One-pot three componenet reaction for the synthesis of 2-alkylthio-3-aroylimidazo[2,1-a]isoquinoline in aqueous media

Article abstract of DOI:10.3987/COM-08-11522

A one-pot, three component reaction between isoquinoline, phenacyl bromide derivatives and thiocyanates leading to imidazo[2,1-a]isoquinoline derivatives in good yields is reported. Reactions are carried out in water or DMF as the solvent at reflux.

Full text of DOI:10.3987/COM-08-11522

HETEROCYCLES, Vol. 78, No. 2, 2009
415
HETEROCYCLES, Vol. 78, No. 2, 2009, pp. 415 - 423. © The Japan Institute of Heterocyclic Chemistry
Received, 14th August, 2008, Accepted, 6th October, 2008, Published online, 9th October, 2008.
DOI: 10.3987/COM-08-11522
ONE-POT THREE COMPONENET REACTION FOR THE SYNTHESIS
OF 2-ALKYLTHIO-3-AROYLIMIDAZO[2,1-a]ISOQUINOLINE IN
AQUEOUS MEDIA
Ebrahim Kianmehr,* Reza Faramarzi, and Hamid Estiri
School of Chemistry, University College of Science, University of Tehran, P.O.
Box 14155-6455 Tehran, Iran
E-mail: kianmehr@khayam.ut.ac.ir
Abstract - A one-pot, three component reaction between isoquinoline, phenacyl
bromide derivatives and thiocyanates leading to imidazo[2,1-a]isoquinoline
derivatives in good yields is reported. Reactions are carried out in water or DMF
as the solvent at reflux.
INTRODUCTION
Synthesis of imidazo[1,2-a]pyridines and imidazo[2,1-a]isoquinolines has attracted significant attention
in recent years due to their pharmacological characteristics.1,2,3,4,5,6,7,8,9,10,11,12 For example this class of
compounds exhibit anti-inflammatory,8 potential antirhinoviral,9 long-acting local anesthetic,10
antiulcer,9,11 and antihelmintic or bacteriostatic activities.12
However several methods reported in the literature for preparation of imidazo[1,2-a]pyridines based on
the use of 2-aminopyridines or other suitably substituted pyridines or approaches based on the use of
substituted imidazoles as starting materials,13,14,15,16,17,18,19,20,21,22,23,24 only a few methods for the
preparation of imidazo[2,1-a]isoquinolines have been reported and there is a definite need to develop a
more structurally flexible method of the synthesis of this class of compounds.
2-Aryl substituted derivatives of imidazo[2,1-a]isoquinolines can be prepared by reaction of N-
phenacylisoquinolinum bromide and hydroxylamine hydrochloride.25 In another method imidazo[2,1-
a]isoquinolines have been prepared by the 1,5-dipolar cyclization reaction of isoquinolinum N-ylids using
N-bis(methylthio)methylenesulfoneamide derivatives which are prepared, in turn, by the condensation of
p-toluenesulfonamide with carbon disulfide in DMSO in the presence of sodium hydroxide and treatment
of the intermediate with dimethyl sulfate.26 Also reaction of -bromoacetophenone
phenylsulfonylhydrazones with isoquinoline has been reported which leads to respective 2-
arylimidazoisoquinoline
formation
together
with
releasing
benzenesulfonamide.27

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HETEROCYCLES, Vol. 78, No. 2, 2009
Phenylsulfonylhydrazones required for this procedure are prepared, in turn, by the reaction of -
bromoketones with phenylsulfonylhydrazine. Also 1,3-dipolar cycloaddition reaction of
trifluoroacetonitrile with heterocycle ylides has been reported which leads to corresponding imidazo[2,1-
a]isoquinolines in 4-20% yield.28 This class of compounds also have been prepared via reaction of 3-
aminocinnamonitrile and 3-aminocrotononitrile with isoquinoline N-oxide in the presence of benzoyl
chloride.29 However, these methods suffer from the difficulties with preparation of suitable starting
materials and/or low yields of conversion.
