Catalyst- and base-controlled site-selective sp2 and sp 3 direct arylation of 5,7-dimethyl-2-phenylpyrazolo[1,5-a]pyrimidine using aryl bromides

Article abstract of DOI:10.1002/ejoc.201101833

The palladium-catalyzed direct C-H arylation of various heterocyclic is now recognized to be the most effective methodology for making aromatic compounds. In this paper, we present a new approach to control the site-selective direct C-H arylation of both

Full text of DOI:10.1002/ejoc.201101833

FULL PAPER
DOI: 10.1002/ejoc.201101833
Catalyst- and Base-Controlled Site-Selective sp2 and sp3 Direct Arylation of
5,7-Dimethyl-2-phenylpyrazolo[1,5-a]pyrimidine Using Aryl Bromides
Ibtissam Bassoude,[a,b] Sabine Berteina-Raboin,*[a] Stéphane Massip,[d] Jean-Michel Leger,[d]
Christian Jarry,[d] El Mokhtar Essassi,[b,c] and Gérald Guillaumet[a]
Keywords: Nitrogen heterocycles / C–H activation / Palladium / Regioselectivity
The palladium-catalyzed direct C–H arylation of various het-
erocyclic is now recognized to be the most effective method-
ology for making aromatic compounds. In this paper, we
present a new approach to control the site-selective direct C–
H arylation of both sp2 and sp3 sites in 5,7-dimethyl-2-phen-
ylpyrazolo[1,5-a]pyrimidine by using aryl bromides. The de-
sired compounds were obtained in satisfactory yields. The
effects of each reaction parameter including catalyst, base,
and solvent were investigated.
ported the Suzuki cross-coupling reactions of 6-aryl-3-
bromopyrazolo[1,5-a]pyrimidines[6] and 3-aryl-6-bromopyr-
azolo[1,5-a]pyrimidines.[7] Liebscher et al. have recently re-
ported two examples of Heck[8] and Sonogashira[9] coupling
of 3-iodopyrazolo[1,5-a]pyrimidines. In the past few years,
direct C–H arylation has been intensively studied as an at-
tractive and simple alternative to traditional cross-coupling
methods to generate heteroaryl–aryl bonds.[10] As far as we
know, there are no examples of direct C–H arylations of
pyrazolo[1,5-a]pyrimidines reported to date.
Introduction
Aryl-substituted pyrazolo[1,5-a]pyrimidines are known
for their potent utility as analgesics, selective peripheral
benzodiazepine receptor ligands, angiogenesis inhibitors,
anti-inflammatory agents, neuropeptide Y (NPY1) receptor
antagonists, COX-2 selective inhibitors, and corticotropin-
releasing hormone receptor type 1 (CRHR1) antagonists.[1]
Our research group has targeted the development of hetero-
cycles with a bridgehead nitrogen atom and has studied
their reactivity toward palladium-mediated cross-cou-
plings.[2] In continuation of our research program, we re-
port here a direct C–H arylation reaction that would enable
the selective arylation of 5,7-dimethyl-2-phenylpyrazolo-
[1,5-a]pyrimidine at both the sp2 and sp3 centers.
Results and Discussion
We started our optimization with the investigation of the
direct arylation of 5,7-dimethyl-2-phenylpyrazolo[1,5-a]pyr-
imidine (1)[11] with 3-bromotoluene (2). We first applied the
reaction conditions already used in our laboratory.[2g] Com-
pound 1 (1 equiv.) was treated with 2 (1.5 equiv.) in the
presence of palladium(II) acetate (10 mol-%), tri-
phenylphosphane (20 mol-%), and K2CO3 (2 equiv.) in tol-
uene at 110 °C for 48 h. Under these experimental condi-
tions, the direct C–H arylation took place at the 3-position
of 1 to give product 3 in 53% yield (Table 1, Entry 1). En-
couraged by this initial result, we decided to evaluate the
influence of each reaction parameter such as catalyst, li-
gands, bases, and solvents. Results are summarized in
Table 1. For example, toluene was found to be a convenient
solvent. On the contrary, DMF, dioxane, and DMA low-
ered the yield to 5, 23, and 4%, respectively (Table 1, En-
tries 2–4). Other catalyst systems as Pd(PPh3)Cl2 and
Pd(OH)2/C[12] (Table 1, Entries 11–13) were also tested.
These experiments confirmed that Pd(OAc)2 is the optimal
palladium catalyst in toluene. To complete our investiga-
tion, we assessed the effect of changing the ligand and/or
base on the cross-coupling Pd-catalyzed arylation reaction.
