A novel synthesis of 2-substituted 2H-imidazo[1,5-b]isoquinoline-1,5-diones by in situ desulfurization

Article abstract of DOI:10.1007/s10593-008-0045-1

A novel synthesis of 2-substituted 2H-imidazo[1,5-b]isoquinoline-1,5-diones by reductive desulfurization of a variety of 2-substituted 3-thioxo-2H- imidazo[1,5-b]isoquinoline-1,5-diones is reported with nickel boride in dry methanol at ambient temperature.

Full text of DOI:10.1007/s10593-008-0045-1

Chemistry of Heterocyclic Compounds, Vol. 44, No. 3, 2008
A NOVEL SYNTHESIS OF 2-SUBSTITUTED
2H-IMIDAZO[1,5-b]ISOQUINOLINE-
1,5-DIONES BY in situ DESULFURIZATION
Jitender M. Khurana and Vandana Sharma
A
novel synthesis of 2-substituted 2H-imidazo[1,5-b]isoquinoline-1,5-diones by reductive
desulfurization of a variety of 2-substituted 3-thioxo-2H-imidazo[1,5-b]isoquinoline-1,5-diones is
reported with nickel boride in dry methanol at ambient temperature.
Keywords: nickel boride, polycyclic isoquinoline, desulfurization.
Polycyclic isoquinoline compounds are well known as anticancer [1] and antitumour [2] agents, and as
acetylcholinesterase [3] and human chymase inhibitors [4]. Recently, the synthesis and biological properties of
isoquinolines spirofused with carbocycles and heterocycles in position 4 have been reviewed [5]. In view of
their importance, we decided to explore the synthesis of a new class of substituted imidazo[1,5-b]isoquinoline-
1,5-dione derivatives by reductive desulfurization of 2-substituted 3-thioxo-2H-imidazo[1,5-b]isoquinoline-
1,5-diones with nickel boride. Nickel boride has been used successfully for desulfurization of the C=S group
flanked by the NH group of dialkyl thioureas [6], 2(1H)-benzimidazolinethiones [6], 1,3-diaryl-2-thioxo-2H,5H-
1,3-dihydropyrimidine-4,6-diones [6], 2-thioxo-4(3H)-quinazolinones [7], and 4-oxo-2-thioxo-5H-pyrano-
[2,3-d]pyrimidines [8]by our research group besides reductions of other functionalities [9–16].
We report herein a convenient and efficient synthesis of 2-substituted 2H-imidazo[1,5-b]isoquinoline-
1,5-diones 2a-f with nickel boride in dry methanol at ambient temperature following a simple workup procedure.
Nickel boride was prepared in situ from anhydrous nickel chloride and sodium borohydride in dry methanol. Various
2-substituted 3-thioxo-2H-imidazo[1,5-b]isoquinoline-1,5-diones 1a–f underwent complete reductive desulfurization
with nickel boride using a 1:7:7 or 1:9:9 molar ratio of substrate/NiCl2/NaBH4 in dry methanol and yielded the
corresponding 2-substituted 2H-imidazo[1,5-b]isoquinoline-1,5-diones 2a–f in nearly quantitative yields. The starting
2-substituted 3-thioxo-2H-imidazo[1,5-b]isoquinoline-1,5-diones were prepared by condensation of 2-formyl-
benzoic acid with 3-substituted 2-thiohydantoins [17].
O
O
NiCl2 / NaBH4
MeOH, r. t.
N
R
N
R
N
N
S
O
O
1a–f
2a–f
1,2 a R = H, b R = Me, c R = i-Pr, d R = Ph, e R = CH2Ph, f R =
CH2 N
O
_________________________________________________________________________________________
Department of Chemistry, University of Delhi, Delhi-110007, India; e-mail:
jmkhurana@chemistry.du.ac.in. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 404-408,
March, 2008. Original article submitted October 11, 2007.
0009-3122/08/4403-0309©2008 Springer Science+Business Media, Inc.
309

