Regioselective and guided C-H activation of 4-nitropyrazoles

Article abstract of DOI:10.1021/jo4025418

A divergent and regioselective approach to 5-aryl-4-nitro-1H-pyrazoles was developed by guided transition-metal-catalyzed arylation of 4-nitro-1H- pyrazoles. This method provides a convenient tool for the functionalization of the pharmacologically relevan

Full text of DOI:10.1021/jo4025418

Article
pubs.acs.org/joc
Regioselective and Guided C−H Activation of 4‑Nitropyrazoles
Viktor O. Iaroshenko,*,†,‡,§ Ashot Gevorgyan,† Olena Davydova,† Alexander Villinger,†
and Peter Langer*,†,⊥
†Institut fur Chemie, Universitat Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Germany
̈
̈
‡National Taras Shevchenko University, 62 Volodymyrska st., Kyiv-33 01033, Ukraine
§Department of Chemistry (MC 111), University Illinois at Chicago, 845 West Taylor Street, RM 4500, Chicago, Illinois 60607,
United States
⊥Leibniz-Institut fur Katalyse e.V. an der Universitat Rostock, Albert-Einstein-Str. 29a, 18059 Rostock, Germany
̈
̈
S
* Supporting Information
ABSTRACT: A divergent and regioselective approach to 5-
aryl-4-nitro-1H-pyrazoles was developed by guided transition-
metal-catalyzed arylation of 4-nitro-1H-pyrazoles. This method
provides a convenient tool for the functionalization of the
pharmacologically relevant pyrazole scaffold. The scope and
limitations of the methodology were studied.
Scheme 1. C−H Activation Reactions of Nitro-Substituted
INTRODUCTION
■
a
Arenes and Hetarenes
The C−H bond is the most widespread structural fragment in
organic chemistry, and its functionalization has been the subject
of intensive studies.1,2 In recent years, transition-metal-
catalyzed C−H activation reactions emerged as one of the
most important methodologies in modern organic chemistry.
The regioselectivity of C−H activation reactions of more
complex functionalized substrates containing two or more
reactive C−H bonds is an important topic of current
research.1−4 The regioselectivity of such reactions is controlled
by the presence of functional groups in the substrate. This
includes directing substituents (e.g., carbonyl, cyano),4 halogen
substituents (mostly fluorine or chlorine),4,5 and ring
heteroatoms (namely, sulfur, nitrogen, and oxygen). The use
of the nitro group as a regiodirecting substituent in C−H
activations has only scarcely been reported to date (Scheme
1).6 Examples include the Pd-catalyzed ortho-arylation of
nitrobenzene derivatives.6a In a second study, the C−H
activation of positions 4 and 5 of 3-nitropyridine was
reported.6b Surprisingly, the electron-poor position 2 remained
unattacked. The result was explained by the assumption that
the nitrogen lone pair of the pyridine moiety plays a prominent
role in shielding the initial attack of the Pd species to position 2.
In the course of our interest in nitrogen heterocycles,7 we
herein report what are, to the best of our knowledge, the first
C−H activation reactions of nitro-substituted pyrazoles.8 These
reactions allow for a convenient synthesis of arylated pyrazoles
which are not readily available by other methods.
a
A: ref 6a. B: ref 6b. C: present study.
The alkylation of commercially available 4-nitro-1H-pyrazole
(1) in DMF in the presence of K2CO3 afforded products 3a−d
in good to excellent yields. The cyclization of commercially
available methyl and aryl hydrazine with nitro-malonaldehyde 2
gave products 3e,f (Scheme 2).
With the desired starting materials 3a−f in hand, we started
to study the direct arylation by C−H activation. Hocek et al.9
and we10a reported the use of a Pd/Cu catalytic system for C−
H activation reactions of purine derivatives. At the same time,
we also demonstrated that related C−H activations can be
conducted by use of Ni catalysts.10b Therefore, we decided to
RESULTS AND DISCUSSION
Our starting point was the synthesis of 4-nitro-1H-pyrazoles
3a−f using two synthetic strategies, as depicted in Scheme 2.
■
Received: December 18, 2013
Published: March 6, 2014
© 2014 American Chemical Society
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a
a
Scheme 2. Synthesis of Nitropyrazoles 3a−f
Scheme 3. Synthesis of Products 4−7
a
Coditions: (i) ArBr (4 equiv), PdCl2(PPh3)2 (5 mol %), CuI (1.2
equiv), PivOH (0.3 equiv), K2CO3 (1.3 equiv), DMF, under Ar, 120
°C, 6−16 h; (ii) ArBr (4 equiv), NiCl2(PPh3)2 (5 mol %), CuI (1.2
equiv), PivOH (0.3 equiv), K2CO3 (1.3 equiv), DMF, under Ar, 120
°C, 16 h; (iii) ArBr (4 equiv), PdCl2(PPh3)2 (5 mol %), CuI (4 equiv),
PivOH (0.3 equiv), K2CO3 (1.3 equiv), DMF, under Ar, 120 °C, 16 h;
(iv) one-pot, ArBr (6 equiv), PdCl2(PPh3)2 (5 mol %), CuI (6 equiv),
PivOH (0.3 equiv), K2CO3 (1.3 equiv), DMF, under Ar, 120 °C, 16 h.
a
Conditions: (i) DMF, R-Br (1.3 equiv), dry K2CO3 (2.3 equiv), 90
°C, 8 h; (ii) DMF, TMSCl, 2 (1.5 equiv), 120 °C, 6 h.
use both catalytic systems to compare their efficiency. In
addition, a number of other transition metal catalysts,1,4 such as
Pt, Rh, Ru, Ir, and Fe as well as Cu and Co, were studied.
As a model reaction for the optimization of the conditions,
we studied the reaction of pyrazole 3e with tolylbromide. First,
the conditions of the Pd/Cu system were optimized (Table 1,
entries 1−6). The best yields of product 4d (up to 83% yield)
were obtained (Scheme 3) when an excess of the aryl halide (4
equiv) was employed using PdCl2(PPh3)2 (5 mol %) as the
catalyst in the presence of CuI (1.2 equiv). The reaction was
carried out in the presence of PivOH (0.3 equiv) and K2CO3
(1.3 equiv) in DMF (120 °C, 16 h) (Table 1, entry 5). It
should be mentioned that in the absence of CuI we got an
unusual product, namely, corresponding structure 4′,11 as a
result of the sequential arylation at position 5 of the pyrazole
ring and subsequent cleavage of the N−N bond (see structure
4′ in Supporting Information).11 In the same time, the
formation of compound 4″11 as a result of directing action of
the pyrazole moiety was never observed. The conditions for the
Ni/Cu system were optimized, as well (Table 1, entries 9−12).
The best conditions, using NiCl2(PPh3)2 (5 mol %) as the
catalyst under otherwise identical conditions, allowed for the
synthesis of 4d in 45% yield (Table 1, entry 12). To our
astonishment, the Ni catalysts proved to be inefficient in the
absence of CuI and, in general, were less active than the Pd/Cu
system (entries 3 and 5). These results are different from our
earlier studies on 1-deazapurine systems.10b
Table 1. Optimization of the Synthesis of 4d
With the optimal reaction conditions in hand, we next
studied the scope and limitations of our methodology. The
reaction of pyrazoles 3a−f with various aryl halides afforded
products 4a−n and 5a−h in excellent yields (Scheme 4). In
general, aryl bromides gave very good yields, while the
corresponding aryl chlorides proved to be unreactive. In the
case of aryl iodides, we observed extensive formation of biaryls
which could only be suppressed by use of a high excess of the
aryl iodide; 4 equiv was enough to increase the overall yields. It
is important to note that the syntheses could be performed on
gram scale. For instance, compound 4h was prepared in 10 g
amount in 78% yield.
Next, we studied the possibility of introducing aryl groups at
position 3. Unfortunately, all of these attempts proved to be
unsuccessful (formation of complex mixtures). Besides Ni and
Pd, we have tested other additives or catalysts, including salts of
Ag, Fe, Ru, Rh, Ir, Co, and Pt. We also tried to change the
regioselectivity by variation of the ligands. Trials included S-
Phos, X-Phos, PCy3, P(tBu)3, (2-biphenyl)di-1-adamantyl-
phosphine, rac-2-(di-tert-butylphosphino)-1,1′-binaphthyl,
(C6H5O)3P, tris(diethylamino)phosphine, (C6F5)3P,
(C6F5)2PhP; bidantate, 1,2-bis(diphenylphosphino)benzene,
1,2-bis(dicyclohexylphosphino)ethane, dppm, dppe, dppp,
dppf, BINAP, DIOP, rac-Synphos, (oxidi-2,1-phenylene)-bis-
(diphenylphosphine), and XantPhos. Unfortunately, the experi-
ments did not meet success. Finally, we have found that
reaction of 3a and 3d with 1-bromo-3-nitrobenzene, in the
presence of 6.0 (instead of 1.2) equiv of CuI, allowed for the
synthesis of 3,5-diaryl-4-nitropyrazoles 7a,b (Schemes 3 and 5).
a
b
Yields of isolated products. 1,2-Bis(diphenylphosphino)ethane
c
nickel(II) chloride. 1,3-Bis(dipenylphosphino)propane nickel(II)
chloride.
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that the free electron pair of the imine nitrogen of pyrazole
shields position 3 (structure A in Scheme 6). Thus,
intermediate B should be more favorable. Addition of a
transition metal (TM) enables the formation of a TM complex
with the nitrogen atom of the pyrazole ring despite the
shielding effect of the lone pair. In addition, the acidity of the
neighboring proton is increased. The ligands as well as the nitro
group might bridge the Pd complex and direct the subsequent
attack of this species. Thus, we consider species B, C, D, and E
to be plausible intermediates of this reaction. For instance, it is
known that the copper-mediated C−H activation of 1,3-
diazoles4,13 and azines4,14 proceeds selectively at the α-position
with regard to the pyridine-like nitrogen atom. In contrast,
under copper-free conditions, the reaction takes place at the β-
position, which was explained by the fact that reaction of the
corresponding diazoles proceeds via formation of a cuprate
(intermediate E). This aspect was very well elucidated in a
number of recent studies.3b,13,14 Due to the strong electron-
withdrawing effect of the nitro group and its good coordinative
nature, the cupration, which follows usually after formation of
the Pd species, is directed to position 3 when an excess of
copper was used.
Scheme 4. Structures and Isolated Yields of 5-Aryl-4-
nitropyrazoles 4 and 5
a
Being motivated by recent works of Baran et al.1c,15 on innate
and guided C−H activation, we decided to turn our attention
toward the innate protocol developed by this group for a
number of heterocycles on the basis of Minisci16 and borono-
Minisci15d reactions, using aromatic carboxylic acids and
boronic acids, respectively. However, all attempts to develop
innate C−H activation reactions of substrates 3 and 4 failed
(formation of inseparable mixtures).
The reduction of the nitro group of products 6, carried out
under standard conditions (Pd/C as the catalyst, normal
pressure of hydrogen), gave rise to the formation of amines
8a,b in good yields (Schemes 7 and 8). When the reduction
was performed in the presence of formaline, the N,N-
dimethylamines 10a−c were obtained.
