Regioselective Synthesis of New 2,4-(Het)aryl-3H-pyrido[1′,2′:1,5]pyrazolo[4,3-d]pyrimidines Involving Palladium-Catalyzed Cross-Coupling Reactions

Article abstract of DOI:10.3390/molecules23112740

The design of some novel di-(het)arylated-3H-pyrido[1′,2′:1,5]pyrazolo[4,3-d]pyrimidine derivatives is reported. The series was developed from 1-aminopyridinium iodide, which afforded the key intermediate bearing two thiomethyl and amide functions, each of them useful for palladium catalyzed cross coupling reactions by alkyl sulfur release and C-O activation, respectively. The two regioselective and successive cross-coupling reactions were first carried out in C-4 by in situ C-O activation and next in C-2 by a methylsulfur release. Process optimization furnished conditions leading to products in high yields. The scope and limitations of the methodologies were evaluated and the final compounds characterized.

Full text of DOI:10.3390/molecules23112740

molecules
Article
Regioselective Synthesis of New 2,4-(Het)aryl-3H-
0
0
pyrido[1 ,2 :1,5]pyrazolo[4,3-d]pyrimidines Involving
Palladium-Catalyzed Cross-Coupling Reactions
Abdelaziz Ejjoummany 1 , Rabia Belaroussi , Ahmed El Hakmaoui , Mohamed Akssira *,
,2
1,2
2
2,
1
1
1,
Gérald Guillaumet , Frédéric Buron
and Sylvain Routier *
1
Institut de Chimie Organique et Analytique, Univ Orleans, UMR CNRS 7311, BP 6759,
F-45067 Orléans CEDEX 2, France; abdelaziz.ejjoummany@univ-orleans.fr (A.E.);
rabia_belaroussi@hotmail.com (R.B.); gerald.guillaumet@univ-orleans.fr (G.G.);
frederic.buron@univ-orleans.fr (F.B.)
2
Laboratoire de Chimie Physique et Chimie Bioorganique, Université Hassan II-Casablanca, B. P. 146,
2
8800 Mohammedia, Morocco; a_elhakmaoui@yahoo.fr
*
Correspondence: ahelhakmaoui@gmail.com (M.A.); sylvain.routier@univ-orleans.fr (S.R.);
Tel.: +212-523-314-705 (M.A.); +33-238-494-853 (S.R.)
ꢀ
ꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀ
ꢁꢂꢃꢄꢅꢆ
Received: 28 September 2018; Accepted: 20 October 2018; Published: 23 October 2018
0
0
Abstract: The design of some novel di-(het)arylated-3H-pyrido[1 ,2 :1,5]pyrazolo[4,3-d]pyrimidine
derivatives is reported. The series was developed from 1-aminopyridinium iodide, which afforded
the key intermediate bearing two thiomethyl and amide functions, each of them useful for palladium
catalyzed cross coupling reactions by alkyl sulfur release and C-O activation, respectively. The two
regioselective and successive cross-coupling reactions were first carried out in C-4 by in situ C-O
activation and next in C-2 by a methylsulfur release. Process optimization furnished conditions
leading to products in high yields. The scope and limitations of the methodologies were evaluated
and the final compounds characterized.
Keywords: pyridopyrazolopyrimidine; pyBroP activation; palladium cross-coupling
1
. Introduction
The exploration of chemical space is a key prior step in the discovery of biologically active
molecules. This strategy in heterocyclic chemistry includes the design and the functionalization of
polynitrogen structures which are chosen for their similarity with major biomarkers and may contain
scaffolds such as indoles, imidazoles, pyrimidine or imidazopyrimidine as well as tricyclic folate
cores [
skeletons have received considerable attention due to the synthetic challenge that they represent [
In this area, tricyclic fused heteroaromatic derivatives with a bridgehead nitrogen have less often been
examined [ ]. There is therefore a need to provide synthetic methods for their functionalization
1–
3]. In view of their potential for the design of bioactive molecules, a variety of polynitrogenated
4].
5,6
through reproducible and versatile strategies.
For several years, our group has been developing efficient methodologies to selectively
functionalize heterocycles such as azaindoles [7–9], pyridopyrimidines [10–16], and more recently,
0
0
tricyclic heterocycles containing a bridgehead nitrogen, such as pyrido[1 ,2 :1,5]pyrazolo[3,4-d]
pyrimidines or pyridazines [17–21].
Apart from the more classical pyrimidine ring, the currently most promising scaffold appears
to be one containing a pyrazolopyridine, which has been used in diverse biologically and
pharmaceutically active molecules including anticancer drugs [22], diuretic [23] and antiherpetic [24
]
drugs, and p38 kinase inhibitors [25]. With a view to increasing molecular diversity, tricyclic
Molecules 2018, 23, 2740; doi:10.3390/molecules23102740
www.mdpi.com/journal/molecules

Molecules 2018, 23, 2740
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0
0
pyrido[1 ,2 :1,5]pyrazolo[3,4-d]pyrimidines have emerged to provide high potential bioactive
0 0
compounds (type I) [24]. Surprisingly, one isomer, the pyrido[1 ,2 :1,5]pyrazolo[4,3-d]pyrimidine
core, has seldom been described, and is reported in only three references, despite its significant
growth potential as therapeutics for the central nervous system (type II, Figure 1) [26] or
male erectile dysfunction treatment (type III) [27]. In order to design polyfunctionalized
0
0
pyrido[1 ,2 :1,5]pyrazolo[4,3-d]pyrimidines, we decided to explore its multiple substitution, an
indispensable step to design future original bioactive molecules.
0 0
Some representative pyrido[1 ,2 :1,5]pyrazolo[3,4-d]pyrimidine derivatives I and
pyrido[1 ,2 :1,5]pyrazolo[4,3-d]pyrimidine II, III.
Figure 1.
0
0
0
0
In order to build C-2 and C-4 disubstituted pyrido[1 ,2 :1,5]pyrazolo[4,3-d]pyrimidine derivatives,
we developed a straightforward strategy which included from a versatile pattern , a C-4
Suzuki-Miyaura cross coupling reaction using an in situ C-O activation [28 29] followed by a C-2
Liebeskind-Srogl cross-coupling reaction [20 30 33]. We report herein the preparation of and its
9
,
,
–
9
regioselective functionalization, the optimization of the experimental conditions and finally the scope
of both reactions on these two identified positions (Figure 2).
Figure 2. Bis(het)arylation of 9 leading to targeted structure IV.
2
. Results and Discussion
To design the platform
9
, we modified the available access (Scheme 1). Starting from the
), the 1,3-dipolar condensations of dimethyl
in 78% yield (versus 29% in the literature [34]) and after
was generated in a quantitative manner (64% in the literature). We next
replaced the reported 4-step synthesis (decarboxylation, methylation, nitration, reduction) [27 34] by a
commercially available 1-aminopyridinium iodide (
acetylenedicarboxylate (DMAD) led to diester
saponification, the di-acid
1
2
3
,
shorter 3-step sequence. The discrimination of carboxylic acid functions was performed using an in situ
anhydride formation followed by its regioselective opening with methanol to give the mono-methyl
ester
acid function to produce, after cleavage of the Boc protective group, the hetaryl amine
condensation of benzoyl isothiocyanate with followed by cyclization furnished in basic media
which was converted to the thiomethyl derivative 9 in satisfactory yield.
In order to tackle the usefulness of as a building block and taking advantage of the presence
4
[
11]. This synthetic strategy allowed us to achieve a Curtius rearrangement on the residual
6. Finally, the
6
8
9
of the amide group, we began by the regioselective functionalization of the C-4 position using a C-O
direct activation involving PyBroP and Et N to generate the required in situ generated O-phosphonium
3

