6-(Aryldiazenyl)pyrazolo[1,5-a]pyrimidines as Strategic Intermediates for the Synthesis of Pyrazolo[5,1-b]purines

Article abstract of DOI:10.1021/acs.joc.6b02431

A microwave-assisted approach for the regioselective synthesis of functionalized 6-(aryldiazenyl)pyrazolo[1,5-a]pyrimidin-7-amines from the cyclization of 3-oxo-2-(2-arylhydrazinylidene)butanenitriles with 5-amino-1H-pyrazoles under solvent-free conditions has been developed. This methodology was distinguished by its broad substrate scope, operational simplicity, high atom economy, and high-yielding without requiring chromatographic purification. In addition, an efficient and versatile palladium-catalyzed reductive azo cleavage is disclosed for the synthesis of diverse heteroaromatic 1,2-diamines, a valuable synthetic building block to develop new fused heteroaromatic systems. As synthetic example, several substituted pyrazolo[5,1-b]purines were synthesized in yields up to 96% by using microwave irradiation in the cyclocondensation of these 1,2-diamines with orthoesters.

Full text of DOI:10.1021/acs.joc.6b02431

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Article
6-(Aryldiazenyl)pyrazolo[1,5-a]pyrimidines as Strategic
Intermediates for the Synthesis of Pyrazolo[5,1-b]purines
Juan-Carlos Castillo, Diego Estupiñan, Manuel Nogueras, Justo Cobo, and Jaime Portilla
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02431 • Publication Date (Web): 28 Nov 2016
Downloaded from http://pubs.acs.org on November 28, 2016
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6-(Aryldiazenyl)pyrazolo[1,5-a]pyrimidines as Strategic Intermediates for
the Synthesis of Pyrazolo[5,1-b]purines
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JuanꢀCarlos Castillo,†,‡ Diego Estupiñan,†,‡ Manuel Nogueras,§ Justo Cobo,§ and Jaime
Portilla*,†
†Bioorganic Compounds Research Group, Department of Chemistry, Universidad de los
Andes, Carrera 1 No. 18Aꢀ10, Bogotá 111711, Colombia
§Departamento de Química Inorgánica
23071 Jaén, Spain
y
Orgánica, Universidad de Jaén,
*Email: jportill@uniandes.edu.co
TOC graphic & Abstract
A microwaveꢀassisted approach for the regioselective synthesis of functionalized 6ꢀ
(aryldiazenyl)pyrazolo[1,5ꢀa]pyrimidinꢀ7ꢀamines from the cyclization of 3ꢀoxoꢀ2ꢀ(2ꢀ
arylhydrazinylidene)butanenitriles with 5ꢀaminoꢀ1Hꢀpyrazoles under solventꢀfree
conditions has been developed. This methodology was distinguished by its broad substrate
scope, operational simplicity, high atom economy and highꢀyielding without requiring
chromatographic purification. In addition, an efficient and versatile palladiumꢀcatalyzed
reductive azo cleavage is disclosed for the synthesis of diverse heteroaromatic 1,2ꢀ
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diamines, a valuable synthetic building block to develop new fused heteroaromatic systems.
As synthetic example, several substituted pyrazolo[5,1ꢀb]purines were synthesized in yields
up to 96% by using microwave irradiation in the cyclocondensation of these 1,2ꢀdiamines
with orthoesters.
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Keywords: Azocompounds, microwave chemistry, pyrazolo[5,1ꢀb]purines, pyrazolo[1,5ꢀ
a]pyrimidines, reductive azo cleavage
Introduction
Analysis of database of U.S. FDA approved drugs reveals that 59% of unique smallꢀ
molecule drugs contain a nitrogen heterocycle.1 In recent years, purineꢀfused tricyclic and
polycyclic derivatives have attracted considerable attention because of their valuable
biological activities, medicinal properties and special conjugated structures.2 Although
great endeavors have been devoted to the synthesis of purineꢀfused polycyclic derivatives
and imidazo[2,1ꢀb]purines, the development of new routes for the preparation of
structurally diverse pyrazolo[5,1ꢀb]purines still remains as an important and challenging
goal for the chemists, due to few existing reports of its synthesis involving several reaction
steps (Figure 1).
Figure 1. The most common type of azolo[b]purines
On the other hand, heterocyclicꢀfused pyrimidine represents one of the most prominent
classes of privileged scaffolds in the field of drugs and pharmaceutical.3 During the last
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decade, the synthesis of pyrazolo[1,5ꢀa]pyrimidine derivatives and the investigation of their
chemical and biological behavior has gained more importance due to pharmaceutical
reasons.4 For example, the hypnotic drug Zaleplon (I), the anticancer agent Dinaciclib (II)
and the fungicide Pyrazophos (III) have this structural motif of pyrazolo[1,5ꢀa]pyrimidine
(examples highlighted in blue, Figure 2).5
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Figure 2. Examples of pyrazolo[1,5ꢀa]pyrimidine drugs
In parallel to medicinal chemistry, recent discoveries in material sciences have proved that
pyrazolo[1,5ꢀa]pyrimidines containing an arylazo or hetarylazo group are useful synthetic
intermediates in the dyestuff industry.6 Consequently, synthetic methodologies for
synthesis of novel pyrazolo[1,5ꢀa]pyrimidine derivatives are of particular interest to
organic and medicinal chemists. The importance of pyrazolo[1,5ꢀa]pyrimidine scaffold has
led to the development of various methods for its synthesis. Most of them involve the
condensation reaction between aminopyrazoles and 1,3ꢀbisꢀelectrophilic reagents, such as
1,2ꢀallenic ketones,7 enaminones,8 enaminonitriles,9 βꢀketonitriles,10 1,3ꢀdicarbonyl
compounds,11 and α,βꢀunsaturated carbonyl compounds.12 Therefore, further research is
required to develop event more efficient methods to access to diversely functionalized
pyrazolo[1,5ꢀa]pyrimidines.
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Currently, microwaveꢀassisted organic synthesis (MAOS) and transformations using
greener reaction media for the synthesis of drugs and biologically active molecules has
proved to be efficient and environmentally benign due to its simplicity in operation, short
reaction times, and clean product formation leading to better yields, selectivities and easier
workꢀup.13,14 An example of such methodology can be found in our recently reported
imination/intramolecular nucleophilic addition work towards the synthesis of 6ꢀ
(phenyldiazenyl)pyrazolo[1,5ꢀa]pyrimidinꢀ7ꢀamine from ‘3ꢀaminoꢀ2ꢀphenyldiazenylbutꢀ2ꢀ
enenitrile’ with 5ꢀaminoꢀ3ꢀphenylꢀ1Hꢀpyrazole as 1,3ꢀN,Nꢀbisꢀnucleophile (Scheme 1a).15
Unambiguous proof of structure and regioselectivity was achieved by singleꢀcrystal Xꢀray
diffraction analysis. In that report, we used a domestic microwave oven to obtain an
efficient conversion to the desired product. However, most major scientific journals not
longer accept manuscripts wherein domestic ovens have been described as heating sources,
since there are many scientific arguments to be made for using dedicated microwave
reactors instead of domestic ovens such as possibility of stirring, continuous power output,
excellent parameter control, possibility of convenient solvent superheating and safety under
high pressure/temperature conditions. Inspired by these earlier studies, and our continuing
interest in the synthesis of Nꢀheterocycles,12,16 we envisioned that microwaveꢀassisted
reaction of 2ꢀarylhydrazinylideneꢀ3ꢀoxobutanenitrile with 5ꢀaminoꢀ1Hꢀpyrazole might
generate an imine intermediate A, which could undergo intramolecular cyclization with
pyrazole moiety. In consequence, leading to the formation of 6ꢀ(aryldiazenyl)pyrazolo[1,5ꢀ
a]pyrimidinꢀ7ꢀamine by using a microwave reactor instead of the domestic oven (Scheme
1b).
