Regioselective Synthesis of 2,4-Substituted Pyrido[1′,2′:1,5]pyrazolo[3,4-d]pyrimidines through Sequential Pd-Catalyzed Arylation and SNAr Reactions

Article abstract of DOI:10.1002/ejoc.201600356

The synthesis and regioselective functionalization of rare 2,4-disubstituted-pyrido[1′,2′:1,5]pyrazolo[3,4-d]pyrimidine derivatives is reported. C-4 aminations were performed by chlorine nucleophilic substitution S_NAr reactions, and their efficiencies were compared with those for direct one-pot amide C–O activation with bromotripyrrolidinophosphonium hexafluorophosphate (PyBroP) as a reagent. The latter method was used to perform palladium-catalyzed C-4 (het)arylation. Finally, two C-4 amino and aryl derivatives were prepared on a large scale and engaged in desulfurative Liebeskind–Srogl-type reactions under microwave irradiation to afford the envisioned compound library. Each step was optimized, and the results are discussed.

Full text of DOI:10.1002/ejoc.201600356

DOI: 10.1002/ejoc.201600356
Full Paper
Palladium Cross-Coupling
Regioselective Synthesis of 2,4-Substituted Pyrido[1′,2′
1,5]pyrazolo[3,4-d]pyrimidines through Sequential Pd-
Catalyzed Arylation and S Ar Reactions
:
N
[a,b]
[b]
[b]
[a]
Rabia Belaroussi,
Ahmed El Hakmaoui, Mohamed Akssira,* Gérald Guillaumet, and
Sylvain Routier*[
a]
Abstract: The synthesis and regioselective functionalization of used to perform palladium-catalyzed C-4 (het)arylation. Finally,
rare 2,4-disubstituted-pyrido[1′,2′:1,5]pyrazolo[3,4-d]pyrimidine two C-4 amino and aryl derivatives were prepared on a large
derivatives is reported. C-4 aminations were performed by scale and engaged in desulfurative Liebeskind–Srogl-type reac-
chlorine nucleophilic substitution S Ar reactions, and their effi- tions under microwave irradiation to afford the envisioned com-
N
ciencies were compared with those for direct one-pot amide pound library. Each step was optimized, and the results are dis-
C–O activation with bromotripyrrolidinophosphonium hexaflu- cussed.
orophosphate (PyBroP) as a reagent. The latter method was
Introduction
[3,4-d]pyrimidines have emerged as a significant motif in drug-
[
5]
discovery programs and have been used as antifolates (IV),
The building of multi-heterocyclic derivatives and the discovery
of new methods for their functionalization are solutions to ob-
tain new compounds and pursue the exploration of chemical
space. Among the nitrogen-containing heterocycles, bicyclic
derivatives have been studied intensively, and many of them
have been used to design bioactive molecules.
[
6]
phospholipase inhibitors, cyclooxygenase (COX) inhibitors
[
7]
(
V), and kinase inhibitors (VI and VII).[8]
Tricyclic fused heteroaromatic derivatives have been re-
searched less frequently, but many of them have been gener-
ated in basic chemistry studies. It now appears necessary to
provide synthetic methods for their functionalization through
reproducible and versatile strategies. To answer this crucial lack
of knowledge, we sought to design and functionalize tricyclic
pyrido[1′,2′:1,5]pyrazolo[3,4-d]pyrimidines with pharmacologi-
cally compatible pyrazolopyridine and pyrazolopyrimidine cores
in the same fused framework. The supplementary ring fusion
will provide a high bioactive potential.
Although the biological properties of pyridopyrimidines are
now well described, the rare pyrazolopyridine derivatives have
[
1]
also shown potent diuretic (I, FK-453, Figure 1) and anti-
[
2]
[3]
herpetic properties (II, GW3733) as well as p38 kinase and
[
4]
melatonin receptor inhibitions (III). Additionally, pyrazolo-
Figure 1. Some examples of bioactive pyrazolopyridines and pyrazolopyrim-
idines.
[
[
a] Univ Orleans, CNRS, Institut de Chimie Organique et Analytique, UMR
311,
7
BP 6759, 45067 Orléans Cedex 2, France
E-mail: sylvain.routier@univ-orleans.fr
http://www.icoa.fr/fr
In our previous research, we focused on the double chlorine
[
9]
discrimination of 1 as this strategy was applied efficiently to
[
10]
b] Laboratoire de Chimie Physique et Chimie Bioorganique, Université Hassan
II-Mohammedia-Casablanca,
the pyridopyrimidine series (Scheme 1).
In this paper, we
wish to present another pathway based on recent advances,
B. P. 146, 28800 Mohammedia, Morocco
E-mail: akssira@yahoo.fr
www.fstm.ac.ma
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under http://dx.doi.org/10.1002/ejoc.201600356.
that is, (1) S Ar reactions, (2) direct functionalization of phenolic
N
compounds by an in situ C–O activation strategy, and (3) our
knowledge of desulfurization through Liebeskind–Srogl cross-
coupling reactions. We used the 2-(methylthio)pyrimidinone 2
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Scheme 1. Synthesis pathway to the thioether 2. Reagents and conditions: (a) TFA/CH
CHCl
2
Cl
2
(1:10), 4 h, r.t.., quantitative; (b) benzoyl isothiocyanate (1.2 equiv.),
3
, 12 h, r.t.., 75 %; (c) EtONa (1.1 equiv.), EtOH, 8 h, reflux, 97 %; (d) MeI (1.0 equiv.), NaOH (1.0 equiv.), EtOH, 2 h, r.t., 79 %.
(
Figure 2), which is a good partner to achieve regiocontrolled iodomethane (1.0 equiv.) in basic media at room temperature
C-2 and C-4 diversification.
afforded the target methyl thioether 2 in an excellent yield after
only 2 h (Scheme 1). This methodology proved to be highly
efficient and amenable to multigram-scale reactions.
To achieve the selective functionalization of the tricyclic
heterocycle, we first envisioned regioselective amination
through a C-4 S Ar reaction (general procedure A, Scheme 2,
N
Table 1). To achieve this objective, we first prepared the chloro
derivative 8 with an excess of POCl at 80 °C in 73 % yield. The
3
N
Scheme 2. Amination at C-4 through S Ar reactions. Reagents and conditions:
1
2
(
a) POCl
3 3
, 80 °C, 3 h, 73 %; (b) HNR R (1.0 equiv.), Et N (1.05 equiv.), THF; see
Figure 2. Regioselective transformations of 2.
Table 1 for other parameters (general procedure A).
Various amines and hetaryl groups were next used to in-
crease the molecular diversity and afford C-2 and C-4 amino/
hetaryl-disubstituted pyridopyrazolopyrimidines of types VIII
and IX.
Table 1. Scope of amination from 8 under S
A) or from 2 by PyBroP in situ activation (general procedure B).
N
Ar conditions (general procedure
Results and Discussion
To prepare the key intermediate 2, the most suitable starting
material was considered to be the previously reported N-Boc-
[
9]
pyrazolopyridineamine 4 (Boc = tert-butyloxycarbonyl), which
was obtained from the commercially available aminopyridinium
iodide salt 3 (Scheme 1). The deprotection of the Boc group
was achieved with trifluoroacetic acid (TFA) to afford amine 5
in quantitative yield. The synthesis of pyrimidinethione 7 was
achieved through the preliminary preparation of several thio-
ureas bearing removable groups.
We chose 4-methoxybenzyl (PMB),[ trimethylsilyl (TMS)[12]
11]
and benzoyl ureas to react with 5; surprisingly, the only efficient
[
13]
reaction was achieved with 5 and benzoyl isothiocyanate,
which led to 6 in a 75 % yield after 12 h at room temperature.
In EtOH under reflux, annulation occurred with a stoichiometric
amount of sodium ethanoate to afford 7 in a near quantitative
yield. As expected, the benzoyl group did not survive under
these basic conditions. Finally, the typical treatment of 7 with
[
a] Isolated yield after column chromatography. [b] The starting material was
recovered (11 %).
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reaction of 8 with primary and secondary aliphatic amines as
well as benzylamines or anilines led to derivatives 9–16 with
yields of 61 to 95 %.
A relative variability of the S Ar method was observed. Al-
N
though reproducible results were obtained for each assay, the
yields depended fully on the nature of the amine used. If the
reactivity of the amine was lower (Table 1, Entries 5–8), a large
increase in the time as well as the temperature was required.
Consequently, degradation was favored, and the yield of the
isolated product decreased significantly.
Scheme 4. One-pot (het)arylation at C-4 from 2 by a C–O amide activation.
The decreased yield for an ortho-methoxyphenyl-substituted
boronic acid (Table 2, Entry 4) indicated a sensitivity to steric
effects for this assay. Reactivity was fully restored for aromatics
The modest results obtained for general procedure A
prompted us to find an alternative. Therefore, we performed
the amination of 2 in one pot through in situ activation of the
[
14]
with para electron-withdrawing groups such as F or CF3
C–O bond
by taking advantage of the tautomerizability of
(
Table 2, Entries 5 and 6), but the use of 3-pyridine strongly
amide 2 (general procedure B, Scheme 3) in basic media.
diminished the yield of the C–O amide hetarylation (Table 2,
Entry 7).
Table 2. Scope of (het)arylation from 2 under C–O amid activation.
Scheme 3. One-pot amination at C-4 through a C–O PyBroP activation.
The first assay with bromotripyrrolidinophosphonium hexa-
[
15]
fluorophosphate (PyBroP)
as the coupling activator showed
excellent reactivity. The activated species formed in situ were
detected by TLC after 4 h. To achieve the S Ar reaction, we next
N
added the desired amine and observed the formation of C-4
amino derivatives 9–16 after only a few additional hours, specif-
ically, 4 h for alkyl- and benzylamines and 12 h for anilines. If
all of the reagents were introduced with 2 at the beginning of
[
16]
the reaction, the S Ar reactions were less efficient. For exam-
N
ple, the reaction of 2 in the direct presence of morpholine, Et N,
3
and PyBroP led to 11 in only 60 % yield whatever the reaction
time (starting material recovered).
[
a] Isolated yield after column chromatography.
