Vilsmeier reagent-mediated synthesis of 6-[(formyloxy)methyl]-pyrazolopyrimidines via a one-pot multiple tandem reaction

Article abstract of DOI:10.1039/c5ra07707a

A new Vilsmeier reagent-mediated one-pot reaction using 5-(2-chloroacetylamino)pyrazoles as the starting material was developed for the efficient synthesis of 6-[(formyloxy)methyl]-1H-pyrazolo[3,4-d]pyrimidine. This new multiple tandem reaction, involving

Full text of DOI:10.1039/c5ra07707a

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Graphical abstract
Vilsmeier reagent mediated synthesis of 6-[(formyl)methyl]-pyrazolopyrimidines
via one-pot multiple tandem reaction
Shi-Han Lu, Po-Lin Liu, and Fung Fuh Wong*
Vilsmeier reagent mediated synthesis of pyrazolopyrimidine
O
H
O
O
Y
O
H
NH2, PBr3
HN
N
N
X = aryl, Y = Cl, Br, I, OH
X
N
X
N
R = Me, t-Bu, p-MePh, p-OMePh
N
N
R
R
- 1 -

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Vilsmeier
reagent
mediated
synthesis
of
6-[(formyloxy)methyl]-pyrazolopyrimidines via one-pot multiple
tandem reaction
ShiꢀHan Lu,a,b PoꢀLin Liu,b,c Fung Fuh Wong,*a,b
aSchool of Pharmacy, China Medical University, No. 91, Hsueh-Shih Rd., Taichung
40402, Taiwan
bGraduate Institute of Pharmaceutical Chemistry, China Medical University, No. 91,
Hsueh-Shih Rd., Taichung 40402, Taiwan
cThe contribution equal to first author.
*Corresponding Author. Tel.: +886 4 2205 3366 ext. 5603; Fax: +886 4 2207 8083.
Eꢀmail address: wongfungfuh@yahoo.com.tw, ffwong@mail.cmu.edu.tw (F. F.
Wong)
Keywords: Pyrazole, pyrazolopyrimidine, Vilsmeierꢀtype reaction, MorganꢀWalls
cyclization, Heterocyclization
Abstract
A
new
Vilsmeier
reagent
mediated
oneꢀpot
reaction
using
5ꢀ(2ꢀchloroacetylamino)pyrazoles as the starting material was developed for the
efficient synthesis of 6ꢀ[(formyloxy)methyl]ꢀ1Hꢀpyrazolo[3,4ꢀd]pyrimidine. This new
multiple tandem reactions involving VilsmeierꢀHaack reaction, MorganꢀWalls
reaction, sequential elimination, substitution reaction, and final hydrolysis reaction
efficiently afforded formyloxymethyl pyrazolo[3,4ꢀd]pyrimidine products in good
yields.
ꢀ 1 ꢀ

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Introduction
As an expressly practical synthetic organic chemistry, the efficient, rapid and
economical strategies were enthusiastically investigated to design the valuable
chemical substances.1,2 Oneꢀpot tandem organic reactions have attracted great
attentions for they can simplify the detection, isolation, and purification of
intermediates in the operation procedure and also diminish the manufacture cost and
environmental pollution.3,4 Additionally, the oneꢀpot multiple processes were also
recommended to the new synthetically efficient method and reaction designed
approach for developing novel lead constructions of pharmaceuticals and even novel
moleculeꢀbased materials.5
Vilsmeierꢀtype reaction is a very versatile method for the construction of many
heterocyclic compounds5,6 and acts an important organic synthetic tool for the
introduction of a formyl group.6ꢀ10 Recently, we have evaluated new Visemeierꢀtype
reaction by studying the reactivity of amide reagents for the preparation of
pyrazolone,11 pyrazole,12 dipyrazolylmethane,13 and fused pyrimidine derivatives.14
Those works indicated the chemoselective products resulted from the different
reactivity of the substituted amides serving as the Vilsmeier reagent by reacting with
POCl3. On the other hands, MorganꢀWalls cyclization reaction has been widely used
for C–C bond formation to build various nitrogen ring systems.15 Herein, we reported
the use of Vilsmeier reagent to initiate the VilsmeierꢀHaack formylation reaction,
MorganꢀWalls cyclization reaction, sequential elimination, substitution reaction, and
hydrolysis for synthesis of the pyrazole fused pyrimidine derivatives via a tandem
multiple reaction.14,16
Pyrimidines fused with a heterocycle such as furoꢀ,17 pyrazoloꢀ,18 pyrroloꢀ,19
pyridopyrazoloꢀ,20 and pyrazolotriazoloꢀpyrimidine21 are important classes of
compounds and also currently of interest to the pharmaceutical industry due to their
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remarkable pharmaceutical applications. Other synthesis approaches of
pyrazolopyrimidines were also found through heterocyclization reaction using
5ꢀaminoꢀ4ꢀformypyrazoles,22
5ꢀaminoꢀ1Hꢀ4ꢀpyrazolcarbonitriles,23
5ꢀaminoꢀ1Hꢀ4ꢀpyrazolcarboxamides23 or other similar chemical reagents as the
starting substrates.24ꢀ26 However, the reported synthetic manipulation for their
preparation requires harsh conditions, long reaction times, complex synthetic
procedures, and tedious purification steps.27 Therefore, new convenient synthetic
routes for the synthesis of pyrimidine fused heterocyclic systems have attracted
considerable attention. In this work, we described a direct and convenient oneꢀpot
multiple method for the synthesis of a series of pyrazolo[3,4ꢀd]pyrimidine derivatives
from 5ꢀ(2ꢀchloroacetylamino)pyrazoles with formamide in the presence of PBr3. This
new multiple tandem reaction was developed to obtain formyloxymethyl
pyrazolo[3,4ꢀd]pyrimidine products in good yields (73–92%).
Result and discussion
Scheme 1 presents the typical reaction conditions for Vilsmeier reagent mediated
synthesis of 1ꢀarylꢀ6ꢀ[(formyloxy)methyl]ꢀ1Hꢀpyrazolo[3,4ꢀd]pyrimidines 17–32
from 5ꢀ(2ꢀChloroacetylamino)pyrazoles 1–16. Starting materials 1–16 were prepared
from the reaction of 5ꢀaminopyrazoles and 2ꢀchloroacetyl chloride as previously
reported.28 Due to 5ꢀ(2ꢀchloroacetylamino)pyrazoles 1–16 possessed the activated
αꢀchloroꢀNꢀarylacetamide moiety, we attempted to introduce the mild nucleophile
iminium
group
on
the
Cꢀ4
position
of
pyrazolic
ring
of
5ꢀ(2ꢀchloroacetylamino)pyrazoles 1–16 via VilsmeierꢀHaack reaction for evaluation
the further intramolecular cyclization reaction condition for synthesis of
6ꢀ[(formyloxy)methyl]ꢀ1Hꢀpyrazolo[3,4ꢀd]pyrimidine in this work.
Scheme 1
To
optimize
the
reaction
conditions,
ꢀ 3 ꢀ

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1,3ꢀdiphenylꢀ5ꢀ(2ꢀchloroacetylamino)pyrazole (1) was used as the model and reacted
with formamide in the presence of various halogenating agents including benzoyl
chloride (PhCOCl), oxalyl chloride (ClCOCOCl), phosphorous tribromide (PBr3),
phosphorous oxychloride (POCl3), thionly chloride (SOCl2), and pꢀtoluenesulfonic
chloride (TsCl) at 50–60 °C for 5.0 h. Without the halogenating agent, virtually no
reaction took place (see entry 1 in Table 1). When 3.0 equivalents of halogenating
agents
were
added,
the
reaction
gave
the
corresponding
1,3ꢀdiphenylꢀ6ꢀ[(formyloxy)methyl]ꢀ1Hꢀpyrazolo[3,4ꢀd]pyrimidine (17) in 26–88%
yields (see entries 2–7 in Table 1). The use of PBr3 provided the best result with the
formation of product 17 in 88% yield (entry 2 in Table 1). The use of POCl3 also gave
a good yield of 17 (73%, entry 2 in Table 1).
