New synthetic route to tetracyclic quinazolin-4(3H)-one ring system

Article abstract of DOI:10.3987/com-02-9508

Reactions of dithiazoles (1a-e) and (9a-b) with 3,4-dimethoxyphenethylamine (2) in CH₂Cl₂ at room temperature produce 3,4-dihydro-3-(3,4-dimethoxyphenethyl)-4-oxoquinazoline-2-carbonitriles (3a-d) and 4-hydroxy-4-phenyl-3,4-dihydroqu

Full text of DOI:10.3987/com-02-9508

HETEROCYCLES, Vol. 57, No. 8, 2002, pp. 1471 - 1485, Received, 7th May, 2002
NEW SYNTHETIC ROUTE TO TETRACYCLIC
QUINAZOLIN-4(3H)-ONE RING SYSTEM
Pramod K. Mohanta and Kyongtae Kim*
School of Chemistry and Molecular Engineering, Seoul National University,
Seoul 151-742, South Korea
Abstract - Reactions of dithiazoles (1a-e) and (9a-b) with 3,4-dimethoxy-
phenethylamine (2) in CH2Cl2 at room temperature produce 3,4-dihydro-3-(3,4-
dimethoxyphenethyl)-4-oxoquinazoline-2-carbonitriles (3a-d) and 4-hydroxy-
4-phenyl-3,4-dihydroquinazoline-2-carbonitriles
(10a-b),
respectively.
Compounds (3a-d) on treatment with TFAA/HCl at 120-130°C gave 3-(3,4-
dimethoxy- phenethyl)quinazoline-2,4(1H,3H)-diones (5a-d) in excellent yields.
Quinazolin-4(3H)-ones (3a-d), quinazoline-2,4(1H,3H)-diones (5a-d) and their
thieno analogs (3e and 5e) as well as 4-hydroxy-3-(3,4-dimethoxyphenethyl)-4-
phenyl-3,4-dihydroquinazoline-2-carbonitriles (10a-b) are cyclized in the
presence of P2O5/POCl3 in xylene at 130°C to tetracyclic benzazepino[2,3-
b]quinazolinones
(8a-d),
isoquino[1,2-b]quinazolinones
(6a-d),
thienopyrimidinones (6e and 8e) as well as isoquino[1,2-c]quinazoline-6-
carbonitriles (11a-b), respectively, in good yields.
Tetracyclic quinazolin-4(3H)-one ring systems form the characteristic framework of numerous
heterocyclic physiologically active compounds. For instance, a number of alkaloids such as tryptanthrin
(also known as couroptitine),1 alantrypinone,2 asperlicin C,3 circumdatin F,3 and sclerotigenin3
comprised of quinazolin-4(3H)-one template in which a bicyclic ring system is fused to the pyrimidine
ring of quinazolin-4(3H)-one. In addition, molecules based on polycyclic quinazolin-4(3H)-one4 skeleton
exhibit a multitude of interesting pharmacological properties such as cardiotonic,5 analgesic,6 cytotoxic7
and neurokinin NK1 receptor activities.8 Similarly, quinazolinedione template appears in a wide rage of
bioactive molecules that interact with G-protein coupled receptors (GPCRs, adrenergic, serotonergic,
dopaminergic, endothelin ETA), and enzymes (cyclooxygenase, collagenase, aldose reductase and

carbonic anhydrase).9 Recently, structure activity relationship study reveals that quinazoline-2,4(1H, 3H)-
diones having N-3 side chain (two carbon tether) are essential for good reactivity, and SGB-1534 and its
analogs in that series are found to be α1A- adrenoceptor antagonistst.10
Over the past few years, we have been working on the development of new synthetic strategies for
nitrogen and sulfur heterocycles,11 which are based on the use of 5-arylimino-4-chloro-5H-1,2,3-
dithiazoles12 as key intermediates. At present, we are interested in devising new synthetic route for
tetracyclic quinazolin-4(3H)-one derivatives from methyl N-(4-chloro-5H-1,2,3-dithiazol-5-
ylidene)anthranilates (1). The synthesis of a novel series of 2-cyanoquinazolin-4(3H)-ones have been
reported in our earlier papers by describing the reaction of 1 with various aliphatic13 and aromatic primary
amines.14 We have supposed that treatment of 1 with 3,4-dimethoxyphenethylamine (2) gives 3,4-
dihydro-3-(3,4-dimethoxyphenethyl)-4-oxoquinazoline-2-carbonitrile (3), which cyclizes into tetracyclic
quinazoline derivatives. In this paper, we discuss the results obtained from the reactions of 3 with
TFAA/HCl and P2O5/POCl3.
Dithiazoles (1a-d), used as starting materials for the synthesis of 3 are prepared according to the reported
procedure13 by condensation of methyl anthranilates with 4,5-dichloro-1,2-3-dithiazolium chloride
(Appel’s salt)15 in pyridine/CH2Cl2 at room temperature. Reaction of 1a with 2 in CH2Cl2 at room
temparature gave 2-cyanoquinazolinone (3a) in 63% yield with extrusion of sulfur (Scheme 1). A number
of tri and tetrasubstituted quinazolinones (3b-d) and thienopyrimidinone (3e) were synthesized from the
reactions of dithiazoles (1b-e) with 2 under similar conditions, respectively. Taking our earlier
experiences into account for the synthesis of quinazolinocarboline natural products,16 3a was treated with
TFAA/HCl at 120°C with a view to obtain quinazolinone derivative (6a). On heating this reaction
mixture for 3.5 h, quinazoline-2,4(1H, 3H)-dione (5a) (lit.,17 202-203°C) (Scheme 1) was obtained
exclusively. The formation of 5a may be due to the hydrolytic elimination of cyano group from
carbocation (4a). Compound (5a) was reported to exhibit sedative and hypertensive properties.17 When
compound (5a) was heated (130°C) with P2O5/POCl3 in m-xylene under Bischler-Napieralski conditions,
isoquino[1,2-b]quinazolin-8-one (6a)18 was obtained in 62 % yield. Similarly compound (3b-d) and the

