A simple synthesis of 5-(2-Aminophenyl)-1H-pyrazoles

Article abstract of DOI:10.1002/hlca.201100055

A four-step synthesis of 1-substituted 5-(2-aminophenyl)-1H-pyrazoles 5 as a novel type of histamine analogs and versatile building blocks for further transformations was developed. The synthesis starts from commercially available 2-nitroacetophenone (12), which is converted into the enamino ketone 13 as the key intermediate. Cyclization of the key intermediate 13 with monosubstituted hydrazines 14a-14l afforded the 5-(2-nitrophenyl)-1H-pyrazoles 17a-17l. Finally, catalytic hydrogenation of the nitro compounds 17a, 17c-17e, and 17g-17j furnished the title compounds 5a, 5c-5e, and 5g-5j, respectively, in good yields. As demonstrated by some further transformations, additional functionalization of compounds 17 and 5 is feasible, either by electrophilic substitution at C(4) of the pyrazole ring, or at the NH₂ group. Copyright

Full text of DOI:10.1002/hlca.201100055

Helvetica Chimica Acta – Vol. 94 (2011)
1703
A Simple Synthesis of 5-(2-Aminophenyl)-1H-pyrazoles
a
a
a
a
a
a
ˇ
by Monika Janjic´ ), Rok Prebil ), Urosˇ Grosˇelj ), David Kralj ), Crt Malavasˇicˇ ), Amalija Golobicˇ ),
Katarina Starea), Georg Dahmannb), Branko Stanovnika), and Jurij Svete*a)
a
ˇ
ˇ
) Faculty of Chemistry and Chemical Technology, University of Ljubljana, Askerceva 5, P.O. Box 537, SI-
1000 Ljubljana (phone: þ 38612419100; fax: þ 38612419220; e-mail: jurij.svete@uni-lj.si)
b) Boehringer Ingelheim Pharma GmbH & Co. KG, Department Chemical Research, D-88397 Biberach
A four-step synthesis of 1-substituted 5-(2-aminophenyl)-1H-pyrazoles 5 as a novel type of
histamine analogs and versatile building blocks for further transformations was developed. The synthesis
starts from commercially available 2-nitroacetophenone (12), which is converted into the enamino
ketone 13 as the key intermediate. Cyclization of the key intermediate 13 with monosubstituted
hydrazines 14a – 14l afforded the 5-(2-nitrophenyl)-1H-pyrazoles 17a – 17l. Finally, catalytic hydro-
genation of the nitro compounds 17a, 17c – 17e, and 17g – 17j furnished the title compounds 5a, 5c – 5e,
and 5g – 5j, respectively, in good yields. As demonstrated by some further transformations, additional
functionalization of compounds 17 and 5 is feasible, either by electrophilic substitution at C(4) of the
pyrazole ring, or at the NH2 group.
Introduction. – In biological processes, histamine, tyramine, dopamine, tryptamine,
serotonin, and melatonin play a crucial role as chemical messengers. Therefore,
preparation of their novel synthetic analogs based on the 2-(heteroaryl)ethylamine
scaffold is an important target in medicinal and synthetic organic chemistry [1].
Pyrazoles are an important class of heterocyclic compounds. Despite their rare
occurrence in nature, numerous pyrazole derivatives have found use in various
applications, and a general interest in their chemistry is still continuing (for a review,
see [2]). Among numerous synthetic options for the construction of the pyrazole ring,
two classical approaches are most frequently employed: a) cyclocondensation of a 1,3-
dicarbonyl compound with a hydrazine derivative and b) 1,3-dipolar cycloaddition of a
CꢀNꢀN type 1,3-dipole (diazoalkane, nitrile imine, or azomethine imine) to a C,C
multiple bond [2].
Recently, a part of our research has been focused on the synthesis of functionalized
pyrazoles utilizing the [3 þ 2] cycloaddition and cyclocondensation approach [3][4].
Within this context, pyrazole derivatives functionalized with an amino acid [5], b-
amino alcohol [6], 2-phenylethylamine [6a], terpene [7], and dipeptide structural motif
[3][4][8] have been prepared. In continuation, we reported a ꢀring switchingꢁ synthesis
of 1-substituted 4-(2-aminoethyl)-1H-pyrazol-5-ols 2 [9] as the pyrazole analogs of
histamine 1 and, soon after, a one-pot parallel solution-phase synthesis of compounds 2
[10]. Next, the syntheses of 1-substituted 5-(2-aminoethyl)-1H-pyrazol-4-carbox-
amides 3 [11] and their bicyclic analogs, 1,5-disubstituted 6,7-dihydro-1H-pyrazo-
lo[4,3-c]pyridin-4(5H)-ones 4 [12] have been reported. In continuation of our work in
this field, we focused our attention on 5-(2-aminophenyl)-1H-pyrazole derivatives 5 as
ꢂ 2011 Verlag Helvetica Chimica Acta AG, Zꢃrich

1704
Helvetica Chimica Acta – Vol. 94 (2011)
another type of histamine analogs. The structures of histamine (1) and its analogs 2 – 5
are depicted in Fig. 1. Compounds 5 are interesting for several reasons: a) to the best of
our knowledge, only a handful of these simple compounds were already known, b)
compounds 5 should be easily accessible from 2-aminoacetophenone (6) or its synthetic
equivalent, c) although a few examples of enaminone-based synthesis of target
compounds 5 were known, the literature did not provide sufficient experimental and
characterization data, and d) because 5-(2-aminophenyl)-1H-pyrazole derivatives
could be useful building blocks for further transformations including combinatorial
studies. As a result of our efforts in this field, we now report a simple enaminone-based
synthesis and some further transformations of 1-substituted 5-(2-aminophenyl)-1H-
pyrazoles 5 as novel histamine analogs.
Fig. 1. Histamine (1) and its pyrazole analogs 2 – 5
Results and Discussion. – First, we tried to synthesize the target compounds from 2-
(2-acetylphenyl)-1H-isoindole-1,3(2H)-dione (7), which was prepared by phthaloyla-
tion of 2-aminoacetophenone (6) according to the procedure described in [13].
Unfortunately, further treatment of 7 with N,N-dimethylformamide dimethyl acetal
(DMFDMA) in refluxing toluene gave isoindolo[2,1-a]quinoline-5,11-dione (11)
instead of the desired enamino ketone 8. This result was not very surprising, since
two examples of base-catalyzed cyclizations of 7 into 11 have already been reported
[14]. The reaction mechanism can be rationalized by initial formation of enaminone 8
(activated analog of 7), which cyclizes to 9, followed by b-elimination of DMFand H2O
to give 11 (Scheme 1).
Because the attempted synthesis of target compounds from the N-phthaloylated 2-
aminoacetophenone 7 failed in the very beginning, we turned our attention to
commercially available 2-nitroacetophenone (12) as another suitable starting material.
Following a slightly modified literature procedure [15], 12 was reacted with DMFDMA
to give (E)-3-(dimethylamino)-1-(2-nitrophenyl)prop-2-en-1-one (13) in 63% yield.
Treatment of the key intermediate 13 with NH2NH2 · H2O (14a) and a series of alkyl-
and arylhydrazines 14b – 14f and 14g – 14l, respectively, in refluxing PrOH gave

Helvetica Chimica Acta – Vol. 94 (2011)
1705
Scheme 1
1-substituted 5-(2-nitrophenyl)pyrazoles 17a – 17l in 53 – 97% yields. The mechanism of
formation of pyrazoles 17 can be explained by initial substitution of the dimethylamino
group to give the ene-hydrazine 15. Intramolecular addition of the hydrazino group to
the C¼O group gives the intermediate 2,3-dihydro-3-hydroxy-1H-pyrazole 16, from
which H2O is eliminated to produce the 1H-pyrazole 17. This proposed mechanism is in
agreement with the mechanism determined previously for reaction of related enamino
ketones with hydrazines [16]. Finally, reduction of the (nitrophenyl)-1H-pyrazoles 17
to the title compounds 5 was carried out by catalytic hydrogenation in the presence of
Pd/C. In this manner, 5-(2-aminoethyl)-1H-pyrazoles 5a, 5c – 5e, and 5g – 5j were
prepared in 62 – 100% yields (Scheme 2 and Table 1).
Scheme 2a)
a) For R and yields of 17 and 5, see Table 1.