The design of multicomponent reactions (MCR) is an important field of research from the point of view
of combinatorial chemistry.30 MCRs are highly efficient,31 not only due to their convergent nature, but
also because of superior atom economy32 and straitforward experimental procedures.
Due to the natural abundance of water as well as the inherent advantages of using water as a solvent,
recently interest has been growing in studying organic reactions in water.33
Ylide research has been developed in recent years and ylides have now become powerful and versatile
synthetic tools in organic chemistry.34
RESULTS AND DISCUSSION
Herein, we report an innovative and efficient synthesis of imidazo[2,1-a]isoquinolines via a one-pot three
component reaction of isoquinolines, phenacyl bromides and thiocyanates, through formation of
isoquinoline ylides in aqueous medium. (Scheme 1)
O
Br
H2O
+
+
RSCN
O
N
N
X
1
2
3
4
N
O
S
R
X
O
Br
+
Ar
+
N
N
Ar
-
Br
K2CO3
O
O
RSCN
O
N
N
N
+
Ar
Ar
Ar
N
-
N
S
S
C
B
A
R
R
Scheme1
To explore the scope and versatility of this method, various reaction conditions were investigated,
including solvent and temperature variations. Highlighted in Table 1 for compound 4b (R=Et, X=H), for
example is the influence of solvent and temperature on the reaction yield. To optimize reaction conditions

HETEROCYCLES, Vol. 78, No. 2, 2009
417
with temperature, the same reaction was carried out, in each solvent, at room temperature and reflux
conditions.
It is shown in Table 1 that the reaction using H2O or DMF as solvent gave the best result (Table 1, entries
8 and 10). So H2O was chosen as the reaction solvent.35
Table 1. Optimization of reaction condition of compound 4b
Yield (%) Time (h)
Solvent
MeCN
MeCN
CH2Cl2
CH2Cl2
THF
THF
H2O
H2O
DMF
DMF
Entry
T (C)
rt
reflux
rt
reflux
rt
reflux
rt
43
67
27
40
30
40
61
74
42
75
10
10
10
10
10
10
10
8
1
2
3
4
5
6
7
8
9
10
reflux
rt
reflux
12
10
The use of these optimal conditions to the reactions of different phenacyl bromide and thiocyanate
derivatives afforded good yields of imidazo[2,1-a]isoquinolines with thioalkyl and aroyl groups
presenting in positions 2 and 3 of the imidazole nucleus (Scheme 1, Table 2).
Table 2. Reaction of 1 with 2 and 3 in H2O as the solvent.
Yield(%)
82
74
68
83
85
78
68
67
R
Me
Et
PhCH2
Me
Et
PhCH2
Et
PhCH2
Me
X
H
H
H
OMe
OMe
OMe
Br
Br
Ph
4
a
b
c
d
e
f
g
h
i
72
76
Et
Ph
j
PhCH2
Ph
k
72
The structures of all the synthesized compounds were established on the basis of their spectroscopic data.
1
The H-NMR spectrum of 4d exhibited two sharp singlet signals readily recognized as arising from
methylthio (= 2.69 ppm) and methoxy (= 3.95 ppm) protons. Two doublet signals at = 7.05 and
=9.05 ppm (J=7.4 Hz) are observed for protons of nitrogen containing ring of isoquinoline moiety.

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Aromatic protons of isoquinoline and methoxyphenyl moiety gave rise to characteristic signals in the
aromatic region of the spectrum. The proton-decoupled 13C NMR spectrum of 4d showed 18 distinct
resonances in agreement with the proposed structure. The carbonyl group of 4d appears at =185.5 ppm.
As the pharmacological profile of imidazo[1,2-a]pyridines has been shown to be critically dependent on
the nature of substituents at 2 and 3 positions,5, 36 it is expected that the above mentioned derivatives of
imidazo[2,1-a]isoquinolines can show interesting pharmacological activities.
Mechanistically, it is conceivable that the reaction involves the initial formation of a nitrogen ylide A by
the reaction of isoquinoline and phenacylbromide derivative followed by deprotonation in the presence of
potassium carbonate as the base. This ylide intermediate then undergoes reaction with thiocyanate to
produce B which leads to C by oxidation (Scheme 1).
