Cascade synthesis of functionalized 2H-imidazo[5,1-a]-isoquinolinium chlorides from isoquinoline, chloroformamidines (=carbamimidoyl chlorides), and isocyanides

Article abstract of DOI:10.1002/hlca.200900216

Stable derivatives of 2H-imidazo[5,1-a]isoquinolinium chloride are obtained in good yields from the cascade reaction between isoquinoline, chloroformamidines (=carbamimidoyl chlorides), and isocyanides in dry MeCN (Scheme 1).

Full text of DOI:10.1002/hlca.200900216

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Helvetica Chimica Acta – Vol. 93 (2010)
Cascade Synthesis of Functionalized 2H-Imidazo[5,1-a]-
isoquinolinium Chlorides from Isoquinoline, Chloroformamidines
(¼Carbamimidoyl Chlorides), and Isocyanides
by Issa Yavari*, Gholamhossein Khalili, and Anvar Mirzaei
Chemistry Department, Tarbiat Modares University, P.O. Box 14115-175, Tehran, Iran
(phone: þ 98-21-82883465; fax: þ 98-21-82883455; e-mail: yavarisa@modares.ac.ir)
Stable derivatives of 2H-imidazo[5,1-a]isoquinolinium chloride are obtained in good yields from the
cascade reaction between isoquinoline, chloroformamidines (¼carbamimidoyl chlorides), and isocya-
nides in dry MeCN (Scheme 1).
Introduction. – Cascade reactions constitute a fascinating branch of organic
chemistry, and one which has been the subject of intense research in recent years, as
witnessed by the number of reviews that have appeared covering various aspects of
these processes [1 – 3]. The undeniable benefits of cascade reactions are well
established, having been recounted on numerous occasions, and include atom economy
[4][5], as well as economies of time, labor, resource management, and waste
generation.
Imidazo[5,1-a]isoquinolines have a wide range of unique biological potentialities
[6][7]. Several multistep pathways have been reported for the synthesis of these
compounds [8 – 13]. Although the synthesis of 1-aminoimidazo[5,1-a]isoquinolinium
salts based on multicomponent reactions of isocyanides has been previously reported
[14], there is no literature precedence for the reaction of isoquinoline (1) with
chloroformamidines (¼carbamimidoyl chlorides) 2 in the presence of isocyanides.
Compounds 2 can be generated from substituted ureas in the presence of Ph3P/CCl4
[15].
As part of our current studies on the development of new routes in heterocyclic
synthesis [16 – 20], we report a one-pot synthesis to 2H-imidazo[5,1-a]isoquinolinium
chlorides 4.
Results and Discussion. – The reaction of isoquinoline (1), isocyanides 3, and
chloroformamidines 2 (prepared in situ from the reaction of trisubstituted ureas, Ph3P,
and CCl4) proceeded smoothly in dry MeCN and was complete within 10 – 15 h
(Scheme 1). The 1H- and 13C-NMR spectra of the crude products clearly indicated the
formation of 2H-imidazo[5,1-a]isoquinolinium chlorides 4a – 4g in 75 – 88% yield.
The structures of compounds 4 were deduced from their IR and 1H- and 13C-NMR
spectra. For example, the 1H-NMR spectrum of 4a in (D6)DMSO showed two singlets
t
for NH and the Bu group together with two multiplets for CH2 groups and
1
characteristic multiplets for H-atoms of the Ph and isoquinolinium residue. The H-
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73
Scheme 1. Synthesis of Functionalized 2H-Imidazo[5,1-a]isoquinolinium Chlorides from Isoquinoline,
Chloroformamidines, and Alkyl Isocyanides
decoupled 13C-NMR spectrum of 4a showed 19 distinct resonances in agreement with
the proposed structure. The IR spectrum of 4a displayed a characteristic NH
(3375 cmꢀ1) band. The 1H- and 13C-NMR spectra of 4b – 4g were similar to those of 4a,
except for the signals of the substituents at the N-atoms, which exhibited characteristic
resonances in the appropriate regions of the spectrum.