Cross-coupling reactions have been extensively used for
the synthesis of heterocyclic compounds.[3] However, only a
few of these publications are devoted to the Pd-catalyzed
coupling of pyrazolo[1,5-a]pyrimidines. Shiota and Yama-
mori[4] have described the regioselective coupling of or-
ganozinc reagents with 5,7-dichloropyrazolo[1,5-a]pyrimid-
ine. Kumar[5] has reported the synthesis of 3-aryl-7-(dieth-
ylamino)pyrazolo[1,5-a]pyrimidines by Suzuki coupling of
3-bromopyrazolo[1,5-a]pyrimidine. Fraley et al. have re-
[a] Institut de Chimie Organique et Analytique,
Université d’Orléans, UMR CNRS 7311,
BP 6759, 45067 Orléans Cedex 2, France
E-mail: sabine.berteina-raboin@univ-orleans.fr
[b] Laboratoire de Chimie Organique Hétérocyclique,
Université Mohammed V-Agdal, Faculté des Sciences,
Avenue Ibn-Batouta, Rabat, Maroc
[c] INANOTECH (Institute of Nanomaterials and
Nanotechnology), MAScIR,
Av. Armée Royale, Rabat, Maroc
[d] EA4318-Pharmacochimie, UFR des Sciences Pharmaceutiques,
Université Victor Ségalen Bordeaux 2,
146 rue Léo Saignat, 33076 Bordeaux Cedex, France
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201101833.
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Catalyst- and Base-Controlled Site-Selective sp2 and sp3 Direct Arylations
Table 1. Optimization of reaction conditions for the C–H arylation of 1 with 3-bromotoluene (2).
Entry
Pd catalyst (mol-%)
Solvent
Base
ArBr [equiv.]
t [h]
Yield [%][a]
3
4
5
1
2
3
4
5
6
7
8
Pd(OAc)2 (10)/PPh3 (20)
Pd(OAc)2 (10)/PPh3 (20)
Pd(OAc)2 (10)/PPh3 (20)
Pd(OAc)2 (10)/PPh3 (20)
Pd(OAc)2 (10)/PPh3 (20)
Pd(OAc)2 (10)/PPh3 (20)
Pd(OAc)2 (10)/PPh3 (20)
Pd(OAc)2 (10)/PPh3 (20)
Pd(OAc)2 (10)/PPh3 (20)
Pd(OAc)2 (10)/PPh3 (20)
PdCl2(PPh3) (10)
toluene
dioxane
DMF
K2CO3
K2CO3
K2CO3
K2CO3
KOAc
Na2CO3
Cs2CO3
Cs2CO3
Cs2CO3
NaH
K2CO3
K2CO3
KOAc
K2CO3
K2CO3
K2CO3
K2CO3
1.5
1.5
1.5
1.5
1.5
1.5
1.5
2
2.5
1.5
1.5
1.5
3
48
48
48
48
48
48
48
48
24
48
48
48
24
48
48
48
48
53
23
5
4
40
8
–
–
–
–
–
2
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
DMA
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
DMA
toluene
toluene
toluene
toluene
–
5
6
27
46
50
–
–
–
–
–
–
–
9
trace
–
10
11
12
13
14
15
16
17
–
–
Pd(OH)2/C (10)
Pd(OH)2/C (10)
Pd(OAc)2 (10)/AsPPh3 (20)
Pd(OAc)2 (10)/PtBu3HBF4 (20)
Pd(OAc)2 (10)/PtBu3HBF4 (20)
Pd(OAc)2 (10)/PtBu3HBF4 (20)
14
22
60
62
51[b]
1.5
1.5
2
2
–
[a] Isolated yield. [b] Using 0.5 equiv. of Ag2CO3.
[13]
It was found that the use of PtBu3HBF4 instead of PPh3 acidic and may be deprotonated in the presence of a strong
in the presence of 10 mol-% of Pd(OAc)2, 3-bromotoluene base such as Cs2CO3. Further to these results, we wanted
(2, 2 equiv.), and K2CO3 (2 equiv.) in toluene at 110 °C for to investigate the scope of both sp2/sp3 C–H arylation of 1.
48 h provided 3 in 62% isolated yield with no change in
selectivity (Table 1, Entry 16). The use of Cs2CO3 in place
of K2CO3 gave 3 and product 4 in 5 and 27% yield, respec-
tively (Table 1, Entry 7). Increasing the quantity of 2 from
1.5 to 2.5 equiv., under same reaction conditions, improved
the selectivity and led predominantly to compound 4 in
50% yield (Table 1, Entry 9). It was noticed that, under
these conditions reaction, only a trace amount of desired
1
product 3 was detected by NMR spectroscopic analysis of
the crude reaction mixture (Table 1, Entry 9) showing that
the base is of importance in determining the sp2/sp3 site
selectivity. It is also possible that the C–H bond acidity
plays a role in the selectivity of these reactions explaining
the selective sp3 arylation at the 7-methyl position.
