Superacid-promoted cyclodehydration leading to the imidazo[2,1-a] isoquinoline ring system

Article abstract of DOI:10.1002/hlca.201200590

A series of heterocycle-substituted acetophenones were prepared and reacted with the Bronsted superacid CF₃SO₃H (triflic acid=trifluoromethanesulfonic acid). Cyclodehydration provided aryl-substituted imidazo[2,1-a]isoquinolines and related products (28-85%, seven examples). A mechanism is proposed involving dicationic intermediates. Copyright

Full text of DOI:10.1002/hlca.201200590

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Superacid-Promoted Cyclodehydration Leading to the
Imidazo[2,1-a]isoquinoline Ring System
by Anila Kethe, Rajasekhar Reddy Naredla, and Douglas A. Klumpp*
Department of Chemistry and Biochemistry, Northern Illinois University, DeKalb, Illinois 60115, USA
(fax: þ 1-98-311-6689732; e-mail: dklumpp@niu.edu)
A series of heterocycle-substituted acetophenones were prepared and reacted with the Brønsted
superacid CF3SO3H (triflic acid ¼ trifluoromethanesulfonic acid). Cyclodehydration provided aryl-
substituted imidazo[2,1-a]isoquinolines and related products (28 – 85%, seven examples). A mechanism
is proposed involving dicationic intermediates.
Introduction. – Functionalized N-heterocycles are important compounds for the
development of new medicinal agents. Heterocycles with bridgehead N-atoms have
been of particular interest. For example, the imidazo[1,2-a]pyridine ring system has a
wide spectrum of biological activity, and it is found in a number of commercial drugs
[1]. These types of heterocyclic systems have also been used in various material-science
applications, in particular as fluorophores [2]. The imidazo[1,2-a]pyridine and the
related pyrido[1,2-a]benzimidazole ring systems have been prepared by condensations
with aminopyridines [3], transition metal-catalyzed oxidative bond-formation [4],
nucleophilic ring-forming reactions [5], and other routes [6]. Some of the previously
reported methodologies utilize expensive or highly toxic reagents, so there is need for
improved synthetic methods. In the following study, we describe an approach to aza-
polycyclic aromatic systems with a bridgehead N-atom, i.e., imidazo[2,1-a]isoquino-
lines. Our strategy involves the use of a superacid-promoted cyclodehydration reaction.
Results and Discussion. – The synthesis begins with the preparation of heterocyclic
ketones suitable for cyclodehydration reactions. Thus, 2-phenyl-1H-imidazole (1) and
2-bromo-3’,4’-dichloroacetophenone (2) provided the functionalized imidazole 3 in
good yield by reaction with Ag2CO3 (Scheme 1). With the Ph substitutent, the ketone
was properly situated to generate a new six-membered ring via cyclodehydration. A
series of heterocyclic ketones, 4 – 9 (Table), were prepared using 2-bromoacetophe-
Scheme 1
ꢀ 2013 Verlag Helvetica Chimica Acta AG, Zꢁrich

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Table. Cyclodehydration Products 10 – 16 from the Reactions of Ketones 3 – 9 with CF3SO3H
Starting material
R1
R2
Product
Yield [%]a)
3
4
5
6
7
8
9
3,4-Cl2ꢀC6H3
Ph
10
11
12
13
14
15
16
85
60
48
61
60
28
51
C6H5ꢀC6H4
Ph
H
H
Cl
4-ClꢀC6H4
Ph
a) Yield of purified product.
none or related substrates. Two analogous methods, but other reaction conditions, were
used to prepare heterocyclic ketones of type 3: halogenated ketones of type 2 and 1
were treated with K2CO3 in DMF or with Et3N/Bu4NBr in MeCN [7]. We also
attempted the conversion of 1 and 2 to 3 with KOH in DMSO, and with pyridine in
dioxane, respectively; however, these methods did not give the desired product.
By the reaction of compounds 3 – 9 in superacid, the expected imidazo[2,1-
a]isoquinolines 10 – 12 were produced (Table). For example, compound 3 reacted in
CF3SO3H at 808 to give heterocycle 10 in 85% yield. Ketones 4 and 5 reacted similarly
to give 11 and 12, respectively, and ketones 6 – 8 also provided the expected
cyclodehydration products, i.e., the benzimidazole derivatives 13 – 15. The conversion
of 8 to 15 is somewhat less efficient than the other conversions. This may be the result
of a modest deactivating effect involving the Cl-substituent or due to the statistical
factor of having one ortho position blocked on the aryl group. We also prepared the
pyrazole-based ketone 9 and found this to provide the cyclodehydration product,
pyrazolo[5,1-a]isoquinoline 16.
Acid-catalyzed cyclodehydration involving aldehydes or ketones generally pro-
ceeds through the carboxonium ion intermediate formed by C¼O protonation. Thus,
we propose a mechanism involving diprotonated or dicationic intermediates leading to
the condensation products (Scheme 2). The initial protonation occurs at the N-
heterocyclic ring of 17, and a second protonation gives the superelectrophilic species 18.

