Microwave-assisted silver(I)-mediated selective O-alkylation of aromatic imidate systems

Article abstract of DOI:10.1055/s-0029-1216878

A novel microwave-assisted protocol has been developed for the selective O-alkylation of aromatic imidate systems with various halides under microwave irradiation using silver carbonate as the base. Products were obtained in short reaction time and in excellent yields. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1216878

PAPER
2725
Microwave-Assisted Silver(I)-Mediated Selective O-Alkylation of Aromatic
Imidate Systems
Selective
O
-Alky
r
lationof
a
A
romatic
I
midate
e
Systems ndra K. Singh,a,b Claudia Cavalluzzo,a Marc De Maeyer,c Zeger Debyser,d Virinder S. Parmar,b
Erik Van der Eycken*a
a
Laboratory for Organic & Microwave-Assisted Chemistry (LOMAC), Katholieke Universiteit Leuven, Celestijnenlaan 200F,
3001 Leuven, Belgium
Fax +3216327990; E-mail: erik.vandereycken@chem.kuleuven.be
Bioorganic Laboratory, Department of Chemistry, University of Delhi, Delhi 110 007, India
Laboratory for Biomolecular Modelling, Katholieke Universiteit Leuven, Celestijnenlaan 200G, 3001 Leuven, Belgium
Molecular Medicine, Katholieke Universiteit Leuven, Kapucijnenvoer 33, 3000 Leuven, Belgium
b
c
d
Received 8 April 2009; revised 23 April 2009
der to get selective O-alkylation in the presence of silver
Abstract: A novel microwave-assisted protocol has been devel-
carbonate as the base applying microwave irradiation.11
oped for the selective O-alkylation of aromatic imidate systems
with various halides under microwave irradiation using silver car-
bonate as the base. Products were obtained in short reaction time
and in excellent yields.
In continuation of our ongoing research on microwave-
assisted organic synthesis (MAOS),12 we report here a
novel microwave-assisted protocol for the selective O-
alkylation of aromatic imidate systems under microwave
irradiation using silver carbonate as base.
Key words: O-alkylation, silver carbonate, microwave, 2-pyri-
dones, 2-(1H)-pyrazinones
In the framework of our recent research related to the syn-
thesis of peptidomimetics, we were interested in the syn-
thesis of compound 3. However, contrary to what we
found in the literature about the selective O-alkylation of
the 6-chloro-3-nitro-2-pyridone (1),13 treatment of 1 with
isopropyl iodode and Ag2CO3 in hexane under conven-
tional heating, resulted in disappointingly low yields
(25% and 33%, respectively, of the desired compound 3,
Scheme 1) after 5 days stirring at room temperature or 3
days at 80 °C, in addition to starting material and an
unidentified side product. In order to improve the yield
and to accelerate the reaction, we decided to study this
alkylation protocol with the aid of microwave irradiation
(Table 1).
Due to the prominence of O-alkylated heterocycles for the
synthesis of both natural products and pharmacologically
active compounds,1,2 a selective N- versus O-alkylation of
aromatic imidate systems remains an important synthetic
goal. Although several methods for selective O-alkylation
using silver salts as bases have been described with vary-
ing success,3 the problem of competitive N-alkylation and
relatively long reaction times are still a longstanding chal-
lenge.
The 2-pyridone system is well known for its peptido-
mimetic utility as, for example, elastase,4 caspase,5 pro-
tease,6 thrombin inhibitor,7 and a-helix mimetic.8
Alkylation of the 2-pyridone system under basic condi-
tions is one of the most studied and interesting examples
of selectivity of ambident anions where the reactive sites
are connected through mesomerism.9 Its salt formation is
very sensitive to the reaction conditions such as the type
of the counterion and the leaving group, the choice of the
solvent and the alkylation agent, as well as the tempera-
ture.3a–e However, the influence of microwave irradiation
for the selective alkylation of these systems has rather
scarcely been investigated. To our knowledge there are
only a few examples dealing with a comparison of the se-
lective alkylation of the 2-pyridone system under conven-
tional heating and microwave irradiation.10 de la Hoz et al.
