Evaluation of the synthesis of 1-(pentafluorophenyl)-4,5-dihydro-1H- pyrazoles using green metrics

Article abstract of DOI:10.1007/s00706-013-0930-x

1-(Pentafluorophenyl)-4,5-dihydro-1H-pyrazoles were synthesized from the cyclocondensation reactions of 4-alkoxy-1,1,1-trihalo-3-alken-2-ones (CX ₃C(O)CH=C(R¹)OR, where X = F, Cl; R = Me, Et; R ¹ = H, Me, Et, n-Pr, i-Pr, n-Bu, i-Pent, Ph, 4-Cl-C₆H ₄, 4-Br-C₆H₄, 4-F-C₆H₄) with pentafluorophenyl hydrazine. Pyrazoles were obtained under microwave irradiation in solvent-free conditions or under conventional heating in the ionic liquid 1-butyl-3-methylimidazolium tetrafluoroborate, [BMIM][BF ₄]. These procedures furnished products in moderate to good yields in a short reaction time. Atom economy, reaction mass efficiency (RME), and environmental factor (E-factor) were determined for the cyclocondensation reaction performed under microwave (MW)/solvent-free and under conventional thermal heating/[BMIM][BF₄] conditions. RME and E-factor indicated that the solvent-free procedure is invariably less green than [BMIM][BF ₄] when the isolated product was considered.

Full text of DOI:10.1007/s00706-013-0930-x

Monatsh Chem (2013) 144:1043–1050
DOI 10.1007/s00706-013-0930-x
ORIGINAL PAPER
Evaluation of the synthesis of 1-(pentafluorophenyl)-4,
5-dihydro-1H-pyrazoles using green metrics
•
Marcos A. P. Martins Paulo H. Beck Lilian Buriol Clarissa P. Frizzo
•
•
•
•
Dayse N. Moreira Mara R. B. Marzari Marcileia Zanatta
•
•
•
Pablo Machado Nilo Zanatta Helio G. Bonacorso
•
Received: 17 July 2012 / Accepted: 16 January 2013 / Published online: 5 March 2013
Ó Springer-Verlag Wien 2013
Abstract 1-(Pentafluorophenyl)-4,5-dihydro-1H-pyrazoles
were synthesized from the cyclocondensation reactions of
4-alkoxy-1,1,1-trihalo-3-alken-2-ones (CX3C(O)CH=C(R1)
OR, where X = F, Cl; R = Me, Et; R1 = H, Me, Et, n-Pr,
i-Pr, n-Bu, i-Pent, Ph, 4-Cl-C6H4, 4-Br-C6H4, 4-F-C6H4)
with pentafluorophenyl hydrazine. Pyrazoles were obtained
under microwave irradiation in solvent-free conditions or
under conventional heating in the ionic liquid 1-butyl-3-
methylimidazolium tetrafluoroborate, [BMIM][BF4]. These
procedures furnished products in moderate to good yields in
a short reaction time. Atom economy, reaction mass effi-
ciency (RME), and environmental factor (E-factor) were
determined for the cyclocondensation reaction performed
under microwave (MW)/solvent-free and under conven-
tional thermal heating/[BMIM][BF4] conditions. RME and
E-factor indicated that the solvent-free procedure is
invariably less green than [BMIM][BF4] when the isolated
product was considered.
Introduction
Efforts to minimize the environmental impacts of a syn-
thetic process should commence in the earliest stage of the
product/process development. Some tools have been
developed to support less aggressive processes [1–10], such
as selecting solvents taking into account environmental,
health, and safety aspects as well as the life cycle assess-
ment (LCA) and economic criteria. Kralisch et al. [11, 12]
evaluated and optimized an approach considering ecolog-
ical and economic aspects of the production of some
reactants and solvents used in synthesis, workup, recycling,
and disposal. To evaluate the greenness of a product or
process the authors used three main criteria: energy factor
(EF), environmental and human health factor (EHF), and
cost factor (CF). Such criteria describe the energy demand,
toxicity, and the cost of chemicals, auxiliaries, and equip-
ment used during a product or process of life cycle stages.
