Synthesis of [3,3′(4H,4′H)-Bi-2H-1,3-oxazine]-4,4′-diones and their hydrolysis

Article abstract of DOI:10.1002/hlca.201200463

The [3,3′(4H,4′H)-bi-2H-1,3-oxazine]-4,4′-diones 3a-3i were obtained by [2+4] cycloaddition reactions of furan-2,3-diones 1a-1c with aromatic aldazines 2a-2d (Scheme 1). So, new derivatives of bi-2H-1,3-oxazines and their hydrolysis products, 3,5-diaryl-1H-pyrazoles 4a-4c (Scheme 3), which are potential biologically active compounds, were synthesized for the first time. Copyright

Full text of DOI:10.1002/hlca.201200463

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Synthesis of [3,3’(4H,4’H)-Bi-2H-1,3-oxazine]-4,4’-diones and
Their Hydrolysis
a
b
˙
by Elif Korkusuz* ) and Ismail Yıldırım )
a) Kayseri Vocational College, Erciyes University, TR-38039 Kayseri
(phone: þ 90-352-2076666/40735; fax: þ 90-352-2310588; e-mail: elifdus@hotmail.com)
b) Department of Chemistry, Faculty of Sciences, Erciyes University, TR-38039 Kayseri
The [3,3’(4H,4’H)-bi-2H-1,3-oxazine]-4,4’-diones 3a – 3i were obtained by [2 þ 4] cycloaddition
reactions of furan-2,3-diones 1a – 1c with aromatic aldazines 2a – 2d (Scheme 1). So, new derivatives of
bi-2H-1,3-oxazines and their hydrolysis products, 3,5-diaryl-1H-pyrazoles 4a – 4c (Scheme 3), which are
potential biologically active compounds, were synthesized for the first time.
Introduction. – The development of novel synthetic methods for the construction of
new analogs of bioactive heterocyclic compounds represents a major challenge in
synthetic organic and medicinal chemistry [1][2]. The bi-2H-1,3-oxazine ring systems
are core structures present in a number of biologically active heterocycles. They are
pivotal intermediates for the synthesis of pharmaceutical molecules. Increasing interest
towards the synthesis of bi-2H-1,3-oxazine derivatives is mainly due to their potential
biological and pharmacological actions such as analgesic, antitubercular, anticancer,
anti-HIV, antihypertensive, antithrombotic, and antiulcer activities. In addition, certain
of their members are of interest as photochromic compounds [3 – 9]. The 3,5-diaryl-1H-
pyrazoles obtained by hydrolysis of bi-2H-1,3-oxazines have also been evaluated as
cytotoxic or as potential antitumor agents [10 – 12]. Due to our interest in bi-2H-1,3-
oxazines and 3,5-diaryl-1H-pyrazoles, we investigated the reactivity and synthetic
applications of these compounds [13].
Furandiones are versatile starting materials for a variety of reactions, e.g.,
generation of diacyl ketenes by thermolysis, cycloaddition of heterocumulenes,
photochemical reactions, as well as addition of nucleophiles, leading to a number of
heterocyclic systems [14 – 18]. Thermal decomposition of the furan-2,3-diones leads to
formation of reactive a-oxoketene (acylketene) intermediates. a-Oxoketenes are
versatile intermediates in organic synthesis; they not only react with various
nucleophiles but also undergo cycloaddition reactions with unsaturated compounds
[18 – 26]. On the other hand, azines (¼alkylidenehydrazones) have attracted attention
because of their ability to be used in the synthesis of a wide variety of heterocyclic
compounds such as 1H-pyrazoles, purines, and pyrimidines. These compounds can be
employed for useful synthetic transformations and possess some unexpected biological
activities [27 – 31]. It was surprising to find that there have been very few reports on
[2 þ 4] cycloaddition reactions with azines as dienophiles. We have focused our interest
on arylaldazines because, to the best of our knowledge, the dienophilic reactivity of
ꢀ 2013 Verlag Helvetica Chimica Acta AG, Zꢁrich

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these compounds have gone unnoticed; nevertheless, they could be excellent systems
for exploring the potential of our way of proceeding as well as for investigating the
scope of azines in [2 þ 4] cycloadditions.