Molecules 2018, 23, 2740
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leaving group [35
catalyst source.
,36]. The second step required the addition of boronic acid, base, water and
Scheme 1. Synthetic pathway to generate 9.
We used conditions exploited in our previous research, which involved Na CO3 and
2
PdCl (dppf).CH Cl under thermal conditions. Under these conditions which have proved to be
2
2
2
useful in diverse heterocyclic series, the reaction was successfully achieved with para-tolylboronic acid
to afford 10 in a good 85% yield (Table 1, entry 1).
To evaluate the effect of boronic acid substituents, we first studied the reaction using other
electron-donating groups such as methoxy in ortho, meta or para positions (entries 2–4). In para position,
no alteration in the reaction efficiency was observed and compound 11 was isolated in 87% yield
(
entry 2). In contrast, the ortho orientation of the OMe group induced steric hindrance and consequently,
a dramatic decrease in yield was observed. An intermediate yield was obtained with the meta-oriented
methyl ester boronic acid (entries 3, 4) as the meta-methoxy group induces an inductive withdrawing
effect. With an electron-withdrawing substituent on the phenylboronic acid, efficiency depends on
the nature and strength of the electronic effects. With a moderate inductive effect, reactivity was
maintained and 14 was isolated in a 90% yield. In the presence of strong electron- withdrawing
substituents such as CF or CN the yields decreased to 70% and 58%, respectively (entries 6, 7).
3
The same behaviour was observed with heteroaryl boronic acids. Electron-rich heterocycles such as
2
-furan were introduced in good yield (74%, entry 9) whereas no reaction occurred with π-deficient
heterocycles such as 4-pyridylboronic acid (entry 10). Finally, we investigated the interference of the
OH group in basic media, which led to a moderate yield compared to its methyl ether equivalent
(
entry 8 vs. 2). In conclusion, the method is suitable with a wide variety of boronic acids, and limits
concern only strongly deactivated (het)aryl boronic acids.
We next investigated the reactivity of the C-2 position. Methyl sulfur release was achieved
using a Liebeskind-Srogl reaction which furnished the desired original 2,4-disubstituted compounds.
The reactivity of the thioether 10 was explored using various (het)aryl boronic acids in the presence of
◦
Pd(PPh ) and copper(I) thiophene-2-carboxylate (CuTc) in THF at 100 C under microwave irradiation
3
4
(
Table 2). As observed during the first cross coupling procedure, the use of electron-rich phenyl boronic
acids was well tolerated and furnished the 4-tolyl- or 4-methoxyphenyl-substituted derivatives 20 and
in excellent yields (entries 1–2). The compartmental similarity between the two reactions is even
2
1
clearer in the following results.
Firstly, the OMe position switch to the 2- or 3-methoxyphenyl boronic acids afforded the desired
products in moderate yields (entries 3 and 4). Secondly, the presence of a strong electron-withdrawing

Molecules 2018, 23, 2740
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CF group on the phenylboronic acid lowered the efficiency of the reaction. Nevertheless, the CF vs. F
3
3
atom exchange fortunately restored the reactivity and led to 24 in a satisfactory 85% yield (entry 6 vs. 5
)
indicating that decreasing the electron-withdrawing character had a major impact on the reaction
rate. This result was confirmed with (het)aryl boronic acids as electron-rich aromatics such as furan
provided the desired product 27 in good yield whereas attempts with 4-pyridineboronic acid totally
failed (entries 8,9).
Table 1. Scope of (het)arylation of 9 under C-O amide activation.
Entry
Product
Yield a Entry
Product
Yield a
1
10
11
85
87
6
7
15
16
70
2
58
3
4
5
12
13
14
67
20
90
8
9
17
18
19
45
74
10
traces
a
Yield is indicated as isolated compound.
To assess whether the nature of the C-4 residue really interferes with the C-2 reactivity, we varied
the nature of 4-arylated tricyclic derivatives and fixed p-tolylboronic acid as sole arylation partner.
0
0
When the pyrido[1 ,2 :1,5]pyrazolo[4,3-d]pyrimidine derivative was substituted by a singly enriched
-MeO-phenyl group at the C-4 position, the reaction gave derivative 29 in very good yield (entry 10),
4
higher than that observed with 10 (entry 1). The inversion of the electronic effect in C-4 reduced the
reactivity of the tricyclic system (entry 11) as was confirmed with the assay conducted starting from 14
that led to 30 in only 53% yield. In conclusion, the C-2 (het)arylation followed the same behavior as
the C-4 cross coupling reaction with an additional favorable parameter i.e., the presence of electron
rich (het)aryl moieties in C-4.

Molecules 2018, 23, 2740
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Table 2. Scope of the desulfurative cross coupling reaction in C-2.
SMe
(Het)Ar
1
3
.5 equiv. (Het)ArB(OH)2
.0 equiv. CuTC
N
N
N
N
1
0 mol% Pd(PPh3)4
N
N
N
THF, 100 °C, 1h30, M.W
N
10
20-28
Entry
Product
Yield a Entry
Product
Yield a
1
20
78
7
26
40
2
3
4
21
22
23
75
48
25
8
9
27
28
29
60
ND
86
10
5
6
24
25
85
60
11
30
53
a
Yield is indicated as isolated compound. ND: Not Detected.

Molecules 2018, 23, 2740
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3
. Materials and Methods
3
.1. General Methods
Reactions were monitored by thin-layer chromatography (TLC) 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 recorded with a Nicolet iS10
×
1
13
instrument (Thermo Scientific, Waltham, MA, USA). The H- and C-NMR spectra were recorded with
1
3
13
13
DPX 250 ( C, 62 MHz), Avance II 250 ( C, 63 MHz), Avance 400 ( C, 101 MHz), or Avance III HD
13
Nanobay 400 ( C, 101 MHz) spectrometers (Bruker, Billerica, MA, USA). The chemical shifts are given
in ppm from tetramethylsilane as an internal standard. The coupling constants (J) are reported in Hz.
High-resolution mass spectra (HRMS) were recorded with a Bruker Maxis 4G instrument Microwave
irradiation was carried out in sealed vessels placed in a Initiator or Initiator + system (400 W maximum
power, Biotage, Uppsala, Sweden). The temperatures were measured externally by IR. Pressure was
measured by a noninvasive sensor integrated in the cavity lid.
3
.2. Procedure to Synthesize Compounds 2–18, 20–27 and 29, 30
Dimethyl pyrazolo[1,5-a]pyridine-2,3-dicarboxylate ( ) [34]: In a 100 mL flask, K CO (0.87 g, 6.3 mmol,
2
2
3
1.4 equiv.) and DMAD (0.96 g, 6.8 mmol, 1.5 equiv.) were added to a solution of 1-aminopyridinium
iodide (1, 1.0 g, 4.5 mmol) in anhydrous DMF (10 mL). The mixture was stirred at r.t. for 18 h.
The solvent was evaporated in vacuo, then, the residue was purified by flash chromatography
◦
(
(
9
EtOAc/petroleum ether, 2/8) to give
2
as yellow solid (744 mg, 76%). M.p. 64–66 C; R = 0.3
f
−
1
EtOAc/petroleum ether, 3/7); IR (ATR diamond, cm ): 3111, 1730, 1685, 1484, 1364, 1213, 1079,
= 8.50 (d, J = 7.0 Hz, 1H), 8.15 (d, J = 7.5 Hz, 1H), 7.45
t, J = 7.0 Hz, 1H), 7.02 (t, J = 7.5 Hz, 1H), 4.01 (s, 3H), 3.91 (s, 3H); 13C-NMR (101 MHz, CDCl3):
1
95, 814; H-NMR (400 MHz, CDCl ):
δ
3
(
δ
= 163.2 (CO), 162.6 (CO), 147.3 (Cq), 141.4 (Cq), 129.2 (CH), 127.9 (CH), 119.9 (CH), 115.2 (CH),
1
13
102.7 (Cq), 53.0 (OCH ), 51.7 (OCH ) ( H-NMR and C-NMR of compounds
2–1
8, 20–27, 29, 30
3
3
+
are in Supplementary Materials); HRMS (ESI): m/z [M + H] calcd for C H N O : 235.0713;
11
11
2
4
found: 235.0716.
Pyrazolo[1,5-a]pyridine-2-dicarboxylic acid (3) [34]: To a mixture of 2 (1.0 g, 4.3 mmol) in methanol
(25 mL) was added a solution of NaOH 2 M in water (5.0 equiv.) and the mixture was refluxed
for 1 h. The solvent was evaporated and the obtained residue was neutralized with an aqueous
solution of 12 N HCl. After filtration, the precipitate obtained was washed with water (50 mL), and
◦
dried, to give
3
as a white solid (880 mg, quantitative). M.p. 216–218 C; R =0.1 (EtOAc/petroleum
f
−
1
1
ether, 9/1); IR (ATR diamond, cm ): 3475, 3341, 1697, 1506, 782; H-NMR (400 MHz, DMSO-d ):
6
δ
= 8.89 (d, J = 7.0 Hz, 1H), 8.17 (d, J = 7.0 Hz, 1H), 7.64 (t, J = 7.0 Hz, 1H). 7.26 (t, J = 7.0 Hz,
13
1H). C-NMR (101 MHz, DMSO-d6):
δ
= 164.7 (CO), 164.6 (CO), 148.2 (Cq), 141.5 (Cq), 130.4 (CH),
+
129.4 (CH), 119.7 (CH), 116.2 (CH), 102.5 (Cq); HRMS: m/z [M + H] calcd for C H N O : 207.0400,
9
7
2
4
found: 207.0400.
2
-Methoxycarbonylpyrazolo[1,5-a]pyridine-3-carboxylic acid (4): To a solution of 3 (0.5 g, 2.43 mmol) in
DMSO/MeOH (1/1, 10 mL) was gradually added a SOCl solution (0.193 mL, 2.67 mmol, 1.1 equiv.)
2
in methanol (10 mL) and the mixture was stirred at reflux for 72 h. The volatiles were evaporated and
1
5 mL of water were added. The resulting precipitate was filtered, then washed with water (3 × 25 mL
)
◦
and dried to give
9
4
as a white solid (0.41 g, 77%). M.p. 214–216 C; R =0.3 (EtOAc/petroleum ether,
f
−
1
1
/1); IR (ATR diamond, cm ): 3012, 2744, 1730, 1440, 771; H-NMR (400 MHz, DMSO-d ):
δ
= 8.86
6
(
3
1
d, J = 7.0 Hz, 1H), 8.10 (d, J = 7.0 Hz, 1H), 7.64 (t, J = 7.0 Hz, 1H), 7.24 (t, J = 7.0 Hz, 1H), 3.90 (s,
13
H); C-NMR (101 MHz, DMSO-d6):
δ
= 164.2 (CO), 163.3 (CO), 147.9 (Cq), 140.8 (Cq), 130.3 (CH),
+
29.4 (CH), 119.3 (CH), 116.1 (CH), 102.4 (Cq), 53.3 (OCH ); HRMS: m/z [M + H] calcd for C H N O :
3
10
9
2
4
2
21.0553, found: 221.0556.