Table 1
Employing the reliable procedure by use of PBr3 as the brominating agent to
5ꢀ(2ꢀchloroacetylamino)pyrazoles 1–8 possessing methyl, chloro, and methoxy
substituents, the tandem oneꢀpot multiple reaction could readily take place to give the
corresponding 1ꢀarylꢀ6ꢀ[(formyloxy)methyl]ꢀ1Hꢀpyrazolo[3,4ꢀd]pyrimidines 17–24 in
73–92% yields (see Scheme 1 and Table 2). We found the mꢀ and pꢀMeꢀPh at the Nꢀ1
substituents
in
pyrazolic
ring
gave
the
1ꢀarylꢀ6ꢀ[(formyloxy)methyl]ꢀ1Hꢀpyrazolo[3,4ꢀd]pyrimidines 19 and 20 in better
isolated yields (85% and 92%). Employing the same conditions to
5ꢀ(2ꢀchloroacetylamino)pyrazoles with methyl, pꢀNO2ꢀPh and pꢀCOOHꢀPh
substituents at the Nꢀ1 position of pyrazolic ring did not give the desired
pyrazolo[3,4ꢀd]pyrimidine products. As a result, we assumed the phenyl group with
electronꢀdonating group as the Nꢀ1 substituents would favor the proceeding of oneꢀpot
multiple reaction.
Table 2
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For further investigation of the substitution effect, the same conditions were
applied to 5ꢀ(2ꢀchloroacetylamino)pyrazoles 9–12 containing methyl, tꢀbutyl,
pꢀMeꢀPh, pꢀClꢀPh, or pꢀOMeꢀPh groups at the Cꢀ3 position and phenyl substituent at
the Nꢀ1 position. The reaction also successfully gave the corresponding 25–28 in
74–81% yields (see Scheme 1 and Table 2). In particular, compound 10 with tꢀbutyl
group at the Cꢀ3 position showed better yield (81%). For further demonstration of
electronic effects of metaꢀ or para substituent at the Nꢀ1 position of pyrazolic ring,
compounds 13 and 14 were synthesized as the starting material to perform the
reaction. The experimental results listed in Table 2 indicated that the Nꢀ1 paraꢀMe
phenyl displayed better yield than metaꢀMe substituent (84% vs. 74%). For
compounds I 15 and 16 bearing respective othorꢀ and paraꢀCl phenyl substituents at
the Nꢀ1 position, the inducted effect of Nꢀ1 paraꢀCl substituent was also better than
othorꢀCl
(77%
>
72%,
see
Table
2).
All
6ꢀ[(formyloxy)methyl]ꢀ1Hꢀpyrazolo[3,4ꢀd]pyrimidines
17–30
were
fully
characterized by spectroscopic methods. Furthermore, the structure of
6ꢀ[(formyloxy)methyl]ꢀ1Hꢀpyrazolo[3,4ꢀd]pyrimidines 24 was also characterized by
Xꢀray crystallographic analyses and the result (ORTEP) was presented in Figure 1.
Figure 1
We then investigated the effect of leaving group at the α position (–(C=O)–CH–X)
for
this
new
transformation.
Starting
materials
including
5ꢀ(2ꢀbromoacetylamino)pyrazole 33, 5ꢀ(2ꢀiodoacetylamino)pyrazole 34, and
5ꢀ(2ꢀhydroxyacetylamino)pyrazole 3529 bearing Br, I, and OH at the αꢀC position
were prepared (see Table 3). By employing the same reaction condition to compounds
33–35, the better results were observed for compounds 33 and 34 in 86% and 87%
yields, respectively (see entry 2 and 3 in Table 3). Although the hydroxyl group is not
good leaving group, compound 35 was also successfully converted to the
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corresponding pyrimidine fused product 22 in 73% yield due to the hydroxyl group
was transformed into an efficient leaving group O(P=O)Br2 in the presence of PBr3
(see Table 3). Based on the results, we found the reactivity of leaving group was I >
Br > Cl > OH. To conceive economic cost and commercial available of reagents, we
selected and synthesized a series of 5ꢀ(2ꢀhydroxyacetylamino)pyrazoles as the starting
materials for our further evaluation.
Table 3
Following the experimental results, we proposed a plausible mechanism for this
new oneꢀpot multiple reaction in Scheme 2. Preliminarily, Vilsmeier reactive species
36 was generated from the reaction of formamide with PBr3 in situ.11ꢀ14,30
1,3ꢀDiphenylꢀ5ꢀ(2ꢀchloroacetylamino)pyrazole 1 then reacted with 36 to undergo the
Vilsmeier–Haack reaction to afford intermediate 37 with introducing imino group on
Cꢀ4 position of pyrazoylic ring (see Scheme 2). In strong acidic conditions, excess
amount of PBr3 would catalyze the MorganꢀWalls reaction to provide 38 and
subsequently convert to generate 39 via intramolecular cyclization reaction.31
Intermediates 37 and 38 with electronꢀwithdrawing groups, such as NO2 and COOH,
would decrease the nucleophilicity of imino group through conjugated effect and
unfavorably took place the heterocyclization reaction. On the other hand,
intermediates 38 including Nꢀ1 aliphatic methyl substituent was harmfully for the
coꢀplane formation to interfere with the intraꢀcyclization reaction. As a result,
5ꢀ(2ꢀchloroacetylamino)pyrazoles with methyl, pꢀNO2ꢀPh and pꢀCOOHꢀPh
substituents in Nꢀ1 position of pyrazolic ring were unable to adapt in this new
developed reaction condition. After the futher deprotonation of intermediate 39,
6ꢀ(chloromethyl)pyrazolo[3,4ꢀd]pyrimidine intermediate 40 was formed. It is well
known that formamide possesses two resonance contributors 42 and 43.32,33 In the
acidic condition, formamide was more favored the C(O–)=N+H2 42 contributor thus
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replaced the chloro atom in 40 to give the substitution product 41. After workꢀup,
intermediate 41 was hydrolyzed to 6ꢀ[(formyl)methyl]ꢀ1Hꢀpyrazolo[3,4ꢀd]pyrimidine
17
as
the
major
product
(88%
yield)
and
(1,3ꢀdiphenylꢀ1Hꢀpyrazolo[3,4ꢀd]pyrimidinꢀ6ꢀyl)methanol 44 as the minor product
(9% yield, see Scheme 2).
Scheme 2
During workꢀup and purification procedures, small amount of 44 was isolated as
the byꢀproduct (see Scheme 2). This result led us to consider that compound 44 might
be equilibria toward compound 17 under the acidic condition. Therefore, we isolated
compound 44 and treated it with formamide and PBr3 under the same condition.
Compound
44
was
successfully
transferred
to
the
corresponding
pyrazolo[3,4ꢀd]pyrimidine product 17 in 81% yield (see Scheme 3). Based on this
controlled experimental result, compounds 44 should be hydrolyzed equilibrium
expression product of compound 17 (see Scheme 3). For the further demonstration of
this conception, the crude resulting solution was added with H2O and kept at room
temperature. The mixture was sampling each 30 mins and monitored by TLC and
1HꢀNMR spectroscopic method. Following the result of TLC and 1HꢀNMR
spectroscopic characteristics, we found that compound 17 was gradually converted to
the hydrolyzed product 44. Therefore, the quenching neutralization procedure must be
effectively carried out to diminish this hydrolysis product 44.