These interesting amido activations of tricyclic heteroaro-
matic complex systems prompted us to explore the C-2 (het)ar-
ylation of 2 by an original PyBroP-mediated C–O activation. The
The previously obtained C-4 aminated and (het)arylated
compounds 9–23 could then be used to achieve the regiocon-
trolled diversification of the pyridopyrazolopyrimidine core and
furnish the target derivatives of types VIII and IX. For this, we
one-pot sequence involved the use of PyBroP and Et N for 18 h
3
to fully consume the starting material 2 (TLC monitoring), and
[17]
used classical Liebeskind–Srogl cross-coupling conditions
then a solution of p-tolylboronic acid (2.0 equiv.), K CO
2
3
with an arylboronic acid in the presence of Pd(PPh ) (10 mol-
3
4
(
3.0 equiv.), and PdCl (PPh ) was added in a dioxane/water
2 3 2
%) and copper(I) thiophene-2-carboxylate (CuTC) in tetrahydro-
furan (THF) at 100 °C under microwave irradiation. The scope
of the method was studied only with 11 and 17, which were
prepared on a gram scale (Scheme 5).
mixture to launch the arylation. After an additional 24 h, the
desired product 17 was formed in an encouraging 18 % yield,
whereas the starting material was recovered in 50 % yield. The
change of the base to Na CO increased the yield of 17 to 51 %,
2
3
and the use of 10 mol-% of catalyst led to a further increase in
efficiency (88 % yield of 17). Finally, the best system for the
quantitative conversion required Pd(dppf)Cl ·CH Cl [10 %,
2
2
2
dppf = 1,1′-bis(diphenylphosphino)ferrocene] as the catalyst.
The C-4 tolyl derivative 17 was now purified in an excellent
9
0 % yield (Scheme 4).
The generalization of this one-pot cross-coupling strategy
Scheme 5. Desulfurative cross-coupling reactions at C-2 to form derivatives
of type VIII and IX.
(
Table 2) was achieved with diverse (het)aryl boronic acids and
led to 17–23. The introduction of para- or meta-methoxyphenyl
From the C-4-morpholino derivative 11, the desulfurative
substituents was successfully achieved without any difficulties. cross-coupling reaction was performed with phenyl boron de-
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Table 3. Scope of the desulfurative cross-coupling reaction at C-2.
[
a] Isolated yield after column chromatography.
rivatives bearing p-OMe, m-OMe, p-OTHP (THP = tetrahydro- imidines offers nice prospects in the organic chemistry and me-
pyranyl), p-CN, and p-CF groups. The assays yielded the desired dicinal chemistry fields.
3
derivatives 24–28 with yields ranging from 41 to 69 % (Table 3).
With 3-pyridinyl boronic acid, the reaction failed (Table 3, Entry
6
), and starting material 11 was fully recovered. From the C-4
Experimental Section
hetarylated derivative 17, phenyl and pyridinyl boronic acids
afforded the attempted derivatives of type IX. The reactivity
for methoxyphenyl boronic acids followed the order
para > meta > ortho (Table 3, Entries 7–9). Whatever the elec-
tronic character of the para aryl group, the yields remained ap-
proximately 65 %. Fortunately, the use of 3-pyridinyl boronic
acid (Table 3, Entry 12) was successful, and the final compound
General: Reactions were monitored by thin-layer chromatography
(
TLC) with using silica gel (60 F254) plates, and the compounds
were visualized by UV irradiation. Flash column chromatography
was performed with silica gel 60 (230–400.13 mesh, 0.040
0.063 mm). The melting points were measured with samples in
open capillary tubes. The infrared spectra of compounds were re-
1
corded with a Thermo Scientific Nicolet iS10 instrument. The
H
3
4 was isolated in a satisfying yield.
13
13
and C NMR spectra were recorded with Bruker DPX 250 ( C,
13
6
(
2 MHz), Bruker Avance II 250 ( C, 63 MHz), Bruker Avance 400
C, 101 MHz), or Bruker Avance III HD Nanobay 400 ( C, 101 MHz)
1
3
13
Conclusions
spectrometers. The chemical shifts are given in ppm from tetra-
methylsilane as an internal standard. The coupling constants (J) are
reported in Hz. High-resolution mass spectra (HRMS) were recorded
with a Maxis Bruker 4G instrument.
We have developed a straightforward strategy to C-4 amino/
(
4
het)Ar and C-2 (het)Ar pyridopyrazolopyrimidines. Although a
-Cl derivative reacted smoothly, the direct C–O activation of
an amide function with PyBroP produced better results. This C-
amination/heteroarylation was achieved in high yields. One-
Methyl 2-Aminopyrazolo[1,5-a]pyridine-3-carboxylate (5): A so-
[
9]
lution of 2-N-Boc-amino ester 4 (1.071 mmol, 0.5 g) in a mixture
4
of CH Cl /TFA (10:1, 3 mL) was stirred at room temperature for 4 h.
2
2
pot strategies reduced the number of steps, decreased the reac-
tion time and temperature, and contributed to eco-efficiency of
these processes. Afterwards, the monosubstituted 2-SMe inter-
After the complete disappearance of the starting material, the sol-
vent was removed in vacuo, and then a saturated (satd.) aqueous
(
aq.) K CO3 solution (10 mL) was added slowly. The residue was
2
mediates reacted under Liebeskind–Srogl conditions. This mul- extracted with EtOAc (3 × 20 mL). The volatiles were evaporated
tiple and regioselective functionalization of pyridopyrazolopyr- under reduced pressure, and the crude material was purified by
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column chromatography (petroleum ether/EtOAc, 4:6) to give 5 as
94.8 (Cq), 13.5 (CH ) ppm. HRMS (ESI): calcd. for C H N OS [M +
3
10 9 4
+
a beige solid in quantitative yield, m.p. 128–129 °C. R (petroleum H] 233.0492; found 233.0490.
f
ether/EtOAc, 4:6) = 0.5. IR [attenuated total reflection (ATR) dia-
4
-Chloro-2-(methylthio)pyrido[1′,2′:1,5]pyrazolo[3,4-d]pyrim-
idine (8): POCl3 (20 mL) was dissolved in a sealed tube of 2
4.3 mmol, 1.0 g). The reaction mixture was stirred at 80 °C for
h, cooled to room temperature, and concentrated under reduced
pressure. The residue was poured into a satd. aq. NaHCO solution
–
1 1
mond]: ν˜ = 3416, 3315, 1530, 1440, 1204, 1122, 784, 715 cm . H
NMR (400 MHz, CDCl ): δ = 8.22 (dt, J = 6.8, J = 1.2 Hz, 1 H), 7.81
3
(
3
(d, J = 8.8 Hz, 1 H), 7.30 (ddd, J = 8.8, J = 6.8 Hz, J = 1.2 Hz, 1 H),
6
.78 (td, J = 6.8, J = 1.2 Hz, 1 H), 5.25 (s, 2 H, NH ), 3.91 (s, 3 H)
2
13
3
ppm. C NMR (101 MHz, CDCl ): δ = 165.2 (CO), 159.9 (Cq),141.9
3
(
50 mL), and the aqueous layer was extracted with CH Cl (3 ×
2 2
(
5
Cq), 128.4 (CH ), 127.5 (CH ), 117.3 (CH ), 112.4 (CH ), 87.65 (Cq),
0.9 (CH ) ppm. HRMS (ESI): calcd. for C H N O [M + H] 192.0770;
3 9 10 3 2
Ar Ar Ar Ar
100 mL). The combined organic layers were dried with MgSO , fil-
+
4
tered, and concentrated under vacuum. The crude solid was then
purified by silica gel flash chromatography (petroleum ether/EtOAc,
6:4) to afford 8 (780 mg, 73 %) as a yellow solid, m.p. 193–194 °C.
found 192.0768.
Methyl 2-(3-Benzoylthioureido)pyrazolo[1,5-a]pyridine-3-carb-
oxylate (6): A suspension of benzoyl isothiocyanate (6.27 mmol,
R
f
(petroleum ether/EtOAc, 4:6) = 0.62. IR (ATR diamond): ν˜ = 2925,
–1 1
0
.84 mL) and amino ester 5 (5.23 mmol, 1.0 g) in CHCl (10 mL) was 1639, 1584, 1502, 1428, 1299, 1176, 1038, 850, 785, 688 cm . H
3
stirred at room temperature overnight. The volatiles were evapo- NMR (250 MHz, CDCl
rated under reduced pressure, and the residue was purified by silica
8.23 (m, 1 H), 7.73 (ddd, J = 8.8, J = 6.8 Hz, J = 1.2 Hz, 1 H), 7.43
gel flash chromatography (petroleum ether/EtOAc, 5:5) to afford the (td, J = 6.8, J = 1.2 Hz, 1 H), 2.70 (s, 3 H) ppm. 13C NMR (101 MHz,
desired thiourea 6 as a yellow solid (1.39 g, 75 %), m.p. 180–181 °C.
CDCl ): δ = 172.6 (Cq), 163.2 (Cq), 155.1 (Cq), 135.8 (Cq), 130.5
R (petroleum ether/EtOAc, 4:6) = 0.8. IR (ATR diamond): ν˜ = 3056, (CHAr), 128.6 (CHAr), 120.0 (CHAr), 119.1 (CHAr), 102.9 (Cq), 15.2 (CH
): δ = 8.84 (dt, J = 6.8, J = 1.2 Hz, 1 H), 8.46–
3
3
)
f
3
–
1
1
+
1
694, 1524, 1448, 1321, 1208, 1029, 1106, 853, 781 cm . H NMR ppm. HRMS (ESI): calcd. for C10
H ClN S [M + H] 251.0153; found
8 4
(
400 MHz, CDCl ): δ = 13.84 (s, 1 H, NH), 9.30 (s, 1 H, NH), 8.60 (s, 1
251.0155.
3
H), 8.06 (d, J = 8.8 Hz, 1 H), 7.99 (d, J = 8.8 Hz, 2 H), 7.69–7.61 (m,
General Procedure A for S Ar Reaction: To a solution of 8
N
1
1
1
1
H), 7.59–7.50 (m, 2 H), 7.46 (t, J = 8.0 Hz, 1 H), 6.99 (t, J = 6.8 Hz,
(
0.39 mmol, 100 mg) in dry THF (7 mL) were successively added the
1
3
H),4.04 (s, 3 H) ppm. C NMR (101 MHz, CDCl ): δ = 176.3 (CO),
3
1 2
corresponding amine R R NH (1.00 equiv.) and Et N (1.05 equiv.,
3
65.6 (CS), 163.9 (CO), 151.3 (Cq), 140.7 (Cq), 133.7 (Cq), 131.7 (CHAr),
29.8 (CH ), 129.2 (2 × CH ), 128.5 (CH ), 127.8 (2 × CH ), 118.5
41 mg). The reaction mixture was stirred at the required tempera-
Ar
Ar
Ar
Ar
ture (see Table 1) until the starting material 8 was converted com-
pletely. The solvent was evaporated under reduced pressure. The
crude residue was purified by silica gel column chromatography to
give the desired mono-aminated compounds 9–16.