Molecules 2018, 23, 2740
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Methyl 3-(tert-butoxycarbonylamino)pyrazolo[1,5-a]pyridine-2-carboxylate (
5
): To a mixture of
4
(1.0 g,
◦
4
.5 mmol) in THF (15 mL) at
−
10 C, was added triethylamine (597 mg, 0.82 mL, 5.9 mmol, 1.3 equiv.)
and the mixture was stirred for 5 min. Ethyl chloroformate (739 mg, 6.8 mmol, 1.5 equiv.) was then
added and the mixture was stirred for 1.5 h at
◦
−
10 C. A solution of NaN (0.501 g, 7.7 mmol, 1.7 equiv.)
3
in water (2 mL) was added and the reaction mixture was stirred for 1.5 h at r.t. After filtration and
evaporation, (15 mL) of water was added, and then the mixture was extracted with ethyl acetate
(
3 × 20 mL). After evaporation of the solvent, tert-butanol (20 mL) was added and the mixture was
refluxed for 6 h. The reaction mixture was concentrated under reduced pressure. The product was
purified by column flash chromatography (EtOAc/petroleum ether, 3/7); to give
5
as a white solid
◦
−1
(
3
0.85 g, 65%). M.p. 183–185 C; R = 0.5 (EtOAc/petroleum ether, 4/6); IR (ATR diamond, cm ): 3412,
f
1
090, 2975, 1542, 782; H-NMR (400 MHz, CDCl ): δ = 8.33 (d, J = 7.1 Hz, 1H), 8.13 (d, J = 7.1 Hz, 1H),
3
13
8.03 (s, NH), 7.05 (t, J = 7.1, 1H), 6.86 (t, J = 7.1Hz, 1H), 4.02 (s, 3H), 1.54 (s, 9H); C-NMR (101 MHz,
CDCl )
δ
= 164.1 (CO), 153.0 (CO), 132.5 (Cq), 128.1 (CH), 121.8 (CH), 121.7 (CH), 116.3 (Cq), 114.8 (CH),
3:
+
9
9.8 (Cq), 80.8 (CO), 52.2 (OCH ), 28.7 (3XCH ); HRMS: m/z [M + H] calcd for C H N O : 292.1293,
3
3
14 18
3
4
found: 292.1291.
Methyl 3-aminopyrazolo[1, 5-a]pyridine-2-carboxylate (
6): A solution of 3-N-Boc-aminoester 5 (0.5 g,
1
.071 mmol) in a mixture of CH Cl /TFA (2/1) (15 mL) was stirred at r.t. for 4 h. After complete
2
2
disappearance of the starting material, the volatiles were removed in vacuo then an aq. satd. solution of
K CO (10 mL) was slowly added. The residue was extracted with EtOAc (3 20 mL). The solvent was
×
2
3
evaporated under reduced pressure and the crude material was purified by column chromatography
EtOAc/petroleum ether, 3/7) to give
◦
(
6
as a yellow solid in quantitative manner. M.p. 186–184 C,
R = 0.4 (EtOAc/petroleum ether, 5/5); IR (ATR diamond, cm ): 3404, 3286, 1696, 1127, 910, 716;
= 8.30 (d, J = 7.0 Hz, 1H), 7.44 (d, J = 7.0 Hz, 1H), 7.0 (t, J = 7.0 Hz,
H), 6.80 (t, J = 7.0 Hz, 1H), 4.06 (s, 2H), 4.01 (s, 3H); 13C-NMR (101 MHz, CDCl3):
−
1
f
1
H-NMR (400 MHz, CDCl3):
δ
1
1
δ
= 164.6 (CO),
30.0 (Cq), 129.1 (Cq), 128.1 (CH), 126.0 (Cq), 119.8 (CH), 117.5 (CH), 114.8 (CH), 51.9 (OCH ); HRMS:
3
+
m/z [M + H] calcd for C H N O : 192.0765, found: 192.0767.
9
10
3
2
Methyl 3-(benzoylcarbamothioylamino)pyrazolo[1,5-a]pyridine-2-carboxylate (
(85 mg, 0.44 mmol) in chloroform (5 mL) was added benzoyl isothiocyanate (87 mg, 0.53 mmol,
.2 equiv.) and the mixture was stirred at r.t. for 12 h. After evaporating the solvent, the crude material
was purified by column chromatography on silica gel, (EtOAc/petroleum ether, 2/8) to give the
7): To a solution of the amine
6
1
◦
−1
desired product
7
as a yellow solid (125 mg, 80%). M.p. 216–218 C, IR (ATR diamond, cm ): 3248,
1
3033, 1722, 1522, 1190, 750, 668; H-NMR (250 MHz, DMSO-d ):
δ
= 12.49 (s, NH), 11.79 (s, NH), 8.71
6
(
2
d, J = 7.1 Hz, 1H), 8.00 (d, J = 8.0 H , 1H), 7.97 (d, J = 8.0 H , 1H), 7.68–7.60 (m, 2H), 7.52 (t, J = 7.1 Hz
,
Z
Z
1
3
H), 7.36–7.29 (m, 1H), 7.10 (t, J = 7.1 Hz, 1H), 3.83 (s, 3H); C-NMR (101 MHz, DMSO-d6):
δ
= 181.3
(
1
CO), 172.6 (CS), 168.8 (CO), 162.3 (Cq), 137.9 (Cq), 135.8 (Cq), 133.7 (CH), 129.6 (CH), 129.2 (2
29.0 (2
calcd for C H N O S: 355.0862, found:355.0859.
×
CH),
+
×
CH), 124.7 (CH), 119.7 (CH), 115.7 (CH), 113.1 (Cq), 52.0 (OCH ); HRMS: m/z [M + H]
3
17
15
4
3
2-Thioxo-1H-pyrido[3,4]pyrazolo[4,3-d]pyrimidin-4-one (8): To a solution of 7 (137 mg, 0.39 mmol) in
ethanol (10 mL) was added a solution of sodium ethoxide (28.9 mg, 0.425 mmol, 1.1 equiv.). The reaction
mixture was refluxed for 8 h. After evaporating the solvent, a mixture of water/acetic acid (4/1) was
added. The obtained precipitate was filtered, washed with diethyl ether (2
×
20 mL) and the product
8
◦
−1
was obtained as a white solid (65 mg, 76%). M.p. 314–316 C; IR (ATR diamond, cm ): 3212, 2920,
1
1
586, 1362, 839, 785; H-NMR (400 MHz, DMSO-d ):
δ
= 13.26 (s, NH), 12.40 (s, NH), 8.80 (d, J = 7.1 Hz
,
6
13
1H), 8.16 (d, J = 7.1 Hz, 1H), 7.40 (t, J = 7.1 Hz, 1H), 7.23 (t, J = 7.1 Hz, 1H); C-NMR (101 MHz,
DMSO-d6):
δ
= 172.9 (CO), 156.1 (CS), 132.9 (Cq), 129.6 (CH), 127.4 (Cq), 124.3 (CH), 120.8 (Cq),
+
1
19.1 (CH), 117.5 (CH); HRMS: m/z [M + H] calcd for C H N OS: 219.0332, found: 219.0335.
9
7
4
2
-Methylsulfanyl-3H-pyrido[3,4]pyrazolo[4,3-d]pyrimidin-4-one (9): To a solution of 8 (0.51 g, 2.33 mmol) in
1
0 mL of DMSO and 20 mL of ethanol was added NaOH (93 mg, 2.33 mmol, 1.0 equiv.). Iodomethane