found that N- and C-benzylations are obtained depending
on the benzyl halide and the heating system.10 However,
applying the described conditions, they never observed O-
alkylation. In another example, extensive decomposition
of the 4-hydroxy-2-quinolone system was observed in or-
NO2
NO2
NO2
OH
O
O
i-PrI, Ag2CO3
n-hexane
N
NH
N
2
1
3
Cl
Cl
Cl
Scheme 1
According to the literature, microwave-assisted alkylation
of aromatic imidate systems seems to be highly sensitive
to the applied temperature.3g Therefore, in order to pre-
vent decomposition, additional irradiation experiments
with simultaneous cooling were preformed in each case,
at a different ceiling temperature and with a different
maximum power applied.
When the reactions were performed at 80 °C for 10 min-
utes with simultaneous cooling applying different micro-
wave power inputs, compound 3 was isolated in 30–47%
yield (Table 1) in addition to recovery of starting material.
Application of the same conditions, but without cooling,
resulted in comparable yields of 36–45% (Table 1). No
SYNTHESIS 2009, No. 16, pp 2725–2728
x
x.
x
x
.
2
0
0
9
Advanced online publication: 26.06.2009
DOI: 10.1055/s-0029-1216878; Art ID: Z06609SS
© Georg Thieme Verlag Stuttgart · New York

2726
B. K. Singh et al.
PAPER
the alkylation.1d,g,3d,e,g Therefore we decided to evaluate an
array of solvents of various polarity applying our micro-
wave-assisted protocol. To our surprise, when running the
reaction in the polar solvent DMF, only decomposition
was observed (Table 3, entry 1) whereas in THF a 1:1
mixture of both N- and O-alkylated compounds was iso-
lated (Table 3, entry 2). Application of all other solvents
resulted in the exclusive formation of the O-alkylated
product 3, however in varying yields (Table 3, entries 3–
12). Notably, except for hexane (Table 3, entry 12), all
other screened solvents could not lead to full conversion
of the starting material, thus leading to poor yields
(Table 3, entries 3–11).
Table 1 Evaluation of the Temperature and Power Input Under
Microwave Irradiationa
Power Yield (%) Yield (%)b Yield (%) Yield (%)Yield (%) Yield(%)
(W) with air without with air without with air without
cooling cooling cooling cooling cooling cooling
at 80 °C at 80 °C at 100 °C at 100 °C at 150 °C at 150 °C
100 30
200 41
300 47
36
39
45
34
42
45
47
52
62
65
72
75
79
79
89c
a All reactions were performed on a 0.57 mmol scale of 2-pyridone us-
ing isopropyl iodide (2 equiv) and Ag2CO3 (1.2 equiv) in anhyd hex-
ane (3 mL) for 10 min applying the indicated conditions.
b When the same reaction was performed under conventional condi-
tions at 80 °C, only 33% yield was obtained after 3 days.
Table 3 Evaluation of the Solventa
c Only in this case was all starting material consumed; in all other
cases products were isolated alongside the starting material.
Entry
1
Solvent
DMF
Yield (%)
0b
improvement of the yields (34–45%) was observed when
the reactions were run at 100 °C with simultaneous cool-
ing. However, a significant increase (47–62%) was ob-
served when performing the reactions at 100 °C but
without cooling. The temperature tolerance was good, as
not even a trace of decomposition was detected. More-
over, when performing the reaction at 150 °C the yields
increased dramatically, especially when no simultaneous
cooling was applied (Table 1). Highest yield of 89% was
obtained when operating at the maximum power level of
300 W at 150 °C without simultaneous cooling (Table 1).
2
THF
41 (O-alkylation) + 41 (N-alkylation)
3
MeOH
EtOH
49c
33c
62c
64c
68c
36c
32c
64c
69c
89
4
5
dioxane
MeCN
CH2Cl2
DCE
6
7
8
9
pentane
toluene
benzene
hexane
Careful assessment of the literature indicates that excess
of alkylating agent influences the outcome of O-alkylated
product.3d,e Interestingly, when the number of equivalents
of alkylating agent was raised from 1.2 to 2.0 equivalents,
this was reflected in a concomitant increase of the yield
from 75–89% (Table 2, entries 1–3). However, further
raising the amount of isopropyl iodide did not result in a
further increase of the yield (Table 2, entries 3–6).