The reaction of pyrazoles 3 with 2-bromobenzaldehydes
afforded products 6a−e (Scheme 9). The hydrogenation of
6a−e afforded pyrazoloisoquinolines 9a−e by reduction of the
nitro to an amino group and subsequent cyclization. The
synthesis of analogues of 6a−e, containing an ethoxycarbonyl,
acyl, or aroyl group, proved to be unsuccessful. Products 9a−e
show a strong fluorescence (see Supporting Information,
pictures 1−3).
a
Products were prepared using the Pd/Cu system; yields in
parentheses refer to employment of the Ni/Cu system.
The reaction of 4i,l,n with aryl bromides in the presence of 4.0
equiv of CuI gave rise to products 7a−d (sequential synthesis).
Although the mechanism of the reactions was not studied, we
assume that they proceed by carboxylate-assisted catalyzed C−
H bond activation12 since the addition of the carboxylic acid,
namely, pivalic acid, was crucial for the success of the reaction.
The regioselectivity might be explained, following the
explanations provided by other authors,6b by the assumption
The structure of the synthesized pyrazoles and derivatives
was mainly established by 1D NMR method. The structures of
compounds 4h, 5f, 7c, 9c 10a, and 4′ were independently
confirmed by X-ray single-crystal analyses (Figures 1−5 in
Supporting Information).17
Scheme 5. Structures and Yields of 3,5-Diaryl-4-
nitropyrazoles 7a−d
In conclusion, we have studied in detail the transition-metal-
catalyzed arylation of 4-nitropyrazoles by two different d-
metals, namely, Pd and Ni, using CuI as additive. The use of Pd
proved to give better yields than Ni. The reactions proceeded
with exclusive C-5 regioselectivity. A mechanistic explanation of
this result was proposed. Furthermore, we succeeded to activate
the C−H bond at carbon C-3 after arylation of C-5. Our
methodology was successfully employed also for the synthesis
of pyrazoloisoquinolines. The developed method shows a
number of advantages, including high experimental simplicity,
catalyst efficiency, functional group compatibility, and low cost
of the catalytic system.
a
b
Yields refer to one-pot reactions. Yields (in parentheses) refer to
consecutive reactions.
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Scheme 6. Proposed Mechanistic Explanation of the Regioselectivity
a
equiv), (CH3)3CCO2H (0.3 equiv), and PdCl2(PPh3)2 (0.05 equiv)
successively were weighed to air and placed in a Schlenk flask,
equipped with a magnetic stir bar, which then was capped with a
rubber septum. The reaction vessel was evacuated and backfilled with
argon (three times). The DMF (8 mL for 0.3 g of 4-nitropyrazole) and
aryl bromide (4 equiv) were added via a syringe, and the reaction was
heated to 120 °C for 6−16 h. Upon completion, the reaction was
cooled to room temperature and concentrated under vacuum. The
residue was purified by column chromatography typically using
heptane/ethyl acetate mixtures to provide the desired arylated
product. Compound 4′ was synthesized following same procedure
but without CuI.
General Procedure for One-Pot Double C−H Arylation of 4-
Nitropyrazoles. Synthesis of Compounds 7a,b: Corresponding 4-
nitropyrazole (1 equiv), CuI (6 equiv), K2CO3 (1.3 equiv),
(CH3)3CCO2H (0.3 equiv), and PdCl2(PPh3)2 (0.05 equiv)
successively were weighed to air and placed in a Schlenk flask,
equipped with a magnetic stir bar, which then was capped with a
rubber septum. The reaction vessel was evacuated and backfilled with
argon (three times). The DMF (8 mL for 0.3 g of 4-nitropyrazole) and
aryl bromide (6 equiv) were added via a syringe, and the reaction was
heated to 120 °C for 6−16 h. Upon completion, the reaction was
cooled to room temperature and concentrated under vacuum. The
residue was purified by column chromatography typically using
heptane/ethyl acetate mixtures to provide the desired arylated
product.
General Procedure for C−H Arylation of the Third Position
of 4-Nitropyrazoles. Synthesis of Compounds 7a−d: Corre-
sponding 4-nitro-5-arylpyrazole (1 equiv), CuI (4 equiv), K2CO3 (1.3
equiv), (CH3)3CCO2H (0.3 equiv), and PdCl2(PPh3)2 (0.05 equiv)
successively were weighed to air and placed in a Schlenk flask,
equipped with a magnetic stir bar, which then was capped with a
rubber septum. The reaction vessel was evacuated and backfilled with
argon (three times). The DMF (8 mL for 0.3 g of 4-nitropyrazole) and
aryl bromide (4 equiv) were added via a syringe, and the reaction was
heated to 120 °C for 16 h. Upon completion, the reaction was cooled
to room temperature and concentrated under vacuum. The residue
was purified by column chromatography typically using heptane/ethyl
acetate mixtures to provide the desired arylated product.
General Procedure for Reduction of 4-Nitropyrazoles.
Synthesis of Compounds 8a,b and 9a−e: To a Schlenk flask
equipped with a magnetic stir bar and filled with corresponding 4-
nitro-5-arylpyrazole (1 equiv) was added 10% Pd/C (0.1 equiv). The
flask was fitted with a rubber septum and then held under vacuum for
3 min, after that, it was filled with MeOH (25 mL for 0.3 g of 4-
nitropyrazole) and hydrogen. Holding under vacuum was repeated
one more time, and after sequential filling with hydrogen, the reaction
mixture was stirred for 5 h under H2 atmosphere. After the reaction
was stopped, the mixture was filtered through a Celite pad, and the
filtrate was evaporated to dryness or (if necessary) was purified by
Scheme 7. Synthesis of Pyrazoles 8 and 10
a
Conditions: (i) MeOH, H2, 10% Pd/C, 20 °C, 5 h; (ii) MeOH, H2,
Pd/C (10 mol %), CH2O in H2O (37%, 6 equiv), 20 °C, 5 h.
EXPERIMENTAL SECTION
■
The dry solvents were purchased. Other solvents were purified by
distillation. All reactions were carried out under an inert atmosphere.
For H and 13C NMR spectra, the deuterated solvents indicated were
1
used. Mass spectrometric data (MS) were obtained by electron
ionization (EI, 70 eV), chemical ionization (CI, isobutane), or
electrospray ionization (ESI, mass analyzer type was ESI-TOF/MS).
For preparative scale chromatography, silica gel 60 (0.063−0.200 mm,
70−230 mesh) was used. The solvents for column chromatography
were distilled before use. Conformation of structure of all compounds
and assignments was performed using 2D NMR methods such as
COSY, HMBC, HSQC, and NOESY.
General Procedure for the Synthesis of 4-Nitropyrazoles by
Alkylation. Synthesis of Compounds 3a−d: Corresponding 4-
nitro-1H-pyrazole (1 equiv) and K2CO3 (2.3 equiv) successively were
weighed to air and placed in a Schlenk flask, equipped with a magnetic
stir bar, which then was capped with a rubber septum. The reaction
vessel was evacuated and backfilled with argon. The DMF (8 mL for 1
g of 4-nitro-1H-pyrazole) and corresponding alkyl bromide (1.3 equiv)
were added via a syringe, and the reaction was heated to 90 °C for 8 h.
Upon completion, the reaction was cooled to room temperature and
concentrated under vacuum. The crude mass was washed with water,
which was extracted with chloroform afterward. Finally, the organic
phase was dried (Na2SO4), filtered, and evaporated to dryness, or (if
necessary) the residue was purified by column chromatography
typically using heptane/ethyl acetate mixtures to provide the desired
alkylated product.
General Procedure for the Synthesis of 4-Nitropyrazoles by
Cyclization. Synthesis of Compounds 3e−f: Corresponding
hydrazine (1 equiv) and nitromalonaldehyde (1.5 equiv) were placed
in a pressure tube under the flow of dry argon and dissolved in dry
DMF (10 mL for 1 g of hydrazine) containing TMSCl (4 mL for 1 g
of hydrazine). The mixture was heated at 120 °C for 6 h. Then the
solution was evaporated under reduced pressure. The residue was
purified by column chromatography typically using heptane/ethyl
acetate mixtures to provide the desired 4-nitropyrazole.
General Procedure for Direct C−H Arylation of 4-Nitro-
pyrazoles. Synthesis of Compounds 4a−n, 4′, 5a−h, and 6a−e:
Corresponding 4-nitropyrazole (1 equiv), CuI (1.2 equiv), K2CO3 (1.3
Scheme 8. Structures and Yields of Pyrazoles 8a,b and 10a−c
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a
Scheme 9. Structures and Yields of Pyrazoles 6a−e and 9a−e
a
Conditions: (i) MeOH, H2, 10% Pd/C, 20 °C, 5 h.
column chromatography typically using heptane/ethyl acetate
mixtures to provide the desired product.
(s, 1H, pyrazole), 9.56 (s, 1H, pyrazole); 13C NMR (62.9 MHz,
DMSO-d6) δ = 20.5 (Me), 119.3, 127.7, 130.0 (CH), 136.1 (C), 136.7
(CH), 137.9 (C).
General Procedure for Reduction of 4-Nitropyrazoles with
Formaldehyde. Synthesis of Compounds 10a−c: To a Schlenk
flask equipped with a magnetic stir bar and filled with corresponding 4-
nitro-5-arylpyrazole (1 equiv) was added 10% Pd/C (0.1 equiv). The
flask was fitted with a rubber septum and then held under vacuum for
3 min, after that, it was filled with MeOH (25 mL for 0.3 g of 4-
nitropyrazole), formaldehyde solution (6 equiv, 37 wt % in H2O,
contains 10−15% methanol as stabilizer), and hydrogen. Holding
under vacuum was repeated one more time, and after sequential filling
with hydrogen, the reaction mixture was stirred for 4−6 h under H2
atmosphere. After the reaction was stopped, the mixture was filtered
through Celite pad and filtrate was evaporated to dryness or (if
necessary) was purified by column chromatography typically using
heptane/ethyl acetate mixtures to provide the desired product.
4-Nitro-1-phenethyl-1H-pyrazole (3a): White solid (0.193 g, 89%),
mp 130−130 °C; 1H NMR (250 MHz, DMSO-d6) δ = 3.14 (d, 2H, 3J
1-Methyl-4-nitro-1H-pyrazole (3f): Yellow solid (0.102 g, 81%),
mp 96−97 °C; 1H NMR (250 MHz, DMSO-d6) δ = 3.91 (s, 3H, Me),
8.22 (s, 1H, pyrazole), 8.83 (s, 1H, pyrazole); 13C NMR (62.9 MHz,
DMSO-d6) δ = 39.6 (Me), 130.9 (CH), 134.8 (C), 135.4 (CH).
5-(3-(Trifluoromethyl)phenyl)-4-nitro-1-p-tolyl-1H-pyrazole (4a):
Brown oil (0.256 g, 74%Pd, 0.156g, 45%Ni); 1H NMR (300 MHz,
CDCl3) δ = 2.32 (s, 3H, Me), 7.04 (d, 2H, 3J = 8.5 Hz, CHAr), 7.12 (d,
2H, 3J = 8.5 Hz, CHAr), 7.49−7.56 (m, 3H, CHAr), 7.66−7.70 (m, 1H,
CHAr), 8.38 (s, 1H, pyrazole); 19F NMR (282 MHz, CDCl3) δ =
−62.9; 13C NMR (75.5 MHz, CDCl3) δ = 21 (Me), 123.4 (q, 1J = 262
Hz, CF3), 126.7 (q, 3J = 4 Hz, CHCCF3), 127.5 (q, 3J = 4 Hz,
2
CHCCF3), 129.0, 129.8, 130.0, 130.9 (CH), 131.0 (q, J = 33 Hz,
CCF3), 133.8 (CH), 134.0, 135.5 (C), 137.3 (CH), 139.1, 139.5 (C);
MS (GC, 70 eV) m/z (%) = 347 (M+, 100), 300(16), 346(14), 262
(11), 91 (25), 65 (14); HRMS (EI) calcd for C17H12N3O2F3 (M+)
347.08761, found 347.08784; IR (ATR, cm−1) ν = 3043 (w), 1556
(w), 1505 (s), 1391 (s), 1311(s), 1266 (m), 1124 (s), 1073 (s), 1024
(m), 904 (m), 868 (w), 830 (s), 699 (s), 646 (m), 529 (m).