Herein, we report the first synthesis of [3,3’(4H,4’H)-bi-2H-1,3-oxazine]-4,4’-diones
3 by [2 þ 4] cycloaddition reactions of some furan-2,3-diones 1 with arylaldazines
(¼1,2-dibenzylidenehydrazines) 2 as dienophiles (Scheme 1). The result of these
experiments is discussed in this study. Our investigation also deals with new 3,5-diaryl-
1H-pyrazoles 4, formed by hydrolysis of some [3,3’(4H,4’H)-bi-2H-1,3-oxazine]-4,4’-
diones and the acylation of 4 to derivatives 5 (Scheme 3). The synthesis of 3,5-
diphenyl-1H-pyrazole has first been achieved by the reaction of hydrazine and
dibenzoylmethane [10][13]. Later, the synthesis of 3,5-diaryl-1H-pyrazoles, e.g., 3,5-
bis(4-methoxyphenyl)-1H-pyrazole, from chalcones by using H2O2 in alkaline media
(!epoxychalcones) fallowed by treatment with hydrazine and dehydration has been
reported by Bhat and co-workers [11].
Results and Discussion. – The substituted furan-2,3-diones 1a – 1c and azine
derivatives 2a – 2d, which were used in the synthesis of the target [3,3’(4H, 4’H)-bi-2H-
1,3-oxazine]-4,4’-diones 3a – 3i, were prepared by literature procedures [19 – 25][27].
The reaction of aldazine 2a (1 mol-equiv.) with 1a (2 mol-equiv.) in benzene proceeded
smoothly to afford the target compound 3a in 51% yield (Scheme 1). Similarly, the
reaction between 1a – 1c and aldazine derivatives 2a – 2d, gave the diones 3b – 3i in 18 –
37% yield. Compounds 3a – 3i are stable solids whose structures were established by
1
IR, H- and 13C-NMR spectroscopy (see also below), and elemental analyses. When
this cycloaddition reaction was carried out with ketazines instead of aldazines 2a – 2d,
1
such as that derived from benzophenone, TLC and H-NMR analyses of the reaction
mixtures indicated a mixture of starting materials and numerous products in poor
amounts.
Scheme 1. Reaction of Furan-2,3-diones 1 with Aromatic Aldazines 1

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The formation of diones 3 can be explained by the thermal decomposition of the 4-
acylfurandiones 1 by loss of CO leading to the diacylketenes as intermediates which can
undergo [2 þ 4] cycloaddition reactions with C¼O, C¼N, and C¼S dienophiles [32].
Thus, reacting twice with aldazines 2 yields the diones 3 (Scheme 2).
Scheme 2. Formation of [3,3’(4H,4’H)-Bi-2H-1,3-oxazine]-4,4’-diones 3
The cycloadition monitoring by TLC revealed a pronounced substituent effect on
the overall reaction time. Electron-donating substituents at the aromatic ring of
aldazine 2 accelerated the reaction, whereas electron-withdrawing substituents
completely prevented the reaction. Because the products 3a – 3i contain two chiral
centers, they were expected to be the racemic mixtures of the enantiomers and the
1
meso-form (Fig. 1). The H-NMR spectrum of 3a revealed a 1:1 ratio of the meso to
the (R)/(S) adducts by the integrals of the two HꢀC(2,2’) s of the bi-2H-1,3-oxazine
moieties at d(H) 5.97 and 5.65 [33][34]. The 13C-NMR spectrum of 3a showed signals
at d 192.23, and 191.70 (PhꢀC¼O), and 165.72, 164.92 (C(6), C(6’)), 164.40, and 161.46
(C(4)¼O, C(4’)¼O), 137.84 – 127.00 (arom. C), 111.98 and 110.71 (C(5), C(5’)), and
92.87 and 92.01 (C(2), C(2’)). Also the optical rotations of the [bi-2 H-1,3-oxazine]-
Fig. 1. The three possible isomers (50% meso and 50% (R)/(S)) of 3a – 3i

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diones 3a – 3i in CHCl3 solution were measured but no optical activity was observed.
1
The H- and 13C-NMR spectra of 3b, 3c, 3e, 3g, and 3i were similar to those of 3a,
except for the characteristic resonance of the Me groups and the correspondingly
substituted aromatic rings. On the other hand, in the 1H-NMR spectra of 3d, 3f, and 3h,
HꢀC(2,2’) gave rise to only one s, and these compounds melted sharply at a constant
temperature, indicating that 3d, 3f, and 3h were meso forms.
We also investigated the hydrolysis of [3,3’(4H,4’H)-bi-2H-1,3-oxazines]-4,4’-
diones 3a-3c in refluxing H2O/AcOH, wich furnished as single products the
corresponding 3,5-diaryl-1H-pyrazoles 4a – 4c (Scheme 3).