1706
Helvetica Chimica Acta – Vol. 94 (2011)
Table 1. Yields of Compounds 5 and 17
Compound
R
Yield [%]
17
5
17a, 5a
17b
17c, 5c
17d, 5d
17e, 5e
17f
17g, 5g
17h
5h
H
Me
Cyclohexyl
tBu
HOCH2CH2
CH2COOEt
Ph
4-NO2ꢀC6H4
4-NH2ꢀC6H4
3-MeOꢀC6H4
4-MeOꢀC6H4
2-ClꢀC6H4
3-ClꢀC6H4
53
74
61
70
69
83
97
73
–
89
79
75
81
94
–
62
92
95
–
93
–
88
95
17i, 5i
17j, 5j
17k
100
–
–
17l
Next, some further transformations of the intermediates 17 and final products 5
were carried out. Electrophilic bromination of 17g proceeded selectively at the
pyrazole ring to afford the 4-Br analog 18 in 85% yield. Nitration of 17g took place at
the heteroaromatic part of the molecule to produce a mixture of regioisomeric products
19 and 20. Subsequent chromatographic separation furnished pure compounds 19 and
20 in 55 and 32% yield, respectively. Loss of regioselectivity in nitration was somewhat
surprising, yet explainable. Nitronium ion as a strong and hard electrophile can attack
free positions in pyrazole 17g, more nucleophilic C(4) and less nucleophilic C(3).
However, C(4) in 17g is hindered, sterically as well as electrostatically, by the 2-
nitrophenyl group at C(5). Consequently, nitration also takes place at less nucleophilic,
yet sterically more accessible C(3). Finally, we tried to perform reductive isopropy-
lation of the amines 5a and 5g. Catalytic hydrogenation of the 1-unsubstituted
compound 5a in the presence of acetone and cyclopentanone afforded stable tricyclic
aminals 21 and 22, and not the expected 5-[2-(1-methylethylamino)phenyl]-1H-
pyrazoles 23 and 24. On the other hand, reductive isopropylation of the 1-phenyl analog
5g in acetone in the presence of 10% Pd/C furnished the desired N-isopropylated
derivative 25 in 58% yield (Scheme 3).
The structures of novel compounds 17c – 17f, 17h – 17l, 5b – 5l, 18 – 20, 22 and 25
1
were determined by spectroscopic methods (IR, H- and 13C-NMR, and NOESY
spectroscopy, and MS) and by elemental analyses. Compounds 17e, 17f, 5d, 5e, 5h, 18,
20, and 22 were not obtained in analytically pure form. Their identities were confirmed
by 13C-NMR and/or EI-HR-MS. Physical and spectroscopic data for known compounds
10 [14], 13 [15], 17a [17], 17b [18], 17g [15], 5a [19], and 21 [20] were in agreement with
the literature data.
The (E)-configuration of the C¼C bond in the enaminone 13 was determined by
3
1H-NMR on the basis of the vicinal coupling constant, J(2,3) ¼ 12.7 Hz, which was in
agreement with the (E)-configuration. The ꢀregiochemistryꢁ of pyrazoles 17b and 17d
was confirmed by NOESY spectroscopy. The absence of NOE between the 1-alkyl

Helvetica Chimica Acta – Vol. 94 (2011)
1707
Scheme 3
t
group (Me or Bu), and HꢀC(4) and HꢀC(3) was in agreement with the proposed
structure (Fig. 2).
Fig. 2. Coupling constants and NOESY results for 13, 17b and 17d
The structures of compounds 13, 17a, 17j, and 22 were determined by X-ray
crystallography (Figs. 3 – 6).
Conclusions. – In summary, a simple three-step synthesis of 1-substituted 5-(2-
aminophenyl)-1H-pyrazoles 5 as novel conformationally constrained analogs of
histamine was developed. The synthesis comprises condensation of commercially
available 2-nitroacetophenone (12) with DMFDMA to give the enamino ketone 13,
followed by regioselective cyclization with monosubstituted hydrazines 14 to give the 5-
(2-nitrophenyl)-1H-pyrazoles 17. Subsequent reduction of the NO2 group by catalytic
hydrogenation afforded the title compounds 5, in good overall yields. Compounds 17

1708
Helvetica Chimica Acta – Vol. 94 (2011)
Fig. 3. Molecular structure of compound 13. Ellipsoids are plotted at 50% probability level. H-Atoms are
drawn as circles of arbitrary radii.
Fig. 4. Molecular structure of compound 17a. Ellipsoids are plotted at 50% probability level. H-Atoms
are drawn as circles of arbitrary radii.
and 5 are also useful building blocks, which can easily be derivatized, either at the
amino function, or at C(3) and C(4) of the pyrazole ring. In conclusion, this work
represents another useful synthetic application of enaminones as versatile reagents in
the diversity-oriented synthesis of histamine analogs and other functionalized hetero-
cycles.

Helvetica Chimica Acta – Vol. 94 (2011)
1709
Fig. 5. Molecular structure of compound 17j. Ellipsoids are plotted at 50% probability level. H-Atoms
are drawn as circles of arbitrary radii.
Fig. 6. Molecular structure of compound 22. Ellipsoids are plotted at 50% probability level. H-Atoms are
drawn as circles of arbitrary radii.
Experimental Part
1. General. Catalytic hydrogenations: Parr Pressure Reaction Hydrogenation Apparatus 500 ml
3916EF. Column chromatography (CC): silica gel (Fluka, silica gel 60, particle size: 0.035 – 0.070 mm).

1710
Helvetica Chimica Acta – Vol. 94 (2011)
TLC: aluminium sheets, silica gel 60 F254 (Fluka). M.p.: Kofler micro hot stage and Stanford Research
Systems MPA100 OptiMelt automated melting point system; uncorrected. IR Spectra: Perkin-Elmer
1
Spectrum BX FTIR spectrophotometer; in cmꢀ1. H- and 13C-NMR spectra: Bruker Avance DPX 300
instrument (300 and 75.5 MHz, resp.) in (D6)DMSO and CDCl3 with TMS as the internal standard
(¼0 ppm), J in Hz. MS and HR-MS: AutoSpecQ spectrometer; in m/z. Elemental analyses: Perkin-
Elmer CHN Analyser 2400 II.
2. Starting Materials. 2-Aminoacetophenone (6), 2-nitroacetophenone (12), DMFDMA, hydrazines
14a – 14l, and 10% Pd/C are commercially available (SigmaꢀAldrich). 2-(2-Acetylphenyl)-1H-isoindole-
1,3(2H)-dione (7) was prepared from 6 according to the procedure described in [13].
3. Synthesis of Isoindolo[2,1-a]quinoline-5,11-dione (11). A mixture of 7 (2.650 g, 10 mmol), anh.
toluene (15 ml), and DMFDMA (1.5 ml, 10 mmol) was heated under reflux for 3 h. Volatile components
were evaporated in vacuo, and the solid residue was crystallized from AcOEt to give 11. Yield: 2.981 g
(93%). Yellow solid. M.p. 260 – 2638 ([14c]: 260 – 2638). Rf (AcOEt) 0.32. IR (KBr): 3051, 1741 (C¼O),
1648 (C¼O), 1592, 1477, 1407, 1344, 1291, 1269, 1190, 1167, 1138, 1094, 1061, 907, 772, 756, 698, 571.
1H-NMR (CDCl3): 6.74 (s, HꢀC(6)); 7.43 (ddd, J ¼ 0.9, 7.2, 8.0, HꢀC(3)); 7.66 (dt, J ¼ 1.1, 7.4, HꢀC(8));
7.70 – 7.78 (m, HꢀC(7), HꢀC(9)); 7.82 (td, J ¼ 0.8, 7.4, HꢀC(10)); 7.97 (td, J ¼ 0.9, 7.4, HꢀC(4)); 8.30 (dd,
J ¼ 1.4, 8.0, HꢀC(2)); 9.11 (dd, J ¼ 0.4, 8.5, HꢀC(1)).
4. Synthesis of (E)-3-(Dimethylamino)-1-(2-nitrophenyl)prop-2-en-1-one (13). Compound 13 was
prepared according to a slightly modified literature procedure [15a]. A mixture of 12 (3.30 g, 20 mmol),
anh. toluene (20 ml), and DMFDMA (3 ml, 20 mmol) was stirred under reflux for 4 h. Volatile
components were evaporated in vacuo, and the solid residue was crystallized from AcOEt/hexanes to
give 13. Yield: 2.77 g (63%). Yellow solid. M.p. 127 – 1298 ([15a]: 128 – 1298, [15c]: 129 – 1328). Rf
(AcOEt) 0.25. IR (KBr): 3031, 2884, 2806, 1640(C¼O), 1549, 1523, 1142, 1412, 1364, 1243, 1103, 1051,
1
974, 855, 729. H-NMR (CDCl3): 2.87, 3.09 (2s, 1:1, Me2N); 5.27 (d, J ¼ 12.7, HꢀC(2)); 7.45 – 7.65 (m,
C6H4); 7.96 (d, J ¼ 12.7, HꢀC(3)).
5. Preparation of 1-Substituted 5-(2-Nitrophenyl)-1H-pyrazoles 17a – 17d and 17g – 17l. General
Procedure 1 (GP 1). Enaminone 13 (1.10 g, 5 mmol) was added to a stirred suspension of hydrazine
derivative1) 14a – 14d and 14g – 14l (5 mmol) in PrOH (20 ml), and the mixture was stirred under reflux
for 2 – 5 h. Volatile components were evaporated in vacuo, and the solid residue was crystallized from
EtOH/H2O to give 17a – 17d and 17g – 17l.
5.1. 5-(2-Nitrophenyl)-1H-pyrazole (17a). Prepared from 13 (1.100 g, 5 mmol) and 14a (0.335 g,
5 mmol) by GP 1 (reflux for 2.5 h). Yield: 503 mg (53%). Yellowish solid. M.p. 75 – 788 ([17]: 74 – 768).
Rf (AcOEt) 0.57. IR (KBr): 3524, 3292, 1636, 1612, 1523, 1462, 1381, 1068, 953, 772, 745. 1H-NMR
(CDCl3): 6.52 (d, J ¼ 2.4, HꢀC(4)); 7.47 (dt, J ¼ 1.5, 7.9, 1 H, C6H4); 7.60 (dt, J ¼ 1.2, 7.6, 1 H, C6H4); 7.63
(d, J ¼ 2.4, HꢀC(3)); 7.74 (dd, J ¼ 1.4, 7.7, 1 H, C6H4); 7.75 (dd, J ¼ 1.2, 7.9, 1 H, C6H4); 10.70 (br. s,
HꢀN(1)). 13C-NMR (CDCl3): 104.8; 123.7; 127.1; 128.8; 131.0; 132.0; 149.3. ESI-MS: 190 ([M þ H]þ).
HR-ESI-MS: 190.0500 ([M þ H]þ, C9H8N3O2þ ; calc. 190.0617). Anal. calc. for C9H7N3O2 (189.17): C
57.14, H 3.73, N 22.21; found: C 56.90, H 3.63, N 22.06.
5.2. 1-Methyl-5-(2-nitrophenyl)-1H-pyrazole (17b) [18]. Prepared from 13 (1.100 g, 5 mmol), 14b
(0.23 g, 0.265 ml, 5 mmol), and 37% aq. HCl (10 drops, ca. 3 mmol) by GP 1 (reflux for 4 h). Yield:
755 mg (74%). Yellowish solid. M.p. 99 – 1018. Rf (AcOEt) 0.63. IR (KBr): 3408, 3265, 1636, 1614, 1526,
1483, 1362, 1187, 984, 851, 754. 1H-NMR (CDCl3): 3.70 (s, Me); 6.24 (d, J ¼ 1.9, HꢀC(4)); 7.44 (dd, J ¼ 1.5,
7.5, 1 H, C6H4); 7.53 (d, J ¼ 1.9, HꢀC(3)); 7.65 (dd, J ¼ 1.7, 7.7, 1 H, C6H4); 7.72 (dd, J ¼ 1.5, 7.5, 1 H, C6H4);
8.07 (dd, J ¼ 1.4, 8.0, 1 H, C6H4). 13C-NMR (CDCl3): 37.1; 106.9; 124.7; 125.8; 130.4; 132.9; 133.1; 138.2;
138.8; 149.3. ESI-MS: 204 ([M þ H]þ). Anal. calc. for C10H9N3O2þ (203.20): C 59.11, H 4.46, N 20.68;
found: C 58.97, H 4.38, N 20.57.
5.3. 1-Cyclohexyl-5-(2-nitrophenyl)-1H-pyrazole (17c). Prepared from 13 (1.100 g, 5 mmol) and 14c
(573 mg, 5 mmol) by GP 1 (reflux for 5 h). Yield: 595 mg (61%). Yellowish solid. M.p. 60 – 628. Rf
(AcOEt) 0.56. IR (KBr): 3451, 3427, 1607, 1524, 1480, 1437, 1375, 1350, 1281, 1207, 1034, 973, 833, 784,
746. 1H-NMR (CDCl3): 1.08 – 1.33 (m, 3 H, C6H11); 1.67 – 1.68 (m, 1 H, C6H11); 1.76 – 2.07 (m, 6 H,
1
)
Hydrazine hydrochlorides 14a, 14c, 14d, 14g, and 14i – 14l were used. In the case of free hydrazines
14b and 14h, 37% aq. HCl (10 drops, ca. 3 mmol) was also added.