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Scheme 1. Strategy for the Synthesis of Pyrazolo[1,5ꢀa]pyrimidinꢀ7ꢀamines
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Results and discussion
At the beginning, aniline derivatives 1a–c were diazotised to give the corresponding
aromatic diazonium salts which underwent a coupling reaction with 3ꢀaminobutꢀ2ꢀ
enenitrile (2) to afford the arylazoꢀdyes in good yields (Scheme 2). Several decades before
Elnagdi et al. reported that these derivatives exist mainly in the hydrazoneꢀimine form 4’
using analysis of their IR, UV and polarographic data.15,17 However, we have confirmed by
accurate mass measurements that the enamine group of these azo dyes was completely
hydrolyzed under those diazotization conditions. Consequently, the structure of these dyes
should have the tautomeric forms enolꢀketo 3/3’ instead of enamineꢀimine 4/4’, suggesting
that future papers should be reported according to our new results (see Supporting
Information for details). The IR, HRMS and NMR spectroscopical data for all the arylazoꢀ
dyes 3/3’ are presented in the Experimental Section. 1H NMR spectra of dyes 3/3’ recorded
at 25 °C in CDCl3 show a double set of signals, confirming that these dyes were obtained as
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mixtures of their corresponding azoꢀenol 3 and hydrazoneꢀketo 3’ tautomers (Scheme 2). In
general, the tautomeric enol (=CH–OH) and hydrazone (=N–NH–) protons appear as broad
singlet signal at 14.69–14.97 ppm and 9.20–9.44 ppm, respectively. In all cases, the azoꢀ
enol form 3 was the major tautomer in solution with the following ratios 3/3’a (69:31),
3/3’b (83:17) and 3/3’c (71:29) (see Supporting Information for details). Notably, the IR
data reveal the absence of the azo group band at 1454 cmꢀ1, which indicated that these dyes
could exist in the hydrazoneꢀketo form in the solid state. The structure of compound 3’a
was solved by singleꢀcrystal Xꢀray diffraction analysis,18 showing that in the solid state the
dyes exist in the hydrazoneꢀketo form 3’ and E configuration as the only stereochemical
isomer. It is wellꢀknown that the applications of azoꢀdyes depend on the optical and
physical properties of their tautomeric forms, azo or hydrazone.19 For example, the
hydrazone form is often commercially preferred because it was found to be rendered higher
photoconductivity to dualꢀlayer photoreceptors.20
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Scheme 2. Tautomeric Forms of Arylazoꢀdyes: Azoꢀenol and Hydrazoneꢀketo
To continue our exploratory study, 3ꢀoxoꢀ2ꢀ(2ꢀphenylhydrazinylidene)butanenitrile (3’a)
and 5ꢀaminoꢀ3ꢀmethylꢀ1Hꢀpyrazole (5a) were prepared and probed as model substrates for
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cyclization reactions (Table 1). Initially, we performed the optimization by varying the
solvent and testing the effect of conventional heating versus microwave irradiation. Heating
to reflux an equimolar mixture of 3’a and 5a in anhydrous ethanol or toluene for 24 h did
not lead to the desired product 6a (Table 1, entries 1–2). To our delight, the use of high
boiling solvents such as DMSO gave 6a in 39% isolated yield as the only detectable
regioisomer (Table 1, entry 3). A slightly higher yield of 6a (43%) was achieved when
DMF was used as solvent (Table 1, entry 4). Interestingly, we found out that higher
temperatures favor the formation of pyrazolo[1,5ꢀa]pyrimidinꢀ7ꢀamine 6a, similarly to our
previous work on the solventꢀfree synthesis of cyclopentapyrazolo[1,5ꢀa]pyrimidines.11d
The use of microwave irradiation to reach higher temperature (180 °C) under solventꢀfree
conditions was performed with a 1:1 mixture of 3a’ and 5a, and after 4 min of reaction in a
sealed tube, we were pleased to find that the pyrazolo[1,5ꢀa]pyrimidinꢀ7ꢀamine 6a was
obtained with high purity and nearly quantitative yield by simple collection with cold
ethanol (Table 1, entry 5). The overall ecoꢀcompatibility of the process is highlighted.
Reaction times below 4 min led to lesser yields of desired compound 6a (Table 1, entries
6–7). Alternatively, we also carry out the reaction under conventional heating in fusion
with acceptable results (Table 1, entries 8ꢀ9), and also under microwave irradiation using
solvent. The formation of product 6a was observed with ethanol in poor yield, whereas with
DMF the reaction proceed in good isolated yield (Table 1 entries 10ꢀ12). For the reaction
with ethanol was not possible to increase the temperature above 140 °C due to system
overpressure. Finally, in the reactions with DMF there is a complete conversion of the
reactants, however, the crude must be isolated by a liquidꢀliquid extraction.
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Table 1. Optimization of the Reaction Conditions for the Preparation of Pyrazolo[1,5ꢀ
a]pyrimidinea
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Entry Solvent T (°C)
Time
Yield
(%)b
–
–
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43
91
77
60
1
2
3
EtOH
PhMe
80c
24 h
24 h
24 h
24 h
4 min
3 min
2 min
10 min 55
20 min 52
4 min
4 min
10 min 63
110c
DMSO 140c
4
DMF
–
–
–
–
–
EtOH
DMF
DMF
140c
180
180
180
180
180
150
180
180
5d
6d
7d
8e
9e
10f
11f
12f
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a Reaction conditions: 3’a (0.50 mmol) and 5a (0.50 mmol). b Isolated yield. c Conventional
d
e
heating. Run in 10 mL sealed tubes at a power of 300 W in the absence of solvent.
f
Conventional heating with a sand bath without solvent (fusion procedure). Run in 10 mL
sealed tubes at a power of 300 W in anhydrous solvent (2 mL).
With these optimized conditions, we set to explore the substrate scope using 2ꢀ
arylhydrazinylidenꢀ3ꢀoxobutanenitriles (3’a–c) and a variety of 5ꢀaminoꢀ1Hꢀpyrazoles (5a–
h). The results are reported in Table 2. A wide variety of pyrazolo[1,5ꢀa]pyrimidines 6a–q
were obtained in good to excellent yields in a regioselective manner, without requiring
chromatographic purification. In general, the reaction of 2ꢀarylhydrazinylidenꢀ3ꢀ
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oxobutanenitriles (3’) with 5ꢀaminoꢀ1Hꢀpyrazoles (5) containing diverse substituents
attached to the carbon atom of the pyrazole ring, proceeded efficiently to give the cyclized
products 6 in up to 94% yield, which clearly indicated the low electronic influence of the
substituents on the reactivity. Notably, this method allows the preparation of a
polyfunctional pyrazolo[1,5ꢀa]pyrimidine scaffold containing the amino and aryldiazenyl
groups. Therefore, these hetarylazo derivatives could be used as intermediates for the
synthesis of biologically active Nꢀfused heteroaromatic compounds. The structures of the
novel synthesized compounds 6a-q were determined by NMR and these result correlate
with our previous work in the synthesis and characterization of 6c, by both NMR and Xꢀray
crystallography.15 In this synthetic work, we have placed a strong emphasis on sustainable
chemistry which resulted in a protocol where: (a) no purification is required, (b) water is
produced as unique byproduct, (c) the reaction time is very short, and in general (d) the
process is highly efficient.
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Table 2. Microwaveꢀassisted Synthesis of Densely Substituted Pyrazolo[1,5ꢀa]pyrimidinesa
Entry 3’ (Ar)
5 (R1)
Product Yield
(%)b
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4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
Ph
Ph
2ꢀMeC6H4
Me
tꢀBu
Ph
4ꢀMeOC6H4
4ꢀMeC6H4
4ꢀClC6H4
4ꢀO2NC6H4
Me
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94
85
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87
91
6a
6b
6c
6d
6e
6f
6g
6h
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2ꢀMeC6H4
2ꢀMeC6H4
2ꢀMeC6H4
2ꢀMeC6H4
2ꢀMeC6H4
tꢀBu
85
76
83
78
72
92
70
88
91
6i
6j
6k
6l
6m
6n
6o
6p
6q
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4ꢀMeOC6H4
4ꢀMeC6H4
4ꢀClC6H4
4ꢀBrC6H4
3,5ꢀ(Me)2C6H3 Me
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3,5ꢀ(Me)2C6H3 4ꢀMeOC6H4
3,5ꢀ(Me)2C6H3 4ꢀMeC6H4
3,5ꢀ(Me)2C6H3 4ꢀClC6H4
a The reactions were carried out with 0.5 mmol of each reaction partner at 180 °C in sealed
b
tubes under microwave irradiation; see Experimental Section for details. Isolated yield.
