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V. Bavetsias et al. / Tetrahedron 63 (2007) 1537–1543
in anhydrous NMP (2.2 mL) was added CuCN (0.068 g,
0.76 mmol). The reaction flask was placed in an oil bath pre-
heated to 150 ꢀC and it was stirred at this temperature for 3 h
under argon. The mixture was then allowed to cool to room
temperature and poured into a mixture of aqueous ammonia
(2 mL) and ice-water (5 mL). This mixture was stirred at
room temperature for 5 min, the brown precipitate was then
collected by filtration and washed with water. This preci-
pitate was then suspended in CH2Cl2 (70 mL), dried
(Na2SO4) and concentrated in vacuo. Purification of the
residue by column chromatography, eluting with 35%
EtOAc in hexane, afforded a brown solid (0.084 g, 45%),
and 2.57 (m, 1H) (7-CH2), 2.90–3.17 (m, 2H, 8-CH2), 4.38
(d, J¼6.0 Hz, 2H, 2-CH2OH), 5.17 (m, 1H, 6-CH), 5.54 (t,
J¼6.1 Hz, 1H, CH2OH), 6.79 (d, J¼8.8 Hz, 2H, 30,50-
ArH), 6.91 (d, J¼7.8 Hz, 1H, N10–H), 7.51 (s, 1H) and
7.91 (s, 1H) (5-H and 9-H), 7.68 (d, J¼8.8 Hz, 2H, 20,60-
ArH), 11.83 (s, 1H, CONH); MS (ESI, m/z) 408 [(M+H)+,
t
65%], 352 [(Mꢁ Bu)+, 100%], 215 (60%); found: C,
67.41; H, 6.20; N, 10.17; C23H25N3O4 requires C, 67.80;
H, 6.18; N, 10.31%.
3.1.12. tert-Butyl 4-{N-[(6RS)-2-hydroxymethyl-4-oxo-
3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl]-N-
(prop-2-ynyl)amino}benzoate (21). To a round-bottomed
flask containing (propargyl)Co2(CO)+6BFꢁ4 13,19 (0.390 g,
0.95 mmol) under argon was added anhydrous dichloro-
methane (14 mL), a nearly clear solution was obtained. To
this solution a suspension of tert-butyl 4-{N-[(6RS)-2-hy-
droxymethyl-4-oxo-3,4,7,8-tetrahydro-6H-cyclopenta[g]-
quinazolin-6-yl]amino}benzoate (0.285 g, 0.71 mmol) in
anhydrous CH2Cl2 (14 mL) and DME (20 mL) was added
in one portion. The mixture was stirred at room temperature
for 10 min under argon, then diisopropylethylamine
(0.14 mL) was added and stirring was continued at room
temperature for 20 min. The reaction mixture was then par-
titioned between EtOAc (350 mL) and brine (100 mL). The
organic layer was washed with 10% aqueous citric acid
(100 mL) and brine (100 mL), dried (Na2SO4) and concen-
trated in vacuo. Purification by chromatography (silica iso-
lute 20 g, 70 mL column), on elution with 70% EtOAc in
CH2Cl2, gave a red solid (0.391 g, 76%), mp 190 ꢀC (dec);
1H NMR (250 MHz, DMSO-d6) 1.52 (s, 9H, C(CH3)3),
2.24 (m, 1H) and 2.60 (m, 1H) (7-CH2), 2.96–3.25 (m, 2H,
8-CH2), 4.37 (d, J¼5.9 Hz, 2H, 2-CH2OH), 4.58 (d,
J¼17.2 Hz, 1H) and 4.73 (d, J¼17.2 Hz, 1H) (N10–CH2),
5.55 (t, J¼6.2 Hz, 1H, CH2OH), 5.80 (t, J¼7.7 Hz, 1H,
6-CH), 6.68 (s, 1H, propargyl H), 7.01 (d, J¼8.8 Hz, 2H,
30,50-ArH), 7.56 (s, 1H) and 7.76 (s, 1H) (5-H and 9-H),
7.79 (d, J¼9.8 Hz, 2H, 20,60-ArH), 11.83 (s, 1H, CONH).
To a solution of this material (0.380 g, 0.52 mmol) in EtOH
(65 mL) was added Fe(NO3)3$9H2O (2.60 g, 6.5 mmol).
