Rapid palladium-catalyzed C3-arylation of 2(1H)-pyrazinones: Effect of simultaneous cooling on microwave-assisted reactions on solid support

Article abstract of DOI:10.1055/s-0028-1083631

An unprecedented microwave-assisted palladium-catalyzed reaction on polymer support with simultaneous cooling has been developed. It has also been illustrated that under simultaneous cooling, certain decomposition and side reactions during the reaction, b

Full text of DOI:10.1055/s-0028-1083631

LETTER
3021
Rapid Palladium-Catalyzed C3-Arylation of 2(1H)-Pyrazinones: Effect of
Simultaneous Cooling on Microwave-Assisted Reactions on Solid Support
R
apid Palladium-
r
Catalyz
e
a
d
C
3-Aryla
j
tion of
e
2(1
H
)-Pyr
n
azinones dra K. Singh,a,b Virinder S. Parmar,b Erik Van der Eycken*a
a
Laboratory for Organic & Microwave-Assisted Chemistry (LOMAC), University of Leuven, Celestijnenlaan 200F, 3001 Leuven,
Belgium
Fax +32(16)327990; E-mail: erik.vandereycken@chem.kuleuven.be
Bioorganic Laboratory, Department of Chemistry, University of Delhi, Delhi 110 007, India
b
Received 27 June 2008
per(I) thiophene-2-carboxylate (CuTC) and palladium(0)
under conventional heating at 50 °C for two days
(Scheme 1). The 1-(4-methoxybenzyl)-3,5-dichloropy-
razin-2(1H)-one (1{1}) was coupled with the commercial-
ly available thiophenol resin A2 as described previously.5
A set of commercially available boronic acids 2{1–5} was
reacted at room temperature in the presence of CuTC and
Pd(PPh3)4 in dry THF according to the Liebeskind–Srogl
protocol.6 The reaction proceeded slowly and reached
completion after seven days, resulting in moderate yields
ranging from 32–41% (Table 1).
Abstract: An unprecedented microwave-assisted palladium-cata-
lyzed reaction on polymer support with simultaneous cooling has
been developed. It has also been illustrated that under simultaneous
cooling, certain decomposition and side reactions during the reac-
tion, because of heating, can be minimized.
Key words: 2(1H)-pyrazinones, palladium catalysis, solid support,
microwave, simultaneous cooling
Progress in chemical biology and medicinal chemistry re-
lies extensively on the availability of combinatorial librar-
ies of novel small molecules. Metal-catalyzed coupling
reactions have been extensively used for the design of
such libraries and have attracted much attention from both
industry and academia.1 Although it has ample been dem-
onstrated that controlled microwave irradiation has revo-
lutionized the art and progress of metal-catalyzed cross-
coupling reactions,2 in some cases the irradiation at high
temperature has a deleterious effect on the compounds
present in the reaction mixture, resulting in relatively low
yields. We have previously demonstrated that simulta-
neous cooling during microwave irradiation could exert a
beneficial effect on the stability of the compounds present
in the reaction mixture resulting in increased yields.3
However, to our knowledge, it has never been demonstrat-
ed that this cooling technique could also be used for solid-
phase organic synthesis (SPOS). In continuation of our
ongoing work concerning the synthesis and decoration of
the 2(1H)-pyrazinone scaffold4 we stipulated to pursue
this technique for SPOS. In this communication, the effect
of simultaneous cooling on microwave-assisted SPOS is
for the first time addressed, through the study of the C3-
arylation of 2(1H)-pyrazinones.
There was no improvement of yield when the reaction
time was prolonged. Moreover, when the washed and
dried resin beads, after the initial seven days of reaction,
were re-subjected to stirring at the same temperature with
a second number of equivalents of the required reagents,
no additional amount of arylated pyrazinone could be iso-
lated.
To improve the yields and to accelerate the reaction, the
temperature was elevated to 35 °C. Although this resulted
in a reduced reaction time of five days, no increase of the
NH
O
PS
S
Tr
A1
OMe
B(OH)2
H
N
O
S
i
ii
S
Tr
+
SH
R
2{1–5}
A1
Cl
N
A2
1{1}
We have recently described the C-3 arylation of 2(1H)-
pyrazones for the development of potent sodium-channel
blockers and cell-adhesion inhibitors using the
Liebeskind–Srogl coupling protocol.5 The pyrazinone
scaffold, which is coupled with the solid support via a
thiophenyl linker, could be simultaneously arylated and
cleaved from the resin (traceless linking) upon treatment
with a suitable aryl boronic acid in the presence of cop-
OMe
H
N
N
O
iii
R
Cl
3{1–5}
{1} R = H, {2} R = 3-CF3, {3} R = 3-OEt, {4} R = 4-OMe, {5} R = 4-t-Bu
Scheme 1 Reagents and conditions: (i) TFA–TES (95:5), r.t., 1 h;
(ii) pyrazinone (4 equiv), Hünig’s base (10 equiv), THF, r.t., 12 h; (iii)
(RC6H4)B(OH)2 (2 equiv), CuTC (2 equiv), Pd(PPh3)4 (6 mol%),
THF (see Table 1).