thieno analog (3e) on treatment with TFAA/HCl at 120-130°C yielded 5a-d and thienopyrimidine-2,4-
dione (5e), which underwent cyclodehydration with P2O5/POCl3 in refluxing xylene to form (6b-d and
6e), respectively. On the other hand, when 3a was treated with POCl3/P2O5 directly in m-xylene, the
linearly fused quinazolinone (8a) was obtained presumably via 7a (Scheme 1).
O
O
R2
R1
R2
R1
N
N
H O
3
OMe
OMe
OMe
OMe
N
N
HN
O
7a-d
8a-d
P O / POCl / m-Xylene /
2
5
3
o
130 C / 12-16 h
O
OMe
OMe
O
R2
R2
R1
OMe
OMe
OMe
CH Cl / rt
2
2
N
+
R1
N
NH2
24-31 h
N
CN
2
Cl
1, 3- 8a, R1 = R2 = H
b, R1 = H, R2 = Br
c, R1 = Cl, R2 = H
d, R1 = R2 = OMe
3a-d
S
S
1a-d
N
TFAA / HCl
o
120-130 C / 3 - 3.5 h
OMe
OMe
OMe
OMe
O
O
R2
R1
R2
R1
H O
2
N
N
N
H
5a-d
O
N
H
CN
4a-d
P O / POCl / m-Xylene /
2
5
o
3
130 C / 12-16 h
O
OMe
OMe
S
O
O
N
OMe
R2
R1
S
N
N
N
Cl
N
3e
CN
S
S
1e
6a-d
N
OMe
OMe
O
N
O
S
OMe
OMe
N
O
S
N
OMe
OMe
S
N
O
N
6e
O
8e
N
H
5e
OMe
OMe
Scheme 1

Table 1. Yield and Reaction Times for the Synthesis of Compounds (3, 5, 6 and 8)
Yield (%) / Time
3
Yield (%) / Time
5
Yield (%) / Time
6
Yield (%) / Time
8
1, 3-8
a, R1 = R2 = H
b, R1 = H, R2 = Br
c, R1 = Cl, R2 = H
63 (24 h)
74 (31 h)
78 (31 h)
71 (29 h)
93 (3 h)
94 (3 h)
97 (3 h)
96 (3.5 h)
62 (12 h)
68 (14 h)
64 (13 h)
68 (16 h)
69 (16 h)
67 (15 h)
65 (14 h)
66 (16 h)
d, R1 = R2 = OMe
O
S
OMe
N
76 (30 h)
96 (3.5 h)
49 (12 h)
51 (12 h)
Cl
S
S
N
e,
The other substituted benzazepino[2,3-b]quinazolinones (8b-d) and their thieno analog (8e) were also
obtained from 3b-d and 3e respectively under similar conditions (Table 1). Dithiazoles (9a and 9b),
prepared from the respective 2-aminobenzophenones, were reacted with 2 in CH2Cl2 at room
MeO
R2
OMe
R1
R2
OH
R2
R1
CH Cl / rt
P O / POCl / m-Xylene
2
2
2
5
3
o
N
O
+ 2
27-30 h
120-130 C / 4-5 h
N
R1
N
10
CN
N
N
Cl
OMe CN
MeO
S
11
N
S
Yield (%) / Reaction time
10 11
60 (30 h) 78 (5 h)
9a-b
a, R1 = H, R2= Cl
b, R1 = Me, R2= H 62 (27 h) 72 (4 h)
Scheme 2
temperature to yield respective 3,4-dihydro-4-hydroxy-4-phenylquinazoline-2-carbonitriles (10a) and
(10b), which underwent cyclodehydration in the presence of P2O5/POCl3 to form isoquino[2,1-
c]quinoline-6-carbonitriles (11a) and (11b) having phenyl group at C-13b position (Scheme 2). The
formation of 11a was evidenced by the appearance of two singlets at δ 6.36 and δ 6.93 due to the
respective H-13 and H-10 aromatic protons19 in the 1H NMR spectrum, while the C-13b carbon of 11a in

the 13C NMR spectrum appeared at δ 66.9. In addition, the N-CH2- proton signals (δ 3.49, 4.07) of
isoquino[2,1-c]quinoline (11a) appeared in downfield with respect to the proton signals (δ 3.25, 3.59) of
N-CH2- of the corresponding 3,4-dihydroquinazoline-2-carbonitrile (10a). The NOE experimental results
of 11a in 1H NMR spectrum are shown in Figure 1.
Cl
(6.65)
H
H*
H (3.49)
8
2
3
1
H
(4.07)
H
(7.12)
H*
4
*
H
13b
(2.75)
2'
3'
4'
9
1'
(6.93)
H*
H*
6
N
13
12
6'
5
H
5'
10
N
H
11
7
(3.07)
H
(7.12)
H*
OMe
(3.53)
CN
MeO
(3.79)
11a
* H-3, H-3', H-4', H-5' = δ 7.34-7.43
* H-4 = δ 7.21; H-13 = δ 6.36
Figure 1
To sum up, quinazolin-4(3H)-ones, quinazoline-2,4(1H, 3H)-diones, tetracyclic quinazolinones and their
thieno analogs were synthesized from methyl N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)anthranilates in
good yields.
EXPERIMENTAL
All melting points were recorded on a Fisher-Johns melting point apparatus and are uncorrected. IR
1
spectra were obtained on a Shimadzu IR-470 spectrophotometer in KBr. H NMR (300 MHz, 500 MHz)
13
and C NMR (75 MHz, 125 MHz) spectra were recorded in CDCl3 or DMSO-d6 using TMS as internal
standard. MS spectra were obtained by electron impact at 70 eV. Elemental analyses were determined by
the National Center for Inter-University Research Facilities, Seoul National University. Dichloromethane
was distilled over P2O5 prior to use. Column chromatography was performed on silica gel (Merck, 70-230
mesh, ASTM). Starting materials methyl N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)anthranilates (1a-e)
and 2-(benzoyl)arylimino-4-chloro-5H-1,2,3-dithiazoles (9a-b) were prepared according to reported