Helvetica Chimica Acta – Vol. 94 (2011)
1711
C6H11); 3.61 – 3.74 (tt, J ¼ 4.2, 11.3, 1 H, C6H11); 6.17 (d, J ¼ 1.9, HꢀC(4)); 7.40 (dd, J ¼ 1.5, 7.5, 1 H, C6H4);
7.57 (d, J ¼ 1.9, HꢀC(3)); 7.64 (dt, J ¼ 1.7, 7.7, 1 H, C6H4); 7.71 (dt, J ¼ 1.5, 7.5, 1 H, C6H4); 8.03 (dd, J ¼ 1.4,
7.9, 1 H, C6H4). 13C-NMR (CDCl3): 25.2; 25.7; 33.1; 58.1; 105.9; 124.5; 126.0; 130.2; 132.8; 132.9; 136.9;
138.6; 149.5. ESI-MS: 272 ([M þ H]þ). HR-ESI-MS: 272.1399 ([M þ H]þ, C15H18N3Oþ2 ; calc. 272.1409).
Anal. calc. for C15H17N3O2 (271.31): C 66.40, H 6.37, N 15.49; found: C 66.32, H 6.37, N 15.46.
5.4. 1-(tert-Butyl)-5-(2-nitrophenyl)-1H-pyrazole (17d). Prepared from 13 (1.100 g, 5 mmol) and 14d
(624 mg, 5 mmol) by GP 1 (reflux for 4.5 h). Yield: 853 mg (70%). Yellowish solid. M.p. 67 – 718. Rf
(AcOEt) 0.64. IR (KBr): 3534, 3466, 2985 1616, 1573, 1528, 1445, 1362, 1261 1130, 924, 853, 781, 755.
1H-NMR (CDCl3): 1.47 (s, t-Bu); 6.07 (d, J ¼ 1.7, HꢀC(4)); 7.47 (dd, J ¼ 1.8, 7.3, 1 H, C6H4); 7.52 (d, J ¼ 1.7,
HꢀC(3)); 7.58 (dt, J ¼ 1.9, 7.5, 1 H, C6H4); 7.63 (dt, J ¼ 1.6, 7.4, 1 H, C6H4); 8.05 (dd, J ¼ 1.7, 7.8, 1 H, C6H4).
13C-NMR (CDCl3): 30.8; 61.7; 108.2; 124.5; 129.4; 130.0; 132.3; 133.3; 136.6; 137.2; 148.9. ESI-MS: 246
([M þ H]þ). HR-ESI-MS: 246.1240 ([M þ H]þ, C13H16N3Oþ2 ; calc. 246.1243). Anal. calc. for C13H15N3O2
(245.28): C 63.66, H 6.16, N 17.1; found: C 63.51, H 6.13, N 16.93.
5.5. 5-(2-Nitrophenyl)-1-phenyl-1H-pyrazole (17g). Prepared from 13 (1.100 g, 5 mmol) and 14g
(536 mg, 5 mmol) by GP 1 (reflux for 2 h). Yield: 951 mg (97%). Yellowish solid. M.p. 120 – 1228 ([15c]:
66 – 708). Rf (33% AcOEt/hexanes) 0.33. IR (KBr): 3410, 3343, 2977, 1648, 1593, 1530, 1495, 1441, 1383,
1337, 1136, 1088, 1049, 808, 756. 1H-NMR (CDCl3): 6.47 (d, J ¼ 1.9, HꢀC(4)); 7.20 – 7.32 (m, Ph); 7.40 (dd,
J ¼ 1.5, 7.5, 1 H, C6H4); 7.55 (dt, J ¼ 1.7, 7.7, 1 H, C6H4); 7.62 (dd, J ¼ 1.5, 7.5, 1 H, C6H4); 7.76 (d, J ¼ 1.9,
HꢀC(3)); 7.90 (dd, J ¼ 1.4, 8.0, 1 H, C6H4). 13C-NMR (CDCl3): 108.5; 124.5; 124.6; 126.0; 127.7; 129.1;
130.0; 132.8; 133.0; 138.0; 139.4; 140.4; 148.8. ESI-MS: 266 ([M þ H]þ). Anal. calc. for C15H11N3O2
(265.27): C 67.92, H 4.18, N 15.84; found: C 67.79, H 4.12, N 15.78.
5.6. 5-(2-Nitrophenyl)-1-(4-nitrophenyl)-1H-pyrazole (17h). Prepared from 13 (1.100 g, 5 mmol),
14h (624 mg, 5 mmol), and 37% aq. HCl (10 drops, ca. 3 mmol) by GP 1 (reflux for 4 h). Yield: 675 mg
(73%). Red-brown solid. M.p. 176 – 1798. Rf (AcOEt) 0.60. IR (KBr): 3468, 3436, 1596, 1520, 1499, 1383,
1349, 853, 751. 1H-NMR (CDCl3): 6.52 (d, J ¼ 1.8, HꢀC(4)); 7.44 (dd, J ¼ 1.5, 7.5, 1 H, C6H4); 7.45 (dt, J ¼
2.2, 9.2, 2 H, C6H4); 7.66 (dt, J ¼ 1.8, 7.6, 1 H, C6H4); 7.71 (dt, J ¼ 1.6, 7.5, 1 H, C6H4); 7.82 (d, J ¼ 1.8,
HꢀC(3)); 8.02 (dd, J ¼ 1.5, 7.8, 1 H, C6H4); 8.17 (dt, J ¼ 2.2, 9.2, 2 H, C6H4). 13C-NMR (CDCl3): 110.5;
124.1; 125.0; 125.3; 125.6; 131.2; 133.0; 133.9; 138.8; 142.0; 144.7; 146.4; 148.9. ESI-MS: 311 ([M þ H]þ).
HR-ESI-MS: 311.0776 ([M þ H]þ, C15H11N4O4þ ; calc. 311.0780). Anal. calc. for C15H10N4Oþ4 (310.26): C
58.07, H 3.25, N 18.06; found: C 57.82, H 3.33, N 17.68.
5.7. 1-(3-Methoxyphenyl)-5-(2-nitrophenyl)-1H-pyrazole (17i). Prepared from 13 and 14i (697 mg,
5 mmol) by GP 1 (reflux for 2 h). Yield: 1.035g (89%). Yellowish solid. M.p. 112 – 1168. Rf (AcOEt) 0.61.
IR (KBr): 3455, 1607, 1525, 1491, 1439, 1377, 1351, 1283, 1210, 1035, 972, 785. 1H-NMR (CDCl3): 3.70 (s,
Me); 6.46 (d, J ¼ 1.9, HꢀC(4)); 6.77 (ddd, J ¼ 0.9, 1.9, 7.9, 1 H, C6H4); 6.82 (ddd, J ¼ 0.9, 2.5, 8.3, 1 H,
C6H4); 6.85 (br. t, J ¼ 2.2, 1 H, C6H4); 7.14 (t, J ¼ 8.1, 1 H, C6H4); 7.40 (dd, J ¼1.5, 7.5, 1 H, C6H4); 7.55 (dt,
J ¼1.7, 7.7, 1 H, C6H4); 7.63 (dd, J ¼1.5, 7.5, 1 H, C6H4); 7.75 (d, J ¼ 1.8, HꢀC(3)); 7.92 (dd, J ¼ 1.4, 8.0, 1 H,
C6H4). 13C-NMR (CDCl3): 55.4; 108.5; 109.9; 113.9; 116.5; 124.5; 126.0; 129.7; 130.0; 132.7; 133.0; 138.0;
140.3; 140.4; 148.8; 160.0. ESI-MS: 296 ([M þ H]þ). Anal. calc. for C16H13N3O3 (295.29): C 65.08, H 4.44,
N 14.23; found: C 65.02, H 4.34, N 14.08.
5.8. 1-(4-Methoxyphenyl)-5-(2-nitrophenyl)-1H-pyrazole (17j). Prepared from 13 (1.100 g, 5 mmol)
and 14j (697 mg, 5 mmol) by GP 1 (reflux for 2 h). Yield: 931 mg (79%). Yellowish solid. M.p. 126 – 1288.
Rf (AcOEt) 0.60. IR (KBr): 3528, 3410, 1636, 1616, 1528, 1515, 1454, 1393, 1340, 1249, 1028, 837, 793, 757.
1H-NMR (CDCl3): 3.77 (s, Me); 6.45 (d, J ¼ 1.9, HꢀC(4)); 6.80 (dt, J ¼ 2.8, 9.0, 2 H, C6H4); 7.16 (dt, J ¼
2.8, 9.0, 2 H, C6H4); 7.39 (dd, J ¼ 1.5, 7.5, 1 H, C6H4); 7.53 (dt, J ¼ 1.7, 7.7, 1 H, C6H4); 7.61 (dt, J ¼ 1.5, 7.5,
1 H, C6H4); 7.73 (d, J ¼ 1.9, HꢀC(3)); 7.89 (dd, J ¼ 1.3, 8.0, 1 H, C6H4). 13C-NMR (CDCl3): 55.5; 108.0;
114.2; 124.5; 126.0; 126.1; 129.9; 132.5; 132.8; 132.9; 138.1; 140.1; 148.9; 159.0. ESI-MS: 296 ([M þ H]þ).
HR-ESI-MS: 296.1033 ([M þ H]þ, C16H14N3O3þ ; calc. 296.1035). Anal. calc. for C16H13N3Oþ3 (295.29): C
65.08, H 4.44, N 14.23; found: 65.08, H 4.36, N 14.20.
5.9. 1-(2-Chlorophenyl)-5-(2-nitrophenyl)-1H-pyrazole (17k). Prepared from 13 (1.100 g, 5 mmol)
and 14k (884 mg, 5 mmol) by GP 1 (reflux for 2.5 h). Yield: 1.116 g (75%). Yellowish solid. M.p. 116 –
1188. Rf (AcOEt) 0.56. IR (KBr): 3497, 3444, 1617, 1524, 1491, 1439, 1383, 1352, 788. 1H-NMR (CDCl3):
6.51 (d, J ¼ 1.9, HꢀC(4)); 7.24 – 7.59 (m, 7 H, C6H4); 7.81 (d, J ¼ 1.9, HꢀC(3)); 7.84 (dd, J ¼ 1.3, 8.0, 1 H,