On the basis of the aforementioned results and literature precedents,9,10 a plausible
mechanism was proposed for the generation of the pyrazolo[1,5ꢀa]pyrimidinꢀ7ꢀamines, as
depicted in Scheme 3. It starts with the condensation of βꢀketonitrile 3’ with exocyclic
amino group of the pyrazole 5 to form the imine intermediate 7. An intramolecular
nucleophilic attack by the NH group of the pyrazole on the nitrile carbon atom occurs to
form the cyclized intermediate 8. Finally, the tautomerization of the hydrazoneꢀimine
intermediate 8 to the stable azoꢀenamine tautomer would explain the formation of 6 as the
only product.
Scheme 3. Plausible Mechanism for the Formation of Pyrazolo[1,5ꢀa]pyrimidinꢀ7ꢀamines 6
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Recently, pyridone and pyrimidine derivatives have attracted considerable interest as Nꢀ
heterocyclic intermediates for the preparation of hetarylazo dyes.6,19c Moreover, the
applications of azoꢀdyes are strongly dependent on the photophysical properties of azoꢀ
hydrazone tautomerism (i.e. as structures 6 or 8 respectively, see Scheme 3). The above
observations have motivated us to carry out a preliminary studies of the solvatochromic
properties for all azoꢀdyes 6a-q in various organic solvents with different dipole moment
parameters (see Supporting Information, Table 1). The absorption spectra of those 6ꢀ
(aryldiazenyl)pyrazolo[1,5ꢀa]pyrimidinꢀ7ꢀamines 6a-q were studied in the range of 200–
800 nm, in organic solvents with different dipole moment parameters (εr) such as polarꢀ
aprotic: DMF (36.7); polarꢀprotic: EtOH (24.5); and nonꢀpolar: CH2Cl2 (8.93). We found
that the absorption spectra of these hetarylazo dyes indicated a regular variation with the
polarity of solvents. In general, the redꢀshifting (bathochromic shift) of λmax ocurrs with the
increase of dipole moment parameters (εr) of the solvents. Nevertheless, the phenomenon is
different in the case of dichloromethane which can be explained by interactions between
the chlorine atoms and the hetarylazo dyes.19c
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Once 7ꢀaminoꢀ6ꢀ(aryldiazenyl)pyrazolo[1,5ꢀa]pyrimidines 6 were obtained and due to the
importance of 1,2ꢀdiamines as synthetic intermediate of pharmacologically active
heterocyclic compounds, we developed an operationally simple method to convert the 6ꢀ
aryldiazenyl group of 6 in an 6ꢀamino group in order to generate the 1,2ꢀdiamine
functionality. To justify the use of derivatives 6 as strategic intermediates to 6,7ꢀdiamino
derivatives 9, we refer to our previous work where the nitrosation of 2,5ꢀ
dimethylpyrazolo[1,5ꢀa]pyrimidinꢀ7ꢀamine 7 and subsequent reduction of the nitroso
group, produced the undesired 3,7ꢀdiamine 8 instead of the 6,7ꢀdiamine 9 (Scheme 4a).21
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Those results can be explained by the better nucleophilicity at the Cꢀ3 position due to the
high electronic density of the πꢀexcedent pyrazole ring. Therefore, we planned the
palladiumꢀcatalyzed reductive cleavage of azocompounds 6 in order to reach the desire
heteroaromatic 1,2ꢀdiamine scaffold (Scheme 4b).
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Scheme 4. Selective Amination in 7ꢀAminopyrazolo[1,5ꢀa]pyrimidines
Gratifyingly, we found that the reductive azo bond cleavage was achieved at 60 °C under
an H2 atmosphere at ambient pressure using Pd/C as catalyst in ethanol, giving the expected
heteroaromatic 1,2ꢀdiamine 9a in 90% yield with the full recovery of aniline (Scheme 5).
Pleasingly, the overall synthesis of pyrazolo[1,5ꢀa]pyrimidineꢀ6,7ꢀdiamines (9) was shown
to be efficient in the presence of various substituents such as methyl, tꢀbutyl and phenyl
groups at pyrazole ring (9a–c, Scheme 5). It is important to emphasize that aniline is
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recovered as the unique byproduct, the reaction is carried out in relatively low
temperatures, and in the absence of acids. Therefore, this method is attractive and
advantageous in organic synthesis to obtain 1,2ꢀdiamines. In addition, this is a new
methodology not reported up to now that allows the efficient access to these heteroaromatic
building blocks.
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Scheme 5. Reductive Cleavage of Azocompounds into Heteroaromatic 1,2ꢀDiamines by
Pd/C–H2 system.a
a Reaction conditions: hetarylazo dye 6 (2.0 mmol) and 10% Pd/C (5 wt %) under an H2
atmosphere at ambient pressure in EtOH (10.0 mL) at 60 °C for 24 h.
Subsequently, we examined the synthesis of bioactive Nꢀheterocycles from those
heteroaromatic 1,2ꢀdiamines 9. Although great endeavors have been devoted to the
synthesis of purineꢀfused polycyclic derivatives, the structural diversity of azolo derivatives
is still very limited.22 Given the need for developing efficient and expeditious methods to
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prepare structurally diverse purineꢀfused tricyclic derivatives, the synthesis of
multisubstituted pyrazolo[5,1ꢀb]purines was tried. As shown in the Scheme 6, the
microwaveꢀassisted cyclocondensation of pyrazolo[1,5ꢀa]pyrimidineꢀ6,7ꢀdiamines 9 with
various orthoesters 10 provided the desired products 11a–e in good to excellent yields (81–
96%). To further evaluate the scope of this methodology, additional studies are currently
underway to expand the range of 5ꢀaminoꢀ1Hꢀazoles containing triazole, imidazole and
pyrrole ring, as well as to study the synthesis of 1,4ꢀdiazepine derivatives via the
cyclocondensation of pyrazolo[1,5ꢀa]pyrimidineꢀ6,7ꢀdiamines 9 with 1,3ꢀbisꢀelectrophiles.
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Scheme 6. Novel Approach to Substituted Pyrazolo[5,1ꢀb]purinesa,b
R1
N
R1
N
R3
O
O
110-120 °C ( W)
5-10 min
N
N
N
N
R2
O
+
R3
R3
H2N
Me
Me
HN
R2
N
NH2
11
9
10
Me
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
Me
Me
Me
Me
Me
HN
HN
HN
Me
HN
HN
N
N
N
N
N
Me
11a (88%)c
11b (91%)c
11c (96%)c
11d (81%)d
11e (84%)d
a
Reaction conditions: heteroaromatic 1,2ꢀdiamine 9 (0.5 mmol) and orthoester 10 (0.6
b
c
mmol); see Supporting Information for detail. Isolated yields are shown. Reaction
performed at 110 °C for 5 min. d Reaction performed at 120 °C for 10 min.
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Conclusions
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In summary, the 1,3ꢀbisꢀelectrophiles αꢀarylhydrazinylideneꢀβꢀketonitriles were
characterized by spectroscopic analysis and singleꢀcrystal Xꢀray diffraction analysis, which
evidence the hydrazoneꢀketo tautomer 3’ as the predominant form in the solid state whereas
in solution the azoꢀenol tautomer 3 is the major form. Notably, we have developed a
regioselective solventꢀfree microwaveꢀassisted reaction to prepare functionalized
pyrazolo[1,5ꢀa]pyrimidinꢀ7ꢀamines containing an aryldiazenyl group in good to excellent
yields with the formation of two new C−N bonds in one step, by reacting 5ꢀaminoꢀ1Hꢀ
pyrazoles and 2ꢀ(2ꢀarylhydrazinylidene)ꢀ3ꢀoxobutanenitriles. In addition, it is important to
mention that this reaction is environmentally sustainable and highly atom economical,
producing water as the unique byproduct under solventꢀfree conditions. Furthermore, we
have successfully developed a palladiumꢀcatalyzed reductive cleavage method at ambient
pressure of hetarylazo compounds, affording pyrazolo[1,5ꢀa]pyrimidineꢀ6,7ꢀdiamines in
good yields. Pleasingly, the pyrazolo[1,5ꢀa]pyrimidineꢀ6,7ꢀdiamine products readily
engage in cyclocondensation reactions with various orthoesters for the synthesis of
structurally diverse pyrazolo[5,1ꢀb]purines in yields up to 96% by using microwave
irradiation. Notably, these tricyclic derivatives were obtained in four reaction steps
(diazotization/cyclization/reduction/cyclization) starting from aniline in 60ꢀ70% overall
yield. This methodology constitutes a new approach to generate tricyclic heteroaromatic
systems and we expect that postꢀmodification strategies could be useful in medicinal
chemistry towards the synthesis of novel drug candidates.