There are some other metrics which can also be used such
as atom economy (AE) [13, 14], reaction mass efficiency
(RME) [15], environmental factor (E-factor) [16–19],
effective mass yield [20], mass intensity [21], and the
process profile [22].
Keywords Pyrazoles ꢀ Atom economy ꢀ
Reaction mass efficiency ꢀ E-factor ꢀ Green chemistry
For about 20 years, our research group has been work-
ing with cyclocondensation reactions to obtain useful
heterocyclic compounds from inexpensive starting materi-
als and clean methodologies [23–29] and recently we
published two reviews in the field [30, 31]. Thus, the aim of
this study was to determine the AE, RME, and E-factor of
the synthesis of 3-alkyl(aryl)-1-(pentafluorophenyl)-5-(tri-
halomethyl)-4,5-dihydro-5-hydroxy-1H-pyrazoles through
a cyclocondensation reaction of 4-alkoxy-1,1,1-trihalo-3-
alken-2-ones with pentafluorophenyl hydrazine in solvent-
free conditions under microwave irradiation and in ionic
liquid under conventional thermal heating conditions.
Electronic supplementary material The online version of this
article (doi:10.1007/s00706-013-0930-x) contains supplementary
material, which is available to authorized users.
M. A. P. Martins ꢀ P. H. Beck ꢀ L. Buriol ꢀ
C. P. Frizzo (&) ꢀ D. N. Moreira ꢀ M. R. B. Marzari ꢀ
M. Zanatta ꢀ P. Machado ꢀ N. Zanatta ꢀ H. G. Bonacorso
´
´
Nucleo de Quımica de Heterociclos (NUQUIMHE),
Departament of Chemistry, Federal University of Santa Maria,
Santa Maria, RS 97105-900, Brazil
e-mail: clarissa.frizzo@yahoo.com.br
M. A. P. Martins
e-mail: mmartins@base.ufsm.br
123

1044
M. A. P. Martins et al.
Results and discussion
Reaction and conditions
Scheme 1
R1
H2N
F
H
O
NH
F
N
X
3C
R
O
N
F
O
F
F
-
H
+
Pyrazoles are the main or secondary parts of important drugs
such as rimonabant [32] and celecoxib [33, 34]. Cyclocon-
densation is the most common, rapid, and simple method to
synthesize pyrazoles. This reaction is particularly useful in
medicinal chemistry when associated with microwave (MW)
assisted organic synthesis and/or use of solvents that accel-
erate the reaction, such as ionic liquids. There are several
reports related to cyclocondensation reactions using ionic
liquid [30] or MW irradiation in solvent-free conditions [31],
whose process is considered green in qualitative terms.
In this study, 1-(pentafluorophenyl)-4,5-dihydro-1H-
pyrazoles 4, 5 were synthesized from the cyclocondensa-
tion reaction of 4-alkoxy-1,1,1-trihalo-3-alken-2-ones 1, 2
with pentafluorophenyl hydrazine 3. A series of novel
3-alkyl(aryl)-1-(pentafluorophenyl)-5-(trihalomethyl)-4,5-
dihydro-1H-pyrazol-5-ols (4a–4e, 4h, 4j, 4k, 5a–5g, 5i–
5k) were synthesized under MW irradiation in solvent-free
conditions (Scheme 1). In addition, a series of 3-alkyl
(aryl)-1-(pentafluorophenyl)-5-(trihalomethyl)-4,5-dihydro-
1H-pyrazol-5-ols (4b–4d, 4f, 4j–4m) were synthesized
under conventional thermal heating in ionic liquid [BMIM]
[BF4] conditions (Scheme 2).