Scheme 3. Hydrolysis of 3a – 3c, and Acylations of 4a – 4c
In acidic solution, the same 1H-pyrazoles 4a and 4b were also always obtained on
hydrolysis of [bi-oxazine]diones 3d – 3i. The spectral and analytical data of 4c – 4c were
in good agreement with the proposed structures. In the IR spectrum of 4c, e.g., the
characteristic absorption band for the NH group at 3139 cmꢀ1, and the skeleton bands
of benzene or pyrazole rings at 1510 – 1440 cmꢀ1 (CꢀC, CꢀN) were observed. The
13C-NMR signals of 4c were found at d(C) 147.70 (C(5)), 123.47 (4 Co), 137.46 (C(3)),
99.39 (C(4)), 129.78 (2 Cp), 129.47 (2 Cipso and 4 Cm), and 21.21 (2 Me), and the
1H-NMR signals at d(H) 13.42 (exchangeable with D2O, NH), 8.30 – 7.01 (arom. H),
and 2.36 and 2.22 (2 Me) [35].
A reasonable mechanism for the formation of (Scheme 4) would involve
protonation of 3 followed by ring opening via nucleophilic attack of H2O to the
antibonding (p*) orbital at the CO C-atoms C(4,4’) of the bi-oxazine moiety to give a
highly reactive intermediate b-keto carboxylic acid. The latter would then decarboxy-
late to give a 1,3-diketone, hydrazine, and an aromatic aldehyde. Nucleophilic attack
of the hydrazine at the 1,3-diketone followed by intramolecular cyclization and
dehydration would yield the 1H-pyrazole 4.
After the successful synthesis of 3,5-diaryl-1H-pyrazoles 4, the next step was their
N-acylation to the corresponding 1-acyl-1H-pyrazoles by using acetyl or benzoyl
chloride. The acylation was carried out in toluene under reflux to give the 1-acyl-1H-
pyrazoles 5 in 91 – 85% yield without opening the 1H-pyrazole ring. The structures of
5a – 5e were elucidated by analysis of their NMR data, as exemplified with 5b. The
1H-NMR spectrum of 5b exhibited one s at d 2.85 for the Me group, two s at d 4.04 and
3.88 for the MeO groups, and a m at d 7.87 – 6.70 (two AA’BB’ systems) for the aromatic

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Scheme 4. Formation of 3,5-Diary-1H-pyrazoles 4
H-atoms. 13C-NMR and DEPT Spectra of 5b confirmed the presence of one Me and
two MeO groups, six quaternary C-atoms in the aromatic region, and one CO group.
We wish to dedicate this article to Yunus AkÅamur, who passed away in 2007, and to Gert Kollenz.
The authors are grateful to the Technology Research and Application Centre for the use of the NMR
spectrometer and to the Scientific Research Projects Chairmanship of Erciyes University for financial
support.
Experimental Part
General. Compounds 1 and azines 2 were prepared according to [13][21][27][36]. Reagents and
solvents were purchased from Merck, Fluka, and Sigma, used without further purification. TLC: Merck
precoated silica gel plates 60 F254. M.p.: Electrothermal-9200 apparatus; uncorrected. Optical rotations:
Perkin-Elmer-241-MC polarimeter, at 589 nm. IR Spectra: Shimadzu-8400-FT-IR spectrometer; ATR ¼
allenuated total reflectance; in cmꢀ1 1H- and 13C-NMR spectra: Bruker-Avance-III-Ultrashield
.

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spectrometer; at 400.13 (1H) and 100.61 MHz (13C) in (D6)DMSO and/or CDCl3; d in ppm, coupling
constants J in Hz; when necessary to identify all C-atoms, COSY and APT (attached-proton test)
experiments were performed. Elemental analyses: Leco-932-CHNS-O analyzer.
Substituted [3,3’(4H,4’H)-Bi-2H-1,3-oxazine]-4,4’-diones 3: General Procedure 1 (G.P.1). Furan-
dione 1 (2 mmol) and azine 2 (1 mmol) were dissolved in dry benzene (30 ml) and heated under reflux
for 16 – 23 h. After cooling to r.t., the white precipitate was filtered off and recrystallized from EtOH: 3 as
colorless crystals.
5,5’-Dibenzoyl-2,2’,6,6’-tetraphenyl-[3,3’(4H,4’H)-bi-2H-1,3-oxazine]-4,4’-dione (3a). According to
the G.P.1 (19 h reflux): 0.36 of 3a (51%). M.p. 167 – 1718. IR (ATR): 3064w (arom. CꢀH), 2893w (aliph.