Molecules 2018, 23, 2740
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was slowly added (0.143 mL, 2.33 mmol, 1.0 equiv.) and the reaction was stirred at r.t. during 2 h. Then,
the volatiles were evaporated and water (20 mL) was added. The resulting precipitate was filtered,
◦
washed with water (2
×
20 mL) and dried to give
9
as a yellow solid (270 mg, 85%). M.p. 302–304 C;
−
1
1
IR (ATR diamond, cm ): 3232, 2927, 1596, 1365, 859, 775, H-NMR (250 MHz, DMSO-d ): δ = 12.52
6
(
1
1
s, 1H), 8.88 (d, J = 7.0 Hz, 1H), 8.07 (d, J = 7.0 Hz, 1H), 7.43 (t, J = 7.0 Hz, 1H), 7.30 (t, J = 7.0 Hz,
H), 2.61 (s, 3H); 13C-NMR (101 MHz, DMSO-d6):
δ = 157.1 (CO), 152.7 (Cq), 135.2 (Cq), 133.5 (Cq),
30.6 (Cq), 129.8 (CH), 124.4 (CH), 118.6 (CH), 117.7 (CH), 13.5 (SCH ); HRMS: m/z [M + H]+ calcd for
3
C H N OS: 233.0489, found: 233.0491.
10
9
4
General procedure A for the direct arylation via C-OH bond activation: In a sealed tube of 10 mL, a
solution of (100 mg, 0.43 mmol) in dioxane (4 mL) was degassed by argon bubbling for 10 min,
9
then PyBroP (240 mg, 0.51 mmol, 1.2 equiv.) and Et N (1.29 mmol, 0.17 mL, 3.0 equiv.) were added
3
◦
successively. After 18 h at 80 C, the reaction mixture was cooled and a solution containing the required
(
(
Het)arylboronic acid (2.0 equiv.), Na CO (5.0 equiv.) and PdCl (dppf).CH Cl (10 mol%) in H O
1 mL) was added. The sealed tube was stirred and heated at 110 C for 24 h. After cooling at r.t. the
2
3
2
◦
2
2
2
volatiles were evaporated under reduced pressure and the crude material diluted in CH Cl (20 mL).
2
2
The organic layers were washed with water (10 mL), dried over MgSO , filtered, and concentrated
4
under vacuum. The crude mixture was purified by column chromatography on silica gel to give the
desired mono-arylated compounds.
2-Methylsulfanyl-4-(p-tolyl)pyrido[3,4]pyrazolo[4,3-d]pyrimidine (10): Using p-tolylboronic acid as
coupling reagent and following the general procedure A, the crude product was purified by flash
chromatography on silica gel (EtOAc/petroleum ether, 0.5/9.5) to afford 10 as a yellow solid in a
◦
−1
8
2
5% yield. M.p. 206–208 C; R = 0.5 (EtOAc/petroleum ether, 0.5/9.5); IR (ATR diamond, cm ):
f
1
922, 1635, 1577, 1528, 1435, 1240, 1184, 1002, 799, 752, 634; H-NMR (400 MHz, CDCl ):
δ = 8.85–8.79
3
(
m, 3H), 8.38 (d, J = 7.0 Hz, 1H), 7.44–7.37 (m, 3H), 7.32 (t, J = 7.0 Hz, 1H), 2.78 (s, 3H), 2.47 (s, 3H);
1
3
C-NMR (101 MHz, CDCl3):
δ = 162.5 (Cq), 154.7 (Cq), 142.1 (Cq), 138.4 (Cq), 136.9 (Cq), 133.5 (Cq),
1
1
33.3 (Cq), 130.3 (2
×
CH), 129.5 (2
×
CH), 128.9 (CH), 123.0 (CH), 119.7 (CH), 119.2 (CH), 21.8 (CH3),
+
4.9 (SCH ); HRMS: m/z [M + H] calculated for C H N S: 307.1013, found: 307.1011.
3
17 15
4
4-(4-Methoxyphenyl)-2-methylsulfanyl-pyrido[3,4]pyrazolo[4,3-d]pyrimidine (11): Using 4-methoxy-
phenylboronic acid as coupling reagent and following the general procedure A, the crude product
was purified by flash chromatography on silica gel (EtOAc/petroleum ether, 0.5/9.5) to afford 11
◦
as a yellow solid in a 87% yield. M.p. 188–190 C; R = 0.5 (EtOAc/petroleum ether, 0.5/9.5); IR
(
f
−
ATR diamond, cm ): 2924, 2866, 1728, 1433, 1272, 1122, 844, 635; H-NMR (250 MHz, CDCl ):
3
1
1
δ = 8.93 (d, J = 6.7 Hz, 2H), 8.77 (d, J = 6.7 Hz, 1H), 8.35 (d, J = 6.7 Hz, 1H), 7.3 (t, J = 6.7 Hz, 1H), 7.29 (t,
13
J = 6.7 Hz, 1H), 7.08 (d, J = 6.7 Hz, 2H), 3.90 (s, 3H), 2.76 (s, 3H); C-NMR (101 MHz, CDCl3):
δ = 162.5
(
1
Cq), 162.3 (Cq), 154.1 (Cq), 138.1 (Cq), 136.7 (Cq), 133.3 (Cq), 132.0 (2
22.8 (CH), 119.6 (CH), 119.0 (CH), 114.1 (2
calcd for C H N OS: 323.0959, found: 323.0961.
×
CH), 128.7 (CH), 128.5 (Cq),
CH), 55.4 (OCH ), 14.8 (SCH ); HRMS: m/z [M + H]
3 3
+
×
17
15
4
4-(3-Methoxyphenyl)-2-methylsulfanyl-pyrido[3,4]pyrazolo[4,3-d]pyrimidine (12): Using 3-methoxy-
phenylboronic acid as coupling reagent and following the general procedure A, the crude product
was purified by flash chromatography on silica gel (EtOAc/petroleum ether, 5/5) to afford 12 as a
◦
yellow solid in a 67% yield. M.p. 154–156 C; R = 0.4 (EtOAc/petroleum ether, 5/5); IR (ATR diamond,
f
−
1
1
cm ): 2919, 2851, 1737, 1635, 1495, 1132, 844, 628; H-NMR (250 MHz, CDCl ):
δ
= 8.82 (d, J = 6.9 Hz,
3
1
7
δ
H), 8.57 (d, J = 6.9 Hz, 1H), 8.51–8.47 (m, 1H), 8.40 (d, J = 6.9 Hz, 1H), 7.46 (dd, J = 15.2, 7.8 Hz, 2H),
.37–7.31 (m, 1H), 7.12 (dd, J = 8.2, 2.9 Hz, 1H), 3.97 (s, 3H), 2.79 (s, 3H); C-NMR (101 MHz, CDCl3):
= 162.3 (Cq), 159.9 (Cq), 154.2 (Cq), 138.6 (Cq), 137.3 (Cq), 136.7 (Cq), 133.3 (Cq), 129.7 (CH), 128.8
13
(
CH), 123.1 (CH), 123.0 (CH), 119.6 (CH), 119.3 (CH), 117.7 (CH), 114.8 (CH), 55.5 (OCH ), 14.9 (SCH );
3 3
+
HRMS: m/z [M + H] calcd for C H N OS: 323.0960, found: 323.0961.
17
15
4