i
R
O
+
F
F
F
X
3C
R1
F
F
1, 2
3
4, 5
i: Solvent-free, MW, 100 °C, 6 min
Entry
X
F
F
F
F
F
F
F
F
R
R1
H
Me
Et
Product Yield (%)a
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
Et
90
94
92
85
78
80
83
75
88
85
93
94
90
73
80
89
90
78
4a
4b
4c
4d
4e
4h
4j
4k
5a
5b
5c
5d
5e
5f
Me
Me
Me
Me
Me
Pr
i-Pr
Ph
Me 4-Br-C6H4
Me
4-F-C6H4
H
Cl Et
Cl Me
Cl Me
Cl Me
Cl Me
Cl Me
Cl Me
Cl Me 4-Cl-C6H4
Cl Me 4-Br-C6H4
Cl Me
Me
Et
Pr
i-Pr
Bu
i-Pent
Atom economy and reaction mass efficiency
5g
5i
Atom economy is a calculation of how much of the reactant
remains in the desired product regardless of the steps to
obtain it. The method to calculate AE ignores the reaction
yield as well as the use of solvents, auxiliaries, and molar
excesses of reactants. Thus, AE is the ratio of the molecular
weight of the target molecule to the sum total of the
molecular weights of all substances produced in the stoi-
chiometric equation for the reaction involved [15]. An ideal
reaction has an AE of 100 %. For most reactions, a 100 %
economy can never be reached owing to the nature of the
reaction. On the other hand, RME takes into account yields,
the actual molar quantities of reactants, and the concepts of
AE. In other words, RME is the percentage of the mass of
the reactants that remains in the product [15]. In this work,
AE and RME for the cyclocondensation reactions were
calculated by Eqs. (1) and (2), respectively [15].
5j
4-F-C6H4
5k
aIsolated product
the molecular weight of reactant R2. In Eq. (2), mass of P
is the mass of product isolated, and mass R1 and mass of
R2 are the mass of reactants R1 and R2, respectively, input
to obtain mass of P.
AE and RME were computed for some products in both
solvent-free/MW and [BMIM][BF4]/conventional thermal
heating methods (Table 1). In all cases, AE is less than
100 % owing to the formation of ROH (R = Me, Et) as a
by-product. In addition, since the product is formed in only
one step, this synthesis is efficient in maintaining the
reagent atoms in the product. There is a small variation in
the AE for different products because the by product formed
was methanol in all cases studied (Table 1). As expected,
RME calculation, which provides a more realistic assess-
ment of the synthetic procedures, takes into account the
yield of reaction and molar excess of pentafluorophenyl
hydrazine (20 %) required for the total conversion of the
ꢀ
ꢁ
mwP
AE ¼
ꢁ 100
ð1Þ
ð2Þ
mwR1 þ mwR2
ꢀ
ꢁ
mass of PðgÞ
RME ¼
ꢁ 100
mass of R1ðgÞ þ mass of R2ðgÞ
In Eq. (1), mwP is the molecular weight of product P,
mwR1 is the molecular weight of reactant R1, and mwR2 is
123

Evaluation of the synthesis
1045
products. Because RME accounts for all reactant mass (i.e.,
actual stoichiometric quantities used), yield, and AE, the
combined metric AE/RME is probably the most helpful
metric for chemists to focus attention on how far from
‘green’ the current processes are being operated [15]. From
the results in Table 1, it is possible to rationalize that
although the reaction occurs with good AE, the poor yields
of the products in [BMIM][BF4]/conventional thermal
heating conditions contributed to lower RME.
rapid processes and is based on generated waste [16–19].
The E-factor may be obtained for (1) the synthesis step
(SYS); (2) for the synthesis and product isolation steps
(SYS ? PIS); and (3) for the synthesis and workup steps
(SYS ? PIS ? PPS) (Fig. 1) [31].
For each case in this study, E-factors were calculated on
the basis of the amount of reactant and the volume of
solvent used in the synthesis (SYS) and synthesis and
isolation (SYS ? PIS). For the synthesis under MW con-
ditions, where purification was needed, E-factors were
calculated for synthesis, isolation, and purification
(SYS ? PIS ? PPS). The E-factor was calculated by
Eq. (3). Ionic liquid and water are not computed in the
E-factor because they can be recovered after the separation
of the product [16–18]. The values of the E-factors for the
reaction in solvent-free/MW and [BMIM][BF4]/conven-
tional thermal heating are shown in Table 2.