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EXPERIMENTAL SECTION
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General Information. All reagents were purchased from commercial sources and used
without further purification, unless otherwise noted. All starting materials were weighed
and handled in air at room temperature. The reactions were monitored by TLC visualized
by UV lamp (254 nm or 365 nm) and/or with pꢀanisaldehyde and H2SO4 in EtOH. Column
chromatography was performed on silica gel (70–230 mesh). Reactions under microwave
irradiation were performed in ovenꢀdried 10.0 mL sealable Pyrex tubes equipped with a
Teflon coated stirring bar (obtained from CEM). All reactions under microwave irradiation
(ν = 2.45 GHz) were performed in a CEM Discover 1ꢀ300W system equipped with a builtꢀ
in pressure measurement sensor. NMR spectra were recorded at 400 MHz (1H) and 100
MHz (13C) at 298 K using tetramethylsilane (0 ppm) as the internal reference. NMR
spectroscopic data were recorded in CDCl3 or [D6]DMSO using as internal standards the
residual nonꢀdeuteriated signal for 1H NMR and the deuteriated solvent signal for 13C NMR
spectroscopy. DEPT spectra were used for the assignment of carbon signals. Chemical
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shifts (δ) are given in ppm and coupling constants (J) are given in Hz. The following
abbreviations are used for multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, dd
= doublet of doublets, and m = multiplet. Melting points were collected using a capillary
melting point apparatus and are uncorrected. IR spectra were recorded on a FTꢀIR
spectrophotometer using KBr discs. Spectra are reported in frequency of absorption in cmꢀ1,
and only selected resonances are reported. Mass spectra were recorded with a spectrometer
(with a direct inlet probe) operating at 70 eV. Highꢀresolution mass spectra (HRMS) were
recorded using a QꢀTOF spectrometer via electrospray ionization (ESI). UVꢀVis absorption
spectra were recorded in 1 cm cuvettes. Crystallographic data were recorded on a
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diffractometer using graphiteꢀmonochromated Mo Kα radiation (λ= 0.71073 Å). Structures
were solved by direct methods in SHELXSꢀ97. Compounds 3/3’ and 5 were prepared by
protocols reported in the literature.11b,23
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General Procedure for the Synthesis of 2-(2-Arylhydrazinylidene)-3-oxo-butanenitrile
3’. A solution of the aniline derivate 1a-c (20.0 mmol) was cooled at 0–5 ºC and
concentrated hydrochloric acid (20.0 mL) was slowly added. An aqueous solution of
sodium nitrite (20.0 mmol in 10.0 mL of water) was added slowly into the cooled stirred
anilineꢀhydrochloride solution. 3ꢀAminobutꢀ2ꢀenenitrile (2, 20.0 mmol) and sodium acetate
(4.0 g, 48.0 mmol) was dissolved in 10.0 mL of 50% aqueous ethanol. The solution was
placed in an ice bath to cool it to 0–5 ºC. To this solution, the diazotized solution was added
slowly with constant stirring for 30 min. The pH of the mixture was maintained at 5–6 by
adding an aqueous solution of sodium acetate (4%). A bright yellow color precipitation was
started to appear. The reaction mixture was stirred at room temperature for additional 2 h.
The resulting precipitate was filtered, washed with cold water, dried and recrystallized from
ethanol–water to give the pure compound as a mixture of the tautomeric forms 3/3’.
3ꢀOxoꢀ2ꢀ(2ꢀphenylhydrazinylidene)butanenitrile 3’a. Following the general procedure, the
reaction of aniline (1a, 1.82 mL, 20.0 mmol) and 3ꢀaminobutꢀ2ꢀenenitrile (2, 1642 mg, 20.0
mmol) afforded desired product as a yellow solid (3292 mg, 88 %) and as mixtures of azoꢀ
enol and hydrazoneꢀketo tautomers (69:31 ratio) after silica gel purification. M.p 159–161
°C (amorphous) (Lit. 168 °C).17 Recrystallization of 3’a from methanol afforded crystalline
yellow prisms suitable for Xꢀray diffraction analysis.18 FTIR: ν = 3229 (N–H), 3060, 2213
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(C≡N), 1644 (C=O), 1540 (N=C) cmꢀ1. Azoꢀenol tautomer 3a: H NMR (CDCl3, 400
5
6
7
MHz):
δ
= 2.50 (s, 3H), 7.21–7.45 (m, 5H), 14.75 (br s, 1H, O–H) ppm. 13C{1H} NMR
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9
(CDCl3, 100 MHz):
δ
= 28.1 (CH3), 112.0 (C), 116.5 (CH), 117.1 (C), 126.9 (CH), 129.7
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(CH), 140.5 (C), 194.1 (C) ppm. Hydrazoneꢀketo tautomer 3’a: H NMR (CDCl3, 400
MHz):
δ
= 2.50 (s, 3H), 7.21–7.45 (m, 5H), 9.44 (br s, 1H, N–H) ppm. 13C{1H} NMR
= 24.5 (CH3), 109.7 (C), 115.7 (CH), 117.1 (C), 125.8 (CH), 129.8
(CDCl3, 100 MHz):
δ
(CH), 140.3 (C), 191.8 (C) ppm. HRMS (ESI+): calcd. For C10H10N3O+ 188.0824 [M +
H]+; found 188.0824. These NMR data matched previously reported data.17
3ꢀOxoꢀ2ꢀ(orthoꢀtolylhydrazinylidene)butanenitrile 3’b. Following the general procedure,
the reaction of orthoꢀmethylaniline (1b, 2.14 mL, 20.0 mmol) and 3ꢀaminobutꢀ2ꢀenenitrile
(2, 1642 mg, 20.0 mmol) afforded desired product as an orange solid (3338 mg, 83 %) and
as mixtures of azoꢀenol and hydrazoneꢀketo tautomers (83:17 ratio) after silica gel
purification. M.p 112–114 °C (amorphous) (Lit. 151 °C).[17] FTIR: ν = 3242 (N–H), 3075,
2217 (C≡N), 1640 (C=O), 1533 (N=C) cmꢀ1. Azoꢀenol tautomer 3b: 1H NMR (CDCl3, 400
MHz):
δ
= 2.38 (s, 3H), 2.52 (s, 3H), 7.12–7.32 (m, 3H), 7.74 (d, J = 7.5 Hz, 1H), 14.97 (br
13
s, 1H, O–H) ppm. C{1H} NMR (CDCl3, 100 MHz):
δ = 16.7 (CH3), 28.0 (CH3), 112.6
(C), 115.5 (CH), 117.2 (C), 125.6 (C), 126.8 (CH), 127.7 (CH), 131.0 (CH), 138.8 (C),
1
194.1 (C) ppm. Hydrazoneꢀketo tautomer 3’b: H NMR (CDCl3, 400 MHz):
δ = 2.41 (s,
3H), 2.50 (s, 3H), 7.12–7.32 (m, 3H), 7.55 (d, J = 7.5 Hz, 1H), 9.20 (br s, 1H, N–H) ppm.
13C{1H} NMR (CDCl3, 100 MHz):
δ
= 16.6 (CH3), 24.5 (CH3), 109.6 (C), 115.6 (CH),
116.7 (C), 124.3 (C), 125.6 (CH), 127.7 (CH), 131.4 (CH), 138.7 (C), 191.7 (C) ppm.
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HRMS (ESI+): calcd. for C11H12N3O+ 202.0980 [M + H]+; found 202.0988. These NMR
data matched previously reported data.17
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3ꢀOxoꢀ2ꢀ(2,6ꢀdimethylphenylhydrazinylidene)butanenitrile 3’c. Following the general
procedure, the reaction of 3,5ꢀdimethylaniline (1c, 2.49 mL, 20.0 mmol) and 3ꢀaminobutꢀ2ꢀ
enenitrile (2, 1642 mg, 20.0 mmol) afforded desired compound as an orange solid (3657
mg, 85 %) and as mixtures of azoꢀenol and hydrazoneꢀketo tautomers (71:29 ratio) after
silica gel purification. M.p 153–156 °C (amorphous). FTIR: ν = 3215 (N–H), 3066, 2215
1
(C≡N), 1651 (C=O), 1528 (N=C) cmꢀ1. Azoꢀenol tautomer 3c: H NMR (CDCl3, 400
MHz):
δ = 2.33 (s, 6H), 2.48 (s, 3H), 6.88 (s, 1H), 7.02 (s, 2H), 14.69 (br s, 1H, O–H) ppm.
