Solvent-free synthesis of 3,5-di-tert-butylpyrazole and 3,5-di-substitutedbutylpyrazol-1-ylethanol

Article abstract of DOI:10.3184/174751912X13397801313284

A high-yield, solvent-free approach to the synthesis of 1,3,5-trisubstituted pyrazoles is reported. Four compounds, (3,5-di-tert-butyl- 1H-pyrazole, (2-(3,5-dimethyl-1H-pyrazol-1-yl)ethanol, 2-(3,5-di-tert-butyl-1H- pyrazol-1-yl)ethanol, 2-(3,5-diphenyl-1

Full text of DOI:10.3184/174751912X13397801313284

474 RESEARCH PAPER
AUGUST, 474–477
JOURNAL OF CHEMICAL RESEARCH 2012
Solvent-free synthesis of 3,5-di-tert-butylpyrazole and 3,5-di-substituted-
butylpyrazol-1-ylethanol
Juanita L. van Wyka, Bernard Omondia, Divambal Appavooa, Ilia A. Guzeia,b, and
James Darkwaa*
aDepartment of Chemistry, University of Johannesburg, PO Box 524, Auckland Park, 2006, South Africa
bDepartment of Chemistry, University of Wisconsin-Madison, Madison, WI 53706, USA
A high-yield, solvent-free approach to the synthesis of 1,3,5-trisubstituted pyrazoles is reported. Four compounds,
(3,5-di-tert-butyl-1H-pyrazole, (2-(3,5-dimethyl-1H-pyrazol-1-yl)ethanol, 2-(3,5-di-tert-butyl-1H-pyrazol-1-yl)ethanol,
2-(3,5-diphenyl-1H-pyrazol-1-yl)ethanol were readily prepared by solvent-free condensation of the appropriate dike-
tone and the respective hydrazine. The crystal structures of the three pyrazolyl-ethanols are typical of N-substituted
pyrazoles. All three pyrazolyl compounds show interesting inter-molecular hydrogen bonding. For the 3,5-dimethyl
compound the molecules form discrete hydrogen bonded dimers within a unit cell, while for the others the hydrogen
bonding is in a head-to-tail arrangement resulting in the formation of chains.
Keywords: solvent-free synthesis, pyrazoles, pyrazolyl
Pyrazoles and their derivatives continue to receive attention
because they are valuable compounds as pharmaceuticals,1–3 as
intermediates for industrial products,4,5 as ligands in coordina-
tion chemistry6 and in catalysis.7 However, access to pyrazoles
usually involve tedious synthetic routes and organic solvents
that are not environmentally friendly. One such synthesis is
that of 3,5-di-tert-butylpyrazole which takes four days of
refluxing and purification, followed by sublimation.8,9 A recent
report by Wang and Qin10 has shown that grinding 2,4-
pentanedione with hydrazines gives the appropriate pyrazole
derivatives, which represents a marked improvement on the
Elguero method.8 The report by Wang and Qin includes the
synthesis of 3,5-di-tert-butylpyrazole. It is, however, difficult
to see how the liquid starting materials for the synthesis of
3,5-di-tert-butylpyrazole, 2,2′,6,6′-tetramethyl-3,5-heptanedione
and hydrazine hydrate, are ground to form the product. We
have prepared 3,5-di-tert-butylpyrazole and the di-substituted
pyrazolylethanol by heating a mixture of liquid synthons,
2,2′,6,6′-tetramethyl-3,5-heptanedione and hydrazine hydrate
or di-substituted 2,4-propanedione and hydrazine ethanol
respectively at 60–70 °C in a solvent-free procedure. We report
here these syntheses.
amount of solvent. In fact for compound 1 there was no need
for any solvent at all making this is the first truly green process
for its synthesis. In contrast, the corresponding synthetic pro-
cedure reported by Wang and Qin10 involves a drop of concen-
trated sulfuric acid, washing with 10% Na2CO3 solution and
Results and discussion
Fig. 1 ORTEP diagram of pyrazole 1 with the ellipsoids drawn
at 50% probability level.