SYNLETT 2008, No. 19, pp 3021–3025
Advanced online publication: 12.11.2008
DOI: 10.1055/s-0028-1083631; Art ID: G22908ST
© Georg Thieme Verlag Stuttgart · New York
x
x
.x
x
.2
0
0
8

3022
B. K. Singh et al.
LETTER
dried resin beads a second time to reaction with fresh re-
agents. Increasing the temperature to 80 °C resulted in
strongly decreased yields. Furthermore, fall in the yields
was observed when switching from THF to dioxane,
MeCN, DMF, DMA, or CH2Cl2. Alternative catalysts as
Pd2(dba)3·CHCl3 and Pd(OAc)2 were investigated, how-
ever, the best results were obtained using 5 mol%
Pd(PPh3)4 (Scheme 2, Table 2).
Table 1 Optimization of Parameters under Conventional Condi-
tions
Product formeda Yield (%)b, time (d)c
r.t.
DT (35 °C) DT (65 °C) DT (80 °C)
3{1}
3{2}
3{3}
3{4}
3{5}
33, 7
37, 7
32, 7
41, 7
36, 7
31, 5
31, 5
33, 5
37, 5
29, 5
39, 2
36, 2
35, 2
38, 2
37, 2
23, 2
25, 2
21, 2
–
We then turned our attention to the investigation of this
solid-support protocol applying microwave irradiation.
When the reactions were performed at a ceiling tempera-
ture of 35 °C or even 50 °C using a maximum power of
250 W, no product formation was observed even after
long irradiation time of two hours. As we observed that
the power input was rather low, we decided to perform the
next experiments that were run at 65 °C with simulta-
neous air cooling. This time the desired compounds could
be isolated in moderate yields ranging from 27–33%
(Table 3). Although these microwave-assisted reactions
are much faster compared to those runs under convention-
al heating conditions at 65 °C (Table 1), inferior yield
were obtained. When the resin was washed and dried
properly after completion of the reaction and re-subjected
to reaction with freshly added reagents, no additional C3-
arylated pyazinone could be isolated. As the same obser-
vation was made for the reactions run under conventional
heating, this clearly suggests a certain decomposition of
the resin-bound pyrazinone during irradiation. Therefore
we surmised that microwave irradiation at relatively low
temperature with simultaneous forced liquid cooling
could solve the problem.3 This should allow to maintain
the power input at the maximum level of 300 W during the
–
a All reactions were performed on a 0.176 mmol scale.
b Isolated yields based on the loading of trityl-protected resin A1; no
improvement of the yield was observed upon subjecting the isolated
and washed resin beads a second time to reaction with another number
of equivalents of reagents.
c Time required for obtaining the maximum yield.
OMe
OMe
B(OH)2
H
N
O
S
H
N
O
i
+
R
Cl
N
R
Cl
N
2{3,4,6}
1{1}
3{3,4,6}
{3} R = 3-OEt, {4} R = 4-OMe, {6} R = 3-Br
Scheme 2 Reagents and conditions: (i) (RC6H4)B(OH)2 (2 equiv),
CuTC (2 equiv), Pd(0) source (6 mol%; see Table 2), THF, DT
(65 °C), 2 d.
Table 2 Screening of the Influence of Catalysta
Table 3 Optimization of Microwave-Irradiation Conditionsa
Product
formed
Yield (%)b,c
Entry
R
Catalyst
Product
3{3}
3{4}
3{6}
3{3}
3{4}
3{6}
3{3}
3{4}
3{6}
Yield (%)b
1
2
3
4
5
6
7
8
9
3-EtO
4-MeO
3-Br
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd2dba3
35
MW and
MW and
MW and
MW and
air coolingd liquid coolinge liquid coolingf liquid coolingg
38
3{1}
3{2}
3{3}
3{4}
3{5}
27
33
29
31
28
29
31
31
35
31
30
33
32
35
34
58
53
60
63
54
35
3-EtO
4-MeO
3-Br
27
Pd2dba3
22
Pd2dba3
31
3-EtO
4-MeO
3-Br
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
13
a All reactions were performed on a 0.176 mmol scale with boronic
acid (3 equiv), Pd(PPh3) (5 mol%), and CuTC (2 equiv) in dry THF
(5 mL) under microwave irradiation.
