Synthesis of 1,2-diphenylpyrazolidin-4-ol and its Derivatives

Article abstract of DOI:10.1007/s00706-007-0602-9

A synthesis of 1,2-diphenylpyrazolidin-4-ol via direct heterocyclization of 1,2-diphenylhydrazine with 1-chloro-2,3-epoxypropane, its O-epoxypropyl-, O-ethyl-, and O-benzylderivatives are described. Novel hydrazone derivatives with pyrazolidine units were

Full text of DOI:10.1007/s00706-007-0602-9

Monatshefte fu¨r Chemie 138, 477–480 (2007)
DOI 10.1007/s00706-007-0602-9
Printed in The Netherlands
Synthesis of 1,2-Diphenylpyrazolidin-4-ol and its Derivatives
ꢀ
Vytautas Getautis, Giedre Sinkeviciute, and Albina Stanisauskaite
Faculty of Chemical Technology, Kaunas University of Technology, Kaunas, Lithuania
Received September 12, 2006; accepted (revised) September 13, 2006; published online March 12, 2007
# Springer-Verlag 2007
Summary. A synthesis of 1,2-diphenylpyrazolidin-4-ol via
L. Balbiano [8] and F. Gerhardt [9] have found that
direct heterocyclization of 1,2-diphenylhydrazine with 1-
chloro-2,3-epoxypropane, its O-epoxypropyl-, O-ethyl-, and
O-benzylderivatives are described. Novel hydrazone deriva-
tives with pyrazolidine units were also synthesized. The com-
pounds were characterized by spectroscopic methods as well
as elemental analyses.
by refluxing phenylhydrazine with 1-chloro-2,3-ep-
oxypropane (CEP) in benzene formation of 1,3-di-
phenylamino-2-propanol hydrochloride is observed.
During its distillation the hydrochloride of phenyl-
hydrazine splits off and 1-phenyl-pyrazolidin-4-ol is
formed. However, the yield of 1-phenyl-pyrazolidin-
4-ol has not been determined since it was not iso-
lated from the reaction mixture, instead ZnCl2 was
added and it was converted to 1-phenylpyrazole. The
formation of N,N-diphenylpyrazolidin-4-ol by reac-
tion of 1,2-diphenylhydrazine (DPH) with an excess
of CEP at room temperature is described in Ref.
[10]. However, the conditions of this reaction have
not been reported. Herein we report on the synthesis
and characterization of 1,2-diphenylpyrazolidin-4-ol
and its derivatives.
Keywords. 1,2-Diphenylhydrazine; 1,2-Diphenylpyrazoli-
din-4-ol; Hydrazone; 1-Chloro-2,3-epoxypropane; Cyclo-
condensation.
Introduction
Among the hydroxy and hydrazinopyrazolidines
some are found to possess biological activity [1].
Compounds, and particularly 1,2-diphenylpyrazoli-
din-4-ol, are not widely investigated. It is known
[2, 3] that 1,2-dimethyl- and 1-methyl-2-phenylhy-
drazines with ꢀ,ꢁ-unsaturated carbonyl compounds
usually form 3-pyrazolines. Only in special cases
[4, 5] the formation of hydroxypyrazolidines, i.e.
cyclic semihydrazynales, was observed. In contrary,
when cyclic hydrazides of dicarboxylic acids (di-
ethylmalonic, succimic, maleic, phthalic) react with
unsaturated aldehydes derivatives of pyrazolidin-3-
oles as the main products are obtained. Formation of
the pyrazolidin-5-ol derivatives was observed also in
the cyclocondensation of 1-formyl-2-isopropylhydra-
zine with acetaldehyde [6], or by cyclocondensation
of 1-benzoyl-2-benzylhydrazine with acrylaldehyde
[7] in non(-)polar solvents such as CCl4 or CDCl3.