13C{1H} NMR (CDCl3, 100 MHz):
δ
= 21.2 (CH3), 28.0 (CH3), 111.6 (C), 114.3 (CH),
117.3 (C), 128.9 (CH), 139.7 (C), 140.4 (C), 194.0 (C) ppm. Hydrazoneꢀketo tautomer 3’c:
1H NMR (CDCl3, 400 MHz):
(br s, 1H, N–H) ppm. 13C{1H} NMR (CDCl3, 100 MHz):
δ
= 2.35 (s, 6H), 2.50 (s, 3H), 6.85 (s, 1H), 6.95 (s, 2H), 9.40
δ
= 21.3 (CH3), 24.6 (CH3),
113.1 (C), 113.6 (CH), 115.3 (C), 127.7 (CH), 139.8 (C), 140.5 (C), 192.0 (C) ppm. HRMS
(ESI+): calcd. for C12H14N3O+ 216.1137 [M + H]+; found 216.1145.
General Procedure for the Synthesis of 2-Substituted-7-amino-6-(aryldiazenyl)-5-
methylpyrazolo[1,5-a]pyrimidines 6a–s: A mixture of 2ꢀ(2ꢀarylhydrazinylidene)ꢀ3ꢀoxoꢀ
butanenitrile (3’a–c, 0.5 mmol) and 5ꢀaminoꢀ1Hꢀpirazole (5a–j, 0.5 mmol) was irradiated
with microwaves at 180–220 °C for 4 min in a sealed tube containing a Teflonꢀcoated
magnetic stirring bar. The resulting reaction mixture was cooled to 55 °C, and the
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precipitated product formed upon the addition of cold ethanol (2.0 mL) was filtered off,
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washed and dried to give the pure product 6.
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(E)ꢀ7ꢀAminoꢀ2,5ꢀdimethylꢀ6ꢀ(phenyldiazenyl)pyrazolo[1,5ꢀa]pyrimidine 6a. The general
procedure at 180 °C for 4 min with 3’a (94 mg, 0.50 mmol) and 5a (49 mg, 0.50 mmol)
afforded product 6a as a yellow solid (114 mg, 86 %). M.p. 231–233 °C (amorphous).
1
FTIR (KBr): ν = 3274 (N–H), 1623 (C=N), 1454 (N=N) cmꢀ1. H NMR (400 MHz,
[D6]DMSO):
δ = 2.41 (s, 3H), 2.73 (s, 3H), 6.24 (s, 1H), 7.41 (t, J = 7.3 Hz,1H), 7.52 (t, J =
7.5 Hz, 2H), 7.83 (d, J = 7.5 Hz, 2H), 9.11 (br s, 1H), 10.25 (br s, 1H) ppm. 13C{1H} NMR
(100 MHz, [D6]DMSO):
δ = 13.7 (CH3), 21.1 (CH3), 95.3 (CH), 116.3 (C), 120.7 (CH),
128.6 (CH), 128.6 (CH), 138.9 (C), 147.6 (C), 152.1 (C), 155.4 (C), 160.0 (C) ppm. HRMS
(ESI+): calcd. for C14H15N6 267.1358 [M + H]+; found 267.1387.
+
(E)ꢀ7ꢀAminoꢀ2ꢀtertꢀbutylꢀ5ꢀmethylꢀ6ꢀ(phenyldiazenyl)pyrazolo[1,5ꢀa]pyrimidine 6b. The
general procedure at 180 °C for 4 min with 3’a (100 mg, 0.53 mmol) and 5b (74 mg, 0.53
mmol) afforded product 6b as a yellow solid (154 mg, 94 %). M.p. 152–154 °C
(amorphous). FTIR (KBr): ν = 3229 (N–H), 1616 (C=N), 1485 (N=N) cmꢀ1. 1H NMR (400
MHz, [D6]DMSO):
δ = 1.38 (s, 9H), 2.75 (s, 3H), 6.35 (s, 1H), 7.42 (t, J = 7.5 Hz, 1H),
7.54 (t, J = 7.5 Hz, 2H), 7.84 (d, J = 7.7 Hz, 2H), 8.70 (br s, 1H), 10.23 (br s, 1H) ppm.
13C{1H} NMR (100 MHz, [D6]DMSO):
δ
= 21.1 (CH3), 29.4 (CH3), 32.1 (C), 92.2 (CH),
115.9 (C), 120.7 (CH), 128.5 (CH), 128.6 (CH), 138.9 (C), 147.3 (C), 152.1 (C), 159.8 (C),
+
168.3 (C) ppm. HRMS (ESI+): calcd. for C17H21N6 309.1828 [M + H]+; found 309.1846.
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(E)ꢀ7ꢀAminoꢀ5ꢀmethylꢀ2ꢀphenylꢀ6ꢀ(phenyldiazenyl)pyrazolo[1,5ꢀa]pyrimidine 6c. The
general procedure at 180 °C for 4 min with 3’a (97 mg, 0.52 mmol) and 5c (83 mg, 0.52
mmol) afforded product 6c as a yellow–orange solid (145 mg, 85 %). M.p. 152–154 °C
(amorphous). Recrystallization of this material from N,Nꢀdimethylformamide afforded
orange crystals suitable for Xꢀray diffraction analysis.[15] FTIR (KBr): ν = 3381 (N–H),
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1618 (C=N), 1457 (N=N) cmꢀ1. 1H NMR (400 MHz, [D6]DMSO):
δ = 2.78 (s, 3H), 6.93 (s,
1H), 7.41–7.56 (m, 6H), 7.86 (d, J = 7.5 Hz, 2H), 8.08 (d, J = 7.5 Hz, 2H), 9.00 (br s, 1H),
13
10.28 (br s, 1H) ppm. C{1H} NMR (100 MHz, [D6]DMSO):
δ = 21.2 (CH3), 92.7 (CH),
116.8 (C), 120.8 (CH), 125.8 (CH), 128.0 (CH), 128.5 (CH), 128.6 (CH), 128.7 (CH),
132.0 (C), 139.0 (C), 148.0 (C), 152.1 (C), 156.2 (C), 160.4 (C) ppm. HRMS (ESI+): calcd.
+
for C19H17N6 329.1515 [M + H]+; found 329.1540.
(E)ꢀ7ꢀAminoꢀ2ꢀ(4ꢀmethoxyphenyl)ꢀ5ꢀmethylꢀ6ꢀ(phenyldiazenyl)pyrazolo[1,5ꢀa]pyrimidine
6d. The general procedure at 180 °C for 4 min with 3’a (95 mg, 0.51 mmol) and 5d (94 mg,
0.50 mmol) afforded product 6d as a yellow solid (140 mg, 78 %). M.p. 250–252 °C
(amorphous). FTIR (KBr): ν = 3442 (N–H), 1619 (C=N), 1453 (N=N) cmꢀ1. 1H NMR (400
MHz, [D6]DMSO):
δ = 2.78 (s, 3H), 3.83 (s, 3H), 6.72 (s, 1H), 7.03 (d, J = 8.1 Hz, 2H),
7.40 (t, J = 7.4 Hz, 1H), 7.51 (t, J = 7.4 Hz, 2H), 7.80 (d, J = 7.5 Hz, 2H), 7.95 (d, J = 8.1
Hz, 2H), 9.22 (br s, 2H) ppm. 13C{1H} NMR (100 MHz, [D6]DMSO):
δ
= 21.0 (CH3), 54.7
(OCH3), 92.1 (CH), 113.8 (CH), 116.7 (C), 120.7 (CH), 124.6 (C), 127.1 (CH), 128.4 (CH),
128.6 (CH), 138.9 (C), 147.9 (C), 152.1 (C), 156.1 (C), 159.9 (C), 160.1 (C) ppm. MS (70
eV, EI): m/z (%) = 358 (100) [M]+, 341 (10), 226 (16). HRMS: calcd. for C20H18N6O+
358.1542 [M]+; found 358.1548.