method.13
3,4-Dihydro-3-(3,4-dimethoxyphenethyl)-4-oxoquinazoline-2-carbonitriles (3a-d), 3,4-Dihydro-3-
(3,4-dimethoxyphenethyl)thieno[3,2-d]-4-oxopyrimidine-2-carbonitrile (3e) and 6-Chloro- (or 7-
Methyl-) 3,4-dihydro-3-(3,4-dimethoxyphenethyl)-4-hydroxy-4-phenylquinazoline-2-carbonitriles
(10a-b); General Procedure: To a stirred solution of dithiazole (1a-e/9a-b) (0.70 – 4.89 mmol) in
CH2Cl2 (25 –35 mL), a solution of 2 (140 - 974 mg, 0.77 – 5.37 mmol) in CH2Cl2 (10 -20 mL) was added
and the reaction mixture was stirred (monitored by TLC) at rt for 24-31 h. The mixture was poured into
water (30 mL) and the organic layer was separated out. The aqueous layer was shaked with CH2Cl2 (2 ×
20 mL) to extract the product [compounds (10a-b) were extracted with CHCl3 (3 × 20 mL)]. The
combined organic extract was washed with water (30 mL), dried (MgSO4) and the solvent was evaporated
under reduced pressure to afford crude 3a-e/10a-b, which was purified by passing through silica gel
column using n-hexane-EtOAc [3a-e (17:3)/ 10a-b (3:2)] as eluent.
3,4-Dihydro-3-(3,4-dimethoxyphenethyl)-4-oxoquinazoline-2-carbonitrile (3a): colorless crystals
(CH2Cl2-n-hexane), mp 159-160˚C; IR (KBr) (ν, cm-1) 1686, 1584, 1510; 1H NMR (CDCl3, 300 MHz, δ)
3.08 (2H, t, J = 7.6 Hz, CH2), 3.79 (3H, s, OMe), 3.86 (3H, s, OMe), 4.48 (2H, t, J = 7.6 Hz, NCH2 ),
6.75-6.79 (3H, m, ArH), 7.58 (1H, td, J = 1.3, 7.5 Hz, ArH ), 7.77 (1H, dd, J = 1.1, 7.7 Hz, ArH), 7.84
(1H, td, J = 1.3, 7.5 Hz, ArH), 8.36 (1H, dd, J = 1.6, 8.0 Hz, ArH); 13C NMR (CDCl3, 75 MHz, δ) 34.3,
48.4, 55.7, 55.8, 111.3, 111.4, 112.0, 121.2, 122.6, 127.0, 128.4, 128.7, 130.0, 131.4, 135.1, 146.3, 148.1,
149.1, 159.8; MS (EI) m/z 335 (M+, 46), 164 (100), 149 (42). Anal. Calcd for C19H17N3O3: C, 68.05; H,
5.11; N, 12.53. Found: C, 68.01; H, 5.09; N, 12.54.
6-Bromo-3,4-dihydro-3-(3,4-dimethoxyphenethyl)-4-oxoquinazoline-2-carbonitrile (3b): colorless
crystals (CHCl3-n-hexane), mp 193-194ºC; IR (KBr) (ν, cm-1) 1686, 1571, 1507, 1459 ; 1H NMR (CDCl3,
300 MHz, δ) 3.08 (2H, t, J = 7.5 Hz, CH2), 3.81 (3H, s, OMe), 3.86 (3H, s, OMe), 4.48 (2H, t, J = 7.6 Hz,
NCH2), 6.73-6.81 (3H, m, ArH ), 7.64 (1H, d, J = 8.6 Hz, ArH), 7.93 (1H, dd, J = 2.6, 8.7 Hz, ArH), 8.47
13
(1H, d, J = 2.3 Hz, ArH); C NMR (CDCl3, 75 MHz, δ) 34.2, 48.6, 55.8, 55.9, 111.3, 111.5, 112.1,
121.23, 123.9, 124.2, 125.9, 129.7, 131.0, 131.7, 138.4, 145.1, 148.3, 149.2, 158.7; MS (EI) m/z 413 (M+,
4.03), 164 (100), 151 (16. 57). Anal. Calcd for C19H16N3O3Br: C, 55.09; H, 3.89; N, 10.14. Found: C,

55.35; H, 3.64; N, 10.34.
7-Chloro-3,4-dihydro-3-(3,4-dimethoxyphenethyl)-4-oxoquinazoline-2-carbonitrile (3c): colorless
1
crystals (CHCl3-n-hexane), mp 180-181˚C; IR (KBr) (ν, cm-1) 1689, 1577, 1510 ; H NMR (CDCl3, 300
MHz, δ) 3.08 (2H, t, J = 7.3 Hz, CH2), 3.81 (3H, s, OMe), 3.86 (3H, s, OMe), 4.47 (2H, t, J = 7.6 Hz,
NCH2 ), 6.73-6.89 (3H, m, ArH), 7.58 (1H, dd, J = 1.4, 8.5 Hz, ArH), 7.75 (1H, s, ArH ), 8.26 (1H, d, J =
13
8.5 Hz, ArH); C NMR (CDCl3, 75 MHz, δ) 34.2, 48.5, 55.8, 55.8, 111.1, 111.4, 112.1, 121.0, 121.2,
127.9, 128.4, 128.5, 130.5, 132.6, 142.0, 147.1, 148.3, 149.2, 159.2; MS (EI) m/z 369 (M+, 7.36), 164
(100), 151 (14.55), 149 (13.95). Anal. Calcd for C19H16N3O3Cl: C, 61.71; H, 4.36; N, 11.36. Found: C,
61.87; H, 4.59; N, 11.42.
3,4-Dihydro-6,7-dimethoxy-3-(3,4-dimethoxyphenethyl)-4-oxoquinazoline-2-carbonitrile (3d): color-
1
less crystals (CHCl3-n-hexane), mp 196-197˚C; IR (KBr) (ν, cm-1) 1664, 1600, 1580, 1452 ; H NMR
(CDCl3, 300 MHz, δ) 3.08 (2H, t, J = 7.5 Hz, CH2), 3.80 (3H, s, OMe), 3.86 (3H, s, OMe), 4.01 (3H, s,
OMe), 4.04 (3H, s, OMe), 4.48 (2H, t, J = 7.5 Hz, NCH2), 6.75-6.79 (3H, m, ArH), 7.14 (1H, s, ArH),
7.64 (1H, s, ArH); 13C NMR (CDCl3, 75 MHz, δ) 34.4, 48.4, 55.7, 55.8, 56.5 (2C), 105.6, 108.4, 111.3,
111.6, 112.0, 116.7, 121.2, 128.8, 129.8, 142.5, 148.1, 149.1, 151.4, 155.3, 159.2; MS (EI) m/z 395 (M+,
4.12); (164, 100), 149 (12.32). Anal. Calcd for C21H21N3O5: C, 63.79; H, 5.35; N, 10.63. Found: C, 63.41;
H, 5.37; N, 10.55.
3,4-Dihydro-3-(3,4-dimethoxyphenethyl)thieno[3,2-d]-4-oxopyrimidine-2-carbonitrile (3e): colorless
1
crystals (CH2Cl2-n-hexane), mp 184-185˚C; IR (KBr) (ν, cm-1) 1673, 1548, 1507; H NMR (CDCl3, 300
MHz, δ) 3.10 (2H, t, J = 7.3 Hz, CH2 ), 3.80 (3H, s, OMe), 3.86 (3H, , s, OMe), 4.52 (2H, t, J = 7.6 Hz,
NCH2), 6.76-6.82 (3H, m, ArH), 7.39 (1H, d, J = 5.1 Hz, ArH), 7.89 (1H, d, J = 5.3 Hz, ArH); 13C NMR
(CDCl3, 75 MHz, δ) 34.4, 48.4, 55.8, 55.9, 111.5, 112.1, 112.2, 125.4, 125.8, 126.5, 128.5, 132.5, 135.6,
148.3, 149.2, 154.9, 155.9; MS (EI) m/z 341 (M+, 5.4), 164 (100), 149 (16.6). Anal. Calcd for
C17H15N3O3S: C, 59.81; H, 4.43; N, 12.31; S, 9.39. Found: C, 59.52, H, 4.41; N, 12.16; S, 9.48.
6-Chloro-3,4-dihydro-4-hydroxy-3-(3,4-dimethoxyphenethyl)-4-phenylquinazoline-2-carbonitrile
(10a): colorless needles (EtOH-benzene), mp 193-194˚C; IR (KBr) (ν, cm-1) 3216, 1584, 1507; 1H NMR