Results and Discussion
First we investigated the course of the reaction of
DPH with CEP in presence of acetic acid [11] using
methanol as the solvent. The reaction was carried
out at 45–50ꢁC for 32 h. Under these reaction con-
ditions the formation of two products was observed
on TLC. 1,2-Diphenylpyrazolidin-4-ol (1) and azo-
benzene were isolated by column chromatography,
using acetone:n-hexane ¼ 1:7 as eluent in yields of
53 and 23%. The elemental analysis and mass spec-
tral data of the first compound supported the molec-
ular formula C15H16N2O. The structure of 1 was
confirmed by the characteristical for pyrazolidi-
noles chemical shifts of carbon atoms at 59.6 and
ꢀ
Corresponding author. E-mail: albina.stanisauskaite@ktu.lt

478
V. Getautis et al.
Scheme 1
74.7 ppm in the 13C NMR spectrum, OH bond at
ꢂꢀ¼ 3555 cmꢂ1 in the IR spectrum, and the molecu-
lar ion peak [M þ H]þ at m=z ¼ 241.4 in the mass
spectrum. The cleavage of N–N and C–C bonds
with the formation of [C6H5NCH2 þ H]þdominant
(100%) in the fragmentation process of 1. The azo-
benzene was identified by its melting point. Forma-
tion of the latter may be explained by the oxidation
of the part of the starting material under these con-
ditions. When we repeated the reaction via direct
heterocyclization under Ar atmosphere the amount
of oxidation product decreased to 2–3%, and the
yield of 1 was 69%. In order to confirm the structure
of 1 some alkylation reactions were carried out. By
the reaction of 1 with CEP in the presence of pow-
dered KOH and Na2SO4 O-epoxypropylated deriva-
tive 2a was obtained. O-Ethylated and O-benzylated
derivatives 2b and 2c were obtained by the reaction
of 1 with iodoethane and benzyl chloride in the pres-
ence of powdered KOH. The nucleophilic opening
of the oxirane ring in 2a was carried out by treating
it with carbazole according to Ref. [11] to give 3.
Vilsmeier formylation of 2c followed by condensa-
tion of the resulting aldehyde 4 with hydrazine deri-
vatives yields hydrazones 5a and 5b. A singlet signal
presence of a carbonyl band and C–H bands in the
IR spectrum at about ꢂꢀ¼ 1676 and 1353 cmꢂ1 refers
to an aromatic aldehyde group in 4.
The IR, MS, and NMR spectral data of all synthe-
sized compounds are in accordance with the
assigned structures and are given in the experimental
part. The newly synthesized hydrazones 5a and 5b
were preliminary investigated as hole transporting
materials. They exhibit good compatibility with
polycarbonate and homogenic films could be pre-
pared. The hole drift mobility, measured by the xero-
graphic time of flight technique [12–14], exceeded
10ꢂ7 cm2=Vs at an electric field of 106 V=cm.
In conclusion, the conditions of alkylation-hetero-
cyclization of DFH with CEP were derived and
novel derivatives of 1 were synthesized. They can
be used as intermediates in the synthesis of hole
transporting materials.
Experimental
Melting points: Electrothermal melting temperature apparatus.
1H, 13C NMR spectra: Varian Unity Inova Instrument (300=
75MHz) in CDCl3 at room temp, TMS as internal standard.
The IR spectra (KBr) were recorded on Perkin Elmar Spec-
trum BX II FT-IR system spectrophotometer. Mass spectra
were recorded on Waters (Micromass) ZQ 2000 (20 V). The
1
in the H NMR spectrum at ꢃ ¼ 9.81 ppm and the

1,2-Diphenylpyrazolidin-4-ol and its Derivatives
479
course of the reactions and the purity of the products were
monitored by TLC on Silufol UV-254 plates and development
˚
with I2 or UV light. Silica gel (grade 62, 60–200 mesh, 150 A,
Aldrich) was used for column chromatography. Microanalyses
were performed at the Microanalytical Laboratory – Organic
Chemistry Department, Kaunas University of Technology, and
the results agreed with the calculated values within experi-
mental errors.