Scheme 3
To gain insight into the reaction mechanism and to establish the formyloxylation
nature of the reaction, the further study was performed as shown in Scheme 2. For
giving more evidences to the proposed mechanism, we also tried to convert
compound
44
to
the
proposed
intermediate
6ꢀ(chloromethyl)pyrazolo[3,4ꢀd]pyrimidine 40 by treating it with thionyl chloride in
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CH2Cl2 (80%, see Scheme 3).34 Consequently, the synthesized intermediate 40 was
reacted towards formamide with PBr3 in the same condition. Fortunately, the
corresponding product 17 was effectively isolated in 74% yield. The results gave
more proof to our proposed mechanism.
Conclusions
We have successfully developed a new oneꢀpot multiple reaction to prepare
6ꢀ(formyloxymethyl)pyrazolo[3,4ꢀd]pyrimidine
by
treating
5ꢀ(2ꢀchloroacetylamino)pyrazoles with formamide in presence of PBr3. Based on the
study of leaving group, we found that the reactivity of leaving group effect is I > Br >
Cl
>
OH.
Following
the
further
mechanistic
study,
key
6ꢀ(chloromethyl)pyrazolo[3,4ꢀd]pyrimidine intermediate 40 was successfully
synthesized from (1,3ꢀdiphenylꢀ1Hꢀpyrazolo[3,4ꢀd]pyrimidinꢀ6ꢀyl)methanol 44 and
then converted to the desired 6ꢀ[(formyloxy)methyl]ꢀ1Hꢀpyrazolo[3,4ꢀd]pyrimidine
17 under the same condition. The mechanistic study significantly demonstrated the
plausible mechanism.
Experimental Section
All chemicals were reagent grade and used as purchased. All reactions were carried
out under nitrogen atmosphere and monitored by TLC analysis. Flash column
chromatography was carried out on silica gel (230–400 mesh). Commercially
1
available reagents were used without further purification unless otherwise noted. H
NMR were recorded at 200, 400, or 500 MHz and 13C NMR recorded at 50, 100, or
125 MHz, respectively, in CDCl3, CH3OD, and DMSOꢀd6 as solvent. The standard
abbreviations s, d, t, q, and m refer to singlet, doublet, triplet, quartet, and multiplet,
respectively. Coupling constant (J), whenever discernible, have been reported in Hz.
Infrared spectra (IR) were recorded as neat solutions or solids; and mass spectra were
recorded using electron impact or electrospray ionization techniques. The
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wavenumbers reported are referenced to the polystyrene 1601 cm–1 absorption. Flash
column chromatography purification of compounds was carried out by gradient
elution using hexanes in ethyl acetate (EA) unless otherwise stated. Highꢀresolution
mass spectra were obtained by means of a JEOL JMSꢀHX110 mass spectrometer.
Standard procedure for synthesis of 5-(2-haloacetylamino)pyrazoles 1–16 and
33–35.28 1ꢀArylꢀ3ꢀarylꢀ5ꢀaminopyrazoles (1.0 equiv) was dissolved in CH2Cl2 (10 mL)
and stirred in iceꢀbath. 2ꢀChloroacetyl chloride, 2ꢀchloroacetyl bromide, or
2ꢀiodoroacetyl chloride (1.2 equiv) in 10 mL of CH2Cl2 or THF were slowly added to
the reaction mixture at 0 °C under N2, respectively. The reaction was stirred at 0–10
°C for 3–4 h. The reaction mixture was washed with water (10 mL) and saturated
aqueous NaHCO3 (10 mL × 2). The organic layer was dried over MgSO4, filtered, and
concentrated under reduced pressure. The residue was purified by column
chromatography on silica gel to give the corresponding acylation product
5ꢀ(2ꢀhaloacetylamino)pyrazoles 1–6 and 33–35 in 73–87% yields.
1
5-(2-Chloroacetylamino)-1-phenyl-3-phenylpyrazole (1). H NMR (CDCl3, 200
MHz) δ 4.18 (s, 2 H, CH2), 7.10 (s, 1 H), 7.23–7.55 (m, 8 H, ArH), 7.86 (dd, 2 H, J =
8.0, 4.0 Hz), 8.63 (br, 1 H, N–H).
5-(2-Chloroacetylamino)-1-(2-methylphenyl)-3-phenylpyrazole (2). 1H NMR
(CDCl3, 200 MHz) δ 2.38 (d, J = 7.6 Hz, 3 H, CH3), 4.10 (s, 2 H, CH2), 6.96 (s, 1 H),
7.38–7.44 (m, 9 H, ArH).
5-(2-Chloroacetylamino)-1-(3-methylphenyl)-3-phenylpyrazole (3). 1H NMR
(CDCl3, 200 MHz) δ 2.13 (s, 3 H, CH3), 4.04 (s, 2 H, CH2), 7.31–7.47 (m, 8 H, ArH),
7.91 (d, J = 3.0 Hz, 2 H, ArH), 8.82 (br, 1 H, N–H).
5-(2-Chloroacetylamino)-1-(4-methylphenyl)-3-phenylpyrazole (4). 1H NMR
(CDCl3, 200 MHz) δ 2.42 (s, 3 H, CH3), 4.18 (s, 2 H, CH2), 7.09 (s, 1 H), 7.25–7.43
(m, 7H, ArH), 7.86 (dd, 2 H, J = 9.6, 8.0 Hz), 8.61 (br, 1 H, N–H).
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5-(2-Chloroacetylamino)-1-(2-chlorophenyl)-3-phenylpyrazole (5). 1H NMR
(CDCl3, 200 MHz) δ 4.13 (s, 2 H, CH2), 7.04 (s, 1 H), 7.25–7.55 (m, 9H, ArH), 8.29
(br, 1 H, N–H).
5-(2-Chloroacetylamino)-1-(3-chlorophenyl)-3-phenylpyrazole (6). Brown solid;
mp 101–102 °C; 1H NMR (CDCl3, 200 MHz) δ 4.20 (s, 2 H, CH2), 7.08 (s, 1 H, ArH),
7.31–7.47 (m, 5 H, ArH), 7.61 (s, 2 H, ArH), 7.85 (d, J = 7.6 Hz, 2 H, ArH), 8.61 (s, 1
H, N–H); 13C NMR (CDCl3, 50 MHz) δ 42.64, 96.23, 122.00, 124.88, 125.76 (2 ×
CH), 128.45, 128.66 (3 × CH), 130.84, 132.42, 135.42, 135.81, 138.64, 152.42,
162.50; IR (KBr) 3046, 2955, 2924, 2853, 1721 (s, C=O), 1201, 764; EIMS m/z: 349
(M+ + 4, 2), 347 (M+ + 2, 9), 345 (M+, 16), 194 (100), 165 (11), 133 (79), 105 (42), 91
(74), 77 (30); HRMS Calcd for C17H13Cl2ON3: 345.0436, Found: 345.0433.
5-(2-Chloroacetylamino)-1-(4-chlorophenyl)-3-phenylpyrazole (7). 1H NMR
(CDCl3, 200 MHz) δ 4.18 (s, 2 H, CH2), 7.04 (s, 1 H), 7.24–7.50 (m, 7H, ArH), 7.79
(dd, 2 H, J = 15.7, 7.8 Hz), 7.29 (br, 1 H, N–H).
5-(2-Chloroacetylamino)-1-(3-methoxyphenyl)-3-phenylpyrazole (8). 1H NMR
(CDCl3, 200 MHz) δ 3.86 (s, 3 H, CH3), 4.17 (s, 2 H, CH2), 7.01–7.07 (m, 3H, ArH),
7.39–7.46 (m, 5H, ArH), 7.83–7.84 (m, 2H, ArH), 8.54 (br, 1 H, N–H).
1
5-(2-Chloroacetylamino)-1-phenyl-3-methylpyrazole (9). H NMR (CDCl3, 200
MHz) δ 2.30 (s, 3 H, CH3), 4.13 (s, 2 H, CH2), 6.55 (s, 1 H), 7.36–7.54 (m, 5H, ArH),
8.52 (br, 1 H, N–H).
