A novel chemoselective synthesis of 1,2-dihydroisoquinolines linked to 2-thiohydantoins in water

Article abstract of DOI:10.3184/174751912X13360585299930

A novel three-component condensation reaction between an isocyanide, isoquinoline and thiohydantoins efficiently generates 1,2-dihydroisoquinoline derivatives in a one-pot reaction in water at 70 °C without using any catalyst. Thiohydantoins and isoquinolines exhibit important medicinal properties.

Full text of DOI:10.3184/174751912X13360585299930

JOURNAL OF CHEMICAL RESEARCH 2012
RESEARCH PAPER 367
JUNE, 367–369
A novel chemoselective synthesis of 1,2-dihydroisoquinolines linked to
2-thiohydantoins in water
Mohammad Mehdi Ghanbari* and Marzieh Jamali
Department of Chemistry, Sarvestan Branch, Islamic Azad University, Sarvestan, Iran
A novel three-component condensation reaction between an isocyanide, isoquinoline and thiohydantoins efficiently
generates 1,2-dihydroisoquinoline derivatives in a one-pot reaction in water at 70 °C without using any catalyst.
Thiohydantoins and isoquinolines exhibit important medicinal properties.
Keywords: three-component condensation reaction, quinoline, thiohydantoin, chemoselectivity
Thiohydantoins and isoquinolines exhibit anti-cancer1, anti-
Synthesis of compound 4; typical procedure
convulsant2, antimycobacterial (antifungal and antibacterial)3,
To a magnetically stirred solution of cyclohexyl isocyanide (0.109 g,
sedative4, antidepressant5 and antiviral activites.6,7 These ring
1 mmol) and thiohyantoin (0.268 g, 1 mmol) in H2O (20 mL) was
added isoquinoline (0.129 g, 1 mmol) and the reaction was heated for
systems can be employed in synthetic chemistry and natural
12 h at 70 °C. After completion of the reaction, as indicated by TLC
product as building blocks.8,9 As part of our recent studies on
(ethyl acetate/n-hexane, 2:1), the reaction mixture was filtered and
the development of new routes to heterocyclic systems,10−12 we
the residue washed with water (2 ×10 mL). The resulting solid was
have designed multi-component reactions in water, without
crystallized from ethanol.
any organic solvents. Here we describe an efficient reaction of
thiohyantoins 1 with isocyanides 2 and isoquinoline 3, which
3-{2-[(Cyclohexylimino)methyl]-1,2-dihydroisoquinolin-1-yl}-5,5-
diphenyl-2-thioxoimidazolidin-4-one (4a): White crystals; m.p.
constitutes a synthesis of 3-{2-[(alkylimino)methyl]-1,2-dihy-
droisoquinolin-1-yl}-5,5-diaryl-2-thioxoimidazolidin-4-one 4
in good yields (Scheme 1).
The reactions of thiohyantoins 1 with isocyanide 2 and iso-
quinoline 3, in water at 70 °C to products 2-dihydroisoquino-
lines 4 have been studied as indicated in Table 1.
A possible rationalisation for the formation of the products
is proposed in Scheme 2. It is assumed that the initial event is
formation of complex 5 from the isocyanide and thiohyantoin.
Complex 5 activates the isocyanide functional group for
further nucleophilic attack by isoquinoline to produce interme-
diate 6. Finally, nucleophilic attack of the conjugated base of
the NH-acid (thiohyantoin) on 6 affords product 4.
(decomp.) 230–232 °C. yield (0.45 g, 90%). IR (KBr): 1756 (C=O),
1
1648 (C=S), 1520 (C=N) cm−1. H NMR (400 MHz, DMSO-d6):
δ = 1.04–1.25 (6 H, m, 3CH2), 1.45–1.48 (4 H, m, 2 CH2), 2.86–2.88
(1 H, m, CH), 4.15 (1 H, s, CH), 6.06–7.78 (16 H, m, H-Ar,
N–CH=CH), 7.9 (1 H, s, CH), 9.4 (1 H, s, NH). 13C NMR (100 MHz,
DMSO-d6): δ = 29.7 (CH2), 30.0 (CH2), 30.3 (CH2), 30.6 (CH2), 31.0
(CH2), 60.1 (CH), 73.4 (C), 90.2 (N–CH–N), 116.3, 124.6, 125.1,
126.4, 126.9, 127.3, 128.0, 128.9, 129.1, 132.8, 135.9, 138.7 (C-Ar,
N–CH=CH), 175.6 (C=O), 181.7 (C=N), 182.9(C=S). MS (EI), m/z
506 (M, < 2%), 195 (1), 165 (3), 129 (2), 83 (8), 77 (14), 43 (100).