With lower ratios of substrate to nickel chloride to sodium borohydride, the reaction was incomplete.
The reaction of 2H-imidazo[1,5-b]isoquinoline-1,5-dione proceeded very slowly and was incomplete even after
24 h, when carried out with nickel boride in dry dichloromethane, tetrahydrofuran, dimethylformamide, and
dioxane using a 1:9:9 molar ratio. Thus dry methanol was considered as a solvent of choice and was employed
in all the reactions. The reaction of compound 1a with nickel boride using hydrated nickel chloride and ordinary
methanol using a 1:9:9 molar ratio also proceeded very slowly and was incomplete even after 24 h. There was no
reaction of compound 1a with anhydrous nickel chloride alone, and the starting material was recovered
unchanged. Also, reaction of compound 1a with sodium borohydride alone yielded a mixture of products along
with the starting material. It is obvious therefore that the desulfurization is undoubtedly proceeding due to the
involvement of nickel boride formed in situ. The reaction of 3-(methylthio)imidazo-[1,5-b]isoquinoline-
1,5-dione (1g) also yielded 2H-imidazo[1,5-b]isoquinoline-1,5-dione (2a). These results are summarized in
Table 1.
O
O
NiCl2 / NaBH4
MeOH, r. t.
NH
N
N
N
SMe
O
O
2a
1g
The reagent shows a high selectivity towards desulfurization in these reactions and does not affect the
amide carbonyl group, as confirmed by the IR spectra which show the characteristic peaks for the two different
carbonyls around 1670 and 1710 cm−1 for all the products. Also, the double bond in position 10 remains
1
unaffected, as confirmed by the peak at δ 7.2 due to CH=C in the H NMR spectra for all the products. No
hydrogenolysis of the benzyl group was observed in the reaction of compound 1e with nickel boride in either of
the attempted molar ratios. Also colloidal sulfur was not formed in any of these reactions; instead the smell of
H2S was observed during the reactions. Desulfurization is proceeding via a transition state in which nickel
coordinates with sulfur and weakens the C=S bond, resulting in in situ generation of a –CH–SH intermediate.
TABLE 1. Reactions of 2-substituted 3-thioxo-2H-imidazo[1,5-b]iso-
quinoline-1,5-diones with nickel boride in dry methanol at ambient
temperature
Molar ratio
Substrate (S)
Time, h
Product
Yield, %
S:NiCl2:NaBH4
1a
1b
1c
1d
1e
1f
1:9:9
1:7:7
1:7:7
1:7:7
1:7:7
1:7:7
1:9:9
1:9:9
2
1.5
1.5
1.5
1
2a
2b
2c
2d
2e
—
2f
75
78
74
76
78
—*
78
76
24
2
1f
1g
3
2a
_________
* Reaction was incomplete.
310

This subsequently undergoes hydrogenolysis to yield the desired product. This is also evidenced by the
reductive desulfurization of compound 1g.
We conclude that 2-substituted 2H-imidazo[1,5-b]isoquinoline-1,5-diones can be prepared by nickel
boride mediated reductive desulfurization of 2-substituted 3-thioxo-2H-imidazo[1,5-b]isoquinoline-1,5-diones.
The procedure offers several advantages like mild reaction conditions, chemoselectivity, and clean reaction
products, which makes it a useful process for the synthesis of novel polycyclic isoquinoline-1,5-dione
derivatives.
EXPERIMENTAL
All the melting points were recorded on Tropical Labequip apparatus and are uncor- rected. IR spectra
1
were recorded on Perkin-Elmer FT-IR SPECTRUM-2000 (nujol) and H NMR spectra were recorded in