Molecules 2018, 23, 2740
9 of 15
4-(2-Methoxyphenyl)-2-methylsulfanyl-pyrido[3,4]pyrazolo[4,3-d]pyrimidine (13): Using 2-methoxy-
phenylboronic acid as coupling reagent and following the general procedure A, the crude product was
purified by flash chromatography on silica gel (EtOAc/petroleum ether, 4/6) to afford 13 as a yellow
◦
−1
solid in a 20% yield. M.p. 194–196 C; R = 0.3 (EtOAc/petroleum ether, 4/6); IR (ATR diamond cm ):
f
1
3
077, 2920, 1600, 1431, 1157, 878, 636; H-NMR (250 MHz, CDCl ):
δ
= 8.75 (d, J = 7.0 Hz, 1H), 8.40 (d,
3
J = 7.0 Hz, 1H), 7.74 (d, J = 7.0 Hz, 1H), 7.52 (t, J = 7.0 Hz, 1H), 7.42 (t, J = 7.0 Hz, 1H), 7.29 (t, J = 7.0 Hz
,
13
1
1
1
H), 7.19–7.11 (m, 2H), 3.85 (s, 3H), 2.77 (s, 3H); C-NMR (101 MHz, CDCl3):
57.0 (Cq), 137.8 (Cq), 137.0 (Cq), 133.5 (Cq), 131.6 (CH), 131.4 (CH), 128.7 (CH), 125.5 (Cq), 122.6 (CH),
δ
= 162.5 (Cq), 157.9 (Cq),
+
20.8 (CH), 119.5 (CH), 118.9 (CH), 112.2 (CH), 56.0 (OCH ), 14.8 (SCH ); HRMS: m/z [M + H] calcd
3
3
for C H N OS: 323.0959, found: 323.0961.
17
15
4
4-(4-Fluorophenyl)-2-methylsulfanyl-pyrido[3,4]pyrazolo[4,3-d]pyrimidine (14): Using 4-fluorophenyl-
boronic acid as coupling reagent and following the general procedure A, the crude product was
purified by flash chromatography on silica gel (EtOAc/petroleum ether, 1/9) to afford 14 as a yellow
◦
solid in a 90% yield. M.p. 140–142 C; R = 0.6 (EtOAc/petroleum ether, 1/9); IR (ATR diamond
f
−
1
1
cm ): 3095, 2920, 2849, 1635, 1556, 1420, 1210, 880, 749, 640, 524; H-NMR (250 MHz, CDCl ): δ = 8.97
3
(
t, J = 6.8 Hz, 2H), 8.79 (d, J = 6.8 Hz, 1H), 8.39 (d, J = 6.8 Hz, 1H), 7.56–7.20 (m, 4H), 2.78 (s, 3H);
13
C-NMR (101 MHz, CDCl3):
Cq), 136.6 (Cq), 133.4 (Cq), 132.4 (d, J = 8.7 Hz, 2
δ = 164.9 (d, J = 254.5 Hz, Cq), 162.4 (Cq), 153.2 (Cq), 138.5 (Cq), 138.5
(
×
CH), 128.7 (CH), 123.1 (CH), 119.5 (d, J = 33.8 Hz,
+
2
× CH), 115.8 (CH), 115.6 (CH), 14.6 (SCH ); HRMS: m/z [M + H] calcd for C H FN S: 311.0762,
3
16 12
4
found: 311.0761.
2-Methylsulfanyl-4-[4-(trifluoromethyl)phenyl]pyrido[3,4]pyrazolo[4,3-d]pyrimidine
(
15):
Using
4-trifluoromethylphenyl boronic acid as coupling reagent and following the general procedure A, the
crude product was purified by flash chromatography on silica gel (EtOAc/petroleum ether, 0.5/9.5) to
◦
afford 15 as a yellow solid in a 70% yield. M.p. 184–186 C; R = 0.6 (EtOAc/petroleum ether, 0.5/9.5);
f
−
1
1
IR (ATR diamond cm ): 3076, 1643, 1541, 1466, 1255, 1230, 1086, 857, 753, 620; H-NMR (400 MHz,
CDCl3): = 9.04 (d, J = 8.2 Hz, 2H), 8.82 (d, J = 6.9 Hz, 1H), 8.42 (t, J = 6.9 Hz, 1H), 7.84 (d, J = 8.2 Hz,
H), 7.48 (t, J = 6.9 Hz, 1H), 7.38 (t, J = 6.9 Hz, 1H), 2.79 (s, 3H); 13C-NMR (101 MHz, CDCl3):
= 162.4
Cq), 152.6 (Cq), 139.1 (q, J = 1.4 Hz, Cq), 139.0 (Cq), 136.7 (Cq), 133.4 (Cq), 132.7 (q, J = 33.0 Hz, Cq),
δ
2
δ
(
1
1
32.5 (Cq), 130.4 (2
×
CH), 128.8(CH), 125.4 (q, J = 3.7 Hz, 2
×
CH), 123.4 (CH), 119.7 (CH), 119.6 (CH),
+
4.7 (SCH ); HRMS: m/z [M + H] calcd for C H F N S: 361.0730, found: 361.0729.
3
17 12
3
4
4-(2-Methylsulfanylpyrido[3,4]pyrazolo[4,3-d]pyrimidin-4-yl)benzonitrile (16): Using 4-cyanophenyl-
boronic acid as coupling reagent and following the general procedure A, the crude product was
purified by flash chromatography on silica gel (EtOAc/petroleum ether, 2/8) to afford 16 as a yellow
◦
solid in a 58% yield. M.p. 230–232 C; R = 0.76 (EtOAc/petroleum ether, 2/8); IR (ATR diamond
f
−
1
1
cm ): 2921, 2223, 1731, 1548, 1494, 1255, 1275, 1018, 877, 748, 631; H-NMR (400 MHz, CDCl ):
3
δ = 9.10
(d, J = 8.5 Hz, 1H), 8.85 (d, J = 6.9 Hz, 1H), 8.46 (d, J = 6.9 Hz, 1H), 7.89 (d, J = 8.5 Hz, 1H), 7.54
13
(t, J = 6.9 Hz, 1H), 7.43 (t, J = 6.9 Hz, 1H), 2.81 (s, 3H); C-NMR (101 MHz, CDCl3):
δ = 162.4 (Cq),
1
1
51.7 (Cq), 139.9 (Cq), 139.3 (Cq), 136.5 (Cq), 133.5(Cq), 132.3 (2
23.6 (CH), 119.9 (CH), 119.8 (CH), 118.7 (Cq), 114.4 (Cq), 14.8 (SCH ); HRMS: m/z [M + H] calcd for
×
CH), 130.5 (2
×
CH), 128.8 (CH),
+
3
C H N S: 318.0808, found: 318.0807.
17
12
5
4-(2-Methylsulfanylpyrido[3,4]pyrazolo[4,3-d]pyrimidin-4-yl)phenol (17): Using 4-hydroxyphenylboronic acid
as coupling reagent and following the general procedure A, the crude product was purified by flash
chromatography on silica gel (EtOAc/petroleum ether, 3/7) to afford 17 as a yellow solid in a 45%
◦
−1
yield. M.p. 254–256 C; R = 0.4 (EtOAc/petroleum ether, 2/8); IR (ATR diamond cm ): 3100,
f
1
2
928, 2214, 1607, 1550, 1494, 1274, 1128, 1021, 877, 748, 631; H-NMR (250 MHz, CDCl ):
δ
= 9.08
3
(
d, J = 8.6 Hz, 2H), 8.83 (d, J = 6.9 Hz, 1H), 8.44 (d, J = 6.9 Hz, 1H), 7.87 (d, J = 8.6 Hz, 1H ), 7.51 (t,
J = 6.9 Hz, 1H), 7.42 (t, J = 6.9 Hz, 1H), 2.79 (s, 3H); 13C-NMR (101 MHz, CDCl3):
= 162.5 (Cq), 151.8
Cq), 139.9 (Cq), 136.5 (Cq), 133.9 (Cq), 132.3 (2 CH), 130.5 (2 CH), 128.8 (CH), 123.6 (CH), 119.9
δ
(
×
×