5-(4-Methoxyphenyl)-4-nitro-1-p-tolyl-1H-pyrazole (4b): Brown
oil (0.188 g, 61%Pd, 0.123g, 40%Ni); 1H NMR (300 MHz, CDCl3) δ =
2.32 (s, 3H, Me), 3.81 (s, 3H, OMe), 6.86−6.89 (m, 2H, CHAr),
7.05−7.12 (m, 4H, CHAr), 7.20−7.23 (m, 2H, CHAr), 8.35 (s, 1H,
pyrazole); 13C NMR (62.9 MHz, CDCl3) δ = 21.1 (Me), 55.3 (OMe),
114 (CH), 118.3 (C), 125.1, 129.9, 131.9 (CH), 133.2, 136.2 (C),
137.4 (CH), 138.8, 140.8, 160.8 (C); MS (GC, 70 eV) m/z (%) = 309
(M+, 100), 224 (11), 91 (21), 65 (14); HRMS (ESI) calcd for
C17H16N3O3 (M + H) 310.11862, found 310.11868; IR (ATR, cm−1)
ν = 3021 (w), 1611 (m), 1558 (w), 1506 (s), 1455 (m), 1392 (s),
1324 (s), 1291 (m), 1250 (m), 1176 (s), 1113 (w), 1026 (m), 1014
(m), 954 (m), 862 (w), 842 (s), 821 (s), 762 (s), 713 (w), 615 (m),
595 (m).
3
= 7.2 Hz, CH2), 4.43 (d, 2H, J = 7.0 Hz, CH2), 7.14−7.31 (m, 5H,
CHAr), 8.25 (s, 1H, pyrazole), 8.75 (s, 1H, pyrazole); 13C NMR (62.9
MHz, DMSO-d6) δ = 35.1, 53.4 (CH2), 126.6, 128.4, 128.6, 130.4
(CH), 134.6 (C), 135.5 (CH), 137.5 (C).
4-Nitro-1-(2-phenoxyethyl)-1H-pyrazole (3b): White solid (0.216
1
g, 93%), mp 127−128 °C; H NMR (250 MHz, DMSO-d6) δ = 4.15
(d, 2H, 3J = 5.3 Hz, CH2), 4.34 (d, 2H, 3J = 5.3 Hz, CH2), 6.64−6.71
(m, 3H, CHAr), 6.98−7.05 (m, 2H, CHAr), 8.03 (s, 1H, pyrazole), 8.71
(s, 1H, pyrazole); 13C NMR (62.9 MHz, DMSO-d6) δ = 52.0, 65.4
(CH2), 114.5, 121.0, 131.0 (CH), 134.9 (C), 135.7 (CH), 157.8 (C).
1-Butyl-4-nitro-1H-pyrazole (3c): Brown solid (0.142 g, 84%), mp
1
3
92−93 °C; H NMR (250 MHz, DMSO-d6) δ = 0.88 (t, 3H, J = 7.4
Hz, CH2CH2CH2CH3), 1.18−1.27 (m, 2H, CH2CH2CH2CH3), 1.72−
1.84 (m, 2H, CH2CH2CH2CH3), 4.17 (t, 2H, 3J = 7.2 Hz,
CH2CH2CH2CH3), 8.24 (s, 1H, pyrazole), 8.90 (s, 1H, pyrazole);
13C NMR (62.9 MHz, DMSO-d6) δ = 13.2 (Me), 18.9, 31.1, 52.0
(CH2), 130.3(CH), 134.7 (C), 135.4 (CH).
4-(4-Nitro-1-p-tolyl-1H-pyrazol-5-yl)benzonitrile (4c): Brown oil
1
1-(4-Methylbenzyl)-4-nitro-1H-pyrazole (3d): White solid (0.180
(0.258 g, 85%Pd, 0.152g, 50%Ni); H NMR (300 MHz, CDCl3) δ =
1
g, 87%), mp 112−113 °C; H NMR (250 MHz, DMSO-d6) δ = 2.27
2.33 (s, 3H, Me), 7.01 (d, 2H, 3J = 8.3 Hz, CHAr), 7.12 (d, 2H, 3J = 8.3
Hz, CHAr), 7.42 (d, 2H, 3J = 8.6 Hz, CHAr), 7.64 (d, 2H, 3J = 8.6 Hz,
CHAr), 8.35 (s, 1H, pyrazole); 13C NMR (62.9 MHz, CDCl3) δ = 21
(Me), 113.8, 117.8 (C), 125.1, 127.8, 129.9, 131.2, 132.0, 132.8 (CH),
134.0, 135.3 (C), 137.3 (CH), 138.6, 139.6, 143.4 (C); MS (GC, 70
eV) m/z (%) = 304 (M+, 100), 303(13), 257 (16), 219 (10) 91 (35),
65 (20); HRMS (ESI) calcd for C17H13N4O2 (M + H) 305.1033,
found 305.10312; IR (ATR, cm−1) ν = 3042 (w), 1557 (w), 1508 (s),
(s, 3H, Me), 5.34 (s, 2H, CH2), 7.14−7.25 (m, 4H, CHAr), 8.25 (s,
1H, pyrazole), 9.00 (s, 1H, pyrazole); 13C NMR (62.9 MHz, DMSO-
d6) δ = 20.6 (Me), 55.6 (CH2), 128.0, 129.2, 130.3 (CH), 132.2,
132.7, 135.0 (C), 135.8, 137.5 (CH).
4-Nitro-1-p-tolyl-1H-pyrazole (3e): Brown solid (0.176 g, 87%),
mp 98−99 °C; 1H NMR (250 MHz, DMSO-d6) δ = 2.35 (s, 3H, Me),
7.34 (d, 2H, 3J = 8.4 Hz, CHAr), 7.81 (d, 2H, 3J = 8.4 Hz, CHAr), 8.50
2910
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Article
1455 (m), 1390 (s), 1322 (s), 1200 (w), 1179 (w), 1112 (w) 1007
(w), 955 (m), 909 (m), 820 (s), 728 (s), 649 (m), 630 (w), 595 (m),
552 (s).
128.2 (C), 130.2 (CH), 132.4 (C), 135.9, 136.7 (CH), 138.8, 147.8,
162.3 (C); MS (GC, 70 eV) m/z (%) = 248 (M+, 100), 163 (26), 117
(52); HRMS (EI) calcd for C10H8N4O4 (M+) 248.05401, found
248.05381; IR (ATR, cm−1) ν = 3068 (w), 1673 (w), 1526 (m), 1505
(m), 1472 (m), 1388 (m), 1349 (s), 1322 (m), 1239 (m) 1172 (w),
1087 (m), 979 (w), 919 (w), 826 (m), 758 (m), 726 (m), 694 (m),
675 (m), 640 (m), 592 (w).
4-Nitro-1,5-di-p-tolyl-1H-pyrazole (4d): Brown oil (0.246 g, 83%Pd,
1
0.131g, 45%Ni); H NMR (300 MHz, CDCl3) δ = 2.33 (s, 3H, Me),
2.37 (s, 3H, Me), 7.09 (m, 4H, CHAr), 7.17 (s, 4H, CHAr), 8.36 (s, 1H,
pyrazole); 13C NMR (62.9 MHz, CDCl3) δ = 21.1, 21.5 (Me), 123.4
(C), 125.1, 128.5, 129.2, 130.2, 130.4 (CH), 133.7, 136.2 (C), 137.4
(CH), 138.8, 140.3, 141.0 (C); MS (GC, 70 eV) m/z (%) = 293 (M+,
100), 249 (11), 246 (15), 209(13), 208 (21), 91 (39), 89 (11), 65
(28); HRMS (ESI) calcd for C17H16N3O2 (M + H) 294.1237, found
294.12351; IR (ATR, cm−1) ν = 3041 (w), 1557 (w), 1505 (s), 1388
(s), 1321 (s), 1178 (w), 1112 (w), 1020 (w), 945 (w), 875 (w) 827
(s), 763 (s), 698 (m), 629 (w), 592 (m).
5-(3-Methoxyphenyl)-1-methyl-4-nitro-1H-pyrazole (4j): Yellow
1
oil (0.193 g, 83%Pd); H NMR (250 MHz, CDCl3) δ = 3.73 (s, 3H,
NMe), 3.84 (s, 3H, OMe), 6.89−6.95 (m, 2H, CHAr), 7.05−7.09 (m,
1H, CHAr), 7.44 (t, 1H, 3J = 7.5 Hz, CHAr), 8.17 (s, 1H, pyrazole); 13
C
NMR (62.9 MHz, CDCl3) δ = 38.0 (NMe), 55.4 (OMe), 115.3, 115.9,
121.7 (CH), 127.7 (C), 130.0, 136.3 (CH), 141.3, 159.7 (C); MS
(GC, 70 eV) m/z (%) = 233 (M+, 100), 148 (30), 133 (30), 115 (30),
95 (76); HRMS (EI) calcd for C11H11N3O3 (M+) 233.07949, found
233.07921; IR (ATR, cm−1) ν = 2923 (w), 1582 (w), 1555 (w), 1499
(m), 1465 (m), 1390 (m), 1348 (m), 1323 (s), 1285 (m), 1257 (m),
1208 (m), 1168 (m), 1044 (m), 1021 (m), 975 (w), 824 (s), 786 (m),
761 (m), 737 (m), 691 (m), 640 (w).
4-Nitro-5-phenyl-1-p-tolyl-1H-pyrazole (4e): Brown oil (0.206 g,
74%Pd, 0.106g, 38%Ni); 1H NMR (300 MHz, CDCl3) δ = 2.32 (s, 3H,
Me), 7.04−7.11 (m, 4H, CHAr), 7.27−7.31 (m, 2H, CHAr), 7.34−7.43
(m, 3H, CHAr), 8.37 (s, 1H, pyrazole); 13C NMR (62.9 MHz, CDCl3)
δ = 21.1 (Me), 125.1 (CH), 126.6 (C), 128.5, 129.6, 130.0, 130.4
(CH), 136.1 (C), 137.4 (CH), 138.9, 140.8 (C); MS (GC, 70 eV) m/z
(%) = 279 (M+, 100), 279 (100), 235 (11), 232 (16), 194 (14), 91
(34), 89 (11), 65 (23); HRMS (ESI) calcd for C16H14N3O2 (M + H)
280.10805, found 280.10789; IR (ATR, cm−1) ν = 3056 (w), 1606
(w), 1556 (w), 1504 (s), 1446 (m), 1386 (s), 1322 (s), 1184 (m),
1116 (w), 1069 (w), 1034 (w), 1007 (w), 949 (m), 915 (m), 861 (m)
821 (s), 754 (s), 709 (m), 690 (s), 646 (m), 594 (m), 528 (s).