Anal.Calcd for C31H30N4OS (506.66): C, 73.49; H, 5.97; N, 11.06; S,
6.33%. Found: C, 73.31; H, 5.90; N, 11.22; S, 6.47%.
Table 1 Synthesis of 1,2-dihydroisoquinoline derivatives in
water
Experimental
Isocyanides 2 and isoquinoline 3 were obtained from Merck and were
used without further purification. Thiohyantoin derivatives 4 were
prepared by known methods.13 Melting points (uncorrected) were
measured on an Electrothermal 9100 apparatus. Elemental analyses
for C, H, N and S were performed using a Heraeus CHN-O-Rapid
analyzer. The experimental data were in good agreement with the cal-
Entry
R
R’
Product Yield/%
1
2
3
4
5
6
7
8
H
Cl
CH3
H
Cl
H
Cyclohexyl
Cyclohexyl
Cyclohexyl
4a
4b
4c
4d
4e
4f
90
86
82
92
85
95
90
85
1,1,3,3-Tetramethylbutyl
1,1,3,3-Tetramethylbutyl
TsCH2
1
culated values. H and 13C NMR spectra (DMSO-d6) were measured
with a Bruker DRX-400 Avance spectrometer. IR spectra were
recorded on a Bruker tensor FT-IR 27 spectrometer. Mass spectra
were recorded on a Hewlet-Packard 5993C spectrometer.
Cl
H
TsCH2
tButyl
4g
4h
Scheme 1 Synthesis of 1,2-dihydroisoquinolines via the one-pot, three-component reaction of isocyanides,
isoquinoline and NH-acids.
* Correspondent. E-mail: ghanbari@gmail.com

368 JOURNAL OF CHEMICAL RESEARCH 2012
Scheme 2 Proposed mechanism.
5,5-bis(4-Chlorophenyl)-3-{2-[(cyclohexylimino)methyl]-1,2-dihy-
droisoquinolin-1-yl}-2-thioxoimidazolidin-4-one (4b): White crystals;
m.p. (decomp.) 310–313 °C. yield (0.49 g, 86%). IR (KBr): 1704
(C=O), 1653 (C=S), 1560 (C=N) cm−1. 1H NMR (400 MHz,
DMSO-d6): δ = 0.93–1.14 (6 H, m, 3CH2), 1.26–1.39 (4 H, m, 2CH2),
2.74–2.81 (1 H, m, CH), 4.22 (1 H, s, CH), 6.11–7.89 (14 H, m, H-Ar,
N–CH=CH), 8.1 (1 H, s, CH), 9.6 (1 H, s, NH). 13C NMR (100 MHz,
DMSO-d6): δ = 28.9 (CH2), 29.8 (CH2), 30.2 (CH2), 30.7 (CH2), 31.0
(CH2), 65.3 (CH), 73.2 (C), 90.8 (N–CH–N), 114.5, 122.8, 123.3,
125.2, 126.0, 127.5, 128.7, 129.9, 130.2, 130.9, 138.3, 142.4 (C-Ar,
N–CH=CH), 172.3 (C=O), 181.4 (C=N), 182.3 (C=S). MS (EI), m/z
574 (M, 2%), 262 (3), 234 (7), 129 (2), 111 (16), 83 (10), 43 (100).
Anal.Calcd forC31H28Cl2N4OS (575.55): C, 64.69; H, 4.90; N, 9.73; S,
5.57%. Found: C, 64.59; H, 4.85; N, 9.65; S, 5.64%.
5,5-bis(4-Chlorophenyl)-2-thioxo-3-{2-[(2,4,4-trimethylpentan-2-
ylimino)methyl]-1,2-dihydroisoquinolin-1-yl}imidazolidin-4-one
(4e): White crystals; m.p. (decomp.) 236–240 °C. yield (0.51 g, 85%).
