Boron-chelate assisted synthesis of new bipyrazole derivatives

Article abstract of DOI:10.1016/j.mencom.2018.11.016

New 2H,3′H-3,4′-bipyrazol-3′-ones were obtained by reaction of hydrazines with difluoroboron chelate of 4-acetyl-5-hydroxy-3-methyl-1-phenyl-1H-pyrazole. Relative isoxazolyl pyrazolone derivative was synthesized from this chelate and hydroxylamine.

Full text of DOI:10.1016/j.mencom.2018.11.016

Mendeleev
Communications
Mendeleev Commun., 2018, 28, 612–614
Boron-chelate assisted synthesis of new bipyrazole derivatives
Maxim A. Zuev,a Anna A. Sukhanova,a Alena G. Smola,a Mikhail A. Prezent,a
Alexey N. Proshin,b Sergey V. Baranin*a and Yurii N. Bubnova
a N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991 Moscow,
Russian Federation. Fax: +7 499 135 5328; e-mail: svbar@ioc.ac.ru
b Institute of Physiologically Active Compounds, Russian Academy of Sciences, 142432 Chernogolovka,
Moscow Region, Russian Federation. Fax: +7 496 524 9508; e-mail: proshin@ipac.ac.ru
DOI: 10.1016/j.mencom.2018.11.016
N
Me2N
New 2H,3'H-3,4'-bipyrazol-3'-ones were obtained by reac-
tion of hydrazines with difluoroboron chelate of 4-acetyl-
5-hydroxy-3-methyl-1-phenyl-1H-pyrazole. Relative isoxazolyl
pyrazolone derivative was synthesized from this chelate and
hydroxylamine.
F
N
O
R
Me
O
B
F
O
Me
O
Me
N
N
N
N
HN N
Ph
Ph
Ph
In the last years, the interest to the chemistry of pyrazoles has
significantly risen due to their numerous applications. Pyrazole
derivatives exhibit agricultural and pharmaceutical activities.1–6
Nucleosides that contain pyrazole substituent as a base were
created.7 Pyrazoles are used in supramolecular and polymer
chemistry, in the food industry, and as cosmetic colorings and UV
stabilizers, while some possess liquid crystal properties8,9 and find
application as ligands in coordination chemistry.10 Over the last
two-three decades, compounds containing two or more pyrazole
fragments have acquired special popularity, since they served as
the basis for various metal complexes including multinuclear
ones. Among them, poly(pyrazol-1-yl)alkanes,11,12 bis(pyrazol-
4-yl)methane,13 poly(pyrazol-1-yl)borates,14 bis- and tris(pyrazol-
1-ylmethyl)amines,15 poly(pyrazol-1-ylmethyl)benzenes,16 2,6-di-
(pyrazol-1-yl)pyridine,17 4,6-di(pyrazol-1-yl)pyrimidine17 can
be mentioned.
Earlier,18 we have described new ligands containing two
pyrazole rings, viz., 1-aryl-2-(pyrazol-3-yl)ethanone azines. Syn-
thesis of these compounds involves the condensation of amide
acetals with the methyl group of aroylacetones difluoroboron
chelates followed by heterocyclization with hydrazine.
In continuation of our design of new pyrazole-containing
ligands, we employed this methodology using difluoroboron
chelate of 4-acetyl-5-hydroxy-3-methyl-1-phenyl-1H-pyrazole as
the key compound.
Pyrazolone 1 was prepared according to the known pro-
cedure19 from phenyl hydrazine and ethyl acetoacetate. Then by
reported reaction20 of compound 1 with triethyl orthoacetate and
further acidosis, 4-acetyl-5-hydroxy-pyrazole 221 was obtained
(Scheme 1).
Difluoroboron chelate 3 was prepared from compound 2
according to the described method22 under mild conditions (~20°C)
by the action of butoxydifluoroboron generated in situ from boron
trifluoride etherate and tributyl borate. The condensation of DMF
dimethyl acetal [Me2NCH(OMe)2] with difluoroboron chelate 3
in THF proceeded at room temperature (see Scheme 1).† The
methyl group at the chelate ring was the reaction site, and chelate
complex 4 containing dimethylaminovinyl fragment was formed.