(
CH ), 114.0 (CH ), 93.0 (Cq), 51.7 (CH ) ppm. HRMS (ESI): calcd. for
Ar Ar 3
+
C H N O S [M + H] 355.0859; found 355.0860.
17 15 4 3
2
(
(
-Thioxo-2,3-dihydropyrido[1′,2′:1,5]pyrazolo[3,4-d]pyrimidin-4
1H)-one (7): To a suspension of 6 (1.41 mmol, 0.5 g) in EtOH
10 mL) was added a solution of NaOEt in EtOH (1.55 mmol, 2.68 ).
General Procedure B (PyBroP-Mediated C–O Activation): In a mi-
crowave vial, 2 (0.43 mmol, 100 mg) and PyBroP (0.51 mmol,
M
The reacting mixture was heated under reflux for 8 h then cooled
to room temperature and neutralized to pH 7 with pure AcOH. The
solvents were evaporated under reduced pressure, and the resulting
precipitate was collected by filtration, washed with water (2 ×
2
40 mg) were dissolved in 1,4-dioxane (4 mL). Et N (1.29 mmol,
3
0.17 mL) was then added, and the mixture was degassed by argon
bubbling for 10 min. The sealed tube was heated at 80 °C for 4 h.
After cooling, the corresponding amine (2.0 equiv.) was added, and
the mixture was stirred for the required time and temperature (see
Table 1). After cooling, the solvents were evaporated under reduced
pressure, and the crude residue was purified by silica gel column
chromatography to give the desired mono-aminated compounds
1
9
0 mL), and dried under vacuum to afford 7 as a white solid (298 g,
7 %), m.p. 387–359 °C. R (petroleum ether/EtOAc, 4:6) = 0.01. IR
f
(
7
ATR diamond): ν˜ = 2994, 1639, 1583, 1429, 1295, 1130, 1062, 826,
–1
1
75, 641 cm .
H NMR {400 MHz, [D ]dimethyl sulfoxide
6
(
[D ]DMSO)}: δ = 13.29 (s, 1 H, NH), 12.03 (s, 1 H, NH), 8.90 (d, J =
6
9–16.
6
.8 Hz, 1 H), 7.94 (d, J = 8.8 Hz, 1 H), 7.69 (t, J = 8.8 Hz, 1 H), 7.28
1
3
(td, J = 6.8, J = 1.2 Hz, 1 H) ppm. C NMR (101 MHz, [D ]DMSO):
2-(Methylthio)-N-propylpyrido[1′,2′:1,5]pyrazolo[3,4-d]pyrim-
6
δ = 176.8 (CO), 157.2 (CO), 154.1 (Cq), 138.3 (Cq), 130.8 (CH ), 130.1 idin-4-amine (9): After purification by silica gel flash chromatogra-
Ar
(
CH ), 117.2 (CH ), 116.3 (CH ), 92.6 (Cq) ppm. HRMS (ESI) calcd.
phy (petroleum ether/EtOAc, 4:6), 9 was obtained as a light brown
solid from n-propylamine in 65 % yield by general procedure A or
Ar
Ar
Ar
+
for C H N OS [M + H] 219.0335; found 219.0334.
9
7 4
in 86 % yield by general procedure B, m.p.195–196 °C. R (petroleum
f
2
-(Methylthio)pyrido[1′,2′:1,5]pyrazolo[3,4-d]pyrimidin-4(3H)-
ether/EtOAc, 3:7) = 0.3. IR (ATR diamond): ν˜ = 3390, 2925, 1636,
one (2): A suspension of thioamide 7 (4.58 mmol, 1.0 g) in EtOH
–
1 1
1
589, 1537, 1359, 1266, 1198, 1144, 992, 792 cm . H NMR
(
(
80 mL) was stirred at room temperature. A solution of NaOH
4.58 mmol, 0.183 g) in water (2 mL) was added dropwise, and the
(
400 MHz, CDCl ): δ = 8.69 (d, J = 6.8 Hz, 1 H), 7.85 (d, J = 8.8 Hz,
3
1
H), 7.49 (ddd, J = 8.8, J = 6.8 Hz, J = 1.2 Hz, 1 H), 7.12 (td, J = 6.8,
resulting mixture was stirred for 15 min. Methyl iodide (4.58 mmol,
.282 mL) was then added; after 2 h, the solvent was removed
under vacuum. The residue was poured into water (30 mL), and the
solution was neutralized to pH 7 with HCl (1 ). The precipitate was
J = 1.2 Hz, 1 H), 5.60 (s, 1 H, NH), 3.76–3.63 (m, 2 H), 2.64 (s, 3 H),
0
1
3
1
.76 (q, J = 7.4 Hz, 2 H), 1.03 (t, J = 7.4 Hz, 3 H) ppm. C NMR
(
101 MHz, CDCl ): δ = 171.6 (Cq), 162.5 (Cq), 157.0 (Cq), 134.6 (Cq),
3
N
1
2
29.6 (CH), 126.3 (CH), 117.2 (CH), 115.2 (CH), 90.8 (Cq), 43.0 (CH2),
3.0 (CH ), 14.3 (CH ), 11.6 (CH ) ppm. HRMS (ESI): calcd. for
collected by filtration, washed with water (10 mL), and dried under
reduced pressure to afford 2 as a white solid (0.840 g, 79 %), m.p.
2
3
3
+
C H N S [M + H] 274.1121; found 274.1124.
13 16 5
2
99–300 °C. R (petroleum ether/EtOAc, 4:6) = 0.32. IR (ATR dia-
f
mond): ν˜ = 3056, 2894, 1675, 1640, 1581, 1431, 1321, 1225, 1158,
N-(4-Methoxybenzyl)-2-(methylthio)pyrido[1′,2′:1,5]pyraz-
olo[3,4-d]pyrimidin-4-amine (10): After purification by silica gel
flash chromatography (petroleum ether/EtOAc, 4:6), 10 was ob-
tained as white solid from p-methoxybenzylamine in 90 % yield by
–
1 1
1
064, 825, 775, 654 cm . H NMR (400 MHz, [D ]DMSO): δ = 12.32
6
(
s, 1 H, NH), 8.87 (d, J = 6.8 Hz, 1 H), 8.00 (d, J = 8.8 Hz, 1 H), 7.62
(
t, J = 8.8 Hz, 1 H), 7.26 (t, J = 6.8 Hz, 1 H), 2.54 (s, 3 H) ppm. 13
C
NMR (101 MHz, [D ]DMSO): δ = 163.2 (CO), 162.0 (Cq), 160.6 (Cq), general procedure A or in 92 % yield by general procedure B, m.p.
6
1
37.6 (Cq), 130.0 (CH ), 128.15 (CH ), 117.9 (CH ), 116.0 (CH ), 231–232 °C. R (petroleum ether/EtOAc, 3:7) = 0.4. IR (ATR diamond):
Ar Ar Ar Ar f
Eur. J. Org. Chem. 2016, 3550–3558
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© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
ν˜ = 3011, 1583, 1510, 1440, 1358, 1250, 1194, 1030, 915, 816, 754 8.8 Hz, 1 H), 7.80–7.69 (m, 3 H), 7.41–7.35 (m, 3 H), 7.17 (td, J = 6.8,
–1
1
13
cm . H NMR (400 MHz, CDCl ): δ = 8.73 (d, J = 6.8 Hz, 1 H), 7.65
J = 1.2 Hz, 1 H),2.50 (s, 3 H) ppm. C NMR (101 MHz, [D ]DMSO):
3
6
(d, J = 8.8 Hz, 1 H), 7.47 (ddd, J = 8.8, J = 6.8 Hz, J = 1.2 Hz, 1 H),
δ = 170.2 (Cq), 163.0 (Cq), 155.1 (Cq), 139.1 (Cq), 134.4 (Cq), 130.0
7
8
2
.39–7.33 (m, 2 H), 7.13 (td, J = 6.8, J = 1.2 Hz, 1 H), 6.90 (d, J = (CH ), 128.8 (2 × CH ), 127.1 (CH ), 123.7 (2 × CH ), 124.6 (CH ),
Ar Ar Ar Ar Ar
.8 Hz, 2 H), 5.32 (NH, s, 1 H), 4.87 (d, J = 5.3 Hz, 2 H), 3.81 (s, 3 H),
119.6 (CH ), 117.2 (CH ), 91.2 (Cq), 14.0 (CH ) ppm. HRMS (ESI):
Ar Ar 3
.66 (s, 3 H) ppm. 1 C NMR (101 MHz, CDCl ): δ = 171.8 (Cq), 162.9
3
calcd. for C H N S [M + H] 308.0964; found 308.0962.
+
3
16 14 5
(
Cq), 159.1 (Cq), 156.5 (Cq), 134.2 (Cq), 130.1 (Cq), 129.5 (CH), 129.3
N-(3-Chlorophenyl)-2-(methylthio)pyrido[1′,2′:1,5]pyrazolo[3,4-
d]pyrimidin-4-amine (15): After purification by silica gel flash chro-
matography (petroleum ether/EtOAc, 5:5), 15 was obtained as a
white solid from 3-chloroaniline in 65 % yield by general procedure
A or in a 82 % yield by general procedure B, m.p. 179–180 °C. Rf
(2 × CH ), 125.9 (CH ), 116.8 (CH ), 115.0 (CH ), 114.1 (2 × CH ),
Ar
Ar
Ar
Ar
Ar
9
0.5 (Cq), 55.1 (CH ), 44.5 (CH ), 14.1 (CH ) ppm. HRMS (ESI): calcd.
3 2 3
+
for C H N OS [M + H] 352.1227; found 352.1231.