DMSO-d6 on Brucker Avance Spectrospin dpx (300 MHz) with TMS as an internal standard. Mass spectra were
recorded on KC-455-TOF mass spectrometer (Micromass, Manchester, U.K.). Analytical data were obtained on
Gmbh Vario EL V3 instrument.
Methanol (S. D. Fine) was used after drying by the reported procedure [18]. Nickel(II) chloride
hexahydrate (Thomas Baker Chemicals) was dried by heating in a crucible till golden yellow. It was then
allowed to cool at room temperature and stored over calcium chloride in a desiccator. Sodium borohydride
(E. Merck) was used in all the reactions. 2-Formylbenzoic acid (Sigma-Aldrich) was used as such for the
preparation of starting materials. Glycine (S. D. Fine) was used as such. Substituted 2-thiohydantoins [19] and
2-substituted 3-thioxo-2H-imidazo[1,5-b]isoquinoline-1,5-diones 1a–f [17] were prepared by the reported
procedures.
A new compound 1c has also been prepared by the reported procedure as given below.
2-Isopropyl-3-thioxo-2H-imidazo[1,5-b]isoquinoline-1,5-dione (1c). 2-Formylbenzoic acid (1.415 g,
9.43 mmol), anhydrous sodium acetate (2.631 g, 32.08 mmol), and 3-isopropyl-2-thiohydantoin (1.5 g,
9.43 mmol) were taken in glacial acetic acid in a round-bottomed flask. The reaction mixture was refluxed for
4 h. After cooling to room temperature, the reaction mixture was poured into cold water (~50 ml). The separated
crystals were collected by filtration and recrystallized from ethanol to give a pale yellow crystalline solid which
was identified to be compound 1c (1.9249 g, 75%); mp 198°C. IR spectrum, νmax, cm−1: 3077.8 (Ar−H), 2924.5
(C−H methyl), 1743.7, 1694.0 (2×C=O), 1597.6 (C=S), 1460.5 (ring), 1386.0 (CHCH3), 755.7 (o-disubstituted
1
ring). H NMR spectrum, δ, ppm (J, Hz): 1.24–1.26 (6H, d, J = 6.1, 2CH3); 4.67-4.84 (1H, m, CHCH3); 7.39
(1H, s, H-10); 7.65 (1H, t, J = 7.3, H-8); 7.71 (1H, t, J = 7.7, H-7); 7.79 (1H, d, J = 6.7, H-9); 8.17 (1H, d,
J = 6.7, H-6). Mass spectrum, m/z (Irel, %): found 272 [M]+(100), calculated 272 [M]+. Found, %: C 61.73;
H 4.45; N 10.29; S 11.78. C14H12N2O2S. Calculated, %: C 61.74; H 4.44; N 10.28; S 11.77.
Desulfurization of 2-Substituted 3-Thioxo-2H-imidazo[1,5-b]isoquinoline-1,5-diones 1 (General
Method). In a typical procedure, compound 1a (0.1 g, 0.44 mmol) and dry MeOH (5 ml) were placed into a
100 ml round-bottomed flask. The flask was mounted over a magnetic stirrer and the contents were stirred.
Anhydrous NiCl2 (0.505 g, 3.91 mmol) was added to the flask followed by cautious addition of NaBH4 (0.149 g,
3.91 mmol) at room temperature. Addition of NaBH4 is highly exothermic. The contents were stirred vigorously.
After complete disappearance of starting material as monitored by TLC (petroleum ether−ethyl acetate, 70:30,
v/v), the reaction mixture was filtered off through a Celite pad (~2.5 cm). Nickel boride precipitate was washed
with methanol (1×15 ml). The combined filtrate was diluted with water (~50 ml) and extracted with ethyl acetate
(3×10 ml). The combined ethyl acetate extract was dried over anhydrous MgSO4, filtered off, and the solvent
was removed on a rotary evaporator followed by vacuum drying to afford 2H-imidazo[1,5-b]isoquinoline-
1,5-dione (2a). Yield 0.065 g (75%) as white powder; mp 250°C dec. IR spectrum, νmax, cm−1: 3160.2 (NH), 1722.8,
311

