2-Hydroxyisoquinoline-1,3(2H,4H)-diones
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 24 7725
(C), 122.4 (C), 130.9 (CH), 131.1 (d, 2CH, 3J ) 8.0 Hz, C2′, C6′),
(CIV), 125.3 (CIV), 128.4 (C2′, C6′), 128.8 (CH), 129.3 (C3′, C5′),
130.2 (CIV), 134.7 (CH), 147.9 (C7), 161.7 (CO), 166.6 (CO).
(v) 2-Benzyloxy-7-chloroisoquinoline-1,3(2H,4H)-dione (5d):
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131.5 (CH), 132.1 (d, J ) 3.0 Hz, C1′), 132.9 (C), 138.1 (CH),
161.3 (d, 1J ) 250.0 Hz, C4′), 168.2 (CO), 169.4 (CO), 172.7 (CO).
Synthesis of the Homophthalic Acids (7h-j). (i) General
Method. A solution of 5-iodohomophthalic acid 4c (0.36 g, 1.0
mmol), arylboronic acid (1.0 mmol), and Pd(PΦ3)4 (30 mg) in
benzene (3.0 mL) and aqueous 2.0 M K2CO3 (3.0 mL) was refluxed
for 3 h. After the mixture had cooled, CHCl3 (5.0 mL) and aqueous
saturated NaHCO3 (5.0 mL) were added. Insoluble materials were
filtered. The aqueous layer was acidified with 1.0 M HCl and
extracted with ethyl acetate. The organic layer was dried over
Na2SO4 and concentrated in vacuo.
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keto form (100%); brown solid; 65% yield; mp 160 °C; H NMR
(DMSO-d6) δ 4.27 (s, 2H, H4), 5.03 (s, 2H, CH2), 7.40-7.56 (m,
6H, H5, H2′-6′), 7.76 (dd, 1H, 3J ) 8.0 Hz, 4J ) 2.4 Hz, H6), 8.00
(d, 1H, 4J ) 2.4 Hz, H8); 13C NMR (DMSO-d6) δ 37.1 (C4), 77.4
(CH2), 126.8 (C8), 127.0 (C8a), 128.4 (C2′, C6′), 128.8 (C4′), 129.4
(C3′, C5′), 130.0 (C5), 132.1 (C7), 133.4 (C1′), 134.0 (C4a), 134.6
(C6), 160.4 (CO), 165.7 (CO).
(vi) 2-Benzyloxy-7-bromoisoquinoline-1,3(2H,4H)-dione (5e):
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keto form (100%); brown solid; 66% yield; mp 170 °C; H NMR
(ii) 2-Carboxymethyl-5-phenylbenzoic acid (7h): white solid;
(DMSO-d6) δ 4.24 (s, 2H, H4), 5.02 (s, 2H, CH2), 7.41 (m, 4H,
76% yield; mp 220 °C; 1H NMR (DMSO-d6) δ 3.97 (s, 2H, CH2),
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H2′-6′), 7.55 (m, 2H, H5, H2′-6′), 7.88 (dd, 1H, J ) 8.2 Hz, J )
2.4 Hz, H6), 8.12 (d, 1H, 4J ) 2.4 Hz, H8); 13C NMR (DMSO-d6)
δ 37.1 (C4), 77.3 (CH2), 120.1 (C7), 127.3 (C8a), 128.4 (C2′, C6′),
128.8 (C4′), 129.3 (C3′, C5′), 129.8 (C8), 130.1 (C5), 134.3 (C4a),
134.5 (C1′), 136.2 (C6), 160.3 (CO), 165.7 (CO).
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7.39-7.54 (m, 2H, HAr), 7.70 (m, 2H, HAr), 7.80 (dd, 1H, J )
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8.0 Hz, J ) 2.0 Hz, H4), 8.13 (m, 2H, HAr), 8.51 (d, 1H, J )
8.2 Hz, H6); 13C NMR (DMSO-d6) δ 39.7 (CH2), 120.3 (CH), 126.0
(CIV), 127.1 (CH), 128.8 (CH), 129.0 (2CH), 129.8 (CH), 130.1
(2CH), 134.1 (CIV), 138.2 (CIV), 139.5 (CIV), 168.3 (CO), 172.4
(CO).