1
CꢀH), 1671s, 1657s (C¼O), 1598s, 1574m, 1493m, 1450s (CꢀC). H-NMR (CDCl3): 8.06 – 6.97 (m, 30
arom. H); 5.97, 5.65 (2s, HꢀC(2), HꢀC(2’)). 13C-NMR (CDCl3): 192.23, 191.70 (PhꢀC¼O); 165.72, 164.92
(C(6), C(6’)); 164.40, 161.46 (C(4)¼O, C(4’)¼O); 137.84, 133.67, 132.98, 130.12, 129.66, 129.43, 129.09,
128.75, 128.43, 128.34, 127.55, 127.14, 127.00 (arom. C); 111.98, 110.71 (C(5), C(5’)); 92.87, 92.01 (C(2),
C(2’)). Anal. calc. for C46H32N2O6 (708.76): C 77.95, H 4.55, N 3.95; found: C 78.01, H 4.51, N 3.97.
5,5’-Bis(4-methoxybenzoyl)-6,6’-bis(4-methoxyphenyl)-2,2’-diphenyl-[3,3’(4H,4’H)-bi-2H-1,3-oxa-
zine]-4,4’-dione (3b). According to the G.P.1 (23 h reflux): 0.31 g of 3b (37%). M.p. 155 – 1598. IR
(ATR): 3057w (arom. CꢀH), 2838w (aliph. CꢀH), 1675s (C¼O), 1599s, 1575m, 1509s, 1459s (CꢀC).
1H-NMR (CDCl3): 7.92 – 6.80 (m, 26 arom. H); 6.69, 6.66 (2s, HꢀC(2), HꢀC(2’)); 3.79, 3.71 (2s, 4 MeO).
13C-NMR (CDCl3): 190.67 (PhꢀC¼O); 165.49, 165.42 (C(6), C(6’)); 163.96, 162.65 (C(4)¼O, C(4’)¼O);
132.96, 132.36, 131.41, 130.95, 130.50, 128.61, 128.39, 123.42, 114.00, 113.97 (arom. C); 109.41 (C(5),
C(5’)), 91.74 (C(2), C(2’)), 55.66, 55.58 (2 MeO). 15N-NMR (40.5 MHz, CDCl3): 199.99. Anal. calc. for
C50H40N2O8 (828.86): C 72.45, H 4.86, N 3.38; found: C 71.98, H 4.59, N 3.36.
5,5’-Bis(4-methylbenzoyl)-6,6’-bis(4-methylphenyl)-2,2’-diphenyl[3,3’(4H,4’H)-bi-2H-1,3-oxazine]-
4,4’dione (3c). According to the G.P.1 (22 h reflux): 0.23 g of 3c (30%). M.p. 180 – 1868. IR (ATR):
3034w (arom. CꢀH), 2966w (aliph. CꢀH), 1707s, 1678s, 1657s (C¼O), 1610m, 1600m, 1554m, 1467m
(CꢀC). 1H-NMR (CDCl3): 8.01 – 6.88 (m, 26 arom. H); 5.91, 5.61 (2s, HꢀC(2), HꢀC(2’)); 2. 25, 2.37 (2s,
4 MeꢀAr). 13C-NMR (CDCl3): 191.26 (ArꢀC¼O); 165.93 (C(6), C(6’)); 164.80 (C(4)¼O, C(4’)¼O);
144.18, 142.50, 135.24, 132.32, 130.32, 129.86, 129.85, 129.21, 129.07, 128.48, 128.24, 128.09 (arom. C);
110.14 (C(5), C(5’)); 91.55 (C(2), C(2’)); 21.71, 21.42 (2 MeꢀAr). Anal. calc. for C50H40N2O6 (764.86): C
78.52, H 5.27, N 3.66; found: C 77.98, H 4.98, N 3.65.
5,5’-Dibenzoyl-6,6’-diphenyl-2,2’-dipyridin-3-yl[3,3’(4H,4’H)-bi-2H-1,3-oxazine]-4,4’-dione (3d).
According to the G.P.1 (19 h reflux): 0.24 g of 3d (33%). M.p. 2508. IR (ATR): 3057w (arom. CꢀH),
2974w (aliph. CꢀH), 1703s, 1689s, 1647s (C¼O), 1608s, 1596w, 1577w, 1448s (CꢀC). 1H-NMR (CDCl3):
8.85 – 7.03 (m, 28 arom. H); 6.65 (s, HꢀC(2), HꢀC(2’)). 13C-NMR (CDCl3): 191.13 (ArꢀC¼O); 166.27
(C(6), C(6’)); 163.82 (C(4)¼O, C(4’)¼O); 152.21, 149.28, 137.33, 135.79, 134.55, 132.87, 130.77, 129.65,
129.53, 129.20, 129.07, 129.00, 128.74, 128.30, 124.14 (arom. C); 110.65, 111.72 (C(5), C(5’)); 90.02 (C(2),
C(2’)). Anal. calc. for C44H30N4O6 (710.73): C 74.36, H 4.25, N 7.88; found: C 73.98, H 4.70, N 8.02.
