Synthesis of Pyrrolo- and Pyrido[1,2-a]xanthene[1,9-de]azepines
Diethyl N-[(4-Methoxy-9H-xanthen-9-yl)methyl]glutamate
(10a). A mixture of 5a (640 mg, 2.6 mmol), diethyl 2-bromopen-
tanodioate (814 mg, 3.05 mmol), and Na2CO3 (1.36 g, 12.8 mmol)
was heated at 105 °C under argon for 2.5 h. The mixture was
partitioned between CH2Cl2 and water, the organic layer was washed
with water, dried with Na2SO4, and filtered, and the solvent was
evaporated. Purification by flash chromatography (SiO2, 1:4 EtOAc/
hexane) gave oil 10a (782 mg, 69%) as a mixture of diastereoi-
somers: IR (NaCl) 3342 (NH), 1732 (CO) cm-1; 1H NMR δ 7.25-
6.82 (m, 7H), 4.10 (q, J ) 7.1 Hz, 2H), 4.07 (q, J ) 7.1 Hz, 2H),
4.05-3.98 (m, 1H), 3.93 (s, 3H, OMe), 3.10-3.05 (m, 1H), 2.90
(dd, J ) 11.7, 6.6 Hz, 1H), 2.66-2.60 (m, 1H), 2.31-2.25 (m,
2H), 1.89-1.72 (m, 2H), 1.45 (bs, 1H, NH), 1.24 (t, J ) 7.1 Hz,
3H), 1.16 (t, J ) 7.1 Hz, 3H); 13C NMR/ DEPT δ 174.9 (CO),
174.8 (CO), 173.6 (CO × 2), 152.5 (C), 152.4 (C), 148.3 (C), 148.2
(C), 142.2 (C), 129.1 (CH), 129.0 (CH), 128.2 (CHx2), 125.1 (C),
125.0 (C), 123.9 (C), 123.7 (CH), 123.6 (CH), 123.2 (CH), 123.1
(CH), 121.0 (CH), 120.9 (CH), 117.1 (CH), 117.0 (CH), 110.8 (CH),
110.7 (CH), 61.2 (CH), 61.0 (CH2), 60.7 (CH2), 56.7 (CH2), 56.6
(OMe), 56.5 (OMe), 40.7 (CH), 40.6 (CH), 30.9 (CH2), 30.8 (CH2),
28.3 (CH2), 14.6 (CH3), 14.5 (CH3); MS (FAB) (m/z) 428 [(M +
H)+, 100]; HRMS (FAB) calcd for C24H30NO6 [(M + H)+]
428.2073, found 428.2075.
1-[(4-Methoxy-9H-xanthen-9-yl)methyl]-5-oxopyrrolidine-2-
carbaldehyde (16a). Dess-Martin periodinane (210 mg, 0.49
mmol) and t-BuOH (47 µL, 0.49 mmol) were added to a solution
of alcohol 15a (168 mg, 0.49 mmol) in dry acetonitrile (15 mL),
and the mixture was stirred at rt for 12 h. The solvent was
evaporated, and the residue was dissolved in CH2Cl2 and treated
with a mixture Na2S2O3/NaHCO3/H2O (5.25 g/0.75 g/12 mL). After
the mixture was stirred for 20 min, the organic phase was washed
with water, dried with Na2SO4, filtered, and concentrated to afford
16a (150 mg, 90%) as an oil: IR (KBr) 1728 (CHO), 1684 (CO)
1
cm-1; H NMR δ 9.17 (d, J ) 4.7 Hz, 1H), 9.15 (d, J ) 4.7 Hz,
1H), 7.31-6.75 (m, 13H), 6.76 (dd, J ) 7.6, 1.3 Hz, 1H), 4.42-
4.37 (m, 2H), 4.05-3.96 (m, 2H), 3.93 (s, 3H, OMe), 3.92 (s, 3H,
OMe), 3.90-3.85 (m, 2H), 3.29 (ddd, J ) 9.5, 3.4, 1.3 Hz, 1H),
3.25 (ddd, J ) 9.4, 3.4, 1.3 Hz, 1H), 2.95-1.84 (m, 8H); 13C NMR/
DEPT δ 198.1 (CHO), 197.0 (CHO), 175.3 (C), 175.2 (C), 152.0
(C), 151.9 (C), 147.9 (C), 147.8 (C), 141.5 (C), 141.4 (C), 128.6
(CH), 128.5 (CH), 128.3 (CH), 128.2 (CH), 123.9 (CH), 123.6 (C),
123.5 (C), 123.3 (CH), 123.2 (CH), 122.8 (C), 122.7 (C), 122.4
(CH), 120.3 (CH), 120.1 (CH), 116.7 (CH × 2), 110.7 (CH × 2),
66.9 (CH), 66.8 (CH), 56.0 (OMe), 55.9 (OMe), 50.4 (CH2), 50.2
(CH2), 37.6 (CH), 37.5 (CH), 28.8 (CH2x2), 19.4 (CH2), 19.3 (CH2);
MS (CI) (m/z) 338 [(M + H)+, 3], 211 (22), 196 (15), 168 (40), 98
(100); HRMS (CI) calcd for C20H20NO4 338.1392, found 338.1396.