4-Ethoxy-1,2-diphenylpyrazolidine (2b, C17H20N2O)
To a solution of 8.7 g 1 (0.036mol) in 20 cm3 butanone 7.3 g
85% powdered KOH (0.11 mol) and 1.9 g K2CO3 (0.014mol)
were added and the mixture was stirred at 50ꢁC for 9 h. Then
5.9 g (3.9cm3) ethyl iodide (0.038mol) were added and
the mixture was stirred for 2 h. The same amounts of ethyl
iodide were added after 2, 4, and 6 h. Then 2 g of 85% pow-
dered KOH (0.03 mol) were added and the mixture was stirred
at 40ꢁC for 70h. After termination of the reaction (eluent:
acetone:diethyl ether:n-hexane¼ 3:2:18), the mixture was
extracted with diethy ether, washed with distilled H2O until
neutral. The organic layer was dried (MgSO4), and the sol-
vent was evaporated by rotary evaporation. The crude product
was purified by column chromatography on silica gel using
acetone:n-hexane (1:7) as eluent. The product was recrys-
tallized from ethanol and dried. Yield 5 g (52%); mp 65–
67ꢁC. IR (KBr): ꢂꢀ¼ 3086, 3062, 3040, 3025 (CHarom),
2972, 2945, 2914, 2873 (CHaliph), 1597, 1506, 1466, 1441
(C¼C, C–N), 745, 691, 667 (CH¼CH of monosubstituted
1,2-Diphenylpyrazolidin-4-ol (1, C15H16N2O)
A. A mixture of 18.4g DPH (0.1mol), 30.1g CEP
(0.325 mol), 25cm3 methanol, and 5 cm3 acetic acid was stir-
red at 50–55ꢁC for 32 h. After termination of the reaction
the excess of CEP, methanol, and acetic acid was removed
by rotary evaporation. The residue was purified by column
chromatography on silica gel using acetone:n-hexane¼ 1:7
as eluent. Two products were obtained. The yield of 1 was
13 g (54%); mp 111–112ꢁC; the yield of azobenzene (mp
65–68ꢁ) – 4 g (23%). For 1: MS (APCI, 20 V): m=z (%) ¼
241.4 ([M þ H]þ, 9), 223.4 ([M þ H]þ-H2O, 19), 136.2
([PhNHCH2CHO þ H]þ, 28), 120.1 ([PhNCH2CHþ H]þ,
18), 106.0 ([PhNCH2 þ H]þ, 100); IR (KBr): ꢂꢀ¼ 3555 (OH),
3087, 3057, 3048, 3035, 3023 (CHarom), 2936, 2917, 2874,
2783 (CHaliph), 1592, 1497, 1460, 1454 (C¼C, C–N), 747,
benzene) cmꢂ1
.
4-Benzyloxy-1,2-diphenylpyrazolidine (2c, C23H22N2O)
A mixture of 7.2 g 1 (0.03 mol), 22.8 g benzylchloride
(0.18 mol), 5.9 g 85% powdered KOH (0.09 mol), and
2.1 g Na2SO4 (0.015 mol) was stirred at 70ꢁC for 3 h (elu-
ent: acetone:n-hexane ¼ 7:18). Then the mixture was left at
room temperature. The crystals formed upon standing were
filtered off, washed with distilled H2O until neutral, and
dried. The product was recrystallized from CHCl3, dried,
and used for synthesis of the aldehyde. Yield 4 g (43%);
mp 121–122ꢁC. IR (KBr): ꢂꢀ¼ 3084, 3064, 3050, 3032,
3019, 3009 (CHarom), 2945, 2920, 2899, 2856, 2779
(CHaliph, C–H combination frequency of aldehyde group),
1596, 1494, 1470, 1461, 1452 (C¼C, C–N), 751, 714,
697, 658 (CH¼CH of monosubstituted benzene) cmꢂ1
;
1H NMR (CDCl3): ꢃ ¼ 7.41–6.55 (m, 10H, Ph), 4.51 (s,
CH(OH)), 3.91–3.18 (m, NCH2CHCH2N), 1.77 (split s, OH)
ppm; 13C NMR (75 MHz, CDCl3): ꢃ ¼ 151.9 (arom C), 129.4,
120.4, 114.3 (arom CH), 74.7 (C-4), 59.6 (C-3, C-5) ppm.