5,5’-Bis(4-methoxybenzoyl)-6,6’-bis(4-methoxyphenyl)-2,2’-dipyridin-3-yl[3,3’(4H,4’H)-bi-2H-1,3-
oxazine]-4,4’-dione (3e). According to the G.P.1 (24 h reflux): 0.26 g of 3e (31%). M.p. 233 – 2368. IR
(ATR): 3057w (arom. CꢀH), 2943w (aliph. CꢀH), 1695s, 1670s, 1647s (C¼O), 1597s, 1506m, 1478m,
1
1460m (CꢀC). H-NMR (CDCl3): 8.91 – 6.92 (m, 24 arom. H); 6.85, 6.77 (2s, HꢀC(2), HꢀC(2’)); 3.92,
3.67 (2s, 4 MeO). 13C-NMR (CDCl3): 189.72 (ArꢀC¼O); 170.89 (C(6), C(6’)); 164.80 (ArꢀC¼O); 164.22,
164.15 (MeOꢀC); 162.82 (C(4)¼O, C(4’)¼O); 151.48, 148.43, 143.00, 136.21, 134.44, 132.58, 131.06,
129.76, 127.36, 115.3, 114.61 (arom. C); 109.40 (C(5), C(5’)); 89.55 (C(2), C(2’)); 56.10, 55.92 (2 MeO).
Anal. calc. for C48H38N4O10 (830.84): C 69.39, H 4.61, N 6.74; found: C 68.67, H 4.45, N 6.71.
5,5’-Dibenzoyl-2,2’-bis(4-methylphenyl)-6,6’-diphenyl[3,3’(4H,4’H)-bi-2H-1,3-oxazine]-4,4’-dione
(3f). According to the G.P.1 (18 h reflux): 0.16 g of 3f (21%). M.p. 1958. IR (ATR): 3060w (arom. CꢀH),
2920w (aliph. CꢀH), 1697s, 1660s (C¼O), 1610m, 1595m, 1512m, 1447m (CꢀC). 1H-NMR (CDCl3):
7.94 – 6.88 (m, 28 arom. H); 5.61 (s, HꢀC(2), HꢀC(2’)); 2.44 (s, 2 Me). 13C-NMR (CDCl3): 191.44
(ArꢀC¼O); 166.06 (C(6), C(6’)); 163.93 (C(4)¼O, C(4’)¼O); 140.59, 137.42, 134.35, 132.61, 131.10,
130.05, 129.50, 129.25, 129.10, 128.85, 128.71, 128.51 (arom. C); 110.61 (C(5), C(5’)); 92.02 (C(2), C(2’));
21.42 (Me). Anal. calc. for C48H36N2O6 (736.81): C 78.24, H 4.92, N 3.80; found: C 77.83, H 4.51, N 3.53.

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5,5’-Bis(4-methoxybenzoyl)-6,6’-bis(4-methoxyphenyl)-2,2’-bis(4-methylphenyl)[3,3’(4H,4’H)-bi-
2H-1,3-oxazine]-4,4’dione (3g). According to the G.P.1 (21 h reflux): 0.27 g of 3g (31%). M.p. 195 – 2008.
IR (ATR): 3057w (arom. CꢀH), 2951w (aliph. CꢀH), 1711s, 1670s (C¼O), 1593m, 1506m, 1487m, 1450m
1
(CꢀC). H-NMR ((D6)DMSO): 7.96 – 6.87 (4 AA’BB’, 24 arom. H); 6.80, 6.70 (2s, HꢀC(2), HꢀC(2’));
3.89 – 3.70 (m, 4 MeO); 2.44 (2s, 2 Me). 13C-NMR ((D6)DMSO): 190.12 (ArꢀC¼O); 164.65 (C(6),
C(6’)); 164.37, 164.10 (MeOꢀC); 162.63 (C(4)¼O, C(4’)¼O); 140.40, 136.00, 132.11, 131.06, 130.54,
130.35, 129.12, 128.50, 126.55 (arom. C); 114.62, 114.52 (C(5), C(5’)); 91.69 (C(2), C(2’)); 56.07, 55.88
(2 MeO); 21.41 (2 Me). Anal. calc. for C52H44N2O10 (856.90): C 72.88, H, 5.18, N 3.27; found: C 72.84, H
5.38, N 3.19.