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(E)ꢀ7ꢀAminoꢀ5ꢀmethylꢀ2ꢀ(4ꢀmethylphenyl)ꢀ6ꢀ(phenyldiazenyl)pyrazolo[1,5ꢀa]pyrimidine
6e. The general procedure at 180 °C for 4 min with 3’a (90 mg, 0.48 mmol) and 5e (83 mg,
0.48 mmol) afforded product 6e as a yellow solid (130 mg, 79 %). M.p. 214–216 °C
(amorphous). FTIR (KBr): ν = 3391 (N–H), 1617 (C=N), 1451 (N=N) cmꢀ1. 1H NMR (400
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MHz, [D6]DMSO):
δ = 2.37 (s, 3H), 2.77 (s, 3H), 6.89 (s, 1H), 7.31 (d, J = 8.0 Hz, 2H),
7.43 (t, J = 7.2 Hz, 1H), 7.54 (t, J = 7.2 Hz, 2H), 7.87 (d, J = 7.3 Hz, 2H), 7.98 (d, J = 8.0
Hz, 2H), 9.02 (br s, 1H), 10.27 (br s, 1H) ppm. 13C{1H} NMR (100 MHz, [D6]DMSO):
δ
=
20.9 (CH3), 22.0 (CH3), 93.0 (CH), 116.9 (C), 121.4 (CH), 126.2 (CH), 129.2 (CH x 2),
129.3 (CH), 129.4 (C), 138.7 (C), 139.4 (C), 148.3 (C), 152.3 (C), 156.4 (C), 160.9 (C)
ppm. MS (70 eV, EI): m/z (%) = 342 (100) [M]+, 237 (18), 210 (13), 77 (11). HRMS: calcd.
for C20H18N6 342.1593 [M]+; found 342.1591.
+
(E)ꢀ7ꢀAminoꢀ2ꢀ(4ꢀchlorophenyl)ꢀ5ꢀmethylꢀ6ꢀ(phenyldiazenyl)pyrazolo[1,5ꢀa]pyrimidine 6f.
The general procedure at 180 °C for 4 min with 3’a (98 mg, 0.52 mmol) and 5f (100 mg,
0.52 mmol) afforded product 6f as a yellow–orange solid (151 mg, 80 %). M.p. 259–260
1
°C (amorphous). FTIR (KBr): ν = 3437 (N–H), 1616 (C=N), 1448 (N=N) cmꢀ1. H NMR
(400 MHz, [D6]DMSO):
δ
= 2.79 (s, 3H), 6.81 (s, 1H), 7.41 (t, J = 7.4 Hz, 1H), 7.48–7.53
13
(m, 4H), 7.81 (d, J = 7.4 Hz, 2H), 8.03 (d, J = 8.0 Hz, 2H), 9.27 (br s, 2H) ppm. C{1H}
NMR (100 MHz, [D6]DMSO):
δ = 21.0 (CH3), 92.7 (CH), 116.8 (C), 120.7 (CH), 127.3
(CH), 128.0 (CH), 128.4 (CH), 128.5 (CH), 130.9 (C), 133.3 (C), 138.8 (C), 148.0 (C),
152.1 (C), 154.9 (C), 160.4 (C) ppm. MS (70 eV, EI): m/z (%) = 364/362 (32/100) [M]+,
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259/257 (8/22), 232/230 (8/23), 77 (11). HRMS: calcd. for C19H15ClN6 362.1047 [M]+;
5
6
found 362.1050.
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(E)ꢀ7ꢀAminoꢀ5ꢀmethylꢀ2ꢀ(4ꢀnitrophenyl)ꢀ6ꢀ(phenyldiazenyl)pyrazolo[1,5ꢀa]pyrimidine 6g.
The general procedure at 180 °C for 4 min with 3’a (100 mg, 0.53 mmol) and 5g (106 mg,
0.52 mmol) afforded product 6g as a yellow solid (169 mg, 87 %). M.p. 288–290 °C
(amorphous). FTIR (KBr): ν = 3419 (N–H), 1617 (C=N), 1534 (NO2), 1453 (N=N), 1353
1
(NO2) cmꢀ1. H NMR (400 MHz, [D6]DMSO):
δ = 2.80 (s, 3H), 6.95 (s, 1H), 7.42 (t, J =
7.5 Hz, 1H), 7.52 (t, J = 7.3 Hz, 2H), 7.82 (d, J = 7.3 Hz, 2H), 8.23–8.32 (m, 4H), 9.34 (br
s, 2H) ppm. 13C{1H} NMR (100 MHz, [D6]DMSO):
δ
= 21.0 (CH3), 93.6 (CH), 115.8 (C),
120.8 (CH), 123.0 (CH), 126.6 (CH), 128.4 (CH), 128.7 (CH), 138.0 (C), 138.8 (C), 147.3
(C), 148.1 (C), 152.1 (C), 153.6 (C), 160.7 (C) ppm. MS (70 eV, EI): m/z (%) = 373 (100)
[M]+, 356 (15), 241 (21), 77 (29). HRMS: calcd. for C19H15N7O2 373.1287 [M]+; found
+
373.1279.
(E)ꢀ7ꢀAminoꢀ2,5ꢀdimethylꢀ6ꢀ(2ꢀmethylphenyldiazenyl)pyrazolo[1,5ꢀa]pyrimidine 6h. The
general procedure at 180 °C for 4 min with 3’b (100 mg, 0.50 mmol) and 5a (49 mg, 0.50
mmol) afforded product 6h as a yellow solid (127 mg, 91 %). M.p. 189–190 °C
(amorphous). FTIR (KBr): ν = 3421 (N–H), 1599 (C=N), 1436 (N=N) cmꢀ1. 1H NMR (400
MHz, [D6]DMSO):
δ = 2.39 (s, 3H), 2.54 (s, 3H), 2.73 (s, 3H), 6.23 (s, 1H), 7.29–7.31 (m,
2H), 7.36–7.38 (m, 1H), 7.61–7.63 (m, 1H), 9.26 (br s, 1H), 10.17 (br s, 1H) ppm. 13C{1H}
NMR (100 MHz, [D6]DMSO):
δ = 14.4 (CH3), 17.8 (CH3), 21.8 (CH3), 95.9 (CH), 114.9
(CH), 117.2 (C), 126.7 (CH), 129.0 (C), 131.1 (CH), 134.4 (CH), 139.4 (C), 147.8 (C),
150.2 (C), 155.9 (C), 160.5 (C) ppm. MS (70 eV, EI): m/z (%) = 280 (100) [M]+, 175 (21),
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148 (31), 91 (49). HRMS (ESI+): calcd. for C15H17N6 281.1515 [M + H]+; found
5
6
281.1514.
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(E)ꢀ7ꢀAminoꢀ2ꢀtertꢀbutylꢀ5ꢀmethylꢀ6ꢀ(2ꢀmethylphenyldiazenyl)pyrazolo[1,5ꢀa]pyrimidine
6i. The general procedure at 180 °C for 4 min with 3’b (104 mg, 0.52 mmol) and 5b (72
mg, 0.52 mmol) afforded product 6i as a yellow–orange solid (142 mg, 85 %). M.p. 86–88
°C (amorphous). FTIR (KBr): ν = 3435 (N–H), 1612 (C=N), 1523 (N=N) cmꢀ1. 1H NMR
(400 MHz, CDCl3):
δ = 1.39 (s, 9H), 2.62 (s, 3H), 2.93 (s, 3H), 6.34 (s, 1H), 7.24–7.34 (m,
4H), 7.69–7.71 (m, 1H), 10.41 (br s, 1H) ppm. 13C{1H} NMR (100 MHz, CDCl3):
δ
= 18.4
(CH3), 21.7 (CH3), 30.1 (CH3), 33.1 (C), 93.2 (CH), 115.4 (CH), 117.8 (C), 126.8 (CH),
129.5 (CH), 131.1 (CH), 134.9 (C), 139.2 (C), 139.7 (C), 150.7 (C), 161.3 (C), 169.8 (C)
ppm. MS (70 eV, EI): m/z (%) = 322 (100) [M]+, 307 (30), 265 (18), 203 (43), 91 (38).
HRMS (ESI+): calcd. for C18H23N6 323.1984 [M + H]+; found 323.2004.
+
(E)ꢀ7ꢀAminoꢀ2ꢀ(4ꢀmethoxyphenyl)ꢀ5ꢀmethylꢀ6ꢀ(2ꢀmethylphenyldiazenyl)pyrazolo[1,5ꢀ
a]pyrimidine 6j. The general procedure at 180 °C for 4 min with 3’b (100 mg, 0.50 mmol)
and 5d (95 mg, 0.50 mmol) afforded product 6j as a yellow solid (141 mg, 76 %). M.p.