In summary, a novel one-pot procedure for the synthesis of imidazo[2,1-a]isoquinolines has been
reported, using isoquinoline, phenacylbromide derivatives and thiocyanates in aqueous medium. The
notable advantages offered by this method are simple operation and environment friendly reaction
conditions, high yields of products and cost effectiveness. Most significantly, this demonstrates the
potential of water as an efficient promoter and provides much promise for the use of water in other
chemical transformations. The conversion represents novel MCR and further studies are ongoing to
explore additional transformations, feasible with these chemotypes.
EXPERIMENTAL
Chemicals were purchased from Merck and were used as received. Column chromatography was
performed on silica gel (0.063-0.200 mm; Merck). IR Spectra: Shimadzu FTIR-4300 spectrometer; in cm-1.
13
1H- and C-NMR Spectra: Bruker DRX -500-Avance instrument; in CDCl3 at 500.1 and 125.7 MHz,
resp; δ in ppm, J in Hz. EI-MS (70 eV): HP 5973 GC-MS instrument; in m/z. Elemental analyses (C, H,
N): Heraeus CHN-O-Rapid analyzer. Melting points: Electrothermal 9200 apparatus.
General procedure for the preparation of compound 4a. Isoquinoline (0.196 g, 1.5 mmol.) and
phenacylbromide (0.3 g, 1.5 mmol.) were taken in water (10 mL) and the mixture was stirred at rt for 1 h.
To this mixture methylthiocyanate (0.074 g, 1.0 mmol.) and potassium carbonate (0.28 g, 2.0 mmol.)
were added and it was allowed to stir at reflux for 8 h. The reaction mixture filtered and purified by
passing through a column of silica gel, eluting with 10%EtOAc in hexane to afford 4a as yellow solid.
Compound (4a)
Yellow solid; Mp 150-151 C; IR (KBr): 3130, 1596, 1575, 1508, 1429, 1352, 1217, 927 cm -1; 1H NMR
(CDCl3): =2.68 (s, 3H), 7.29 (d, J=7.4 Hz, 1H), 7.56 (m, 2H), 7.65 (m, 1H), 7.73 (m, 2H), 7.78 (m, 2H),
7.84 (m, 1H), 8.76 (m, 1H), 9.20 (d, J=7.4 Hz, 1H); 13C NMR (CDCl3): =15.6, 114.4, 122.4, 124.9,

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419
125.0, 127.2, 128.6, 128.9, 129.1, 130.3, 131.6, 132.3, 140.2, 146.4, 153.8, 186.5 (C=O); MS (EI, 70ev):
m/z (%) = 318 (M+, 100), 285 (80), 257 (35), 227 (17), 213 (23), 167 (41), 149 (97), 128 (48), 105 (34),
77 (54); Anal. Calcd for C19H14N2OS: C, 71.68; H, 4.43; N, 8.80. Found: C, 71.58; H, 4.47; N, 8.89.
Compound (4b)
Yellow solid; Mp 129-130 C; IR (KBr): 3471, 2958, 1612, 1525, 1456, 1431, 1348, 1249, 1220, 925 cm -1;
1H NMR (CDCl3): =1.38 (t, J=7.3 Hz, 3H), 3.30 (q, J=7.3 Hz, 2H), 7.28 (d, J=7.4 Hz, 1H), 7.56 (m,
13
2H), 7.64 (m, 1H), 7.73 (m, 2H), 7.79 (m, 2H), 7.84 (m, 1H), 8.76 (m, 1H), 9.17 (d, J=7.4 Hz, 1H); C
NMR (CDCl3): =15.3, 27.1, 114.2, 122.4, 124.9, 125.0, 127.2, 128.6, 129.0, 129.1, 130.3, 131.6, 132.4,
140.2, 153.0, 186.0 (C=O); MS (EI, 70ev): m/z (%) = 332 (M+, 69), 315 (15), 299 (88), 284 (36), 271
(24), 242 (15), 227 (43), 155 (12), 128 (43), 105 (100), 77 (87); Anal. Calcd for C20H16N2OS: C, 72.26;
H, 4.85; N, 8.43. Found: C, 72.38; H, 4.78; N, 8.46.