5,5’-Dibenzoyl-2,2’-bis(4-methoxyphenyl)-6,6’-diphenyl[3,3’(4H,4’H)-bi-2H-(1,3-oxazine)]-4,4’dione
(3h). According to the G.P.1 (16 h reflux): 0.15 g of 3h (21%). M.p. 1778. IR (ATR): 3073w (arom.
CꢀH), 2942w (aliph. CꢀH), 1700s, 1678s, 1663s (C¼O), 1600m, 1589m, 1502m, 1447m (CꢀC). 1H-NMR
(CDCl3): 8.07 – 6.89 (m, 28 arom. H); 5.63 (s, HꢀC(2), HꢀC(2’)); 3.89 (s, 2 MeO). 13C-NMR (CDCl3):
191.58 (ArꢀC¼O); 166.50 (C(6), C(6’)); 164.75 (MeOꢀC); 161.14 (C(4)¼O, C(4’)¼O); 137.59, 133.37,
133.37, 131.87, 130.98, 130.77, 130.17, 129.89, 129.63. 128.93, 128.30, 113.46 (arom. C); 92.55 (C(5), C(5’));
91.22 (C(2), C(2’)); 55.36 (2 MeO). Anal. calc. for C48H36N2O8 (768.81): C 74.99, H 4.72, N 3.80; found: C
75.49, H 4.74, N 4.36.
5,5’-Bis(4-methoxybenzoyl)-2,2’,6,6’-tetrakis(4-methoxyphenyl)[3,3’(4H,4’H)-bi-2H-1,3-oxazine]-
4,4’-dione (3i). According to the G.P.1 (20 h reflux): 0.21 g of 3i (23%). M.p. 176 – 1828. IR (ATR):
3080w (arom. CꢀH), 2860w (aliph. CꢀH), 1703m, 1670s (C¼O), 1608m, 1589m, 1506m, 1460m (CꢀC).
1H-NMR (CDCl3): 7.97 – 6.88 (6 AA’BB’, 24 arom. H); 6.75, 6.70 (2s, HꢀC(2), HꢀC(2’)); 3.91, 3.80, 3.73
(3s, 6 MeO). 13C-NMR (CDCl3): 190.50 (ArꢀC¼O); 165.23 (C(6), C(6’)); 163.71, 163.50, 162.95
(MeOꢀC); 160.96 (C(4)¼O, C(4’)¼O); 132.13, 131.97, 131.15, 130.83, 129.85, 129.77, 125.12, 123.36,
114.31, 113.75, 113.71, 113.42 (arom. C); 109.27 (C(5), C(5’)); 91.88, 91.53 (C(2), C(2’)); 55.57, 55.46,
55.38, 55.32 (6 MeO). Anal. calc. for C52H44N2O12 (888.92): C 70.26, H 4.99, N 3.15; found: C 70.31, H
4.99, N 3.25.
Disubstituted 1H-Pyrazoles 4: General Procedure 2. Compound 3 was dissolved in AcOH (20 ml)
and H2O (4 ml) and heated under reflux for 12 h. After evaporation of the solvent, the residue was
crystallized from EtOH: pure 4.
3,5-Diphenyl-1H-pyrazole (4a): Colorless crystals. M.p. 1988 ([11]: 2008) from MeOH. 1H- and
13C-NMR: identical with those reported in the literature.
3,5-Bis(4-methoxyphenyl)-1H-pyrazole (4b): From 3b (0.83 g): 0.08 g (30%) of 4b. M.p. 2248. IR
(ATR): 3416m (NꢀH), 3022w (arom. CꢀH), 2957w (aliph. CꢀH), 1610m, 1501m, 1439m (CꢀC, CꢀN),
1
1247m (CꢀO). H-NMR (CDCl3): 8.50 (s, NH); 7.75 (d, J ¼ 8.4, 4 Ho); 6.95 (d, J ¼ 8.4, 4 Hm); 6.73 (s,
HꢀC(4)); 3.80 (2s, 2 MeO). 13C-NMR (CDCl3): 159.58 (2 Cp); 148.48 (C(3), C(5)); 131.00 (4 Co); 126.95
(Cipso at C(3)); 124.01 (Cipso at C(5)); 114.15 (4 Cm); 98.84 (C(4)); 55.24 (MeO). Anal. calc. for C17H16N2
(267.30): C 72.84, H 5.75, N 9.99; found: C 73.00, H 5.70, N 9.96.