Scheme 1. Deuterium incorporation of 1.
The results summarized in Table 2 reveal that the opti-
Deuterium incorporation experiments were carried out mized conditions described above can be applied to a wide
to study the role that the acidity of the C–H functionality variety of aryl bromides. A variety of substitution patterns
plays in the site selectivity of these reactions (Scheme 1). including ortho, meta, and para are tolerated on the aryl
Deuterium exchange of 1 by treatment with KOH (1 equiv.) bromides. Both electron-rich (R = Me, OMe) and electron-
in a mixture of D2O/dioxane at 55 °C shows that the 7- poor (R = F, CO2Me) groups reacted to give desired prod-
methyl position exchanges at a significantly faster rate than ucts 3a–h in good yields of 55–78%.
the 5-methyl position. It is to note that under these condi-
The scope of the sp3 arylation of compound 1 is outlined
tions, no exchange at the sp2 position was detected (see the in Table 3. The results showed that the variety of substitu-
Supporting Information). These results indicate that the C– tion patterns including ortho, meta, and para are tolerated
H bond of the methyl group in the 7-position is the most on the aryl bromides. Both electron-rich (R = Me, OMe)
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S. Berteina-Raboin et al.
Table 3. Scope of the sp3 C–H arylation of 1.
FULL PAPER
Table 2. Scope of the sp2 C–H arylation of 1.
[a] Isolated yield. [b] Using 3 equiv. of ArBr.
and electron-poor (R = F, CO2Me) groups reacted to give
expected products 4a–h in good yields of 50–63%. However,
when compound 1 was treated with 4-bromopyridine under
sp3 C–H arylation conditions, no reaction occurred and
only the starting material was recovered (Table 3, Entry 6).
[a] Isolated yield.
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Catalyst- and Base-Controlled Site-Selective sp2 and sp3 Direct Arylations
This result can be explained by the formation of a stable
A plausible mechanism is proposed in Scheme 2. The
palladacycle similar to that reported by Fagnou et al.[15a] active Pd0 catalyst oxidatively inserts into the aryl halide
which is unable to participate in the reaction.
bond to generate intermediate [A]. The next step, pallad-
Structures of products 3a, 4b, and 4c were established by ation of 1, determines site selectivity and is base dependant.
single-crystal X-ray diffraction analysis. ORTEP diagrams When using K2CO3 as base, the reaction takes place at the
of these compounds are shown in Figure 1.
C3 position of the 5,7-dimethyl-2-phenylpyrazolo[1,5-a]pyr-
Figure 1. ORTEP drawings of crystal structures of 3a, 4b, and 4c.
Scheme 2. Proposed mechanism.
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S. Berteina-Raboin et al.
FULL PAPER
158.3, 155.6, 149.7, 145.2, 133.2, 128.7, 128.7, 126.5, 108.3, 92.6,
imidine. The six-membered transition state of a concerted
metalation–deprotonation (CMD) pathway[14] activates the
sp2 position giving, after reductive elimination, compounds
3a–h. The formation of 4a–h can be explained by a depro-
tonation–palladation pathway. With a strong and soluble
base such as Cs2CO3, the most acidic sp3 7-methyl position
may be deprotonated and proceeds through a pathway sim-
ilar to that reported[15] to generate [II] and giving, after re-
ductive elimination, intermediate [III]. Afterwards, [III] re-
acts rapidly in the catalytic cycle due to the high acidity of
the 7-methyl position monoarylated to generate, after re-
ductive elimination, desired products 4a–h.
24.6, 17.1 ppm. MS (ESI): m/z = 224 [M + H]+.
Preparation of PtBu3HBF4: This procedure has been described.[13]
HBF4 (48 wt.-% aqueous solution; 0.72 mL, 11.5 mmol) was added
to a solution of P(tBu3) (0.4 mL, 1.65 mmol) in CH2Cl2 (15 mL),
and the resulting mixture was stirred vigorously for 5–10 min. The
organic layer was then separated from the aqueous layer, dried with
MgSO4, and filtered. The residue was purified by recrystallization
(ethanol) and gave the desired compound in 84% yield as a white
1
powder. 1H NMR (400 MHz, CDCl3): δ = 6.18 (d, JPH = 468 Hz,
1 H), 1.66 (d, 3JPH = 15.3 Hz, 27 H) ppm. 13C NMR (100.62 MHz,
1
CDCl3): δ = 37.2 (d, JPC = 29 Hz, C), 30.1 ppm.