5-(2-Fluorophenyl)-4-nitro-1-p-tolyl-1H-pyrazole (4f): Brown oil
(0.130 g, 44%Pd, 0.056g, 19%Ni); 1H NMR (300 MHz, DMSO-d6) δ =
2.29 (s, 3H, Me), 7.16−7.22 (m, 4H, CHAr), 7.23−7.35 (m, 2H,
CHAr), 7.46−7.59 (m, 2H, CHAr), 8.69 (s, 1H, pyrazole); 19F NMR
(282 MHz, DMSO-d6) δ = −112.7 (CF); 13C NMR (75.5 MHz,
DMSO-d6) δ = 20.5 (Me), 114.6 (d, J = 14 Hz, C), 115.7 (d, J = 24
Hz, CH), 124.6 (d, J = 3 Hz, CH), 125.0, 129.6, 132.2 (CH), 133.0 (d,
J = 8 Hz, CH), 134.7 (d, J = 79 Hz, CF), 135.5 (C), 137.2 (CH),
139.1, 157.6, 160.9 (C); MS (GC, 70 eV) m/z (%) = 297 (M+, 100),
132 (17), 91 (66), 65 (44); HRMS (ESI) calcd for C16H12N3O2F (M
+ H) 298.09863, found 298.09895; IR (ATR, cm−1) ν = 2923 (w),
1711 (w), 1623 (w), 1559 (w), 1507 (s), 1460 (m), 1392 (s), 1324
(s), 1265 (w), 1224 (m), 1178 (w), 1109 (w), 1035 (w), 957 (w), 866
(w), 815 (s), 757 (s), 710 (w), 646 (w), 595 (w), 550 (w).
5-(3-(Trifluoromethyl)phenyl)-4-nitro-1-phenethyl-1H-pyrazole
(4k): Yellow oil (0.281 g, 78%Pd); 1H NMR (250 MHz, DMSO-d6) δ =
3.04 (d, 2H, 3J = 6.3 Hz, CH2), 4.14 (d, 2H, 3J = 6.3 Hz, CH2), 6.81−
6.85 (m, 2H, CHAr), 7.17−7.22 (m, 3H, CHAr), 7.34−7.38 (m, 2H,
3
3
CHAr), 7.67 (t, 1H, J = 7.9 Hz, CHAr), 7.88 (d, 1H, J = 8.0 Hz,
CHAr), 8.52 (s, 1H, pyrazole); 19F NMR (282 MHz, DMSO-d6) δ =
−61.0 (CF3); 13C NMR (62.9 MHz, DMSO-d6) δ = 34.9, 51.3 (CH2),
1
3
123.7 (q, J = 272 Hz, CF3), 126.4 (q, J = 4 Hz, CH), 126.7 (CH),
3
2
126.8 (q, J = 4 Hz, CH), 127.3 (C), 128.5 (CH), 129.0 (q, J = 32
Hz, CCF3), 129.6 (CH), 132.5 (C), 133.8, 136.5 (CH), 137.4, 140.1
(C); MS (GC, 70 eV) m/z (%) = 361 (M+, 1), 104 (100), 91 (24);
HRMS (ESI) calcd for C18H15N3O2F3 (M + H) 362.11109, found
362.11081; IR (ATR, cm−1) ν = 1558 (w), 1506 (s), 1462 (m), 1399
(m), 1309 (s), 1245 (m), 1163 (s), 1123 (s), 1096 (m), 1074 (s),
1028 (m), 932 (w), 902 (m), 869 (m), 829 (s), 809 (m), 758 (s), 700
(s), 645 (w), 593 (m), 558 (m).
4-Nitro-5-(3-nitrophenyl)-1-phenethyl-1H-pyrazol (4l): Brown oil
1
(0.321 g, 95%Pd, 0.169g, 50%Ni); H NMR (300 MHz, DMSO) δ =
3
3.13 (t, 2H, J = 6.1 Hz, CH2), 4.16 (t, 2H, 3J = 6.1 Hz, CH2), 6.73−
6.78 (m, 2H, CHAr), 6.95−6.99 (m, 1H, CHAr), 7.15−7.28 (m, 3H,
3
4
CHAr), 7.51 (t, 1H, J = 8.0 Hz, CHAr), 7.62 (t, 1H, J = 1.4 Hz,
CHAr), 8.26−8.31 (m, 2H, CHAr, pyrazole); 13C NMR (75.5 MHz,
DMSO) δ = 35.9, 51.9 (CH2), 124.8, 127.4 (CH), 127.9 (C), 128.6,
128.9, 129.6, 135.5 (CH), 136.7 (C), 136.8 (CH), 139.6, 148.0 (C);
MS (GC, 70 eV) m/z (%) = 338 (M+, 1), 104 (100), 91(29); HRMS
(ESI) calcd for C17H14N4O4 (M + H) 339.109, found 339.109; IR
(ATR, cm−1) ν = 2923 (w), 1559 (w), 1525 (s), 1499 (s), 1455 (m),
1398 (s), 1346 (s), 1322 (s), 1254 (m), 1178 (m), 1098 (w), 1077
(w), 1030 (w), 978 (w), 904 (w), 871 (m), 825 (s), 736 (s), 697 (s),
647 (m), 560 (m).
5-(4-Methoxyphenyl)-1-methyl-4-nitro-1H-pyrazole (4g): Brown
1
solid (0.144 g, 62%Pd, 0.051g, 22%Ni), mp 67−68 °C; H NMR (300
MHz, DMSO-d6) δ = 3.70 (s, 3H, NMe), 3.85 (s, 3H, OMe), 7.09 (d,
3
2H, 3J = 8.6 Hz, CHAr), 7.50 (d, 2H, J = 8.6 Hz, CHAr), 8.35 (s, 1H,
pyrazole); 13C NMR (62.9 MHz, DMSO-d6) δ = 37.9 (NMe), 55.3
(OMe), 114.0 (CH), 118.1 (C), 131.6 (CH), 132.2 (C), 136.0 (CH),
141.1, 160.5 (C); MS (GC, 70 eV) m/z (%) = 233 (M+, 100), 148
(25), 133 (28), 101 (15); HRMS (ESI) calcd for C11H12N3O3 (M +
H) 234.08732, found 234.08738; IR (ATR, cm−1) ν = 2837 (w), 1609
(m), 1575 (w), 1505 (s), 1459 (m), 1440 (m), 1391 (s), 1321 (s),
1297 (m), 1259 (s), 1175 (s), 1111 (m), 1034 (m), 970 (m), 945 (w),
867 (m), 834 (s), 798 (m), 762 (s), 696 (w), 642 (m), 615 (m), 586
(s), 530 (m).
1-Butyl-4-nitro-5-p-tolyl-1H-pyrazole (4m): Yellow solid (0.215 g,
1
83%Pd), mp 163−164 °C; H NMR (300 MHz, DMSO-d6) δ = 0.73
(t, 3H, 3J = 7.7 Hz, CH2CH2CH2CH3), 1.05−1.17 (m, 2H,
CH2CH2CH2CH3), 1.59−1.68 (m, 2H, CH2CH2CH2CH3), 2.41 (s,
3H, Me), 3.93 (t, 3H, 3J = 6.7 Hz, CH2CH2CH2CH3), 7.35−7.42 (m,
4H, CHAr), 8.38 (s, 1H, pyrazole); 13C NMR (62.9 MHz, DMSO-d6)
δ = 13.2 (Me), 18.7 (CH2), 21.0 (Me), 30.9, 49.4 (CH2), 123.5 (C),
129.2, 129.6 (CH), 132.2 (C), 136.17 (CH), 139.8, 141.3 (C); MS
(GC, 70 eV) m/z (%) = 270 (M+, 17), 227 (100); HRMS (ESI) calcd
for C14H18N3O2 (M + H) 260.13935, found 260.13948; IR (ATR,
cm−1) ν = 3126 (w), 2953 (w), 2232 (m), 1555 (w), 1500 (s), 14960
(m), 1396 (s), 1320 (s), 1251 (m), 1195 (m), 1113 (w), 1027 (w),
983 (w), 880 (w), 846 (s), 763 (s), 685 (w), 595 (w), 569 (m), 548
(s).
1-(3-(1-Methyl-4-nitro-1H-pyrazol-5-yl)phenyl)ethanone (4h):
Brown solid (0.198 g, 78%Pd), mp 109−111 °C; 1H NMR (300
MHz, DMSO-d6) δ = 2.63 (s, 3H, C(O)Me), 3.71 (s, 3H, Me), 7.70−
7.75 (m, 1H, CHAr), 7.83−7.87 (m, 1H, CHAr), 8.12−8.17 (m, 2H,
CHAr), 8.41 (s, 1H, pyrazole); 13C NMR (62.9 MHz, DMSO-d6) δ =
26.8, 38.0 (Me), 127.1 (C), 129.1, 129.7, 129.8 (CH), 132.6 (C),
134.5, 136.0 (CH), 137.0, 140.3, 197.4 (C); MS (GC, 70 eV) m/z (%)
= 245 (M+, 37), 230 (100), 43 (42); HRMS (EI) calcd for
C12H11N3O3 (M+) 245.07949, found 245.07931; IR (ATR, cm−1) ν
= 3064 (w), 1678 (s), 1605 (m), 1552 (w), 1483 (s), 1423 (m), 1392
(s), 1220 (s), 1169 (m), 1037 (w), 962 (w), 944 (w), 860 (m), 828
(s), 802 (s), 761 (s), 693 (m), 588 (m).
1-Methyl-4-nitro-5-(3-nitrophenyl)-1H-pyrazole (4i): Brown solid
(0.235 g, 95%Pd), mp 126−128 °C; 1H NMR (300 MHz, DMSO-d6) δ
= 3.73 (s, 3H, Me), 7.85−7.95 (m, 1H, CHAr), 8.05−8.09 (m, 1H,
CHAr), 8.41−8.45 (m, 2H, CHAr, pyrazole), 8.53−8.54 (m, 1H, CHAr);
13C NMR (62.9 MHz, DMSO-d6) δ = 38.1 (Me), 125.0, 125.2 (CH),
1-(4-Methylbenzyl)-4-nitro-5-(3-nitrophenyl)-1H-pyrazole (4n):
Yellow solid (0.246 g, 73%Pd), mp 157−158 °C; 1H NMR (300
MHz, CDCl3) δ = 2.30 (s, 3H, NMe), 5.13 (s, 2H, CH2), 6.86 (d, 2H,
3
3J = 7.9 Hz, CHAr), 7.08 (d, 2H, J = 7.9 Hz, CHAr), 7.56−7.60 (m,
1H, CHAr), 7.67 (t, 1H, 3J = 8.0 Hz, CHAr), 8.08−8.10 (m, 1H, CHAr),
8.26 (s, 1H, pyrazole), 8.36−8.40 (m, 1H, CHAr); 13C NMR (62.9
MHz, CDCl3) δ = 21.1 (Me), 54.8 (CH2), 125.0, 125.1, 127.3 (CH),
2911
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Article
128.3 (C), 129.7, 129.9 (CH), 131.5, 133.9 (C), 135.9, 136.5 (CH),
138.7, 148.1 (C); MS (GC, 70 eV) m/z (%) = 338 (M+, 1), 105
(100); HRMS (EI) calcd for C17H14N4O4 (M+) 338.10096, found
338.10021; IR (ATR, cm−1) ν = 3117 (w), 2919 (w), 1620 (w), 1565
(w), 1530 (s), 1498 (s), 1477 (s), 1453 (m), 1400 (s), 1344 (s), 1322
(s), 1247 (m), 1184 (m), 1085 (w), 1035 (w), 1006 (w), 900 (m), 871
(m), 829 (s), 773 (s), 740 (s), 696 (m), 680 (m), 651 (w), 607 (m),
534 (w).