Note that the reaction between Me2NCH(OMe)2 and pyrazole 2
Me
Me
O
N
Me
O
N
Me
Ph
i
ii
Me
OH
N
N
O
O
F
Ph
N
N
B
F
Ph
1
2
3
Me
Me
N
†
1H NMR spectra were recorded on a Bruker AM-300 spectrometer
N
NMe2
N
(300 MHz), 13C NMR, 1H NOE, 2D 1H–13C HMBC, and 1H–1H gNOESY
spectra were recorded on a Bruker Avance 600 spectrometer (600 and
150 MHz for 1H and 13C, respectively). Residual signals of the deuterated
solvent (d 7.27 for CDCl3 and d 2.50 for DMSO-d6) were used as a
reference in the 1H NMR spectra. Multiplet signals of the deuterated
solvent (d 39.50 for DMSO-d6 and d 77.00 for CDCl3) were the reference
in the 13C NMR spectra. 11B NMR spectra were recorded on a Bruker
AC-200P instrument (64.21 MHz) with BF3·OEt2 as the external standard.
Positive chemical shifts in 11B NMR spectra are located downfield in
respect to the signal of BF3·Et2O. IR spectra were recorded on a Bruker
Alpha spectrometer. High resolution mass spectra were measured on a
Bruker micrOTOF II instrument (ESI). Measurements were carried out in
the positive ranges (capillary voltage was 4500V). The masses were scanned
in the range m/z 50–3000 Da using an external and an internal calibration
(Electrospray Calibrant Solution, Fluka). An acetonitrile solution of a com-
pound was injected by a syringe, the flow rate was 3 mm min–1, nitrogen
was a sprayer gas (4 dm3 min–1), the interface temperature was 180°C.
Ph
N
iii
iv
Ph
O
O
B
O
F
O
HN
F
F
NH
R
B
F
4
Me
N1
N
5
N2
4
N
R
O
3
4'
3'
Me
Me
O
a R = Ph
5'
HN1' N 2'
HN N
b R = 4-ClC6H4
c R = 4-MeC6H4
d R = Me
Ph
Ph
5a–d
5'd (not formed)
Scheme 1 Reagents and conditions: i, MeC(OEt)3, then AcOH–H2O, D;
ii, B(OBu)3, BF3 ·OEt2; iii, Me2NCH(OMe)2; iv, RNHNH2.
© 2018 Mendeleev Communications. Published by ELSEVIER B.V.
on behalf of the N. D. Zelinsky Institute of Organic Chemistry of the
Russian Academy of Sciences.
– 612 –

Mendeleev Commun., 2018, 28, 612–614
under drastic refluxing in xylene caused resinification and none
of product could be identified.
ether, and insoluble in hexane. Their mass spectra show peaks
1
of the ions [M+H]+. The H NMR spectra of compounds 5a–c
Chelates 3 and 4 were isolated in 80 and 65% yields, respec-
tively. They are white (3) and orange (4) crystalline compounds
stable in air, soluble in DMF, DMSO, pyridine, chloroform, acetone,
poorly soluble in THF, acetonitrile, ethanol, and insoluble in Et2O
and hexane. The 11B NMR spectra of complexes 3 and 4 show
signals in the field of four-coordinate B atom, and the mass
spectra contain peaks of the ions [M–BF2]+ for chelate 3 and
[M+H]+ for compound 4. In the 1H NMR spectrum of complex
3 (in CDCl3), two singlets for the methyl groups protons at
d 2.52 and 2.67 ppm, as well as signals from protons of phenyl
substituent are observed. The 1H NMR spectrum of chelate 4 (in
DMSO-d6) is characterized by one set of signals with singlets for
the protons of the NMe2 group at d 3.21 ppm and Me group at
d 3.3 ppm. The coupling constant of the doublets for the protons
at the double bond of dimethylaminovinyl group of compound 4
(d 5.53 and 8.38 ppm) has a value of ~9 Hz, which is characteristic
of E-configuration of such enamines.