5-(2-Chloroacetylamino)-1-phenyl-3-tetrabutanyl pyrazole (10). 1H NMR (CDCl3,
200 MHz) δ 1.33 (s, 9 H, CH3), 4.13 (s, 2 H, CH2), 6.63 (s, 1 H), 7.46–7.48 (m, 5H,
ArH), 8.58 (br, 1 H, N–H).
1
5-(2-Chloroacetylamino)-1-phenyl-3-(4-methylphenyl) pyrazole (11). H NMR
(CDCl3, 200 MHz) δ 2.36 (s, 3 H, CH3), 4.15 (s, 2 H, CH2), 6.74 (s, 1 H), 7.06–7.54
(m, 7H, ArH), 7.72 (d, J = 6.4 Hz, 2 H, ArH), 8.65 (br, 1 H, N–H).
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1
5-(2-Chloroacetylamino)-1-phenyl-3-(4-methoxyphenyl) pyrazole (12). H NMR
(CDCl3, 200 MHz) δ 3.82 (s, 3 H, CH3), 4.18 (s, 2 H, CH2), 6.93 (d, J = 8.8 Hz, 2 H,
ArH), 7.04 (s, 1 H), 7.43–7.55 (m, 5H, ArH), 7.80 (dd, 2 H, J = 8.8, 4.4 Hz), 8.62 (br,
1 H, N–H).
5-(2-Chloroacetylamino)-1-(3-methlyphenyl)-3-(4-methoxyphenyl) pyrazole (13).
1H NMR (CDCl3, 200 MHz) δ 2.42 (s, 3 H, CH3), 3.82 (s, 3 H, CH3), 4.17 (s, 2 H,
CH2), 6.92 (dd, 2 H, J = 8.8, 6.8 Hz), 7.03 (s, 1 H), 7.26–7.41 (m, 4H, ArH), 7.80 (dd,
2 H, J = 8.8, 6.8 Hz), 8.66 (br, 1 H, N–H).
5-(2-Chloroacetylamino)-1-(4-methlyphenyl)-3-(4-methoxyphenyl) pyrazole (14).
1H NMR (CDCl3, 200 MHz) δ 2.39 (s, 3 H, CH3), 3.82 (s, 3 H, CH3), 4.17 (s, 2 H,
CH2), 6.92 (dd, 2 H, J = 8.8, 4.4 Hz), 7.02 (s, 1 H), 7.30–7.42 (m, 4H, ArH), 7.78 (dd,
2 H, J = 8.8, 6.8 Hz), 8.60 (br, 1 H, N–H).
5-(2-Chloroacetylamino)-1-(2-chlorophenyl)-3-tetrabutanyl pyrazole (15). 1H
NMR (CDCl3, 200 MHz) δ 1.35 (s, 9 H, CH3), 4.08 (s, 2 H, CH2), 6.56 (s, 1 H),
7.38–7.56 (m, 4H, ArH), 8.20 (br, 1 H, N–H); 13C NMR (CDCl3, 50 MHz) δ 30.27 (3
× CH), 32.53, 42.49, 94.85, 128.24, 130.26, 130.58, 130.84, 131.61, 135.07, 135.55,
162.53, 163.29.
5-(2-Chloroacetylamino)-1-(4-chlorophenyl)-3-tetrabutanyl pyrazole (16). 1H
NMR (CDCl3, 200 MHz) δ 1.29 (s, 9 H, CH3), 4.11 (s, 2 H, CH2), 6.56 (s, 1 H),
7.39–7.46 (m, 4H, ArH), 8.49 (br, 1 H, N–H).
5-(2-Bromoacetylamino)-1-(3-chlorophenyl)-3-phenylpyrazole (33). Yellow solid;
mp 106–107 °C; 1H NMR (CDCl3, 400 MHz) δ 4.01 (s, 2 H, CH2), 7.05 (s, 1 H, ArH),
7.31–7.47 (m, 6 H, ArH), 7.61 (s, 1 H, ArH), 7.85 (d, J = 7.6 Hz, 2 H, ArH), 8.48 (s, 1
H, N–H); 13C NMR (CDCl3, 100 MHz) δ 42.63, 96.23, 121.99, 124.87, 125.76 (2 ×
CH), 127.99, 128.66 (3 × CH), 130.84, 132.40, 135.42, 135.81, 138.61, 152.43,
162.50; IR (KBr) 3046, 2955, 2924, 2853, 1721 (s, C=O), 1201, 764; EIMS m/z: 393
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(M+ + 4, 25), 391 (M+ + 2, 100), 389 (M+, 76), 296 (11), 271 (30), 269 (93), 233 (35),
102 (69), 77 (16); HRMS Calcd for C17H13BrClON3: 388.9931, Found: 388.9932.
1-(3-Chlorophenyl)-5-(2-iodoacetylamino)-3-phenylpyrazole (34). Yellow solid;
mp 103–104 °C; 1H NMR (CDCl3, 200 MHz) δ 4.20 (s, 2 H, CH2), 7.08 (s, 1 H, ArH),
7.22 (m, 2 H, ArH), 7.42 (m, 4 H, ArH), 7.61 (s, 1 H, ArH), 7.85 (m, 2 H, ArH), 8.62
(s, 1 H, N–H); 13C NMR (CDCl3, 50 MHz) δ 32.88, 90.21, 126.21, 127.26, 129.94 (2
× CH), 128.45, 132.54 (3 × CH), 134.52, 134.77, 135.69, 139.72, 1345.34, 152.43,
165.23; IR (KBr) 3229, 2920, 1674 (s, C=O), 1593, 1558, 1366, 1076, 763, 1201, 764;
EIMS m/z: 439 (M+ + 2, 13),437 (M+, 52), 345 (32), 269 (100), 233 (39), 102 (90), 91
(12), 77 (27); HRMS Calcd for C17H13ClION3: 436.9792, Found: 436.9793.
Standard
procedure
for
synthesis
of
1,3-diphenyl-6-[(formyloxy)methyl]-1H-pyrazolo-[3,4-d]pyrimidine
17
and
(1,3-diphenyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)methanol 44. The reliable
procedure involved the treatment of 5ꢀ(2ꢀchloroacetylamino)pyrazoles 1 (203 mg,
0.58 mmol, 1.0 equiv), with PBr3 (1.77 mmol, ~ 0.2 mL, ~3.0 equiv) in formamide
solution (2 mL) at 50–60 °C within 5 h. When the reaction was completed, the
reaction mixture was added to saturate sodium bicarbonate (15 mL) and extracted
with dichloromethane (15 mL × 2). The combined organic layer was washed sodium
bicarbonate (15 mL), dried over MgSO4, filtered, and concentrated under reduced
pressure. The residue solution was purified by column chromatography on silica gel
to give the corresponding 6ꢀ(formylmethyl)pyrazolo[3,4ꢀd]pyrimidines 17 (168 mg,
0.51
mmol)
in
88
%
yield
and
byꢀproduct
(1,3ꢀdiphenylꢀ
1Hꢀpyrazolo[3,4ꢀd]pyrimidinꢀ6ꢀyl)methanol 44 (17.1 mg, 0.049 mmol) in 9% yield.