tracesc
23
b Isolated yields based on the loading of trityl-protected resin A1; the
compounds were purified by column chromatography on silica gel.
c No improvement of the yields was observed upon subjecting the iso-
lated and washed resin beads a second time to reaction with another
number of equivalents of reagents.
a All reactions were performed on a 0.176 mmol scale.
b Isolated yields based on the loading of trityl-protected resin A1.
c Detected by CI-MS.
d Conditions: 65 °C, 250 W, 30 min.
e Conditions: 35 °C, 300 W, 1 h.
yields was obtained (Table 1). When the reaction was per-
formed at 65 °C it reached completion in two days with a f Conditions: 35 °C, 300 W, 2 h.
g Conditions: 35 °C, 300 W, 1 + 1 h. (The resin was washed and dried
slight improvement of the yield. However, no further im-
provement of the yields was observed upon prolonging
the reaction time or upon re-subjecting the washed and
properly after 1 h and subjected a second time to reaction with freshly
added reagents.)
Synlett 2008, No. 19, 3021–3025 © Thieme Stuttgart · New York

LETTER
Rapid Palladium-Catalyzed C3-Arylation of 2(1H)-Pyrazinones
3023
Figure 1 TLC (EtOAc–hexane, 15:85) profile of reactions run under different conditions. The spots marked by an arrow represent the desired
product 3, with the circled ones representing side product 4. A: boronic acid 2 (3 equiv), Pd(PPh3)4 (5 mol%), CuTC (2 equiv) in anhyd THF
(5 mL) without resin-bound pyrazinone under conventional heating at 65 °C for 2 d; B: resin-bound pyrazinone 1 (0.176 mmol), boronic acid
2 (3 equiv), Pd(PPh3)4, (5 mol%), CuTC (2 equiv) in anhyd THF (5 mL) under conventional condition at r.t. for 7 d; C: as for B under conven-
tional heating at 65 °C for 2 d; D: as for B upon microwave irradiation with simultaneous air cooling at 65 °C with a maximum power of 250
W for 30 min; E: as for B upon microwave irradiation with simultaneous liquid cooling at 35 °C continuously at 300 W power for 1 h.
Table 4 Scope and Limitations: Variation of the Boronic Acidsa
full run of the reaction, while keeping the bulk of material
at a relatively low temperature.7 When the reactions were
run with simultaneous liquid cooling8 at 0 °C, 10 °C, or
20 °C for one hour, no arylated pyrazinone was formed.
At 30 °C only traces of the desired compounds were de-
tected.
OMe
OMe
+
B(OH)2
MW and
simultaneous
cooling
H
N
N
O
H
N
O
S
However, increasing the temperature to 35 °C resulted in
the requested arylation after one hour of irradiation, al-
though still with comparable moderate yields as for the
microwave-assisted reactions that were run at 65 °C with
air cooling (Table 3). Prolonging the irradiation time to
two hours did not result in a significant increase of the
yields. Interestingly TLC analysis revealed that reactions
run with simultaneous liquid cooling did not show side-
product formation (Figure 1). Isolation of this side com-
pound from the reaction mixture obtained upon micro-
wave irradiation with air cooling, yielded 11% of the N1-
deprotected pyrazinone 4, although the reason for its for-
mation is not quite clear. We also observed that, even after
a relatively long irradiation time of two hours, the color of
the resin did not turn into black, as was observed in all pre-
vious cases under conventional heating as well as upon
microwave irradiation without simultaneous liquid cool-
ing. Most probably upon prolonged heating the catalyst
starts to decompose while the boronic acid might undergo
protodeboronation, resulting in incomplete arylation of
the resin-bound pyrazinone which is thermally decompos-
ing on the resin. However, if microwave irradiation with
simultaneous liquid cooling was used, no thermal decom-
position of the unreacted pyrazinone bound to the solid
support takes place. Consequently, when the reaction was
worked up after one hour of irradiation with simultaneous
liquid cooling, and the washed and dried resin beads were
brought into reaction with fresh reagents for an additional
hour of microwave irradiation with simultaneous cooling,
R
Cl
R
Cl
N
1{1}
2{7–32}
3{7–32}
Entry
1
R
Product
3{7}
Yield (%)b
2-F
58
60
59
61
54
33
56
51
Tracesc
54
21
59
62
57
59
0d
2
3-F
3{8}
3
4-F
3{9}
4
2,4-F
3,4-F
2-Cl
3{10}
3{11}
3{12}
3{13}
3{14}
3{15}
3{16}
3{17}
3{18}
3{19}
3{20}
3{21}
3{22}
3{23}
3{24}
3{25}
3{26}
5
6
7
3-Cl
8
4-Cl
9
2,4-Cl
3,4-Cl
2-Me
3-Me
4-Me
3,4-Me
3,5-Me
3-NO2
4-CN
10
11
12
13
14
15
the arylated compounds could be isolated in greatly in- 16
creased yields ranging from 53–63% (Table 3).