18 18 5
4
-[2-(Methylthio)pyrido(1′,2′:1,5)pyrazolo[3,4-d]pyrimidin-4-
yl]morpholine (11): After purification by silica gel flash chromatog- (petroleum ether/EtOAc, 3:7) = 0.22. IR (ATR diamond): ν˜ = 3242,
–
1 1
raphy (petroleum ether/EtOAc, 4:6), 11 was obtained as a white
2921, 1635, 1530, 1435, 1266, 1202, 1111, 905, 761 cm . H NMR
solid from morpholine in 95 % yield by general procedure A or in
(400 MHz, [D ]DMSO): δ = 9.87 (NH, s, 1 H), 9.06 (d, J = 6.8 Hz, 1 H),
6
8
9 % yield by general procedure B, m.p. 214–215 °C. R (petroleum
8.87 (d, J = 8.8 Hz, 1 H), 7.96 (s, 1 H), 7.83 (ddd, J = 8.8, J = 6.8 Hz,
f
ether/EtOAc, 3:7) = 0.42. IR (ATR diamond): ν˜ = 2859, 1627, 1525, J = 1.2 Hz, 1 H), 7.75 (d, J = 8.8 Hz, 1 H), 7.56–7.40 (m, 2 H), 7.25 (d,
–
1
1
13
1
429, 1367, 1266, 1202, 1108, 970, 862, 747 cm . H NMR (250 MHz,
J = 8.8 Hz, 1 H), 2.51 (s, 3 H) ppm. C NMR (101 MHz, [D ]DMSO):
6
CDCl ): δ = 8.75 (dt, J = 6.8, 1.2 Hz, 1 H), 7.68 (dt, J = 8.8, J = 1.2 Hz, δ = 168.7 (Cq), 160.2 (Cq), 154.3 (Cq), 139.8 (Cq),134.4 (Cq), 132.7
3
1
H), 7.55 (ddd, J = 8.8, J = 6.8 Hz, J = 1.2 Hz, 1 H), 7.21 (td, J = 6.8,
(Cq), 130.2 (CH ), 130.15 (CH ), 128.0 (CH ), 124.4 (CH ), 123.3
Ar Ar Ar Ar
13
J = 1.2 Hz, 1 H), 3.97–3.74 (m, 8 H), 2.65 (s, 3 H) ppm. C NMR
63 MHz, CDCl ): δ = 170.9 (Cq), 164.3 (Cq), 160.0 (Cq), 134.2 (Cq),
(CH ),122.1 (CH ), 119.7 (CH ),117.7 (CH ), 91.2 (Cq), 13.8 (CH )
Ar Ar Ar Ar 3
+
(
ppm. HRMS (ESI): calcd. for C H ClN S [M + H] 342.0575; found
16 13 5
3
1
29.6 (CH ), 126.2 (CH ), 118.8 (CH ), 115.6 (CH ), 92.3 (Cq), 66.7 342.0572.
Ar Ar Ar Ar
(
2 × CH ), 48.3 (2 × CH ), 14.3 (CH ) ppm. HRMS (ESI): calcd. for
2 2 3
N-(4-Methoxyphenyl)-2-(methylthio)pyrido[1′,2′:1,5]pyraz-
olo[3,4-d]pyrimidin-4-amine (16): After purification by silica gel
flash chromatography (petroleum ether/EtOAc, 4:6), 16 was ob-
tained as a white solid from p-anisidine in 74 % yield by general
procedure A or in 88 % yield by general procedure B, m.p. 262–
263 °C. R (petroleum ether/EtOAc, 3:7) = 0.5. IR (ATR diamond): ν =
+
C H N OS [M + H] 302.1070; found 302.1071.
14 16 5
2
-(Methylthio)-4-(piperidin-1-yl)pyrido[1′,2′:1,5]pyrazolo[3,4-
d]pyrimidine (12): After purification by silica gel flash chromatog-
raphy (petroleum ether/EtOAc, 4:6), 12 was obtained as a white
solid from cyclohexylamine in 90 % yield by general procedure A
f
˜
1
–1
or in 95 % yield by general procedure B, m.p. 169–170 °C; R (petro- 2954, 1644, 1565, 1505, 1367, 1245, 1107, 1062, 828,752 cm . H
f
leum ether/EtOAc, 3:7) = 0.57. IR (ATR diamond): ν˜ = 2928, 1628, NMR (400 MHz, CDCl ): δ = 8.70 (d, J = 6.8 Hz, 1 H), 7.49–7.41 (m,
3
–
1 1
1
556, 1525, 1375, 1299, 1240, 1188, 1025, 950, 793 cm . H NMR 2 H), 7.34 (ddd, J = 8.8, J = 6.8 Hz, J = 1.2 Hz, 1 H), 7.13 (t, J =
(
400 MHz, CDCl ): δ = 8.73 (d, J = 6.8 Hz, 1 H), 7.72 (d, J = 8.8 Hz,
6.8 Hz, 1 H), 7.02 (d, J = 8.8 Hz, 1 H), 6.95–6.86 (m, 2 H), 3.83 (s, 3
3
1
4
1
H), 7.51 (t, J = 8.8 Hz, 1 H), 7.17 (t, J = 6.8 Hz, 1 H), 3.83–3.68 (m,
H), 2.65 (s, 3 H) ppm. 13C NMR (101 MHz, CDCl ): δ = 171.4 (Cq),
3
1
3
H), 2.65 (s, 3 H), 1.79 (s, 6 H) ppm. C NMR (101 MHz, CDCl ): δ = 163.5 (Cq), 157.4 (Cq), 155.8 (Cq), 134.6 (Cq), 131.3 (Cq), 129.6 (CHAr),
3
70.5 (Cq), 164.0 (Cq), 159.8 (Cq), 134.3 (Cq), 129.3 (CH ), 125.6
126.3 (CH ), 125.1 (2 × CH ), 118.6 (CH ), 115.8 (CH ), 114.6 (2 ×
Ar
Ar Ar Ar Ar
(
CH ), 118.6 (CH ), 115.0 (CH ), 92.2 (Cq), 48.7 (2 × CH ), 25.7 (2 ×
CH ), 91.0 (Cq), 55.7 (CH ), 14.3 (CH ) ppm. HRMS (ESI): calcd. for
Ar 3 3
C H N OS [M + H] 338.1070; found 338.1070.
17 16 5
Ar
Ar
Ar
2
+
CH ), 24.4 (CH ), 14.0 (CH ) ppm. HRMS (ESI): calcd. for C H N S
[
2
2
3
15 18
5
+
M + H] 300.1277; found 300.1276.
General Procedure C for the Direct Arylation by C–OH Bond
Activation: To an argon-degassed solution of 2 (0.43 mmol,
100 mg) in dioxane (4 mL) in a sealed tube were added successively
N-Cyclohexyl-2-(methylthio)pyrido[1′,2′:1,5]pyrazolo[3,4-d]pyr-
imidin-4-amine (13): After purification by silica gel flash chroma-
tography (petroleum ether/EtOAc, 4:6), 13 was obtained as a white
solid from piperidine in 61 % yield by general procedure A or in
PyBroP (0.51 mmol, 240 mg) and Et N (1.29 mmol, 0.17 mL). After
3
18 h at 80 °C, the reaction mixture was cooled, and a solution con-
taining the required arylboronic acid (2.0 equiv.), Na CO
3
8
1 % yield by general procedure B, m.p. 191–192 °C. R (petroleum
f
2
ether/EtOAc, 3:7) = 0.47. IR (ATR diamond): ν˜ = 3485, 2924, 1636, (5.0 equiv.), and PdCl (dppf)·CH Cl (10 mol-%) in H O (1 mL) was
2
2
2
2
–
1 1
1
533, 1359, 1274, 1202, 1138, 990, 791, 741 cm . H NMR (400 MHz,
added. The sealed vial was heated at 110 °C and stirred for an
CDCl ): δ = 8.66 (d, J = 6.8 Hz, 1 H), 7.73 (d, J = 8.8 Hz, 1 H), 7.47 additional 24 h. After cooling to room temperature, the volatiles
3
(
4
t, J = 8.8 Hz, 1 H), 7.09 (t, J = 6.8 Hz, 1 H), 5.10 (d, J = 7.4 Hz, 1 H),
.39–4.27 (m, 1 H), 2.63 (s, 3 H), 2.23–2.09 (m, 2 H), 1.83–1.70 (m, 2
were evaporated under reduced pressure, and the crude material
was diluted in CH Cl (20 mL). The organic layer was washed with
2
2
H), 1.73–1.62 (m, 1 H), 1.55–1.38 (m, 2 H), 1.40–1.16 (m, 3 H) ppm.
water (10 mL), dried with MgSO , filtered, and concentrated under
4
13
C NMR (101 MHz, CDCl ): δ = 171.8 (Cq), 163.05 (Cq), 156.2 (Cq), vacuum. The crude mixture was purified by silica gel column chro-
3
1
34.4 (Cq), 129.4 (CH ), 126.0 (CH ), 117.0 (CH ), 115.0 (CH ), 90.7 matography to give the desired monoarylated compounds 17–23.
Ar Ar Ar Ar
(
Cq), 49.55 (CH), 33.25 (2 × CH ), 25.7 (CH ), 24.95 (2 × CH ), 14.3
2 2 2
2
-(Methylthio)-4-(p-tolyl)pyrido[1′,2′:1,5]pyrazolo[3,4-d]pyr-
+
(CH ) ppm. HRMS (ESI): calcd. for C H N S [M + H] 314.1434;
3
16 20 5
imidine (17): With p-tolylboronic acid as the coupling reagent and
by general procedure C, 17 was isolated as a yellow solid in 90 %
yield after purification by silica gel flash chromatography (petro-
found 314.1431.
2
-(Methylthio)-N-phenylpyrido[1′,2′:1,5]pyrazolo[3,4-d]pyrim-
idin-4-amine (14): After purification by silica gel flash chromatog-
raphy (petroleum ether/EtOAc, 4:6), 14 was obtained as a white
solid from aniline in 85 % yield by general procedure A or by 85 %
leum ether/EtOAc, 6:4), m.p. 185–184 °C; R (petroleum ether/EtOAc,
f
3:7) = 0.52. IR (ATR diamond): ν˜ = 2922, 1635, 1577, 1528, 1435,
–
1 1
1240, 1184, 1002, 799, 752, 634 cm . H NMR (400 MHz, CDCl ):
3
yield by general procedure B, m.p.228–229 °C. R (petroleum ether/
δ = 8.84 (d, J = 6.8 Hz, 1 H), 7.99 (d, J = 8.8 Hz, 1 H), 7.81 (d, J =
f
EtOAc, 3:7) = 0.62. IR (ATR diamond): ν˜ = 3005, 1634, 1522, 1438, 7.7 Hz, 2 H), 7.48 (t, J = 8.8 Hz, 1 H), 7.40 (d, J = 7.7 Hz, 2 H), 7.31
–
1
1
13
1
301, 1195, 1065, 951, 790, 747 cm . H NMR (400 MHz, [D ]DMSO):
(t, J = 6.8 Hz, 1 H), 2.74 (s, 3 H), 2.49 (s, 3 H) ppm. C NMR (101 MHz,
6
δ = 9.27 (NH, s, 1 H), 9.01 (dt, J = 6.8, J = 1.2 Hz, 1 H), 8.65 (d, J =
CDCl ): δ = 172.3 (Cq), 163.7 (Cq), 163.1 (Cq), 141.3 (Cq), 135.9 (Cq),
3
Eur. J. Org. Chem. 2016, 3550–3558
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© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
2
1
34.8 (Cq), 129.8 (CH ), 129.7 (2 × CH ), 128.8 (2 × CH ), 126.7
130.0 (CH ), 127.0 (CH ), 119.2 (CH ), 118.0 (CH ), 116.2 (d, J
=
Ar
Ar
Ar
Ar
Ar
Ar
Ar
C,F
(
CH ), 119.5 (CH ), 117.8 (CH ), 101.75 (Cq), 21.7 (CH ), 14.6 (CH ) 21.8 Hz, 2 × CH), 101.65 (Cq), 14.6 (S-CH ) ppm. HRMS (ESI): calcd.