1
IR (KBr): 1710 (C=O), 1640 (C=S), 1553 (C=N) cm−1. H NMR
(400 MHz,DMSO-d6): δ = 1.03 (9 H,s, 3CH3), 1.31 (6 H, s, 2CH3),
1.64 (2 H, d, CH2), 4.18 (1 H, s, CH), 6.06–7.81 (14 H, m, H-Ar, N–
CH=CH), 8.18 (1 H, s, CH), 9.68 (1 H, s, NH). 13C NMR (100 MHz,
DMSO-d6): δ = 29.5 (C(CH3)2), 30.3 (C(CH3)2), 31.9 (C(CH3)3), 32.4
(CH2), 56.8 (C(CH3)3), 60.1 (C(CH3)2), 82.1 (C), 92.0 (N–CH–N),
112.7, 124.8, 126.1, 126.9, 127.2, 127.9, 128.8, 130.1, 131.8, 132.0,
135.9, 140.3 (C-Ar, N–CH=CH), 168.2 (C=O), 177.9 (C=N), 183.1
(C=S). Anal.Calcd for C33H34Cl2N4OS (605.62): C, 65.45; H, 5.66; N,
9.25; S, 5.29%. Found: C, 65.54; H, 5.70; N, 9.32; S, 5.22%.
5,5-Diphenyl-2-thioxo-3-{2-[(tosylmethylimino)methyl]-1,2-dihy-
droisoquinolin-1-yl}imidazolidin-4-one (4f): White crystals; m.p.
(decomp.) 284–287 °C. yield (0.56 g, 95%). IR (KBr): 1715 (C=O),
3-{2-[(Cyclohexylimino)methyl]-1,2-dihydroisoquinolin-1-yl}-2-
thioxo-5,5-di-p-tolylimidazolidin-4-one (4c): White crystals; m.p.
(decomp.) 232–236 °C. yield (0.43 g, 82%). IR (KBr): 1698 (C=O),
1
1652 (C=S), 1557 (C=N) cm−1. H NMR (400 MHz, DMSO-d6):
δ = 2.45 (3 H,s, CH3), 4.66–4.67 (2 H, d, CH2), 4.25 (1 H, s, CH),
6.08–7.69 (20 H, m, H-Ar, N–CH=CH), 8.04 (1 H, s, CH), 9.54 (1 H,
s, NH); 13C NMR (100 MHz, DMSO-d6): δ = 25.3 (CH3), 82.1 (C),
87.0 (CH2), 90.3 (N–CH–N), 115.8, 122.9, 124.4, 125.6, 126.2, 127.3,
127.4, 128.0, 128.1, 129.0, 129.4, 129.8, 135.8, 136.0 (C-Ar,
N–CH=CH), 173.8 (C=O), 179.6 (C=N), 182.9 (C=S). Anal.Calcd for
C33H28N4O3S2 (592.73): C, 66.87; H, 4.76; N, 9.45; S, 10.82%. Found:
C, 66.90; H, 4.71; N, 9.53; S, 10.70%.
1
1658 (C=S), 1554 (C=N) cm−1. H NMR (400 MHz, DMSO-d6):
δ = 1.02–1.46 (10 H, m, 5CH2), 2.37 (3 H, s, CH3), 2.38 (3 H, s, CH3),
2.73–2.75 (1 H, m, CH), 4.34 (1 H, s, CH), 6.08–7.65 (14 H, m, H-Ar,
N–CH=CH), 7.90 (1 H, s, CH), 9.4 (1 H, s, NH). 13C NMR (100 MHz,
DMSO-d6): δ = 29.2 (CH2), 29.9 (CH2), 30.5 (CH2), 30.9 (CH2), 31.2
(CH2), 55.3 (CH), 72.9 (C), 90.0 (N–CH–N), 115.1, 122.4, 124.5,
125.7, 126.2, 127.3, 128.2, 129.0, 130.1, 131.3, 136.8, 143.9 (C-Ar,
N–CH=CH), 176.5 (C=O), 182.7 (C=N), 182.9 (C=S). MS (EI), m/z
534 (M, 2%), 222 (3), 520 (6), 194 (2), 91 (15), 83 (9), 43 (100). Anal.
Calcd for C33H34N4OS (534.71): C, 74.12; H, 6.41; N, 10.48; S, 6.00%.
Found: C, 74.20; H, 6.32; N, 10.56; S, 6.12%.
5,5-bis(4-Chlorophenyl)-2-thioxo-3-{2-[(tosylmethylimino)methyl]-
1,2-dihydroisoquinolin-1-yl}imidazolidin-4-one (4g): White crystals;
m.p. 226–228 °C. yield (0.59 g, 90%). IR (KBr): 1699 (C=O), 1648
1
(C=S), 1560 (C=N) cm−1. H NMR (400 MHz, DMSO-d6): δ = 2.33
(3 H, s, CH3), 4.66–4.67 (2 H, d, CH2), 4.37 (1 H, s, CH), 6.11–7.51
(18 H, m, H-Ar, N–CH=CH), 8.10 (1 H, s, CH), 9.59 (1 H, s, NH).