Cyclization of Aldehydes 16a-c: 7-Methoxy-2,3,12b,13-tet-
rahydro-1H-pyrrolo[1,2-a]xantheno[1,9-de]azepin-1-one (8a). A
mixture of aldehyde (16a) (200 mg, 0.59 mmol), AcOH (4 mL),
and concd HCl (1.4 mL) was heated at 80 °C for 30 min, diluted
with water, and extracted with CH2Cl2. The organic layer was
washed with 1 M NaOH and then with water, dried with Na2SO4,
filtered, and concentrated. Flash chromatography (SiO2, 99:1 CH2-
Cl2/MeOH) gave 8a (124 mg, 65%), which was recrystallized from
Ethyl 1-[(4-Methoxy-9H-xanthen-9-yl)methyl]-5-oxoprolinate
(11a). Compound 10a (600 mg, 1.40 mmol) was heated at 130 °C
under argon for 3 days. Flash chromatography (SiO2, 95:5 CH2-
Cl2/MeOH) gave oil 11a (481 mg, 90%) as a mixture of diastere-
1
oisomers: IR (NaCl) 1739 (CO), 1698 (CO) cm-1; H NMR δ
7.35 (d, J ) 7.1 Hz, 1H), 7.32-7.22 (m, 3H), 7.15-7.06 (m, 4H),
7.02 (t, J ) 8.2 Hz, 2H), 6.94 (dd, J ) 7.7, 1.5 Hz, 1H), 6.89 (dd,
J ) 8.1, 1.4 Hz, 1H), 6.86 (dd, J ) 8, 1.5 Hz, 1H), 6.73 (dd, J )
7.6, 1.4 Hz, 1H), 4.37 (dd, J ) 9.2, 5.5 Hz, 2H), 4.17-4.01 (m,
6H), 3.95 (s, 3H, OMe), 3.94 (s, 3H, OMe), 3.29 (dd, J ) 9.1, 2.4
Hz, 1H), 3.22 (dd, J ) 9.1, 2.4 Hz, 1H), 2.81 (dd, J ) 9.3, 6.6 Hz,
1H), 2.76 (dd, J ) 9.3, 6.6 Hz, 1H), 2.44-1.80 (m, 8H), 1.17 (t,
J ) 7.1 Hz, 3H), 1.16 (t, J ) 7.1, 3H); 13C NMR/ DEPT δ 175.9
(CO), 172.1 (CO), 172.0 (CO), 152.4 (C), 152.3 (C), 148.4 (C),
148.3 (C), 142.1 (C), 141.9 (C), 129.1 (CH), 129.0 (CH), 128.8
(CH), 128.7 (CH), 124.6 (C), 124.2 (CH), 124.1 (C), 123.8 (CH),
123.6 (CH), 123.4 (C), 123.2 (CH), 123.0 (C), 120.9 (CH), 120.7
(CH), 117.2 (CH), 111.1 (CH), 111.0 (CH), 61.9 (CH2), 61.8 (CH),
61.7 (CH), 56.5 (OMe), 50.8 (CH2), 50.5 (CH2), 38.1 (CH), 38.0
(CH), 29.6 (CH2), 23.7 (CH2), 23.6 (CH2), 14.4 (CH3); MS (FAB)
(m/z) 382 [(M + H)+, 100]; HRMS (FAB) calcd for C22H24NO5
[(M + H)+] 382.1654, found 382.1652.
CH2Cl2/hexane: mp 175 °C; IR (KBr) 1719 (CO), 1658 (CO) cm-1
;
1H NMR δ 7.40 (d, J ) 7.7 Hz, 1H), 7.22 (dd, J ) 8.2, 1.4 Hz,
1H), 7.15-7-06 (m, 2H), 6.81 (d, J ) 8.5 Hz, 1H), 6.76 (d, J )
8.5 Hz, 1H), 5.60 (s, 1H), 4.82 (d, J ) 13.5 Hz, 1H), 4.12 (d, J )
8.5 Hz, 1H), 3.92 (s, 3H, OMe), 3.38 (dd, J ) 13.5, 8.5 Hz, 1H),
2.94-2.74 (m, 2H), 2.66-2.60 (m, 2H); 13C NMR/ DEPT δ 175.3
(CO), 150.6 (C), 146.2 (C), 139.6 (C), 138.9 (C), 130.0 (CH), 129.0
(CH), 128.1 (C), 123.9 (CH), 123.0 (CH), 121.5 (C), 120.2 (C),
117.0 (CH), 111.1 (CH), 103.0 (CH), 56.7 (OMe), 53.3 (CH2), 37.6
(CH), 29.7 (CH2), 24.9 (CH2); MS (EI) (m/z) 319 (M+, 85), 304
(53), 288 (39), 163 (60), 42 (100); HRMS (EI) calcd for C20H17-
NO3 319.1208, found 319.1208. Anal. Calcd for C20H17NO3: C,
75.22; H, 5.37; N, 4.39. Found: C, 75.02; H, 5.07; N, 4.23.