The four compounds (1–4) were readily prepared at mild
temperatures via the condensation of 2,2′,6,6′-tetramethyl-3,5-
heptandedione with hydrazine in the case of compound 1, and
for the rest of the compounds via the condensation of the cor-
responding dione with 2-hydroxyethylhydrazine. All reactions
were performed under solvent-free conditions (Scheme 1), a
critical finding that has produced promising results. All four
compounds were isolated and worked up using a minimal
Scheme 1
Fig. 2 ORTEP diagram of pyrazole 3 with the ellipsoids drawn
at 50% probability level.
* Correspondent. E-mail: jdarkwa@uj.ac.za

JOURNAL OF CHEMICAL RESEARCH 2012 475
Fig. 3 ORTEP diagram of pyrazole 4 with the ellipsoids drawn at 40% probability level. Some H atoms are omitted for clarity.
water. Our yield of 89% compares favourably with the 96%
yield reported by Wang and Qin.10 Our reaction time for the
synthesis of 1 is also considerably shorter than the procedure
reported by Elquero and co-workers,8 which is the most
commonly followed procedure for the synthesis of 1.
in the crystal structure of compound 4, but they are formed
differently and run in the crystallographic a direction. In 4, the
four molecules are arranged pairwise in a head-to-tail fashion
and there are four discrete hydrogen bonds among them. These
O–H…N type bonds are fairly strong with the average O…N
separation of 2.823(14) Å and average O-H…N angle of
172(1)°. The graph set notation for each interaction is the
same, D(2). Thus, the four symmetry independent molecules
can be considered as one “set”, and these “sets” are linked by
hydrogen bonds and propagate along the a axis in the crystal.
Similarly, all the (pyrazol-1-yl)ethanol compounds (2–4)
were formed in the absence of solvents, in contrast to the
3,5-dimethyl-11,12and 3,5-diphenyl-12 analogues reported in the
literature where the reactions were performed in absolute etha-
nol. Even with the work-up for 2–4 that requires small amounts
of solvents, our procedure11,12 is substantially greener than the
reported literature procedures for 1–4. Another major advan-
tage of our processes is short reaction times; hence using less
energy. The yields for 2–4 are also very good to excellent.
We were able to grow crystals of 2–4 by slow evaporation of
methanol solutions of 2 and 4, whilst crystals of 3 were grown
from hexane. Table 1 lists the crystallographic data and refine-
ment details for compounds 2, 3 and 4. The molecular param-
eters of the three structures are similar and fall in the usual
ranges. The N–C–C–O torsion angles in the three compounds
differ, presumably due to different packing effects and hydro-
gen bonding interactions. The most interesting aspect of the
structures are the intermolecular interactions. In solid state,
compound 2 forms O–H…N bonded dimers with the O…N
separation of 2.8512(14) Å and O–H…N angle of 177.6(15)°.
The dimers can be described with a first order graph set
notation R22(12).
Conclusions
In summary this paper reports new solvent-free synthesis
of four known pyrazoles using very mild reaction conditions
that lead to high to excellent yields. The scale on which we
performed our reactions is small but the reactions can be scaled
up, thereby offering those who need large amounts of these
compounds suitable procedures to make them.
Experimental
All chemicals were of reagent grade and used as received. All solvents
were dried over the appropriate drying agent and distilled prior to use.
Reactions and manipulation were carried out using a dual vacuum/
nitrogen line and standard Schlenk techniques unless otherwise stated.
1H NMR and 13C{1H}NMR were recorded on a Bruker Ultrashield
400 (1H NMR 400MHz, 13C{1H} NMR 100MHz) in CDCl3 and
chemical shifts were referenced to residual protons in CDCl3.
CCDC reference numbers 830774-830076.