Compound (4c)
Yellow solid; Mp 134-135 C; IR (KBr): 3058, 2924, 1610, 1573, 1510, 1433, 1348, 1274, 1222, 925 cm -1;
1H NMR (CDCl3): =4.6 (s, 2H), 7.25 (m, 1H), 7.29 (m, 3H), 7.42 (m, 2H), 7.51 (m, 2H), 7.61 (tt, J=7.5,
1.3 Hz, 1H), 7.75 (m, 4H), 7.84 (m, 1H), 8.80 (m, 1H), 9.14 (d, J=7.4 Hz, 1H); 13C NMR (CDCl3):
=37.0, 114.4, 122.48, 122.52, 124.9, 125.0, 127.2, 127.5, 128.7, 128.8, 129.0, 129.2, 129.6, 130.3,
131.6, 132.5, 138.6, 140.0, 146.3, 152.0, 186.5 (C=O); MS (EI, 70ev): m/z (%) = 394 (M+, 20), 377 (2),
361 (26), 303 (10), 289 (10), 279 (34), 167 (79), 149 (100), 128 (11), 113 (25), 105 (24), 84 (53), 71 (47);
Anal. Calcd for C25H18N2OS: C, 76.12; H, 4.60; N, 7.10; Found: C, 76.02; H, 4.56; N, 7.17.
Compound (4d)
Yellow solid; Mp 140-142 C; IR (KBr): 3043, 1595, 1510, 1436, 1348, 1251, 1170, 1028, 925 cm -1; 1H
NMR (CDCl3): =2.69 (s, 3H), 3.95 (s, 3H), 7.05 (d, J= 8.6 Hz, 2H), 7.26 (d, J= 7.0 Hz, 1H), 7.71 (m,
13
2H), 7.82 (d, J= 8.6 Hz, 2H), 7.84 (m, 1H), 8.75 (m, 1H), 9.06 (d, J= 7.0 Hz, 1H); C NMR (CDCl3):
=15.7, 55.9, 114.2, 114.3, 122.5, 122.7, 124.77, 124.87, 127.2, 128.6, 130.1, 131.4, 131.6, 132.5, 146.2,
152.2, 163.6, 185.5 (C=O); MS (EI, 70ev): m/z (%) = 348 (M+, 2), 279 (42), 167 (99), 149 (100), 135
(29), 121 (6), 113 (32), 104 (17), 83 (23), 71 (56); Anal. Calcd for C20H16N2O2S: C, 68.95; H, 4.63; N,
8.04. Found: C, 68.83; H, 4.70; N, 8.12.
Compound (4e)
Yellow solid; Mp 123-125 C; IR (KBr): 3138, 1593, 1433, 1409, 1346, 1257, 1172, 1026, 927 cm -1; 1H
NMR (CDCl3): =1.39 (t, J=7.3 Hz, 3H), 3.31 (q, J=7.3 Hz, 2H), 3.95 (s, 3H), 7.05 (d, J=8.5 Hz, 2H),
7.24 (d, J=7.4 Hz, 1H), 7.71 (m, 2H), 7.81 (m, 1H), 7.83 (d, J=8.5 Hz, 2H), 8.74 (m, 1H), 9.02 (d, J=7.4
13
Hz, 1H); C NMR (125.7 MHz, CDCl3): =15.4, 27.3, 55.9, 114.0, 114.2, 122.6, 123.0, 124.7, 124.9,
127.2, 128.5, 130.1, 131.4, 131.8, 132.5, 146.2, 151.2, 163.6, 185.6 (C=O); MS (EI, 70ev): m/z (%) = 362

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(M+, 20), 329 (19), 314 (7), 279 (17), 227 (12), 167 (38), 149 (100), 135 (37), 113 (11), 71 (22); Anal.
Calcd for C21H18N2O2S: C, 69.59; H, 5.01; N, 7.73. Found: C, 69.51; H, 5.05; N, 7.71.