(DMSO- d6, 300 MHz, δ) 2.41 (1H, td, J = 5.1, 12.3 Hz, CH2), 2.88 (1H, td, J = 5.3, 12.1 Hz, CH2),
3.25 (1H, td, J = 5.4, 12.4 Hz, NCH2), 3.59 (1H, td, J = 5.1, 11.9 Hz, NCH2), 3.72 (3H, s, OMe), 3.74 (3H,
s, OMe), 6.47 (1H, d, J = 1.5 Hz, ArH), 6.52 (1H, dd, J = 1.6, 9.7 Hz, ArH), 6.77 (1H, d, J = 8.1 Hz,
ArH), 6.85 (1H, d, J = 2.0 Hz, ArH), 7.24-7.32 (1H, m, ArH), 7.35-7.42 (2H, m, ArH), 7.46 (1H, d, J =
6.8 Hz, ArH), 7.53 (2H, d, J = 7.7 Hz, ArH), 7.85 (1H, s, ArH); 13C NMR (DMSO-d6, 75 MHz, δ) 37.0,
48.9, 55.5, 55.7, 85.7, 112.2 (2 C), 113.2, 120.5, 126.9, 127.1 (2 C), 127.4, 128.6 (2 C), 128.8, 129.4,
130.2, 130.5, 130.7, 133.2, 138.1, 144.3, 147.8, 150.0; FAB-MS m/z 448 (M++1, 11.94), 447 (M+, 7.18),
267 (13.34), 165 (100), 154 (60.82). Anal. Calcd for C25H22N3O3Cl: C, 67.04; H, 4.95; N, 9.38. Found: C,
67.27, H, 4.71; N, 9.14.
3,4-Dihydro-4-hydroxy-3-(3,4-Dimethoxyphenethyl)-7-methyl-4-phenylquinazoline-2-carbonitrile
(10b): colorless needles (EtOH-benzene), mp 182-183˚C; IR (KBr) (ν, cm-1) 3168, 1584, 1548, 1507;
1H NMR (DMSO-d6, 300 MHz, δ) 2.23 (3H, s, CH3), 2.44 (1H, td, J = 5.0, 11.9 Hz, CH2), 2.84 (1H, td,
J = 5.3, 12.3 Hz, CH2), 3.45 (1H, td, J = 5.1, 11.4 Hz, NCH2), 3.67 (1H, td, J = 4.9, 11.7 Hz, NCH2), 3.73
(3H, s, OMe), 3.78 (3H, s, OMe), 6.34 (1H, d, J = 1.5 Hz, ArH), 6.45 (1H, dd, J = 7.6, 1.5 Hz, ArH), 6.70
(1H, d, J = 7.9 Hz, ArH), 6.81 (1H, d, J = 6.8 Hz, ArH), 6.89 (1H, s, ArH), 6.94 (1H, dd, J = 1.2, 7.9 Hz,
ArH), 7.36-7.45 (3H, m, ArH), 7.52 (2H, d, J = 7.1 Hz, ArH); 13C NMR (DMSO-d6, 75 MHz, δ) 20.9,
36.6, 49.6, 56.7, 56.9, 86.2, 111.4, 111.8, 112.3, 120.6, 124.1, 125.4, 128.0 (2 C), 128.1 (2 C), 128.5,
128.5, 128.9, 130.2, 133.5, 138.8, 139.3, 143.4, 147.7, 149.0; FAB-MS m/z 428 (M++1, 25.98), 427 (M+,
12.22), 307 (13.10), 247 (12.50), 165 (43.18), 154 (100), 136 (81.07). Anal. Calcd for C26H25N3O3: C,
73.05; H, 5.89; N, 9.83. Found: C, 73.32, H, 5.65; N, 9.74.
3-(3,4-Dimethoxyphenethyl)quinazoline-2,4(1H,3H)-diones (5a-d) and 3-(3,4-dimethoxyphene-
thyl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione (5e); General Procedure
A mixture of 3 (0.48 – 0.81 mmol), HCl (37%) (1.6 - 2.8 mL) and TFAA (11.32 – 19.11 mmol, 1.6 – 2.7
mL) was heated at 120-130°C for 3.0-3.5 h (monitored by TLC). The reaction mixture was cooled to rt
and was poured onto crushed ice. The solid precipitated out was filtered, washed with water repeatedly
till the residue become free from acid. The residue was recrystallized from CHCl3-n-hexane.
3-(3,4-Dimethoxyphenethyl)quinazoline-2,4(1H,3H)-dione (5a): colorless crystals, mp 199-200˚C