(m), 1119 (m), 1052 (w), 999 (w), 972 (m), 920 (m), 878 (m), 828
(m), 761 (m), 716 (s), 694 (m), 641 (m), 628 (m), 594 (m), 539 (s).
5-(1-(4-Methylbenzyl)-4-nitro-1H-pyrazol-5-yl)pyrimidine (5e):
Yellow solid (0.230 g, 78%Pd), mp 106−108 °C; 1H NMR (250
MHz, DMSO-d6) δ = 2.25 (s, 3H, Me), 5.31 (s, 2H, CH2), 6.90 (d,
3
2H, J = 8.3 Hz, CHAr), 7.09 (d, 2H, 3J = 8.3 Hz, CHAr), 8.54 (s, 1H,
pyrimidine), 8.94 (s, 2H, pyrimidine), 9.33 (s, 1H, pyrazole); 13C
NMR (62.9 MHz, DMSO-d6) δ = 20.6 (Me), 53.9 (CH2), 122.0 (C),
127.2, 129.2 (CH), 132.2, 134.0, 135.6 (C), 136.5 (CH), 137.3 (C),
157.5, 159.2 (CH); MS (GC, 70 eV) m/z (%) = 295 (M+, 78), 105
(100), 77 (28); HRMS (EI) calcd for C15H13N5O2 (M+) 295.10638,
found 295.10704; IR (ATR, cm−1) ν = 3128 (w), 1599 (w), 1549 (m),
1514 (m), 1470 (m), 1441 (w), 1399 (s), 1354 (m), 1324 (m), 1260
(m), 1187 (m), 1009 (w), 1055 (w), 987 (w), 913 (w), 870 (m), 824
(m), 772 (m), 757 (s), 722 (s), 629 (m), 612 (s), 538 (m).
(Z)-3-(p-Tolylamino)-2-nitro-3-p-tolylacrylonitrile (4′): Yellow
solid (0.067 g, 23%Pd), mp 171−173 °C; 1H NMR (300 MHz,
DMSO) δ = 2.19 (s, 3H, Me), 2.27 (s, 3H, Me), 6.95−7.04 (m, 4H,
3
3
CHAr), 7.19 (d, 2H, J = 8.0 Hz, CHAr), 7.35 (d, 2H, J = 8.0 Hz,
CHAr), 12.07 (s, 1H, NH); 13C NMR (62.9 MHz, DMSO) δ = 20.4,
20.9 (Me), 104.1, 114.0 (C), 126.0, 126.1 (CH), 127.2 (C), 128.5,
129.1, 129.2 (CH), 134.5, 136.8, 141.0 (C); MS (GC, 70 eV) m/z (%)
= 293 (M+, 100); HRMS (ESI) calcd for C17H16N3O2 (M + H)
294.1237, found 293.12375; IR (ATR, cm−1) ν = 3208 (w), 2920 (w),
2217 (w), 1707 (w), 1590 (m), 1559 (s), 1506 (s), 1426 (m), 1362
(m), 1324 (w), 1274 (s), 1195 (s), 1159 (s), 1111 (m), 1020 (m), 955
(w), 818 (s), 765 (m), 719 (m), 700 (m), 665 (w), 572 (w).
3-(1-(4-Methylbenzyl)-4-nitro-1H-pyrazol-5-yl)pyridine (5f): Yel-
1
low solid (0.244 g, 83%Pd), mp 113−115 °C; H NMR (300 MHz,
DMSO-d6) δ = 2.24 (s, 3H, Me), 5.21 (s, 2H, CH2), 6.87 (d, 2H, 3J =
3
8.1 Hz, CHAr), 7.08 (d, 2H, J = 8.1 Hz, CHAr), 7.54−7.58 (m, 1H,
CHAr), 7.92−7.96 (m, 1H, CHAr), 8.50 (s, 1H, pyrazole), 8.65−8.73
(m, 2H, CHAr); 13C NMR (62.9 MHz, DMSO-d6) δ = 20.6 (Me), 53.5
(CH2), 123.5, 127.1, 129.1 (CH), 132.4, 133.4 (C), 136.5 (CH), 137.2
(C), 137.7 (CH), 138.6 (C), 149.8, 151.0 (CH); MS (GC, 70 eV) m/z
(%) = 294 (M+, 84), 105 (100); HRMS (EI) calcd for C16H14N4O2
(M+) 294.11113, found 294.11093; IR (ATR, cm−1) ν = 2918 (w),
1602 (w), 1573 (w), 1552 (w), 1498 (s), 1466 (m), 1400 (s), 1355
(w), 1324 (s), 1258 (m); 1190 (m), 1101 (w), 1029 (m), 996 (m),
873 (w), 839 (m), 813 (m), 798 (s), 763 (m), 708 (m), 614 (m).
3-(4-Nitro-1-(2-phenoxyethyl)-1H-pyrazol-5-yl)pyridine (5g):
Dark brown oil (0.282 g, 91%Pd, 0.130g, 42%Ni); 1H NMR (250
MHz, DMSO-d6) δ = 4.32 (br. s, 4H, 2xCH2), 6.81−6.94 (m, 3H,
CHAr), 7.21−7.27 (m, 2H, CHAr), 7.55−7.66 (m, 2H, CHAr), 8.13 (br.
s, 1H, CHAr), 8.51 (s, 1H, pyrazole); 13C NMR (62.9 MHz, DMSO-
d6) δ = 49.4, 65.3 (CH2), 114.2, 120.9, 128.5, 128.7, 129.4 (CH),
131.3 (C), 131.4, 131.9 (CH), 133.1 (C), 136.7 (CH), 157.5 (C); MS
(GC, 70 eV) m/z (%) = 310 (M+, 22), 217 (51), 170 (16), 120 (100),
77 (66); HRMS (EI) calcd for C16H14N4O3 (M+) 310.10604, found
310.10655; IR (ATR, cm−1) ν = 3076 (w), 1598 (w), 1552 (w), 1496
(s), 1405 (m), 1361 8w), 1321 (m), 1272 (w), 1248 (m), 1178 (w),
1151 (w), 1082 (w), 1048 (w), 1011 (w), 995 (w), 906 (w), 830 (m),
753 (s), 708 (m), 693 (s), 615 (m), 539 (w).
2-(4-Nitro-1-p-tolyl-1H-pyrazol-5-yl)pyrimidine (5a): Yellow solid
(0.123 g, 44%Pd), mp 204−206 °C; 1H NMR (300 MHz, DMSO-d6) δ
= 2.28 (s, 3H, Me), 7.15−7.23 (m, 4H, CHAr), 7.65 (t, 1H, 3J = 4.9 Hz,
3
CHAr), 8.69 (s, 1H, pyrazole), 8.96 (d, 2H, J = 4.9 Hz, pyrimidine);
13C NMR (62.9 MHz, DMSO-d6) δ =20.5 (Me), 122.0, 124.3, 129.8
(CH), 134.2, 135.6 (C), 136.7 (CH), 138.2, 139.1, 155.8 (C), 158.1
(CH); MS (GC, 70 eV) m/z (%) = 281 (M+, 50), 264 (77), 234
(100), 91 (41); HRMS (EI) calcd for C14H11N5O2 (M+) 281.09073,
found 281.09078; IR (ATR, cm−1) ν = 1558 (w), 1512 (s), 1465 (m),
1394 (s), 1324 (s), 1288 (m), 1218 (w), 1176 (w), 1099 (w), 1042
(w), 988 (w), 960 (m), 868 (w), 818 (s), 758 (m), 732 (w), 709 (m),
667 (w), 650 (w), 625 (m), 596 (m), 534 (m).
3-(4-Nitro-1-p-tolyl-1H-pyrazol-5-yl)pyridine (5b): Brown oil
1
(0.235 g, 84%Pd, 0.092g, 33%Ni); H NMR (300 MHz, CDCl3) δ =
2.32 (s, 3H, Me), 7.04 (d, 2H, 3J = 8.5 Hz, CHAr), 7.12 (d, 2H, 3J = 8.5
Hz, CHAr),7.32−7.36 (m, 1H, pyridine), 7.67−7.71 (m, 1H, pyridine),
8.39 (s, 1H, pyrazole) 8.47 (s, 1H, pyridine), 8.64 (d, 1H, pyridine);
13C NMR (62.9 MHz, CDCl3) δ = 21.1 (Me), 123.2, 125.3, 130.0
(CH), 134.4, 135.5 (C), 137.5 (CH), 137.6 (C), 138.1 (CH), 139.6
(C), 150.5, 150.7 (CH); MS (GC, 70 eV) m/z (%) = 280 (M+, 100),
280 (100), 279 (70), 236 (16), 234 (14), 233 (52), 232 (17), 220
(11), 195 (11), 91 (33), 65 (26); HRMS (ESI) calcd for C15H13N4O2
(M + H) 281.1033, found 281.1033; IR (ATR, cm−1) ν = 3054 (w),
1599 (w), 1549 (w), 1494 (s), 1471 (m), 1392 (s), 1318 (s), 1192
(m), 1179 (w), 1110 (w), 1031 (m), 1005 (w), 955 (m), 920 (w), 861
(m) 824 (s), 761 (s), 706 (s), 620 (m), 533 (s).
5-(4-Nitro-1-phenethyl-1H-pyrazol-5-yl)pyrimidine (5h): Yellow
1
oil (0.256 g, 87%Pd); H NMR (300 MHz, DMSO-d6) δ = 3.05 (d,
2H, 3J = 7.0 Hz, CH2), 4.25 (d, 2H, 3J = 7.0 Hz, CH2), 6.86−6.89 (m,
2H, CHAr), 7.18−7.23 (m, 3H, CHAr), 8.47 (s, 2H, pyrimidine), 8.57
(s, 1H, pyrazole), 9.29 (s, 1H, pyrimidine); 13C NMR (75.5 MHz,
CDCl3) δ = 35.1, 51.6 (CH2), 121.6 (C), 126.8, 128.6 (CH), 133.2,
135.8 (C), 136.7 (CH), 137.3 (C), 157.2, 159.0 (CH); MS (GC, 70
eV) m/z (%) = 295 (M+, 1), 104 (100), 91 (45); HRMS (ESI) calcd
for C15H14N5O2 (M + H) 296.1142, found 296.11452; IR (ATR,
cm−1) ν = 2929 (w), 2223 (m), 1599 (w), 1550 (m), 1499 (s), 1465
(m), 1399 (s), 1322 (s), 1263 (m), 1178 (m), 1077 (w), 1031 (w),
974 (w), 915 (w), 867 (w), 826 (s), 748 (m), 724 (m), 701 (s), 627
(m), 561 (w).
