Synthesis of 2,3-dihydroimidazo[1,2-b]isoquinoline-5(1H)-one and derivatives

Article abstract of DOI:10.1055/s-2005-918505

A novel and efficient synthesis of 2,3-dihydroimidazo[1,2-b]isoquinoline- 5(1H)-one by microwave irradiation is reported. Several new derivatives of 2,3-dihydroimidazo[1,2-b]isoquinoline-5(1H)-one have been synthesized by acylation using DMAP as catalyst. A kinetic study employing HPLC allowed the determination of the N- and C-acylated isomers formed. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-918505

PAPER
237
Synthesis of 2,3-Dihydroimidazo[1,2-b]isoquinoline-5(1H)-one and
Derivatives
2
, 3-Dihydroimidazo[
1
a
b
]isoquin
r
oline-5(
i
1
H
)-on
e
e
and
D
eriv
l
ativesa Bollini, Silvia E. Asís, Ana María Bruno*
Centro de Síntesis y Estudio de Nuevos Compuestos Antineoplásicos y Antiparasitarios. Departamento de Química Orgánica,
Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Junín 956, 1113 Buenos Aires, Argentina
Fax +54(11)49648252; E-mail: anabruno@ffyb.uba.ar
Received 17 May 2005; revised 15 July 2005
In recent years, microwave-assisted reactions5,6 are of
great interest because of their simplicity in operation, en-
hanced reaction rates and greater selectivity. Particularly,
solvent-free reactions have gained popularity as they pro-
Abstract: A novel and efficient synthesis of 2,3-dihydroimida-
zo[1,2-b]isoquinoline-5(1H)-one by microwave irradiation is re-
ported. Several new derivatives of 2,3-dihydroimidazo[1,2-
b]isoquinoline-5(1H)-one have been synthesized by acylation using
DMAP as catalyst. A kinetic study employing HPLC allowed the vide an opportunity to work with open vessels. This
determination of the N- and C-acylated isomers formed.
avoids the risk of the development of high pressure and
provides the possibility of scaling-up the reaction.
Key words: acylation, DMAP, isomerizations, heterocycles, mi-
crowave synthesis
A novel and efficient approach for the synthesis of 1 in
solvent-free conditions is of much interest. Such a synthe-
sis has been achieved now by us by treating homophthalic
acid with ethylenediamine under microwave irradiation
over six minutes to afford compound 1 in 96% yield. The
microwave irradiation was carried out using a domestic
microwave oven at constant power with a reflux condens-
er (Scheme 1).
There are several human protozoal parasites that cause
devastating diseases (malaria, sleeping sickness, Chagas’
disease and leishmaniasis) in the underdeveloped regions
of the world. So far, there is no effective treatment and the
intensive use of commercial drugs has led to the develop-
ment of resistant parasites.1 There is an urgent need for
new rather than economic drugs for the treatment of these
diseases.
Isoquinolines generally constitute an important branch of
heterocyclic compounds and are used nowadays against
parasitic infections. Imidazoisoquinolinones are valuable
substrates for the synthesis of potential biologically active
compounds with structural features different from that of
existing drugs. We required a synthesis of 2,3-dihydroim-
idazo[1,2-b]isoquinoline-5(1H)-one (1) and chemical ex-
ploration of this heterocycle, in order to determine what
kind of derivatives can be achieved and find a ‘prototype’
molecule.
Scheme 1
In order to obtain new compounds related to the isoquin-
oline 1 in a large scale and low cost, we developed an ex-
ploration of the chemical reactions of heterocycle 1. In the
first attempt we explored the acylation reaction by two
regular methods: Schotten–Baumann reaction and using
In 1976, Grinberg et al.2 reported the synthesis of this het- 4-(dimethylamino)pyridine (DMAP) as catalyst.7,8 In the
erocycle by condensation of homophthalic anhydride with acylation of the heterocycle 1 by acid chlorides using
ethylenediamine, and isolating the intermediate amide, Schotten–Baumann method, N-1 selective acylation is fa-
which upon heating to its melting point, loses two water vored, however we found the C-10 isomer as a side-prod-
molecules to give 1 in poor yield. Other authors3,4 pub- uct of the reaction. This mixture can be resolved by
lished the condensation of homophthalic acid with two chromatography although the subsequent separation con-
mol equivalents of ethylenediamine in o-dichlorobenzene stituted a problem and it reduced yields. In general, the
under reflux for six hours to give 1 in 91% yield. Howev- tested acid chlorides gave N-1 acylation products with an
er, these classical methods required high temperatures, amount of C-10 isomer. The corresponding C-10 isomers
prolonged reaction times and drastic reaction conditions were detectable by TLC.