3,5-Bis(4-methylphenyl)-1H-pyrazole (4c). From 3c (0.77 g): 0.17 g (59%) of 4c. M.p. 2388. IR
(ATR): 3142m (NꢀH), 3015w (arom. CꢀH), 2920w, 2860w (aliph. CꢀH), 1510m, 1443m, 1440m (CꢀC,
1
CꢀN). H-NMR ((D6)DMSO): 12.42 (s, NH); 7.77 (d, J ¼ 8.30, 4 Ho); 7.15 (d, J ¼ 8.30, 4 Hm); 6.95 (s,
HꢀC(4)); 2.36, 2.22 (2s, 2 Me). 13C-NMR ((D6)DMSO): 147.70 (C(3)); 137.46 (C(5)); 129.78 (2 Cp);
129.47 (2 Cipso, 4 Cm); 123.47 (4 Co); 99.39 (C(4)); 21.21 (2 Me). Anal. calc. for C17H16N2O2 (280.32): C
82.22, H 6.49, N 11.28; found: C 82.27, H 6.54, N 11.34.
Trisubstituted 1H-Pyrazoles 5. General Procedure 3. To a stirred mixture of 4 (1 mmol) and AcCl or
BzCl (1 mmol) in toluene (20 ml) was added pyridine (cat. amount). The mixture was heated under
reflux on a steam bath for 3 – 5 h with stirring. The solvent was evaported, the residue treated with
petroleum ether, and the solid filtered off, recrystallized from the proper solvent and dried (P2O5): 5.
1-(3,5-Diphenyl-1H-pyrazol-1-yl)ethanone (5a): From 4a (0.22 g): 0.24 g (91%) of 5a. M.p. 888
(MeOH). IR (ATR): 3044w (arom. CꢀH), 2993w (aliph. CꢀH), 1748s (C¼O), 1578m, 1554m, 1483m,
1452m (CꢀC, CꢀN). 1H-NMR (CDCl3): 7.94 – 7.24 (m, 10 arom. H); 6.75 (s, HꢀC(4)); 2.85 (s, Me).
13C-NMR (CDCl3): 170.59 (C¼O); 153.40 (C(5) or C(3)); 148.73 (C(3) or C(5)); 147.22, 131.77, 130.97,
129.21, 128.94, 128.48, 127.90, 125.70 (arom. C); 109.87 (C(4)); 23.78 (Me). Anal. calc. for C17H14N2O
(262.31): C 77.84, H 5.84, N 10.68; found: C 77.83, H 5.88, N 10.67.

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Helvetica Chimica Acta – Vol. 96 (2013)
1-[3,5-bis(4-methoxyphenyl)-1H-pyrazol-1-yl]ethanone (5b): From 4b (0.28 g): 0.28 g (87%) of 5b.
M.p. 948 (MeOH). IR (ATR): 3051w (arom. CꢀH), 2847w (aliph. CꢀH), 1739s (C¼O), 1610m, 1493m,
4
1435m, 1425m (CꢀC, CꢀN), 1285s, 1246s (CꢀOꢀC). 1H-NMR (CDCl3): 7.84 (dd, 3J ¼ 8.6, J ¼ 2.6, 2 Ho
near C(3)); 7.42 (d, 3J ¼ 8.6, 2 Ho near C(5)); 7.00 (d, 3J ¼ 8.6, 2 Hm near C(3)); 7.43 (dd, 3J ¼ 8.6, 4J ¼ 2.6,
2 Hm near C(3)); 6.70 (s, HꢀC(4)); 4.04, 3.88 (2s, 2 MeO), 2.75 (s, Me). 13C-NMR (APT, 100 MHz,
CDCl3): 170.62 (ꢀ); 160.52 (ꢀ); 159.95 (ꢀ); 153.40 (ꢀ); 148.73 (ꢀ); 133.79 (þ); 130.33 (þ); 129.44 (þ);
124.76 (ꢀ); 121.45 (ꢀ); 114.23 (þ); 110.94 (þ); 56.30 (þ); 55.35 (þ); 55.30 (þ); 23.83 (þ). Anal. calc. for
C19H18N2O3 (322.36): C 70.79, H 5.63, N 8.69; found: C 71.00, H 5.64, N 8.72.
1-[3,5-Bis(4-methylphenyl)-1H-pyrazol-1-yl]ethanone (5c): From 4c (0.25 g): 0.25 g (85%) of 5c.