Molecules 2018, 23, 2740
10 of 15
+
(
CH), 119.8 (CH), 118.7 (Cq), 114.6 (Cq), 14.8 (SCH ); HRMS: m/z [M + H] calcd for C H N OS:
3 16 13 4
3
09.0805, measured: 309.0804.
4-(2-Furyl)-2-methylsulfanyl-pyrido[3,4]pyrazolo[4,3-d]pyrimidine (18): Using 2-furanylboronic acid as
coupling reagent and following the general procedure A, the crude product was purified by flash
chromatography on silica gel (EtOAc/petroleum ether, 4/6) to afford 18 as a green solid in a 74% yield.
◦
−1
M.p. 190–192 C; R = 0.6 (EtOAc/petroleum ether, 3/7); IR (ATR diamond cm ): 2917, 2849, 1737,
1
f
1
1
523, 1497, 1233, 1165, 1018, 885, 747, 516; H-NMR (400 MHz, CDCl ): H-NMR (400 MHz, CDCl ):
3 3
δ = 8.83 (d, J = 7.0 Hz, 1H), 8.38 (d, J = 7.0 Hz, 1H), 8.06 (d, J = 4.4 Hz, 1H), 7.85 (d, J = 2.8 Hz, 1H),
7
.46 (t, J = 7.0 Hz, 1H), 7.35 (t, J = 7.0 Hz, 1H), 6.73 (dd, J = 4.4, 2.8 Hz, 1H), 2.78 (s, 3H); 13C-NMR
(
1
101 MHz, CDCl3):
δ
= 162.6 (Cq), 149.7 (Cq), 146.6 (CH), 145.2 (Cq), 137.7 (Cq), 134.4 (Cq), 133.6 (Cq),
+
28.9 (CH), 123.2 (CH), 119.5 (CH), 119.1 (2CH), 112.8 (CH), 14.7 (SCH ); HRMS
:
m/z [M + H] calcd
3
for C H N OS: 283.0649, found: 283.0648.
14
11
4
General procedure B for C-2 Liebeskind–Srogl cross-coupling reaction: Compound 10
, 11 or 14 (0.15 mmol),
aryl boronic acid (1.5 equiv.), Cu-(I) thiophene-2-carboxylate (CuTc) (3.0 equiv.), and Pd(PPh ) (10
3
4
mol%) were dissolved in anhydrous THF (5 mL) under argon in a microwave sealed vial. The reaction
◦
mixture was irradiated under microwave at 100 C for 1h30. After cooling, the solvent was evaporated
under reduced pressure and the residue was diluted in an aq. satd. NaHCO solution (10 mL). The
3
aqueous layer was extracted with CH Cl (3
with water (5 mL), dried with anhydrous MgSO , filtered, and concentrated under reduced pressure.
×
10 mL). The combined organic layers were washed
2
2
4
The residue was purified by flash chromatography on silica gel to afford the desired compounds.
2,4-Bis(p-tolyl)pyrido[3,4]pyrazolo[4,3-d]pyrimidine (20): Starting from 10, using p-tolylboronic acid as
coupling reagent and following the general procedure B, the crude product was purified by flash
chromatography on silica gel (EtOAc/petroleum ether, 1/9) to afford 20 as a yellow solid in a 78%
◦
−1
yield. M.p. 176–178 C; R = 0.7 (EtOAc/petroleum ether, 2/8); IR (ATR diamond, cm ): 2922, 2851,
f
1
1
704, 1524, 1495, 1134, 1017, 834, 746; H-NMR (400 MHz, CDCl ):
δ
= 8.94 (d, J = 7.9 Hz, 2H), 8.83
3
(
2
1
1
[
d, J = 7.0 Hz, 1H), 8.60 (d, J = 7.9 Hz, 2H), 8.49 (d, J = 7.0 Hz, 1H), 7.48–7.38 (m, 3H), 7.37–7.29 (m, 3H),
.47 (s, 3H), 2.43 (s, 3H); 13C-NMR (101 MHz, CDCl3):
= 156.5 (Cq), 153.9 (Cq), 141.5 (Cq), 139.5 (Cq),
38.2 (Cq), 137.5 (Cq), 136.3 (Cq), 134.8 (Cq), 134.0 (Cq), 130.0 (2 CH), 129.4 (2
CH), 129.3 (2 × CH),
CH), 123.2 (CH), 119.7 (CH), 119.2 (CH), 21.7 (CH ), 21.5 (CH ); HRMS: m/z
δ
×
×
28.9 (CH), 128.0 (2
×
3
3
+
M + H] calcd for C H N : 351.1525, found: 351.1524.
23
19
4
2-(4-Methoxyphenyl)-4-(p-tolyl)pyrido[3,4]pyrazolo[4,3-d]pyrimidine (21): Starting from 10, using
4-methoxyphenylboronic acid as coupling reagent and following the general procedure B, the crude
product was purified by flash chromatography on silica gel (EtOAc/petroleum ether, 1/9) to afford
◦
2
1
as an orange solid in a 75% yield. M.p. 202–204 C; R = 0.6 (EtOAc/petroleum ether, 1.5/8.5);
f
−
1
1
IR (ATR diamond, cm ): 2921, 2851, 1608, 1524, 1495, 1234, 1024, 750; H-NMR (400 MHz, CDCl ):
3
δ = 8.98 (d, J = 8.5 Hz, 2H), 8.88 (d, J = 7.0 Hz, 1H), 8.71 (d, J = 8.5 Hz, 2H), 8.53 (d, J = 7.0 Hz, 1H),
7
3
.50 (t, J = 7.0 Hz, 1H), 7.46 (d, J = 8.5 Hz, 2H) 7.38 (t, J = 7.0 Hz, 1H), 7.10 (d, J = 8.5 Hz, 2H), 3.94 (s,
13
H), 2.52 (s, 3H); C-NMR (101 MHz, CDCl ): δ = 161.0 (Cq), 156.4 (Cq), 154.0 (Cq), 141.5 (Cq), 138.2
3
(
1
[
Cq), 137.4 (Cq), 134.7 (Cq), 134.0 (Cq), 131.9 (Cq), 130.0 (2
×
CH), 129.6 (2
×
CH), 129.4 (2
×
CH),
28.9 (CH), 123.1 (CH), 119.7 (CH), 119.2 (CH), 113.9 (2
×
CH), 55.4 (OCH ), 21.7 (CH ); HRMS: m/z
3
3
+
M + H] calcd for C H N O: 367.1554, found: 367.1553.
23
19
4
2-(3-Methoxyphenyl)-4-(p-tolyl)pyrido[3,4]pyrazolo[4,3-d]pyrimidine (22): Starting from 10, using
3-methoxyphenylboronic acid as coupling reagent and following the general procedure B, the crude
product was purified by flash chromatography on silica gel (EtOAc/petroleum ether, 3/7) to afford 22
◦
as a yellow solid in a 48% yield. M.p. 130–132 C; R = 0.5 (EtOAc/petroleum ether, 5/5); IR (ATR
f
−
1
1
diamond, cm ): 2922, 2801, 1722, 1584, 1486, 1240, 1036, 745; H-NMR (250 MHz, CDCl ):
δ
= 8.97
3
(
1
d, J = 8.5 Hz, 2H), 8.87 (d, J = 7.0 Hz, 1H), 8.53 (d, J = 8.5 Hz, 1H), 8.35 (d, J = 8.5 Hz, 1H), 8.31 (s,
H), 7.53–7.34 (m, 5H), 7.04 (d, J = 7.0 Hz, 1H), 3.99 (s, 3H), 2.50 (s, 3H); 1 C-NMR (101 MHz, CDCl3):
3