5-(4-Nitro-1-p-tolyl-1H-pyrazol-5-yl)pyrimidine (5c): Brown oil
1
(0.230 g, 82%Pd); H NMR (300 MHz, CDCl3) δ = 2.35 (s, 3H,
Me), 7.05 (d, 2H, 3J = 8.5 Hz, CHAr), 7.17 (d, 2H, 3J = 8.5 Hz, CHAr),
8.42 (s, 1H, pyrazole), 8.68 (s, 2H, pyrimidine), 9.22 (s, 1H,
pyrimidine); 13C NMR (75.5 MHz, CDCl3) δ = 21.2 (Me), 122.1 (C),
125.5, 130.3 (CH), 134.4, 134.7, 135.0 (C), 137.6 (CH), 140.3 (C),
157.8, 159.1 (CH); MS (GC, 70 eV) m/z (%) = 281 (M+, 100), 280
(16), 264 (26), 237 (22), 235 (13), 234 (68), 221 (12), 207 (18), 91
(49), 65 (33); HRMS (EI) calcd for C14H11N5O2 (M+) 281.09073,
found 281.09048; IR (ATR, cm−1) ν = 3046 (w), 1598 (w), 1556 (m),
1495 (s), 1463 (m), 1396 (s), 1320 (s), 1286 (m), 1212 (m), 1165
(w), 1111 (w), 1039 (w), 1002 (w), 957 (m), 918 (w), 862 (w) 825
(s), 762 (s), 743 (w), 723 (s), 628 (s), 539 (m).
4,5-Dimethoxy-2-(4-nitro-1-p-tolyl-1H-pyrazol-5-yl)benzal-
dehyde (6a): Brown oil (0.176 g, 48%Pd); 1H NMR (300 MHz,
CDCl3) δ = 2.31 (s, 3H, Me), 3.82 (s, 3H, OMe), 3.97 (s, 3H, OMe),
6.72 (s, 1H, CHAr), 7.02−7.10 (m, 4H, CHAr), 7.41 (s, 1H, CHAr),
8.41 (s, 1H, pyrazole), 9.66 (s, 1H, COH); 13C NMR (62.9 MHz,
CDCl3) δ = 21.1 (Me), 56.2 (OMe), 56.4 (OMe), 111.3, 113.5 (CH),
122.7 (C), 124.7 (CH), 128.5 (C), 129.8 (CH), 135.7 (C), 137.2
(CH), 137.9, 139.3, 150.6, 153.4 (C), 188.1 (CH); MS (GC, 70 eV)
m/z (%) = 367 (M+, 16), 367 (16), 350 (12), 322 (34), 321 (100),
319(28), 309 (12), 308 (15), 306 (15), 305 (13), 277 (13), 254 (11),
91 (22), 65 (17); HRMS (ESI) calcd for C19H18N3O5 (M + H)
368.1241, found 368.12386; IR (ATR, cm−1) ν = 3010 (w), 1683 (m),
1592 (w), 1557 (w), 1505 (s), 1456 (m), 1394 (s), 1316 (s), 1281 (s),
1221 (m), 1163 (m), 1118 (s), 1016 (s), 976 (w), 875 (m) 817 (s),
785 (m), 763 (w), 746 (m), 716 (w), 629 (w), 584 (w).
5-(1-Methyl-4-nitro-1H-pyrazol-5-yl)pyrimidine (5d): Brown solid
(0.188 g, 92%Pd), mp 177−179 °C; 1H NMR (300 MHz, DMSO-d6) δ
= 3.82 (s, 3H, Me), 8.47 (s, 1H, pyrazole), 9.11 (s, 2H, pyrimidine),
9.37 (s, 1H, pyrimidine); 13C NMR (62.9 MHz, DMSO-d6) δ = 38.3
(Me), 122.0 (C), 128.6, 131.4 (CH), 131.9, 135.4 (C), 136.1, 157.8,
159.1 (CH); MS (GC, 70 eV) m/z (%) = 205 (M+, 100), 175 (27),
161 (25), 134 (42), 120 (31), 1075 (34), 79 (27), 62 (78); HRMS
(EI) calcd for C8H7N5O2 (M+) 205.05943, found 205.05932; IR
(ATR, cm−1) ν = 2961 (w), 1713 (w), 1674 (w), 1598 (w), 1556 (m),
1496 (m), 1471 (m), 1392 (s), 1320 (s), 1248 (m), 1193 (m), 1154
2912
dx.doi.org/10.1021/jo4025418 | J. Org. Chem. 2014, 79, 2906−2915

The Journal of Organic Chemistry
Article
2-(1-(4-Methylbenzyl)-4-nitro-1H-pyrazol-5-yl)benzaldehyde
1525 (s), 1499 (s), 1477 (m), 1455 (m), 1398 (s), 1346 (s), 1322 (s),
1254 (m), 1178 (m), 1098 (w), 1077 (w), 1030 (w), 978 (w), 931
(w), 904 (w), 871 (m), 825 (s), 736 (s), 697 (s), 676 (s), 647 (m),
607 (w), 560 (m).
1
(6b): Yellow oil (0.215 g, 67%Pd); H NMR (300 MHz, DMSO-d6) δ
= 2.22 (s, 3H, Me), 5.05−5.06 (m, 2H, CH2), 6.81 (d, 2H, 3J = 8.0 Hz,
3
CHAr), 7.03 (d, 2H, J = 8.0 Hz, CHAr), 7.51−7.54 (m, 1H, CHAr),
7.81−7.84 (m, 2H, CHAr), 8.06−8.09 (m, 1H, CHAr), 8.47 (s, 1H,
pyrazole), 9.73 (s, 1H, CHO); 13C NMR (62.9 MHz, DMSO-d6) δ =
20.6 (Me), 53.7 (CH2), 126.6 (C), 127.5, 128.9, 131.1, 131.3 (CH),
132.1 (C), 132.2 (CH), 133.6 (C), 134.1 (CH), 134.4 (C), 136.1
(CH), 137.2, 139.4 (C), 191.4 (CHO); MS (GC, 70 eV) m/z (%) =
321 (M+, 100), 77 (18); HRMS (ESI) calcd for C18H15N3O3 (M + H)
322.11862, found 322.11825; IR (ATR, cm−1) ν = 3129 (w), 1706 (s),
1564 (m), 1497 (s), 1459 (m), 1399 (s), 1350 (m), 1321 (s), 1295
(m), 1268 (m), 1244 (m), 1195 (m), 1133 (w), 1042 (w), 1021 (w),
922 (w), 879 (w), 831 (s), 811 (m), 781 (s), 762 (s), 732 (m), 667
(m), 602 (m), 534 (m).
2-(1-(4-Methylbenzyl)-4-nitro-1H-pyrazol-5-yl)-4,5-dimethoxy-
benzaldehyde (6c): Yellow solid (0.205 g, 54%Pd), mp 68−69 °C; 1H
NMR (300 MHz, DMSO-d6) δ = 2.28 (s, 3H, Me), 3.82 (s, 3H,
OMe), 3.90 (s, 3H, OMe), 5.34 (s, 2H, CH2), 7.16−7.24 (m, 4H,
CHAr), 7.32 (d, 2H, 4J = 3.9 Hz, CHAr), 8.25 (s, 1H, CHAr), 9.0 (s, 1H,
pyrazole), 10.07 (s, 1H, CHO); 13C NMR (62.9 MHz, DMSO-d6) δ =
20.7 (Me), 55.6 (CH2), 55.7, 56.5 (OMe), 110.5, 116.0 (CH), 119.3,
125.7 (C), 128.0, 129.2, 130.4 (CH), 132.7 (C), 135.8 (CH), 137.5,
148.6, 154.5 (C), 190.2 (CHO); MS (GC, 70 eV) m/z (%) = 381
(M+, 58), 335 (34), 105 (100); HRMS (EI) calcd for C20H19N3O5
(M+) 381.13192, found 381.13183; IR (ATR, cm−1) ν = 1667 (m),
1584 (m), 1504 (s), 1470 (m), 1444 (m), 1385 (m), 1340 (w), 1311
(w), 1269 (s), 1217 (m), 1154 (s), 1041 (m), 1014 (m), 979 (m), 866
(s), 811 (s), 756 (m), 737 (s), 654 (m), 588 (s), 555 (m).
1-(4-Methylbenzyl)-4-nitro-3,5-bis(3-nitrophenyl)-1H-pyrazole
(7b): Yellow solid (0.243 g, 53%one‑pot, 0.312 g, 68%consecutive), mp 131−
132 °C; 1H NMR (250 MHz, CDCl3) δ = 2.31 (s, 3H, NMe), 5.18 (s,
3
3
2H, CH2), 6.90 (d, 2H, J = 8.0 Hz, CHAr), 7.09 (d, 2H, J = 8.0 Hz,
CHAr), 7.59−7.74 (m, 3H, CHAr), 8.04−8.14 (m, 2H, CHAr), 8.31−
8.44 (m, 2H, CHAr), 8.62−8.64 (m, 1H, CHAr); 13C NMR, due to bed
solubility in DMSO-d6, it was not possible to measure; MS (GC, 70
eV) m/z (%) = 459 (M+, 62), 105 (100); HRMS (EI) calcd for
C23H17N5O6 (M+) 459.11733, found 459.11682; IR (ATR, cm−1) ν =
3086 (w), 2922 (s), 2852 (w), 1620 (w), 1524 (s), 1454 (m), 1345
(s), 1244 (w), 1201 (w), 1097 (m), 1041 (w), 909 (m), 870 (w), 842
(m), 808 (m), 736 (s), 677 (s), 570 (w).
3-(4-(Trifluoromethyl)phenyl)-1-methyl-4-nitro-5-(3-nitro-
phenyl)-1H-pyrazole (7c): White solid (0.333 g, 85%consecutive), mp
1
202−204 °C; H NMR (300 MHz, CDCl3) δ = 3.81 (s, 3H, Me),
7.71−7.77 (m, 2H, CHAr), 7.78−7.93 (m, 4H, CHAr), 8.35−8.36 (m,
3
4
1H, CHAr), 8.44 (dt, 1H, J = 7.1 Hz, J = 2.5 Hz, CHAr); 19F NMR
(282 MHz, CDCl3) δ = −62.8 (CF3); 13C NMR (62.9 MHz, CDCl3)
1
δ = 38.3 (Me), 124.0 (q, J = 272 Hz, CF3), 124.9 (CH), 125.2 (C),
125.2, 125.3, 125.4 (CH), 128.6 (C), 129.6, 130.2 (CH), 131.4 (q, 2J =
33 Hz, CH), 133.6 (C), 135.7 (CH), 140.6, 146.3, 148.4 (C); MS
(GC, 70 eV) m/z (%) = 392 (M+, 100), 373 (16), 316 (14), 174 (28),
163 (40), 117 (40); HRMS (EI) calcd for C17H11N4O4F3 (M+)
392.07269, found 392.07271; IR (ATR, cm−1) ν = 3087 (w), 1525
(m), 1505 (m), 1451 (m), 1350 (s), 1321 (s), 1239 (m), 1191 (w),
1166 (m), 1108 (s), 1063 (s), 1013 (m), 964 (w), 916 (m), 877 (w),
849 (s), 815 (m), 800 (m), 769 (w), 731 (s), 697 (s), 678 (m), 656
(m), 647 (m), 595 (m).