(lit.,17 202-203˚C); IR (KBr) (ν, cm-1) 3456, 1702, 1648, 1510; 1H NMR (CDCl3, 300 MHz, δ) 2.98 (2H, t,
J = 7.9 Hz, CH2), 3.83 (3H, s, OMe), 3.86 (3H, s, OMe), 4.32 (2H, t, J = 7.9 Hz, NCH2), 6.79-6.95 (3H,
m, ArH), 7.16 (1H, d, J = 8.1 Hz, ArH), 7.26 (1H, t, J = 7.4 Hz, ArH), 7.50 (1H, t, J = 7.5 Hz, ArH), 8.15
(1H, d, J = 8.8 Hz, ArH), 10.84 (1H, br s, NH, D2O-exchangeable); 13C NMR (CDCl3, 75 MHz, δ) 34.1,
42.9, 56.2, 56.7, 111.6, 112.5, 115.0, 115.6, 121.3, 123.9, 128.7, 131.5, 135.5, 139.1, 148.1, 149.2, 152.7,
162.7; FAB-MS m/z 327 (M++ 1, 50.5), 326 (M+, 40.2), 164 (89.8), 154 (100). Anal. Calcd for
C18H18N2O4: C, 66.25; H, 5.56; N, 8.58. Found: C, 66.51; H, 5.51; N, 8.52.
6-Bromo-3-(3,4-dimethoxyphenethyl)quinazoline-2,4(1H,3H)-dione (5b): colorless solid, mp 231-
1
233ºC; IR (KBr) (ν, cm-1) 3340, 1708, 1648, 1507; H NMR (DMSO-d6, 300 MHz, δ) 2.83 (2H, t, J =
6.7 Hz, CH2), 3.75 (6H, s, 2 x OMe), 4.01 (2H, t, J = 6.4 Hz, NCH2), 6.76 (1H, d, J = 8.5 Hz, ArH), 6.82
(1H, s, ArH), 6.91 (1H, dd, J = 8.2, 2.9 Hz, ArH), 7.16 (1H, dd, J = 8.7, 3.8 Hz, ArH), 7.83 (1H, m, ArH),
8.0 (1H, dd, J = 4.4, 2,2 Hz, ArH), 11.60 (1H, br s, NH); 13C NMR (DMSO-d6, 75 MHz, δ) 32.9, 41.7,
55.5, 55.6, 112.1, 112.5, 114.1, 115.7, 117.7, 120.7, 129.4, 131.8, 137.7, 138.8, 147.6, 148.8, 149.9,
160.9; MS (EI) m/z 404 (M+, 8.5), 226 (4.04), 164 (100), 151 (14.19). Anal. Calcd for C18H17N2O4Br: C,
53.35; H, 4.23; N, 6.91. Found: C, 53.47; H, 4.55; N, 6.72.
7-Chloro-3-(3,4-dimethoxyphenethyl)quinazoline-2,4(1H,3H)-dione (5c): colorless solid, mp 226-
1
228˚C; IR (KBr) (ν, cm-1) 3292, 1715, 1644, 1587; H NMR (DMSO-d6, 300 MHz, δ) 2.80 (2H, t, J =
7.1 Hz, CH2), 3.40 (3H, s, OMe), 3.73 (3H, s, OMe), 4.08 (2H, t, J = 7.4 Hz, NCH2), 6.70 (1H, dd, J = 1.7,
8.0 Hz, ArH), 6.78 (1H, s, ArH), 6.85 (1H, d, J = 8.1 Hz, ArH), 7.15 (1H, d, J = 1.8 Hz, ArH), 7.20 (1H,
dd, J = 1.9, 8.4 Hz, ArH), 7.89 (1H, dd, J = 1.9, 8.4 Hz, ArH), 11.52 (1H, br s, NH); 13C NMR (DMSO-d6,
75 MHz, δ) 33.0, 41.7, 55.5, 55.7, 112.1, 112.5, 112.9, 114.6, 120.7, 122.9, 129.6, 131.1, 139.5, 140.6,
147.6, 148.8, 150.1, 161.3; MS (EI) m/z 360 (M+, 9.5), 310 (4.67), 180 (7.44), 164 (100), 151 (14.19).
Anal. Calcd for C18H17N2O4Cl: C, 59.92; H, 4.75; N, 7.76. Found: C, 59.81; H, 4.64; N, 7.97.
6,7-Dimethoxy-3-(3,4-dimethoxyphenethyl)quinazoline-2,4(1H,3H)-dione (5d): colorless solid, mp
233-234˚C; IR (KBr) (ν, cm-1) 3392, 1702, 1644, 1612, 1504; 1H NMR (CDCl3, 300 MHz, δ) 2.95 (2H, t,
J = 8.0 Hz, CH2), 3.80 (3H, s, OMe), 3.81 (3H, s, OMe), 3.84 (3H, s, OMe), 3.85 (3H, s, OMe), 4.23 (2H,
t, J = 7.9 Hz, NCH2), 6.50 (1H, s, ArH), 6.78-6.91 (3H, m, ArH), 7.61 (1H, s, ArH), 9.60 (1H, br s, NH);