A mechanistic rationalization for the reaction is given in Scheme 2. The initial event
is the formation of chloroformamidine 2 from the corresponding trisubstituted ureas in
the presence of Ph3P and CCl4. Nucleophilic attack of isoquinoline on 2 leads to
intermediate 5, which is attacked by alkyl isocyanide 3 to generate 6. Compound 4 is
produced by cyclization of 6 to 7 and subsequent 1,3-H shift.
In summary, we report a synthesis of stable 2H-imidazo[5,1-a]isoquinolinium
chlorides from the cascade reaction between isoquinoline and chloroformamidines in
Scheme 2

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Helvetica Chimica Acta – Vol. 93 (2010)
the presence of alkyl isocyanides in dry MeCN. The present procedure has the
advantage that the reactants can be mixed without any prior activation or modification.
Experimental Part
General. Isoquinoline (1) and isocyanides 3 were obtained from Merck and used without further
purification. Chloroformamidines 2 were prepared in situ from the reaction of trisubstituted ureas, Ph3P,
and CCl4. M.p.: Electrothermal-9100 apparatus; uncorrected. IR Spectra: Shimadzu-IR-460 spectrom-
eter; ˜n in cmꢀ1. 1H- and 13C-NMR Spectra: Bruker-DRX-500-Avance instrument; in CDCl3 at 500.1 and
125.7 MHz, resp.; d in ppm, J in Hz. MS: Finnigan-MAT-8430 mass spectrometer at 70 eV; in m/z (rel.
%). Elemental analyses (C, H, N): Heraeus-CHN-O-Rapid analyzer.
2H-Imidazo[5,1-a]isoquinolinium Chlorides 4: General Procedure. To a mixture of Ph3P (0.31 g,
1.2 mmol) and the trisubstituted urea (1 mmol) in dry MeCN was added CCl4 (0.17 g). The resulting soln.
was stirred at r.t. for 5 h. Then, isoquinoline (1; 0.13 g, 1 mmol) and isocyanide 3 (1 mmol) were added,
and stirring was continued at r.t. After completion of the reaction (5 – 10 h), as indicated by TLC
(AcOEt/hexane 2 :1), the solvent was evaporated, and the residue was washed with hot AcOEt (4 ml) to
afford pure title compounds.
1-[(tert-Butyl)amino]-3-(morpholin-4-yl)-2-phenyl-2H-imidazo[5,1-a]isoquinolinium Chloride
(4a): Yield 0.38 g (88%). White powder. M.p. 275 – 2778 (dec.). IR (KBr): 3375 (NH), 1647, 1547,
1593, 1550, 1497, 1446, 1362, 1362, 1206, 1103, 980, 774. 1H-NMR (500 MHz, (D6)DMSO): 0.91 (s, tBu);
3.03 – 3.10 (m, 2 CH2N); 3.55 – 3.60 (m, 2 CH2O); 4.93 (s, NH); 7.41 (d, 3J ¼ 7.5, CH); 7.65 – 7.71 (m,
2 CH); 7.72 – 7.75 (m, 5 CH); 7.90 (d, 3J ¼ 7.7, CH); 8.08 (d, 3J ¼ 7.5, CH); 8.90 (d, 3J ¼ 8.0, CH). 13C-NMR
(125.7 MHz, (D6)DMSO): 30.0 (Me3C); 48.9 (2 CH2N); 54.9 (Me3C); 68.8 (2 CH2O); 117.5 (CH); 119.1
(CH); 119.3 (C); 123.2 (C); 123.5 (CH); 126.4 (C); 127.4 (C); 127.9 (CH); 128.8 (2 CH); 128.9 (CH);
129.0 (CH); 129.4 (2 CH); 130.7 (CH); 132.4 (C); 135.4 (C). EI-MS: 437 (2, Mþ), 344 (100), 285 (25),
231 (35), 155 (60), 129 (55), 77 (48), 56 (25), 41 (33). Anal. calc. for C25H29ClN4O (436.97): C 68.71, H
6.68, N 12.82; found: C 68.64, H 6.58, N 12.54.