M.p. 858 (MeOH). IR (ATR): 3030w (arom. CꢀH), 2928w (aliph. CꢀH), 1742s (C¼O), 1610w, 1501m,
1485m, 1441m (CꢀC, CꢀN), 1279s (CꢀOꢀC). 1H-NMR (CDCl3): 7.83 (d, 3J ¼ 8.1, 2 Ho near C(3)); 7.40
(d, 3J ¼ 8.0, 2 Ho near C(5)); 7.29 (d, 3J ¼ 8.0, 2 Hm near C(5)); 7.23 (d, 3J ¼ 8.1, 2 Hm near C(3)); 6.75 (s,
HꢀC(4)); 2.85 (s, Me); 2.45, 2.35 (2s, 2 MeꢀC6H4). 13C-NMR (CDCl3): 170.61 (C¼O); 153.41 (C(3));
147.26 (2 Co near C(5)); 139.15 (2 Cp near C(3)); 138.72 (C(5)); 129.52 (Cispo near C(3)); 128.88 (2 Cm
near C(5)); 128.41 (2 Co near C(3)); 128.25 (2 Cm near C(3)); 126.39 (2 Co near C(5)); 126.14 (Cispo near
C(5)); 109.61 (C(4)); 23.85 (Me); 21.42 (2 MeꢀC6H4). Anal. calc. for C19H18N2O (290.36): C 78.59, H
6.25, N 9.65; found: C 78.63, H 6.24, N 9.64.
[3,5-Bis(4-methoxyphenyl)-1H-pyrazol-1-yl]phenylmethanone (5d): From 4b (0.28 g): 0.33 g (85%)
of 5d. M.p. 1188 (EtOH). IR (ATR): 3059w (arom. CꢀH), 2964w (aliph. CꢀH), 1664s (C¼O), 1598m,
1569m, 1450m (CꢀC, CꢀN), 1259s (CꢀOꢀC). 1H-NMR (CDCl3): 8.00 (dd, 3J ¼ 7.8, 4J ¼ 1.2, 2 Ho og Ph);
7.82 (d, 3J ¼ 8.4, 2 Ho near C(3)); 7.60 (tt, 3J ¼ 7.8, 4J ¼ 1.2, Hp of Ph); 7.54 (td, 3J ¼ 7.8, 4J ¼ 1.2, 2 Hm of Ph);
7.48 (d, 3J ¼ 8.3, 2 Ho near C(5)); 7.20 (d, 3J ¼ 8.3, 2 Hm at C(5)); 7.15 (d, 3J ¼ 8.4, 2 Hm near C(3)); 6.75 (s,
HꢀC(4)); 3.77, 3.75 (2s, 2 MeO). 13C-NMR (APT, 100 MHz, CDCl3): 190.68 (ꢀ); 164.15 (ꢀ); 135.91 (ꢀ);
133.91 (ꢀ); 133.81 (þ); 131.23 (þ); 128.91 (þ); 128.76 (þ); 127.45 (ꢀ); 119.00 (ꢀ); 114.22 (þ); 114.17 (þ);
113.69 (þ); 66.56 (þ); 55.57 (þ). Anal. calc. for C24H20N2O3 (384.43): C 74.98, H 5.24, N 7.29; found: C
74.96, H 5.20, N 7.27.
[3,5-Bis(4-methylphenyl)-1H-pyrazol-1-yl]phenylmethanone 5e: From 4c (0.25 g): 0.32 g (89%) of
5e. M.p. 1348 (EtOH). IR (ATR): 3024w (arom. CꢀH), 2980w (aliph. CꢀH), 1705s (C¼O), 1595s,
1501m, 1447m (CꢀC, CꢀN), 1265s (CꢀOꢀC). 1H-NMR (CDCl3): 8.17 (ꢂddꢃ, 3J ¼ 7.2, 4J ¼ 1.1, 2 Ho of Ph);
7.80 (d, 3J ¼ 7.5, 2 Ho near C(3)); 7.65 (tt, 3J ¼ 7.3, 4J ¼ 1.1, Hp of Ph); 7.54 (td, 3J ¼ 7.2, 4J ¼ 1.1, 2 Hm of Ph);
7.43 (d, 3J ¼ 8.1, 2 Ho near C(5)); 7.27 (d, 3J ¼ 8.1, 2 Hm near C(5)); 7.26 (d, 3J ¼ 7.5, 2 Hm near C(3)); 6.85
(s, HꢀC(4)); 2.55, 2.45 (2s, 2 Me). 13C-NMR (CDCl3): 167.50 (C¼O); 153.62 (C(3)); 139.06 (Cp near
C(3)); 138.75 (Cp near C(5)); 133.08 (C(3)); 132.65 (Cipso of Ph); 129.46, 129.08, 129.02, 128.38, 128.23,
128.00, 126.27 (arom. C); 108.68 (C(4)); 21.42 (2Me). Anal. calc. for C24H20N2O (352.43): C 81.79, H 5.72,
N 7.95; found: C 81.77, H 5.70, N 7.98.
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Received August 14, 2012