10
11
12
a All reactions were performed on a 0.57 mmol scale of 2-pyridone us-
ing isopropyl iodide (2 equiv) and Ag2CO3 (1.2 equiv) in the indicated
anhyd solvent (3 mL) under microwave irradiation at a ceiling tem-
perature of 150 °C and a maximum power level of 300 W for 10 min
without simultaneous cooling.
As has been reported by different authors, the nature of
the solvent has a significant influence on the selectivity of
b Only decomposition was observed.
c The desired compound 3 was isolated, in addition to unreacted start-
ing material.
Table 2 Evaluation of the Number of Equivalents of Isopropyl
Iodidea
Next, various silver salts were evaluated like silver nitrate,
silver oxide,1g,3k silver acetate,3i,j silver sulfate, silver flu-
oride, silver bromide, silver trifluoroacetate, and silver tri-
fluoromethanesulfonate; however, in all cases the reaction
did not take place. This clearly highlights the importance
of the application of silver carbonate. Interestingly, when
using sodium or potassium carbonate applying our opti-
mized procedure, no reaction took place even after an ir-
radiation time of 45 minutes; only the starting material
was recovered. Conversely, when switching from hexane
to DMF, only N-alkylated product was isolated in 71%
and 73% yield, respectively, after 10 minutes of irradia-
tion with sodium or potassium carbonate as base.
Entry
Isopropyl iodide (equiv)
Yield (%)
1
2
3
4
5
6
1.2
1.8
2.0
2.2
2.5
3.0
75
79
89
87
89
90
a All reactions were performed on a 0.57 mmol scale of 2-pyridone us-
ing isopropyl iodide (equiv as indicated) and Ag2CO3 (1.2 equiv) in
anhyd hexane (3 mL) under microwave irradiation at a ceiling tem-
perature of 150 °C and a maximum power level of 300 W for 10 min
without simultaneous cooling.
The scope of the optimized microwave-assisted process
was next investigated applying variously substituted 2-
Synthesis 2009, No. 16, 2725–2728 © Thieme Stuttgart · New York

PAPER
Selective O-Alkylation of Aromatic Imidate Systems
2727
pyridone systems and different halides. Exclusively O- good substrates for selective O-alkylation applying our
alkylated products were obtained using various alkyl io- microwave-assisted protocol. Using the 5-chloro-3-(phe-
dides (Table 4, entries 1–5). However, when methyl io- nylthio)pyrazin-2-ol as substrate, which suffers from
dide was used, the temperature had to be reduced to 60 °C problems of selective O-alkylation,15 all alkyl halides
due to the high internal pressure built up during irradiation tried yielded exclusively the desired O-alkylated products
(Table 4, entries 2, 8, and 14). When performing the alky- in excellent yields ranging from 75–89% (Table 5).
lation with the corresponding alkyl bromides, except for
Table 5 Evaluation of the Protocol for the 2-(1H)-Pyrazinone
the benzylation (Table 4, entries 6, 12, and 18), no reac-
tion was observed.