1672.0 (2×C=O), 1464.4 (ring). 1H NMR spectrum, δ, ppm (J, Hz): 5.25 (2H, s, H-3); 7.24 (1H, s, H-10); 7.63
(1H, t, J = 7.6, H-8); 7.8 (1H, t, J = 7.0, H-7); 7.90 (1H, d, J = 8.0, H-9); 8.27 (1H, d, J = 8.0, H-6); 9.62 (1H, s, NH).
Mass spectrum, m/z (Irel, %): found 201 [M + H]+ (100), calculated 201 [M + H]+. Found, %: C 65.98; H 4.03;
N 13.97. C11H8N2O2. Calculated, %: C 65.99; H 4.02; N 13.99.
2H-Imidazo[1,5-b]isoquinoline-1,5-dione (2a) from compound 1g. Yield 0.066 g (76%); mp 252°C
(dec.). IR spectrum, νmax, cm−1: 3160.2 (NH), 2924.0 (Ar-H), 2854.5 (CH), 1722.8, 1672.0 (2×C=O), 1464.3
(ring), 766.4 (ring). 1H NMR spectrum, δ, ppm (J, Hz): 5.34 (2H, s, H-3); 7.33 (1H, s, H-10); 7.73 (1H, t, J = 7.8,
H-8); 7.88 (1H, t, J = 7.8, H-7); 8.00 (1H, d, J = 7.8, H-9); 8.36 (1H, d, J = 7.8, H-6); 9.70 (1H, s, NH).
Mass spectrum, m/z (Irel, %): found 201 [M + H]+ (100), calculated 201 [M + H]+. Found, %: C 65.98; H 4.03;
N 13.97. C11H8N2O2. Calculated, %: C 65.99; H 4.02; N 13.99.
Compounds 2b–f were obtained in a similar manner.
2-Methyl-2H-imidazo[1,5-b]isoquinoline-1,5-dione (2b). Yield 0.068 g (78%); mp 210°C. IR
spectrum, νmax, cm−1: 2924.3 (CH, Ar), 2854.9 (C−H), 1712.0, 1692.1 (2×C=O), 1464.8 (ring), 766.35 (o-disubsti-
tuted ring). 1H NMR spectrum, δ, ppm (J, Hz): 3.16 (3H, s, CH3); 5.34 (2H, s, H-3); 7.62 (1H, t, J = 7.7, H-8); 7.78
(1H, t, J = 7.5, H-7); 7.84 (1H, d, J = 7.7, H-9); 7.23 (1H, s, H-10); 8.34 (1H, d, J = 7.7, H-6). Mass spectrum,
m/z (Irel, %): found 215 [M + H]+ (100), calculated 215 [M + H]+. Found, %: C 67.29; H 4.70; N 13.07.
C12H10N2O2. Calculated, %: C 67.28; H 4.70; N 13.07.
2-Isopropyl-2H-imidazo[1,5-b]isoquinoline-1,5-dione (2c). Yield 0.066 g (74%); mp 240–242°C. IR
spectrum, νmax, cm−1: 2924.1 (Ar-H), 2854.5 (CH), 1703.3, 1667.6 (2× C=O), 1462.9 (ring), 1318.0 (CHCH3),
1
768.3 (o-disubstituted ring). H NMR spectrum, δ, ppm (J, Hz):1.29-1.31 (6H, d, 2CH3); 4.37-4.42 (1H, m,
CHCH3); 5.32 (2H, s, H-3); 7.27 (1H, s, H-10); 7.65 (1H, t, J = 7.1, H-8); 7.81 (1H, t, J = 7.1, H-7); 7.93 (1H, d,
J = 7.9, H-9); 8.30 (1H, d, J = 7.9, H-6). Mass spectrum, m/z (Irel, %): found 243 [M + H]+ (100), calculated 243
[M + H]+. Found, %: C 69.41; H 5.81; N 11.57. C14H14N2O2. Calculated, %: C 69.40; H 5.82; N 11.56.
2-Phenyl-2H-imidazo[1,5-b]isoquinoline-1,5-dione (2d). Yield 0.041 g (76%); mp 250°C (dec.). IR
spectrum, νmax, cm−1: 2924.5 (Ar-H), 2855.0 (CH), 1711.1, 1669.0 (2×C=O), 1463.0 (ring), 761.7 (o-disubstituted
1
ring), 700.1 (monosubstituted ring). H NMR spectrum, δ, ppm (J, Hz): 5.96 (2H, s, H-3); 7.39 (1H, s, H-10);
7.42–7.61 (5H, m, C6H5); 7.76 (1H, t, J = 7.8, H-8); 7.85 (1H, t, J = 7.8, H-7); 7.94 (1H, d, J = 8.6, H-9); 8.09
(1H, d, J = 7.6, H-6). Mass spectrum, m/z (Irel, %): found 278 [M + 2H]+ (100), calculated 278 [M + 2H]+. Found,
%: C 73.91; H 4.38; N 10.14. C17H12N2O2. Calculated, %: C 73.9; H 4.37; N 10.13.
2-Benzyl-2H-imidazo[1,5-b]isoquinoline-1,5-dione (2e). Yield 0.043 g (78%); mp 243–245°C (dec.).
IR spectrum, νmax, cm−1: 2924.4 (Ar-H), 2854.6 (CH), 1704.0, 1665.7 (2×C=O), 1461.4 (ring), 763.3 (ring),
1
637.5. H NMR spectrum, δ, ppm (J, Hz):4.78 (2H, s, CH2, benzyl); 5.24 (2H, s, H-3); 7.33 (1H, s, H-10);
7.38-7.39 (5H, m, Ar-H); 7.63 (1H, t, J = 7.4, H-8); 7.79 (1H, t, J = 7.4, H-7); 7.91 (1H, d, J = 8.1, H-9); 8.29 (1H,
d, J = 8.1, H-6). Mass spectrum, m/z (Irel, %): found 291 [M + H]+ (100), calculated 291 [M + H]+. Found, %:
C 74.45; H 4.87; N 9.67. C18H14N2O2. Calculated, %: C 74.46; H 4.86; N 9.66.
2-(4-Morpholinomethyl)-2H-imidazo[1,5-b]isoquinoline-1,5-dione (2f). Yield 0.063 g (78%); mp
280-282°C (dec.). IR spectrum, νmax, cm−1: 2924.6 (Ar-H); 2855.0 (CH), 1716.7, 1671.6 (2×C=O), 1464.3 (ring),
767.0 (C=C ring). 1H NMR spectrum, δ, ppm (J, Hz): 1.98–2.52 (4H, m, 2H-2', 2H-6', morpholino); 3.30–3.78
(4H, m, 2H-3', 2H-5', morpholino); 4.63 (2H, s, CH2, morpholinyl methylene); 5.28 (2H, s, H-3); 7.22 (1H, s,
H-10); 7.64 (1H, t, J = 7.7, H-8); 7.77 (1H, t, J = 7.0, H-7); 7.87 (1H, d, J = 7.9, H-9); 8.32 (1H, d, J = 8.0, H-6).
Mass spectrum, m/z (Irel, %): found 300 [M + H]+ (100), calculated 300 [M + H]+. Found, %: C 64.21; H 5.73;
N 14.02. C16H17N3O3. Calculated, %: C 64.20; H 5.72; N 14.03.
Financial support for the project by UGC, New Delhi (Project No. F.No.32-203/2006-SR) and fellowships
(JRF and SRF) to VS by CSIR, New Delhi, is gratefully acknowledged.
312

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