General Procedure for the sp2 Direct Arylation: Under an atmo-
sphere of argon, a mixture of 5,7-dimethyl-2-phenylpyrazolo[1,5-a]-
pyrimidine 1 (0.1 g, 0.45 mmol), aryl or heteroaryl bromide 2
(0.9 mmol, 2 equiv.), K2CO3 (0.9 mmol, 2 equiv.), PtBu3HBF4
(0.09 mmol, 0.2 equiv.), and Pd(OAc)2 (0.045 mmol, 0.1 equiv.) in
toluene (2 mL), in air, was heated to 110 °C. The reaction mixture
was stirred for 48 h, and the mixture was then allowed to cool to
room temperature. After evaporation of the solvent under reduced
pressure and the addition of water (15 mL), the residue was ex-
tracted with CH2Cl2 (3ϫ15 mL). The combined organic layers
were dried with MgSO4 and concentrated under vacuum. The resi-
due was purified by column chromatography on silica gel (EtOAc/
petroleum ether).
Conclusions
In summary, we have described new methodology al-
lowing the control of the direct arylation site of 5,7-di-
methyl-2-phenylpyrazolo[1,5-a]pyrimidine; the reaction
may be induced to occur at either an sp3 or an sp2 carbon
atom. The scope of this procedure was established by the
synthesis of a library of various mono-/diarylated 5,7-di-
methyl-2-phenylpyrazolo[1,5-a]pyrimidines, which should
make this approach useful for the rapid derivatization of
heterocyclic compounds such as bioactive derivatives con-
taining the pyrazolo[1,5-a]pyrimidine core structure.
5,7-Dimethyl-2-phenyl-3-m-tolylpyrazolo[1,5-a]pyrimidine (3a): Col-
umn chromatography: EtOAc/petroleum ether, 1:9. Brown solid
1
(87 mg), m.p. 134–135 °C. H NMR (400 MHz, CDCl3): δ = 7.66–
7.64 (m, 2 H, HAr), 7.39 (s, 1 H, HAr), 7.35–7.34 (m, 3 H, HAr),
7.29 (d, J = 7.6 Hz, 1 H, HAr), 7.23 (t, J = 7.6 Hz, 1 H, HAr), 7.08
(d, J = 7.6 Hz, 1 H, HAr), 6.58 (s, H6), 2.80 (s, 3 H, CH3-C7),
2.57 (s, 3 H, CH3-C5), 2.34 (CH3, s) ppm. 13C NMR (100.62 MHz,
CDCl3): δ = 158.7, 153.6, 146.9, 145.0, 137.9, 133.8, 132.3, 130.8,
129.2, 128.5, 128.4, 128.3, 127.4, 127.4, 109.0, 108.3, 25.0, 21.7,
17.2 ppm. HRMS: calcd. for C21H19N3 [M + H]+ 314.1657; found
314.1645.
Experimental Section
General: Melting points were determined with a Büchi apparatus.
1H NMR and 13C NMR were recorded with a Bruker DPX 250 or
AV 400 spectrometer (250.19 MHz for H, 62.89 MHz for 13C) by
1
using tetramethylsilane as the internal standard, multiplicities were
determined by using a DEPT 135 sequence. Splitting patterns are
designated as s, singlet; d, doublet, dd, doublet of doublets; ddd,
doublet of doublets of doublets; t, triplet, dt, doublet of triplets;
m, multiplet. High-resolution mass spectra (HRMS) were recorded
with a MAXIS Q-TOF Bruker TOF spectrometer in the electro-
spray ionization (ESI) mode or in chemical ionization (CI) mode.
All commercial solvents were used without further purification.
Column chromatography was carried out by using silica gel 60N
(spherical, neutral, 40–63 μm). Thin-layer chromatography (TLC)
was carried out on silica gel 60F254 precoated plates. Visualization
was achieved with ultraviolet light. Compounds 1, 3b, and 3e are
known compounds, which were identified by comparison of their
spectral data with that reported.[11,16]
5,7-Dimethyl-2,3-diphenylpyrazolo[1,5-a]pyrimidine (3b): Column
chromatography: EtOAc/petroleum ether, 1:9. White solid
(86.8 mg, 65% yield), m.p. 161–162 °C.[16] 1H NMR (400 MHz,
CDCl3): δ = 7.66–7.63 (m, 2 H, HAr), 7.55 (d, J = 7.2 Hz, 2 H,
HAr), 7.37–7.34 (m, 5 H, HAr), 7.28–7.24 (m, 1 H, HAr), 6.58 (d, J
= 0.8 Hz, H6), 2.80 (d, J = 0.4 Hz, 3 H, CH3-C7), 2.58 (s, 3 H,
CH3-C5) ppm. 13C NMR (100.62 MHz, CDCl3): δ = 158.9, 153.7,
146, 145.04, 133.8, 132.5, 130.1, 129.3, 128.5, 128.4, 126.5, 109.0,
108.2, 25.1, 17.2 ppm. MS (ESI): m/z = 300 [M + H]+.