Molecules 2018, 23, 2740
11 of 15
δ = 159.9 (Cq), 156.1 (Cq), 153.9 (Cq), 141.6 (Cq), 140.5 (Cq), 138.2 (Cq), 137.6 (Cq), 137.6 (Cq), 134.9
(
(
Cq), 130.0 (2
×
CH), 129.5 (CH), 129.4 (2
×
CH), 129.0 (CH), 123.4 (CH), 120.7 (CH), 119.7 (CH), 119.3
+
CH), 115.6 (CH), 113.1 (CH), 55.5 (OCH ), 21.7 (CH ); HRMS: m/z [M + H] calcd for C H N O:
3
3
23 19
4
3
67.1554, found: 367.1553.
2-(2-Methoxyphenyl)-4-(p-tolyl)pyrido[3,4]pyrazolo[4,3-d]pyrimidine (23): Starting from 10, using
3-methoxyphenylboronic acid as coupling reagent and following the general procedure B, the crude
product was purified by flash chromatography on silica gel (EtOAc/petroleum ether, 4/6) to afford
◦
2
(
3
as a yellow solid in a 25% yield. M.p. 160–162 C; R = 0.5 (EtOAc/petroleum ether, 6/4); IR
f
−
ATR diamond, cm ): 3068, 2923, 2836, 2211, 1636, 1543, 1188, 935, 736; H-NMR (250 MHz, CDCl ):
3
1
1
δ = 8.89 (d, J = 8.3 Hz, 3H), 8.56 (d, J = 8.3 Hz, 1H), 7.94 (d, J = 7.5 Hz, 1H), 7.52–7.35 (m, 5H), 7.17–7.08
m, 2H), 3.93 (s, 3H), 2.47 (s, 3H); 13C-NMR (101 MHz, CDCl3):
= 157.9 (Cq), 157.3 (Cq), 154.2 (Cq),
41.5 (Cq), 137.8 (Cq), 137.1 (Cq), 134.8 (Cq), 133.9 (Cq), 132.1 (Cq), 130.1 (CH), 130.1 (2 CH), 129.9
(
δ
1
×
(
(
CH), 129.4 (2
×
CH), 128.9 (CH), 123.3 (CH), 120.8 (CH), 119.8 (CH), 119.2 (CH), 112.5 (CH), 56.2
+
OCH ), 21.7 (CH ); HRMS: m/z [M + H] calcd for C H N O: 367.1554, found: 367.1553.
3
3
23 19
4
2-(4-Fluorophenyl)-4-(p-tolyl)pyrido[3,4]pyrazolo[4,3-d]pyrimidine (24): Starting from 10
, using
4-fluorophenylboronic acid as coupling reagent and following the general procedure B, the crude
product was purified by flash chromatography on silica gel (EtOAc/petroleum ether, 1/9) to afford
◦
2
(
4
as a yellow solid in a 85% yield. M.p. 156–158 C; R = 0.6 (EtOAc/petroleum ether, 1.5/8.5); IR
f
−
ATR diamond, cm ): 3061, 2920, 1524, 1493, 1427, 1375, 1208, 1135, 748; H-NMR (400 MHz, CDCl ):
3
1
1
δ = 8.94 (d, J = 8.2 Hz, 2H), 8.84 (d, J = 6.9 Hz, 1H), 8.71 (d, J = 8.2 Hz, 2H), 8.48 (d, J = 6.9 Hz, 1H),
7
3
.48 (t, J = 6.9 Hz, 1H), 7.43 (d, J = 8.2 Hz, 2H), 7.34 (d, J = 6.9 Hz, 1H), 7.22 (d, J = 8.2 Hz, 2H), 2.50 (s,
13
H); C-NMR (101 MHz, CDCl3):
δ
= 164.0 (d, J = 251.8 Hz, Cq), 155.5 (Cq), 153.9 (Cq), 141.7 (Cq),
CH),
CH), 115.4 (CH), 115.2
1
1
38.1 (Cq), 137.4 (Cq), 135.2 (d, J = 2.9 Hz, Cq), 134.7 (Cq), 133.8 (Cq), 130.0 (d, J = 8.4 Hz, 2
30.0 (2 × CH), 129.4 (2
×
×
CH), 129.0 (CH), 123.3 (CH), 119.5 (d, J = 28.9 Hz, 2
×
+
(CH), 21.7 (CH ); HRMS: m/z [M + H] calcd for C H FN : 355.1355, found: 355.1353.
3
22 16
4
4
4
-(p-Tolyl)-2-[4-(trifluoromethyl)phenyl]pyrido[3,4]pyrazolo[4,3-d]pyrimidine (25): Starting from 10, using
-trifluoromethylphenylboronic acid as coupling reagent and following the general procedure B,
compound was purified by flash chromatography on silica gel (EtOAc/petroleum ether, 1/9) to afford
◦
2
5
as a yellow solid in a 60% yield. M.p. 174–176 C; R = 0.7 (EtOAc/petroleum ether, 2/8); IR (ATR
f
−
1
1
diamond, cm ): 2953, 2924, 2852, 1615, 1527, 1508, 1429, 1355, 1295, 1177, 797; 736; H-NMR (400 MHz,
CDCl3): = 8.91 (d, J = 8.0 Hz, 2H), 8.83 (d, J = 7.0 Hz, 1H), 8.79 (d, J = 8.0 Hz, 2H), 8.46 (d, J = 7.0 Hz
H), 7.77 (d, J = 8.0 Hz, 2H), 7.49 (t, J = 7.0 Hz, 1H), 7.42 (d, J = 8.0 Hz, 2H), 7.36 (t, J = 7.0 Hz, 1H), 2.49
s, 3H); 13C-NMR (101 MHz, CDCl3)
= 154.6 (Cq), 153.8 (Cq), 142.3 (q, J = 1.3 Hz, Cq) 141.8 (Cq),
38.1 (Cq), 137.5 (Cq), 134.9 (Cq), 133.6 (Cq), 130.8 ( Cq), 130.0 (2 CH), 129.3 (q, J = 251.3, CF ),129.4
δ
,
1
(
1
δ
×
3
(
2
2 × CH), 129.0 (CH), 128.2 (2
×
CH), 125.3 (q, J = 3.8 Hz, 2
×
CH), 123.7 (CH), 119.6 (CH), 119.5 (CH),
+
1.7 (CH ); HRMS: m/z [M + H] calcd for C H F N : 405.1320, found: 405.1321.
3
23 16
3
4
4-[4-(p-Tolyl)pyrido[3,4]pyrazolo[4,3-d]pyrimidin-2-yl]phenol
(
26):
Starting from 10
,
using
4-hydroxyphenylboronic acid as coupling reagent and following the general procedure B, the
crude product was purified by flash chromatography on silica gel (EtOAc/petroleum ether, 2.5/7.5) to
◦
afford 26 as a yellow solid in a 40% yield. M.p. 182–184 C; R = 0.4 (EtOAc/petroleum ether, 3/7); IR
f
−
1
1
(
(
ATR diamond, cm ): 3108, 2923, 2215, 1615, 1547, 1508, 1429, 1355, 1293, 1157, 787, 746; H-NMR
250 MHz, Acetone-d6): = 9.08 (t, J = 7.8 Hz, 3H), 8.63 (d, J = 8.7 Hz, 2H), 8.54 (d, J = 7.8 Hz, 1H),
.75–7.59 (m, 2H), 7.48 (d, J = 7.8 Hz, 2H), 7.02 (d, J = 8.7 Hz, 2H), 2.48 (s, 3H); 13C-NMR (101 MHz,
δ
7
Acetone-d6): δ = 159.2 (Cq), 155.9 (Cq), 153.0 (Cq), 141.6 (Cq), 138.2 (Cq), 136.9 (Cq), 134.5 (Cq), 134.1
(
1
Cq), 130.6 (Cq), 129.9 (2
19.1 (CH), 115.2 (2
found: 353.1396.
×
CH), 129.5 (2
×
CH), 129.3 (CH), 129.2 (2
×
CH), 124.0 (CH), 120.0 (CH),
+
×
CH), 20.7 (CH ); HRMS: m/z [M + H] calculated for C H N O: 353.1397,
3
22 17
4