1712
Helvetica Chimica Acta – Vol. 94 (2011)
C6H4). ESI-MS: 300 ([M þ H]þ). HR-ESI-MS: 300.0542 ([M þ H]þ, C15H11ClN3Oþ2 ; calc. 300.0540).
Anal. calc. for C15H10ClN3O2 (299.71): C 60.16, H 3.36, N 14.02; found: C 59.82, H 3.14, N 13.77.
5.10. 1-(3-Chlorophenyl)-5-(2-nitrophenyl)-1H-pyrazole (17l). Prepared from 13 (1.100 g, 5 mmol)
and 14l (884 mg, 5 mmol) by GP 1 (reflux for 2.5 h). Yield: 1.209 mg (81%). Yellowish solid. M.p. 95 –
978. Rf (AcOEt) 0.54. IR (KBr): 3516, 3410, 1619, 1593, 1528, 1485, 1428, 1373, 1356, 872, 793. 1H-NMR
(CDCl3): 6.47 (d, J ¼ 1.8, HꢀC(4)); 7.09 (dt, J ¼ 1.7, 7.6, 1 H, C6H4); 7.18 (t, J ¼ 7.8, 1 H, C6H4); 7.26 (dt, J ¼
1.6, 8.1, 1 H, C6H4); 7.32 (t, J ¼ 1.9, 1 H, C6H4); 7.40 (dd, J ¼ 1.7, 7.4, 1 H, C6H4); 7.59 (dt, J ¼ 1.7, 7.7, 1 H,
C6H4); 7.66 (dt, J ¼ 1.5, 7.5, 1 H, C6H4); 7.76 (d, J ¼ 1.8, HꢀC(3)); 7.96 (dd, J ¼ 1.4, 7.9, 1 H, C6H4).
13C-NMR (CDCl3): 109.0; 122.3; 124.7; 124.8; 125.7; 127.8; 130.0; 130.3; 132.8; 133.2; 134.8; 138.2; 140.5;
140.9; 148.8. ESI-MS: 300 ([M þ H]þ). HR-ESI-MS: 300.0543 ([M þ H]þ, C15H11ClN3Oþ2 ; calc.
300.0540). Anal. calc. for C15H10ClN3O2 (299.71): C 60.11, H 3.36, N 14.02; found: C 60.00, H 3.30, N
13.94.
6. Preparation of 1-Substituted 5-(2-Nitrophenyl)-1H-pyrazoles 17e and 17f. General Procedure 2
(GP 2). Enaminone 13 (1.100 g, 5 mmol) was added to a stirred suspension of hydrazine derivative2) 14
(5 mmol) in PrOH (20 ml), and the mixture was stirred under reflux for 2 – 5 h. Volatile components
were evaporated in vacuo, and the oily residue was purified by CC (AcOEt). Fractions containing the
product were combined and evaporated in vacuo to give 17e and 17f.
6.1. 1-(2-Hydroxyethyl)-5-(2-nitrophenyl)-1H-pyrazole (¼2-[5-(2-Nitrophenyl)-1H-pyrazol-1-yl]-
ethanol; 17e). Prepared from 13 (1.100 g, 5 mmol) and 14e (380 mg, 5 mmol) by GP 2 (reflux for 4 h).
Yield: 753 mg (69%). Yellow oil. Rf (AcOEt) 0.43. IR (NaCl): 3356, 2945, 1615, 1573, 1528, 1406, 1349,
1
1063, 852, 786, 752. H-NMR (CDCl3): 3.47 (br. t, J ¼ 5.6, OH); 3.92 – 3.98 (m, CH2); 4.00 – 4.05 (m,
CH2); 6.26 (d, J ¼ 1.9, HꢀC(4)); 7.45 (dd, J ¼ 1.6, 7.4, 1 H, C6H4); 7.59 (d, J ¼ 1.9, HꢀC(3)); 7.66 (dd, J ¼
1.7, 7.7, 1 H, C6H4); 7.72 (dtd, J ¼1.5, 7.5, 1 H, C6H4); 8.05 (dd, J ¼ 1.4, 8.0, 1 H, C6H4). 13C-NMR (CDCl3):
51.3; 61.5; 106.7; 124.6; 125.3; 130.6; 133.1; 138.7; 139.2; 149.3; 162.4. EI-MS: 233 (Mþ). HR-EI-MS:
233.0810 (Mþ, C11H11N3Oþ3 ; calc. 233.0800).
6.2. 1-(2-Ethoxy-2-oxoethyl)-5-(2-nitrophenyl)-1H-pyrazole (¼ Ethyl [5-(2-Nitrophenyl)-1H-pyra-
zol-1-yl]acetate; 17f). Prepared from 13 (1.100 g, 5 mmol) and 14f (779 mg, 5 mmol) by GP 2 (reflux for
2 h). Yield: 1.146 g (83%). Brownish oil. Rf (AcOEt) 0.61. IR (NaCl): 3458, 3104, 2984, 1715, 1616, 1573,
1
1530, 1478, 1458, 1407, 1351, 1203, 1025, 928, 852, 787, 750. H-NMR (CDCl3): 1.22 (t, J ¼ 7.1, CH2Me);
4.15 (q, J ¼ 7.1, CH2Me); 4.76 (s, CH2COOEt); 6.29 (d, J ¼ 1.9, HꢀC(4)); 7.52 (dd, J ¼ 1.8, 7.2, 1 H, C6H4);
7.61 (d, J ¼ 1.9, HꢀC(3)); 7.64 (dt, J ¼ 1.9, 7.4, 1 H, C6H4); 7.69 (dt, J ¼ 1.7, 7.5, 1 H, C6H4); 8.02 (dd, J ¼ 1.6,
7.7, 1 H, C6H4). 13C-NMR (CDCl3): 14.2; 51.3; 61.9; 107.7; 124.4; 124.9; 130.7; 132.9; 133.4; 138.7; 139.8;
149.4; 167.8. EI-MS: 275 (Mþ). HR-EI-MS: 275.0913 (Mþ, C13H13N3Oþ4 : 275.0906).
7. Reduction of 1-Substituted 5-(2-Nitrophenyl)-1H-pyrazoles 17. General Procedure for the
Preparation of 1-Substituted 5-(2-Aminophenyl)-1H-pyrazoles 5a, 5c – 5e, and 5g – 5j. A mixture of
17a, 17c – 17e, and 17g – 17j (1 mmol), EtOH (10 ml), and 10% Pd/C (100 mg) was hydrogenated (3 bar
of H2) at r.t. for 3 h. The catalyst was removed by filtration through a fritted funnel, washed with EtOH
(5 ml), and the combined filtrate was evaporated in vacuo to give 5a, 5c – 5e, and 5g – 5j. Amine 5c was
dissolved in EtOH (3 ml), and a 3.6m soln. of HCl in Et2O (10 ml) was added. The precipitate was
collected by filtration to give 5c hydrochloride.
7.1. 5-(2-Aminophenyl)-1H-pyrazole (¼2-(1H-Pyrazol-5-yl)benzenamine; 5a). Prepared from 17a
(189 mg, 1 mmol). Yield: 149 mg (94%). White solid. M.p. 124 – 1268 (from EtOH/H2O) ([18]: 122 –
1238). Rf (AcOEt) 0.59. IR (KBr): 3407, 3266, 3177, 1607, 1591, 1530, 1507, 1470, 1446, 1350, 1309,
1194, 1153, 1065, 1039, 947, 765. 1H-NMR ((D6)DMSO): 6.29 (s, NH2); 6.55 (dt, J ¼ 1.1, 7.4, 1 H, C6H4);
6.68 (d, J ¼ 1.8, HꢀC(4)); 6.71 (dd, J ¼ 0.9, 8.1, 1 H, C6H4); 6.97 (dt, J ¼ 1.4, 7.6, 1 H, C6H4); 7.50 (dd, J ¼
1.3, 7.8, 1 H, C6H4); 7.78 (d, J ¼ 2.3, HꢀC(3)); 12.83 (s, HꢀN(1)). 13C-NMR ((D6)DMSO): 102.1; 115.4;
115.5; 115.6; 127.8; 128.9; 145.6; 145.7; 151.5. EI-MS: 159 (Mþ). HR-EI-MS: 159.0796 (Mþ, C9H9N3þ ; calc.
159.0803). Anal. calc. for C9H9N3 · 1/8 H2O (159.19): C 66.96, H 5.78, N 26.03; found: C 66.94, H 5.54, N
26.14.
7.2. 5-(2-Aminophenyl)-1-cyclohexyl-1H-pyrazole Hydrochloride (¼2-(1-Cyclohexyl-1H-pyrazol-5-
yl)benzenamine Hydrochloride; 5c · HCl). Prepared from 17c (271m g, 1 mmol). Yield: 196 mg (62%).
2
)
Hydrazine hydrochlorides 14e and 14f were used.