Whereas compounds 2 and 3 crystallised with one molecule
each in the asymmetric unit, compound 4 has four symmetry-
independent molecules in the asymmetric unit. In the crystals
of all three compounds the molecules are linked together
through intermolecular O–H…N hydrogen bonds (Table 3). In
the crystal the molecules of 3 are arranged in a head-to-tail
fashion. The strong hydrogen bonds of the type O–H…N (O…
N distance is 2.8216(16) Å, the O–H…N angle spans 171(1)°)
link molecules into spiral chains running parallel to the crys-
tallographic b axis. The graph set notation for this hydrogen
bonding interaction is C(6). Similar spiral chains are observed
3,5-di-tert-Butyl-1H-pyrazole (1): A mixture of 2,2′,6,6′-tetra-
methyl-3,5-heptanedione (0.22 g, 1.0 mmol) and hydrazine monohy-
drate (0.05 g, 1.0 mmol) was heated at 70 °C in a round bottom flask
for 2 h. The reaction mixture started to solidify after 1 h during the
heating process. By the end of the reaction time the product was a
white solid mass which needed no further purification. Yield: 0.16 g
(89%); m.p. 194.0 °C (lit. 193.0 °C).8 1H NMR (CDCl3): δ 1.29 (s,
18H, C(CH3)3); 5.88 (s, 1H, pz-H). 13C{1H} NMR (CDCl3): δ 30.4,
31.8, 97.2.
2-(3,5-Dimethyl-1H-pyrazol-1-yl)ethanol (2): 2,4-Pentanedione
(1.03 g, 10 mmol) was added to 2-hydroxyethylhydrazine (0.76 g,
10.0 mmol) in a round bottom flask immersed in an ice bath. This was

476 JOURNAL OF CHEMICAL RESEARCH 2012
Table 1 Crystallographic data for the compounds 2–4
Compound
2
3
4
Empirical formula
Formula weight
Temperature (K)
Wavelength (Å)
Crystal system
Space group
a (Å)
C7H12N2O
140.19
100(2)
1.54178
Monoclinic
P21/c
4.4035(15)
16.165(5)
10.366(3)
90.
99.46(2)
90
C13H24N2O
224.34
C17H16N2O
264.32
100(2)
100(2)
0.71073
Monoclinic
C2/c
a = 28.801(4)
b = 5.7090(8)
c = 18.589(3)
α = 90
0.71073
Triclinic
–
P1
a = 10.5400(8)
b = 12.2432(9)
c = 22.0008(17)
α = 85.087(2)
β = 76.369(2)
γ = 89.665(2)
2748.7(4)
b (Å)
c (Å)
α (°)
β (°)
β = 115.851(3)
γ = 90
γ (°)
Volume (Å3)
Z
727.8(4)
4
2750.6(7)
8
8
ρ (calcd) (Mg m−3)
µ (mm-1)
1.279
1.083
1.277
0.707
0.069
0.081
F(000)
304
992
1120
Crystal size (mm3)
0.40 x 0.29 x 0.20
0.49 x 0.08 x 0.08
1.57 to 28.60°.
–38<=h<=38,
–7<=k<=7,
–24<=l<=25
38715
0.32 x 0.13 x 0.05
0.96 to 28.50°.
–14<=h<=14,
–16<=k<=16,
–29<=l<=29
103128
Theta range for data collection (°) 5.12 to 71.94.