and in the method reported by Grinberg, the yields are far
DMAP is well-established in synthetic chemistry as an ex-
from satisfactory due to the occurrence of several side re-
tremely useful ‘hypernucleophilic’ acylation catalyst, and
actions.
thus is routinely employed to accelerate the acylation of
nucleophilic nitrogen atom.9–11 Inclusion of DMAP in
acylation reaction mixture leads directly to carbon acyla-
tion, as it seems to be a regioselective reaction. This reac-
SYNTHESIS 2006, No. 2, pp 0237–0242
x
x
.
x
x
.2
0
0
5
tion was kinetically studied by HPLC at different
temperatures. During the first minutes of reaction, 80% of
Advanced online publication: 21.12.2005
DOI: 10.1055/s-2005-918505; Art ID: M03605SS
© Georg Thieme Verlag Stuttgart · New York

238
M. Bollini et al.
PAPER
the product was C-10 acylated and 20% N-1 acylated. As Scheme 2 as example. N-Acylation is kinetically favored,
the reaction proceeded, an increase of C-10 isomer frac- a nucleophilic attack by DMAP on carbonyl group would
tion was evidenced. A complete conversion to C-10 acyl afford the acylated pyridinium ion 2a, expelling the anion
isomer was observed after 90 minutes reaction time. This 2b in the process. Subsequent attack by the rearranged 2c
suggested a migratory process of N-1 acylation to C-10 would afford the carbon-functionalized isomer
acylation product. We verified that the migratory process (Scheme 2).
9
was viable for all substrates and we could determine that
the migration was a general phenomenon.
DMAP retained its efficacy in halogenated solvents. Both,
dichloromethane and chloroform allowed a faster and
A mixture of N- and C- isomers obtained from Schotten– complete rearrangement than the more polar dimethylfor-
Baumann reaction in dichloromethane solution was treat- mamide. DMF slowed the reaction considerably, consis-
ed with DMAP and the reaction was monitored by HPLC. tent with solvation and partial separation of the ionic
We observed that DMAP caused the disappearance of species. In the non-polar solvent hexane a mixture was ob-
N-1 acylated product with an accompanying marked in- tained without any rearrangement. A series of 15 deriva-
crease of C-10 acylated product (Figure 1).
tives employing sulfonyl, alkyl and aryl acyl chloride
were obtained in good to excellent yields (Scheme 3).
In conclusion, we have synthesized the starting heterocy-
cle with a novel and efficient method. We prompted the
acylation reaction by two methods: Schotten-Baumann
reaction and DMAP as catalyst. Inclusion of DMAP
seems to be a regioselective reaction. Migration of N-acyl
product to C-isomer was monitored by HPLC.
Melting points were determined in a capillary Electrothermal 9100
SERIES-Digital apparatus and are uncorrected. IR spectra were re-
corded with a FT Perkin-Elmer Spectrum One from KBr discs. UV
spectra were measured with a Jasco V-5570 UV/Vis/NIR spectro-
photometer. H NMR and 13C NMR spectra were obtained with a
Bruker spectrometer (200 MHz) at r.t. The chromatographic system
was performed using preparative centrifugally accelerated chroma-
tography (Chromatotron®) and silica gel Merck 60 PF-254. The
1
Figure 1 Rearrangement of compound 2 to compound 9 isomers via
DMAP catalysis
Acylation reactions employing acid chlorides and cata- HPLC chromatograms were obtained in a KoniK-500-A SERIES
chromatograph, using spherisorb silica 5-m (250 × 4.6 mm) alltech.