Helvetica Chimica Acta – Vol. 94 (2011)
1713
Beige solid. M.p. 124 – 1268. Rf (AcOEt) 0.57. IR (KBr): 3473, 3419, 3146, 1622, 1597, 1550, 1513, 1494,
1
1472, 1406, 1254, 1192, 1164, 919, 808, 772. H-NMR ((D6)DMSO): 0.93 (m, 4 H, C6H11); 1.61 (m, 6 H,
C6H11); 3.60 (m, 1 H, C6H11); 5.68 (br. s, NH3þ); 6.29 (d, J ¼ 1.8, HꢀC(4)); 6.97 – 7.06 (m, 2 H, C6H4); 7.15
(br. d, J ¼ 7.9, 1 H, C6H4); 7.19 – 7.27 (m, 1 H, C6H4); 7.38 (d, J ¼ 1.8, HꢀC(3)). 13C-NMR ((D6)DMSO):
24.9; 25.1; 33.0; 57.5; 107.6; 124.4; 124.7; 128.0; 130.3; 131.2; 131.5; 136.1; 137.7. EI-MS: 241 (Mþ). HR-EI-
MS: 241.1584 (Mþ, C15H19N3þ ; calc. 241.1579). Anal. calc. for C15H19N3 · 2 HCl (314.25) C 57.33, H 6.74, N
13.37; found: C 57.64, H 6.84, N 13.38.
7.3. 5-(2-Aminophenyl)-1-(tert-butyl)-1H-pyrazole (¼2-[1-(tert-Butyl)-1H-pyrazol-5-yl]benzen-
amine; 5d). Prepared from 17d (245 mg, 1 mmol). Yield: 197 mg (92%). Beige solid. M.p. 119 – 1238
(from EtOH/H2O). Rf (AcOEt) 0.65. IR (KBr): 3458, 3317, 3198, 2990, 2970, 1628, 1574, 1532, 1485,
1452, 1344, 1310, 1236, 1126, 974, 787, 756. 1H-NMR ((D6)DMSO): 1.41 (s, t-Bu); 4.57 (s, NH2); 6.08 (d,
J ¼ 1.7, HꢀC(4)); 6.59 (dt, J ¼ 1.1, 7.4, 1 H, C6H4); 6.71 (dd, J ¼ 0.9, 8.1, 1 H, C6H4); 6.95 (dd, J ¼ 1.5, 7.5,
1 H, C6H4); 7.11 (dt, J ¼ 1.6, 7.8, 1 H, C6H4); 7.46 (d, J ¼ 1.7, HꢀC(3)). 13C-NMR ((D6)DMSO): 30.0; 60.4;
108.3; 114.4; 115.5; 117.6; 129.5; 131.1; 136.6; 138.7; 146.8. EI-MS: 215 (Mþ). HR-EI-MS: 215.1422 (Mþ,
C13H17Nþ3 ; calc. 215.1430). Anal. calc. for C13H17N3 · 1/3 H2O (215.29): C 70.56, H 8.05, N 18.99; found: C
70.78, H 7.76, N 18.99.
7.4. 5-(2-Aminophenyl)-1-(2-hydroxyethyl)-1H-pyrazole (¼2-[5-(2-Aminophenyl)-1H-pyrazol-1-
yl]ethanol; 5e). Prepared from 17e (233 mg, 1 mmol). Yield: 194 mg (95%). White solid. M.p. 123 –
1268. Rf (AcOEt) 0.17. IR (KBr): 3456, 3343, 3217, 1634, 1575, 1487, 1453, 1395, 1312, 1217, 1136, 1055,
1
935, 758. H-NMR ((D6)DMSO): 3.67 (q, J ¼ 6.1, CH2CH2OH); 3.93 (t, J ¼ 6.3, CH2CH2OH); 4.79 (s,
NH2); 4.81 (br. s, OH); 6.22 (d, J ¼ 1.8, HꢀC(4)); 6.62 (dt, J ¼ 1.1, 7.4, 1 H, C6H4); 6.77 (dd, J ¼ 0.9, 8.1,
1 H, C6H4); 7.01 (dd, J ¼ 1.5, 7.6, 1 H, C6H4); 7.12 (dt, J ¼ 1.6, 7.7, 1 H, C6H4); 7.53 (d, J ¼ 1.8, HꢀC(3)).
13C-NMR ((D6)DMSO): 50.9; 59.9; 105.8; 114.3; 115.0; 116.0; 129.7; 130.9; 138.5; 140.5; 146.6. EI-MS:
203 (Mþ). HR-EI-MS: 203.1065 (Mþ, C11H13N3Oþ; calc. 203.1059). Anal. calc. for C11H13N3O · 1ꢄ4 H2O
(203.24): C 63.60, H 6.55, N 20.23; found: C 63.57, H 6.26, N 20.24.
7.5. 5-(2-Aminophenyl)-1-phenyl-1H-pyrazole (¼2-(1-Phenyl-1H-pyrazol-5-yl)benzenamine; 5g).
Prepared from 17g (265 mg, 1 mmol). Yield: 218 mg (93%). White solid. M.p. 100 – 1038. Rf (AcOEt)
0.73. IR (KBr): 3462, 3373, 1614, 1600, 1487, 1456, 1384, 1306, 1228, 1135, 959, 919, 797, 763, 692. 1H-NMR
((D6)DMSO): 4.86 (s, NH2); 6.47 (dt, J ¼ 1.1, 7.4, 1 H, C6H4); 6.52 (d, J ¼ 1.8, HꢀC(4)); 6.71 (dd, J ¼ 0.8,
8.1, 1 H, C6H4); 6.75 (dd, J ¼ 1.5, 7.6, 1 H, C6H4); 7.05 (ddd, J ¼ 1.6, 7.4, 8.1, 1 H, C6H4); 7.22 – 7.37 (m, Ph);
7.77 (d, J ¼ 2.3, HꢀC(3)). 13C-NMR ((D6)DMSO): 108.4; 114.5; 114.9; 115.9; 123.8; 126.9; 128.7; 129.6;
130.7; 139.8; 139.9; 140.1; 146.4. EI-MS: 235 (Mþ). HR-EI-MS: 235.1115 (Mþ, C15H13N3þ ; calc.
1235.1109). Anal. calc. for C15H13N3 (235.28): C 76.57, H 5.57, N 17.86; found: C 76.30, H 5.40, N 17.77.
7.6. 5-(2-Aminophenyl)-1-(4-aminophenyl)-1H-pyrazole (¼2-[1-(4-Aminophenyl)-1H-pyrazol-5-
yl]benzenamine; 5h). Prepared from 17h (310 mg, 1 mmol). Yield: 220 mg (88%). Gray solid. M.p.
194 – 1978. Rf (AcOEt) 0.42. IR (KBr): 3375, 2863, 2588, 1626, 1568, 1514, 1450, 1389, 1138, 964, 832, 766.
1H-NMR ((D6)DMSO): 4.76, 5.16 (2s, 1:1, 2 NH2); 6.42 (d, J ¼ 1.8, HꢀC(4)); 6.44 (dt, J ¼ 2.4, 8.8, 2 H, p-
C6H4); 6.47 (br. dt, J ¼ 1.1, 7.8, 1 H, o-C6H4); 6.68 (dd, J ¼ 0.9, 8.1, 1 H, o-C6H4); 6.73 (dd, J ¼ 1.5, 7.6, 1 H,
o-C6H4); 6.91 (dt, J ¼ 2.4, 8.8, 2 H, p-C6H4); 7.01 (ddd, J ¼ 1.6, 7.6, 8.1, 1 H, o-C6H4); 7.65 (d, J ¼ 1.8,
HꢀC(3)). 13C-NMR ((D6)DMSO): 109.8; 122.5; 122.6; 123.5; 125.4; 126.0; 130.1; 131.6; 133.9; 137.6;
138.5; 140.4; 142.1. EI-MS: 250 (Mþ). HR-EI-MS: 250.1219 (Mþ, C15H14Nþ4 ; calc. 250.1218).
7.7. 5-(2-Aminophenyl)-1-(3-methoxyphenyl)-1H-pyrazole (¼2-[1-(3-Methoxyphenyl)-1H-pyrazol-
5-yl]benzenamine; 5i). Prepared from 17i (295 mg, 1 mmol). Yield: 251 mg (95%). Beige solid. M.p. 80 –
838 (from EtOH/H2O). Rf (AcOEt) 0.61. IR (KBr): 3443, 3319, 3219, 1611, 1577, 1536, 1491, 1462, 1435,
1379, 1290, 1221, 1041, 968, 929, 800, 756. 1H-NMR ((D6)DMSO): 3.62 (s, MeO); 4.85 (s, NH2); 6.50 (dt,
J ¼ 1.2, 7.3, 1 H, C6H4); 6.51 (d, J ¼ 1.8, HꢀC(4)); 6.72 (dd, J ¼ 0.9, 8.1, 1 H, C6H4); 6.78 (dd, J ¼ 1.4, 7.5,
1 H, C6H4); 6.82 (ddd, J ¼ 0.8, 2.5, 8.3, 1 H, C6H4); 6.88 (dd, J ¼ 1.4, 2.6, 1 H, C6H4); 6.89 (ddd, J ¼ 1.4, 2.5,
10.9, 1 H, C6H4); 7.07 (ddd, J ¼ 1.6, 7.3, 8.2, 1 H, C6H4); 7.22 (dt, J ¼ 0.6, 8.1, 1 H, C6H4); 7.77 (d, J ¼ 1.8,
HꢀC(3)). 13C-NMR ((D6)DMSO): 55.0; 108.6; 109.2; 112.6; 114.7; 114.9; 115.7; 116.0; 129.4; 129.7;
130.7; 139.9; 140.0; 140.9; 146.5; 159.1. EI-MS: 265 (Mþ). HR-EI-MS: 265.1221 (Mþ, C16H15N3Oþ; calc.
265.1215). Anal. calc. for C16H15N3O (265.31): C 72.43, H 5.70, N 15.84; found: C 72.05, H 5.53, N 15.64.
7.8. 5-(2-Aminophenyl)-1-(4-methoxyphenyl)-1H-pyrazole (¼2-[1-(4-Methoxyphenyl)-1H-pyrazol-
5-yl]benzenamine; 5j). Prepared from 17j (295 mg, 1 mmol). Yield: 265 mg (100%). White solid. M.p.