Index ranges
–5<=h<=5,
–19<=k<=18,
–12<=l<=12
Reflections collected
10782
Independent reflections
Completeness to theta = 28.60°
Absorption correction
1411 [R(int) = 0.0183]
100.0%
3512 [R(int) = 0.0770]
99.4%
Semi-empirical from
equivalents
0.9945 and 0.9671
13837 [R(int) = 0.0442]
99.1%
Semi-empirical from
equivalents
0.9960 and 0.9746
Empirical with SADABS
Max. / min. transmission
Refinement method
0.8691 and 0.7641
Full-matrix least-squares on F2 Full-matrix least-squares on F2 Full-matrix least-squares
on F2
Data / restraints / parameters
Goodness-of-fit on F2
Final R indices [I>2sigma(I)]
R indices (all data)
1411 / 0 / 140
3512 / 0 / 153
13837 / 0 / 725
1.149
1.053
1.024
R1 = 0.0324, wR2 = 0.0842
R1 = 0.0330, wR2 = 0.0846
0.0058(9)
R1 = 0.0457, wR2 = 0.1023
R1 = 0.0850, wR2 = 0.1270
0.0024(5)
R1 = 0.0503, wR2 = 0.1210
R1 = 0.0665, wR2 = 0.1299
0.302
Extinction coefficient
Largest diff. peak and hole (e Å−3) 0.273 and –0.204
0.282 and –0.186 e Å−3
–0.285 e Å−3
Table 2 Selected bond distances and angles for compounds 2–4
Bond distances/Å
2
3
4A
4B
4C
4D
O(1)–C(1)
N(1)–C(3)
N(1)–N(2)
N(1)–C(2)
N(2)–C(5)
1.4153(13)
1.3527(14)
1.3644(13)
1.4536(14)
1.3354(14)
1.4129(18)
1.3614(18)
1.3672(16)
1.4530(18)
1.3330(18)
1.420(2)
1.361(2)
1.3563(18)
1.466(2)
1.345(2)
1.419(2)
1.362(2)
1.3580(18)
1.466(2)
1.343(2)
1.419(2)
1.359(2)
1.3589(18)
1.466(2)
1.344(2)
1.422(2)
1.361(2)
1.3572(18)
1.466(2)
1.338(2)
Bond angles/°
N(1)–N(2)–C(5)
C(2)–N(1)–N(2)
C(2)–N(1)–C(3)
C(3)–N(1)–N(2)
N(1)–C(3)–C(4)
N(2)–C(5)–C(4)
105.16(9)
119.91(9)
128.06(9)
112.01(9)
106.38(9)
110.54(9)
105.58(11)
116.59(11)
131.19(12)
112.07(11)
105.37(12)
109.95(13)
105.37(13)
118.68(13)
129.03(13)
112.04(13)
106.37(14)
110.47(14)
105.44(13)
118.77(13)
129.52(13)
111.65(13)
106.63(14)
110.61(14)
105.45(13)
118.79(13)
129.13(13)
111.80(13)
106.44(14)
110.62(14)
105.26(13)
118.67(13)
129.18(13)
112.00(13)
106.34(14)
110.86(14)
1
accompanied by evolution of heat. The addition was maintained at a
rate precluding overheating, but was generally completed within
10 min. The resultant liquid was stirred in an ice bath for 1 h and
the solid product started forming within 30 min. The product was
recrystallised from a minimum amount of diethylether at –20 °C.
vacuo. Yield: 0.18g (80%); m.p. 88.9–90.0 °C. H NMR (CDCl3):
δ 1.14 (9H, s, pz-C(CH3)3) 1.22 (9H, s, pz-C(CH3)3) 3.85 (2H, t,
J = 4.6 Hz, CH2), 4.13 (2H, t, J = 4.6 Hz, CH2), 5.77 (1H, s, pz-H).
13C{1H} NMR (CDCl3): δ 29.7, 30.1, 51.5, 61.4, 98.7, 152.0, 159.3.
Anal. Calcd for C13H24N2O (224.34): C, 69.60; H, 10.78; N, 12.49.
Found: C, 69.27; H, 10.95; N, 12.37%.
1
Yield: 1.17 g (84%); m.p. 62.0–63.5 °C. H NMR (CDCl3): δ 2.10
(3H, s, pz-CH3), 2.16 (3H, s, pz-CH3), 3.81 (2H, t, J = 5.4 Hz, CH2),
3.94 (2H, t, J = 5.4 Hz, CH2) 4.85 (1H, br s, OH) 5.70 (1H, s, pz-H).
13C{1H} NMR (CDCl3): δ 10.6, 12. 9, 49.8, 60.8, 104.5, 139.4, 147.1.
Anal. Calcd for C7H12N2O (140.19): C, 59.98; H, 8.63; N, 19.98.