Molecules 2018, 23, 2740
12 of 15
2-(2-Furyl)-4-(p-tolyl)pyrido[3,4]pyrazolo[4,3-d]pyrimidine (27): Starting from 10, using 2-furanylboronic
acid as coupling reagent and following the general procedure B, the crude product was purified by
flash chromatography on silica gel (EtOAc/petroleum ether, 2/8) to afford 27 as a yellow solid in a
◦
−1
6
3
0% yield. M.p. 146–148 C; R = 0.6 (EtOAc/petroleum ether, 3/7); IR (ATR diamond, cm ): 3542,
f
1
100, 2922, 2852, 1715, 1525, 1508, 1356, 1275, 1182, 783, 753,612; H-NMR (400 MHz, CDCl )
δ 8.93
3
(
(
d, J = 8.2 Hz, 2H), 8.88 (d, J = 6.9 Hz, 1H), 8.60 (d, J = 6.9 Hz, 1H), 7.71 (d, J = 3.6 Hz, 1H), 7.54–7.48
m, 2H), 7.45 (d, J = 8.2 Hz, 2H), 7.39 (t, J = 6.9 Hz, 1H), 6.65 (dd, J = 3.6, 1.7 Hz, 1H), 2.51 (s, 3H);
1
3
C-NMR (101 MHz, CDCl3):
δ = 154.6 (Cq), 153.6 (Cq), 150.1 (Cq), 144.2 (CH), 141.8 (Cq), 137.4 (Cq),
1
37.3 (Cq), 134.6 (Cq), 133.4 (Cq), 130.0 (2
×
CH), 129.4 (2
×
CH), 128.9 (CH), 123.4 (CH), 119.8 (CH),
+
119.3 (CH), 112.1 (CH), 112.0 (CH), 21.7 (CH ); HRMS: m/z [M + H] calcd for C H N O: 327.1241,
3
20 15
4
found: 327.1240.
2-(2-Tolyl)-4-(p-methoxyphenyl)pyrido[3,4]pyrazolo[4,3-d]pyrimidine (29): Starting from 11, using
p-tolylboronic acid as coupling reagent and following the general procedure B, the crude product was
purified by flash chromatography on silica gel (EtOAc/petroleum ether, 3/7) to afford 29 in a 86%
◦
−1
yield. M.p. 210–212 C; R = 0.4 (EtOAc/petroleum ether, 3/7); IR (ATR diamond, cm ): 3012, 1633,
f
1
1
531, 1432, 1254, 1114, 1021, 804, 744; H-NMR (400 MHz, CDCl ):
δ
= 8.90 (d, J = 6.8 Hz, 1H), 8.74
3
(
7
1
d, J = 8.8 Hz, 2H), 8.10 (d, J = 8.8 Hz, 1H), 7.94 (d, J = 8.8 Hz, 2H), 7.55–7.39 (m, 3H), 7.38–7.26 (m, 1H),
.03 (d, J = 8.8 Hz, 2H), 3.90 (s, 3H), 2.52 (s, 3H) ppm; 13C-NMR (101 MHz, CDCl3):
=164.4 (Cq),
63.9 (Cq), 162.4 (Cq), 141.6 (Cq), 136.4 (Cq), 136.1 (Cq), 131.8 (Cq), 131.3 (2 CH), 130.2 (CH), 130.2
δ
×
(
(
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
+
+
OCH ), 22.2 (CH ); HRMS: m/z [M + H] calcd for C H N O [M + H] 367.1553, found 367.1556.
3
3
23 19
4
2-(2-Tolyl)-4-(p-fluorophenyl)pyrido[3,4]pyrazolo[4,3-d]pyrimidine (30):
Starting from 14
,
using
p-tolyl-boronic acid as coupling reagent and following the general procedure B, the crude product was
purified by flash chromatography on silica gel (EtOAc/petroleum ether, 2/8) to afford 30 in a 53%
◦
−1
yield. M.p. 160–162 C; R = 0.6 (EtOAc/petroleum ether, 2/8); IR (ATR diamond, cm ): 3061, 2920,
f
1
1
524, 1493, 1427, 1375, 1208, 1135, 748; H-NMR (400 MHz, CDCl )
δ
= 9.13 (d, J = 8.7, Hz, 2H), 8.87 (d,
3
J = 6.9 Hz, 1H), 8.63 (d, J = 7.8 Hz, 2H), 8.54 (d, J = 6.9 Hz, 1H), 7.52 (t, J = 6.9 Hz, 1H), 7.43–7.30 (m,
H), 2.49 (s, 3H); 13C-NMR (101 MHz, CDCl3)
= 164.8 (d, J = 251.8 Hz, Cq), 156.5 (Cq), 152.5 (Cq),
39.6 (Cq), 138.4 (Cq), 137.3 (Cq), 136.1 (Cq), 134.8 (Cq), 132.9 (d, J = 3.0 Hz, Cq), 132.3 (d, J = 8.6 Hz,
5
δ
1
2
× CH), 129.3 (2
×
CH), 128.9 (CH), 127.9 (2
×
CH), 123.4 (CH), 119.6 (d, J = 32.1 Hz, 2
×
CH), 115.8
+
(CH), 115.5 (CH), 21.4 (CH ); HRMS: m/z [M + H] calcd for C H FN : 355.1354, found: 355.1352.
3
22 16
4
4
. Conclusions
In summary, we have described in this work a synthetic pathway for the preparation of an original
0
0
pyrido[1 ,2 :1,5]pyrazolo[4,3-d]pyrimidine platform, and then, have developed several arylations
at its C-2 and C-4 positions. First, the amide function in C-4 position was reacted in a direct
C–O activation with PyBroP as activator followed by a Suzuki-Miyaura cross coupling reaction
to generate a library of C-4 (het)arylated derivatives and next a Liebeskind–Srogl reaction furnished
the desired di-(het)arylated derivatives. The scope of the two reactions was investigated and showed
a strong influence of electronic effect and steric hindrance. In both cases electron enrichment of
the systems, i.e., the tricyclic core as well as the boronic partner, improved efficiency. This route
will offer the opportunity to explore other metal catalyzed cross coupling reactions and to open
a new chemical space area to generate new bioactive compounds containing polyfunctionalized
0
0
pyrido[1 ,2 :1,5]pyrazolo[4,3-d]pyrimidines.
Supplementary Materials: The following are available online: H-NMR and 13C-NMR of compounds
1
2–18, 20–27,
2
9, 30.
Author Contributions: A.E. and R.B. performed the experiments; G.G., A.E.H., M.A., F.B. and S.R. designed and
supervised the study. S.R. and F.B. wrote the paper.
Funding: This research received no external funding.

Molecules 2018, 23, 2740
13 of 15
Acknowledgments: We thank the Ligue Contre le Cancer du Grand Ouest, (Comités des Deux Sèvres, du Finistère,
0
de l Ile et Vilaine, du Loir-et-Cher, de la Loire Atlantique, du Loiret, de la Vienne), the Région Centre Val de
Loire/FEDER (IMAD and Cosmi programs), the Cancéropôle Grand Ouest (“network: valorization of marine
products”), the Labex IRON (ANR-11-LABX-0018-01), and Campus France for Financial support.
Conflicts of Interest: The authors declare no conflict of interest.
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2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons Attribution
(CC BY) license (http://creativecommons.org/licenses/by/4.0/).