E-factor
The E-factor is the ratio of generated waste weight and end
product total weight. It is a useful tool for the evaluation of
Scheme 2
R1
mreactants ꢂ mproduct minput materials ꢂ mproduct
H2N
E ꢂ factor ¼
¼
H
O
NH
mproduct
mproduct
N
F
3C
N
O
OMe
R1
F
F
F
F
+
i
MeOH
+
ð3Þ
F
F
F
F
3C
As expected, the best E-factor values were found in the
reactions performed in solvent-free/MW conditions when
the SYS step is considered in the calculation. When the
product extraction solvent was computed, E-factor values
increased dramatically. This increase reflects the huge
amount of ethyl acetate and drying agent used in the
extraction, despite the MW reaction being solvent-
free. Products of the reaction in [BMIM][BF4] were
extracted with dichloromethane and a smaller amount of
solvent was necessary. However, the E-factor values in
relation to solvent-free/MW synthesis were similar. Note
that dichloromethane and [BMIM][BF4] are as toxic as
ethyl acetate, but this fact is not considered in the E-factor.
When considering the purification step (necessary only for
the solvent-free reaction), the E-factor for the solvent-free/
MW synthesis has higher values. The great amount of
solvent used in the product extraction in both methods was
more important than the yield in determining the E-factor
values. Consequently, the inclusion of solvents and drying
F
F
1
F
3
4
i: [BMIM][BF4], 80 °C, 1h
Entry
1
R1
Product Yield (%)a
Me
74
82
56
61
72
43
79
58
4b
4c
4d
4f
2
3
4
5
6
7
8
Et
Pr
Bu
4-Br-C6H4
4-F-C6H4
i-Bu
4j
4k
4l
4-Me-C6H4
4m
aIsolated product
Table 1 AE and RME for solvent-free/MW and [BMIM][BF4]/conventional thermal heating
Compound
Solvent-free/MW
AE (%)
[BMIM][BF4]/conventional thermal heating
Yield (%)a
RME (%)
Yield (%)a
RME (%)
4b
4c
4d
4j
91.3
91.6
91.9
93.5
92.8
94
92
85
83
75
77
76
71
72
64
74
82
56
72
43
61
68
47
62
37
4k
a
Isolated product
123

1046
M. A. P. Martins et al.
Fig. 1 Procedure to obtain
products: synthesis step (SYS),
product isolation steps (PIS),
and product purification step
(PPS)
PI
PP
SY
Product + Waste
Crude Product
Product
Reactants
Work-up
Table 2 E-factor for the reaction in solvent-free/MW and [BMIM][BF4]/conventional thermal heating
Compound
E-factor solvent-free/MW
E-factor [BMIM][BF4]/conventional thermal heating
Yield (%)a
SYS
SYS ? PIS
SYS ? PIS ? PPS
Yield (%)a
SYS
SYS ? PIS
4b
4c
4d
4j
4k
a
94
92
85
83
75
0.29
0.31
0.41
0.39
0.56
124.8
122.4
127.4
99.7
250.6
245.8
255.8
200.1
253.6
74
82
56
72
43
0.64
0.47
1.14
0.6
84.3
72.9
103.1
61.2
126.4
1.73
117.8
Isolated product
agent when computing the E-factor values give us an idea
of the importance of this step in generating waste on the
laboratory scale. In addition, these results show that when
we take into account the isolated product, the solvent-free/
MW procedure is invariably less green than [BMIM][BF4]/
conventional thermal heating.
without further purification. 1H and 13C NMR spectra were
recorded on a Bruker DPX 400 (1H at 400.13 MHz and 13
C
at 100.62 MHz) or Bruker DPX 200 (1H at 200.13 MHz
and 13C at 50.32 MHz) in CDCl3 or (CD3)C = O/TMS
solutions at 298 K. The general reproducibility of chemical
shift data was estimated to be not greater than 0.01 ppm.
All spectra were acquired in a 5-mm tube, at natural
abundance. J values are given in Hz. Mass spectra were
registered on an HP 5973 MSD connected to an HP 6890
GC system and interfaced to a Pentium PC. The gas
chromatograph was equipped with a split/split less
injector, cross-linked to an HP-5 capillary column (30 m,
0.32 mm internal diameter), and helium was used as the
carrier gas. The melting points were measured using a
Thus, we also observed that the solvent-free/MW
method furnished higher values of RME, whereas higher
E-factor values (considering isolated product) reflected the
large amounts of waste produced. On the other hand, the
reaction in the [BMIM][BF4]/conventional thermal heating
method furnished lower RME, whereas lower E-factor
values reflected a lower waste production.