251–252 °C (amorphous). FTIR (KBr): ν = 3395 (N–H), 1606 (C=N), 1456 (N=N) cmꢀ1. 1H
NMR (400 MHz, [D6]DMSO):
δ = 2.60 (s, 3H), 2.80 (s, 3H), 3.84 (s, 3H), 6.72 (s, 1H),
7.04 (d, J = 8.0 Hz, 2H), 7.29–7.38 (m, 3H), 7.61–7.63 (m, 1H), 7.95 (d, J = 8.0 Hz, 2H),
13
9.28 (br s, 2H) ppm. C{1H} NMR (100 MHz, [D6]DMSO):
δ = 16.9 (CH3), 21.0 (CH3),
54.7 (CH3), 92.1 (CH), 113.7 (CH), 115.0 (CH), 117.3 (C), 124.6 (C), 125.9 (CH), 127.1
(CH), 128.3 (CH), 130.3 (CH), 133.5 (C), 138.9 (C), 147.9 (C), 150.3 (C), 156.1 (C), 159.8
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(C), 160.0 (C) ppm. MS (70 eV, EI): m/z (%) = 372 (100) [M]+, 357 (20), 355 (18), 253
(23), 226 (22), 91 (11). HRMS (ESI+): calcd. for C21H21N6O+ 373.1777 [M + H]+; found
373.1795.
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(E)ꢀ7ꢀAminoꢀ5ꢀmethylꢀ2ꢀ(4ꢀmethylphenyl)ꢀ6ꢀ(2ꢀmethylphenyldiazenyl)pyrazolo[1,5ꢀ
a]pyrimidine 6k. The general procedure at 180 °C for 4 min with 3’b (110 mg, 0.55 mmol)
and 5e (95 mg, 0.55 mmol) afforded product 6k as a yellow–orange solid (162 mg, 83 %).
M.p. 242–244 °C (amorphous). FTIR (KBr): ν = 3421 (N–H), 1613 (C=N), 1456 (N=N)
cmꢀ1. 1H NMR (400 MHz, [D6]DMSO):
δ = 2.38 (s, 3H), 2.61 (s, 3H), 2.80 (s, 3H), 6.77 (s,
1H), 7.27–7.38 (m, 5H), 7.61–7.64 (m, 1H), 7.92 (d, J = 8.0 Hz, 2H), 9.31 (br s, 2H) ppm.
13C{1H} NMR (100 MHz, [D6]DMSO):
δ
= 16.9 (CH3), 20.0 (CH3), 21.0 (CH3), 92.4 (CH),
115.0 (CH), 117.3 (C), 125.6 (CH), 125.9 (CH), 128.3 (CH), 128.5 (CH), 129.4 (C), 130.4
(CH), 133.6 (C), 138.0 (C), 139.0 (C), 147.9 (C), 150.3 (C), 156.3 (C), 160.1 (C) ppm. MS
(70 eV, EI): m/z (%) = 356 (100) [M]+, 341 (21), 237 (27), 210 (20), 91 (17). HRMS
+
(ESI+): calcd. for C21H21N6 357.1828 [M + H]+; found 357.1836.
(E)ꢀ7ꢀAminoꢀ2ꢀ(4ꢀchlorophenyl)ꢀ5ꢀmethylꢀ6ꢀ(2ꢀmethylphenyldiazenyl)pyrazolo[1,5ꢀ
a]pyrimidine 6l. The general procedure at 180 °C for 4 min with 3’b (105 mg, 0.52 mmol)
and 5f (101 mg, 0.52 mmol) afforded product 6l as a yellow–orange solid (152 mg, 78 %).
M.p. 284–286 °C (amorphous). FTIR (KBr): ν = 3446 (N–H), 1610 (C=N), 1450 (N=N)
1
cmꢀ1. H NMR (400 MHz, [D6]DMSO):
δ = 2.60 (s, 3H), 2.82 (s, 3H), 6.84 (s, 1H), 7.30–
7.40 (m, 3H), 7.53 (d, J = 8.5 Hz, 2H), 7.61–7.65 (m, 1H), 8.05 (d, J = 8.5 Hz, 2H), 9.31
13
(br s, 2H) ppm. C{1H} NMR (100 MHz, [D6]DMSO):
δ = 16.9 (CH3), 21.1 (CH3), 92.7
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(CH), 115.0 (CH), 117.7 (C), 126.0 (CH), 127.3 (CH), 128.0 (CH), 128.4 (CH), 128.9 (C),
130.4 (CH), 133.3 (C), 133.6 (C), 139.5 (C), 148.0 (C), 153.4 (C), 158.5 (C), 162.8 (C)
ppm. MS (70 eV, EI): m/z (%) = 378/376 (33/100) [M]+, 363/361 (8/25), 359 (16), 259/257
+
(9/20), 232/230 (9/24), 91 (18). HRMS (ESI+): calcd. for C20H18ClN6 377.1281 [M + H]+;
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found 377.1303.
(E)ꢀ7ꢀAminoꢀ2ꢀ(4ꢀbromophenyl)ꢀ5ꢀmethylꢀ6ꢀ(2ꢀmethylphenyldiazenyl)pyrazolo[1,5ꢀ
a]pyrimidine 6m. The general procedure at 180 °C for 4 min with 3’b (108 mg, 0.54 mmol)
and 5h (128 mg, 0.54 mmol) afforded product 6m as a yellow–orange solid (163 mg, 72
%). M.p. 289–290 °C (amorphous). FTIR (KBr): ν = 3439 (N–H), 1619 (C=N), 1452
(N=N) cmꢀ1. 1H NMR (400 MHz, [D6]DMSO):
δ = 2.60 (s, 3H), 2.80 (s, 3H), 6.82 (s, 1H),
7.29–7.38 (m, 3H), 7.60–7.64 (m, 1H), 7.65 (d, J = 8.6 Hz, 2H), 7.96 (d, J = 8.6 Hz, 2H),
9.31 (br s, 2H) ppm. 13C{1H} NMR (100 MHz, [D6]DMSO):
δ
= 16.9 (CH3), 21.0 (CH3),
92.7 (CH), 115.0 (CH), 117.4 (C), 121.7 (C), 126.0 (CH), 127.6 (CH), 128.4 (CH), 130.4
(CH), 130.9 (CH), 131.2 (C), 133.6 (C), 138.9 (C), 148.0 (C), 150.3 (C), 154.9 (C), 160.3
(C) ppm. MS (70 eV, EI): m/z (%) = 422/420 (94/100) [M]+, 393/391 (12/13), 303/301
+
(26/27), 276/274 (19/21), 91 (21). HRMS (ESI+): calcd. for C20H18BrN6 421.0776 [M +
H]+; found 421.0794.
(E)ꢀ7ꢀAminoꢀ2,5ꢀdimethylꢀ6ꢀ(3,5ꢀdimethylphenyldiazenyl)pyrazolo[1,5ꢀa]pyrimidine
6n.
The general procedure at 180 °C for 4 min with 3’c (108 mg, 0.50 mmol) and 5a (49 mg,
0.50 mmol) afforded product 6n as a yellow solid (135 mg, 92 %). M.p. 265–267 °C
(amorphous). FTIR (KBr): ν = 3308 (N–H), 1619, 8 (C=N), 1498 (N=N) cmꢀ1. 1H NMR
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(400 MHz, CDCl3):
δ
= 2.40 (s, 6H), 2.46 (s, 3H), 2.88 (s, 3H), 6.21 (s, 1H), 7.04 (br s,
5
6
7
2H), 7.40 (s, 2H), 10.44 (br s, 1H) ppm. 13C{1H} NMR (100 MHz, CDCl3):
δ = 14.7 (CH3),
8
9
21.3 (CH3), 22.1 (CH3), 96.3 (CH), 117.1 (C), 119.4 (CH), 131.2 (CH), 138.8 (C), 139.2
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(C), 148.2 (C), 152.7 (C), 156.7 (C), 161.6 (C) ppm. MS (70 eV, EI): m/z (%) = 294 (100)
+
[M]+, 279 (25), 265 (28), 161 (38), 134 (19). HRMS: calcd. for C16H18N6 294.1593 [M]+;
found 294.1591.