B. The mixture of 55.3 g DFH (0.3mol), 89.7g CEP
(0.975 mol), 75 cm3 methanol, and 15cm3 acetic acid was
stirred at 50–55ꢁC for 32h under Ar. After termination
of the reaction the excess of CEP, methanol, and acetic acid
was removed by rotary evaporation. The residue was dissolved
in the mixture of butanone:n-hexane ¼ 1:3. The formed crys-
tals were filtered off, washed with the same mixture and re-
crystallized from butanone:n-hexane ¼ 1:3 to afford colorless
needles. Yield 50g (69%); mp 111–112ꢁC.
697, 667 (CH¼CH of monosubstituted benzene) cmꢂ1
;
1H NMR (CDCl3): ꢃ ¼ 7.47–6.78 (m, 15H, Ph), 4.42–4.29
(m, CHOCH2), 3.90–3.40 (m, 4H, NCH2CHCH2N) ppm;
13C NMR (75 MHz, CDCl3): ꢃ ¼ 151.9 (arom C), 129.4,
120.4, 114.3 (arom CH), 74.7 (C-4), 59.6 (C-3, C-5) ppm.
4-(2,3-Epoxypropoxy)-1,2-diphenylpyrazolidine
1-(1,2-Diphenylpyrazolidin-4-oxy)-3-(carbazol-9-yl)-
2-propanol (3, C30H29N3O2)
(2a, C18H20N2O2)
A mixture of 5.1g 1 (0.02 mol), 19.4g CEP (0.21 mol), 4.2 g
85% powdered KOH (0.064 mol), and 3 g anhydrous Na2SO4
(0.02 mol) was stirred at 50ꢁC until 1 was completely con-
sumed. Then the mixture was extracted with diethyl ether,
washed with distilled H2O until neutral, dried (MgSO4), and
the solvents were removed by rotary evaporation. The residue
was left at room temperature. The crystals formed upon stand-
ing were filtered off, washed with 2-propanol, and dried. Yield
5 g (79%); mp 66–67ꢁC. IR (KBr): ꢂꢀ¼ 3088, 3057, 3020,
3003 (CHarom), 2933, 2914, 2854 (CHaliph), 1595, 1493,
1459, 1452 (C¼C, C–N), 1262 (cycle of oxyrane), 755,
To a solution of 3 g 2a (0.01 mol) and 1.7 g carbazole
(0.01 mol), 2 g 85% powdered KOH (0.03 mol), and 0.7 g
anhydrous Na2SO4 (0.005 mol) were added. The mix-
ture was stirred at room temperature for 4 h (eluent: ace-
tone:n-hexane ¼ 7:18). Then the mixture was extracted
with ethyl acetate as described above for 2b. The solid
residue was purified by column chromatography using
acetone:n-hexane ¼ 3:22 as eluent. Yield 4 g (86%) 3;
mp 134–136ꢁC. IR (KBr): ꢂꢀ¼ 3553 (OH), 3045, 3022,
3003 (CHarom), 2936, 2911, 2870 (CHaliph), 1625, 1594,
1491, 1461, 1452 (C¼C, C–N), 756, 734, 726, 698, 667
748, 696, 653 (CH¼CH of monosubstituted benzene) cmꢂ1
;
1H NMR (CDCl3): ꢃ ¼ 7.28–6.78 (m, 10H, Ph), 4.44–4.36
(m, 1H, CH2OCH), 3.92–3.20 (m, 6H, NCH2CHCH2N,
OCH2CH), 2.92–2.84 (m, 1H, CH2 of epoxy group), 2.63–
2.56 (m, 1H, CH2 of epoxy group), 2.33–2.22 (m, 1H,
OCH2CH) ppm.
(CH¼CH monosubstituted benzene) cmꢂ1
;
1H NMR
(CDCl3): ꢃ ¼ 8.03 (d, 2H, J ¼ 7.7 Hz, 4-H Het), 7.65–6.68
(m, 16H, Het, Ph), 4.20–3.60 (m, 5H, NCH2CHCH2N,
CH2OCH), 3.50–3.00 (m, 5H, OCH2CHCH2N), 1.78 (s,
OH) ppm.