In summary, this study showed that AE is more useful to
compare alternative routes to obtain the same products;
however, it may also be useful as an organizing concept in
combination with other metrics. RME and E-factor take
into account the yield of reaction and the need for a molar
excess. In particular, E-factor takes into account the solvent
and drying agents (and other inputs) that are not computed
in RME. In this work, RME and E-factor indicated that the
solvent-free/MW method is invariably less green than the
[BMIM][BF4]/conventional thermal heating method when
we consider the isolated product. Thus, RME and E-factor
appear to be a useful metric to focus on deriving chemical
procedures that may lead to more sustainable business
practices.
´
Microquımica MQAPF 301. The experiments were per-
formed in an MW Discover CEM using the simultaneous
cooling operation mode. The ionic liquid 1-butyl-3-
methylimidazolium tetrafluoroborate, [BMIM][BF4], was
prepared according to procedures from the literature [23].
4-Alkoxy-1,1,1-trihalo-3-alken-2-ones 1, 2 were obtained
from the acylation reaction of enol ether or acetal with
trifluoroacetic anhydride or trichloroacetyl chloride in
accordance with the methodology developed in our lab-
oratory [29]. Pentafluorophenyl hydrazine was obtained
commercially.
Typical procedure for the synthesis of 4,5-dihydro-1H-
pyrazoles 4, 5 in solvent-free/MW conditions
Experimental
A mixture of 4-alkoxy-1,1,1-trihalo-3-alken-2-ones 1, 2
(1 mmol) and pentafluorophenyl hydrazine (1.2 mmol) was
irradiated by a Discover CEM microwave for 6 min at
100 °C. Water (10 cm3) was added to the reaction mixture
Unless otherwise indicated, all common reagents and sol-
vents were used as obtained from commercial suppliers
123

Evaluation of the synthesis
1047
1-(Pentafluorophenyl)-3-propyl-5-(trifluoromethyl)-4,5-
and products 4, 5 were extracted with ethyl acetate
(2 9 20 cm3) and dried with 3.25 g MgSO4 (27 mmol).
The solvent was removed in a rotary evaporator and the
product was obtained in high purity. When necessary, the
product was recrystallized from cyclohexane (40 cm3) or
hexane (60 cm3).
dihydro-5-hydroxy-1H-pyrazole (4d, C13H10F8N2O)
Yield 85 % (MW), 56 % (conventional); m.p.:
103–105 °C; 1H NMR (400 MHz, CDCl3): d = 0.98 (t,
3H, H9), 1.63 (q, 2H, H8), 2.38 (t, 2H, H7), 3.25 (d, 1H,
2
2J = 18 Hz, H4a), 3.45 (d, 1H, J = 18 Hz, H4b) ppm;
13C NMR (100 MHz, (CD3)2CO): d = 14.9 (CH3), 21.2,
33.1 (CH2), 46.9 (C4), 95.1 (q, 2J = 31 Hz, C5), 125.5 (q,
1J = 282 Hz, CF3), 149.8, 147.3, 144.1, 140.7, 138.3,
119.5 (PhF5), 156.2 (C3) ppm; MS (EI, 70 eV): m/
z (%) = 362 (M?, 25), 345 (1), 293 (100), 196 (15).
Typical procedure for the synthesis of 4,5-dihydro-1H-
pyrazoles 4 in [BMIM][BF4]/conventional thermal
heating
A
mixture of 4-alkoxy-1,1,1-trihalo-3-alken-2-ones 1
3-(1-Methylethyl)-1-(pentafluorophenyl)-5-
(trifluoromethyl)-4,5-dihydro-5-hydroxy-1H-pyrazole
(4e, C13H10F8N2O)
(1 mmol), pentafluorophenyl hydrazine (1.2 mmol), and
[BMIM][BF4] (1 mmol) was stirred at 80 °C for 1 h.
Products 4 were extracted with dichloromethane (10 cm3),
washed with water (3 9 10 cm3), and dried with 7.40 g
Na2SO4 (52 mmol). The solvent was removed in a rotary
evaporator to afford the product in high purity and further
purification was not necessary.
