V. E. Kalugin, A. M. Shestopalov / Tetrahedron Letters 52 (2011) 1557–1560
1559
X = CO2Me
1
R
CN
O
NH2
X
X
R
tBuOK
O
X = CN
13
10, X = CO2Me
12, X = CN
14, X= CO2Me
15, X= CN
Scheme 5. Proposed mechanism for the formation of benzofuro[3,2-c]isoquinolines 1 and 13.
starting from 1-cyano-2-naphthol10 (16) and methyl 2-(chloro-
methyl)benzoate (9) or 2-(chloromethyl)benzonitrile (11) gave
naphtho[10,20:4,5]furo[3,2-c]isoquinoline-5(6H)-on (18) or 5-ami-
no naphtho[10,20:4,5]furo[3,2-c]isoquinoline (20) in good yields
(Scheme 6).
C16H13NO3: C, 71.90; H, 4.90; N, 5.24. Found: C, 71.86; H, 4.61;
N, 4.53.
1.2. General procedure for the synthesis of compounds 1a–c and
18
In conclusion, we have developed a convenient method for the
synthesis of benzofuro[3,2-c]isoquinolines 1a–c and 13a–c in good
yields and short reaction times, using substituted salicylonitriles
7a–c and methyl 2-(chloromethyl)benzoate (9) or 2-(chloro-
methyl)benzonitrile (11) as starting materials. This method was
also useful for the synthesis of novel fused naphtho[10,20:4,
5]furo[3,2-c]isoquinoline heterocycles 18 and 20.
To a solution of 10a–c or 17 (3 mmol) in DMF (3 ml) was added
tBuOK (0.5 g, 4.5 mmol). The mixture was stirred at 40 °C for
30 min and then poured into a mixture of H2O (30 ml) and AcOH
(0.5 ml). The resulting crystals were filtered, washed with H2O,
dried, and recrystallized from an appropriate solvent.
1.2.1. Compound 1a
1.1. General procedure for the synthesis of compounds 10a–c
and 17
Yield 80%, mp 304–305 °C (DMF–MeOH) [Lit.3 310 °C (EtOH)].
1H NMR (300 MHz, DMSO-d6) d: 7.39 (t, J = 7.3 Hz, 1H, H-8), 7.48
(t, J = 8.1 Hz, 1H, H-9), 7.60 (t, J = 7.3 Hz, 1H, H-2), 7.72 (d,
J = 8.1 Hz, 1H, H-10), 7.88 (t, J = 7.3 Hz, 1H, H-3), 8.02 (m, 2H, H-
1, H-7), 8.33 (d, J = 8.1 Hz, 1H, H-4), 12.33 (s, 1H, NH). 13C NMR
(75 MHz, DMSO-d6) d: 112.64, 119.69, 120.05, 120.33, 122.17,
124.02, 124.83, 127.44, 127.58, 128.17, 129.07, 133.95, 135.93,
To a solution of 7a–c or 16 (4 mmol) and methyl 2-(chloro-
methyl)benzoate6 (9) (0.74 g, 4 mmol) in DMF (4 ml) was added
dry K2CO3 (1.1 g, 8 mmol). The mixture was stirred at 50–55 °C
for 40 min, poured into H2O (30 ml), and extracted with CHCl3
(15 ml ꢀ 3). The extract was washed with H2O (20 ml ꢀ 2) and
dried over Na2SO4. The solvent was evaporated in vacuo and the
product crystallized from an appropriate solvent.
154.73, 161.89. IR (KBr) m: 1652, 1640, 1604, 1588, 1548, 1456,
1352, 1324, 1208, 1060, 860, 764, 740 cmꢁ1. Anal. Calcd for
C15H9NO2: C, 76.59; H, 3.86; N, 5.95. Found: C, 76.66; H, 3.74; N,
5.83.
1.1.1. Compound 10a
Yield 62%, mp 96–97 °C (CHCl3–hexane). 1H NMR (300 MHz,
DMSO-d6) d: 3.81 (s, 3H, OCH3), 5.56 (s, 2H, OCH2), 7.11 (t,
J = 7.3 Hz, 1H, ArH), 7.27 (d, J = 8.1 Hz, 1H, ArH), 7.51 (t,
J = 8.8 Hz, 1H, ArH), 7.69 (m, 4H, ArH), 7.93 (d, J = 7.3 Hz, 1H,
ArH). 13C NMR (75 MHz, DMSO-d6) d: 52.68, 69.13, 100.97,
113.71, 116.81, 121.93, 129.02, 129.22, 129.41, 130.90, 133.00,
1.3. General procedure for the synthesis of compounds 12a–c
and 19
To a stirred solution of 7a–c or 16 (4 mmol) and 2-(chloro-
methyl)benzonitrile9 (11) (0.6 g, 4 mmol) in DMF (4 ml) was added
dry K2CO3 (1.1 g, 8 mmol). The mixture was stirred at 50–55 °C for
40 min, poured into H2O (30 ml), and extracted with CHCl3
(15 ml ꢀ 3). The extract was washed with H2O (20 ml ꢀ 2) and
134.18, 135.69, 137.05, 160.29, 167.47. IR (KBr)
m: 2948, 2224,
1720, 1584, 1496, 1260, 1024, 748 cmꢁ1
.
Anal. Calcd for
O
HN
CN
CO2Me
9
a
O
b
O
CN
OH
18 (74%)
17 (72%)
NH2
16
N
CN
11
CN
a
c
O
O
20 (85%)
19 (93%)
Scheme 6. Reagents and conditions: (a) 2 equiv K2CO3, DMF, 50–55 °C, 40 min; (b) 1.5 equiv tBuOK, DMF, 40 °C, 30 min; (c) 1 equiv tBuOK, DMF, 40 °C.