1,3-Diphenyl-6-[(formyloxy)methyl]-1H-pyrazolo[3,4-d]pyrimidine (17). Yellow
1
solid; mp 126–127 °C; H NMR (CDCl3, 200 MHz) δ 5.55 (s, 2 H, CH2), 7.33–7.37
(m, 1 H, ArH), 7.46–7.58 (m, 5 H, ArH), 8.01 (dd, J = 1.6, 7.9 Hz, 2 H, ArH), 8.28
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(dd, J = 1.6, 7.9 Hz, 2 H, ArH), 8.33 (s, 1 H, CHO), 9.43 (s, 1 H, Pyrimidine–H);13C
NMR (CDCl3, 50 MHz) δ 65.60, 113.14, 121.16 (2 × CH), 126.73, 127.26 (2 × CH),
129.14, 129.63 (4 × CH), 131.29, 138.39, 144.96, 152.97, 153.59, 160.50, 161.48; IR
(KBr) 2955, 1721(s, C=O), 1585, 1497, 1416, 1200, 753; EIMS m/z: 330 (M+, 100),
301 (38), 286 (79), 273 (15), 271 (12), 180 (7), 142 (10), 91 (14), 77 (51); HRMS
Calcd for C19H14O2N4: 330.1117, Found: 330.1121.
(1,3-Diphenyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)methanol (44). Yellow solid; mp
1
101–102 °C; H NMR (CDCl3, 400 MHz) δ 4.99 (s, 2 H, CH2), 7.34–7.38 (m, 1 H,
ArH), 7.48–7.57 (m, 5 H, ArH), 8.04 (d, J = 7.2 Hz, 2 H, ArH), 8.26 (d, J = 7.2 Hz, 2
13
H, ArH), 9.44 (s, 1 H, Pyrimidine–H); C NMR (CDCl3, 100 MHz) δ 64.85, 113.21,
121.49 (2 × CH), 126.92, 127.36 (2 × CH), 129.22 (4 × CH), 129.70, 131.40, 138.39,
145.25, 152.82, 153.55, 166.22; IR (KBr) 3395 (OH, Br), 2916, 1651, 1543, 748;
EIMS m/z: 302 (M+, 100), 301 (53), 273 (25), 273 (15), 271 (20), 91 (16), 77 (49);
HRMS Calcd for C18H14ON4: 302.1168, Found: 302.1161.
Standard
Procedure
for
Synthesis
of
6-(Formyloxymethyl)pyrazolo[3,4-d]pyrimidines 18–32. The reliable procedure
involved the treatment of 5ꢀ(2ꢀchloroacetylamino)pyrazoles (2–16, 1.0 equiv), with
PBr3 (~3.0 equiv) in formamide solution (2 mL) at 50–60 °C within 5 h. When the
reaction was completed, the reaction mixture was added to saturate sodium
bicarbonate (15 mL) and extracted with dichloromethane (15 mL × 2). The combined
organic layer was washed sodium bicarbonate (15 mL), dried over MgSO4, filtered,
and concentrated under reduced pressure. The residue solution was purified by
column chromatography on silica gel to give the corresponding
6ꢀ(formylmethyl)pyrazolo[3,4ꢀd]pyrimidines 18–32 in 73–92 % yields.
6-[(Formyloxy)methyl]-1-(2-methylphenyl)-3-phenyl-1H-pyrazolo[3,4-d]pyrimidi
1
ne (18). White solid; mp 133–134 °C; H NMR (CDCl3, 400 MHz) δ 2.22 (s, 3 H,
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CH3), 5.47 (s, 2 H, CH2), 7.37–7.57 (m, 7 H, ArH), 8.03 (d, J = 7.6 Hz, 2 H, ArH),
8.23 (s, 1 H, CHO), 9.53 (s, 1 H, Pyrimidine–H); 13C NMR (CDCl3, 100 MHz) δ
18.44, 65.69, 111.90, 126.69, 127.29 (2 × CH), 127.61, 129.24 (2 × CH), 129.41,
129.58, 131.43, 131.63, 135.40, 136.11, 145.16, 153.04, 154.55, 160.47, 161.72; IR
(KBr) 2920, 2851, 1721 (s, C=O), 1589, 1458, 1265, 1184, 752; EIMS m/z: 344 (M+,
13), 299 (32) , 298 (100) , 256 (17) , 202 (11), 189 (17), 155 (14), 133 (31), 91 (41),
88 (28), 77 (17); HRMS Calcd for C20H16O2N4: 344.1273, Found: 344.1274.
6-[(Formyloxy)methyl]-1-(3-methylphenyl)-3-phenyl-1H-pyrazolo[3,4-d]pyrimidi
1
ne (19). White solid; mp 127–128 °C; H NMR (CDCl3, 200 MHz) δ 2.22 (s, 3 H,
CH3), 5.47 (s, 2 H, CH2), 7.34–7.59 (m, 5 H, ArH), 7.53 (d, J = 7.5 Hz, 2 H, ArH),
8.04 (dd, J = 1.4, 7.8 Hz, 2 H, ArH), 8.23 (s, 1 H, CHO), 9.49 (s, 1 H, Pyrimidine–H);
13C NMR (CDCl3, 50 MHz) δ 18.43, 65.66, 111.88, 126.68, 127.27 (2 × CH), 127.60,
129.23 (2 × CH), 129.39, 129.57, 131.42, 131.60, 135.38, 136.08, 145.14, 153.03,
154.53, 160.46, 161.70; IR (KBr) 3059 (m),2916, 2847, 1724 (s, C=O), 1589, 1504,
1458, 1184, 1134, 760; EIMS m/z: 344 (M+, 15), 298 (100), 256 (19), 163 (20), 146
(47), 134 (35), 120 (55), 115 (58), 99 (84), 77 (30); HRMS Calcd for C20H16O2N4:
344.1273, Found: 344.1268.
6-[(Formyloxy)methyl]-1-(4-methylphenyl)-3-phenyl-1H-pyrazolo[3,4-d]pyrimidi
1
ne (20). White solid; mp 107–108 °C; H NMR (CDCl3, 400 MHz) δ 2.42 (s, 3 H,
CH3), 5.55 (s, 2 H, CH2), 7.34 (d, J = 8.0 Hz, 2 H, ArH), 7.56 (s, 1 H, ArH), 8.04 (d, J
= 8.0 Hz, 2 H, ArH), 8.14 (d, J = 8.0 Hz, 2 H, ArH), 8. 23 (s, 1 H, CHO), 9.46 (s, 1 H,
Pyrimidine–H); 13C NMR (CDCl3, 50 MHz) δ 21.10, 65.68, 113.06, 121.35 (2 × CH),
127.34 (2 × CH), 129.22 (2 × CH), 129.71, 129.73 (2 × CH), 131.46, 135.97, 136.79,
144.87, 152.99, 153.45, 160.53, 161.42; IR (KBr) 2922, 1726 (s, C=O), 1514, 1454,
1184, 1172, 957, 816, 766; EIMS m/z: 344 (M+, 100), 301 (37), 208 (11),91 (19), 77
(10); HRMS Calcd for C20H16O2N4: 344.1273, Found: 344.1276.
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1-(2-Chlorophenyl)-6-[(formyloxy)methyl]-3-phenyl-1H-pyrazolo[3,4-d]pyrimidi
ne (21). Yellow solid; mp 81–82 °C; 1H NMR (CDCl3, 200MHz) δ 5.47 (s, 2 H, CH2),
7.45–7.64 (m, 7 H, ArH), 8.02 (dd, J = 1.4, 7.7 Hz, 2 H, ArH), 8.24 (s, 1 H, CHO),
9.48 (s, 1 H, Pyrimidine–H); 13C NMR (CDCl3, 50 MHz) δ 65.61, 112.02, 127.37 (2 ×
CH), 127.59, 129.24 (2 × CH), 129.61, 129.72, 130.69, 130.78, 131.35, 132.09,
134.74, 145.79, 153.03, 154.99, 160.45, 161.92; IR (KBr) 3059,2922, 2851, 1722 (s,
C=O), 1591, 1503, 1410, 1184, 1132, 980, 756; EIMS m/z: 366 (M+ + 2, 35), 364 (M+,
100), 335 (34), 329 (13), 320 (83), 307 (15), 271 (13), 133 (29), 91 (24), 77 (27);
HRMS Calcd for C19H13ClO2N4: 364.0721, Found: 364.0725.