1714
Helvetica Chimica Acta – Vol. 94 (2011)
113 – 1158 (from EtOH/H2O). Rf (AcOEt) 0.58. IR (KBr): 3464, 3368, 3233, 1616, 1578, 1516, 1487, 1440,
1387, 1302, 1246, 1179, 1023, 926, 837, 751. 1H-NMR ((D6)DMSO): 3.73 (s, Me); 4.83 (s, NH2); 6.47 (dt,
J ¼ 1.1, 7.9, 1 H, C6H4); 6.48 (d, J ¼ 1.9, HꢀC(4)); 6.69 (dd, J ¼ 0.8, 8.1, 1 H, C6H4); 6.75 (dd, J ¼ 1.5, 7.6,
1 H, C6H4); 6.88 (dt, J ¼ 2.8, 9.0, 2 H, C6H4); 7.04 (dt, J ¼ 1.6, 8.3, 1 H, C6H4); 7.21 (dt, J ¼ 2.8, 9.0, 2 H,
C6H4); 7.72 (d, J ¼ 1.8, HꢀC(3)). 13C-NMR ((D6)DMSO): 55.2; 107.8; 113.8; 114.5; 114.9; 115.9; 125.4;
129.5; 130.7; 133.1; 139.6; 139.7; 146.4; 158.0. EI-MS: 265 (Mþ). HR-EI-HR: 265.1222 (Mþ, C16H15N3Oþ;
calc. 265.1215). Anal. calc. for C16H15N3O (265.31): C 72.43, H 5.70, N 15.84; found: C 72.15, H 5.51, N
15.83.
8. Synthesis of 4-Bromo-5-(2-nitrophenyl)-1-phenyl-1H-pyrazole (18). A soln. of Br2 (2m in AcOH,
1 ml, 2 mmol) was added to a stirred soln. of 17g (265 mg, 1 mmol) in AcOH (100%, 2 ml), and the
mixture was stirred at r.t. for 48 h. Volatile components were evaporated in vacuo, and the residue was
purified by CC (20% AcOEt/hexanes). Fractions containing the product were combined and evaporated
in vacuo to give 18. Yield: 291 mg (85%). Yellow oil. Rf (20%AcOEt/hexanes) 0.27. IR (NaCl): 3098,
3068, 2922, 2867, 1596, 1528, 1498, 1385, 1349, 1070, 952, 852, 756. 1H-NMR (CDCl3): 7.20 – 7.29 (m, Ph);
7.38 (dd, J ¼ 1.8, 7.3, 1 H, C6H4); 7.59 (dt, J ¼ 1.7, 7.6, 1 H, C6H4); 7.66 (dt, J ¼ 1.6, 7.5, 1 H, C6H4); 7.76 (s,
HꢀC(3)); 8.06 (br. dd, J ¼ 1.5, 7.9, 1 H, C6H4). 13C-NMR (CDCl3): 96.7; 124.4; 124.5; 125.3; 128.3; 129.4;
130.9; 133.5; 133.7; 137.4; 139.5; 141.1; 148.9. ESI-MS: 344 ([M þ H]þ). HR-ESI-MS: 344.0044 ([M þ
H]þ, C15H10BrN3Oþ2 ; calc. 344.0035).
9. Synthesis of 3-Nitro-5-(2-nitrophenyl)-1-phenyl-1H-pyrazole (19) and Its 4-Nitro Isomer 20. Conc.
HNO3 (65%, 0.4 ml) was added to a stirred soln. of 17g (265 mg, 1 mmol) in Ac2O (2.5 ml) at ꢀ 58. The
mixture was stirred at r.t. for 12 h, poured on crushed ice (ca. 75 g), and then left at r.t., until all the ice
had melted. The product was extracted with CH2Cl2 (3 ꢁ 20 ml), the combined org. phases were washed
with sat. aq. NaHCO3 (2 ꢁ 20 ml), dried (Na2SO4), filtered, and the filtrate was evaporated in vacuo to
give a mixture of regioisomers 19 and 20, which were separated by CC (33% AcOEt/hexanes). Fractions
containing the products were combined and evaporated in vacuo to give 19 and 20.
9.1. 3-Nitro-5-(2-nitrophenyl)-1-phenyl-1H-pyrazole (19). Yield: 170 mg (55%). Yellow solid. M.p.
118 – 1308. Rf (33% AcOEt/hexanes) 0.32. IR (NaCl): 3149, 2925, 2855, 1595, 1574, 1529, 1497, 1455, 1411,
1
1374, 1337, 1252, 1204, 1089, 1075, 999, 972, 912, 853, 827, 766, 751, 732, 689. H-NMR (CDCl3): 7.08 (s,
HꢀC(4)); 7.22 – 7.36 (m, Ph); 7.51 (dd, J ¼ 1.7, 7.3, 1 H, C6H4); 7.66 (dt, J ¼ 1.6, 7.6, 1 H, C6H4); 7.74 (dt, J ¼
1.5, 7.5, 1 H, C6H4); 8.02 (dd, J ¼ 1.3, 8.0, 1 H, C6H4). 13C-NMR (CDCl3): 104.3; 123.7; 125.1; 125.4; 129.6;
129.6; 131.7; 133.1; 134.1; 138.1; 141.7; 148.4; 156.5. ESI-MS: 333 ([M þ Na]þ), 311 ([M þ H]þ). Anal.
calc. for C15H10N4O4 (310.26): C 58.07, H 3.25, N 18.06; found: C 57.94, H 3.09, N 17.88.
9.2. 4-Nitro-5-(2-nitrophenyl)-1-phenyl-1H-pyrazole (20). Yield: 99 mg (32%). Yellow oil. Rf (33%
AcOEt/hexanes) 0.38. IR (NaCl): 3127, 2924, 1617, 1595, 1558, 1529, 1504, 1458, 1399, 1348, 1325, 1201,
1
1087, 1008, 955, 912, 854, 826, 788, 765, 731, 709, 692. H-NMR (CDCl3): 7.25 – 7.35 (m, Ph, 1 H, C6H4);
7.59 – 7.68 (m, 2 H, C6H4); 8.19 – 8.24 (m, 1 H, C6H4); 8.38 (s, HꢀC(4)). 13C-NMR (CDCl3): 122.6; 124.7;
125.0; 125.1; 125.3; 129.3; 131.4; 132.3; 133.7; 137.1; 137.7; 137.9; 148.4. ESI-MS: 333 ([M þ Na]þ), 311
([M þ H]þ). HR-ESI-MS: 311.0785 ([M þ H]þ, C15H10N4Oþ4 ; calc. 311.0780).
10. Synthesis of 5,6-Dihydropyrazolo[1,5-c]quinazolines 21 and 22. A mixture of 5 (1 mmol), EtOH
(10 ml), 10% Pd/C (20 mg), and acetone or cyclopentanone (2 ml) was hydrogenated (3 bar of H2) at r.t.
for 5 h. The catalyst was removed by filtration through a fritted funnel and washed with EtOH (2 ꢁ 5 ml).
The combined filtrate was evaporated in vacuo to give 21 and 22.
10.1. 5,6-Dihydro-5,5-dimethylpyrazolo[1,5-c]quinazoline (21) [20]. Prepared from 5a (159 mg,
1 mmol) and acetone. Yield: 187 mg (94%). White solid. M.p. 104 – 1068 ([20]: 1168). Rf (AcOEt) 0.60.
IR (KBr): 3370, 3251, 3217, 1614, 1587, 1503, 1480, 1383, 1311, 1270, 1196, 1050, 785, 757. 1H-NMR
(CDCl3): 1.73 (s, CHMe2); 4.31 (s, HꢀN(6)); 6.48 (d, J ¼ 1.9, HꢀC(1)); 6.70 (br. d, J ¼ 8.0, HꢀC(7)); 6.85
(br. t, J ¼ 7.2, HꢀC(9)); 7.12 (dt, J ¼ 1.3, 7.9, HꢀC(8)); 7.44 (br. d, J ¼ 7.6, HꢀC(10)); 7.53 (d, J ¼ 1.8,
HꢀC(2)). 13C-NMR (CDCl3): 28.0; 72.3; 99.9; 114.9; 115.5; 119.9; 124.1; 129.3; 136.5; 139.3; 139.4. EI-
MS: 200 ([M þ H]þ). HR-ESI-MS: 200.1176 ([M þ H]þ, C12H14N3þ ; calc. 200.1188). Anal. calc. for
C12H13N3 · 1/10 H2O (199.25): C 71.69, H 6.62, N 21.09; found: C 71.67, H 6.42, N 21.00.
10.2. 6’H-Spiro[cyclopentane-1,5’(6’H)-pyrazolo[1,5-c]quinazoline] (22). Prepared from 5a (159 mg,
1 mmol) and cyclopentanone. Yield: 227 mg (83%). White solid. M.p. 75 – 778. Rf (AcOEt) 0.68. IR
(KBr): 3289, 2957, 2872, 1616, 1590, 1550, 1496, 1480, 1436, 1379, 1333, 1306, 1264, 1196, 1155, 1097, 1042,