Chelate complex 4 containing dimethylaminovinyl substituent
reacts with one equivalent of arylhydrazines in refluxing EtOH to
afford the corresponding 2-aryl-5'-methyl-2'-phenyl-1',2'-dihydro-
2H,3'H-3,4'-bipyrazol-3'-ones 5a–c in 53–75% yields (see
Scheme 1). Compounds 5a–c are white or light-yellow crystal-
line substances well soluble in DMSO, acetonitrile, ethanol and
acetone, poorly soluble in ethyl acetate, chloroform and diethyl
in DMSO-d6 contain singlet for the protons of methyl group
at d ~1.8 ppm and signals for the protons of the pyrazole rings at
d ~6.5 and ~7.7 ppm.
The initial step of the process is replacement of the Me2N
group by the NH2 group of aryl hydrazines. Subsequent step
involves cyclization with opening of the chelate ring and debora-
tion. The exclusive formation of pyrazolones 5a–c was con-
firmed by 2D NMR spectroscopy (i.e., boron chelate 4 under-
goes regioselective transformation according to Scheme 1). The
NOESY spectrum of compound 5b reveals cross peaks due
to interaction between the methyl protons and ortho-protons of
the aryl group. It means that the aryl substituent is located
at N2 atom of pyrazole ring formed. Previously,18 it was shown
that reaction of phenylhydrazine with difluoroboron chelate of
benzoylacetone resulting in the pyrazol ring formation occurs
similarly to the process outlined in Scheme 1.
Methylhydrazine reacts with nonsymmetric β-dicarbonyl
compounds to give two regioisomers of the corresponding
pyrazole derivatives.23 Therefore, one could expect the forma-
tion of two isomers from chelate 4, namely, 5d (see Scheme 1)
and 5'd, when the cyclization could involve an initial replacement
of the Me2N group by the MeNH one of methylhydrazine. In fact,
this reaction afforded exclusively (1-methylpyrazol-5-yl)-sub-
stituted pyrazolone 5d with no traces of isomer 5'd. Bipyrazole
5d appears as a is light green crystalline substance well soluble in
DMSO, acetonitrile, ethanol and acetone, poorly soluble in ethyl
acetate, diethyl ether, and insoluble in chloroform and hexane.
Position of the NMe group in compound 5d was confirmed by
2D NMR spectra. Its 2D 1H–13C HMBC spectrum in DMSO-d6
demonstrates the correlation between protons of NMe and carbon
atom C3, whereas no correlations is observed between the NMe
protons and carbon atom C5.
4-Acetyl-5-hydroxy-3-methyl-1-phenyl-1H-pyrazole difluoroboron
chelate 3. Tributyl borate (0.45 ml, 1.7 mmol) was added to a solution
of compound 2 (1.0 g, 4.6 mmol) in THF (5 ml). The mixture was
stirred for 15 min, then BF3·OEt2 (0.43 ml, 3.4 mmol) was added
dropwise, and this was stirred at 20°C for 2 h. The precipitate formed
was filtered off and recrystallized from MeCN. Yield 0.97 g (80%), mp
1
215–216°C. H NMR (CDCl3) d: 2.52 (s, 3H, Me), 2.67 (s, 3H, Me),
7.40 (t, 1H, p-HPh, J 8 Hz), 7.52 (t, 2H, m-HPh, J 8 Hz), 7.88 (d, 2H,
o-HPh, J 8 Hz). 11B NMR (CDCl3) d: 1.27. HRMS (ESI), m/z: 217.0954
[M–BF2]+ (calc. for C12H14N2O2, m/z: 217.0953).
Reactions of chelate 4 with both hydrazine hydrate and
hydroxylamine proceed smoothly in boiling ethanol resulting in
(E)-3-Dimethylamino-1-(5-hydroxy-3-methyl-1-phenyl-1H-pyrazol-
4-yl)prop-2-en-1-one difluoroboron chelate 4. Me2NCH(OMe)2 (0.28 ml,
2.1 mmol) was added to a suspension of chelate 3 (0.5 g, 1.8 mmol) in
THF (5 ml). The mixture was stirred at 20°C for 2 h, the precipitate
formed was filtered off and recrystallized from MeCN. Yield 0.38 g
5'-Methyl-2'-phenyl-1',2'-dihydro-2 H,3' H-3,4'-bipyrazol-3'-one 6.