13C NMR (100 MHz, DMSO-d6): δ = 23.8 (CH3), 80.2 (C), 89.1 (CH2),
93.5 (N–CH–N), 113.8, 123.2, 125.4, 125.9, 126.0, 126.9, 127.8,
128.2, 129.1, 129.7, 129.9, 130.8, 136.5, 139.7 (C-Ar, N–CH=CH),
173.2(C=O),180.1(C=N),183.2(C=S).Anal.CalcdforC33H26Cl2N4O3S2
(661.62): C, 59.91; H, 3.96; N, 8.47; S, 9.69%. Found: C, 59.82; H,
3.85; N, 8.58; S, 9.52%.
3-{2-[(t-Butylimino)methyl]-1,2-dihydroisoquinolin-1-yl}-5,5-diphe-
nyl-2-thioxoimidazolidin-4-one (4h): White crystals; m.p. (decomp.)
209–211 °C. yield (0.40 g, 85%). IR (KBr): 1709 (C=O), 1654 (C=S),
1561 (C=N) cm−1. 1H NMR (400 MHz, DMSO-d6): δ = 1.25 (9 H, s,
3CH3), 4.18 (1 H, s, CH), 6.04–7.54 (16 H, m, H-Ar, N–CH=CH),
8.62 (1 H, s, CH), 9.54 (1 H, s, NH). 13C NMR (100 MHz, DMSO-d6):
5,5-Diphenyl-2-thioxo-3-{2-[(2,4,4-trimethylpentan-2-ylimino)-
methyl]-1,2-dihydroisoquinolin-1-yl}imidazolidin-4-one (4d): White
crystals; m.p. 217–220 °C. yield (0.49 g, 92%). IR (KBr): 1702 (C=O),
1
1657 (C=S), 1550 (C=N) cm−1. H NMR (400 MHz, DMSO-d6):
δ = 1.25 (9 H,s, 3CH3), 1.27 (3 H, s, CH3), 1.31 (3 H, s, CH3), 1.64
(2 H, d, CH2), 4.23 (1 H, s, CH), 6.14–7.52 (16 H, m, H-Ar, N–
CH=CH), 8.04 (1 H, s, CH), 9.54 (1 H, s, NH). 13C NMR (100 MHz,
DMSO-d6): δ = 29.1 (C(CH3)2), 29.9 (C(CH3)2), 31.6 (C(CH3)3), 32.0
(CH2), 55.2 (C(CH3)3), 58.1 (C(CH3)2), 80.4 (C), 90.3 (N–CH–N),
116.8, 124.3, 125.9, 126.7, 126.9, 127.8, 128.4, 129.1, 130.5, 132.4,
135.1, 139.3 (C-Ar, N–CH=CH), 168.8 (C=O), 178.7 (C=N), 182.7
(C=S). Anal.Calcd for C33H36N4OS (536.73): C, 73.85; H, 6.76; N,
10.44; S, 5.97%. Found: C, 73.74; H, 6.86; N, 10.50; S, 5.89%.

JOURNAL OF CHEMICAL RESEARCH 2012 369
4
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δ = 29.5 (CH3), 44.7 (C(CH3)3), 72.1 (C), 90.1 (N–CH–N), 115.9,
123.6, 125.8, 126.2, 127.3, 127.8, 128.0, 128.1, 129.0, 131.9, 135.6,
136.8 (C-Ar, N–CH=CH), 176.6 (C=O), 180.2 (C=N), 183.5 (C=S).
MS (EI), m/z 480 (M, 3%), 195 (1), 165 (3), 129 (2), 77 (20), 58 (17),
43 (100). Anal.Calcd for C29H28N4OS (480.62): C, 72.47; H, 5.87; N,
11.66; S, 6.67%. Found: C, 72.33; H, 5.71; N, 11.82; S, 6.53%.
Z. Debyser, S. Massa and M. Botta, Bioorg. Med. Chem. Lett., 2009, 19,
Received 21 February 2012; accepted 27 March 2012
Paper 1201176 doi: 10.3184/174751912X13360585299930
Published online: 4 June 2012
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