The purity of all compounds was checked using HPLC, employing
ODS Hypersil column (5 mm, 200 × 4.6 mm) Hewlett Packard. Mi-
crowave-assisted reaction was carried out in a household MW oven
(BGH-QUICK Chef 15240). The apparatus was modified for labo-
ratory applications with an external reflux condenser.
lyzed by DMAP are known to proceed via acylation of py-
ridine ring to afford highly reactive pyridinium species.
This entity then undergoes facile nucleophilic attack af-
fording the acylated product and regenerating the cata-
lyst.12,13 We propose that a similar species is operative in
our migration reaction; the sequence is depicted in
Scheme 2
Synthesis 2006, No. 2, 237–242 © Thieme Stuttgart · New York

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2,3-Dihydroimidazo[1,2-b]isoquinoline-5(1H)-one and Derivatives
239
Scheme 3 Reagents and conditions: a) DMAP, RSO2Cl, CH2Cl2, 0 °C; b) aq 10% KOH, RSO2Cl, CH2Cl2, 0 °C; c) DMAP, RCOCl, CH2Cl2,
0 °C; d) aq 10% KOH, RCOCl, CH2Cl2, 0 °C
2,3-Dihydroimidazo[1,2-b]isoquinoline-5(1H)-one (1)
A suspension of homophthalic acid (Aldrich, 5 g, 24 mmol) and eth-
ylenediamine (Merck, 35 mL, 48 mmol) was stirred and subjected
to microwave irradiation operating at 240 Watts for 6 min, using a
household MW oven. The product was collected by filtration and
crystallized from EtOH to yield 1 (4.8 g, 96%) as yellow needles;
mp 217–218 °C (Lit.3 mp 210–211 °C).
allowed to warm to r.t. for an additional 2 h. The organic layer was
separated, dried (MgSO4), filtered and evaporated under reduced
pressure. The products were purified by an appropriate method.
1-[(4-Nitrophenyl)carbonyl]-2,3-dihydroimidazo[1,2-b]iso-
quinoline-5(1H)-one (2)
4-Nitrobenzoyl chloride and compound 1 afforded an N-acyl and C-
acyl isomer mixture. The crude product was purified using Chroma-
totron® and EtOAc–hexane (60:40) as eluent to give 2 (0.27 g,
30%); mp 192–194 °C.
IR (KBr): 3213, 1664, 1531, 767, 690 cm–1.
1H NMR (DMSO-d6): d = 7.93 (ddd, J = 8.11, 1.28, 0.72 Hz, 1 H,
H-6), 7.39 (t, J = 8.11 Hz, 1 H, H-7), 7.26 (t, J = 8.11 Hz, 1 H, H-
8), 7.00 (dd, J = 8.0, 1.28 Hz, 2 H, H-9, NH, exchangeable with
D2O), 5.53, (s, 1 H, H-10), 4.05 (t, J = 7.9 Hz, 2 H, H-2), 3.6 (t, J =
7.18 Hz, 2 H, H-3).
13C NMR (CCl3D): d = 160, 148.9, 140.9, 132.1, 126.6, 123, 121.0,
119.2, 77.6, 43.9, 41.9.
IR (KBr): 3130–3052, 1616, 1599, 836, 761–693 cm–1.
1H NMR (DMSO-d6): d = 8.4 (dd, J = 6.91, 1.9 Hz, 2 Harom), 8.14
(d, J = 7.39 Hz, 1 H, H-6), 7.94 (dd, J = 6.92, 1.9 Hz, 2 Harom), 7.64–
7.92 (m, 2 H, H-7, H-9), 7.36–7.41 (m, 1 H, H-8), 7.1 (s, 1 H, H-10),
4.0–4.1 (m, 4 H, H-2, H-3).
Anal. Calcd for C18H13N3O4: C, 64.47; H, 3.91; N, 12.53. Found: C,
64.83; H, 4.29; N, 12.18.
Anal. Calcd for C11H10N2O: C, 70.95; H, 5.41; N, 15.04. Found: C,
71.16; H, 5.72; N, 14.87.
1-(Phenylcarbonyl)-2,3-dihydroimidazo[1,2-b]isoquinoline-
5(1H)-one (3)
Method 1: Benzoyl chloride and compound 1 afforded only com-
pound 3 which was crystallized from EtOH; yield: 0.62 g (80%);
white powder; mp 180–181 °C (Lit.3 mp 178–180 °C).