Systema
N
OH
N
O
R2
Ag2CO3, n-hexane
Table 4 Evaluation of the Scope of the Protocola
R2X
+
150 °C, 300 W, 10 min
Cl
N
SPh
OH
Cl
N
SPh
O
R2
Ag2CO3, n-hexane
R2X
+
31
7,9–12
32–36
N
N
150 °C, 300 W, 10 min
R1
4–6
R1
Entry
R2
Product
32
Yield (%)
7–12
13–30
1
2
3
4
5
i-Pr (7)
Et (9)
88
89
76
75
83
Entry R1
R2X
Product Yield (%)
33
1
2
3-NO2,6-Cl (4)
3-NO2,6-Cl (4)
3-NO2,6-Cl (4)
3-NO2,6-Cl (4)
3-NO2,6-Cl (4)
3-NO2,6-Cl (4)
4-NO2 (5)
4-NO2 (5)
4-NO2 (5)
4-NO2 (5)
4-NO2 (5)
4-NO2 (5)
H (6)
i-PrI (7)
MeI (8)b
EtI (9)
1313
1413
15
88
83
85
88
93
72
90
88
94
90
96
78
85
72
79
85
91
70
Pr (10)
Bu (11)
Bn (12)
34
35
3
36
4
PrI (10)
BuI (11)
16
a All reactions were performed on a 0.28 mmol scale of 2-(1H)-
pyrazinone using alkyl iodide or bromide as indicated (2 equiv) and
Ag2CO3 (1.2 equiv) in anhyd hexane (3 mL) under microwave irradi-
ation at a ceiling temperature of 150 °C and a maximum power level
of 300 W for 10 min without simultaneous cooling.
5
17
6
BnBr (12) 1813
7
i-PrI (7)
MeI (8)b
EtI (9)
19c
20c
21c
22c
23c
8
In conclusion, we have developed an efficient silver car-
bonate-mediated microwave-assisted protocol for the
selective O-alkylation of different aromatic imidate sys-
tems. The protocol works well with various alkyl iodides
as well as with benzyl bromides. This novel process al-
lows the rapid synthesis of O-alkylated imidate com-
pounds.
9
10
11
12
13
14
15
16
17
18
PrI (10)
BuI (11)
BnBr (12) 24c
i-PrI (7)
MeI (8)b
EtI (9)
25c
26c
27c
28c
29c
H (6)
O-Alkylation of 2-Pyridones and 2-(1H)-Pyrazinones; General
Procedure
H (6)
To a suspension of 2-pyridone or 2-(1H)-pyrazinone (0.57 mmol) in
hexane were added the appropriate halide (2 equiv) and Ag2CO3
(1.2 equiv). The mixture was irradiated at 150 °C for 10 min in a
dedicated CEM-Discover monomode microwave apparatus (CEM
Corporation, NC, USA), operating at a frequency of 2.45 GHz with
continuous irradiation power from 0 to 300 W. Reaction mixtures
were efficiently stirred with a magnetic stirrer. The reactions were
carried out in an open 5 mL glass vial. The temperature of the reac-
tions was measured by infrared. After completion of the reaction,
the insoluble residue was filtered off through Celite. The yellow oil
obtained was purified by column eluted with a mixture of heptane–
EtOAc (9:1). The solvent was concentrated in vacuum to provide
the corresponding O-alkylated product (Tables 4 and 5). The prod-
ucts were characterized by comparison with authentic samples or
literature data.
H (6)
PrI (10)
BuI (11)
H (6)
H (6)
BnBr (12) 30c
a All reactions were performed on a 0.28 mmol scale of 2-pyridone us-
ing alkyl iodide or bromide as indicated (2 equiv) and Ag2CO3 (1.2
equiv) in anhyd hexane (3 mL) under microwave irradiation at a ceil-
ing temperature of 150 °C and a maximum power of 300 W for 10
min without simultaneous cooling.
b Because of the high internal pressure built up during irradiation, the
reaction was performed at a lower ceiling temperature of 60 °C, but
for a prolonged period of 60 min to drive the reaction to completion.
c Products are commercially available.
Encouraged by the efficiency of our microwave-assisted
alkylation protocol for the above described 2-pyridone
systems, we were eager to know whether the biologically
important 2-(1H)-pyrazinone systems14 should also be
Acknowledgment
Support was provided by the Research Fund of the University of
Leuven (IDO06/006) and the F.W.O. (Fund for Scientific Research
– Flanders, Belgium).
Synthesis 2009, No. 16, 2725–2728 © Thieme Stuttgart · New York

2728
B. K. Singh et al.
PAPER
C.; Gomes, B.; Kosmider, B. J.; Krell, R. D.; Shaw, A.;
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Synthesis 2009, No. 16, 2725–2728 © Thieme Stuttgart · New York