Yield 78 %; m.p.: 120–123 °C; 1H NMR (400 MHz,
CDCl3): d = 1.19 (d, 6H, H8), 2.69 (m, 1H, H7), 3.03 (d,
1H, 2J = 18 Hz, H4a), 3.37 (d, 1H, 2J = 18 Hz, H4b) ppm;
13C NMR (100 MHz, CDCl3): d = 19.7 (CH3), 19.9 (CH3),
2
29.4 (CH), 43.7 (C4), 92.9 (q, J = 31 Hz, C5), 122.0 (q,
1J = 282 Hz, CF3), 147.7, 145.2, 142.6, 140.1, 138.9, 136.4
(PhF5), 158.8 (C3) ppm; MS (EI, 70 eV): m/z (%) = 362
(M?, 90), 345 (1), 303 (10), 293 (100), 195 (15).
1-(Pentafluorophenyl)-5-(trifluoromethyl)-4,5-dihydro-5-
hydroxy-1H-pyrazole (4a, C10H4F8N2O)
Yield 90 %; oil; 1H NMR (400 MHz, CDCl3): d = 3.33 (d,
1H, 2J = 18 Hz, H4a), 3.51 (d, 1H, 2J = 18 Hz, H4b),
7.16 (s, 1H, H3) ppm; 13C NMR (100 MHz, (CD3)2CO):
d = 46.0 (C4), 93.8 (q, 2J = 31 Hz, C5), 125.5 (q,
1J = 282 Hz, CF3), 149.8, 147.3, 140.7, 140.8, 138.8,
150.0 (PhF5), 147.3 (C3) ppm; MS (EI, 70 eV):
m/z (%) = 320 (M?, 35), 303 (1), 251 (100), 84 (5).
3-Butyl-1-(pentafluorophenyl)-5-(trifluoromethyl)-4,5-
dihydro-5-hydroxy-1H-pyrazole (4f, C14H12F8N2O)
Yield 61 %; oil; 1H NMR (200 MHz, CDCl3): d = 1.95 (t,
3H, CH3), 2.40 (st, 2H,CH2), 2.60 (qui, 2H, CH2), 3.04 (t,
2
2H, CH2), 3.90 (d, 1H, J = 19 Hz, H4a), 4.41 (d, 1H,
2J = 19 Hz, H4b) ppm; 13C NMR (100 MHz, CDCl3):
d = 13.6 (CH3), 22.2 (CH2), 28.4 (CH2), 29.4 (CH2), 45.5
3-Methyl-1-(pentafluorophenyl)-5-(trifluoromethyl)-4,5-
dihydro-5-hydroxy-1H-pyrazole (4b, C11H6F8N2O)
Yield 94 % (MW), 74 % (conventional); m.p.:
2
1
(C4), 92.4 (q, J = 32 Hz, C5), 122.7 (q, J = 283 Hz,
CF3), 149.1, 144.9, 140.1, 135.5 (PhF5), 154.4 (C3) ppm;
MS (EI, 70 eV): m/z (%) = 376 (M?, 22), 317 (74), 307
(100), 181 (43).
1
130–131 °C; H NMR (400 MHz, CDCl3): d = 2.04 (s,
3H, H7), 3.21 (d, 1H, 2J = 18 Hz, H4a), 3.47 (d, 1H,
2J = 18 Hz, H4b) ppm; 13C NMR (100 MHz, (CD3)2CO):
1-(Pentafluorophenyl)-3-phenyl-5-(trifluoromethyl)-4,5-
dihydro-5-hydroxy-1H-pyrazole (4h, C16H8F8N2O)
Yield 80 %; m.p.: 98–101 °C; 1H NMR (400 MHz,
2
d = 16.3 (C7), 48.2 (C4), 95.4 (q, J = 31 Hz, C5), 125.4
(q, J = 282 Hz, CF3), 149.8, 147.3, 144.2, 141.6, 140.8,
1
2
138.2 (PhF5), 152.9 (C3) ppm; MS (EI, 70 eV):
m/z (%) = 334 (M?, 30), 317 (10), 265 (100), 98 (1).