IR (KBr): 3130, 3052, 1706, 1614, 1548, 761, 700, 693 cm–1.
Synthesis 2006, No. 2, 237–242 © Thieme Stuttgart · New York
Acylation of Compound 1 with Acyl Chlorides and Sulfonyl
Chlorides; (Schotten–Baumann Reaction); General Procedure
Method 1: To a magnetically stirred mixture of compound 1 (0.5 g,
2.7 mmol) in CH2Cl2 (15 mL) and 20% aq solution KOH (5 mL),
was slowly added dropwise a solution of acyl or sulfonyl chloride
in CH2Cl2 (10 mL, 3.3 mmol) at 0–5 °C and the mixture was then

240
M. Bollini et al.
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1H NMR (CDCl3): d = 8.3 (d, J = 6.67 Hz, 1 H, H-6), 7.36–7.65 (m,
8 Harom), 6.85 (s, 1 H, H-10), 4.29 (t, J = 6.92 Hz, 2 H, H-2), 4.19 (t,
J = 6.92 Hz, 2 H, H-3).
J = 6.65 Hz, 2 Harom), 6.98 (s, 1 H, H-10), 4.11–4.16 (m, 4 H, H-2,
H-3), 3.33 (s, 3 H, OCH3).
Anal. Calcd for C19H16N2O3: C, 71.24; H, 5.03; N, 8.74. Found: C,
71.12; H, 5.23; N, 8.85.
Anal. Calcd for C18H14N2O2: C, 74.47; H, 4.86; N, 9.65. Found: C,
74.70; H, 5.04; N, 9.72.
1-(Methanesulfonyl)-2,3-dihydroimidazo[1,2-b]isoquinoline-
5(1H)-one (7)
Method 1: Methanesulfonyl chloride and compound 1 yielded the ti-
tle compound 7. The solid was crystallized from CH2Cl2–cyclohex-
ane to give 7; 0.49 g (70%); mp 184–185 °C (Lit.3 mp 171–176 °C).
Method 2: To a suspension of compound 1 (0.5 g, 2.7 mmol) in
CH2Cl2 (5 mL), were added dropwise pyridine (0.5 mL, 6.7 mmol)
and benzoyl chloride (1.4 mL, 3.3 mmol) with stirring at 0–5 °C.
The temperature of the reaction was allowed to rise to r.t. and the
mixture was stirred overnight. The pyridine was evaporated under
reduced pressure. The solid product was crystallized from EtOH to
yield 3 (0.23 g, 30%), whose physical properties and elemental
analysis are identical with the product obtained by Method 1.
IR (KBr): 2920, 1659, 1551, 750, 689 cm–1.
1H NMR (CDCl3): d = 8.31 (d, J = 7.43 Hz, 1 H, H-6), 7.62 (dt, J =
6.93, 1.28 Hz, 1 H, H-8), 7.45 (d, J = 7.69 Hz, 1 H, H-9), 7.36 (dt,
J = 6.93, 1.28 Hz, 1 H, H-7), 6.49 (s, 1 H, H-10), 4.30 (t, J = 7.95
Hz, 2 H, H-2), 4.10 (t, J = 6.67 Hz, 2 H, H-3), 3.09 (s, 3 H,
RSO2CH3).
Method 3: Compound 1 (0.5 g, 2.7 mmol) and DMAP (0.6 g, 4.4
mmol) were suspended in CH2Cl2 (5 mL). After 5 min, benzoyl
chloride was added over a period of several min with stirring at 0–
5 °C for 2 h. The organic layer was dried (MgSO4), filtered and
evaporated under reduced pressure. The solid was crystallized from
EtOH to give 3 (0.18 g, 23%), whose physical properties and ele-
mental analysis are identical with the product obtained by Method
1.
Anal. Calcd for C12H12N2O3S: C, 54.53; H, 4.58; N, 10.60. Found:
C, 54.65; H, 4.93; N, 10.28.
Method 2: To a suspension of compound 1 (0.5 g, 2.7 mmol) in py-
ridine (5 mL) was added dropwise methanesulfonyl chloride (0.5
mL, 3.1 mmol) with stirring at 0–5 °C. The reaction temperature
was allowed to rise to r.t. and the mixture was stirred overnight. The
pyridine was evaporated under reduced pressure and the residual
viscous oil obtained was triturated with EtOH to give 0.11 g (15%)
of product 7, whose physical properties and elemental analysis are
identical with the product obtained by Method 1.
1-Acetyl-2,3-dihydroimidazo[1,2-b]isoquinoline-5(1H)-one (4)
Method 1 : Acetyl chloride and compound 1 afforded the title com-
pound 4, which was crystallized from benzene yield: 0.24 g (40%);
mp 240–241 °C (Lit.3 mp 235–236 °C).
IR (KBr): 2973, 1689, 1600, 828, 758, 692 cm–1.
1H NMR (DMSO-d6): d = 8.12 (ddd, J = 8.11, 1.28, 0.72 Hz, 1 H,
H-6), 7.62 (t, J = 8.11 Hz, 2 H, H-8), 7.30–7.38 (m, 2 H, H-7, H-9),
7.19 (s, 1 H, H-10), 4.19 (br s, 4 H, H-2, H-3), 2.25 (s, 3 H, COCH3).
1-[(4-Methylphenyl)sulfonyl]-2,3-dihydroimidazo[1,2-b]iso-
quinoline-5(1H)-one (8)
Method 1
Tosyl chloride and compound 1 afforded the title compound 8. It
was crystallized from CH2Cl2–MeOH; yield: 0.32 g (35%); mp
207–210 °C (Lit.3 mp 195–198 °C).
IR (KBr): 1660, 1624, 1596, 1360, 752, 668 cm–1.
1H NMR (CDCl3): d = 8.27 (d, J = 8 Hz, 1 H, H-6), 7.81 (d, J = 8
Hz, 2 Harom), 7.53–7.64 (m, 2 Harom), 7.28–7.36 (m, 3 Harom), 6.79 (s,
1 H, H-10), 4.05 (br s, 4 H, H-2, H-3), 2.39 (s, 3 H, CH3).
Anal. Calcd for C13H12N2O2: C, 68.41; H, 5.30; N, 12.27. Found: C,
68.20; H, 5.21; N, 12.35.
Method 2: A mixture (0.5 g, 2.7 mmol) of compound 1 in Ac2O (1.5
mL, 16 mmol) was heated at 70–80 °C for 2 h whence a white solid
precipitated. After cooling, compound 4 was collected by filtration
and crystallized from benzene to give 0.49 g (80%) of the com-
pound, whose physical properties and elemental analysis were iden-
tical with the product obtained by Method 1.
Anal. Calcd for C18H16N2O3S: C, 63.51; H, 4.74; N, 8.23. Found: C,
63.47; H, 4.82; N, 8.12.
1-(Hexanoyl)-2,3-dihydroimidazo[1,2-b]isoquinoline-5(1H)-one
(5)
Method 1: Hexanoyl chloride and compound 1 afforded the title
compound 5. The solid was triturated with EtOH; yield: 0.38 g
(50%); mp 180–182 °C.
C-Acylation of Compound 1 via DMAP Catalysis; General Pro-
cedure
To a suspension of compound 1 (0.5 g, 2.7 mmol) in CH2Cl2 (10
mL) was added DMAP (0.6 g, 4.4 mmol) with stirring. After 5 min,
the acyl chloride (3.5 mmol) was added over a period of several min
and the mixture was stirred at 0–5 °C for 2 h. The organic layer was
washed with H2O (20 mL) and then with 10% aq solution of K2CO3
(3 × 20 mL). The organic layer was then dried (MgSO4), filtered,
and evaporated under reduced pressure to afford the crude product.
Purification was effected as noted below in each case.
IR (KBr): 2924, 1662, 1585, 880, 692 cm–1.
1H NMR (CDCl3): d = 8.12 (d, J = 6.67 Hz, 1 H, H-6), 7.55–7.56
(m, 1 Harom), 7.53–7.54 (m, 1 Harom), 7.29–7.32 (m, 2 H, 1 Harom, H-
10), 4.17 (t, J = 8.21 Hz, 2 H, H-2), 4.14 (t, J = 7.18 Hz, 2 H, H-3),
2.45 (s, 2 H, NCOCH2R), 1.71–1.81 (m, 2 H, NCOCH2CH2R),
1.36–1.41 (m, 4 H, NCOCH2CH2CH2CH2CH3), 0.92–0.94 (m, 3 H,
CH2CH3).
10-[(4-Nitrophenyl)carbonyl]-2,3-dihydroimidazo[1,2-b]iso-
quinoline-5(1H)-one (9)
4-Nitrobenzoyl chloride and compound 1 afforded the title com-
pound 9. The red powder was triturated with EtOH; yield: 0.72 g
(80%); mp 280–281 °C.
Anal. Calcd for C17H20N2O2: C, 71.81; H, 7.09; N, 9.85. Found: C,
71.92; H, 6.71; N, 9.88.
1-[(Methoxyphenyl)carbonyl]-2,3-dihydroimidazo[1,2-b]iso-
quinoline-5(1H)-one (6)
Method 1: 4-Methoxybenzoyl chloride and compound 1 afforded an
N-acyl and C-acyl isomeric mixture. The crude product was puri-
fied by Chromatotron® using EtOAc–hexane (60:40) as eluent to
give 6 (0.17 g, 20%); mp 168–170 °C.
IR (KBr): 3303, 1651, 1558, 758, 668 cm–1.
1H NMR (CDCl3): d = 8.89 (s, 1 H, NH, exchangeable with D2O),
8.23–8.27 (m, 2 Harom, H-6), 7.68 (d, J = 8.9 Hz, 2 Harom), 7.14–7.18
(m, 2 H, H-7, H-9), 6.70–6.74 (m, 1 H, H-8), 4.39 (t, J = 8.72 Hz, 2
H, H-2), 4.37 (t, J = 7.69 Hz, 2 H, H-3).
IR (KBr): 1668, 1601, 1549, 1306, 753, 689 cm–1.
UV (CH2Cl2): lmax = 240, 260, 283 nm.
1H NMR (DMSO-d6): d = 8.12 (d, J = 7.12 Hz, 1 H, H-6), 7.57–7.67
(m, 4 H, 2 Harom, H-6, H-9), 7.32–7.37 (m, 1 H, H-8), 7.05 (d,
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2,3-Dihydroimidazo[1,2-b]isoquinoline-5(1H)-one and Derivatives
241
Anal. Calcd for C18H13N3O4: C, 64.47; H, 3.91; N; 12.53. Found: C,
64.51; H, 4.07; N, 12.39.
IR (KBr): 3308, 1669, 1541, 930, 770, 690 cm–1.
1H NMR (DMSO-d6): d = 8.21 (s, 1 H, NH), 8.06 (d, J = 7.4 Hz, 1
H, H-6), 7.91 (m, 1 Hthienyl), 7.4–7.0 (m, 5 H, 2 Hthienyl, H-7, H-8, H-
9), 4.55 (t, J = 8.32 Hz, 2 H, H-2), 4.17 (t, J = 7.4 Hz, 2 H, H-3)
10-[(4-Methylphenyl)carbonyl]-2,3-dihydroimidazo[1,2-b]iso-
quinoline-5(1H)-one (10)
4-Methylbenzoyl chloride and compound 1 afforded the title com-
pound 10. The crude product was crystallized from EtOH; yield:
0.41 g (50%); mp 201–202 °C.
Anal. Calcd for C16H16N2O2S: C, 63.98; H, 5.37; N, 9.33. Found: C,
64.12; H, 5.47; N, 9.10.
C-Acylation with Sulfonyl Derivatives of Compound 1 via
DMAP Catalysis; General Procedure
IR (KBr): 3297, 1652, 720, 690 cm–1.
1H NMR (DMSO-d6): d = 8.47 (s, 1 H, NH, exchangeable with
D2O), 8.22 (d, J = 7.16 Hz, 1 H, H-6), 7.46 (d, J = 6 Hz, 2 Harom),
7.19 (d, J = 6 Hz, 2 Harom), 7.14 (t, J = 6.2 Hz, 1 H, H-8), 7.07 (t,
J = 6.2 Hz, 1 H, H-7), 6.94 (ddd, J = 7.92, 1.43, 0.48 Hz 1 H, H-9),
4.38 (t, J = 7.63 Hz, 2 H, H-2), 3.94 (t, J = 8.58 Hz, 2 H, H-3), 2.40
(s, 3 H, CH3).
A solution of compound 1 (0.5 g, 2.7 mmol) in CH2Cl2 (10 mL) was
added to a 100 mL two-necked flask, fitted with rubber septum, and
N2 inlet. A solution of tosyl chloride (667 mg, 3.5 mmol) in CH2Cl2
(5 mL) was added dropwise with stirring at 0–5 °C. After 5 min, a
solution of DMAP (4.9 mmol) in CH2Cl2 (5 mL) was added over a
period of several min. The heterogeneous mixture was allowed to
raise to r.t. overnight and the organic layer was washed with 10% aq
solution of NaOH (3 × 15) and then with H2O (20 mL). The organic
layer was dried (MgSO4), filtered and evaporated under reduced
pressure to afford the crude product. Purification was effected as
noted below for each case.
Anal. Calcd for C19H16N2O2: C, 74.98; H, 5.30; N, 9.20. Found: C,
75.03; H, 5.41; N, 9.17.
10-[(2,4-Dichloro-5-fluorphenyl)carbonyl]-2,3-dihydroimida-
zo[1,2-b]isoquinoline-5(1H)-one (11)
2,4-Dichloro-5-fluorobenzoyl chloride and compound 1 afforded
the title compound 11. The crude product was washed with EtOH;
yield: 0.41 g (40%); mp 250–252 °C.
IR (KBr): 3119, 1677, 1626, 1096, 1057, 824, 691 cm–1.
1H NMR (DMSO-d6): d = 9.5 (s, 1 H NH), 8.13 (d, J = 7.92 Hz, 1
H, H-6), 8.07 (d, JH,m-F = 6.46 Hz, 1 Harom), 7.86 (d, JH,o-F = 8.8 Hz,
1 H), 7.68–765 (m, 1 H, H-7), 7.42–7.39 (m, 2 H, H-8, H-9), 4.14
(t, J = 8.22 Hz, 2 H, H-2), 3.91 (s, 2 H, H-3).
10-[(4-Methylphenyl)sulfonyl]-2,3-dihydroimidazo[1,2-b]iso-
quinoline-5(1H)-one (15)
Tosyl chloride and compound 1 afforded the title compound 15. The
yellow powder was washed with EtOH; yield: 0.36 g (40%); mp
269–270 °C (Lit.3 mp 270–273 °C).
IR (KBr): 3297, 1605, 1549, 1344, 1135, 750, 665 cm–1.
1H NMR (CDCl3): d = 8.20 (dd, J = 7.95, 1.54 Hz, 1 H, H-6), 7.94
(t, J = 8.47 Hz, 1 H, H-7), 7.84 (d, J = 7.18 Hz, 2 Harom), 7.62 (s, 1
H, exchangeable with D2O), 7.46 (t, J = 8.5 Hz, 1 H, H-8), 7.43 (d,
J = 7.18 Hz, 2 Harom), 7.17 (dd, J = 7.95, 0.77 Hz, 1 H, H-9), 4.32 (t,
J = 8.6 Hz, 2 H, H-2), 3.92 (t, J = 8.21 Hz, 2 H, H-3), 2.36 (s, 3 H,
CH3).
Anal. Calcd for C18H11Cl2FN2O2: C, 57.32; H, 2.94; N, 7.43. Found:
C, 57.29; H, 2.98; N, 7.21.
10-(2-Chloroethanoyl)-2,3-dihydroimidazo[1,2-b]isoquinoline-
5(1H)-one (12)
Chloroacetyl chloride and compound 1 afforded the title compound
12. The crude product was triturated with benzene; yield: 0.36 g
(64%); mp 239–240 °C.
Anal. Calcd for C16H16N2O2S: C, 63.51; H, 4.74; N, 8.23. Found: C,
63.37; H, 4.81; N, 8.44.
10-(Methanesulfonyl)-2,3-dihydroimidazo[1,2-b]isoquinoline-
5(1H)-one (16)
IR (KBr): 3321, 1650, 838, 765 cm–1.