Ar Ar Ar 3 3 3
+
+
ppm. HRMS (ESI): calcd. for C H N S [M + H] 307.1012; found for C H FN S [M + H] 311.0761; found 311.0763.
1
7
15
4
16 12
4
3
07.1016.
2
-(Methylthio)-4-[4-(trifluoromethyl)phenyl]pyrido[1′,2′:1,5]-
4
-(4-Methoxyphenyl)-2-(methylthio)pyrido[1′,2′:1,5]pyraz-
pyrazolo[3,4-d]pyrimidine (22): With 4-trifluoromethylphenylbo-
ronic acid as the coupling reagent and by general procedure C, 22
was isolated as a yellow solid in 84 % yield after purification by
silica gel flash chromatography (petroleum ether/EtOAc, 5:5), m.p.
olo[3,4-d]pyrimidine (18): With 4-methoxyphenylboronic acid as
the coupling reagent and by general procedure C, 18 was isolated
as a yellow solid in 89 % yield after purification by silica gel flash
chromatography (petroleum ether/EtOAc, 5:5), m.p. 219–220 °C. Rf
197–199 °C. R
(petroleum ether/EtOAc, 3:7) = 0.7. IR (ATR diamond):
f
–1
(
petroleum ether/EtOAc, 3:7) = 0.47. IR (ATR diamond): ν˜ = 2918, ν˜ = 3066, 1633, 1531, 1434, 1325, 1240, 1066, 859, 757, 639 cm .
–
1
1
1
1
633, 1533, 1507, 1344, 1261, 1185, 1021, 841, 755, 621 cm . H
H NMR (400 MHz, CDCl ): δ = 8.87 (d, J = 6.8 Hz, 1 H), 8.03 (d, J =
3
NMR (400 MHz, CDCl ): δ = 8.84 (d, J = 6.8 Hz, 1 H), 8.03 (dt, J =
7.7 Hz, 2 H), 7.88 (d, J = 7.7 Hz, 3 H), 7.54 (t, J = 8.8 Hz, 1 H), 7.37
(t, J = 6.8 Hz, 1 H), 2.74 (s, 3 H) ppm. 13C NMR (101 MHz, CDCl
):
δ = 172.4 (Cq), 163.0 (Cq), 161.8 (Cq), 141.0 (Cq), 135.5 (Cq), 132.7
3
8
.8, 1.2 Hz, 1 H), 7.93–7.86 (m, 2 H), 7.50 (ddd, J = 8.8, J = 6.8 Hz,
3
J = 1.2 Hz, 1 H), 7.31 (td, J = 6.8, J = 1.2 Hz, 1 H), 7.18–7.07 (m, 2
1
3
2
H), 3.93 (s, 3 H), 2.74 (s, 3 H) ppm. C NMR (101 MHz, CDCl ): δ = (q, JC,F3 = 32.8 Hz, Cq), 130.0 (CHAr), 129.3 (2 × CHAr), 127.2 (CHAr),
3
3
1
1
72.2 (Cq), 163.2 (Cq), 162.0 (Cq), 135.9 (Cq), 130.6 (2 × CH ), 130.0 126.0 (q, JC,F3 = 3.8 Hz, 2 × CHAr), 121.1 (q, JC,F3 = 279 Hz, CF
3
),
) ppm. HRMS (ESI):
CH ), 101.6 (Cq), 55.6 (CH ), 14.6 (CH ) ppm. HRMS (ESI): calcd. for calcd. for C17H F N S [M + H] 361.0729; found 361.0733.
12 3 4
Ar
(
Cq), 129.9 (CH ), 126.7 (CH ), 119.4 (CH ), 117.8 (CH ), 114.4 (2 ×
119.1 (CHAr), 118.3 (CHAr), 101.6 (Cq), 14.6 (CH
3
Ar
Ar
Ar
Ar
+
Ar
3
3
+
C H N OS [M + H] 323.0961; found 323.0964.
7
1
15
4
2-(Methylthio)-4-(pyridin-3-yl)pyrido[1′,2′:1,5]pyrazolo[3,4-d]-
pyrimidine (23): With 3-pyridinylboronic acid as the coupling rea-
gent and by general procedure C, 23 was isolated as a yellow solid
in 35 % yield after purification by silica gel flash chromatography
4
-(3-Methoxyphenyl)-2-(methylthio)pyrido[1′,2′:1,5]pyraz-
olo[3,4-d]pyrimidine (19): With 3-methoxyphenylboronic acid as
the coupling reagent and by general procedure C, 19 was isolated
as a yellow solid in 83 % yield after purification by silica gel flash
chromatography (petroleum ether/EtOAc, 5:5), m.p. 226–227 °C. Rf
(
petroleum ether/EtOAc, 1:9), m.p. 252–253 °C. R (petroleum ether/
f
EtOAc, 3:7) = 0.01. IR (ATR diamond): ν˜ = 3073, 1631, 1431, 1352,
–
1 1
1
241, 1181, 1027, 836, 752 cm . H NMR (400 MHz, CDCl ): δ =
(
1
petroleum ether/EtOAc, 3:7) = 0.6. IR (ATR diamond): ν = 3002,
637, 1520, 1432, 1286, 1188, 1025, 872, 757 cm . H NMR
3
˜
–
1
1
9.17 (s, 1 H), 9.00–8.80 (m, 2 H), 8.26 (dt, J = 8.8, J = 1.2 Hz, 1 H),
7
1
1
.93 (d, J = 8.8 Hz, 1 H), 7.64–7.46 (m, 2 H), 7.37 (td, J = 6.8, 1.2 Hz,
(
400 MHz, CDCl ): δ = 8.82 (d, J = 6.8 Hz, 1 H), 7.59 (dd, J = 6.8, J =
3
H), 2.75 (s, 3 H) ppm. 13C NMR (101 MHz, CDCl ): δ = 172.4 (Cq),
1
7
3
1
1
1
.2 Hz, 1 H), 7.54 (td, J = 8.8, J = 1.2 Hz, 1 H),7.47–7.37 (m, 2 H),
3
62.9 (Cq), 160.3 (Cq), 151.7 (CH ), 149.4 (CH ), 136.4 (CH ), 135.4
.33–7.24 (m, 1 H), 7.16 (t, J = 7.4 Hz, 1 H), 7.10 (d, J = 8.8 Hz, 1 H),
Ar
Ar
Ar
1
3
(Cq), 133.5 (Cq), 130.0 (CH ), 127.2 (CH ), 123.9 (CH ), 119.0 (CH ),
.69 (s, CH ), 2.74 (s, CH ) ppm. C NMR (101 MHz, CDCl ): δ =
Ar Ar Ar Ar
3
3
3
1
18.2 (CHAr), 101.7 (Cq), 14.5 (CH ) ppm. HRMS (ESI): calcd. for
71.9 (Cq), 162.0 (Cq), 160.9 (Cq), 156.5 (Cq), 135.8 (Cq), 131.4 (CHAr),
30.5 (CHAr), 129.2 (CHAr), 126.4 (Cq), 126.1 (CHAr), 121.1 (CHAr),
3
+
C H N S [M + H] 394.0808; found 394.0807.
15 12
5
19.3 (CH ), 117.3 (CH ), 110.9 (CH ), 103.3 (Cq), 55.3 (CH ), 14.2
Ar
Ar
Ar
3
General Procedure D for C-2 Liebeskind–Srogl Cross-Coupling
Reaction: Compound 11 or 17 (70 mg, 1 equiv.), arylboronic acid
+
(CH ) ppm. HRMS (ESI): calcd. for C H N OS [M + H] 323.0961;
3 17 15 4
found 323.0959.
(1.5 equiv.), CuTC (3 equiv.), and Pd(PPh3)4 (10 mol-%) were dis-
solved in anhydrous THF (5 mL) under argon in a microwave vial.
The reaction was heated at 100 °C under microwave irradiation for
4
-(2-Methoxyphenyl)-2-(methylthio)pyrido[1′,2′:1,5]pyraz-
olo[3,4-d]pyrimidine (20): With 2-methoxyphenylboronic acid as
the coupling reagent and by general procedure C, 20 was isolated
as a yellow solid in 76 % yield after purification by silica gel flash
chromatography (petroleum ether/EtOAc, 5:5), m.p. 208–209 °C. Rf
90 min. After cooling, the solvent was evaporated under reduced
pressure, and the residue was diluted in aq. satd. NaHCO solution
3
(
10 mL). The aqueous layer was extracted with CH Cl (3 × 10 mL).
2 2
The combined organic layers were washed with water (5 mL), dried
(
1
petroleum ether/EtOAc, 3:7) = 0.5. IR (ATR diamond): ν˜ = 2920,
–
1
1
with anhydrous MgSO , filtered, and concentrated under reduced
633, 1526, 1434, 1264, 1183, 1038, 841, 763 cm
.
H NMR
4
pressure. The residue was purified by silica gel flash chromatogra-
phy to afford the desired compounds 24–34.
(400 MHz, CDCl ): δ = 8.85 (d, J = 6.8 Hz, 1 H) 7.99 (d, J = 8.8 Hz, 1
3
H), 7.56–7.40 (m, 4 H), 7.32 (t, J = 6.8 Hz, 1 H),7.21–7.05 (m, 1 H),
1
3
3
.90 (s, 3 H), 2.74 (s, 3 H) ppm. C NMR (101 MHz, CDCl ): δ = 172.3
4-[2-(4-Methoxyphenyl)pyrido(1′,2′:1,5)pyrazolo[3,4-d]pyr-
Cq), 163.5 (Cq),162.1 (Cq),160.2 (Cq), 138.9 (Cq),135.8 (Cq),130.0 imidin-4-yl]morpholine (24): From 11 with 4-methoxyphenyl-
boronic acid as the coupling reagent and by general procedure D,
CH ), 117.0 (CH ), 113.8 (CH ), 101.7 (Cq), 55.6 (CH ), 14.6 (CH ) 24 was isolated as a white solid in 69 % yield after purification by
ppm. HRMS (ESI): calcd. for C H N OS [M + H] 323.0961; found silica gel flash chromatography (petroleum ether/EtOAc, 4:6), m.p.