1-(Cyclohexylamino)-3-(morpholin-4-yl)-2-phenyl-2H-imidazo[5,1-a]isoquinolinium Chloride (4b):
Yield 0.37 g (80%). White powder. M.p. 228 – 2308 (dec.). IR (KBr): 3385 (NH), 1650, 1593, 1555, 1497,
1450, 1259, 1104, 789, 694. 1H-NMR (500 MHz, (D6)DMSO): 0.95 – 1.80 (m, 5 CH2); 3.02 – 3.09 (m,
3
3
2 CH2N); 3.54 – 3.59 (m, 2 CH2O); 4.54 – 4.59 (m, CHN); 5.20 (d, J ¼ 6.4, NH); 7.34 (d, J ¼ 7.5, CH);
7.59 (t, 3J ¼ 7.5, CH); 7.68 – 7.69 (m, CH); 7.70 – 7.75 (m, CH); 7.85 (d, 3J ¼ 7.7, CH); 8.01 (d, 3J ¼ 7.5, CH);
8.58 (d, 3J ¼ 8.0, CH). 13C-NMR (125.7 MHz, (D6)DMSO): 24.5 (2 CH2); 25.1 (CH2); 33.1 (2 CH2); 40.0
(2 CH2N); 56.9 (2 CH2O); 65.7 (CHN); 115.1 (CH); 117.5 (CH); 119.0 (C); 122.9 (C); 123.3 (CH); 126.9
(C); 127.9 (C); 128.3 (CH); 128.4 (2 CH); 128.6 (CH); 129.3 (CH); 129.6 (2 CH); 130.8 (CH); 132.2 (C);
134.7 (C). EI-MS: 463 (2, Mþ), 394 (100), 231 (40), 155 (65), 129 (50), 77 (42), 67 (25), 39 (50). Anal.
calc. for C27H31ClN4O (463.00): C 70.03, H 6.74, N 12.10; found: C 70.16, H 6.45, N 12.51.
1-[(tert-Butyl)amino]-3-(dimethylamino)-2-phenyl-2H-imidazo[5,1-a]isoquinolinium Chloride
(4c): Yield 0.33 g (85%). White powder. M.p. 241 – 2448 (dec.). IR (KBr): 3375 (NH), 1602, 1582,
t
1497, 1457, 1423, 1206, 823, 689. 1H-NMR (500 MHz, (D6)DMSO): 0.91 (s, Bu); 2.76 (s, 2 Me); 4.97 (s,
3
3
NH); 7.37 (d, J ¼ 7.5, CH); 7.63 – 7.66 (m, 2 CH); 7.67 – 7.74 (m, 5 CH); 7.86 (d, J ¼ 8.2, CH); 8.05 (d,
3J ¼ 7.5, CH); 8.89 (d, J ¼ 8.0, CH). 13C-NMR (125.7 MHz, (D6)DMSO): 30.0 (Me3C); 54.6 (Me3C);
3
54.9 (2 Me); 117.1 (CH); 119.0 (CH); 119.3 (C); 123.3 (C); 123.6 (CH); 125.8 (C); 127.4 (C); 127.9 (CH);
128.6 (2 CH); 128.7 (CH); 128.8 (CH); 129.4 (2 CH); 130.4 (CH); 132.7 (C); 137.3 (C). EI-MS: 395 (2,
Mþ), 302 (100), 189 (40), 155 (70), 129 (48), 77 (50), 41 (45). Anal. calc. for C23H27ClN4 (394.98): C
69.94, H 6.89, N 14.18; found: C 70.24, H 6.75, N 14.32.
