cmK1 (N]O); ESI-MS: (MHC) 357.
2.15.4. N-(4-Chlorobenzyl)-4-oxo-6-[(phenylacetyl)
amino]-1-{4-[(phenylacetyl)amino]benzyl}-1,4-dihydro-
cinnoline-3-carboxamide (17d). dH (600 MHz DMSO-D6)
3.59–3.68 (4H, m, PhCH2CO), 4.56 (2H, d, p-ClC6H4CH2),
5.78 (2H, m, ArCH2N1 cinnoline), 7.23 (2H, d, JZ8.5 Hz,
C2H, C6H 4-[(phenylacetyl)amino]phenylmethyl), 7.27–
7.34 (12H, m, PhCH2CO), 7.54 (2H, d, JZ8.5 Hz, C3H,
C5H 4-[(phenylacetyl)amino]phenylmethyl); 7.9 (1H, d,
JZ9.5 Hz, C8H cinnoline), 7.98 (1H, dd, JZ9.5, 2.4 Hz,
C7H cinnoline), 8.57 (1H, d, JZ2.4 Hz, C5H cinnoline),
10.03 (1H, t, JZ6.0 Hz, p-ClC6H4CH2NHCO), 10.19 (1H,
broad s, CONH 4-[(phenylacetyl) amino]phenylmethyl),
10.67 (1H, CONHC6 cinnoline); HRMS (FABS): MHC
found 670.2208. C39H32ClN5O4 requires 670.2216.
2.15. Acylation of the aniline bound to the polymeric
support
To resin bearing aminocinnolin (120 mg) suspended in
DCM (2 mL) was added DIPEA (71 mL, 330 mmol), DMAP
(2 mg) and cyclopropylcarbonylchloride (30 mL, 330 mmol)
the reaction mixture was shaken for 16 h.
The resin was washed with five alternating washes of water
and DMF (3 mL each) then with five alternating washes of
MeOH and DCM (3 mL each).
2.15.5. N-Cyclopentyl-6-[(cyclopropylcarbonyl)amino]-
1-methyl-4-oxo-1,4-dihydrocinnoline-3-carboxamide
(17e). dH (600 MHz DMSO-D6) 0.78–4.23 (17H, m, HC,
CH2 cyclopropyl, cyclopentyl, N1Me cinnoline), 7.95 (1H,
d, JZ9.3 Hz, C8H cinnoline), 8.09 (1H, dd, JZ9.3, 2.4 Hz,
C7H cinnoline), 8.55 (1H, d, JZ2.4 Hz, C5H cinnoline),
9.76 (1H, d, JZ7.1 Hz, CONHC5H9), 10.7 CONHC3H5);
HRMS (FABS): MHC, found 355.1773. C19H22N4O3
requires 355.1765.
2.15.1. 6-[(Cyclopropylcarbonyl)amino]-1-({4-[(cyclo-
propylcarbonyl)amino]cyclohexa-2,4-dien-1-yl}methyl)-
N-(4-methoxy-2-methylphenyl)-4-oxo-1,4-dihydrocinno-
line-3-carboxamide (17a). dH (500 MHz DMSO-D6) 0.75
(4H, m, CH2 cyclopropyl), 0.81 (4H, d, JZ6.1 Hz, CH2
cyclopropyl), 1.73, 1.8 (2H, 2m, C1H, cyclopropyl), 2.38
(3H, s, C2Me 4-methoxy 2-methylanilide), 3.74 (3H, s,
OMe 4-methoxy 2-methylanilide), 4.85 (2H, s, ArCH2N1
cinnoline), 6.81 (1H, dd, JZ8.8, 2.9 Hz, C5H 4-methoxy
2-methylanilide), 6.88 (1H, d, JZ2.9 Hz, C3H 4-methoxy
2-methylanilide), 7.26 (1H, d, JZ8.5 Hz, C3H, C5H
(4-cyclopropanecarboxamidophenylmethyl), 7.54 (2H, d,
JZ8.5 Hz, C2H, C6H (4-cyclopropanecarboxamidophenyl-
methyl), 7.96 (1H, dd, C7H cinnoline), 7.99 (1H, d, C8H
cinnoline), 8.12 (1H, d, JZ8.8 Hz, C6H 4-methoxy
2-methylanilide), 8.72 (1H, d, JZ2 Hz, C5H cinnoline),
10.21, 10.72, 11.89 (3H, 3 broad s, CONH). HRMS (FABS):
MHC 566.2379, C32 H31 N5 O5 requires 566.2398.