2-(1-Butyl-4-nitro-1H-pyrazol-5-yl)benzaldehyde (6d): Dark
1
brown oil (0.174 g, 64%Pd); H NMR (250 MHz, DMSO-d6) δ =
0.70 (t, 3H, 3J = 7.2 Hz, CH2CH2CH2CH3), 1.05−1.17 (m, 2H,
CH2CH2CH2CH3), 1.53−1.64 (m, 2H, CH2CH2CH2CH3), 3.78−3.85
(m, 2H, CH2CH2CH2CH3), 7.61−7.64 (m, 1H, CHAr), 7.86−7.90 (m,
2H, CHAr), 8.15−8.18 (m, 1H, CHAr), 8.44 (s, 1H, pyrazole), 9.92 (s,
1H, CHO); 13C NMR (62.9 MHz, DMSO-d6) δ = 13.1 (Me), 18.7,
30.6, 49.5 (CH2), 126.6 (C), 131.2, 131.4 (CH), 132.2 (C), 132.7
(CH), 133.0 (C), 134.3 (CH), 134.5 (C), 136.0 (CH), 139.3 (C),
192.0 (CHO); MS (GC, 70 eV) m/z (%) = 273 (M+, 1), 227 (100),
183 (18), 171 (55), 129 (29), 115 (23), 102 (26); HRMS (EI) calcd
for C14H15O3N3 (M+) 273.11079, found 273.11081; IR (ATR, cm−1) ν
= 3391 (w), 2958 (w), 1703 (m), 1599 (w), 1558 (w), 1500 (s), 1461
(m), 1401 (s9, 1321 (s), 1271 (m), 1242 (m), 1197 (m), 1023 (w),
845 (w), 826 (s), 758 (s), 605 (w).
3-(1-Methyl-4-nitro-5-(3-nitrophenyl)-1H-pyrazol-3-yl)pyridine
(7d): Brown solid (0.201 g, 62%consecutive), mp 202−204 °C; 1H NMR
(300 MHz, CDCl3) δ = 3.77 (s, 3H, NMe), 7.57−7.63 (m, 1H, CHAr),
7.74−7.76 (m, 2H, CHAr), 7.96−7.99 (m, 1H, CHAr), 8.25−8.31 (m,
2H, CHAr), 8.38−8.42 (m, 1H, CHAr), 8.54 (t, 1H, 4J = 1.9 Hz, CHAr);
13C NMR, due to bed solubility in DMSO-d6, it was not possible to
measure; MS (GC, 70 eV) m/z (%) = 325 (M+, 100), 163 (23), 117
(25); HRMS (EI) calcd for C15H11N5O4 (M+) 325.0811, found
325.08113; IR (ATR, cm−1) ν = 3098 (w), 2929 (w), 1620 (w), 1524
(s), 1503 (m), 1454 (m), 1379 (w), 1346 (s), 1235 (m), 1087 (m),
1002 (w), 901 (m), 840 (m), 799 (m), 768 (w), 737 (s), 720 (m), 696
(s), 673 (m), 646 (m).
2-(4-Nitro-1-(2-phenoxyethyl)-1H-pyrazol-5-yl)benzaldehyde
1
(6e): Yellow solid (0.219 g, 65%Pd), mp 98−100 °C; H NMR (250
1-(2-Phenoxyethyl)-5-(pyridin-3-yl)-1H-pyrazol-4-amine (8a):
1
Brown oil (0.246 g, 88%); H NMR (300 MHz, CDCl3) δ = 2.99−
MHz, DMSO-d6) δ = 4.21−4.28 (m, 4H, 2xCH2), 6.75−6.78 (m, 2H,
CHAr), 6.87−6.93 (m, 1H, CHAr), 7.19−7.26 (m, 2H, CHAr), 7.64−
7.67 (m, 1H, CHAr), 7.81−7.91 (m, 2H, CHAr), 9.51 (s, 1H, pyrazole),
9.89 (s, 1H, CHO); 13C NMR (62.9 MHz, DMSO-d6) δ = 49.4, 65.2
(CH2), 114.2, 121.0 (CH), 127.0 (C), 129.4, 131.1, 131.4, 131.6
(CH), 133.4 (C), 134.1 (CH), 136.5 (CH), 140.0, 157.6 (C), 191.7
(CHO); MS (GC, 70 eV) m/z (%) = 337 (M+, 1), 231 (100), 146
(65), 120 (43), 75 (63); HRMS (ESI) calcd for C18H15N3O4 (M + H)
338.11353, found 338.11364; IR (ATR, cm−1) ν = 1713 (w), 1600
(w), 1553 (w), 1497 (s), 1475 (m), 1394 (m), 1320 (s), 1234 (s),
1159 (m), 1079 (m), 1045 (m), 1002 (m), 897 (w), 869 (m), 823 (s),
795 (m), 748 (s), 683 (m), 610 (m), 577 (m), 533 (m).
3.14 (br. s, 2H, NH2), 4.21−4.35 (m, 4H, 2xCH2), 6.66−6.70 (m, 2H,
CHAr), 6.82−6.88 (m, 1H, CHAr), 7.12−7.19 (m, 3H, CHAr), 7.34−
7.39 (m, 1H, CHAr), 7.74−7.77 (m, 1H, CHAr); 13C NMR (75.5 MHz,
CDCl3) δ = 49.1, 66.6 (CH2), 114.4, 121.2, 123.8 (CH), 125.9, 127.6,
128.2 (C), 129.5, 131.3, 137.4, 149.3, 150.4 (CH) 158.1 (C); MS
(GC, 70 eV) m/z (%) = 280 (M+, 100), 173 (34), 160 (81), 105 (28),
77 (30); HRMS (EI) calcd for C16H16N4O (M+) 280.13186, found
280.13186; IR (ATR, cm−1) ν = 3321 (w), 2929 (w), 1666 (w), 1597
(m), 1494 (m), 1460 (w), 1411 (m), 1370 (m), 1291 (w), 1238 (s),
1172 (m), 1081 (w), 1054 (m), 1003 (w), 959 (w), 903 (w), 814 (m),
789 (w), 753 (s), 711 (s), 690 (s), 618 (m).
1-(4-Methylbenzyl)-5-(pyrimidin-5-yl)-1H-pyrazol-4-amine (8b):
4-Nitro-3,5-bis(3-nitrophenyl)-1-phenethyl-1H-pyrazole (7a): Yel-
low solid (0.220 g, 48%one‑pot, 0.284 g, 62%consecutive), mp 148−150 °C;
1H NMR (250 MHz, CDCl3) δ = 3.18 (t, 2H, 3J = 6.4 Hz, CH2), 4.21
1
Brown oil (0.220 g, 83%); H NMR (300 MHz, CDCl3) δ = 2.19
3
(br. s, 5H, NH2, Me), 5.08 (s, 2H, CH2), 6.74 (d, 2H, J = 8.0 Hz,
CHAr), 6.95 (d, 2H, 3J = 8.0 Hz, CHAr), 7.17 (s, 1H, pyrazole), 8.52 (s,
2H, pyrimidine), 9.08 (s, 1H, pyrimidine); 13C NMR (62.9 MHz,
CDCl3) δ = 21.0 (Me), 54.1 (CH2), 123.7, 124.6 (C), 126.5 (CH)
129.1, 129.5, 131.0 (CH), 133.8, 137.7 (C), 156.9 (CH), 158.0 (C);
MS (GC, 70 eV) m/z (%) = 265 (M+, 87), 105 (100); HRMS (EI)
calcd for C15H15N5 (M+) 265.13220, found 265.13228; IR (ATR,
cm−1) ν = 2922 (w), 1682 (w), 1545 (m), 1515 (m), 1406 (s), 1315
(m), 1187 (m), 1119 (w), 1038 (w), 998 (m), 912 (w), 793 (s), 752
(m), 724 (s), 657 (m), 627 (s).
3
(t, 2H, J = 6.4 Hz, CH2), 6.80−6.84 (m, 2H, CHAr), 7.07−7.11 (m,
1H, CHAr), 7.19−7.32 (m, 3H, CHAr), 7.56 (t, 1H, 3J = 8.0 Hz, CHAr),
7.69 (t, 2H, 3J = 8.0 Hz, CHAr), 7.74 (t, 1H, 4J = 1.7 Hz, CHAr), 8.06−
8.10 (m, 2H, CHAr), 8.30−8.38 (m, 1H, CHAr); 13C NMR (62.9 MHz,
CDCl3) δ = 34.9, 51.2 (CH2), 123.2, 123.5, 123.8, 124.1, 126.5 (CH),
127.1 (C), 127.6, 128.0, 128.3, 128.8 (CH), 131.0 (C), 134.4, 134.5
(CH), 135.6, 140.6, 144.7, 147.1, 147.2 (C); MS (GC, 70 eV) m/z
(%) = 459 (M+, 1), 104 (100); HRMS (EI) calcd for C23H17N5O6
(M+) 459.11733, found 459.11773; IR (ATR, cm−1) ν = 2923 (w),
2913
dx.doi.org/10.1021/jo4025418 | J. Org. Chem. 2014, 79, 2906−2915

The Journal of Organic Chemistry
Article
7,8-Dimethoxy-1-p-tolyl-1H-pyrazolo[4,3-c]isoquinoline (9a):
(m), 1412 (m), 1346 (m), 1313 (w), 1275 (m), 1232 (w), 1086 (w),
1053 (m), 978 (m), 930 (m), 875 (m), 859 (m), 781 (s), 743 (s), 700
(s), 596 (w), 569 (s).
1
Gray solid (0.297 g, 93%), mp 180−182 °C; H NMR (300 MHz,
DMSO-d6) δ = 2.46 (s, 3H, Me), 3.51 (s, 3H, OMe), 3.92 (s, 3H,
3
5-(4-Methoxyphenyl)-N,N-dimethyl-1-p-tolyl-1H-pyrazol-4-
amine (10a): Orange oil (0.273 g, 89%); 1H NMR (300 MHz,
CDCl3) δ = 2.30 (s, 3H, Me), 2.56 (s, 6H, NMe2), 3.80 (s, 3H, OMe),
6.84 (d, 2H, 3J = 8.5 Hz, CHAr), 7.06 (br. s, 4H, CHAr), 7.20 (d, 2H, 3J
= 8.5 Hz, CHAr), 7.51 (s, 1H, pyrazole); 13C NMR (62.9 MHz,
CDCl3) δ = 21.0 (Me), 44.7 (NMe2), 55.2 (OMe), 113.8 (CH), 123.0
(C), 124.8, 129.2 (CH) 131.2 (C), 131.2 (CH), 131.6, 136.6, 136.9,
138.1, 159.2 (C); MS (GC, 70 eV) m/z (%) = 307 (M+, 100), 307
(100), 306 (10), 224 (40), 146 (13), 132 (19), 91 (18), 65 (13);
HRMS (ESI) calcd for C16H15N3O2 (M + H) 308.17600, found
308.17655; IR (ATR, cm−1) ν = 3011 (w), 1614 (w), 1565 (w), 1513
(s), 1456 (m), 1384 (m), 1287 (w), 1245 (s), 1176 (m), 1086 (w),
1035 (m), 962 (s), 926 (w), 813 (s), 740 (w) 661 (m), 631 (m), 576
(m), 528 (m).
OMe), 6.83 (s, 1H, CHAr), 7.48 (d, 2H, J = 8.1 Hz, CHAr), 7.54(d,
3
2H, J = 8.1 Hz, CHAr), 7.73 (s, 1H, CHAr), 8.45 (s, 1H, pyrazole),
8.95 (s, 1H, Py); 13C NMR (62.9 MHz, DMSO-d6) δ = 20.8 (Me),
55.0, 55.7 (OMe), 100.8, 108.6 (CH), 117.6, 122.7 (C), 126.9, 127.9
(CH), 129.8 (C), 135.3 (CH), 135.9, 138.1, 138.9 (C), 147.9 (CH),
149.3, 151.8 (C); MS (GC, 70 eV) m/z (%) = 319 (M+, 100); HRMS
(EI) calcd for C19H17N3O2 (M+) 319.13153, found 319.13144; IR
(ATR, cm−1) ν = 2905 (w), 1622 (w), 1518 (w), 1492 (s), 1455 (m),
1437 (m), 1385 (m), 1295 (w), 1258 (s), 1205 (m), 1174 (m), 1137
(s), 1084 (m), 944 (m), 925 (m), 865 (m), 824 (s), 796 (s), 713 (m),
664 (w), 630 (w), 573 (m), 563 (m).