13C NMR (CDCl3, 75 MHz, δ) 33.7, 42.4, 55.9 (2 C), 56.3 (2 C), 107.0, 108.23, 111.4, 112.3, 120.9,
125.9, 131.2, 134.2, 146.3, 147.8, 149.0, 151.7, 155.6, 161.8; MS (EI) m/z 386 (M+, 4.52), 207 (4.03),
164 (100), 149 (9.90). Anal. Calcd for C20H22N2O6: C, 62.17; H, 5.74; N, 7.25. Found: C, 62.11; H, 5.52;
N, 7.47.
3-(3,4-Dimethoxyphenethyl)thieno[3,2-b]pyrimidine-2,4(1H, 3H)-dione (5e): colorless solid, mp 207-
208ºC; IR (KBr) (υ, cm-1) 3291, 1702, 1638, 1510, 1436; 1H NMR (CDCl3, 300 MHz, δ) 2.96 (2H, t, J =
7.9 Hz, CH2), 3.85 (3H, s, OMe), 3.87 (3H, s, OMe), 4.27 (2H, t, J = 7.9 Hz, NCH2), 6.79-6.88 (3H, m,
13
ArH), 6.92 (1H, d, J = 5.1 Hz, ArH), 7.85 (1H, d, J = 5.1 Hz, ArH), 10.82 (1H, br s, NH); C NMR
(CDCl3, 75 MHz, δ) 33.6, 42.5, 55.8, 55.8, 111.2, 112.1, 113.1, 116.5, 120.9, 131.0, 135.3, 143.5,
147.62, 148.8, 153.0, 158.4; MS (EI) m/z 332 (M+, 10.68), 318 (96), 164 (100), 149 (13.86). Anal. Calcd
for C16H16N2O4S: C, 57.82; H, 4.85; N, 8.43; S, 9.65. Found: C, 58.03; H, 4.98; N, 8.23; S, 9.48.
5,6-Dihydro-2,3-dimethoxyisoquino[1,2-b]quinazolin-8-ones (6a-d); 5,6-Dihydro-2,3-dimethoxythie-
no[3′,2′:4,5]pyrimido[2,1-a]isoquinolin-8-one (6e); 5,6-Dihydro-2,3-dimethoxy[3]benzazepino[2,3-
b]quinazoline-8,14-dione (8a-e) and 9,13b-Dihydro-11,12-dimethoxy-13b-phenyl-8(H)-isoquino[2,1-
c]quinazoline-6-carbonitriles (11a-b); General Procedure
To a suspension of 3a-e/5a-e/10a-b (0.45 – 0.73 mmol) and P2O5 (640 – 1036 mg, 5.5 – 7.3 mmol) in m-
xylene (20 - 25 mL), POCl3 (1.23 – 1.97 mL, 13.17 – 21.37 mmol) was added at rt and the reaction
mixture was heated at 130°C for 12-16 h [4-5 h in case of 10a-b] (monitored by TLC). The mixture was
cooled down to rt, poured slowly into saturated potassium bicarbonate solution. The upper xylene layer
was separated out. Aqueous layer was extracted with CHCl3 (3 × 20 mL). The combined organic extract
was washed with water (20 mL), dried (MgSO4) and the solvent was evaporated under reduced pressure
to afford crude 8a-e/6a-e/11a-b, which was purified by passing through silica gel column using n-hexane-
EtOAc [8a-e (3:2)/6a-e (3:1)/11a-b (4:1)] as eluent.
5,6-Dihydro-2,3-dimethoxyisoquino[1,2-b]quinazolin-8-one (6a): colorless crystals (CH2Cl2-n-hex-
ane), mp 248-249˚C (lit.,18a 249-250 ˚C); IR, 1H and 13C NMR and MS spectroscopic data are reported in
the literature.18
10-Bromo-5,6-dihydro-2,3-dimethoxyisoquino[1,2-b]quinazolin-8-one (6b): colorless needles (CHCl3-

n-hexane), mp 238-240ºC; IR (KBr) (υ, cm-1) 1657, 1587, 1548; 1H NMR (CDCl3, 300 MHz, δ) 3.04 (2H,
t, J = 6.5 Hz, CH2), 3.97 (3H, s, OMe), 4.03 (3H, s, OMe), 4.39 (2H, t, J = 6.5 Hz, CH2), 6.74 (1H, s,
ArH), 7.63 (1H, d, J = 8.7 Hz, ArH), 7.81 (1H, dd, J = 8.7, 2.7 Hz, ArH), 7.94 (1H, s, ArH), 8.42 (1H, d,
J = 1.9 Hz, ArH); 13C NMR (CDCl3, 75 MHz, δ) 26.9, 39.9, 56.1, 56.2, 109.7, 109.9, 119.4, 121.5,
121.8, 129.1, 129.4, 131.0, 137.3, 146.8, 148.6, 149.7, 152.4, 160.7. MS (EI) m/z 386 (M+, 100), 371
(27.30), 355 (14.02). Anal. Calcd for C18H15N2O3Br: C, 55.83; H, 3.90; N, 7.23. Found: C, 55.59; H,
3.78; N, 7.36.
11-Chloro-5,6-dihydro-2,3-dimethoxyisoquino[1,2-b]quinazolin-8-one (6c): colorless needles (CHCl3-
n-hexane), mp 240-242˚C; IR (KBr) (ν, cm-1) 1664, 1584, 1545; 1H NMR (CDCl3, 300 MHz, δ) 2.99 (2H,
t, J = 6.5 Hz, CH2), 3.81 (3H, s, OMe), 3.99 (3H, s, OMe), 4.35 (2H, t, J = 6.4 Hz, NCH2 ), 6.69 (1H, s,
ArH), 7.33 (1H, dd, J = 1.7, 8.6 Hz, ArH), 7.71 (1H, d, J = 2.0 Hz, ArH), 7.90 (1H, s, ArH), 8.19 (1H, d,
J = 8.5 Hz, ArH); 13C NMR (CDCl3, 75 MHz, δ) 26.9, 39.7, 56.1, 56.2, 109.6, 110.0, 118.8, 121.4,
125.9, 126.7, 128.3, 131.1, 140.3, 148.6, 148.9, 150.4, 152.5, 161.3; MS (EI) m/z 342 (M+, 100), 327
(31.31), 311 (22.31). Anal. Calcd for C18H15N2O3Cl : C, 63.07; H, 4.41; N, 8.17. Found: C, 62.96; H,
4.59; N, 8.31.
5,6-Dihydro-2,3,10,11-tetramethoxyisoquino[1,2-b]quinazolin-8-one (6d): colorless solid (CHCl3 -n-
hexane), mp 259-261°C; IR (KBr) (ν, cm-1) 1668, 1587, 1541; 1H NMR (CDCl3, 300 MHz, δ) 3.02 (2H, t,
J = 6.5 Hz, CH2), 3.96 (3H, s, OMe), 4.01 (3H, s, OMe), 4.04 (6H, s, 2 x OMe), 4.40 (2H, t, J = 6.5 Hz,
NCH2), 6.73 (1H, s, ArH), 7.18 (1H, s, ArH), 7.60 (1H, s, ArH), 7.95 (1H, s, ArH); 13C NMR (CDCl3, 75
MHz, δ) 28.9, 39.6, 56.1, 56.2, 56.3, 56.4, 108.6, 109.7, 111.2, 112.1, 120.9, 127.8, 134.1, 143.3, 146.2,
147.6, 148.9, 152.3, 155.4, 161.7; MS (EI) m/z 369 (M++1, 7.14), 355 (38.13), 341 (8.99), 281 (67.64),
221 (33.24), 207 (100), 191 (10.64), 147 (29.89). Anal. Calcd for C20H20N2O5 : C, 65.21; H, 5.47; N, 7.60.
Found: C, 65.46; H, 5.68; N, 7.41.
5,6-Dihydro-2,3-dimethoxythieno[3′,2′:4,5]pyrimido[2,1-a]isoquinolin-8-one (6e): colorless solid
1
(CHCl3-n-hexane), mp 257-258 º C (decomp); IR (KBr) (ν, cm-1) 1657, 1536, 1500; H NMR (CDCl3,
300 MHz, δ) 3.04 (2H, t, J = 6.1 Hz, CH2), 3.97 (3H, s, OMe), 4.03 (3H, s, OMe), 4.43 (2H, t, J = 6.1 Hz,
NCH2), 6.75 (1H, s, ArH), 7.36 (1H, d, J = 5.3 Hz, ArH), 7.77 (1H, d, J = 5.3 Hz, ArH), 7.92 (1H, s,
13
ArH); C NMR (CDCl3, 75 MHz, δ) 27.1, 39.6, 56.1, 56.2, 109.6, 109.9, 121.7, 125.2, 125.9, 130.7,
134.1, 148.6, 151.2, 152.2, 156.6, 158.0; MS (EI) m/z 314 (M+, 100), 299 (21.28), 283 (9.7). Anal.