1-(3-Chlorophenyl)-6-[(formyloxy)methyl]-3-phenyl-1H-pyrazolo[3,4-d]pyrimidi
1
ne (22). Yellow solid; mp 128–129 °C; H NMR (CDCl3, 400 MHz) δ 5.58 (s, 2 H,
CH2), 7.32 (d, J = 7.2 Hz, 1 H, ArH), 7.44–7.59 (m, 3 H, ArH), 7.57 (s, 1 H, ArH),
8.04 (d, J = 8.0, 2 H, ArH), 8.31 (d, J = 8.0 Hz, 1 H, ArH), 8.34 (s, 1 H, ArH ), 8.44 (s,
1 H, Pyrimidine–H), 9.46 (s, 1 H, CHO); 13C NMR (CDCl3, 100 MHz) δ 65.46,
113.42, 118.81, 121.05, 126.58, 127.37 (2 × CH), 129.24 (2 × CH), 129.88, 130.15,
131.09, 134.90, 139.52, 145.51, 153.12, 153.97, 160.38, 161.88; IR (KBr) 3059,2922,
2851, 1722 (s, C=O), 1591, 1503, 1410, 1184, 1132, 980, 756; EIMS m/z: 366 (M+ +
2, 34), 364 (M+, 100), 355 (16), 335 (53), 320 (77), 307 (22), 281 (18), 221 (18), 111
(12), 77 (18); HRMS Calcd for C19H13ClO2N4: 364.0721, Found: 364.0725.
1-(4-Chlorophenyl)-6-[(formyloxy)methyl]-3-phenyl-1H-pyrazolo[3,4-d]pyrimidi
1
ne (23). Yellow solid; mp 127–128 °C; H NMR (CDCl3, 200MHz) δ 5.56 (s, 2 H,
CH2), 7.48–7.57 (m, 5 H, ArH), 8.03 (dd, J = 1.5, 8.4, 2 H, ArH), 8.31 (d, J = 8.4, 2 H,
ArH), 8.33(s, 1 H, CHO ), 9.46 (s, 1 H, Pyrimidine–H); 13C NMR (CDCl3, 100 MHz)
δ 65.61, 113.36, 122.26, 125.75, 127.40, 129.32, 129.90 (2 × CH), 131.18, 132.21,
137.08, 145.41, 153.19, 153.78, 160.50, 161.81; IR (KBr) 3059,2922, 2851, 1722 (s,
C=O), 1591, 1503, 1410, 1184, 1132, 980, 756; EIMS m/z: 366 (M+ + 2, 2), 364 (M+,
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7), 284 (21), 217 (11), 135 (100), 91 (16), 77 (9); HRMS Calcd for C19H13ClO2N4:
364.0721, Found: 364.0718.
6-[(Formyloxy)methyl]-1-(3-methoxyphenyl)-3-phenyl-1H-pyrazolo-[3,4-d]pyrim
1
idine (24). Yellow solid; mp 90–91 °C; H NMR (CDCl3, 400 MHz) δ 3.87 (s, 3 H,
CH3), 5.54 (s, 2 H, CH2), 7.06 (d, J = 8.0 Hz, 2 H, ArH), 7.48–7.57 (m, 2 H, ArH),
7.55 (s, 1 H, ArH), 8.03 (d, J = 8.0 Hz, 2 H, ArH), 8.14 (dd, J = 2.0, 8.0 Hz, 2 H, ArH),
8.32 (s, 1 H, CHO), 9.45 (s, 1 H, Pyrimidine–H); 13C NMR (CDCl3, 100 MHz) δ55.58,
65.73, 112.91, 114.38 (2 × CH), 123.01 (2 × CH), 127.32 (2 × CH), 129.22 (2 × CH),
129.57, 131.55, 131.72, 144.71, 153.01, 153.29, 158.45, 160.51, 161.46; IR (KBr)
2924, 1728 (s, C=O), 1585, 1512, 1458, 1250, 1173, 1030, 829, 764; EIMS m/z: 360
(M+, 100), 331 (13), 316 (12), 77 (10); HRMS Calcd for C20H16O3N4: 360.1222,
Found: 360.1224.
6-[(Formyloxy)methyl]-3-methyl-1-phenyl-1H-pyrazolo[3,4-d]-pyrimidine (25).
Brown solid; mp 85–86 °C; 1H NMR (CDCl3, 400 MHz) δ 2.69 (s, 3 H, CH3), 5.52 (s,
2 H, CH2), 7.29–7.33 (m, 1 H, ArH), 7.48–7.52 (m, 1 H, ArH), 7.50 (s, 1 H, ArH),
8.19 (d, J = 8.0 Hz, 2 H, ArH), 8.30 (s, 1 H, CHO), 9.12 (s, 1 H, Pyrimidine–H); 13C
NMR (CDCl3, 100 MHz) δ 12.58, 65.74, 114.77, 120.87 (2 × CH), 126.41, 129.11 (2
× CH), 138.44, 143.41, 151.95, 153.12, 160.45, 161.58; IR (KBr) 2924, 2854, 1732 (s,
C=O), 1589, 1508, 1458, 1161, 752; EIMS m/z: 268 (M+, 89), 239 (46), 224 (100),
211 (20), 142 (12), 91 (13), 77 (53); HRMS Calcd for C14H12O2N4: 268.0960, Found:
268.0963.
3-tetra-Butanyl-6-[(formyloxy)methyl]-1-phenyl-1H-pyrazolo[3,4-d]pyrimidine
1
(26). Brown solid; mp 91–92 °C; H NMR (CDCl3, 200 MHz) δ 1.56 (s, 9 H, CH3),
5.51 (s, 2 H, CH2), 7.25–7.33 (m, 1 H, ArH), 7.46–7.53 (m, 2 H, ArH), 7.50 (s, 1 H,
ArH), 8.22 (d, J = 8.0 Hz, 2 H, ArH), 8.30 (s, 1 H, CHO), 9.29 (s, 1 H, Pyrimidine–H);
13C NMR (CDCl3, 50 MHz) δ 30.02 (3 × CH), 65.74, 113.02, 120.99 (2 × CH),
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126.28, 129.08 (2 × CH), 138.62, 153.07, 153.53, 154.98, 160.54, 160.90; IR (KBr)
2963, 2924, 1732 (s, C=O), 1582, 1508, 1420, 1366, 1157, 756; EIMS m/z: 310 (M+,
21), 295 (30), 265 (12), 159 (15), 113 (12), 98 (13), 91 (100), 77 (20); HRMS Calcd
for C17H18O2N4: 310.1434, Found: 310.1430.
6-[(Formyloxy)methyl]-3-(4-methylphenyl)-1-phenyl-1H-pyrazolo[3,4-d]pyrimidi
ne (27). Yield: 87%; yellow liquid; 1H NMR (CDCl3, 200 MHz) δ 2.44 (s, 3 H, CH3),
5.55 (s, 2 H, CH2), 7.36 (d, J = 8.1 Hz, 2 H, ArH), 7.53 (dd, J = 8.0, 7.4 Hz, 2 H, ArH),
7.94 (d, J = 8.1 Hz, 2 H, ArH), 8.30 (d, J = 8.1 Hz, 2 H, ArH), 8.32 (s, 1 H, CHO),
9.44 (s, 1 H, Pyrimidine–H); 13C NMR (CDCl3, 50 MHz) δ 29.69, 65.70, 113.28,
121.27 (2 × CH), 126.72, 127.24 (2 × CH), 128.58, 129.16 (2 × CH), 129.93 (2 × CH),
138.53, 139.89, 145.19, 153.05, 153.68, 160.51, 160.51, 161.51; IR (KBr) 2920, 2851,
1717 (s, C=O), 1589, 1501, 1411, 1200, 1134, 980, 756 cm–1; EIMS m/z: 344 (M+,
100), 315 (36), 300 (51), 287 (11), 91 (13),77 (17); HRMS Calcd for C20H16O2N4:
344.1273, Found: 344.1275.