17
0d
This represents an improvement of the yield with 17–25%
and a reduction of the reaction time from two days to two
hours, compared to the best conditions obtained under
conventional heating (DT = 65 °C, Table 1). Clearly si-
multaneous liquid cooling prevents the decomposition of
18
2-CO2Et
4-CO2Et
2-CHO
26
61
0d
19
20
the resin-bound pyrazinone during prolonged irradiation.
Synlett 2008, No. 19, 3021–3025 © Thieme Stuttgart · New York

3024
B. K. Singh et al.
LETTER
Table 4 Scope and Limitations: Variation of the Boronic Acidsa
(continued)
The scope and limitations of the new protocol were inves-
tigated by varying the boronic acids (Table 4). The aryla-
tion does not work well with bulky substituents in the
ortho position of the boronic acid (entries 6, 9, 11, 18, and
20). Also a strong electron-withdrawing group as cyano in
the para position seems to be deleterious for the reaction
(entry 17).
OMe
OMe
+
B(OH)2
MW and
simultaneous
cooling
H
N
N
O
H
N
O
S
R
Cl
R
Finally we investigated the applicability of the procedure
for differently substituted 2(1H)-pyrazinones at the N1-
and C6-position (Table 5). Applying the same conditions
of microwave irradiation with simultaneous liquid cool-
ing at 35 °C, excellent yields for all different substrates
were obtained (entries 1–9).
Cl
N
1{1}
2{7–32}
3{7–32}
Entry
21
R
Product
3{27}
3{28}
3{29}
3{30}
3{31}
3{32}
Yield (%)b
4-CHO
4-OH
59
51
0d
56
0d
0d
In conclusion, we have demonstrated that the technique of
microwave irradiation with simultaneous forced liquid
cooling is applicable to solid-phase organic synthesis. The
C3-position of the 2(1H)-pyrazinone scaffold could be ef-
ficiently arylated using the Liebeskind–Srogl protocol.9 It
was demonstrated that the use of microwave irradiation
with simultaneous liquid cooling resulted in significantly
increased yields together with dramatically shortened re-
action times compared to the conventional protocols.
Cooling prevents the resin-bound pyrazinone from de-
composition during irradiation. The scope of this tech-
nique for SPOS is under current investigation.
22
23
4-CO2H
24
4-COMe
4-NHMe2
4-CONH2
25
26
a All reactions were performed on a 0.176 mmol scale with boronic
acid (3 equiv), Pd(PPh3) (5 mol%), and CuTC (2 equiv) in dry THF (5
mL) under microwave irradiation with simultaneous cooling at 35 °C
for 1 + 1 h; the resin was washed and dried properly after 1 h and re-
subjected for the second time to reaction with freshly added reagents.
b Isolated yields based on the loading of trityl-protected resin A1; the
compounds were purified by column chromatography on silica gel.
c Detected by CI-MS.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
d After filtration of the reaction mixture, no pyrazinone-related prod-
uct was detected in the filtrate.
Table 5 Scope and Limitations: Variation of the Pyrazinone Parta
R1
R1
N
MW and
simultaneous
cooling
R6
N
O
R6
O
S
R
+
(HO)2B
Cl
N
R
Cl
N
2{3–4}
3{33–41}
1{2–6}
{3} R = 3-OEt
{4} R = 4-OMe
3{33–37} R = 4-OMe
3{38–41} R = 3-OEt
Entry
R1
R6
3{7–15}
3{33}
3{34}
3{35}
3{36}
3{37}
3{38}
3{39}
3{40}
3{41}
Yield (%)b
1
2
3
4
5
6
7
8
9
CH2C6H11
(CH2)3Ph
Bn
H
54
60
62
63
57
52
59
61
60
H
Me
Me
H
Me
C6H11
CH2C6H11
(CH2)3Ph
Bn
H
H
Me
Me
Me
a All reactions were performed on a 0.176 mmol scale with boronic acid (3 equiv), Pd(PPh3) (5 mol%), and CuTC (2 equiv) in dry THF (5 mL)
under microwave irradiation with simultaneous cooling at 35 °C for 1 + 1 h; the resin was washed and dried properly after 1 h and re-subjected
for the second time to reaction with freshly added reagents.
b Isolated yields based on the loading of trityl-protected resin A1; the compounds were purified by column chromatography on silica gel.