Calcd for C16H14N2O3S : C, 61.13; H, 4.49; N, 8.91; S, 10.20. Found: C, 60.93; H, 4.61; N, 8.74; S, 10.36.
5,6-Dihydro-2,3-dimethoxy[3]benzazepino[2,3-b]quinazoline-8,14-dione (8a): colorless solid
1
(CH2Cl2-n- hexane), mp 269-271˚C (decomp); IR (KBr) (ν, cm-1) 1664, 1587, 1507; H NMR (CDCl3,
300 MHz, δ) 3.38 (2H, t, J = 5.3 Hz, CH2), 3.94 (6H, br s, 2 x OMe), 4.64 (2H, t, J = 5.0 Hz, NCH2), 6.69
(1H, s, ArH), 7.47 (1H, s, ArH), 7.55 (1H, t, J = 6.7 Hz, ArH), 7.76-7.84 (2H, m, ArH), 8.33 (1H, d, J =
7.9 Hz, ArH); 13C NMR (CDCl3, 75 MHz, δ) 34.5, 41.8, 56.0, 56.2, 111.9, 112.50, 121.9, 125.9, 126.9,
127.4, 128.1, 128.7, 134.7, 134.8, 147.5, 148.1, 153.7, 160.0, 187.8; FAB-MS m/z 336 (M+, 100), 321
(40.55), 308 (23.83), 293 (12.24), 191 (15.06), 168 (10.72). Anal. Calcd for C19H16N2O4: C, 67.85; H,
4.79; N, 8.33. Found: C, 67.74; H, 4.63; N, 8.54.
10-Bromo--5,6-dihydro-2,3-dimethoxy[3]benzazepino[2,3-b]quinazoline-8,14-dione (8b): colorless
1
needles (CHCl3-n-hexane), mp 261-263ºC; IR (KBr) (ν, cm-1) 1676, 1593, 1507; H NMR (CDCl3, 300
MHz, δ) 3.37 (2H, t, J = 5.3 Hz, CH2), 3.94 (6H, s, 2 x OMe ), 4.63 (2H, t, J = 4.9, CH2), 6.16 (1H, s,
ArH), 7.46 (1H, s, ArH), 7.69 (1H, d, J = 8.7 Hz, ArH), 7.86 (1H, dd, J = 8.6, 2.0 Hz, ArH), 8.46 (1H, d,
J = 2.0 Hz, ArH); 13C NMR (CDCl3, 75 MHz, δ) 34.4, 42.0, 56.1, 56.3, 111.9, 112.5, 122.0, 123.2,
127.2, 129.5, 130.4, 134.8, 138.0, 146.4, 148.2, 153.8, 154.0, 158.9, 187.5; MS (EI) m/z 416 (M++2,
95.64), 415 (M++1, 38.47), 414 (M+, 100), 399 (40.06), 385 (27.03), 207 (10.28), 191 (19.70). Anal.
Calcd for C19H15N2O4Br: C, 54.96; H, 3.64; N, 6.75. Found: C, 55.07; H, 3.55; N, 6.67.
11-Chloro-5,6-dihydro-2,3-dimethoxy[3]benzazepino[2,3-b]quinazoline-8,14-dione (8c): colorless
1
needles (CHCl3-n-hexane), mp 254-255˚C; IR (KBr) (ν, cm-1) 1676, 1648, 1587; H NMR (CDCl3, 300
MHz, δ) 3.37 (2H, t, J = 5.6 Hz, CH2), 3.94 (6H, s, 2 x OMe), 4.61 (2H, t, J = 4.9 Hz, CH2), 6.69 (1H, s,
ArH), 7.45 (1H, s, ArH), 7.49 (1H, dd, J = 2.0, 8.6 Hz, ArH), 7.78 (1H, d , J = 2.6 Hz, ArH), 8.25 (1H, d,
13
J = 8.5 Hz, ArH); C NMR (CDCl3, 75 MHz, δ) 34.4, 41.3, 56.07, 55.3, 111.9, 112.5, 120.3, 127.2,
128.1, 128.4, 128.7, 134.8, 141.0, 148.2, 148.5, 153.9, 154.8, 159.4, 187.5; MS (EI) m/z 372 (M++2,
37.61), 371 (M++1, 33.25), 370 (M+, 100), 355 (46.12), 341 (26.22), 327 (12.79), 311 (11.78), 299
(12.34), 191 (16.53). Anal. Calcd for C19H15N2O4Cl: C, 61.55; H, 4.08; N, 7.56. Found: C, 61.37; H, 3.85;
N, 7.66.
5,6-Dihydro-2,3,10,11-tetramethoxy[3]benzazepino[2,3-b]quinazoline-8,14-dione (8d): colorless