(E)ꢀ7ꢀAminoꢀ2ꢀ(4ꢀmethoxyphenyl)ꢀ5ꢀmethylꢀ6ꢀ(3,5ꢀdimethylphenyldiazenyl)pyrazolo[1,5ꢀ
a]pyrimidine 6o. The general procedure at 180 °C for 4 min with 3’c (110 mg, 0.51 mmol)
and 5d (96 mg, 0.51 mmol) afforded product 6o as a yellow solid (138 mg, 70 %). M.p.
265–266 °C (amorphous). FTIR (KBr): ν = 3245 (N–H), 1617 (C=N), 1505 (N=N) cmꢀ1.
1H NMR (400 MHz, [D6]DMSO):
δ
= 2.39 (s, 6H), 2.79 (s, 3H), 3.85 (s, 3H), 6.72 (s, 1H),
13
7.04–7.07 (m, 3H), 7.43 (s, 2H), 7.97 (d, J = 8.0 Hz, 2H), 9.20 (br s, 2H) ppm. C{1H}
NMR (100 MHz, [D6]DMSO):
δ = 20.0 (CH3), 20.9 (CH3), 54.7 (OCH3), 92.0 (CH), 113.8
(CH), 116.6 (C), 118.5 (CH), 124.6 (C), 127.1 (CH), 130.0 (CH), 137.7 (C), 138.9 (C),
148.2 (C), 152.3 (C), 156.1 (C), 159.9 (C), 160.0 (C) ppm. MS (70 eV, EI): m/z (%) = 386
(100) [M]+, 371 (25), 105 (72), 77 (52). HRMS (ESI+): calcd. for C22H23N6O+ 387.1933 [M
+ H]+; found 387.1950.
(E)ꢀ7ꢀAminoꢀ5ꢀmethylꢀ2ꢀ(4ꢀmethylphenyl)ꢀ6ꢀ(3,5ꢀdimethylphenyldiazenyl)pyrazolo[1,5ꢀ
a]pyrimidine 6p. The general procedure at 180 °C for 4 min with 3’c (118 mg, 0.55 mmol)
and 5e (95 mg, 0.55 mmol) afforded product 6p as a yellow–orange solid (179 mg, 88 %).
M.p. 227–229 °C (amorphous). FTIR (KBr): ν = 3301 (N–H), 1614 (C=N), 1497 (N=N)
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cmꢀ1. 1H NMR (400 MHz, [D6]DMSO):
δ
= 2.40 (s, 9H), 2.81 (s, 3H), 6.71 (s, 1H), 7.08 (s,
3
4
5
6
1H), 7.30 (d, J = 7.6 Hz, 2H), 7.42 (s, 2H), 7.90 (d, J = 7.6 Hz, 2H), 9.03 (br s, 2H) ppm.
7
8
9
13C{1H} NMR (100 MHz, [D6]DMSO):
δ = 19.6 (CH3), 20.6 (CH3), 21.5 (CH3), 92.1 (CH),
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116.6 (C), 118.2 (CH), 125.5 (CH), 128.2 (CH), 129.7 (CH), 130.8 (C), 137.5 (C), 137.8
(C), 138.7 (C), 148.4 (C), 152.3 (C), 156.2 (C), 159.8 (C) ppm. HRMS (ESI+): calcd. for
+
C22H23N6 371.1984 [M + H]+; found 371.1995.
(E)ꢀ7ꢀAminoꢀ2ꢀ(4ꢀchlorophenyl)ꢀ5ꢀmethylꢀ6ꢀ(3,5ꢀdimethylphenyldiazenyl)pyrazolo[1,5ꢀ
a]pyrimidine 6q. The general procedure at 180 °C for 4 min with 3’c (114 mg, 0.53 mmol)
and 5f (103 mg, 0.53 mmol) afforded product 6q as a yellow solid (188 mg, 91 %). M.p.
254–256 °C (amorphous). FTIR (KBr): ν = 3301 (N–H), 1610 (C=N), 1502 (N=N) cmꢀ1.
1H NMR (400 MHz, [D6]DMSO):
δ = 2.39 (s, 6H), 2.81 (s, 3H), 6.78 (s, 1H), 7.08 (s, 1H),
7.43 (s, 2H), 7.51 (d, J = 8.5 Hz, 2H), 8.03 (d, J = 8.5 Hz, 2H), 9.11 (br s, 2H) ppm.
13C{1H} NMR (100 MHz, [D6]DMSO):
δ
= 19.8 (CH3), 20.7 (CH3), 92.4 (CH), 116.7 (C),
118.3 (CH), 127.2 (CH), 127.8 (CH), 129.9 (CH), 130.8 (C), 133.2 (C), 137.6 (C), 138.7
(C), 147.9 (C), 152.2 (C), 154.8 (C), 160.1 (C) ppm. MS (70 eV, EI): m/z (%) = 391/389
+
(27/63) [M]+, 376/374 (14/35), 105 (100), 77 (89). HRMS (ESI+): calcd. for C21H20ClN6
391.1438 [M + H]+; found 391.1457.
General Procedure for the Synthesis of 2-Substituted-5-methylpyrazolo[1,5-
a]pyrimidine-6,7-diamines 9: A solution of 6ꢀ(aryldiazenyl)pyrazolo[1,5ꢀa]pyrimidinꢀ7ꢀ
amine (6, 2.0 mmol) in EtOH (10.0 mL) was treated with 10% Pd/C (5 wt % of substrate).
The reaction mixture was vigorously stirred and heated at 60 °C under an H2 atmosphere at
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The Journal of Organic Chemistry
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ambient pressure for 24 h. After the reaction was cooled to room temperature, the reaction
mixture was filtered through a Celite pad and washed with EtOH (2 x 5.0 mL). The filtrate
was evaporated under reduced pressure, and the residue was purified by column
chromatography on silica gel (eluent: CH2Cl2/MeOH = 15:1–20:1) to give the desired
heteroaromatic 1,2ꢀdiamine 9.
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2,5ꢀDimethylpyrazolo[1,5ꢀa]pyrimidineꢀ6,7ꢀdiamine 9a. Following the general procedure,
the reaction of (E)ꢀ2,5ꢀdimethylꢀ6ꢀ(phenyldiazenyl)pyrazolo[1,5ꢀa]pyrimidinꢀ7ꢀamine (6a,
700 mg, 2.6 mmol) and 10% Pd/C (35 mg) in 10.0 mL of EtOH at 60 °C for 24 h,
compound 9a was obtained as a white solid (419 mg, 90 %) after silica gel purification
(CH2Cl2/MeOH = 20:1). M.p. 165–166 °C (amorphous). 1H NMR (400 MHz, CDCl3):
2.44 (br s, 2H), 2.45 (s, 3H), 2.50 (s, 3H), 5.80 (br s, 2H), 6.13 (s, 1H) ppm. 13C{1H} NMR
δ =
(100 MHz, CDCl3):
δ
= 14.5 (CH3), 21.5 (CH3), 93.3 (CH), 105.7 (C), 142.6 (C), 147.1 (C),
+
154.0 (C), 154.2 (C) ppm. HRMS (ESI+): calcd. for C8H12N5 178.1093 [M + H]+; found
178.1087.
2ꢀ(tertꢀButyl)ꢀ5ꢀmethylpyrazolo[1,5ꢀa]pyrimidineꢀ6,7ꢀdiamine 9b. Following the general
procedure, the reaction of (E)ꢀ2ꢀ(tertꢀbutyl)ꢀ5ꢀmethylꢀ6ꢀ(phenyldiazenyl)pyrazolo[1,5ꢀ
a]pyrimidinꢀ7ꢀamine (6b, 620 mg, 2.0 mmol) and 10% Pd/C (31 mg) in 10.0 mL of EtOH
at 60 °C for 24 h, compound 9b was obtained as a white solid (405 mg, 92 %) after silica
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gel purification (CH2Cl2/MeOH = 20:1). M.p. 215–217 °C (amorphous). H NMR (400
MHz, CDCl3):
δ
= 1.37 (s, 9H), 2.48 (s, 3H), 3.03 (br s, 2H), 6.00 (br s, 2H), 6.17 (s, 1H)
= 21.1 (CH3), 30.4 (CH3), 32.8 (C), 89.7 (CH),
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ppm. C{1H} NMR (100 MHz, CDCl3):
δ
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