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Cyclization occurs at the adjacent Ph substituent leading to ring formation to give 19.
Dehydration would generate the dicationic intermediate 20, which provides the
imidazo[1,2-a]pyridine 10 by deprotonation steps.
Scheme 2
The cyclodehydration was also attempted with 1H-tetrazole derivative 21; however,
only starting material was found in the product mixture. In this case, multiple
protonations at the tetrazole ring may inhibit the cyclodehydration, either preventing
C¼O protonation or deactivating the Ph ring towards electrophilic attack. The
heterocyclic amide 22 and ester 23 were also prepared. Both substances undergo bond
cleavage under the reaction conditions to yield 2-phenyl-1H-imidazole. Although the
respective carboxonium ions 24 are likely to be formed under the reaction conditions,
cyclodehydration does not occur – presumably due to the relative low electrophilic
reactivities of the carboxonium ions 24.
Conclusions. – We found that imidazo[2,1-a]isoquinolines, benzimidazo[2,1-a]iso-
quinolines, and a pyrazolo[5,1-a]isoquinoline may be prepared in fair-to-good yields by
superacid-promoted cyclodehydration with heterocyclic ketones. A mechanism is
proposed involving diprotonated, superelectrophilic intermediates leading to the aza-
polycyclic aromatic compounds.
We gratefully acknowledge the financial support of the National Science Foundation (CHE-
0749907).