1-(Cyclohexylamino)-3-(dimethylamino)-2-phenyl-2H-imidazo[5,1-a]isoquinolinium Chloride (4d):
Yield 0.32 g (78%). Pale yellow powder. M.p. 310 – 3128 (dec.). IR (KBr): 3380 (NH), 1606, 1556, 1473,
1343, 1270, 1137, 791, 651. 1H-NMR (500 MHz, (D6)DMSO): 1.14 – 2.21 (m, 5 CH2); 3.33 (s, 2 Me); 4.52 –
3
3
3
4.57 (m, CHN); 5.61 (d, J ¼ 7.0, NH); 7.39 (d, J ¼ 7.4, CH); 7.62 (t, J ¼ 7.6, CH); 7.65 – 7.69 (m, CH);
7.69 – 7.73 (m, 5 CH); 7.86 (d, 3J ¼ 7.5, CH); 8.13 (d, 3J ¼ 7.4, CH); 8.44 (d, 3J ¼ 8.0, CH). 13C-NMR
(125.7 MHz, (D6)DMSO): 24.7 (2 CH2); 25.1 (CH2); 33.2 (2 CH2); 54.6 (2 Me); 57.5 (CHN); 117.9 (CH);

Helvetica Chimica Acta – Vol. 93 (2010)
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118.2 (CH); 119.3 (C); 121.6 (C); 122.7 (CH); 123.0 (C); 124.2 (C); 127.0 (CH); 128.1 (2 CH); 128.5
(CH); 128.7 (CH); 129.5 (2 CH); 130.0 (CH); 132.6 (C); 136.0 (C). EI-MS: 421 (3, Mþ), 302 (100), 189
(45), 155 (68), 129 (53), 77 (43), 41 (56), 39 (35). Anal. calc. for C25H29ClN4 (420.97): C 71.32, H 6.94, N
13.31; found: C 71.12, H 6.57, N 13.68.
1-(Cyclohexylamino)-2-methyl-3-(methylamino)-2H-imidazo[5,1-a]isoquinolinium Chloride (4e):
Yield 0.25 g (75%). White powder. M.p. 312 – 3158 (dec.). IR (KBr): 3378 (NH), 1647, 1606, 1556,
1
1473, 1343, 1270, 1137, 791. H-NMR (500 MHz, (D6)DMSO): 1.14 – 1.82 (m, 5 CH2); 1.88 (s, MeNH);
2.49 (s, MeN); 4.55 – 4.58 (m, CHN); 5.65 (d, 3J ¼ 6.8, NH); 7.39 (d, 3J ¼ 7.4, CH); 7.63 (t, 3J ¼ 7.5, CH);
7.74 (t, 3J ¼ 7.4, CH); 7.85 (d, 3J ¼ 7.7, CH); 8.15 (d, 3J ¼ 7.3, CH); 8.44 (d, 3J ¼ 8.0, CH); 9.94 – 9.99 (br. s,
NH). 13C-NMR (125.7 MHz, (D6)DMSO): 24.6 (2 CH2); 25.1 (CH2); 33.1 (2 CH2); 33.5 (Me); 54.5
(Me); 57.5 (CHN); 117.9 (CH); 118.1 (CH); 121.5 (C); 122.7 (CH); 122.9 (C); 124.2 (C); 126.9 (CH);
128.0 (CH); 128.6 (CH); 129.4 (C); 129.9 (C). EI-MS: 345 (4, Mþ), 226 (100), 113 (35), 155 (63), 129
(48), 77 (43), 44 (63), 39 (35). Anal. calc. for C19H25ClN4 (344.88): C 66.16, H 7.30, N 16.24; found: C
65.89, H 7.12, N 16.54.