Compound (4f)
Yellow solid; Mp 137-139C; IR (KBr): 3240, 1616, 1608, 1508, 1454, 1344, 1218, 1172, 1028 cm -1; 1H
NMR (CDCl3): =3.93 (s, 3H), 4.59 (s, 2H), 7.0 (d, J=8.7 Hz, 2H), 7.24 (d, J=7.4 Hz, 1H), 7.25 (m, 1H),
7.30 (m, 2H), 7.44 (d, J=7.2 Hz, 2H), 7.73 (m, 2H), 7.78 (d, J=8.7 Hz, 2H), 7.82 (m, 1H), 8.80 (m, 1H),
9.01 (d, J=7.4 Hz, 1H); 13C NMR (125.7 MHz, CDCl3): =37.2, 55.8, 114.2, 114.3, 122.6, 122.8, 124.7,
124.8, 127.2, 127.5, 128.6, 128.8, 129.6, 130.1, 131.4, 131.8, 132.3, 138.7, 146.0, 150.4, 163.6, 185.4
(C=O); MS (EI, 70ev): m/z (%) = 424 (M+, 2), 391 (2), 296 (6), 279 (43), 267 (6), 191 (5), 167 (87), 149
(100), 132 (6), 113 (24), 71 (34); Anal. Calcd for C26H20N2O2S: C, 73.56; H, 4.75; N, 6.60. Found: C,
73.69; H, 4.67; N, 6.63.
Compound (4g)
-1
Yellow solid; Mp 161-164C; IR (KBr): 3176, 1602, 1585, 1508, 1427, 1344, 1221, 1066, 1015, 927cm ;
1H NMR (CDCl3): =1.36 (t, J=7.5 Hz, 3H), 3.28 (q, J=7.5, 2H), 7.25 (d, J=7.5 Hz, 1H), 7.62 (dd, J=8.5,
2.0 Hz, 2H), 7.66 (dd, J=8.5, 2.0 Hz, 2H), 7.70 (m, 2H), 7.80 (m, 1H), 8.71 (m, 1H), 9.11 (d, J=7.5Hz,
1H); 13C NMR (CDCl3): =14.9, 26.7, 114.0, 121.8, 121.9, 124.3, 124.6, 126.7, 126.8, 128.2, 130.0,
130.2, 131.2, 131.8, 138.4, 146.2, 152.8, 184.8 (C=O); MS (EI, 70ev): m/z (%) = 412 (M+, 81Br, 40), 410
(M+, 79Br, 39), 395 (9), 439 (12), 377 (36), 351 (9), 298 (34), 279 (35), 227 (72), 167 (87), 149 (100), 128
(41), 113 (29), 71 (52); Anal. Calcd for C26H20N2O2S: C, 58.40; H, 3.68; N, 6.81. Found: C, 58.51; H,
3.63; N, 6.88.
Compound (4h)
Yellow solid; Mp 157-158 C; IR (KBr): 3161, 1605, 1500, 1433, 1377, 1272, 1174, 1066, 925 cm -1; 1H
NMR (CDCl3): =4.58 (s, 2H), 7.28 (m, 4H), 7.42 (d, J=7.2 Hz, 2H), 7.62 (m, 4H), 7.75 (m, 2H), 7.83
13
(m, 1H), 8.80 (m, 1H), 9.11 (d, J=7.4 Hz, 1H); C NMR (CDCl3): =37.0, 114.5, 122.3, 122.4, 124.8,
125.0, 127.2, 127.4, 127.6, 128.80, 128.83, 129.6, 130.5, 130.8, 131.6, 132.3, 138.5, 138.6, 146.4, 152.2,
81
79
185.2 (C=O); MS (EI, 70ev): m/z (%) = 474 (M+, Br, 12), 472 (M+, Br, 11), 441 (12), 439 (12), 360
(4), 302 (8), 289 (14), 279 (16), 167 (38), 149 (100), 128 (10), 113 (11), 91 (28), 71 (17). Anal. Calcd for
C25H17BrN2OS: C, 63.43; H, 3.62; N, 5.92. Found: C, 63.38; H, 3.69; N, 5.80.