3
(
(
(
CH ), 129.9 (CH ), 126.8 (CH ), 121.1 (CH ), 119.5 (CH ), 118.0
Ar
Ar
Ar
Ar
Ar
Ar
Ar
Ar
3
3
+
1
7 15 4
3
23.0960.
206–208 °C. R (petroleum ether/EtOAc, 4:6) = 0.12. IR (ATR dia-
f
mond): ν˜ = 3002, 1606, 1531, 1440, 1411, 1246, 1156, 1102, 1021,
4
-(4-Fluorophenyl)-2-(methylthio)pyrido[1′,2′:1,5]pyrazolo-
–
1 1
9
6
43, 842, 796 cm . H NMR (400 MHz, CDCl ): δ = 8.83 (d, J =
3
[
3,4-d]pyrimidine (21): With 4-fluorophenylboronic acid as the
.8 Hz, 1 H), 8.60 (d, J = 8.0 Hz, 2 H), 7.75 (d, J = 8.8 Hz, 1 H), 7.55
coupling reagent and by general procedure C, 21 was isolated as a
yellow solid in 95 % yield after purification by silica gel flash chro-
matography (petroleum ether/EtOAc, 5:5), m.p. 248–249 °C. R (pe-
(
8
t, J = 8.8 Hz, 1 H), 7.23 (td, J = 6.8, J = 1.2 Hz, 1 H), 7.00 (d, J =
.0 Hz, 2 H), 4.02–3.81 (m, 8 H + 3 H) ppm. 13C NMR (101 MHz,
f
CDCl ): δ = 162.6 (Cq), 165.0 (Cq), 161.6 (Cq), 161.1 (Cq), 134.0 (Cq),
3
troleum ether/EtOAc, 3:7) = 0.57. IR (ATR diamond): ν˜ = 3081, 1632,
–
1
1
131.2 (Cq), 130.4 (2 × CHAr), 129.6 (CHAr), 125.7 (CHAr), 119.0
1
561, 1503, 1431, 1340, 1181, 1116, 869, 758 cm . H NMR
(
CH ),115.7 (CH ), 113.5 (2 × CH ), 93.4 (Cq), 66.7 (2 × CH ), 55.3
Ar Ar Ar 2
(
(
(
(
(
400 MHz, CDCl ): δ = 8.85 (dt, J = 6.8, J = 1.2 Hz, 1 H), 7.96–7.91
m, 3 H), 7.52 (ddd, J = 8.8, J = 6.8 Hz, J = 1.2 Hz, 1 H), 7.37–7.28
m, 3 H), 2.74 (s, 3 H) ppm. C NMR (101 MHz, CDCl ): δ = 172.3
Cq), 164.5 (d, J = 251.4 Hz, CF), 163.15 (Cq), 162.4 (Cq), 135.7
3
(
CH ), 48.4 (2 × CH ) ppm. HRMS (ESI): calcd. for C H N O [M +
3
2
20 20 5 2
+
1
3
H] 362.1612; found 362.1610.
3
1
4-[2-(3-Methoxyphenyl)pyrido(1′,2′:1,5)pyrazolo[3,4-d]pyrim-
idin-4-yl]morpholine (25): From 11 with 3-methoxyphenylboronic
C,F
4
3
Cq), 133.7 (d, JC,F = 3.2 Hz, Cq), 131.0 (d, J = 8.6 Hz, 2 × CH),
C,F
Eur. J. Org. Chem. 2016, 3550–3558
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© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
+
acid as the coupling reagent and by general procedure D, 25 was
isolated as a yellow solid in 42 % yield after purification by silica
gel flash chromatography (petroleum ether/EtOAc, 5:5), m.p. 195–
ppm. HRMS (ESI): calcd. for C H N O [M + H] 432.2030; found
24 26 5 3
432.2028.
-(4-Methoxyphenyl)-4-(p-tolyl)pyrido[1′,2′:1,5]pyrazolo-
3,4-d]pyrimidine (29): From 17 with 4-methoxyphenylboronic
acid as the coupling reagent and by general procedure D, 29 was
isolated as a white solid in 67 % yield after purification by silica gel
flash chromatography (petroleum ether/EtOAc, 4:6), m.p. 216–
17 °C. R (petroleum ether/EtOAc, 4:6) = 0.5. IR (ATR diamond): ν =
012, 1633, 1531, 1432, 1254, 1114, 1021, 804, 744 cm . H NMR
400 MHz, CDCl ): δ = 8.90 (d, J = 6.8 Hz, 1 H), 8.74 (d, J = 8.8 Hz,
H), 8.10 (d, J = 8.8 Hz, 1 H), 7.94 (d, J = 8.8 Hz, 2 H), 7.55–7.39 (m,
H), 7.38–7.26 (m, 1 H), 7.03 (d, J = 8.8 Hz, 2 H), 3.90 (s, 3 H), 2.52
s, 3 H) ppm. C NMR (101 MHz, CDCl ): δ = 164.45 (Cq), 163.9 (Cq),
62.4 (Cq), 141.6 (Cq), 136.4 (Cq), 136.1 (Cq), 131.8 (Cq), 131.3 (2 ×
CH), 130.2 (CH), 130.2 (2 × CH), 129.5 (2 × CH), 126.6 (CH), 120.3
(CH), 118.4 (CH), 114.3 (2 × CH), 103.3 (Cq), 91.0 (Cq), 56.0 (CH ),
O [M + H] 367.1553;
2
[
1
96 °C. R (petroleum ether/EtOAc, 4:6) = 0.15. IR (ATR diamond):
f
–
1
ν˜ = 2962, 1633, 1531, 1435, 1320, 1228, 1105, 1026, 882, 792 cm .
1
H NMR (400 MHz, CDCl ): δ = 8.84 (d, J = 6.8 Hz, 1 H), 8.28–8.21
3
(m, 2 H), 7.78 (d, J = 8.8 Hz, 1 H), 7.57 (t, J = 8.8 Hz, 1 H), 7.39 (t,
J = 6.8 Hz, 1 H), 7.27–7.22 (m, 1 H), 7.07–7.02 (m, 1 H), 3.96–3.91
2
3
f
˜
(
(
(
(
m, 11 H) ppm. 13C NMR (101 MHz, CDCl ): δ = 165.0 (Cq), 162.6
–1 1
3
Cq), 161.2 (Cq), 159.8 (Cq), 140.2 (Cq), 134.1 (Cq), 129.7 (CH ), 129.2
Ar
(
3
CH ), 126.0 (CH ), 121.5 (CH ), 119.3 (CH ), 117.0 (CH ), 116.1
Ar
Ar
Ar
Ar
Ar
2
3
(
CH ), 113.4 (CH ), 93.8 (Cq), 66.9 (2 × CH ), 55.5 (CH ), 48.6 (2 ×
Ar
Ar
2
3
+
CH ) ppm. HRMS (ESI): calcd. for C H N O [M + H] 362.1612;
13
2
20 20 5 2
3
found 362.1610.
1
4
-(4-Morpholinopyrido[1′,2′:1,5]pyrazolo[3,4-d]pyrimidin-2-yl)-
benzonitrile (26): From 11 with 4-cyanophenylboronic acid as the
coupling reagent and by general procedure D, 26 was isolated as a
yellow solid in 55 % yield after purification by silica gel flash chro-
3
+
22.2 (CH
) ppm. HRMS (ESI): calcd. for C23H N
19 4
3
found 367.1556.
matography (petroleum ether/EtOAc, 3:7), m.p. 281–282 °C. R (pe-
f
2-(3-Methoxyphenyl)-4-(p-tolyl)pyrido[1′,2′:1,5]pyrazolo[3,4-d]-
pyrimidine (30): From 17, with 3-methoxyphenylboronic acid as
the coupling reagent and by general procedure D, 30 was isolated
as a yellow solid in 42 % yield after purification by silica gel flash
chromatography (petroleum ether/EtOAc, 4:6), m.p. 218–219 °C. Rf
troleum ether/EtOAc, 4:6) = 0.17. IR (ATR diamond): ν˜ = 2851, 2224,
–
1
1
629, 1526, 1436, 1331, 1231, 1105, 1015, 946, 860, 794, 744 cm .
1
H NMR (400 MHz, CDCl ): δ = 8.87 (d, J = 6.8 Hz, 1 H), 8.73 (d, J =
3
8
(
.0 Hz, 2 H), 7.82 (d, J = 8.8 Hz, 1 H), 7.76 (d, J = 8.0 Hz, 2 H), 7.62
t, J = 8.8 Hz, 1 H), 7.31 (t, J = 6.8 Hz, 1 H), 3.96 (s, 8 H) ppm. 13
NMR (101 MHz, CDCl ): δ = 164.6 (Cq), 161.2 (Cq), 160.8 (Cq), 142.8
C
(
petroleum ether/EtOAc, 4:6) = 0.47. IR (ATR diamond): ν˜ = 2835,
–1 1
3
1635, 1534, 1434, 1356, 1045, 1264, 789, 722 cm . H NMR
(
Cq), 134.0 (Cq), 132.0 (2 × CHAr), 129.7 (CHAr), 129.1 (2 × CHAr),
(250 MHz, CDCl ): δ = 8.94 (d, J = 6.8 Hz, 1 H), 8.55–8.31 (m, 2 H),
3
1
26.2 (CH ), 119.4 (CH ), 119.0 (Cq), 116.3 (CH ), 113.4 (Cq), 93.9
Ar Ar Ar
8.15 (d, J = 8.8 Hz, 1 H), 7.97 (d, J = 8.8 Hz, 2 H), 7.63–7.31 (m, 5 H),
(
Cq), 66.7 (2 × CH ), 48.4 (2 × CH ) ppm. HRMS (ESI): calcd. for
13
2
+
2
7.06 (d, J = 8.8 Hz, 1 H), 3.95 (s, 3 H), 2.53 (s, 3 H) ppm. C NMR
C H N O [M + H] 357.1458; found 357.1457.