480
V. Getautis et al.: 1,2-Diphenylpyrazolidin-4-ol and its Derivatives
10cm3 methanol was added. The time of the reaction was 1 h
(eluent: acetone:n-hexane¼ 1:4). The mixture was extracted
with CHCl3. The organic layer was dried (MgSO4), filtered,
and solvents were removed by rotary evaporation. The residue
was purified by column chromatography using acetone:n-
hexane¼ 3:22 as eluent. Fractions containing resulting pro-
duct were collected and the eluent was evaporated. Then the
20% solution of 5b in 14cm3 toluene was poured with inten-
sive stirring into a 10-fold excess of n-hexane to obtain 2.8 g
4-Benzyloxy-1-phenyl-2-(4-formylphenyl)pyrazolidine
(4, C23H22N2O2)
To a 100 cm3 3-neck round bottom flask equipped with ther-
mometer, magnetical stirrer, and additional funnel 3.3cm3
DMF (0.0432mol) were added. The content was cooled in a
NaCl=ice bath. When the temperature inside the flask reached
0ꢁC, 2 cm3 POCl3 (0.0216 mol) were added slowly. During the
addition of POCl3, the temperature of the mixture was not
allowed to rise above 5ꢁC. When the addition was completed,
the reaction mixture was allowed to warm to room tempera-
ture. A solution of 6 g 2c (0.018mol) in 15 cm3 DMF was
added and the mixture was heated to 70–75ꢁC for 3 h. The hot
reaction mixture was poured into a 250 cm3 beaker containing
100 g ice. The mixture was neutralized by adding the solution
of 6.42g CH3COONa in 16 g H2O and allowed to stand at 5ꢁC
for 24 h. The formed greenish solid was filtered off, washed
repeatedly with H2O followed by 2-propanol, and dried.
The crude product was recrystallized from methanol:ethyl
acetate ¼ 1:1. The crystals formed upon standing were filtered
off and washed with 2-propanol. Yield 2.5 g (39%); mp 145–
148ꢁC. IR (KBr): ꢂꢀ¼ 3086, 3065, 3033, 3009 (CHarom), 2942,
2922, 2899, 2859 (CHaliph), 1599, 1493, 1469, 1454 (C¼C,
C–N), 748, 710, 695, 678 (CH¼CH of monosubstituted
1
(69%) 7; mp 168–170ꢁC. H NMR (CDCl3): ꢃ ¼ 7.47–7.07
(several m, 25H, Ph, CH¼N), 6.74–6.69 (m, 1H, 4-H
CH2-Ph), 6.55–6.52 (m, 4H, 1,4-disubstituted benzene),
4.61 (s, OCH2), 3.91–3.89 (m, OCH), 3.45–3.22 (m, 4H,
NCH2CHCH2N) ppm.
Acknowledgements
Financial support of this research by the Lithuanian
Science and Studies Foundation (B-18=2006) is gratefully
acknowledged.
1
References
benzene); H NMR (CDCl3): ꢃ ¼ 9.81 (s, CHO), 7.86–7.69
(m, 2H, Ph), 7.40–6.80 (m, 12H, Ph), 4.53–4.31 (m, 3H,
CHOCH2), 3.95–3.53 (m, 4H, NCH2CHCH2N).
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N-methyl-N-phenylhydrazone (5a, C30H30N4O)
To a solution of 1 g 4 (2.9 mmol) in 1 cm3 toluene:2-propa-
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148ꢁC. IR (KBr): ꢂꢀ¼ 3083, 3059, 3028, 3006 (CHarom), 2987,
2954, 2926, 2009, 2889, 2859 (CHaliph), 1598, 1498, 1461,
1454 (C¼C, C–N), 751, 696, 664 (CH¼CH monosubstituted
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Ph), 7.48 (s, CH¼N), 7.40–7.19 (m, 11H, Ph), 7.01–6.82 (m,
8H, Ph), 4.49–4.38 (m, OCH), 4.41 (s, OCH2), 3.92–3.46 (m,
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of 1.7 g N,N-diphenylhydrazine hydrochloride (0.0078 mol) in
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