(vii) 2-Benzyloxy-7-iodoisoquinoline-1,3(2H,4H)-dione (5f):
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keto form (100%); white solid; 80% yield; mp 180 °C; H NMR
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(iii) 2-Carboxymethyl-5-(4-methoxyphenyl)benzoic acid (7i):
(DMSO-d6) δ 4.22 (s, 2H, H4), 5.01 (s, 2H, CH2), 7.22 (d, 1H, J
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beige solid; 56% yield; mp 207 °C; H NMR (DMSO-d6) δ 3.85
) 8.2 Hz, H5), 7.40-7.56 (m, 5H, H2′-6′), 8.02 (dd, 1H, J ) 8.2
(s, 3H, OMe), 4.09 (s, 2H, CH2), 7.05 (d, 2H, 3J ) 9.0 Hz, HAr),
Hz, J ) 2.4 Hz, H6), 8.29 (d, 1H, J ) 2.4 Hz, H8); 13C NMR
(DMSO-d6) δ 37.1 (C4), 77.4 (CH2), 91.8 (C7), 127.3 (C8a), 128.4
(C2′, C6′), 128.8 (C4′), 129.3 (C3′, C5′), 130.1 (C5), 134.5 (C1′), 134.8
(C4a), 135.4 (C8), 143.1 (C6), 160.4 (CO), 165.7 (CO).
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7.42 (d, 1H, J ) 8.0 Hz, H3), 7.65 (d, 2H, J ) 9.0 Hz, HAr),
7.77 (dd, 1H, 3J ) 8.0 Hz, 4J ) 2.0 Hz, H4), 8.26 (d, 1H, 3J ) 8.2
Hz, H6); 13C NMR (DMSO-d6) δ 40.1 (CH2), 55.7 (OMe), 115.3
(2CH), 128.8 (2CH), 129.2 (CIV), 129.6 (CH), 130.7 (CH), 131.0
(CIV), 131.5 (CIV), 133.0 (CIV), 133.9 (CH), 136.1 (CIV), 168.7 (CO),
172.6 (CO).
(viii) 2-Benzyloxy-7-hydroxyisoquinoline-1,3(2H,4H)-dione
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(5g): keto form (100%); pink solid; 40% yield; mp 188 °C; H
NMR (DMSO-d6) δ 4.15 (s, 2H, H4), 5.01 (s, 2H, CH2), 7.08 (dd,
1H, 3J ) 8.5 Hz, 4J ) 2.1 Hz, H6), 7.22 (d, 1H, 3J ) 8.5 Hz, H5),
7.40-7.58 (m, 6H, H8, H2′-6′), 9.92 (s, 1H, OH); 13C NMR (DMSO-
d6) δ 36.6 (C4), 77.3 (CH2), 112.9 (C8), 121.8 (C6), 125.0 (C8a),
128.4 (C2′, C6′), 128.5 (C4a), 128.8 (C4′), 129.1 (C5), 129.4 (C3′,
C5′), 134.7 (C1′), 156.5 (C7), 161.3 (CO), 166.3 (CO).
(iv) 2-Carboxymethyl-5-(3,4-dimethoxyphenyl)benzoic acid
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(7j): black solid; 60% yield; mp 116 °C; H NMR (DMSO-d6) δ
3.82 (s, 3H, OMe), 3.88 (s, 3H, OMe), 4.06 (s, 2H, CH2), 7.02 (d,
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1H, J ) 8.5 Hz, H5′), 7.20 (d, 1H, J ) 2.0 Hz, H2′), 7.24 (dd,
1H, 3J ) 8.5 Hz, 4J ) 2.0 Hz, H6′), 7.39 (d, 1H, 3J ) 8.0 Hz, H3),
7.74 (dd, 1H, 3J ) 8.0 Hz, 4J ) 2.0 Hz, H4), 8.23 (d, 1H, 4J ) 2.0
Hz, H6); 13C NMR (DMSO-d6) δ 39.6 (CH2), 55.8 (OMe), 55.9
(OMe), 106.7 (C2′), 115.5 (C5′), 123.0 (CH), 127.0 (CH), 127.6
(CH), 129.6 (CH), 130.1 (CIV), 134.3 (CIV), 138.6 (CIV), 140.7 (CIV),
149.1 (C3′), 152.1 (C4′), 168.7 (CO), 172.6 (CO).