Compound (4i)
Yellow solid; Mp 178-179 C; IR (KBr): 3411, 2919, 1598, 1558, 1506, 1429, 1346, 1257, 1218, 925 cm -1;
1H NMR (CDCl3): =2.7 (s, 3H), 7.29 (d, J=7.5 Hz, 1H), 7.45 (m, 1H), 7.53 (m, 2H), 7.74 (m, 4H), 7.80
(d, J=8.0 Hz, 2H), 7.84 (m, 1H), 7.88 (d, J=8.0 Hz, 2H), 8.77 (m, 1H), 9.18 (d, J=7.5 Hz, 1H);
13C NMR (CDCl3): =15.6, 114.4, 122.4, 122.5, 124.9, 125.0, 127.2, 127.71, 127.74, 128.5, 128.6, 129.3,
129.7, 130.3, 131.6, 138.9, 140.6, 145.2, 146.4, 153.5, 186.1 (C=O); MS (EI, 70ev): m/z (%) = 394 (M+,

HETEROCYCLES, Vol. 78, No. 2, 2009
421
18), 361 (13), 441 (12), 333 (6), 279 (34), 231 (8), 181 (16), 167 (75), 149 (100), 128 (7), 113 (21), 71
(32); Anal. Calcd for C25H18Br N2OS: C, 76.12; H, 4.60; N ,7.10. Found: C 76.20, H 4.62, N 7.15.
Compound (4j)
Yellow solid; Mp 127-129 C; IR (KBr): 3138, 1615, 1552, 1508, 1454, 1348, 1251, 1220, 1151, 929 cm -1;
1H NMR (CDCl3): =1.4 (t, J=7.3 Hz, 3H), 3.33 (q, J=7.3 Hz, 2H), 7.29 (d, J=7.4 Hz, 1H), 7.45 (m, 1H),
7.53 (m, 2H), 7.73 (m, 4H), 7.80 (d, J=8.2 Hz, 2H), 7.84 (m, 1H), 7.89 (d, J=8.2 Hz, 2H), 8.77 (m, 1H),
9.16 (d, J=7.4 Hz, 1H); 13C NMR (CDCl3): =15.4, 27.2, 114.2, 122.5, 122.8, 124.9, 125.0, 127.2, 127.6,
127.7, 128.4, 128.6, 129.3, 129.9, 130.3, 131.6, 138.8, 140.6, 145.2, 146.4, 152.6, 186.2 (C=O); MS (EI,
70ev): m/z (%) = 408 (M+, 4), 394 (1), 375 (5), 279 (37), 227 (4), 181 (6), 167 (86), 149 (100), 113 (28),
71 (48); Anal. Calcd for C26H20N2OS: C, 76.44; H, 4.93; N, 6.86. Found: C, 76.35; H, 4.85; N, 6.81.
Compound (4k)
Yellow solid; Mp 151-153 C; IR (KBr): 3082, 1602, 1579, 1508, 1454, 1433, 1411, 1350, 1272, 1191,
929 cm -1; 1H NMR (CDCl3): =4.6 (s, 2H), 7.23 (m, 1H), 7.29 (m, 3H), 7.43 (m, 3H), 7.52 (m, 2H), 7.74
13
(m, 6H), 7.84 (m, 3H), 8.81 (m, 1H), 9.12 (d, J=7.4 Hz, 1H); C NMR (CDCl3): =37.1, 114.4, 122.5,
122.7, 124.8, 124.9, 127.2, 127.5, 127.6, 127.7, 128.5, 128.7, 128.8, 129.3, 129.6, 129.9, 130.3, 131.6,
138.5, 138.6, 140.6, 145.3, 146.2, 151.7, 186 (C=O); MS (EI, 70ev): m/z (%) = 470 (M+, 2), 437 (2), 415
(3), 279 (40), 237 (6), 181 (13), 167 (94), 149 (100), 132 (6), 113 (31), 104 (17), 71 (51); Anal. Calcd for
C31H22N2OS: C, 79.12; H, 4.71; N, 5.95. Found: C, 79.15; H, 4.80; N 6.03.
ACKNOWLEDGEMENTS
Financial support by the research council of the University of Tehran is gratefully acknowledged.
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