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Experimental Part
General. Using oven-dried glassware, reactions were performed under Ar. Trifluoromethanesulfonic
acid, CF3SO3H, was distilled (Ar atmosphere) prior to use. Column chromatography (CC): ASTM silica
gel 60 (230 – 400 mesh) using a forced flow of 0.5 – 1.0 bar. NMR Spectra: Bruker Avance III
spectrometer, at 300 or 500 (1H), and 75 or 125 MHz (13C); chemical shifts rel. to the solvent peak
(CDCl3 or CD3OD). GC/MS: Agilent Technologies 5973N (electron ionization; EI). HR-MS: Performed
at the University of Illinois at Urbana-Champaign, Analytical Services Lab; in m/z.
General Procedure A: Synthesis of Heterocyclic Ketones 3, 4, 6, and 8, and Heterocyclic Amide 22.
The heterocyclic substrate (1.4 mmol), the bromo ketone or amide (1.4 mmol), and Ag2CO3 (382 mg,
1.5 mmol) in dry MeCN (10 ml) were heated to reflux for 12 h. The mixture was then partitioned between
CHCl3 and H2O, and the org. extracts were subsequently washed with brine. The crude product was dried
(Na2SO4) and concentrated by removal of solvent. CC (hexane/Et2O) gave the pure product.
General Procedure B: Synthesis of Heterocyclic Ketone 5 and Heterocyclic Ester 23. Adapting a
published procedure [7], the heterocyclic substrate (3.47 mmol), the bromo ketone/ester (4.16 mmol),
(benzyl)(triethyl)ammonium bromide (80 mg, 0.3 mmol), and Et3N (350 mg, 3.47 mmol) in dry MeCN
(10 ml) were heated to reflux for 12 h. The mixture was worked up as described above.
General Procedure C: Synthesis of Heterocyclic Ketones 7, 9, and 21. The heterocyclic substrate
(2.6 mmol), the bromo ketone (2.6 mmol), and K2CO3 (1.4 g, 10.3 mmol) in anh. acetone (10 ml) were
heated to reflux for 24 h. The mixture was worked up as described above.
General Procedure D: Cyclodehydration of 10 – 16. The ketone substrate (1 mmol) was dissolved in
neat CF3SO3H (3 ml, 34 mmol), and the mixture was stirred for 12 h at 808. The reaction was quenched
by pouring the contents over several grams of ice, and the resulting mixture was then extracted twice with
CHCl3. The org. layer was then washed with H2O and brine, dried (Na2SO4), and concentrated in vacuo.
CC (hexane/AcOEt) afforded the pure product.
1-(3,4-Dichlorophenyl)-2-(2-phenyl-1H-imidazol-1-yl)ethanone (3). 2-Phenylimidazole (1; 498 mg,
3.5 mmol) and 2-bromo-3’,4’-dichloroacetophenone (2; 1.3 g, 3.5 mmol) afforded 3 in 76% yield (878 mg,
1
2.6 mmol). Brown oil. H-NMR (300 MHz, CDCl3): 5.38 (s, 2 H); 7.00 (s, 1 H); 7.20 (s, 1 H); 7.41 – 7.45
(m, 5 H); 7.57 (d, J ¼ 8.1, 1 H); 7.71 (dd, J ¼ 8.4, 1.8, 1 H); 7.97(d, J ¼ 1.8, 1 H). 13C-NMR (75 MHz,
CDCl3): 52.8; 121.9; 126.9; 128.6; 128.8; 129.4; 129.7; 130.0; 131.2; 133.5; 134.0; 139.2; 148.4; 190.4. HR-
MS: 330.0332 (C17H12Cl2N2Oþ; calc. 331.1960).
6-(3,4-Dichlorophenyl)imidazo[2,1-a]isoquinoline (10). From 3 (389 mg, 1.3 mmol). Yield: 85%
(345 mg, 1.1 mmol). Dark solid. M.p. 124 – 1258. 1H-NMR (300 MHz, CDCl3): 7.31 (dd, J ¼ 8.2, 2, 1 H);
7.53 – 7.63 (m, 7 H); 7.86 (s, 1 H); 8.70 (d, J ¼ 7.9, 1 H). 13C-NMR (75 MHz, CDCl3): 114.3; 122.2; 123.6;
124.2; 125.2; 128.4; 128.5; 129.5; 130.6; 131.6; 131.9; 132.5; 132.9; 136.2; 142.6; two peaks are missing due
to the magnetic equivalence of 300-MHz NMR. HR-MS: 312.0219 (C17H10Cl2Nþ2 ; calc. 312.0221).
6-Phenylimidazo[2,1-a]isoquinoline (11). Known compound; see [8].
6-[1,1’-Biphenyl-4-yl]imidazo[2,1-a]isoquinoline (12). From 5 (101 mg, 0.3 mmol). Yield: 48%
1
(0.14 mmol). Orange oil. H-NMR (300 MHz, CDCl3): 6.60 (dd, J ¼ 7.8, 1, 1 H); 6.90 (d, J ¼ 0.9, 1 H);
7.01 (d, J ¼ 7.6, 2 H); 7.07 (dt, J ¼ 7.7, 1.2, 1 H); 7.23 (t, J ¼ 7.5, 2 H); 7.29 (br. s, 1 H); 7.36 (dt, J ¼ 7.6, 1,
1 H); 7.44 (t, J ¼ 4, 2 H); 7.47 – 7.76 (m, 2 H); 7.81 (d, J ¼ 8, 2 H); 8.24 (d, J ¼ 7.6, 1 H). 13C-NMR
(75 MHz, CDCl3): 119.9; 120.4; 124.2; 124.4; 125.7; 127.2; 128.1; 128.3; 128.6; 128.9; 129.0; 129.4; 136.8;
140.1; 147.7; four peaks are missing due to the magnetic equivalence of 300 MHz NMR. LR-MS: 320
(Mþ), 304, 291, 252, 160. HR-MS: 320.1321 (C23H16N2þ ; calc. 320.1313).
6-Phenylbenzimidazo[2,1-a]isoquinoline (13). From 6 (140 mg, 0.371 mmol). Yield: 61% (132.7 mg,
0.367 mmol). Brown solid. M.p. 152 – 1568. 1H-NMR (300 MHz, CDCl3): 7.38 – 7.51 (m, 1 H); 7.51 – 7.80
(m, 10 H); 8.04 (d, J ¼ 8.1, 1 H); 8.09 (s, 1 H); 8.94 (d, J ¼ 7.5, 1 H). 13C-NMR (75 MHz, CDCl3): 109.8;
119.9; 120.3; 121.9; 123.5; 124.7; 125.3; 125.9; 128.1; 128.2; 129.0; 129.4; 129.9; 130.1; 130.3; 131.5; 136.3;
143.8; 146.9. MS: 294 (Mþ), 264, 190, 147. HR-MS: 294.1153 (C21H14Nþ2 ; calc. 294.1157).
6-(4-Chlorophenyl)benzimidazo[2,1-a]isoquinoline (14). From 7 (329 mg, 0.95 mmol). Yield: 60%
(187 mg, 0.57 mmol). Light-brown solid. M.p. 177 – 1788. 1H-NMR (300 MHz, CDCl3): 7.46 – 7.48 (m,
1 H); 7.49 – 7.54 (m, 5 H); 7.60 – 7.70 (m, 3 H); 7.78 (d, J ¼ 8.1, 1 H); 8.01 (d, J ¼ 8.1, 1 H); 8.01 (s, 1 H);
8.89 (d, J ¼ 7.8, 1 H). 13C-NMR (75 MHz, CDCl3): 109.8; 119.9; 120.4; 122.0; 123.4 (d; J ¼ 6.7 Hz) 124.9;