1
solid (CHCl3-n-hexane), mp 277-278 ºC; IR (KBr) (ν, cm-1) 1660, 1651, 1596, 1497, 1449; H NMR
(CDCl3, 300 MHz, δ) 3.36 (2H, t, J = 5.6 Hz, CH2), 3.93 (6H, s, 2 × OMe), 3.97 (3H, s, OMe), 4.02 (3H,
s, OMe), 4.64 (2H, t, J = 3.8 Hz, NCH2), 6.68 (1H, s, ArH), 7.24 (1H, s, ArH), 7.48 (1H, s, ArH), 7.63
(1H, s, ArH); 13C NMR (CDCl3, 75 MHz, δ) 34.1, 41.8, 56.1, 56.2, 56.3, 56.4, 105.9, 109.1, 112.1,
112.7, 115.5, 127.6, 134.9, 143.8, 148.2, 150.2, 153.7, 155.2, 159.2, 187.7; FAB-MS m/z 397 (M+, 100),
381 (15.13), 257 (11.47), 164 (39.75), 154 (43.57), 149 (63.35), 136 (60.42). Anal. Calcd for C21H20N2O6:
C, 63.63; H, 5.09; N, 7.07. Found: C, 63.71; H, 5.13; N, 7.41.
5,6-Dihydro-2,3-dimethoxythieno[2′,3′:4,5]pyrimido[2,1-b][3]benzazepine-3,13-dione
(8e)
light
yellow solid (CH2Cl2-n-hexane), mp 257-258˚C; IR (KBr) (ν, cm-1) 1664, 1590, 1507; 1H NMR (CDCl3,
300 MHz, δ) 3.37 (2H, t, J = 4.8 Hz, CH2), 3.94 (6H, br s, 2 x OMe), 4.67 (2H, t, J = 5.0 Hz, NCH2),
13
6.68 (1H, s, ArH), 7.41 (1H, d, J = 5.3 Hz, ArH), 7.46 (1H, s, ArH), 7.82 (1H, d, J = 5.5 Hz, ArH); C
NMR (CDCl3, 75 MHz, δ) 34.4, 41.5, 56.1, 56.3, 111.9, 112.5, 123.9, 125.9, 126.1, 127.3, 134.8, 135.0,
148.2, 153.9, 156.0, 156.4, 187.6; MS (EI) m/z 342 (M+, 100), 327 (45.59), 312 (25.53). Anal. Calcd for
C17H14N2O4S: C, 59.64; H, 4.12; N, 8.18, S, 9.37. Found: C, 59.42; H, 4.25; N, 8.21; S, 9.16.
2-Chloro-9,13b-dihydro-11,12-dimethoxy-13b-phenyl-8(H)-isoquino[2,1-c]quinazoline-6-carbonit-
rile (11a): colorless needles (EtOH-benzene), mp: 222-223 ˚C; IR (KBr) (ν, cm-1) 1593, 1571, 1539; 1H
NMR (DMSO-d6, 500 MHz, δ) 2.75 (1H, dd, J = 4.0, 16.9 Hz, CH2); 3.07 (1H, ddd, J = 5.0, 9.1, 16.8
Hz, CH2), 3.49 (1H, ddd, J = 2.8, 5.4, 12.5 Hz, NCH2), 3.53 (3H, s, OMe), 3.79 (3H, s, OMe), 4.07 (1H,
dd, J = 5.4, 13.9 Hz, NCH2), 6.36 (1H, s, ArH), 6.65 (1H, d, J = 2.2 Hz, ArH), 6.93 (1H, s, ArH), 7.12
(2H, d, J = 6.9 Hz, ArH), 7.21 (1H, d, J = 8.4 Hz, ArH), 7.34-7.43 (4H, m, ArH);13C NMR (DMSO-d6,
125 MHz, δ) 28.3, 45.5, 56.4, 56.4, 66.9, 112.2, 113.4, 113.9, 127.2, 127.4, 128.4, 128.6, 129.0 (2C),
129.1, 129.4 (2C), 129.7, 130.0, 131.8, 136.2, 140.0, 145.4, 147.6, 149.5; FAB-MS m/z 430 (M++1,
53.93), 429 (M+, 12.13), 352 (61.56), 321 (40.55), 308 (23.83), 289 (9.54), 154 (100), 136 (84.14). Anal.
Calcd for C25H20N3O2Cl: C, 69.85; H, 4.69; N, 9.77. Found: C, 69.73; H, 4.53; N, 9.51.
9,13b-Dihydro-11,12-dimethoxy-3-methyl-13b-phenyl-8(H)-isoquino[2,1-c]quinazoline-6-carboni-
trile (11b): colorless needles (EtOH-benzene), mp 216-217˚C, IR (KBr) (ν, cm-1) 1584, 1548, 1509,

1
1456; H NMR (DMSO-d6, 300 MHz, δ) 2.31(3H, s, CH3), 2.68 (1H, dd, J = 4.7, 16.3 Hz, CH2), 3.26
(1H, ddd, J = 3.4, 7.2, 16.5 Hz, CH2), 3.42 (1H, ddd, J = 2.8, 4.9, 14.0 Hz, NCH2), 3.64 (3H, s, OMe),
3.89 (3H, s, OMe), 4.06 (1H, ddd, J = 1.5, 6.9, 14.2 Hz, NCH2), 6.51 (1H, s, ArH), 6.54 (1H, s, ArH),
6.66 (1H, s, ArH), 6.92 (1H, dd, J = 0.9, 7.9 Hz, ArH), 7.04 (1H, s, ArH), 7.15 (2H, br t, J = 3.8 Hz, ArH),
13
7.30 (3H, m, ArH); C NMR (DMSO-d6, 75 MHz, δ) 20.9, 27.5, 44.0, 55.9, 55.9, 67.0, 111.0, 112.1,
112.7, 124.4, 125.4, 125.9, 127.7, 127.9, 128.2, 128.9, 129.0 (2C), 129.9, 135.6, 138.9, 139.7, 145.7,
147.0, 148.6; FAB-MS m/z 410 (M++1, 72.55 %), 409 (M+, 5.15), 383 (3.0), 332 (100), 165 (9.65), 91
(8.84), 77 (8.68). Anal. Calcd for C26H23N3O2: C, 76.26; H, 5.66; N, 10.26. Found: C, 76.42; H, 5.82; N,
9.98.
ACKNOWLEDGEMENTS
The authors thank Brain Korea-21 Research Foundation for financial support.
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