Helvetica Chimica Acta – Vol. 94 (2011)
1715
999, 954, 928, 779, 750. 1H-NMR (CDCl3): 1.72 – 1.84 (m, 2 H, cyclopent.); 1.86 – 1.99 (m, 4 H,
cyclopent.); 2.42 – 2.55 (m, 2 H, cyclopent.); 4.33 (br. s, HꢀC(6’)); 6.49 (d, J ¼ 1.8, HꢀC(1’)); 6.73 (br. d,
J ¼ 8.0, HꢀC(7’)); 6.87 (br. t, J ¼ 7.2, HꢀC(9’)); 7.12 (dt, J ¼ 1.2, 7.9, HꢀC(8’)); 7.44 (br. d, J ¼ 7.6,
HꢀC(10’)); 7.50 (d, J ¼ 1.8, HꢀC(2’)). 13C-NMR (CDCl3): 24.1; 38.7; 82.5; 100.2; 115.8; 115.9; 120.2;
124.1; 129.1; 137.2; 139.3; 139.7. ESI-MS: 226 ([M þ H]þ). HR-ESI-MS: 226.1337 ([M þ H]þ, C14H16N3þ ;
calc. 226.1344). Anal. calc. for C14H15N3 · 1/3 H2O (225.29): C 72.70, H 6.83, N 18.17; found: C 72.78, H
6.64, N 18.21.
11. Synthesis of 5-[2-(Isopropylamino)phenyl]-1-phenyl-1H-pyrazole (¼ N-(1-Methylethyl)-2-(1-
phenyl-1H-pyrazol-5-yl)benzenamine; 25) Solvate with Hexane. A mixture of 5g (235 mg, 1 mmol),
acetone (25 ml), and 10% Pd/C (70 mg) was hydrogenated (3 bar of H2) at r.t. for 24 h. The catalyst was
removed by filtration through a fritted funnel and washed with acetone (2 ꢁ 10 ml). The combined
filtrate was evaporated in vacuo, and the residue was purified by CC (20% AcOEt/hexanes). Fractions
containing the product were combined and evaporated in vacuo to give 25. Yield: 161 mg (58%) of
yellowish solid. M.p. 84 – 888. Rf (20% AcOEt/hexanes) 0.43. IR (KBr): 3450, 2963, 2926, 1636, 1498,
1458, 1379, 1318, 1261, 1176, 1096, 958, 924, 912, 796, 764, 754. 1H-NMR (CDCl3): 0.88 (m, 2.2 H, 2 Me of
hexane); 0.96 (d, J ¼ 6.2, CHMe2); 1.26 (m, 3 H, 4 Me of hexane); 3.53 (sept., J ¼ 6.2, CHMe2); 3.66 (br. s,
NH); 6.46 (d, J ¼ 1.8, HꢀC(4)); 6.58 (dt, J ¼ 1.1, 7.4, 1 H, C6H4); 6.60 (dd, J ¼ 1.3, 8.5, 1 H, C6H4); 6.96 (dd,
J ¼ 1.6, 7.7, 1 H, C6H4); 7.18 – 7.35 (m, Ph, 1 H, C6H4); 7.78 (d, J ¼ 1.8, HꢀC(3)). 13C-NMR (CDCl3): 14.3
(2 Me of hexane); 22.5, 22.8 (2 CH2 of hexane); 30.1 (2 CH2 of hexane); 43.5; 108.8; 111.0; 115.7; 116.1;
123.4; 126.9; 128.7; 130.2; 131.2; 139.9; 140.0; 140.6; 145.1. ESI-MS: 278 ([M þ H]þ). HR-ESI-MS:
278.1646 ([M þ H]þ, C18H20N3þ ; calc. 278.1657). Anal. calc. for C18H19N3 · 3/8 hexane (277.36) C 78.54, H
7.89, N 13.57; found: C 78.72, H 7.58, N 13.18.
Table 2. Crystal Data, Data Collection, and Structure Refinement for Compounds 13, 17a, 17j, and 22
13
17a
17j
22
Formula
Rel. formula weight
Crystal system
Space group
a [ꢅ]
b [ꢅ]
c [ꢅ]
b [8]
V [ꢅ3]
C11H12N2O3
220.23
C9H7N3O2
189.17
C16H13N3O3
295.30
C14H15N3
225.29
Orthorhombic
P212121, No. 19
7.4332(2)
11.8131(2)
12.6750(2)
90.00
1112.98(4)
4
1.314
Monoclinic
P21/n, No. 14
11.4686(3)
5.1831(1)
5.9689(4)
110.348(1)
890.00(4)
4
1.412
0.104
293(2)
27.5
Orthorhombic
Pna21, No. 33
17.5869(4)
12.1416(2)
6.6759(1)
90.00
1425.53(5)
4
1.376
Trigonal
ꢀ
R3, No. 148
31.9814(5)
31.9814(5)
6.6003(1)
90
5846.4(2)
18
1.150
0.071
293(2)
27.5
Z
Dx [Mg mꢀ3
]
m [mmꢀ1
T [K]
]
0.097
293(2)
26.4
0.098
293(2)
27.5
qmax [8]
Integrated refl.
Rint
30494
0.031
16320
0.028
16994
0.035
37197
0.036
Independent refl.
Observed refl.
Threshold criterion
Refinement on
No. of contrib. refl.
No. of parameters
Final R, Rw
1311
1256
F2 > 2.0s(F2)
F
1296
145
0.044, 0.031
0.16, ꢀ 0.23
2021
1592
F2 > 2.0s(F2)
F
1869
127
0.044, 0.043
0.19, ꢀ 0.22
1768
1485
F2 > 2.0s(F2)
F
1674
199
0.045, 0.028
0.24, ꢀ 0.33
2966
2199
F2 > 2.0s(F2)
F
2705
158
0.083, 0.056
0.50, ꢀ 0.62
D1max, D1min [e ꢅꢀ3
]