Yield 60%, mp 205–206°C. IR (KBr, n/cm–1): 3248 (NH), 2922–2588
(CH=), 1640 (C=O), 1596, 1500. H NMR (DMSO-d6) d: 2.41 (s, 3H,
1
Me), 5.40 (br.s, 2H, NH), 6.50 (s, 1H, CH=), 7.19 (t, 1H, p-HPh, J 8 Hz),
7.45 (t, 2H, m-HPh, J 8 Hz), 7.61 (s, 1H, N=CH), 7.80 (d, 2H, o-HPh
,
1
(65%), mp 269–270°C. 1H NMR (DMSO-d6,) d: H NMR (CDCl3) d:
J 8 Hz). HRMS (ESI), m/z: 241.1092 [M+H]+ (calc. for C20H19N4O,
m/z: 241.1084).
3.21 (s, 6H, 2Me), 2.67 (s, 3H, Me), 5.53 (d, 1H, CH=, J 9 Hz), 7.35
(t, 1H, p-HPh, J 8 Hz), 7.52 (t, 2H, m-HPh, J 8 Hz), 7.79 (d, 2H, o-Ph,
J 8 Hz), 8.38 (d, 1H, CH=, J 9 Hz). 11B NMR (CDCl3) d: 1.29. HRMS
(ESI), m/z: 320.1382 [M+H]+ (calc. for C15H17BF2N3O2, m/z: 320.1379).
Bipyrazoles 5a,d and 6 (general procedure). The corresponding
hydrazine (1.1 mmol) was added to the suspension of chelate 4 (1 mmol)
in ethanol (5 ml). The mixture was refluxed for 3 h. The solvent was
removed, the residue was crystallized from MeCN, washed with diethtl
ether and dried in vacuo.
Compounds 5b,c (general procedure). The corresponding hydrazine
hydrochloride (1.1 mmol) and AcONa (1.1 mmol) were added to a suspen-
sion of chelate 4 (1 mmol) in ethanol (5 ml),. The mixture was refluxed
for 6 h, cooled to 20°C, and 10 ml of water was added. The solution was
extracted with ethyl acetate (3×10 ml), the organic extracts were combined
and dried over sodium sulfate, the solvent was removed, the residue was
washed with diethyl ether and dried in vacuo.
2-(4-Chlorophenyl)-5'-methyl-2'-phenyl-1',2'-dihydro-2H,3'H-3,4'-bi-
5'-Methyl-2,2'-diphenyl-1',2'-dihydro-2 H,3' H-3,4'-bipyrazol-3'-one
5a. Yield 53%, mp 202–203°C. IR (KBr, n/cm–1): 3045–2608 (CH=),
1627 (C=O), 1594, 1500. 1H NMR (DMSO-d6) d: 1.82 (s, 3H, Me),
pyrazol-3'-one 5b. Yield 70%, mp 261–262 °C. IR (KBr, n/cm–1):
1
3099–2605 (CH=), 1619 (C=O), 1593, 1497. H NMR (DMSO-d6) d:
1.89 (s, 3H, Me), 6.51 (s, 1H, CH=), 7.24 (t, 1H, p-HPh, J 8 Hz), 7.47 (m,
6H, m-HPh + C6H4Cl), 7.67 (m, 2H, o-HPh), 7.78 (s, 1H, N=CH). 13C NMR
(DMSO-d6) d: 12.44 (Me), 93.74 (C4'), 109.73 (C4), 120.37 (o-CPh),
125.18 (o-C6H4), 125.42 (p-CPh), 128.85 and 128.90 (m-CPh and m-CC H ),
6.51 (s, 1H, CH=), 7.28 (t, 1H, p-HPh, J 8 Hz), 7.32 (t, 1H, p-HPh
,
J 8 Hz), 7.43 (m, 4H, m-HPh), 7.65 (m, 4H, o-HPh), 7.78 (s, 1H, CH=).
HRMS (ESI), m/z: 317.1396 [M+H]+ (calc. for C19H17N4O, m/z:
317.1397).
6
4
131.29 (C–Cl), 133.87 (C3), 137.89 (ipso-CPh), 139.20 (ipso-CC H ),
6
4
140.36 (C5), 147.07 (C5'), signal C4' was not observed. HRMS (ESI),
m/z: 351.0996 [M+H]+ (calc. for C19H16ClN4O, m/z: 351.1007).