8-Methoxy-3,4,13b,14-tetrahydropyrido[1,2-a]xantheno[1,9-
de]azepin-1(2H)-one (8b). Aldehyde 16b (600 mg, 1.7 mmol),
concd HCl (2.2 mL), and AcOH (6 mL) were heated at 75 °C for
45 min. After workup as described for 8a, the residue (464 mg)
was taken into ether/hexane and 8b (285 mg, 50%) was filtered
5-(Hydroxymethyl)-1-[(4-methoxy-9H-xanthen-9-yl)methyl]-
pyrrolidin-2-one (15a). LiCl (66 mg, 1.52 mmol) and NaBH4 (59
mg, 1.52 mmol) were added to a solution of ester 11a (290 mg,
0.76 mmol) in THF (6 mL). The mixture was cooled to 0 °C, and
EtOH (12 mL) was added dropwise. After 12 h at rt, AcOH was
added until neutral pH, and the solvents were removed under
reduced pressure. The residue was partitioned between CH2Cl2 and
water, and the organic layer was washed with brine, dried with
Na2SO4, filtered, and concentrated to afford 15a (239 mg, 93%) as
a foam: IR (KBr) 3378 (OH), 1667 (CO) cm-1; 1H NMR δ 7.33-
6.75 (m, 13H), 6.76 (dd, J ) 7.6, 1.3 Hz, 1H), 4.49-4.43 (m, 2H),
3.94 (s, 6H, OMe), 3.70-3.62 (m, 2H), 3.43 (dd, J ) 12.0, 5.0
Hz, 1H), 3.42 (t, J ) 6.0 Hz, 1H), 3.23 (t, J ) 7.6 Hz, 1H), 3.22
(dd, J ) 8.6, 4.5 Hz, 1H), 3.02 (dd, J ) 8.8, 6.7 Hz, 1H), 2.97 (dd,
J ) 8.8, 6.7 Hz, 1H), 2.85-2.75 (m, 2H), 2.41-1.82 (m, 10H);
13C NMR/ DEPT δ 176.2 (CO × 2), 151.6 (C × 2), 147.5 (C),
147.4 (C), 141.2 (C), 141.1 (C), 128.5 (CH), 128.3 (CH), 127.8
(CH × 2), 123.9 (C × 2), 123.6 (C × 2), 123.2 (CH), 122.9 (CH
× 2), 122.5 (CH), 120.2 (CH), 120.0 (CH), 116.3 (CH), 116.2 (CH),
110.3 (CH × 2), 61.6 (CH2 × 2), 60.7 (CH × 2), 56.6 (OMe × 2),
48.7 (CH2), 48.5 (CH2), 36.8 (CH × 2), 30.0 (CH2 × 2), 21.0 (CH2
× 2); MS (CI) (m/z) 340 [(M + H)+,100], 211 (12), 168 (10);
HRMS (CI) calcd for C20H22NO4 340.1549, found 340.1540.
1
out: mp 165 °C; IR (KBr) 1662 (CO) cm-1; H NMR δ 7.75 (d,
J ) 8.0 Hz, 1H), 7.24-7.07 (m, 3H), 6.85 (d, J) 8.5 Hz, 1H),
6.78 (d, J ) 8.5 Hz, 1H), 5.66 (s, 1H), 5.53 (d, J ) 13.5 Hz, 1H),
3.97-3.93 (m, 1H), 3.93 (s, 3H, OMe), 3.05 (dd, J ) 13.5, 7.1
Hz, 1H), 2.72-2.64 (m, 4H), 1.99-1.86 (m 2H); 13C NMR/ DEPT
δ 168.6 (CO), 149.8 (C), 145.9 (C), 138.7 (C), 135.0 (C), 129.6
(CH), 128.2 (CH), 127.8 (C), 124.4 (CH), 123.4 (CH), 122.0 (C),
120.3 (C), 116.2 (CH), 110.0 (CH), 108.8 (CH), 56.1 (OMe), 52.7
(CH2), 39.1 (CH), 32.7 (CH2), 32.6 (CH2), 20.3 (CH2); MS (EI)
(m/z) 333 (M+, 100), 318 (41), 302 (19); HRMS (EI) calcd for
C21H19NO3 333.1365, found 333.1372.
7-Methoxy-1,2,3,12b-tetrahydro-13H-pyrrolo[1,2-a]xantheno-
[1,9-de]azepin-13-one (8c). Aldehyde 16c (380 mg, 1.12 mmol)
was dissolved in AcOH (4 mL), concd HCl (1.4 mL) was added,
and the mixture was heated at 70 °C for 20 min. After workup as
in the preparation of 8a, the residue was purified by column
chromatography (Al2O3, CH2Cl2) giving 8c (167 mg, 47%): mp
210 °C; IR (KBr) 1662 (CO); 1H NMR δ 7.68-6.97 (m, 4H), 6.92
(d, J ) 8.5 Hz, 1H), 6.88 (d, J ) 8.5 Hz, 1H), 6.29 (s, 1H), 4.45
J. Org. Chem, Vol. 72, No. 23, 2007 8809