6-[(Formyloxy)methyl]-3-(4-methoxyphenyl)-1-phenyl-1H-pyrazolo-[3,4-d]pyrim
1
idine (28). Yellow solid; mp 165–167 °C; H NMR (CDCl3, 200MHz) δ 3.88 (s, 3 H,
CH3), 5.55 (s, 2 H, CH2), 7.07 (d, J = 8.8 Hz, 2 H, ArH), 7.33–7.37(m, 1 H, ArH),
7.49–7.57 (m, 2 H, ArH), 8.29 (dd, J = 1.0, 8.8 Hz, 2 H, ArH), 8.32 (s, 1 H, CHO),
9.41 (s, 1 H, Pyrimidine–H); 13C NMR (CDCl3, 100 MHz) δ 55.42, 65.69, 113.19,
114.66 (2 × CH), 121.19 (2 × CH), 123.96, 126.24, 128.66 (2 × CH), 129.14 (2 × CH),
138.52, 144.92, 152.97, 153.61, 160.51, 160.83, 161.46; IR (KBr) 2922, 1715 (s,
C=O), 1585, 1504, 1412, 1199, 1030, 982, 787 cm–1; EIMS m/z: 360 (M+, 100), 331
(24), 316 (29), 77 (15); HRMS Calcd for C20H16O3N4: 360.1222, Found: 360.1217.
6-[(Formyloxy)methyl]-1-(3-methlyphenyl)-3-(4-methoxyphenyl)-1H-pyrazolo[3,
1
4-d]pyrimidine (29). Yellow solid; mp 138–139 °C; H NMR (CDCl3, 400MHz) δ
2.47 (s, 3 H, CH3), 3.89 (s, 3 H, OCH3), 5.55 (s, 2 H, CH2), 7.08 (d, J = 8.4 Hz, 2 H,
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ArH), 7.17 (m, 1 H, ArH), 7.41 (m, 1 H, ArH), 7.99 (d, J = 8.4 Hz, 2 H, ArH), 8.08 (m,
13
2 H, ArH), 8.32 (s, 1 H, CHO), 9.42 (s, 1 H, Pyrimidine–H); C NMR (CDCl3, 100
MHz) δ 21.62, 55.45, 65.73, 113.19, 114.72 (2 × CH), 118.50, 121.94, 124.10, 127.54,
128.72 (2 × CH), 128.97, 138.46, 139.19, 144.89, 152.97, 153.65, 160.49, 160.88,
161.46; IR (KBr) 2953, 1717 (s, C=O), 1585, 1503, 1408, 1175, 1134, 837, 787;
EIMS m/z: 374 (M+, 100), 345 (19), 330 (24), 91 (8); HRMS Calcd for C21H18O3N4:
374.1379, Found: 374.1383.
6-[(Formyloxy)methyl]-1-(4-methlyphenyl)-3-(4-methoxyphenyl)-1H-pyrazolo[3,
1
4-d]pyrimidine (30). Yellow solid; mp 152–154 °C; H NMR (CDCl3, 200 MHz) δ
2.42 (s, 3 H, CH3), 3.89 (s, 3 H, OCH3), 5.54 (s, 2 H, CH2), 7.07 (d, J = 8.0 Hz, 2 H,
ArH), 7.33 (d, J = 8.0 Hz, 2 H, ArH), 7.98 (d, J = 8.0 Hz, 2 H, ArH), 8.13 (d, J = 8.0
Hz, 2 H, ArH), 8.31 (s, 1 H, CHO), 9.41 (s, 1 H, Pyrimidine–H); 13C NMR (CDCl3,
100 MHz) δ 21.62, 55.45, 65.73, 113.19, 114.72 (2 × CH), 118.50, 121.94, 124.10,
127.54, 128.72 (2 × CH), 128.97, 138.46, 139.19, 144.89, 152.97, 153.65, 160.49,
160.88, 161.46; IR (KBr) 2922, 1732 (s, C=O), 1585, 1504, 1412, 1199, 1136, 839,
754; EIMS m/z: 374 (M+, 100), 345 (19), 330 (25), 226 (22), 210 (13), 180 (15), 167
(36), 135 (18), 125 (20), 111 (40), 97 (51), 91 (17); HRMS Calcd for C21H18O3N4:
374.1379, Found: 374.1381.
3-tetra-Butyl-1-(2-chlorophenyl)-6-[(formyloxy)methyl]-1H-pyrazolo[3,4-d]pyri
1
midine (31). Yellow solid; mp 138–139 °C; H NMR (CDCl3, 200 MHz) δ 1.56 (s, 9
H, CH3), 5.52 (s, 2 H, CH2), 7.25–7.33 (m, 1 H, ArH), 7.46–7.53 (m, 2 H, ArH), 8.22
(d, J = 8.0 Hz, 2 H, ArH), 8.23 (s, 1 H, CHO), 9.46 (s, 1 H, Pyrimidine–H); 13C NMR
(CDCl3, 50 MHz) δ 30.01 (3 × CH), 67.54, 112.03, 121.97 (2 × CH), 128.72, 129.08
(2 × CH), 139.63, 153.07, 153.53, 154.98, 156.35, 161.93; IR (KBr) 2916, 1721 (s,
C=O), 1578, 1558, 1458, 1261, 1165, 760, 694; EIMS m/z: 346 (M+ + 2, 30), 344 (M+,
100), 345 (19), 330 (25), 226 (22), 210 (13), 180 (15), 167 (36), 135 (18), 125 (20),
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111 (40), 97 (51), 91 (17); HRMS Calcd for C17H17ClO4N2: 344.1040, Found:
344.1044.
3-Tetrabutanyl-1-(4-chlorophenyl)-6-[(formyloxy)methyl]-1H-pyrazolo[3,4-d]pyr
imidine (32). Yellow solid; mp 147–148 °C; 1H NMR (CDCl3, 200 MHz) δ 1.55 (s, 9
H, CH3), 5.51 (s, 2 H, CH2), 7.49 (m, 2 H, ArH), 8.25 (m, 2H, ArH), 8.30 (s, 1 H,
CHO), 9.29 (s, 1 H, Pyrimidine–H); 13C NMR (CDCl3, 50 MHz) δ 30.27 (3 × CH),
65.70, 128.24 (2 × CH), 130.26, 130.58, 130.84 (2 × CH), 131.61, 135.07, 135.55,
145.19, 153.05, 162.53, 163.29; IR (KBr) 2922, 1721 (s, C=O), 1585, 1252, 1175,
1026, 781; EIMS m/z: 346 (M+ + 2, 37), 344 (M+, 94), 345 (19), 330 (25), 226 (22),
210 (13), 180 (15), 167 (36), 135 (18), 125 (20), 111 (40), 97 (51), 91 (17); HRMS
Calcd for C17H17ClO4N2: 344.1040, Found: 344.1043. (100), 55 (44); HRMS calcd.
for C17H22N4O3, 330.1692; found 330.1696.