(ix) N-[2-(Benzyloxy)-1,3-dioxo-1,2,3,4-tetrahydroisoquinolin-
7-yl]pentanamide (5i): keto form (100%); yellow solid; 72% yield;
mp 179 °C; 1H NMR (DMSO-d6) δ 0.90 (t, 3H, 3J ) 7.5 Hz, CH3),
1.33 (sext, 2H, 3J ) 8.5 Hz, 4J ) 2.5 Hz, H3′), 1.59 (quint, 2H, 3J
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) 7.3 Hz, H2′), 2.34 (t, 2H, J ) 7.3 Hz, H1′), 4.20 (s, 2H, CH2),
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Synthesis of 2-Benzyloxyisoquinoline-1,3(2H,4H)-dione De-
rivatives. (i) General Method. A solution of homophthalic acids
or anhydrides (1.3 mmol) and O-benzylhydroxylamine (1.6 mmol;
obtained from its hydrochloride salt) in toluene (250 mL) was
refluxed using a Dean-Stark apparatus. Reaction was followed by
TLC analysis (approximately 12 h). The hot solution was filtered
and concentrated under reduced pressure. The residue was purified
by column chromatography with hexane and ethyl acetate (8/2 to
5/5, % v/v).
(ii) 2-Benzyloxyisoquinoline-1,3-(2H,4H)-dione (5a): keto form
(100%); white solid; 85% yield; mp 144 °C; 1H NMR (DMSO-d6)
δ 4.20 (s, 2H, H4), 5.15 (s, 2H, CH2), 7.25-7.62 (m, 7H, H7, H5,
H2′-6′), 7.70 (td, 1H, 3J ) 8.5 Hz, 4J ) 2.4 Hz, H6), 8.25 (dd, 1H,
3J ) 8.5 Hz, 4J ) 2.4 Hz, H8); 13C NMR (DMSO-d6) δ 37.5 (C4),
78.3 (CH2), 125.2 (C8a), 127.3 (CH), 127.9 (CH), 128.4 (C2′, C6′),
128.9 (CH), 129.0 (C4a), 129.8 (C3′, C5′), 133.2 (CH), 133.8 (C1′),
133.9 (CH), 161.4 (CO), 165.7 (CO).
7.31-7.42 (m, 4H, HAr), 7.55 (m, 2H, HAr), 7.88 (dd, 1H, J )
8.5 Hz, 4J ) 2.5 Hz, H6), 8.35 (d, 1H, 4J ) 2.2 Hz, H8), 10.16 (s,
1H, NH); 13C NMR (DMSO-d6) δ 13.7 (CH3), 21.8 (CH2), 27.1
(CH2), 36.1 (CH2), 36.9 (CH2), 77.3 (OCH2), 117.4 (C), 124.4 (C),
125.3 (C), 128.1 (C), 128.3 (2C), 128.8 (CH), 129.0 (CH), 129.4
(2C), 134.6 (CH), 138.5 (CH), 161.3 (CO), 166.1 (CO), 171.6 (CO).
(x) N-[2-(Benzyloxy)-1,3-dioxo-1,2,3,4-tetrahydroisoquinolin-
7-yl]benzamide (5j): keto form (100%); orange solid; 85% yield;
mp 201 °C; 1H NMR (DMSO-d6) δ 4.26 (s, 2H, H4), 5.06 (s, 2H,
OCH2), 7.75 (m, 9H, HAr), 8.00 (m, 3H, HAr), 8.55 (d, 1H, 4J )
2.0 Hz, H8), 10.56 (s, 1H, NH); 13C NMR (DMSO-d6) δ 37.3 (CH2),
77.3 (OCH2), 118.8 (C), 125.3 (CH), 125.6 (C), 128.3 (2CH), 128.4
(C), 128.8 (2CH), 129.2 (CH), 129.4 (2CH), 129.7 (CH), 131.8
(C), 134.5 (C), 134.7 (CH), 138.5 (CH), 161.3 (CO), 165.7 (CO),
166.1 (CO).
(xi) N-[2-(Benzyloxy)-1,3-dioxo-1,2,3,4-tetrahydroisoquinolin-
7-yl]-4-fluorobenzamide (5k): keto form (100%); yellow solid;
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(iii) 2-Benzyloxy-7-nitroisoquinoline-1,3(2H,4H)-dione (5b):
keto form (100%); red solid; 60% yield; mp 236 °C; 1H NMR
(DMSO-d6) δ 4.44 (s, 2H, H4), 5.06 (s, 2H, CH2), 7.42 (m, 3H,
15% yield; mp 218 °C; H NMR (DMSO-d6) δ 4.26 (s, 2H, H4),
5.04 (s, 2H, OCH2), 7.39 (m, 6H, HAr), 7.56 (m, 2H, HAr), 8.05
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(m, 3H, HAr), 8.50 (d, 1H, J ) 2.0 Hz, H8), 10.55 (s, 1H, NH);
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H2′-6′), 7.59 (m, 2H, H2′-6′), 7.72 (d, 1H, J ) 8.5 Hz, H5), 8.50
13C NMR (DMSO-d6) δ 36.2 (CH2), 78.0 (OCH2), 115.7 (d, 2CH,
(dd, 1H, 3J ) 8.5 Hz, 4J ) 2.4 Hz, H6), 8.71 (d, 1H, 4J ) 2.4 Hz,
H8); 13C NMR (DMSO-d6) δ 36.9 (C4), 76.7 (CH2), 122.1 (CH),
126.4 (CIV), 127.3 (CH), 128.2 (C2′, C6′), 128.7 (CIV), 129.2 (C3′,
C5′), 129.5 (CH), 134.3 (CH), 142.0 (CIV), 146.3 (C7), 159.6 (CO),
164.8 (CO).
2J ) 21.0 Hz, C3′, C5′), 118.5 (C), 124.0 (C), 125.5 (d, J ) 3.0
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Hz, C1′), 128.5 (C), 129.0 (2CH), 129.8 (CH), 130.1 (2CH), 130.7
(CH), 130.9 (d, 2CH, 3J ) 8.0 Hz, C2′, C6′), 131.2 (C), 134.5 (CH),
138.5 (CH), 163.5 (d, 1J ) 250.0 Hz, C4′), 163.9 (CO), 164.1 (CO),
164.7 (CO).
(iv) 7-Amino-2-benzyloxyisoquinoline-1,3(2H,4H)-dione (5c):
keto form (100%); yellow solid; 70% yield; mp 171 °C; 1H NMR
(DMSO-d6) δ 4.07 (s, 2H, H4), 5.00 (s, 2H, CH2), 6.88 (dd, 1H, 3J
) 8.5 Hz, 4J ) 2.4 Hz, H6), 7.04 (d, 1H, 3J ) 8.5 Hz, H5), 7.24 (d,
1H, 4J ) 2.4 Hz, H8), 7.39-7.57 (m, 5H, H2′-6′); 13C NMR
(DMSO-d6) δ 36.6 (C4), 77.2 (CH2), 111.2 (CH), 120.4 (CH), 121.2
(xii) N-[2-(Benzyloxy)-1,3-dioxo-1,2,3,4-tetrahydroisoquinolin-
7-yl]-3-nitrobenzamide (5l): keto form (100%); orange solid; 67%
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yield; mp 218 °C; H NMR (DMSO-d6) δ 4.34 (s, 2H, H4), 5.12
(s, 2H, OCH2), 7.42-7.53 (m, 4H, HAr), 7.61-7.67 (m, 2H, HAr),
7.93 (dd, 1H, 3J ) 8.2 Hz, 4J ) 2.1 Hz, HAr), 8.17 (dd, 1H, 3J )
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8.3 Hz, J ) 2.1 Hz, HAr), 8.51 (m, 2H, HAr), 8.59 (d, 1H, J )