5,7-Dimethyl-2-phenyl-3-p-tolylpyrazolo[1,5-a]pyrimidine (3c): Col-
umn chromatography: EtOAc/petroleum ether, 1:9. Yellow solid
(85 mg, 61% yield), m.p. 167–168 °C. 1H NMR (400 MHz,
CDCl3): δ = 7.67–7.65 (m, 2 H, HAr), 7.43 (d, J = 8 Hz, 2 H, HAr),
7.36 (dd, J = 5.2, 2 Hz, 3 H, HAr), 7.17 (d, J = 8 Hz, 2 H, HAr),
6.58 (s, H6), 2.79 (s, 3 H, CH3-C7), 2.57 (s, 3 H, CH3-C5), 2.37 (s,
3 H, CH3) ppm. 13C NMR (100.62 MHz, CDCl3): δ = 158.7, 153.5,
146.9, 144.9, 136.1, 133.9, 130.0, 129.4, 129.2, 128.5, 128.4, 108.9,
108.2, 25.0, 21.4, 17.2 ppm. HRMS: calcd. for C21H20N3 [M +
H]+ 314.1657; found 314.1637.
Procedure for the Synthesis of 5,7-Dimethyl-2-phenylpyrazolo[1,5-
a]pyrimidines 1: Prepared according to a literature procedure.[11]
A
round-bottomed flask was charged with 3-amino-5-phenylpyrazole
(1 g, 6.282 mmol), acetyl acetone (7.02 mmol), and 37% hydro-
chloric acid (7 mL). The mixture was heated at reflux for 10 h.
After the reaction was complete, the mixture was cooled, neutral-
ized with aq. Na2CO3, and extracted with CHCl3 (3ϫ40 mL). The
combined organic layers were dried with anhydrous MgSO4. The
solvent was evaporated, and the crude product was purified by
recrystallization (ethanol/hexane, 4:1) and gave a beige solid (72%).
5,7-Dimethyl-2-phenyl-3-o-tolylpyrazolo[1,5-a]pyrimidine (3d): Col-
umn chromatography: EtOAc/petroleum ether, 1:9. Yellow solid
M.p. 154–155 °C. 1H NMR (400 MHz, CDCl3): δ = 8.01 (d, J = (81 mg, 58% yield), m.p. 109–110 °C. 1H NMR (400 MHz,
8.0 Hz, 2 H, HAr), 7.46 (t, J = 7.5 Hz, 2 H, HAr), 7.38 (t, J = CDCl3): δ = 7.53–7.51 (m, 2 H, HAr), 7.21–7.16 (m, 7 H, HAr), 6.49
7.3 Hz, 1 H, HAr), 6.85 (s, H3), 6.54 (s, H6), 2.79 (s, 3 H, CH3-C7), (d, J = 0.8 Hz, 1 H, H6), 2.74 (d, J = 0.4 Hz, 3 H, CH3-C7), 2.45
2.56 (s, 3 H, CH3-C5) ppm. 13C NMR (100.62 MHz, CDCl3): δ = (s, 3 H, CH3-C5), 2.00 (s, 3 H, CH3) ppm. 13C NMR (100.62 MHz,
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Catalyst- and Base-Controlled Site-Selective sp2 and sp3 Direct Arylations
CDCl3): δ = 158.5, 153.3, 147.1, 144.9, 138.2, 133.9, 132.1, 132.0,
130.4, 128.5, 128.3, 128.1, 127.7, 125.9, 108.8, 108.1, 24.9, 20.5,
17.1 ppm. HRMS: calcd. for C21H20N3 [M + H]+ 314.165544;
found 314.165174.
solid (90 mg, 50 %), m.p. 144–145 °C. 1H NMR (400 MHz,
CDCl3): δ = 7.89 (d, J = 7.2 Hz, 2 H, HAr), 7.41 (t, J = 7.4 Hz, 2
H, HAr), 7.34 (t, J = 7.2 Hz, 1 H, HAr), 7.22 (t, J = 7.4 Hz, 2 H,
HAr), 7.10–7.01 (m, 6 H, HAr), 6.83 (s, H3), 6.44 (s, H6), 6.26 (s, 1
H, CH-C7), 2.54 (s, 3 H, CH3-C5), 2.32 (s, 6 H, 2ϫCH3) ppm. 13C
NMR (100.62 MHz, CDCl3): δ = 158.4, 155.3, 150.4, 149.9, 139.3,
138.4, 133.4, 130.2, 128.8, 128.7, 128.6, 128.2, 126.7, 126.5, 108.9,
92.6, 51.0, 25.1, 21.6 ppm. HRMS: calcd. for C28H25N3 [M + H]+
404.2127; found 404.2138.