1716
Helvetica Chimica Acta – Vol. 94 (2011)
12. X-Ray Crystal-Structure Analysis for Compounds 13, 17a, 17j, and 22. Single-crystal X-ray
diffraction data of compounds 13, 17a, 17j, and 22 were collected at r.t. on a Nonius Kappa CCD
diffractometer using the Nonius Collect Software [21]. DENZO and SCALEPACK [22] were used for
indexing and scaling of the diffraction data. All structures were solved by direct methods using SIR97
[23] and refined by Xtal3.6 [24] program package. Structures were refined on F values using the full-
matrix least-squares procedure. Some of the positions of H-atoms were obtained from difference Fourier
map, and some were geometrically calculated. The non-H-atoms were refined anisotropically, while the
positional and isotropic atomic displacement parameters of H-atoms were not refined. The resulting
crystal data, and details concerning data collection and refinement for all four compounds are compiled
in Table 2. The structure 22 is slightly disordered. This is reflected mainly in the fact that most of the
solvent (CHCl3) molecules left the structure. They were originally positioned in the channels parallel to c
axis. Crystallographic data (excluding structure factors) for compounds 13, 17a, 17j, and 22 have been
deposited with the Cambridge Crystallographic Data Centre as supplementary publication Nos. CCDC
788696 – 788699, resp. Copies of the data can be obtained, free of charge, on application to CCDC, 12
Union Road, Cambridge, CB21EZ, UK [fax: þ 44(0)-1223-336033 or e-mail: deposit@ccdc.cam.ac.uk.
We gratefully acknowledge the financial supports from Boehringer-Ingelheim Pharma GmbH & Co.
KG (D-Biberach) and Slovenian Research Agency, grants P1-0179 and J1-0972.
REFERENCES
[1] G. L. Patrick, in ꢀAn Introduction to Medicinal Chemistryꢁ, 3rd edn., Oxford University Press,
Oxford, 2005; Y. Kazuta, K. Hirano, K. Natsume, S. Yamada, R. Kimura, S.-i. Matsumoto, K.
Furuichi, A. Matsuda, S. Shuto, J. Med. Chem. 2003, 46, 1980; J. Liebscher, M. Pꢆtzel, Synlett 1994,
471; M. Pullagurla, M. Dukat, B. L. Roth, V. Setola, R. A. Glennon, Med. Chem. Res. 2005, 14, 1; M.
Paillet-Loilier, F. Fabis, A. Lepailleur, R. Bureau, S. Butt-Gueulle, F. Dauphin, A. Lesnard, C.
Delarue, H. Vaudry, S. Rault, Bioorg. Med. Chem. Lett. 2007, 17, 3018.
[2] L. Yet, in ꢀPyrazolesꢁ, in ꢀComprehensive Heterocyclic Chemistry IIIꢁ, Eds. A. R. Katritzky, C. A.
Ramsden, E. F. V. Scriven, R. J. K. Taylor, Vol. 4, Ed. J. Joule, Elsevier Science, Oxford, 2008, p. 1,
and refs. cit. therein; B. Stanovnik, J. Svete, in ꢀPyrazolesꢁ, in ꢀScience of Synthesis, Houben-Weyl
Methods of Organic Transformationsꢁ, Vol. 12, Ed. R. Neier, Georg Thieme Verlag, Stuttgart, 2002,
ˇ
p. 15 – 225, and refs. cit. therein; B. Stanovnik, U. Groselj, Adv. Heterocycl. Chem. 2010, 100, 145.
[3] J. Svete, ꢀ(4R*,5R*)-4-Benzoylamino-5-phenyl-3-pyrazolidinone – A Useful Building Block in the
Synthesis of Functionalized Pyrazolesꢁ, in ꢀStereochemistry Research Trendsꢁ, Eds. M. A. Horvat,
J. H. Golob, Nova Science Publishers, New York, 2008, p. 129 – 181, and refs. cit. therein.
[4] B. Stanovnik, J. Svete, Chem. Rev. 2004, 104, 2433 and refs. cit. therein; J. Svete, Monatsh. Chem.
2004, 135, 629; J. Svete, ARKIVOC 2006, vii, 35.
ˇ
ˇ ˇ
[5] U. Ursic, D. Bevk, S. Pirc, L. Pezdirc, B. Stanovnik, J. Svete, Synthesis 2006, 2376; M. Skof, J. Svete, B.
Stanovnik, Heterocycles 2000, 53, 339.
ˇ
ˇ
[6] a) S. Pirc, D. Bevk, A. Golobic, B. Stanovnik, J. Svete, S. Golic-Grdadolnik, Helv. Chim. Acta 2006,
ˇ
89, 30; b) M. Skof, J. Svete, B. Stanovnik, Helv. Chim. Acta 2000, 83, 760.
ˇ
ˇ
ˇ
[7] U. Groselj, D. Bevk, R. Jakse, S. Recnik, A. Meden, B. Stanovnik, J. Svete, Tetrahedron 2005, 61,
ˇ
ˇ
3991; U. Groselj, S. Recnik, A. Meden, B. Stanovnik, J. Svete, Acta Chim. Slov. 2006, 53, 245.
[8] L. Pezdirc, B. Stanovnik, J. Svete, Aust. J. Chem. 2009, 62, 1661; L. Pezdirc, B. Stanovnik, J. Svete,
Coll. Czech. Chem. Commun. 2009, 74, 835; L. Pezdirc, D. Bevk, S. Pirc, J. Svete, Acta Chim. Slov.
2009, 56, 545.
ˇ
[9] D. Kralj, U. Groselj, A. Meden, G. Dahmann, B. Stanovnik, J. Svete, Tetrahedron 2007, 63, 11213.
ˇ
[10] D. Kralj, A. Novak, G. Dahmann, U. Groselj, A. Meden, J. Svete, J. Comb. Chem. 2008, 10, 664.
ˇ
[11] D. Kralj, M. Friedrich, U. Groselj, S. Kiraly-Potpara, A. Meden, J. Wagger, G. Dahmann, B.
Stanovnik, J. Svete, Tetrahedron 2009, 65, 7151.
ˇ
ˇ
ˇ
ˇ ˇ
ˇ
[12] D. Zerovnik, U. Groselj, D. Kralj, C. Malavasic, J. Bezensek, G. Dahmann, K. Stare, A. Meden, B.
Stanovnik, J. Svete, Synthesis 2010, 3363.

Helvetica Chimica Acta – Vol. 94 (2011)
1717
[13] H. Z. Alkhathlan, M. A. Al-Jaradah, K. A. Al-Fahran, A. A. Mousa, Phosphorus, Sulfur Silicon
Relat. Elem. 2004, 197, 373.
[14] a) H. Z. Alkhathlan, Synth. Commun. 1992, 22, 2659; b) G. Kim, G. Keum, Heterocycles 1997, 45,
ˇ
ˇ
ˇ
´
´
1979; c) Z. Hamersak, M. Litvic, D. Sepac, A. Lesac, Z. Raza, V. Sunjic, Synthesis 2002, 2174.
[15] a) P. K. Agarwal, S. K. Sharma, D. Sawant, B. Kundu, Tetrahedron 2009, 65, 1153; b) V. M. Paradkar,
ˇ
T. B. Latham, A. Krishnaswami, J. Heterocycl. Chem. 1993, 30, 1497; c) M. Tisler, B. Stanovnik, B.
ˇ
Vercek, Vestn. Slov. Kem. Drus. 1980, 27, 65.
ˇ ˇ
ˇ
ˇ
[16] A. Hanzlowsky, B. Jelencic, S. Recnik, J. Svete, A. Golobic, B. Stanovnik, J. Heterocycl. Chem. 2003,
40, 487.
[17] R. Grandi, W. Messerotti, U. M. Pagnoni, R. Trave, J. Org. Chem. 1977, 42, 1352.
[18] Y. Hu, B. Xu, Y. Liao, K. Nawoschik, Y. Liu, A. Sandrasagra, R. Fathi, Z. Yang, U.S. Pat. Appl. US
2006183751, A1 20060817, 2006, (Chem. Abstr. 2006, 145, 249201); J. D. Speake, F. Navas III, M. J.
Bishop, D. T. Garrison, E. C. Bigham, S. J. Hodson, D. L. Saussy, J. A. Liacos, P. E. Irving, B. W.
Sherman, Bioorg. Med. Chem. Lett. 2003, 13, 1183; E. C. Bigham, M. J. Bishop, D. H. Drewry, D. T.
Garrison, S. J. Hodson, F. Navas III, J. D. Speake, Int. Pat. Appl. WO 2000066563, A1 20001109,
2000, (Chem. Abstr. 2000, 133, 350215).
[19] M. Gerecke, E. Kyburz, R. Borer, W. Gassner, Heterocycles 1994, 39, 693.
[20] G. deStevens, H. Blatter, Angew. Chem. 1962, 74, 249.
[21] Collect Software. Nonius, BV, Delft, 1998.
[22] Z. Otwinowski, W. Minor, Methods Enzymol. 1997, 276, 307.
[23] A. Altomare, M. C. Burla, M. Camalli, G. L. Cascarano, C. Giacovazzo, A. Guagliardi, A. G. G.
Moliterni, G. Polidori, R. Spagna, J. Appl. Crystallogr. 1999, 32, 115.
[24] Eds. S. R. Hall, D. J. du Boulay, R. Olthof-Hazekamp, in ꢀXtal3.6 Systemꢁ, University of Western
Australia, Lamb, Perth, 1999.
Received February 2, 2011