20
17
6
(63 MHz, CDCl ): δ = 163.9 (Cq), 163.5 (Cq), 163.3 (Cq), 159.8 (Cq),
3
1
41.1 (Cq), 139.9 (Cq), 135.6 (Cq), 135.4 (Cq), 129.6 (CH ), 129.6 (2 ×
4
-{2-[4-(Trifluoromethyl)phenyl]pyrido(1′,2′:1,5)pyrazolo[3,4-
Ar
CH ), 129.3 (CH ), 128.9 (2 × CH ), 126.1 (CH ), 121.7 (CH ), 119.8
d]pyrimidin-4-yl}morpholine (27): From 11 with 4-trifluorometh-
ylphenylboronic acid as the coupling reagent and by general proce-
dure D, 27 was isolated as a yellow solid in 59 % yield after purifica-
tion by silica gel flash chromatography (petroleum ether/EtOAc,
Ar
Ar
Ar
Ar
Ar
(CH ), 118.1 (CH ), 117.4 (CH ), 113.2 (CH ), 110.1 (Cq), 55.5 (CH ),
Ar Ar Ar Ar 3
+
2
1.6 (CH ) ppm. HRMS (ESI): calcd. for C H N O [M + H] 367.1553;
3 23 19 4
found 367.1553.
5
:5), m.p. 236–237 °C. R (petroleum ether/EtOAc, 4:6) = 0.25. IR (ATR 2-(2-Methoxyphenyl)-4-(p-tolyl)pyrido[1′,2′:1,5]pyrazolo[3,4-d]-
f
diamond): ν˜ = 2951, 1632, 1529, 1436, 1313, 1156, 1098, 1064, 944, pyrimidine (31): From 17 with 2-methoxyphenylboronic acid as
–1 1
7
44 cm . H NMR (400 MHz, [D ]DMSO): δ = 9.12 (d, J = 6.8 Hz, 1
the coupling reagent and by general procedure D, 31 was isolated
H), 8.68 (d, J = 8.8 Hz, 2 H), 8.03 (d, J = 8.8 Hz, 1 H), 7.88 (d, J = as a yellow solid in 31 % yield after purification by silica gel flash
6
8
3
1
.8 Hz, 2 H), 7.78 (t, J = 8.8 Hz, 1 H), 7.50 (t, J = 6.8 Hz, 1 H), 4.01–
chromatography (petroleum ether/EtOAc, 4:6), m.p. 175–176 °C. Rf
.79 (m, 8 H) ppm. 13C NMR (101 MHz, [D ]DMSO): δ = 163.8 (Cq), (petroleum ether/EtOAc, 4:6) = 0.1. IR (ATR diamond): ν = 2833,
6
˜
2
–1 1
60.4 (Cq),159.6 (Cq), 142.3 (Cq), 133.5 (Cq), 130.1 (q, JC-F3
=
1633, 1556, 1508, 1428, 1242, 1129, 1020, 812, 754, 633 cm . H
3
0.9 Hz, Cq), 129.8 (CH ), 128.7 (2 × CH ), 127.1 (CH ), 125.2 (q,
NMR (400 MHz, CDCl ): δ = 8.96 (d, J = 6.8 Hz, 1 H), 8.13 (d, J =
Ar
Ar
Ar
3
3
1
JC,F3 = 3.8 Hz, 2 × CH ), 124.2 (q, JC,F3 = 271.8 Hz, Cq), 120.0
8.8 Hz, 1 H), 7.96 (dd, J = 8.8, J = 1.2 Hz, 1 H), 7.91 (d, J = 7.7 Hz, 2
Ar
(CH ), 92.8 (Cq), 117.1 (CH ), 66.0 (2 × CH ), 47.8 (2 × CH ) ppm.
H), 7.55–7.48 (m, 1 H), 7.42 (t, J = 7.2 Hz, 3 H), 7.37 (td, J = 6.8, J =
Ar
Ar
2
2
+
13
HRMS (ESI): calcd. for C20H17F N O [M + H] 400.1380; found
4
1.2 Hz, 1 H), 7.12–7.04 (m, 2 H), 3.93 (s, 3 H), 2.50 (s, 3 H) ppm.
C
3
5
00.1378.
NMR (101 MHz, CDCl ): δ = 164.7 (Cq), 163.9 (Cq), 163.1 (Cq), 158.2
3
(
1
Cq), 141.1 (Cq), 135.5 (Cq), 135.4 (Cq), 132.3 (CH ), 130.8 (CH ),
Ar Ar
4
-(2-{4-[(Tetrahydro-2H-pyran-2-yl)oxy]phenyl}pyrido(1′,2′:1,5)-
29.9 (CH ), 129.7 (2 × CH ), 129.5 (Cq), 129.0 (2 × CH ), 126.2
Ar Ar Ar
pyrazolo[3,4-d]pyrimidin-4-yl)morpholine (28): From 11 with 4-
tetrahydro-2H-pyran-2-yloxy)phenylboronic acid as the coupling
(
(
[
CH ), 120.7 (CH ), 119.9 (CH ), 118.3 (CH ), 112.4 (CH ), 102.9
Cq), 56.3 (CH ), 21.7 (CH ) ppm. HRMS (ESI): calcd. for C H N O
Ar Ar Ar Ar Ar
(
3
3
23 19 4
reagent and by general procedure D, 28 was isolated as a white
solid in 41 % yield after purification by silica gel flash chromatogra-
+
M + H] 367.1553; found 367.1553.
phy (petroleum ether/EtOAc, 4:6), m.p. 152–153 °C. R (petroleum
4-(p-Tolyl)-2-[4-(trifluoromethyl)phenyl]pyrido[1′,2′:1,5]pyraz-
olo[3,4-d]pyrimidine (32): From 17, with 4-trifluoromethylphenyl-
boronic acid as the coupling reagent and by general procedure D,
32 was isolated as a yellow solid in 65 % yield after purification by
silica gel flash chromatography (petroleum ether/EtOAc, 5:5), m.p.
f
ether/EtOAc, 4:6) = 0.17. IR (ATR diamond): ν = 831, 947, 1238, 1437,
˜
–1 1
1
532, 2161, 2959 cm . H NMR (400 MHz, CDCl ): δ = 8.81 (d, J =
3
6
.8 Hz, 1 H), 8.57 (d, J = 8.0 Hz, 2 H), 7.73 (d, J = 8.8 Hz, 1 H), 7.53
(t, J = 8.8 Hz, 1 H), 7.21 (t, J = 6.8 Hz, 1 H), 7.13 (d, J = 8.0 Hz, 2 H),
5
1
.52 (t, J = 3.3 Hz, 1 H), 3.99–3.85 (m, 9 H), 3.69–3.56 (m, 1 H), 2.11–
179–180 °C. R (petroleum ether/EtOAc, 4:6) = 0.75. IR (ATR dia-
f
.96 (m, 1 H), 1.93–1.85 (m, 2 H), 1.78–1.56 (m, 3 H) ppm. 13C NMR mond): ν˜ = 3039, 1633, 1509, 1432, 1321, 1164, 1105, 1065, 1016,
–
1 1
(101 MHz, CDCl ): δ = 164.8 (Cq), 162.4 (Cq), 160.9 (Cq), 158.9 (Cq),
805, 695 cm . H NMR (400 MHz, CDCl ): δ = 8.97 (d, J = 6.8 Hz, 1
3
3
1
1
33.8 (Cq), 131.8 (Cq), 130.1 (2 × CH ), 129.3 (CH ), 125.5 (CH ),
H), 8.89 (d, J = 8.0 Hz, 2 H), 8.17 (d, J = 8.8 Hz, 1 H), 7.95 (d, J =
8.0 Hz, 2 H), 7.76 (d, J = 8.0 Hz, 2 H), 7.54 (t, J = 8.8 Hz, 1 H), 7.47
Ar
Ar
Ar
18.8 (CH ), 115.7 (2 × CH ), 115.5 (CH ), 96.0 (CH), 93.2 (Cq), 66.5
Ar
Ar
Ar
1
3
(2 × CH ), 61.8 (CH ), 48.2 (2 × CH ), 30.1 (CH ), 25.0 (CH ), 18.5 (CH ) (d, J = 8.0 Hz, 2 H), 7.39 (t, J = 6.8 Hz, 1 H), 2.53 (s, 3 H) ppm.
C
2
2
2
2
2
2
Eur. J. Org. Chem. 2016, 3550–3558
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© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

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NMR (101 MHz, CDCl ): δ = 164.3 (Cq), 163.4 (Cq), 162.2 (Cq), 141.9
2005, 7, 4753–4756; b) M. Cheung, P. A. Harris, J. G. Badiang, G. E. Peck-
ham, S. D. Chamberlain, M. J. Alberti, D. K. Jung, S. S. Harris, N. H. Bram-
son, A. H. Epperly, S. A. Stimpson, M. R. Peel, Bioorg. Med. Chem. Lett.
2008, 18, 5428–5430.
4] T. Koike, T. Takai, Y. Hoashi, M. Nakayama, Y. Kosugi, M. Nakashima, S.-i.
Yoshikubo, K. Hirai, O. Uchikawa, J. Med. Chem. 2011, 54, 4207–4218.
5] H. Tamta, S. Kalra, A. K. Mukhopadhyay, Biochemistry (Mosc.) 2006, 71,
S49–54.
6] A. Kulkarni, P. Quang, V. Curry, R. Keyes, W. Zhou, H. Cho, J. Baffoe, B.
Török, K. Stieglitz, Chem. Biol. Drug Des. 2014, 84, 270–281.
7] A. H. Abdelazeem, S. A. Abdelatef, M. T. El-Saadi, H. A. Omar, S. I. Khan,
C. R. McCurdy, S. M. El-Moghay, Eur. J. Pharm. Sci. 2014, 62, 197–211.
8] a) P. Dinér, J. P. Alao, J. Söderlund, P. Sunnerhagen, M. Grøtli, J. Med.
Chem. 2012, 55, 4872–4876; b) J. Y. Le Brazidec, A. Pasis, B. Tam, C. Boy-
kin, C. Black, D. Wang, G. Claassen, J. H. Chong, J. Chao, J. Fan, K. Nguyen,
L. Silvian, L. Ling, L. Zhang, M. Choi, M. Teng, N. Pathan, S. Zhao, T. Li, A.
Taveras, Bioorg. Med. Chem. Lett. 2012, 22, 2070–2074; c) J. Kaplan, J. C.
Verheijen, N. Brooijmans, L. Toral-Barza, I. Hollander, K. Yu, A. Zask, Bioorg.
Med. Chem. Lett. 2010, 20, 640–643.