3-(4-Methoxyphenyl)-5,7-dimethyl-2-phenylpyrazolo[1,5-a]-
pyrimidine (3e): Column chromatography: EtOAc/petroleum ether,
1:9. White solid (115 mg, 78% yield), m.p. 173–174 °C.[16] 1H NMR
(400 MHz, CDCl3): δ = 7.67–7.64 (m, 2 H, HAr), 7.46 (d, J =
8.8 Hz, 2 H, HAr), 7.35 (dd, J = 5.2, 1.6 Hz, 3 H, HAr), 6.92 (d, J
= 8.8 Hz, 2 H, HAr), 6.57 (s, H6), 3.83 (s, 3 H, CH3-O), 2.79 (s, 3
H, CH3-C7), 2.57 (s, 3 H, CH3-C5) ppm. 13C NMR (100.62 MHz,
CDCl3): δ = 158.6, 158.4, 153.4, 146.8, 145.0, 133.9, 131.2, 129.2,
128.5, 128.4, 124.8, 114.1, 108.9, 107.9, 55.4, 25.0, 17.2 ppm. MS
(ESI): m/z = 330 [M + H]+.
7-(Diphenylmethyl)-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidine
(4b): Column chromatography: EtOAc/petroleum ether, 1:9. Beige
solid (96 mg, 57% yield), m.p. 209–210 °C. 1H NMR (400 MHz,
CDCl3): δ = 7.87 (d, J = 7.2 Hz, 2 H, HAr), 7.39 (d, J = 7.2 Hz, 2
H, HAr), 7.30 (dd, J = 7.2, 16 Hz, 7 H, HAr), 7.25–7.23 (m, 4 H,
H
Ar), 6.84 (s, H3), 6.51 (s, H6), 6.24 (s, 1 H, CH-C7), 2.52 (s, 3 H,
3-(4-Fluorophenyl)-5,7-dimethyl-2-phenylpyrazolo[1,5-a]pyrimidine
(3f): Column chromatography: EtOAc/petroleum ether, 1:9. Yellow
CH3-C5) ppm. 13C NMR (100.62 MHz, CDCl3): δ = 158.3, 155.3,
150.2, 149.9, 139.2, 133.3, 130.2, 129.4, 128.8, 128.7, 127.4, 126.6,
108.8, 92.7, 51.1, 25.1 ppm. HRMS: calcd. for C26H21N3
[M + H]+ 376.1814; found 376.1819.
1
solid (91.5 mg, 64% yield), m.p. 152–153 °C. H NMR (400 MHz,
CDCl3): δ = 7.63–7.60 (m, 2 H, HAr), 7.50 (dd, JH,H = 8.8, 4 Hz,
JH,F = 5.6 Hz, 2 H, HAr), 7.37–7.35 (m, 3 H, HAr), 7.04 (t, JH,H
=
3 Hz, JH,F = 8.8 Hz, 2 H, HAr), 6.59 (s, H6), 2.79 (s, 3 H, CH3-C7),
2.57 (s, 3 H, CH3-C5) ppm. 13C NMR (100.62 MHz, CDCl3): δ =
7-(Di-p-tolylmethyl)-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidine
(4c): Column chromatography: EtOAc/petroleum ether, 1:9. White
solid (99 mg, 55% yield), m.p. 150–151 °C. 1H NMR (400 MHz,
CDCl3): δ = 7.89 (d, J = 7.2 Hz, 2 H, HAr), 7.40 (t, J = 7.6 Hz, 2
H, HAr), 7.33 (t, J = 7.2 Hz, 2 H, HAr), 7.12 (s, 8 H, HAr), 6.82 (s,
H3), 6.43 (s, H6), 6.26 (s, 1 H, CH-C7), 2.53 (s, 3 H, CH3-C5), 2.33
(s, 6 H, 2ϫCH3) ppm. 13C NMR (100.62 MHz, CDCl3): δ = 158.3,
155.2, 150.6, 149.8, 136.9, 136.4, 133.3, 129.4, 129.2, 128.7, 128.7,
126.6, 108.6, 92.5, 50.2, 25.1, 21.2 ppm. HRMS: calcd. for
C28H26N3 [M + H]+ 404.2127; found 404.2146.
1
161.8 (d, JCF = 245.1 Hz), 159.0, 153.6, 146.8, 145.1, 133.6, 131.6
3
4
(d, JCF = 7.8 Hz), 129.2, 128.6, 128.5, 128.4 (d, JCF = 3.3 Hz),
2
115.4 (d, JCF = 21.3 Hz), 109.1, 107.1, 25.0, 17.2 ppm. HRMS:
calcd. for C20H16FN3 [M + H]+ 318.1407; found 318.1422.