Found: C, 59.51; H, 8.88; N, 20.03%.
2-(3,5-di-tert-Butyl-1H-pyrazol-1-yl)ethanol (3): A mixture of 2,2′,6,6′-
tetramethyl-3,5-heptanedione (0.21 g, 1.0 mmol) and 2-hydroxyethyl-
hydrazine (0.11 g, 1.5 mmol) was heated at 70 °C in a round-bottom
flask for 2 h. The reaction mixture was cooled to –20 °C, and the
resultant sticky solid mass was washed with cold water and dried in
2-(3,5-Diphenyl-1H-pyrazol-1-yl)ethanol (4): Synthesis of this
compound was performed in a similar manner to 3 using dibenzoyl-
methane (0.23 g, 1.0 mmol) and 2-hydroxyethylhydrazine (0.11 g,
1.5 mmol). Yield: 0.22 g (90%); m.p. 101.4–103.0 °C. 1H NMR
(CDCl3): δ 3.75 (1H, br s, OH) 4.01 (2H, t, J = 5.5 Hz, CH2), 4.22 (2H,
t, J = 5.5 Hz, CH2), 6.63 (1H, s, pz-H), 7.34 (1H, m, pz-C6H5), 7.42
(7H, m, pz-C6H5), 7.45 (2H, d, J = 7.10 Hz, pz-C6H5); 13C{1H} NMR
(CDCl3): δ 50.7, 61.6, 103.1, 125.4, 127.7, 128.6, 128.9, 130.0,
132.8,145.5, 150.7. Anal. Calcd for C17H16N2O (264.32): C, 77.25; H,
6.10; N, 10.60. Found: C, 77.10; H, 6.11; N, 10.48%.

JOURNAL OF CHEMICAL RESEARCH 2012 477
Table 3 Geometric parameters for intermolecular O-H…N and C-H…O hydrogen bonding (Å, °)
X–H…Y
X–H
H…Y
X…Y
<X–H…Y
Symmetry code
2
O(1)–H(1)…N(2)
C(2)–H(8)…O(1)
3
0.867(18)
0.966(5)
1.985(18)
2.586(15)
2.812(15)
3.5095(19)
177.6(15)
160.1(12)
1–x, 1–y, 1-–z
1+x, ½-y, ½+z
O(1)–H(1)…N(1)
C(1)–H(1A)…O(1)
C(2)–H(8)…O(1)
4
O(1A)–H(1A)…N(2C)
O(1B)–H(1B)…N(2D)
O(1C)–H(1C)…N(2B)
O(1D)–H(1D)…N(2A)
C(1B)–H(1B2)…O(1C)
C(13A)–H(13A)…O(1A)
C(13C)–H(13C)…O(1C)
C(1D)–H(1D2)…O(1B)
0.95(3)
0.98
1.88(3)
2.57
2.819(2)
3.484(3)
3.470(2)
171(3)
156
½–x, -½+y, ½–z
½–x, ½+y, ½-–z
½–x, ½-y, –z
0.98
2.50
170
0.84
0.84
0.84
0.4
0.99
0.95
0.95
0.99
1.97
2.00
1.99
1.99
2.60
2.43
2.44
2.57
2.8051(19)
2.8390(18)
2.8241(19)
2.8218(19)
3.475(2)
171
172
171
171
148
155
155
150
x, y, z
x, y, z
x, y, z
1+x, y, z
3.316(2)
3.327(2)
3.4630(19)
3
4
5
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We are grateful to the National Research Foundation (NRF),
South Africa and the University of Johannesburg for financial
support. Postdoctoral fellowships from the NRF and Univer-
sity of Johannesburg to JLvW are gratefully acknowledged.
6
7
8
9
Received 1 February 2012; accepted 23 May 2012
Paper 1201116 doi: 10.3184/174751912X13397801313284
Published online: 8 August 2012
10 Z-X. Wang and H-L. Qin, Green Chem., 2004, 6, 90.
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