1-(3-Chlorophenyl)-3phenyl-5-(2-hydroxyacetylamino)pyrazole (35)29 A solution
of 5ꢀ(2ꢀchloroacetylamino)pyrazole (6, 1.0 equiv) and cesium formate (HCO2Cs, 3.0
equiv) in dry MeOH (10 mL) was heated at reflux for >2.0 h. When the reaction was
completed, the solution was filtered to remove the excess amount of HCO2Cs and the
filtrate was concentrated under reduced pressure. The residue was purified by column
chromatography on silica gel or reꢀcrystallization to give the corresponding
1
5ꢀ(2ꢀhydroxyacetylamino)pyrazole 35 in 84% yield. yellow solid; mp 98–99 °C; H
NMR (CDCl3, 200 MHz) δ 4.15 (s, 2 H, CH2), 7.06 (s, 1 H, ArH), 7.32–7.44 (m, 7 H,
ArH), 7.56 (m, 1 H, ArH), 7.83 (dd, J = 4.5, 8.2 Hz, 2 H, ArH), 8.79 (s, 1 H, NH); 13C
NMR (CDCl3, 50 MHz) δ 62.12, 95.94, 122.08, 124.87, 125.78 (2 × CH), 128.46,
128.54, 128.66 (2 × CH), 130.74, 132.44, 135.61, 136.03, 138.75, 152.51, 168.37; IR
(KBr) 3429, 2359, 1591, 1184, 966, 756; EIMS m/z: 329 (M+ + 2, 33), 327 (M+, 73),
329 (33), 270 (32), 235 (20), 220 (39), 207 (25), 195 (58), 180 (97), 162 (24), 135
(94), 121 (100), 102 (36), 91 (56), 81 (77); HRMS Calcd for C17H14ClO2N3: 327.0775,
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DOI: 10.1039/C5RA07707A
Found: 327.0776.
6-(Chloromethyl)pyrazolo[3,4-d]pyrimidine
(40).
The
treatment
of
1,3ꢀdiphenylꢀ1Hꢀpyrazolo[3,4ꢀd]pyrimidinꢀ6ꢀyl)methanol (44, 1.0 equiv), with SOCl2
(~3.0 equiv) in formamide solution (2 mL) at 50–60 °C within 3 h. When the reaction
was completed, the reaction mixture was added to saturate sodium bicarbonate (15
mL) and extracted with dichloromethane (15 mL × 2). The combined organic layer
was washed sodium bicarbonate (15 mL), dried over MgSO4, filtered, and
concentrated under reduced pressure. The residue solution was purified by column
chromatography
on
silica
gel
to
give
the
corresponding
6ꢀ(chloromethyl)pyrazolo[3,4ꢀd]pyrimidine 40 in 80 % yields: yellow solid; mp
1
133–134 °C; H NMR (CDCl3, 200 MHz) δ 4.89 (s, 2 H, CH2), 7.32–7.40 (m, 1 H,
ArH), 7.49–7.61 (m, 5 H, ArH), 8.05 (dd, J = 7.2, Hz, 2 H, ArH), 8.26 (dd, J = 7.2
Hz, 2 H, ArH), 9.49 (s, 1 H, Pyrimidine–H); 13C NMR (CDCl3, 50 MHz) δ 47.33,
112.95, 121.33 (2 × CH), 126.87, 127.37 (2 × CH), 129.24 (3 × CH), 129.73, 131.38,
138.50, 145.07, 153.37, 153.88, 162.99; IR (KBr) 2920, 1581, 1501, 1226, 1134, 976,
756, 691; EIMS m/z: 320 (M+, 100), 319 (38), 294 (35), 251 (24), 221 (20), 207 (48),
140 (15), 91 (39), 77 (56); HRMS Calcd for C18H13ClN4: 320.0829; Found: 320.0828.
Acknowledgments
We are grateful to the Tsuzuki Institute for Traditional Medicine, and the
Ministry of the National Science Council Taiwan (NSCꢀ102ꢀ2113ꢀMꢀ039ꢀ003) for
financial support.
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Table 1 Optimization of the Oneꢀpot Multiple Tandem Reaction by Various of
Halogenating Agents.
O
N
H
O
O
O
Cl
N
HN
H
NH2
halogenating agent (3.0 equiv)
N
N
N
50-60 oC for 5 h
N
Ph
Ph
1
17
entry
halogenating agents (3.0 equiv)
yields of 17 (%)a,b
c
1
2
3
4
5
6
7
–
PBr3
–
88
73
41
31
26
33
POCl3
SOCl2
TsCl
PhCOCl
ClCOCOCl
abased on the weight of starting material 5ꢀ(2ꢀchloroacetylamino)pyrazole 1.
bAll of results were the isolated yields.
cnot detectable
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Table 2 Synthesis of 1ꢀArylꢀ6[(formyloxy)methyl]ꢀ1Hꢀpyrazolo[3,4ꢀd]pyrimidines
17–32 via the Tandem Oneꢀpot Multiple reaction.
O
H
O
O
O
Cl
X
X
N
N
HN
H
NH2, PBr3
50-60 oC for 5 h
X = H, o-Me, o-Cl, m-Me, m-Cl,
p-Me, p-Cl, p-OMe
N
N
N
N
R
R
R = Me, t-Bu, p-MePh, p-OMePh
17-32
1-16
S.M.
X
R
No.
Yields (%)a
H
oꢀMe
mꢀMe
pꢀMe
oꢀCl
mꢀCl
pꢀCl
pꢀOMe
H
Ph
88
1
2
17
Ph
Ph
77
85
92
83
81
84
73
78
81
74
75
74
84
72
77
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
3
Ph
4
Ph
5
Ph
6
Ph
7
Ph
8
Me
9
H
tꢀBu
10
11
12
13
14
15
16
H
pꢀMeꢀPh
pꢀOMeꢀPh
pꢀOMeꢀPh
pꢀOMeꢀPh
tꢀBu
H
mꢀMe
pꢀMe
oꢀCl
pꢀCl
tꢀBu
aAll of results were the isolated yields.
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Table 3 Optimization of the Oneꢀpot Multiple Tandem Reaction by Various of
Leaving Groups.
O
N
H
O
O
O
Y
Cl
Cl
N
HN
H
NH2, PBr3
N
50-60 oC for 5 h
Y = Cl, Br, I, OH
N
N
N
Ph
Ph
6, 33-35
22
Entry
S.M.
Y
Products
Yields (%)a
1
2
3
4
Cl
81
6
22
Br
I
86
87
73
33
34
35
22
22
22
OH
aAll of results were the isolated yields.
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Figure
1
An
ORTEP
Diagram
of
1ꢀ(pꢀMethoxyphenyl)ꢀ3ꢀphenylꢀ6ꢀ[(formyl)methyl]ꢀ1Hꢀpyrazolo[3,4ꢀd]pyrimidine
(24).
O
H
O
O
O
Cl
X
X
N
N
HN
H
NH2, PBr3
50-60 oC for 5 h
X = H, o-Me, o-Cl, m-Me, m-Cl,
p-Me, p-Cl, p-OMe
N
N
N
N
R
R
R = Me, t-Bu, p-MePh, p-OMePh
17-32
1-16
Scheme
1
The New Oneꢀpot Multiple Reaction for the Synthesis of
1ꢀArylꢀ6ꢀ[(formyloxy)methyl]ꢀ1Hꢀparasol[3,4ꢀd]pyrimidines 17–32.
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O
O
N
H
OH
O
Cl
O
HN
H
NH2, PBr3
N
N
N
+
N
N
N
N
N
N
Ph
Ph
Ph
Br
H
H
17. 88%
44. 9%
1
C N
H
36. Reactive species
Vilsmeier-
Haack Reaction
Hydrolysis
O
N
H
O
Cl
NH2
HN
N
NH
N
H
N
N
H
N
Ph
Ph
37
41
H
O
H
H
PBr3
O
O
Morgan-Walls
Reaction
N
H
NH2
PBr3
42
43
Cl
Br
N
Cl
H
Br
Cl
N
N
N
N
:
B
NH
H
H
N
N
N
N
H
N
N
Ph
Ph
Ph
38
39
40
Scheme
2
Proposed
Mechanism
for
Synthesis
17–32
of
form
1ꢀArylꢀ6ꢀ[(formyl)methyl]ꢀ1Hꢀpyrazolo[3,4ꢀd]pyrimidines
5ꢀ(2ꢀchloroacetylamino)pyrazoles 1–16.
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