Helvetica Chimica Acta – Vol. 96 (2013)
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125.3; 125.6; 128.3; 129.0; 130.0; 130.1; 131.2; 131.6; 134.3; 134.7; 143.7; 146.8. MS: 330/328 (Mþ), 293,
292, 190, 146. HR-MS: 328.0764 (C21H13ClNþ2 ; calc. 328.0767).
10-Chloro-6-phenylbenzimidazo[2,1-a]isoquinoline (15). From 8 (140 mg, 0.371 mmol). Yield: 28%
1
(132.7 mg, 0.367 mmol). Pale-yellow semisolid. H-NMR (300 MHz, CDCl3): 7.46 – 7.64 (m, 9 H); 7.80
(dd, J ¼ 17, 7.8, 2 H); 8.18 (m, 2 H). 13C-NMR (75 MHz, CDCl3): 109.5; 121.0; 121.3; 122.7; 124.3; 124.8
(d, J ¼ 9.7); 128.4; 128.8; 129.16; 129.23; 130.4; 130.9; 132.8; 134.3; 136.3; 143.6; 144.7. MS: 330/328
(Mþ), 293, 292, 190, 146. HR-MS: 328.0764 (C21H13ClNþ2 ; calc. 328.0767).
2,6-Diphenylpyrazolo[5,1-a]isoquinoline (16). From 9 (140 mg, 0.371 mmol). Yield: 51% (132.7 mg,
1
0.367 mmol). Light-brown oil. H-NMR (300 MHz, CDCl3): 7.34 (d, J ¼ 0.6, 1 H); 7.34 – 7.48 (m, 2 H);
7.50 – 7.78 (m, 8 H); 7.76 (d, J ¼ 7.8, 1 H); 8.06 – 8.11 (m, 2 H); 8.20 (dd, J ¼ 8.1, 1.2, 1 H); 8.29 (s, 1 H).
13C-NMR (75 MHz, CDCl3): 94.6; 112.5; 124.0; 125.3; 126.0; 126.4; 127.7; 127.9; 128.0; 128.2; 128.4; 128.7;
128.8; 128.9; 130.2; 133.2; 136.4; 139.3; 153.1. MS: 320 (Mþ), 243, 216, 189, 160. HR-MS: 320.1307
(C23H16Nþ2 ; calc. 320.1313).
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Received October 23, 2012