5'-Methyl-2'-phenyl-2-(p-tolyl)-1',2'-dihydro-2H,3'H-(3,4'-bipyrazol)-
3'-one 5c. Yield 55%, mp 214–215°C. IR (KBr, n/cm–1): 3037–2786
2,5'-Dimethyl-2'-phenyl-1',2'-dihydro-2H,3' H-3,4'-bipyrazol-3'-one
5d. Yield 45%, mp 88–89°C. IR (KBr, n/cm–1): 2923–2666 (CH=),
1610 (C=O), 1589, 1499. 1H NMR (DMSO-d6) d: 2.11 (s, 3H, Me),
3.74 (s, 3H, NMe), 6.25 (s, 1H, CH=), 7.25 (t, 1H, p-HPh), 7.44 (t, 2H,
m-HPh, J 8 Hz), 7.49 (s, 1H, N=CH), 7.74 (d, 2H, o-HPh, J 8 Hz).
13C NMR (DMSO-d6) d: 12.20 (Me), 36.73 (MeN), 106.57 (C4), 120.40
(o-CPh), 125.23 (p-CPh), 128.76 (m-CPh), 133.60 (C3), 137.60 (C5),
signals C5', C4' and C3' are not observed. HRMS (ESI), m/z: 255.1251
[M+H]+ (calc. for C14H15N4O, m/z: 255.1240).
1
(CH=), 1625 (C=O), 1593, 1501. H NMR (DMSO-d6) d: 1.82 (s, 3H,
Me), 2.35 (s, 3 H, 4-MeC6H4), 6.51 (s, 1H, CH=), 7.21 (t, 1H, p-HPh
,
J 8 Hz), 7.35 (m, 6H, m-HPh +4-MeC6H4), 7.68 (m, 2H, o-Ph), 7.73 (s,
1H, N=CH). HRMS (ESI), m/z: 331.1543 [M+H]+ (calc. for C20H19N4O,
m/z: 331.1553).
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Mendeleev Commun., 2018, 28, 612–614
N
N
References
NH
O
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H2NNH2
EtOH,
H2NOH
EtOH,
4
Me
O
Me
O
HN
N
HN N
Ph
Ph
6
7
Scheme 2
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bipyrazole 6 and isoxazolyl pyrazolone 7, respectively (Scheme 2).‡
These compound are light-green crystalline substances well
soluble in DMSO, acetonitrile, ethanol and acetone, poorly soluble
in ethyl acetate, chloroform and diethyl ether, and insoluble in
hexane. Their mass spectra contain peaks of [M+H]+. The
1H NMR spectrum of compound 6 in DMSO-d6 reveals signals
for the pyrazole protons (d ~6.5 and ~7.6 ppm). In the 1H NMR
spectrum of derivative 7 (CDCl3), the signals for the isoxazol
protons are observed at d ~6.5 and ~8.1 ppm. Both spectra
contain the signals for the methyl group and phenyl substituent
protons.
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pyrazole derivatives is yet another example of an efficient applica-
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The synthesis of the starting 4-acetyl-5-hydroxy-1-phenyl-
1H-pyrazole 3 was carried out within the framework of the State
task for 2018 (no. 0090-2017-0023).
‡
4-(Isoxazol-5-yl)-5-methyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one 7.
Hydroxyl amine (1.1 mmol) was added to a suspension of chelate 4
(1 mmol) in ethanol (5 ml) . The mixture was refluxed for 6 h, during
which the solid completely dissolved. The solution was cooled to 20°C,
and water (10 ml) was added. The mixture was extracted with EtOAc
(3×10 ml), the combined extracts were dried over sodium sulfate, the
solvent was removed, the residue was washed with diethyl ether and
dried in vacuo. Yield 76%, mp 170–171°C. IR (KBr, n/cm–1): 3206
(NH), 2902–2590 (CH=), 1637 (C=O), 1598, 1505. 1H NMR (CDCl3) d:
2.41 (s, 3H, Me), 6.45 (s, 1H, CH=), 7.10 (t, 1H, p-HPh, J 8 Hz), 7.22 (t,
2H, m-HPh), 7.40 (d, 2H, o-HPh, J 8 Hz), 8.15 (s, 1H, N=CH). HRMS
(ESI), m/z: 242.0933 [M+H]+ (calc. for C13H12N3O2, m/z: 242.0924).
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Received: 22nd June 2018; Com. 18/5619
– 614 –