1-(2-Phenoxyethyl)-1H-pyrazolo[4,3-c]isoquinoline (9b)L. Yellow
solid (0.254 g, 88%), mp 117−119 °C; 1H NMR (300 MHz, DMSO-
d6) δ = 4.51 (t, 2H, 3J = 5.3 Hz, CH2), 5.24 (t, 2H, 3J = 5.3 Hz, CH2),
6.68−6.72 (m, 2H, CHAr), 6.82−6.88 (m, 1H, CHAr), 7.13−7.20 (m,
1H, CHAr), 7.78−7.83 (m, 1H, CHAr), 7.93−7.99 (m, 1H, CHAr),
4-(4-(Dimethylamino)-1-p-tolyl-1H-pyrazol-5-yl)benzonitrile
1
(10b): Orange oil (0.257 g, 85%); H NMR (300 MHz, CDCl3) δ =
2.33 (s, 3H, Me), 2.56 (s, 6H, NMe2), 7.02 (d, 2H, 3J = 8.3 Hz, CHAr),
7.10 (d, 2H, 3J = 8.3 Hz, CHAr), 7.42 (d, 2H, 3J = 8.3 Hz, CHAr), 7.56
8.29−8.32 (m, 1H, CHAr), 8.37 (s, 1H, pyrazole), 9.07 (s, 1H, Py); 13
C
NMR (62.9 MHz, DMSO-d6) δ = 51.5, 66.8 (CH2), 114.2, 120.8,
122.0 (CH), 122.6, 126.8 (C), 127.3 (CH), 128.1 (C), 129.3, 129.4,
130.8, 134.2 (CH), 136.3 (C), 149.4 (CH), 157.9 (C); MS (GC, 70
eV) m/z (%) = 289 (M+, 24), 196 (26), 182 (31), 169 (100), 128
(51), 77 (47); HRMS (ESI) calcd for C18H16N3O (M + H)
290.12879, found 290.1288; IR (ATR, cm−1) ν = 3033 (w), 1622
(w), 1588 (m), 1531 (w), 1496 (m), 1445 (m), 1416 (m), 1350 (w),
1286 (m), 1241 (s), 1133 (w), 1061 (m), 1021 (w), 950 (m), 906
(m), 827 (m), 789 (m), 741 (s), 686 (s), 592 (m), 574 (s).
3
(d, 2H, J = 8.3 Hz, CHAr), 7.57 (s, 1H, pyrazole); 13C NMR (75.5
MHz, CDCl3) δ = 21.1 (Me), 44.9 (NMe2), 111.2, 118.6 (C), 125.1,
129.6 (CH), 130.0 (C), 130.2, 131.8, 132.0 (CH), 135.2, 137,6. 138,1
(C); MS (GC, 70 eV) m/z (%) = 302 (M+, 100), 303 (23), 302 (100),
301 (13), 276 (11), 260 (10), 219 (34), 146 (12), 132 (20), 91 (25),
65 (14); HRMS (ESI) calcd for C19H19N4 (M + H) 303.1610, found
303.16064; IR (ATR, cm−1) ν = 2942 (w), 2777 (w), 1558 (w), 1513
(s), 1452 (w), 1411 (w), 1382 (m), 1312 (w), 1232 (w), 1180 (w),
1149 (w), 1086 (w), 1031 (w), 1015 (w), 961 (m), 926 (w), 818 (s),
771 (w), 729 (w), 700 (w), 660 (w), 629 (w), 593 (w), 573 (w).
N,N-Dimethyl-1,5-di-p-tolyl-1H-pyrazol-4-amine (10c): Orange
1-(4-Methylbenzyl)-7,8-dimethoxy-1H-pyrazolo[4,3-c]isoquino-
line (9c): Gray solid (0.300 g, 90%), mp 168−170 °C; 1H NMR (250
MHz, CDCl3) δ = 2.27 (s, 3H, Me), 3.77 (s, 3H, OMe), 4.00 (s, 3H,
1
3
oil (0.250 g, 86%); H NMR (300 MHz, CDCl3) δ = 2.30 (s, 3H,
OMe), 5.96 (s, 2H, CH2), 6.97 (d, 2H, J = 8.1 Hz, CHAr), 7.08 (d,
3
Me), 2.33 (s, 3H, Me), 2.56 (s, 6H, NMe2), 6.99−7.21 (m, 8H, CHAr),
7.49 (s, 1H, pyrazole); 13C NMR (62.9 MHz, CDCl3) δ = 21.0 (Me),
21.3 (Me), 44.8 (NMe2), 124.8 (CH), 127.7 (C), 129.0, 129.2, 129.9,
131.2 (CH) 131.7, 136.6, 136.7, 138.0, 138.1 (C); MS (GC, 70 eV)
m/z (%) = 291 (M+, 100), 291 (100), 290 (10), 276 (11), 208 (36),
146 (11), 132 (20), 91 (19), 65 (11); HRMS (ESI) calcd for
C19H22N3 (M + H) 292.17355, found 292.18126; IR (ATR, cm−1) ν =
2946 (w), 1558 (w), 1515 (m), 1556 (w), 1420 (w), 1382 (m), 1327
(s), 1271 (w), 1230 (w), 1175 (m), 1148 (m), 1121 (s), 1095 (m),
1073 (m), 1031 (m), 971 (m), 926 (m), 908 (m), 810 (s), 717 (m),
702 (m), 694 (m), 658 (m), 582 (m).
2H, J = 8.1 Hz, CHAr), 7.28 (s, 1H, CHAr), 7.38 (s, 1H, CHAr), 8.34
(s, 1H, pyrazole), 8.87 (s, 1H, Py); 13C NMR (75.5 MHz, CDCl3) δ =
21.0 (Me), 56.0 (OMe), 56.1 (CH2), 56.3 (OMe), 101.9, 108.2 (CH),
118.8, 122.7 (C), 125.7, 128.4 (CH), 128.5 (C), 129.8, 132.0 (CH),
132.1 (C), 133.8 (CH), 133.9, 135.9, 137.7 (C), 147.4 (CH), 149.4,
152.8 (C); MS (GC, 70 eV) m/z (%) = 333 (M+, 100), 105 (72);
HRMS (EI) calcd for C20H19N3O2 (M+) 333.14718, found 333.14682;
IR (ATR, cm−1) ν = 2920 (w), 1622 (w), 1582 (w), 1495 (m), 1436
(m), 1405 (m), 1265 (m), 1191 (m), 1154 (s), 1117 (s), 1072 (m),
1016 (m), 926 (m), 850 (m), 803 (m), 783 (m), 753 (m), 719 (s),
693 (s), 575 (m), 538 (s).
1-(4-Methylbenzyl)-1H-pyrazolo[4,3-c]isoquinoline (9d): Light
1
yellow solid (0.256 g, 94%), mp 163−164 °C; H NMR (300 MHz,
ASSOCIATED CONTENT
■
DMSO-d6) δ = 2.18 (s, 3H, Me), 6.06 (s, 2H, CH2), 6.98 (d, 2H, 3J =
8.4 Hz, CHAr), 7.07 (d, 2H, J = 8.4 Hz, CHAr), 7.69−7.75 (m, 1H,
3
S
* Supporting Information
Detailed experimental procedures and characterization data for
all new compounds. This material is available free of charge via
the Internet at http://pubs.acs.org. X-ray crystallographic data
(excluding structure factors) for the structure 4h, 5f, 7c, 9c 10a,
and 4′ reported in this paper have been deposited with the
Cambridge Crystallographic Data Centre as supplementary
publication nos. 949372-949376 and 977379 can be obtained
free of charge on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK; Fax: +44(1223)336033; E-mail:
deposit@ccdc.cam.ac.uk, or via www.ccdc.cam.ac.uk/data_
request/cif.
CHAr), 7.80−7.86 (m, 1H, CHAr), 8.25−8.32 (m, 2H, CHAr), 8.43 (s,
1H, pyrazole), 9.08 (s, 1H, Py); 13C NMR (62.9 MHz, DMSO-d6) δ =
20.5 (Me), 55.1 (CH2), 121.5 (CH), 122.2 (C), 126.1 (CH), 126.7
(C), 127.2, 129.3, 131.1, 134.0 (CH), 134.1, 136.6, 136.7 (C), 149.5
(CH); MS (GC, 70 eV) m/z (%) = 273 (M+, 75), 105 (100); HRMS
(ESI) calcd for C18H16N3 (M + H) 274.13387, found 274.13397; IR
(ATR, cm−1) ν = 3129 (w), 1621 (w), 1531 (w), 1512 (w), 1474 (w),
1415 (m), 1349 (m), 1309 (m), 1179 (w), 11052 (w), 1063 (m), 1019
(w), 994 (w), 952 (w), 927 (w), 889 (m), 836 (m), 793 (s), 759 (s),
734 (m), 698 (m), 615 (w), 578 (s).
1-Butyl-1H-pyrazolo[4,3-c]isoquinoline (9e): Yellow solid (0.209 g,
93%), mp 137−139 °C; 1H NMR (250 MHz, CDCl3) δ = 0.98 (t, 3H,
3J
= 7.5 Hz, CH2CH2 CH2CH3), 1.39−1.54 (m, 2H,
CH2CH2CH2CH3), 1.93−2.05 (m, 2H, CH2CH2CH2CH3), 4.80 (t,
2H, 3J = 7.5 Hz, CH2CH2CH2CH3), 7.69−7.76 (m, 1H, CHAr), 7.87−
7.93 (m, 1H, CHAr), 8.15−8.18 (m, 1H, CHAr), 8.26−8.30 (m, 2H,
pyrazole, CHAr), 9.03 (s, 1H, Py); 13C NMR (62.9 MHz, CDCl3) δ =
13.7 (Me), 19.9, 31.9, 52.8 (CH2), 121.1 (CH), 123.5 (C), 127.1,
129.8, 131.3, 133.6 (CH), 136.1, 147.6, 149.0 (C); MS (GC, 70 eV)
m/z (%) = 225 (M+, 20), 182 (100), 169 (35), 128 (28); HRMS (EI)
calcd for C14H15N3 (M+) 225.12605, found 225.12597; IR (ATR,
cm−1) ν = 2955 (w), 2930 (w), 2205 (w), 2063 (m), 1958 (m), 1463
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: iva108@gmail.com. Fax: 00 49 381 4986412. Phone:
00 49 381 4986416.
*E-mail: peter.langer@uni-rostock.de.
Notes
The authors declare no competing financial interest.
2914
dx.doi.org/10.1021/jo4025418 | J. Org. Chem. 2014, 79, 2906−2915

The Journal of Organic Chemistry
Article
(11) After we conducted arylation of pyrazole 3e without CuI, we
detected the compound 4′ instead of expected 4″. The substance 4′
was isolated by preparative column chromatography, and its structure
was unambiguously corroborated by X-ray analysis (for details, see
Supporting Information).
ACKNOWLEDGMENTS
■
Financial support by the DAAD (scholarship for A.G.) and by
the State of Mecklenburg-Vorpommern is gratefully acknowl-
edged. We are grateful to Satenik Mkrtchyan for the
preparation of the Supporting Information, and to Enamine
Ltd. Company (Ukraine) for support.
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