2.15.6. N-Cyclopentyl-1-ethyl-4-oxo-6-[(phenylacetyl)
amino]-1,4-dihydrocinnoline-3-carboxamide (17f). dH
(600 MHz DMSO-D6) 1.42 (3H, t, JZ7.2 Hz, MeCH2),
1.44–1.98 (8H, m, CH2 cyclopentyl), 3.71 (2H, m,
PhCOCH2), 4.23 (1H, m, C1H cyclopentyl), 4.62 (2H, q,
JZ7.2 Hz, MeCH2), 7.22–738 (5H, m, Ph), 8.04 (1H, dd,
JZ9.3 Hz, C8H cinnoline), 8.08 (dd, JZ9.3, 2.2 Hz, C7H
cinnoline), 8.58 (1H, d, JZ2.4 Hz, C5H cinnoline), 9.75
(1H, d, JZ7.1 Hz, COHNC5H9); 10.69 (1H, s, CONH);
HRMS (FABS): MHC, found 419.2082. C24H26N4O3
requires 419.2078.
2.15.2. N-(4-Chlorobenzyl)-6-[(cyclopropylcarbonyl)
amino]-1-ethyl-4-oxo-1,4-dihydrocinnoline-3-carbox
amide (17b). dH (600 MHz DMSO-D6) 0.84 (4H, dd, JZ7.6,
3.4 Hz, CH2 cyclopropyl); 1.43 (3H, t, JZ7.2 Hz, CH2Me),
1.81 (1H, m, CHCO cyclopropylcarbonyl), 4.55 (2H, d, JZ
6.1 Hz, p-ClC6H4CH2), 4.63 (2H, q, JZ7.2 Hz, CH2Me),
7.39 (4H, m, p-ClC6H4CH2), 8.05 (1H, d, JZ9.3 Hz, C8H
cinnoline); 8.11 (1H, dd, JZ9.3, 2.4 Hz, C7H cinnoline),
8.55 (1H, d, JZ2.4 Hz, C5H cinnoline), 10.1 (1H, t, JZ
6.0 Hz, p-ClC6H4CH2NHCO), 10.72 (1H, broad s, CONH
cyclopapanecarboxamide); HRMS (FABS): MHC, found
425.1387 C22H21ClN4O3 requires 425.1375.
2.15.7. N-[1-Methyl-4-oxo-3-(piperazin-1-ylcarbonyl)-
1,4-dihydrocinnolin-6-yl]-2-phenylacetamide (17g). dH
(500 MHz DMSO-D6) 2.6, 2.72 (4H, 2m, C3H2, C5H2
piperazine), 3.15, 3.52 (4H, 2m, C2H2, C6H2 piperazine),
3.69 (2H, m, PhCOCH2), 4.08 (3H, s, N1Me cinnoline),
7.22–7.27 (1H, m, C4H Ph), 7.30–7.37 (4H, m, C2H, C3H,
C5H, C6H Ph); 7.82 (2H, d, JZ9.3 Hz, C8H cinnoline),
8.06 (1H, dd, JZ9.3, 2.5 Hz, C7H cinnoline), 8.45 (d, JZ
2.4 Hz, C5H cinnoline), 10.68 (1H, s, CONH phenylaceta-
mide); HRMS (FABS): MHC, found 406.1885.
C22H23N5O3 requires 406.1874.