Synlett 2008, No. 19, 3021–3025 © Thieme Stuttgart · New York

LETTER
Rapid Palladium-Catalyzed C3-Arylation of 2(1H)-Pyrazinones
(4) Kaval, N.; Appukkuttan, P.; Van der Eycken, E. The
3025
Acknowledgment
Chemistry of 2(1H)-pyrazinones in Solution and on Solid
Support in Microwave-Assisted Synthesis of Heterocycles,
In Topics in Heterocyclic Chemistry, Vol. 1; Van der
Eycken, E.; Kappe, O., Eds.; Springer: Heidelberg, 2006,
267.
Support was provided by the Research Fund of the University of
Leuven and the F.W.O. [Fund for Scientific Research – Flanders
(Belgium)].
(5) Kaval, N.; Singh, B. K.; Ermolat’ev, D.; Claerhout, S.;
Parmar, V. S.; Van der Eycken, J.; Van der Eycken, E.
J. Comb. Chem. 2007, 9, 446.
References and Notes
(1) (a) Transition Metals for Organic Synthesis: Building
Blocks and Fine Chemicals, 2nd ed., Vol. 2; Beller, M.;
Bolm, C., Eds.; Wiley-VCH: Weinheim, 2004. (b) Metal-
Catalyzed Cross-Coupling Reactions, 2nd ed., Vol. 1 and 2;
de Meijere, A.; Diederich, F., Eds.; Wiley-VCH: Weinheim,
2004. (c) Handbook of Organopalladium Chemistry for
Organic Synthesis, Vol. 1; Negishi, E.-I.; Beller, M.; Zapf,
A., Eds.; Wiley: New York, 2002, 1209. (d) Ley, S. V.;
Thomas, A. W. Angew. Chem. Int. Ed. 2003, 42, 5400.
(2) (a) Kappe, C. O. Angew. Chem. Int. Ed. 2004, 43, 6250.
(b) Kappe, C. O.; Stadler, A. Microwaves in Organic and
Medicinal Chemistry; Wiley-VCH: Weinheim, 2005.
(c) Kappe, C. O.; Dallinger, D. Nat. Rev. Drug Discovery
2006, 5, 51.
(3) (a) Appukkuttan, P.; Hussain, M.; Gupta, R. K.; Parmar,
V. S.; Van der Eycken, E. Synlett 2006, 1491. (b) Singh, B.
K.; Appukkuttan, P.; Claerhout, S.; Parmar, V. S.; Van der
Eycken, E. Org. Lett. 2006, 8, 1863. (c) Singh, B. K.;
Mehta, V. P.; Parmar, V. S.; Van der Eycken, E. Org.
Biomol. Chem. 2007, 5, 2962.
(6) Liebeskind, L. S.; Srogl, J. Org. Lett. 2002, 4, 979.
(7) See power profile in Supporting Information.
(8) All microwave-irradiation experiments were carried out in a
dedicated CEM-Discover-Coolmate monomode microwave
apparatus (CEM Corporation P.O. Box 200 Matthews, NC
28106), operating at a frequency of 2.45 GHz with
continuous irradiation power from 0–300 W. Reaction
mixtures were efficiently stirred with a magnetic stirrer. The
reactions were carried out in an open 10 mL double-walled
glass vial which was cooled to 0–35 °C using a microwave
transparent cooling liquid. The temperature of the cooling
liquid was between 15 °C and 18 °C. Irradiation and cooling
were started simultaneously, starting with the reaction
mixture at r.t. The temperature was measured with a fiber-
optic probe device inserted into the reaction vessel; a
schematic representation of the setup can be found at
http://cemsynthesis.com
(9) Experimental details and characterization data (1H NMR,
13C NMR, and HRMS) of all new compounds are available
in the Supporting Information.
Synlett 2008, No. 19, 3021–3025 © Thieme Stuttgart · New York