5,7-Dimethyl-2-phenyl-3-(pyridine-4-yl)pyrazolo[1,5-a]pyrimidine
(3g): Column chromatography: acetone/petroleum ether, 2:8. Yel-
low solid (57.8 mg, 43 % yield for 2 equiv. of 4-bromopyridine;
73.5 mg, 55 % yield for 3 equiv. of 4-bromopyridine), m.p. 141–
142 °C. 1H NMR (400 MHz, CDCl3): δ = 8.53 (d, J = 5.6 Hz, 2
H, HAr), 7.63–7.60 (m, 2 H, HAr), 7.56 (d, J = 6.0 Hz, 2 H, HAr),
7.43–7.41 (m, 3 H, HAr), 6.68 (s, H6), 2.81 (s, 3 H, CH3-C7), 2.63
(s, 3 H, CH3-C5) ppm. 13C NMR (100.62 MHz, CDCl3): δ = 160.0,
154.6, 149.7, 147.1, 145.6, 140.8, 133.3, 129.4, 129.0, 128.8, 123.9,
109.7, 105.0, 25.1, 17.2 ppm. HRMS: calcd. for C19H16N4
[M + H]+ 301.1453; found 301.1461.
7-(Di-o-tolylmethyl)-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidine
(4d): Column chromatography: EtOAc/petroleum ether, 1:9. Brown
1
solid (92.6 mg, 51% yield), m.p. 205–206 °C. H NMR (400 MHz,
CDCl3): δ = 7.89 (d, J = 6.8 Hz, 2 H, HAr), 7.37 (dt, J = 7.4 Hz, 3
H, HAr), 7.24–7.19 (m, 4 H, HAr), 7.11 (t, J = 7.4 Hz, 2 H, HAr),
6.91 (d, J = 7.6 Hz, 2 H, HAr), 6.85 (s, 1 H, H3), 6.69 (s, 1 H, H6),
6.15 (s, 1 H, CH-C7), 2.53 (s, 3 H, CH3-C5), 2.32 (s, 6 H, 2
CH3) ppm. 13C NMR (100.62 MHz, CDCl3): δ = 158.3,155.3,
149.8, 137.4, 137.1, 133.3, 130.9, 128.8, 128.7, 128.3, 127.5, 126.6,
126.2, 108.8, 92.6, 44.6, 25.1, 19.7 ppm. HRMS: calcd. for
C28H25N3Na [M + Na]+ 426.194119; found 426.194069.
Methyl-4-(5,7-dimethyl-2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)-
benzoate (3h): Column chromatography: EtOAc/petroleum ether,
1
2:8. Yellow solid (93.9 mg, 59% yield), m.p. 205–206 °C. H NMR
(400 MHz, CDCl3): δ = 8.01 (d, J = 8.4 Hz, 2 H, HAr), 7.66 (d, J
= 8.4 Hz, 2 H, HAr), 7.62–7.60 (m, 2 H, HAr), 7.39–7.37 (m, 3 H,
HAr), 6.64 (s, H6), 3.91 (s, 3 H, CH3-O), 2.81 (s, 3 H, CH3-C7),
2.60 (s, 3 H, CH3-C5) ppm. 13C NMR (100.62 MHz, CDCl3): δ =
167.4,159.5, 154.1, 146.9, 145.3, 137.6, 133.5, 129.7, 129.6, 129.3,
128.7, 128.7, 127.7, 109.4, 107.1, 52.1, 25.1, 17.2 ppm. HRMS:
calcd. for C22H19N3O2 [M + H]+ 358.1556; found 358.1571.
7-[Bis(4-methoxyphenyl)methyl]-5-methyl-2-phenylpyrazolo[1,5-a]-
pyrimidine (4e): Column chromatography: acetone/petroleum ether,
1
1:9. Yellow solid (104 mg, 53% yield), m.p. 131–132 °C. H NMR
(400 MHz, CDCl3): δ = 7.89 (d, J = 7.2 Hz, 2 H, HAr), 7.37 (ddd,
J = 6.8, 7.6, 27.6 Hz, 3 H, HAr), 7.14 (d, J = 8.8 Hz, 4 H, HAr),
6.86 (d, J = 8.8 Hz, 4 H, HAr), 6.83 (s, H3), 6.40 (s, H6), 6.24 (s, 1
H, CH-C7), 3.79 (s, 6 H, 2 OCH3), 2.53 (s, 3 H, CH3-C5) ppm. 13
C
General Procedure for the sp3 Direct Arylation: Under an atmo-
sphere of argon, a mixture of 5,7-dimethyl-2-phenylpyrazolo[1,5-a]-
pyrimidine 1 (0.1 g, 0.45 mmol), aryl or heteroaryl bromide 2
(1.12 mmol, 2.5 equiv.), Cs2CO3 (0.9 mmol, 2 equiv.), PPh3
(0.09 mmol, 0.2 equiv.), and Pd(OAc)2 (0.045 mmol, 0.1 equiv.) in
toluene (2 mL) was heated to 110 °C. The reaction mixture was
stirred for 24 h, and the mixture was then allowed to cool to room
temperature. After evaporation of the solvent under reduced pres-
sure and the addition of water (15 mL), the residue was extracted
with CH2Cl2 (3ϫ15 mL). The combined organic layers were dried
with MgSO4 and concentrated under vacuum and the residue was
purified by column chromatography on silica gel (EtOAc/petroleum
Ether).