1-(Cyclohexylamino)-2-phenyl-3-(piperidin-1-yl)-2H-imidazo[5,1-a]isoquinolinium Chloride (4f):
Yield 0.36 g (80%). Yellow powder. M.p. 258 – 2608 (dec.). IR (KBr): 3384 (NH), 1651, 1593, 1554,
1497, 1459, 1342, 1263, 1024, 793, 770. 1H-NMR (500 MHz, (D6)DMSO): 0.89 – 2.10 (m, 8 CH2); 3.02 –
3
3
3
3.07 (m, 2 CH2N); 4.60 – 4.64 (m, CHN); 5.16 (d, J ¼ 6.1, NH); 7.29 (d, J ¼ 7.5, CH); 7.57 (t, J ¼ 7.5,
CH); 7.60 – 7.64 (m, CH); 7.64 – 7.76 (m, 5 CH); 7.81 (d, 3J ¼ 7.7, CH); 7.85 (d, 3J ¼ 7.5, CH); 8.57 (d, 3J ¼
8.0, CH). 13C-NMR (125.7 MHz, (D6)DMSO): 22.8 (2 CH2); 24.5 (CH2); 25.0 (CH2); 33.2 (2 CH2); 49.9
(2 CH2); 56.8 (2 CH2); 57.5 (CHN); 114.9 (CH); 117.3 (CH); 119.0 (C); 122.9 (C); 123.4 (CH); 126.9 (C);
127.8 (C); 128.0 (CH); 128.2 (2 CH); 128.4 (CH); 129.2 (CH); 129.5 (2 CH); 130.6 (CH); 132.4 (C); 136.1
(C). EI-MS: 461 (2, Mþ), 346 (100), 233 (55), 155 (70), 129 (62), 77 (38), 39 (43). Anal. calc. for
C28H33ClN4 (461.03): C 72.94, H 7.21, N 12.15; found: C 72.65, H 7.14, N 12.45.
3-(Morpholin-4-yl)-1-{[2-(morphlin-4-yl)ethyl]amino}-2-phenyl-2H-imidazo[5,1-a]isoquinolinium
Chloride (4g): Yield 0.38 g (77%). Pale yellow powder. M.p. 185 – 1888 (dec.). IR (KBr): 3380 (NH),
1648, 1610, 1554, 1439, 1366, 1259, 1107, 971, 795, 745, 689. 1H-NMR (500 MHz, (D6)DMSO): 2.93 – 2.98
(m, 3 CH2N); 3.21 – 3.26 (m, 2 CH2N); 3.33 – 3.39 (m, CH2N); 3.53 – 3.58 (m, 2 CH2O); 3.72 – 3.78 (m,
2 CH2O); 6.11 – 6.18 (m, NH); 7.39 (d, 3J ¼ 7.5, CH); 7.63 (t, 3J ¼ 7.4, CH); 7.64 – 7.69 (m, CH); 7.69 – 7.90
(m, 5 CH); 7.92 – 7.96 (m, CH); 8.06 (d, 3J ¼ 7.5, CH); 8.57 (d, 3J ¼ 7.8, CH). 13C-NMR (125.7 MHz,
(D6)DMSO): 31.7 (2 CH2N); 32.2 (2 CH2N); 48.9 (CH2N); 51.0 (CH2N); 62.9 (2 CH2O); 65.7 (2 CH2O);
116.5 (CH); 117.6 (CH); 119.0 (C); 122.7 (C); 123.0 (CH); 127.0 (C); 127.9 (C); 128.6 (CH); 129.7
(2 CH); 129.8 (CH); 130.3 (CH); 131.0 (2 CH); 131.9 (CH); 134.0 (C); 135.5 (C). EI-MS: 494 (5, Mþ),
344 (100), 231 (63), 155 (56), 77 (38), 41 (38). Anal. calc. for C27H32ClN5O2 (494.02): C 65.63, H 6.52, N
14.17; found: C 65.59, H 6.32, N 14.46.
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Received June 6, 2009