3
2
(Cq), 141.5 (Cq), 140.2 (Cq), 135.5 (Cq), 132.1 (q, JC,F3 = 32.0 Hz, Cq),
1
1
2
29.9 (CH ), 129.8 (2 × CH ), 129.4 (2 × CH ), 129.0 (2 × CH ),
Ar Ar Ar Ar
3
1
26.5 (CH ), 125.3 (q, J
= 4.0 Hz, 2 × CH ), 124.4 (q, J
=
Ar
C,F3
Ar
C,F3
[
[
[
[
[
73.0 Hz, Cq), 120.1 (CH ), 118.6 (CH ), 103.8 (Cq), 21.7 (CH ) ppm.
Ar
Ar
3
HRMS (ESI): calcd. for C23H16F3N4 [M + H]+ 405.1322; found
4
05.1320.
4
-[4-(p-Tolyl)pyrido(1′,2′:1,5)pyrazolo[3,4-d]pyrimidin-2-yl]-
benzonitrile (33): From 17 with 4-cyanophenylboronic acid as the
coupling reagent and by general procedure D, 33 was isolated as a
yellow solid in 64 % yield after purification by silica gel flash chro-
matography (petroleum ether/EtOAc, 4:6), m.p. 263–264 °C. R (pe-
f
troleum ether/EtOAc, 4:6) = 0.55. IR (ATR diamond): ν˜ = 2921, 2221,
–
1 1
1
634, 1557, 1509, 1433, 1266, 1117, 978, 801, 752 cm . H NMR
(
400 MHz, CDCl ): δ = 8.97 (d, J = 6.8 Hz, 1 H), 8.89 (d, J = 8.0 Hz,
3
2
8
H), 8.19 (d, J = 8.8 Hz, 1 H), 7.95 (d, J = 8.0 Hz, 2 H), 7.80 (d, J =
.0 Hz, 2 H), 7.57 (t, J = 8.8 Hz, 1 H), 7.48 (d, J = 8.0 Hz, 2 H), 7.42
1
3
[9] R. Belaroussi, A. El Bouakher, M. Marchivie, S. Massip, C. Jarry, A. El Hak-
(t, J = 6.8 Hz, 1 H), 2.54 (s, 3 H) ppm. C NMR (101 MHz, CDCl3):
maoui, G. Guillaumet, S. Routier, M. Akssira, Synthesis 2013, 45, 2557–
δ = 164.3 (Cq), 163.3 (CN), 161.5 (Cq), 142.7 (Cq), 141.6 (Cq), 135.6
2
566.
(
Cq), 135.2 (Cq), 132.2 (2 × CH), 129.9 (CH ), 129.8 (2 × CH ), 129.5
Ar Ar
[10] a) O. Dehbi, A. Tikad, S. Bourg, P. Bonnet, O. Lozach, L. Meijer, M. Aadil,
M. Akssira, G. Guillaumet, S. Routier, Eur. J. Med. Chem. 2014, 80, 352–
363; b) A. Tikad, O. Dehbi, M. Akssira, M. Aadil, S. Massip, J. M. Leger, C.
Jarry, G. Guillaumet, S. Routier, Synthesis 2013, 45, 491–500; c) A. Tikad,
M. Akssira, S. Massip, J. M. Leger, C. Jarry, G. Guillaumet, S. Routier, Eur.
J. Org. Chem. 2012, 4523–4532; d) A. Tikad, S. Routier, M. Akssira, G.
Guillaumet, Org. Biomol. Chem. 2009, 7, 5113–5118; e) A. Tikad, S. Rou-
tier, M. Akssira, J. M. Leger, C. Jarry, G. Guillaumet, Synthesis 2009, 2379–
2284; f) A. Tikad, S. Routier, M. Akssira, J. M. Leger, C. Jarry, G. Guillaumet,
Org. Lett. 2007, 9, 4673–4676; g) A. Tikad, S. Routier, M. Akssira, J. M.
Leger, C. Jarry, G. Guillaumet, Synlett 2006, 1938–1942.
[11] a) M. Redondo, J. G. Zarruk, P. Ceballos, D. I. Pérez, C. Pérez, A. Perez-
Castillo, M. A. Moro, J. Brea, C. Val, M. I. Cadavid, M. I. Loza, N. E. Campillo,
A. Martínez, C. Gil, Eur. J. Med. Chem. 2012, 47, 175–185; b) A. Castro,
M. J. Jerez, C. Gil, F. Calderon, T. Domenech, A. Nueda, A. Martinez, Eur.
J. Med. Chem. 2008, 43, 1349–1359; c) Z. Li, H. Huang, H. Sun, H. Jiang,
H. Liu, J. Comb. Chem. 2008, 10, 484–486.
(
2 × CH ), 128.9 (2 × CH ), 126.7 (CH ), 120.1 (CH ), 119.1 (Cq),
Ar Ar Ar Ar
1
18.8 (CHAr),113.7 (Cq), 103.7 (Cq), 21.7 (CH ) ppm. HRMS (ESI):
3
+
calcd. for C H N [M + H] 362.1400; found 362.1399.
23 16 5
2
-(Pyridin-3-yl)-4-(p-tolyl)pyrido[1′,2′:1,5]pyrazolo[3,4-d]pyr-
imidine (34): From 17 with 3-pyridinylboronic acid as the coupling
reagent and by general procedure D, 34 was isolated as a yellow
solid in 44 % yield after purification by silica gel flash chromatogra-
phy (petroleum ether/EtOAc, 4:6), m.p. 238–239 °C. R (petroleum
f
ether/EtOAc, 4:6) = 0.05. IR (ATR diamond): ν˜ = 2919, 1634, 1533,
–
1
1
1
434, 1357, 1273, 1128, 1023, 834, 801, 714 cm . H NMR (400 MHz,
CDCl ): δ = 9.96 (s, 1 H), 9.02 (d, J = 8.8 Hz, 1 H), 8.96 (d, J = 6.8 Hz,
3
1
7
2
H), 8.74 (s, 1 H), 8.18 (d, J = 8.8 Hz, 1 H), 7.97 (d, J = 8.0 Hz, 2 H),
.56 (t, J = 8.8 Hz, 1 H), 7.52–7.42 (m, 3 H), 7.40 (t, J = 6.8 Hz, 1 H),
.54 (s, 3 H) ppm. 1 C NMR (101 MHz, CDCl ): δ = 164.4 (Cq), 163.4
3
3
(
Cq), 161.8 (Cq), 151.2 (CH ), 150.8 (CH ), 142.6 (Cq), 141.5 (Cq),
Ar Ar
[12] D. R. Guda, T. Wang, H. M. Cho, M. E. Lee, Tetrahedron Lett. 2012, 53,
5238–5242.
1
36.4 (Cq), 135.6 (Cq), 135.4 (CH ), 129.9 (CH ), 129.8 (2 × CH ),
Ar Ar Ar
1
29.0 (2 × CH ), 126.6 (CH ), 123.4 (CH ), 120.1 (CH ), 118.6
[13] A. Santagati, J. Longmore, S. Guccione, T. Langer, E. Tonnel, M. Modica,
M. Santagati, L. M. Scolaro, F. Russo, Eur. J. Med. Chem. 1997, 32, 973–
985.
Ar
Ar
Ar
Ar
(CH ), 103.6 (Cq), 21.7 (CH ) ppm. HRMS (ESI): calcd. for C H N
Ar 3 21 16 5
+
[
M + H] 338.1400; found 338.1400.
[
14] a) S.-M. Li, J. Huang, G.-J. Chen, F.-S. Han, Chem. Commun. 2011, 47,
2840–12842; b) F.-A. Kang, Z. Sui, W. V. Murray, J. Am. Chem. Soc. 2008,
Supporting Information (see footnote on the first page of this
article): H, C, and C DEPT NMR spectra for all compounds.
1
1
13
13
130, 11300–11302; c) C. Shi, C. C. Aldrich, Org. Lett. 2010, 12, 2286–2289;
d) V. P. Mehta, S. G. Modha, E. V. Van der Eycken, J. Org. Chem. 2010, 75,
9
76–979; e) A. Sharma, D. Vachhani, E. Van der Eycken, Org. Lett. 2012,
Acknowledgments
14, 1854–1857.
[
15] a) F.-A. Kang, Z. Sui, W. V. Murray, Eur. J. Org. Chem. 2009, 461–479; b) J.
Coste, E. Frerot, P. Jouin, J. Org. Chem. 1994, 59, 2437–2446; c) E. Frérot,
J. Coste, A. Pantaloni, M.-N. Dufour, P. Jouin, Tetrahedron 1991, 47, 259–
The authors acknowledge the Office Mediterranéen de la Jeu-
nesse (OMJ) for financial support to R. B.
2
70; G.-J. Chen, J. Huang, L.-X. Gao, F.-S. Han, Chem. Eur. J. 2011, 17,
4
038–4042.
Keywords: Synthesis design · Cross-coupling · Nucleophilic
substitution · Nitrogen heterocycles · Palladium
[
16] F.-A. Kang, J. Kodah, Q. Guan, X. Li, W. V. Murray, J. Org. Chem. 2005, 70,
1957–1960.
[
17] a) Q. Sun, F. Suzenet, G. Guillaumet, J. Org. Chem. 2010, 75, 3473–3476;
b) M. Egi, L. S. Liebeskind, Org. Lett. 2003, 5, 801–802; c) F. A. Alphonse,
F. Suzenet, A. Keromnes, B. Lebret, G. Guillaumet, Synlett 2002, 447–450;
d) F. A. Alphonse, F. Suzenet, A. Keromnes, B. Lebret, G. Guillaumet, Org.
Lett. 2003, 5, 803–805; e) L. S. Liebeskind, J. Srogl, Org. Lett. 2002, 4,
979–981; f) H. Prokopcov, O. Kappe, Angew. Chem. Int. Ed. 2009, 48,
2276–2286; Angew. Chem. 2009, 121, 2312.
[
[
[
1] A. Akahane, H. Katayama, T. Mitsunaga, T. Kato, T. Kinoshita, Y. Kita, T.
Kusunoki, T. Terai, K. Yoshida, Y. Shiokawa, J. Med. Chem. 1999, 42, 779–
783.
2] B. A. Johns, K. S. Gudmundsson, E. M. Turner, S. H. Allen, V. A. Samano,
J. A. Ray, G. A. Freeman, F. L. Boyd Jr., C. J. Sexton, D. W. Selleseth, K. L.
Creech, K. R. Moniri, Bioorg. Med. Chem. 2005, 13, 2397–2411.
3] a) K. L. Stevens, D. K. Jung, M. J. Alberti, J. G. Badiang, G. E. Peckham,
J. M. Veal, M. Cheung, P. A. Harris, S. D. Chamberlain, M. R. Peel, Org. Lett.
Received: March 22, 2016
Published Online: July 4, 2016
Eur. J. Org. Chem. 2016, 3550–3558
www.eurjoc.org
3558
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim