Microwave-assisted rapid and efficient synthesis of C-alkyl imidazoisoquinolinone derivatives

Article abstract of DOI:10.1016/j.tetlet.2009.01.083

The synthesis of a set of 10-benzyl-2,3-dihydroimidazo[1,2-b]isoquinolin-5(1H)-one and 5-oxo-imidazo[1,2-b]isoquinolin-10-yl)-N-phenylacetamide derivatives was achieved by exposing the corresponding alkylating agent and imidazoisoquinolinone to microwave

Full text of DOI:10.1016/j.tetlet.2009.01.083

Tetrahedron Letters 50 (2009) 1507–1509
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Microwave-assisted rapid and efficient synthesis of C-alkyl
imidazoisoquinolinone derivatives
*
Mariela Bollini, Mariángeles González, Ana María Bruno
Departamento de Química Orgánica, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Junín 956, 1113 Buenos Aires, Argentina
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of a set of 10-benzyl-2,3-dihydroimidazo[1,2-b]isoquinolin-5(1H)-one and 5-oxo-imi-
dazo[1,2-b]isoquinolin-10-yl)-N-phenylacetamide derivatives was achieved by exposing the correspond-
ing alkylating agent and imidazoisoquinolinone to microwave irradiation and traditional oil bath heating
in the presence of K2CO3 and DMAP. The microwave technique as well as DMAP as base accelerated the
alkylation reaction for 2–6 min giving 79–88% yields.
Received 16 December 2008
Revised 14 January 2009
Accepted 15 January 2009
Available online 20 January 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Microwave-assisted synthesis
C-Alkyl imidazoisoquinolinones
DMAP
Isoquinolines generally constitute an important branch of het-
erocyclic compounds and are currently used against parasitic
infections.1 Imidazoisoquinolinones are valuable substrates for
the synthesis of potentially biologically active compounds with
structural features different from those of existing drugs. In this re-
gard, we have previously synthesized a series of C-10 and N-1
substituted imidazoisoquinolinones, which possess a planar struc-
ture with a tricycle heterocyclic scaffold present in antiprotozoal
agents.2
In this work, we report an efficient and good yielding method
for the synthesis of 10-benzyl-2,3-dihydroimidazo[1,2-b]isoquino-
lin-5(1H)-one and 5-oxo-imidazo[1,2-b]isoquinolin-10-yl)-N-
phenylacetamide derivatives under microwave irradiation.
The introduction of microwave heating has greatly impacted
many aspects of chemical synthesis. There are several reviews
and reports on the broad use of microwave irradiation in organic
synthesis.3 It has been demonstrated that the use of microwave
heating can dramatically reduce the reaction time, increase the
product purity and yields and allow a precise control of the reac-
tion conditions.
cess of conversion of 1 was completed, giving 80% of the desired
product, 10-(4-chlorobenzyl)-2,3-dihydroimidazo[1,2-b]isoquino-
lin-5(1H)-one (3) (Table 1). Under this condition, another base,
4-dimethylaminopyridine (DMAP), was used to investigate its
influence on the alkylation reaction (Table 1). Interestingly, the
reaction time was reduced from 40 min to 6 min with a similar
yield.
It is accepted that both a thermal effect and a specific micro-
wave effect may induce the acceleration of some reactions. In or-
der to testify whether microwave irradiation speeds up
alkylation, the synthesis of compound 2–5 was carried out in
DMF as solvent, using the same bases, but heating in an oil bath.
The time course results of the model reaction are plotted in Fig-
ure 1. Microwave-heated reactions produced, along all the pro-
cesses,
a higher conversion of the starting material and a
higher yield of the product than when heated in a traditional
oil bath. In addition, the best result was obtained using DMAP
as
a base, using either microwave or conventional heating
(Fig. 1, Table 1). The differences were specially significant within
To optimize the reaction conditions, the alkylation of 2,3-
dihydroimidazo[1,2-b]isoquinolin-5(1H)-one (1) with 4-chloro-
benzyl chloride was selected as a model reaction. A mixture of
compound 1, 3 equiv of 4-chlorobenzyl chloride and 4 equiv of
K2CO3 was exposed to microwave irradiation at 480 W for
10 min (Scheme 1).4,5 The TLC test indicated that the reaction
was incomplete. When increasing the time to 40 min, the pro-
O
O
CH2Cl
base
N
N
N
N
MW or Δ
H
H
R
1
R
2-5
* Corresponding author. Tel.: +54 1149648251.
E-mail address: anabruno@ffyb.uba.ar (A.M. Bruno).
Scheme 1.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.01.083

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M. Bollini et al. / Tetrahedron Letters 50 (2009) 1507–1509
Table 1
Product
R
Conventional heating
Microwave irradiationb
DMAP
K2CO3
DMAP
K2CO3
Time (h)
Yielda (%)
Time (h)
Yielda (%)
Time (min)
Yielda (%)
Time (min)
Yielda (%)
2
3
4
5
–CH3
–Cl
–NO2
–H
48
48
24
72
2
3
2
2
NR
168
72
—
3
2
2
6
1
3
80
88
80
79
40
40
15
45
80
80
75
87
168
4
a
Yields refer to pure products.
Pulsed irradiated at 450 W.
b
the first 5 min of the reaction: 98% conversions with the micro-
wave technique using DMAP, but only 28% when using K2CO3 as
a base. The completion of the reaction took only 6 min with
DMAP and 40 min with K2CO3. When the reaction was carried
out under conventional heating, we encountered longer reaction
times (68–168 h) and lower yields (3%) for both bases (Table 1).
These results may elucidate that microwave irradiation may play
a certain role in alkylation.
To expand the scope of this chemistry to the synthesis of other
C-alkyl imidazoisoquinolinone derivatives, we selected diverse
substrates 6a–g and exposed each of them and compound 1
(2.7 mmol) to microwave irradiation at 480 W using DMAP
(2.7 mmol) and 0.1 mL of DMF as solvent (Scheme 2, Table 2).
The desired products 7–13 were isolated and purified in good to
excellent yields (63–98%).6,5 In general, the properties of R dis-
played an effect on the isolated products. When the aromatic ring
(R) was substituted with 4-chloro or 4-fluoro group (entries a and
b), we obtained a product with a relatively higher yield than N-
phenylacetamides and substituted N-phenylacetamides containing
an electron-donating group (entries c–e).
However, when we used alkyl halides (1-bromobutane, 1,4-dibro-
mobutane, (2-chloroethyl)diethylamine, (3-chloropropyl)dimethyl-
amine) in an attempt to obtain C-alkyl imidazoisoquinolinone
derivatives, the reaction yielded complicated mixtures of carbona-
ceous compounds and impurities using either microwave or
conventional heating.
In conclusion, in the present work, we developed an efficient
and novel methodology for the preparation of a series of 10-ben-
zyl-2,3-dihydroimidazo[1,2-b]isoquinolin-5(1H)-one derivatives
under microwave irradiation and in the presence of DMAP as the
best base.
The reaction time was dramatically reduced from 72 to 24 h
(traditional oil bath heating) to 2–6 min using the microwave tech-
nique. A diverse range of 5-oxo-imidazo[1,2-b]isoquinolin-10-yl)-
N-phenylacetamide derivatives were synthesized to demonstrate
that the reported method provides an opportunity to acquire many
other analogues.
Melting points were determined in a capillary with an Elec-
trothermal 9100 SERIES-Digital apparatus and were uncorrected.
IR spectra were recorded with an FT Perkin Elmer Spectrum One
from KBr discs. UV spectra were measured with a Jasco V-570
UV/vis/NIR spectrophotometer. 1H NMR (300 MHz) spectra were
obtained with a Bruker spectrometer at room temperature with
tetramethylsilane as an internal standard. Chemical shifts (d)
are reported in ppm and coupling constants (J) in Hertz. Elemen-
tal analysis was carried out in our laboratories with a Coleman
Analyser.
Table 2
Reation times, yields and melting points of compounds 7–13
Entry
R0
Product
Time (min)
Yielda (%)
90
Mp (°C)
The microwave-assisted reaction was carried out in a household
microwave oven (BGH-QUICK chef 15240). The apparatus was
modified for laboratory application with an external reflux
condenser.
F
NH
a
7
2
201–203
6a
Cl
NH
b
c
d
e
f
8
9
2
3
4
2
2
98
63
70
80
85
310–311
151–153
210–212
270–273
283–284
6b
Cl
NH
6b
H3C
NH
10
11
12
6d
NH
6e
N
NH
S
Cl
6f
NH
g
13
4
75
109–111
O
Ph
Figure 1. Comparison of the effect of microwave irradiation and oil-bath heating on
the alkylation reaction in the presence of DMAP or K2CO3 as bases: Kinetic curves of
conversion determined by HPLC at 256 nm. —N— MW DMAP; —j— MW K2CO3; —
6g
a
Yields refer to pure products.
ꢀ—
D
DMAP; —ꢀ—
D K2CO3.

M. Bollini et al. / Tetrahedron Letters 50 (2009) 1507–1509
1509
NH2
O
R: 4-F
4-Cl
4-OCH3
4-CH3
H
N
Cl
NH2
or
+
Cl
S
R
2-Cl-4-COPh
Benzene,
Reflux, 4h
O
O
O
N
DMF, DMAP
MW
cat
N
Cl
+
HN
R´
N
H
N
CH2
O
H
1
HN
6a-g
R´
7-13
Scheme 2.
G. N.; Panda, G. Tetrahedron Lett. 2006, 47, 3357; (h) Ding, D.; Li, X.; Wang, X.;
Du, Y.; Shen, J. Tetrahedron Lett. 2006, 47, 6997.
Acknowledgement
4. Typical procedures for compounds 2–5: (A) Conventional heating: A mixture of
compound 1 (0.5 g, 2.7 mmol), the corresponding alkylating agent (7.6 mmol),
K2CO3 or DMAP (10.8 mmol) and DMF (5 mL) was stirred at reflux for 24–168 h
(see Table 1). Then, the mixture was allowed to remain at room temperature and
the solvent was evaporated under reduced pressure. The oil product was diluted
with CH2Cl2 and washed with water (3 ꢀ 15 mL), then the organic layer was
dried over MgSO4 and evaporated in vacuo. The residue was collected and
recrystallized with ethanol. (B) Microwave assistant: A mixture of compound 1
(0.5 g, 2.7 mmol), 10.8 mmol K2CO3 or DMAP and the corresponding alkylating
This work was supported by a grant from University of Buenos
Aires UBACyT B020.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.01.083.
agent (7.6 mmol) was introduced into
a bottom flask and subjected to
microwave irradiation at 480 W for 2–45 min (Table 2). The reaction was
monitored by thin layer chromatography. After complete conversion, the
product was recrystallized with ethanol.
References and notes
5. See Supplementary data.
6. Typical procedure for compounds 7–13:
1. Bringman, G.; Hamm, A.; Gunther, C.; Michael, M.; Brun, R.; Mudogo, V. J. Nat.
Prod. 2000, 63, 1465.
2. Bollini, M.; Asís, S. E.; Bruno, A. M. Synthesis 2006, 2, 237.
3. (a) Das, S. K. Synlett 2004, 915; (b) Lidstrom, P.; Tierney, J.; Wathey, B.;
Westman, J. Tetrahedron 2001, 57, 9225; (c) Mavandadi, F.; Lidstrom, P. Curr. Top.
Med. Chem. 2004, 4, 773; (d) Kappe, C. O. Angew Chem., Int. Ed. 2004, 43, 6250; (e)
Yin, W.; Ma, Y.; Xu, J. X.; Zhao, Y. F. J. Org. Chem. 2006, 71, 4312; (f) Cui, S. L.; Lin,
X. F.; Wang, Y. G. J. Org. Chem. 2005, 70, 2866; (g) Mishra, J. K.; Rao, J. K.; Sastry,
A
mixture of compound
1
(0.5 g,
2.7 mmol), DMAP (0.6 g, 2.7 mmol),
the corresponding
N-
phenylchloroacetamide and 0.1 mL DMF was introduced into a bottom flask
and subjected to microwave irradiation at 480 W for 2–4 min. The reaction
mixture was diluted with CH2Cl2 (3 ꢀ 15 mL) and washed with water
(3 ꢀ 10 mL) and brine (10 mL). It was then dried with anhyd MgSO4 and
concentrated under reduced pressure to give
recrystallized with water–ethanol.
a solid product, and was