The mixture was stirred at room temperature for 2.5 h,
brine (w200 mL) was then added into the reaction mix-
ture that was extracted with EtOAc (3ꢂ150 mL). The com-
bined organic extracts were washed with brine (120 mL),
dried (Na2SO4) and concentrated in vacuo. Purification
by column chromatography, eluting with 5% MeOH in
EtOAc, gave an off-white solid (0.161 g, 70%), mp 195–
197 ꢀC; 1H NMR (250 MHz, DMSO-d6,) 1.52 (s, 9H,
C(CH3)3), 2.17 (m, 1H) and 2.55 (m, coincides with solvent
peak, 1H) (7-CH2), 2.90–3.20 (m, 3H, C^CH, 8-CH2), 3.87
(d, J¼18.7 Hz, 1H) and 4.10 (d, J¼18.7 Hz, 1H) (N10–CH2),
4.38 (d, J¼5.8 Hz, 2H, 2-CH2OH), 5.56 (br t, 1H, CH2OH),
5.78 (t, J¼8.7 Hz, 1H, 6-CH), 7.02 (d, J¼9.0 Hz, 2H,
30,50-ArH), 7.55 (s, 1H) and 7.80 (s, 1H) (5-H and 9-H),
7.76 (d, J¼9.8 Hz, 2H, 20,60-ArH), 11.82 (s, 1H, CONH);
MS (ESI, m/z) 468 [(M+Na)+, 60%], 446 [(M+H)+, 50%],
1
mp 194–195 ꢀC; H NMR (250 MHz, CDCl3) 1.55 (s, 9H,
C(CH3)3), 1.95 (m, 1H) and 2.64 (m, 1H) (2-CH2 indanyl),
2.99 (m, 2H, 3-CH2 indanyl), 4.13 (s, 2H) and 4.72 (s, 2H)
(PhCH2 and OCH2CO), 4.22 (d, J¼8.1 Hz, 1H, N10–H),
5.05 (m, 1H, 1-CH indanyl), 6.65 (d, J¼8.7 Hz, 2H,
3,5-ArH), 7.39 (m, 5H, PhCH2), 7.54 (s, 1H) and 8.37 (s,
1H) (4-H and 7-H), 7.86 (d, J¼8.7 Hz, 2H, 2,6-ArH), 9.06
(s, 1H, CONH); MS (ESI, m/z) 520 [(M+Na)+, 100%]; found:
C, 72.26; H, 6.26; N, 8.41; C30H31N3O4 requires C, 72.41; H,
6.28; N, 8.44%.
3.1.10. tert-Butyl 4-{N-[(6RS)-2-benzyloxymethyl-4-oxo-
3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl]-
amino}benzoate (18). To a stirred, ice-bath cooled mixture
of tert-butyl 4-[N-(5-(2-benzyloxy-ethanoylamino)-6-cya-
noindan-1-yl)amino]-benzoate (3.77 g, 7.59 mmol), EtOH
(70 mL) and H2O (11 mL) was added 30% H2O2 (8.05 mL)
followed by granulated NaOH pellets (0.640 g, 16.0 mmol).
The reaction mixture was stirred at 0 ꢀC for 10 min, then
placed in an oil bath preheated to 55 ꢀC and stirred at this
temperature for 1 h. The solvents were then removed
in vacuo; the residue was treated with H2O (80 mL) and
the pH was adjusted tow5 with 1 M HCl. The pale yellow
solid was collected by filtration, washed with H2O and
dried in vacuo over P2O5 (3.56 g, 95%), mp 194–195 ꢀC;
1H NMR (250 MHz, DMSO-d6) 1.52 (s, 9H, C(CH3)3),
1.90 (m, 1H) and 2.62 (m, 1H) (7-CH2), 2.90–3.17 (m,
2H, 8-CH2), 4.43 (s, 2H) and 4.60 (s, 2H) (PhCH2
and OCH2C]N), 5.18 (q, J¼7.4 Hz, 1H, 6-CH), 6.79
(d, J¼8.8 Hz, 2H, 30,50-ArH), 6.87 (d, J¼8.0 Hz, 1H,
N10–H), 7.34 (m, 5H, PhCH2), 7.54 (s, 1H) and 7.92
(s, 1H) (5-H and 9-H), 7.68 (d, J¼8.9 Hz, 2H, 20,60-
ArH), 12.20 (s, 1H, CONH); MS (ESI, m/z) 520
[(M+Na)+, 90%], 498 [(M+H)+, 100%]; found: C, 72.13;
H, 6.25; N, 8.38; C30H31N3O4 requires C, 72.41; H, 6.28;
N, 8.44%.
3.1.11. tert-Butyl 4-{N-[(6RS)-2-hydroxymethyl-4-
oxo-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-
yl]amino}benzoate (19). To a solution of tert-butyl
4-{N-[(6RS)-2-benzyloxymethyl-4-oxo-3,4,7,8-tetrahydro-
6H-cyclopenta[g]quinazolin-6-yl]amino}benzoate (1.40 g,
2.8 mmol) in EtOH (150 mL) was added 10% Pd/C
(0.665 g). The mixture was stirred at 45 ꢀC for 3 h, then
more catalyst (0.200 g) was added and stirring was con-
tinued at 50 ꢀC for 6 h. The catalyst was removed by filtra-
tion, washed with EtOH and the filtrate was concentrated
in vacuo. Purification of the residue by column chromato-
graphy, eluting with 8% methanol in EtOAc, gave a white
solid (0.679 g, 60%), mp 265–266 ꢀC; 1H NMR
(250 MHz, DMSO-d6) 1.52 (s, 9H, C(CH3)3), 1.88 (m, 1H)
t
390 [(Mꢁ Bu)+, 70%], 215 (100%); found: C, 69.63;
H, 6.13; N, 9.31; C26H27N3O4 requires C, 70.09; H, 6.11;
N, 9.43%.
3.1.13. 4-{N-[(6RS)-2-Hydroxymethyl-4-oxo-3,4,7,8-tet-
rahydro-6H-cyclopenta[g]quinazolin-6-yl]-N-(prop-
2-ynyl)amino}benzoic acid (4). Method A: a solution of