1H NMR (DMSO-d6): d = 9.29 (s, 1 H, NH, exchangeable with
D2O), 8.11 (d, J = 8 Hz, 1 H, H-6), 7.60–7.69 (m, 2 H, H-7, H-8),
7.24 (d, J = 8 Hz, 1 H, H-9), 4.78 (s, 2 H, RCOCH2Cl), 4.13 (t, J =
8.8 Hz, 2 H, H-2), 3.84 (t, J = 7.6 Hz, 2 H, H-3)
MeSO2Cl and compound 1 afforded the title compound 16. The sol-
id was crystallized from CH2Cl2–cyclohexane; yield: 0.36 g (50%);
mp 265–266 °C.
IR (KBr): 3387, 2668, 1556, 1300, 1115, 720, 698 cm–1.
1H NMR (DMSO-d6): d = 8.10 (m, 2 H, H-6, H-7), 7.89 (s, 1 H, NH,
exchangeable with D2O), 7.63–7.68 (m, 1 H, H-8), 7.20–7.28 (m, 1
H, H-9), 4.13 (t, J = 8.21 Hz, 2 H, H-2), 3.73 (t, J = 8.72 Hz, 2 H,
H-3), 3.15 (s, 1 H, CH3).
Anal. Calcd for C13H11ClN2O2: C, 59.44; H, 4.22; N, 10.66. Found:
C, 59.35; H, 4.17; N, 10.41.
10-(2-Furoyl)- 2,3-dihydroimidazo[1,2-b]isoquinoline-5(1H)-
one (13)
2-Furoyl chloride and compound 1 afforded the title compound 13.
The solid was crystallized as yellow needles from EtOH; yield: 0.38
g (50%); mp 207–208 °C.
Anal. Calcd for C12H12N2O3S: C, 54.53; H, 4.58; N, 10.60. Found:
C, 54.77; H, 4.87; N, 10.35.
Rearrangement of N-Acyl Derivatives to C-Acylated Isomers
via DMAP Catalysis; General Procedure
IR (KBr): 3300, 1673, 1659, 1000, 770, 735 cm–1.
1H NMR (DMSO-d6): d = 8.25 (d, J = 6.41 Hz, 1 H, H-6), 8.13 (s,
1 H, NH), 7.46–7.47 (m, 1 Hfuryl), 7.34 (dd, J = 6.94, 1.54 Hz, 1 H,
H-7), 7.18 (dd, J = 6.92, 1.54 Hz, 1 H, H-8), 7.04–7.08 (m, J = 7.0
Hz, 2 H, 1 Hfuryl, H-9), 6.51–6.53 (m, 1 Hfuryl), 4.36 (t, J = 8.47 Hz,
2 H, H-2), 3.93 (t, J = 7.44 Hz, 2 H, H-3).
A 50 mL flask was charged with a mixture of N-acyl and C-acyl de-
rivatives (0.5 g, 80:20) obtained from Schotten–Baumann method
in CH2Cl2 (10 mL). To this solution was added DMAP (0.6 g), and
the mixture was stirred for 2 d. The C-isomer was proved to be the
unique product. The physical and spectroscopic data are in agree-
ment with corresponding compound. The rearrangement was mon-
itored by HPLC using EtOAc–hexane (60:40) as mobile phase with
a flow rate of 1.3 mL/min; lmax = 254 nm; retention time of N-acyl
isomer was 5.75 min and C-acyl isomer was 8.04 min. Reaction
samples were taken off at various time points (n) and the percentage
of acylated isomer was calculated as given in equation 1:
Anal. Calcd for C16H16N2O3: C, 67.59; H, 5.67; N, 9.85. Found: C,
67.69; H, 5.73; N, 10.03.
10-(2-Thienyl-2-carbonyl)-2,3-dihydroimidazo[1,2-b]isoquino-
line-5(1H)-one (14)
Thiophene-2-carbonyl chloride and compound 1 afforded the title
compound 14. The yellow powder was crystallized from EtOH;
yield: 0.48 g (60%); mp 198–200 °C.
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242
M. Bollini et al.
PAPER
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Acknowledgment
This work was supported by a grant from Universidad de Buenos
Aires UBACyT B020.
We are grateful to Mariángeles González, Nicolás Torres Fuenzali-
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Synthesis 2006, No. 2, 237–242 © Thieme Stuttgart · New York