NMR (100.62 MHz, CDCl3): δ = 158.8,158.4, 155.3, 150.9, 149.9,
133.4, 131.6, 130.4, 128.8, 128.7, 126.6, 114.1, 108.6, 92.6, 55.4,
49.5, 25.1 ppm. HRMS: calcd. for C28H25N3O2 [M + H]+ 436.2025;
found 436.2026.
7-[Bis(4-fluorophenyl)methyl]-5-methyl-2-phenylpyrazolo[1,5-a]-
pyrimidine (4f): Column chromatography: dichloromethane. Brown
solid (115.4 mg, 63% yield), m.p. 170–171 °C. 1H NMR (400 MHz,
CDCl3): δ = 7.86 (d, J = 6.8 Hz, 2 H, HAr), 7.41 (t, J = 7.2 Hz, 2
H, HAr), 7.35 (t, J = 7.2 Hz, 1 H, HAr), 7.18 (dd, JH,H = 8.4 Hz,
4JH,F = 5.2 Hz, 4 H, HAr), 7.04 (t, JH,H
=
3JH,F = 8.4 Hz, 4 H,
HAr), 6.85 (s, H3), 6.44 (s, H6), 6.18 (s, 1 H, CH-C7), 2.54 (s, 3 H,
CH3-C5) ppm. 13C NMR (100.62 MHz, CDCl3): δ = 162.2 (d, 1JCF
4
7-(Di-m-tolylmethyl)-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidine = 246.6 Hz), 158.4, 155.6, 149.9, 149.7, 134.8 (d, JCF = 3.3 Hz),
(4a): Column chromatography: EtOAc/petroleum ether, 2:8. Brown
3
2
133.1, 130.9 (d, JCF = 8 Hz), 129.0, 128.8, 126.6, 115.9 (d, JCF
=
Eur. J. Org. Chem. 2012, 2572–2578
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2577

S. Berteina-Raboin et al.
FULL PAPER
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21.5 Hz), 108.6, 92.9, 49.6, 25.14 ppm. HRMS: calcd. for
C26H19F2N3 [M + H]+ 412.1625; found 412.1640.
Dimethyl 4,4Ј-{(5-Methyl-2-phenylpyrazolo[1,5-a]pyrimidin-7-yl)-
methylene}dibenzoate (4h): Column chromatography: acetone/
petroleum ether, 1.5:8.5. Yellow solid (111 mg, 50% yield), m.p.
1
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224–225 °C. H NMR (400 MHz, CDCl3): δ = 8.03 (d, J = 8 Hz,
4 H, HAr), 7.83 (d, J = 7.2 Hz, 2 H, HAr), 7.41–7.34 (m, 3 H, HAr),
7.30 (d, J = 8 Hz, 4 H, HAr), 6.86 (s, H3), 6.56 (s, H6), 6.17 (s, 1
H, C7-CH), 3.91 (s, 6 H, 2 CH3O), 2.53 (s, 3 H, CH3-C5) ppm. 13C
NMR (100.62 MHz, CDCl3): δ = 166.8, 158.4, 155.7, 149.8, 148.5,
143.6, 133.0, 130.3, 129.7, 129.4, 129.0, 128.8, 126.6, 108.9, 93.0,
52.3, 51.1, 25.1 ppm. HRMS: calcd. for C30H25N3O4 [M + H]+
492.1923; found 492.1901.
CCDC-793971 (for 3a), -793972 (for 4b), and -793973 (for 4a) con-
tains the supplementary crystallographic data for this paper. These
data can be obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Supporting Information (see footnote on the first page of this arti-
cle): Copies of all NMR spectra (1H and 13C) and additional X-
ray crystallography data for 3a, 4b, and 4c.
Acknowledgments
We thank Egide and the Programme Hubert Curien Volubilis for
financial support.
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Received: December 21, 2011
Published Online: March 21, 2012
2578
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© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 2572–2578