CDCl3): d = 3.47 (d, 1H, J = 18 Hz, H4a), 3.74 (d, 1H,
2J = 18 Hz, H4b), 7.38–7.41 (m, 3H, H–Ar), 7.59–7.62
(m, 2H, H–Ar) ppm; 13C NMR (100 MHz, (CD3)2CO):
d = 44.5 (C4), 95.7 (q, 2J = 33 Hz, C5), 125.2 (q,
1J = 283 Hz, CF3), 128.1, 130.5, 131.6, 133.2 (C Ph),
119.1, 137.1, 142.0, 145.9, 150.9, 156.1 (PhF5), 152.5 (C3)
ppm; MS (EI, 70 eV): m/z (%) = 396 (M?, 100), 379 (20),
327 (80), 141 (5).
3-Ethyl-1-(pentafluorophenyl)-5-(trifluoromethyl)-4,5-
dihydro-5-hydroxy-1H-pyrazole (4c, C12H8F8N2O)
Yield 92 % (MW), 82 % (conventional); m.p.: 93–95 °C;
1H NMR (400 MHz, CDCl3): d = 1.19 (t, 3H, H8), 2.41
2
(q, 2H, H7), 3.24 (d, 1H, J = 18 Hz, H4a), 3.47 (d, 1H,
2J = 18 Hz, H4b) ppm; 13C NMR (100 MHz, (CD3)2CO):
d = 11.9 (CH3), 24.7 (CH2), 46.7 (C4), 95.2 (q,
2J = 31 Hz, C5), 125.5 (q, 1J = 282 Hz, CF3), 149.9,
147.3, 144.1, 140.9, 140.8, 138.3 (PhF5), 157.3 (C3) ppm;
MS (EI, 70 eV): m/z (%) = 348 (M?, 95), 331 (15), 279
(100), 181 (100), 112 (10).
3-(4-Bromophenyl)-1-(pentafluorophenyl)-5-(trifluoro-
methyl)-4,5-dihydro-5-hydroxy-1H-pyrazole
(4j, C16H7BrF8N2O)
Yield 83 % (MW), 72 % (conventional); m.p.:
1
143–147 °C; H NMR (400 MHz, CDCl3): d = 3.76 (d,
123

1048
M. A. P. Martins et al.
1H, 2J = 18 Hz, H4a), 3.87 (d, 1H, 2J = 18 Hz, H4b),
7.59 (d, 2H, H–Ar), 7.67 (d, 2H, H–Ar) ppm; 13C NMR
(100 MHz, (CD3)2CO): d = 44.3 (C4), 95.7 (q,
2J = 33 Hz, C5), 122.6 (q, 1J = 283 Hz, CF3), 147.6,
145.1, 142.8, 140.7, 136.5, 132.0 (PhF5), 140.3, 129.5,
127.4, 124.5 (PhBr), 151.5 (C3) ppm; MS (EI, 70 eV): m/
z (%) = 476 (M ? 2, 20), 474 (M?, 70), 472 (30), 395
(10), 308 (10), 152 (10).
151.7 (C3) ppm; MS (EI, 70 eV): m/z (%) = 351 (M?
– OH, 1), 316 (60), 315 (100), 251 (1).
3-Methyl-1-(pentafluorophenyl)-5-(trichloromethyl)-4,5-
dihydro-5-hydroxy-1H-pyrazole (5b, C11H6Cl3F5N2O)
Yield 85 %; m.p.: 109–110 °C; 1H NMR (400 MHz,
2
CDCl3): d = 2.33 (s, 3H, H7), 3.27 (d, 1H, J = 18 Hz,
H4a), 3.75 (d, 1H, 2J = 19 Hz, H4b) ppm; 13C NMR
(100 MHz, CDCl3): d = 15.4 (CH3), 49.7 (C4), 101.6
(C5), 103.3 (CCl3), 145.7, 142.8, 138.9, 136.4, 140.5, 117.1
(PhF5), 151.3 (C3) ppm; MS (EI, 70 eV): m/z (%) = 381
(M?, 1), 330 (100), 264 (100), 83 (2).
3-(4-Fluorophenyl)-1-(pentafluorophenyl)-5-
(trifluoromethyl)-4,5-dihydro-5-hydroxy-1H-pyrazole
(4k, C16H7F9N2O)
Yield 75 % (MW), 43 % (conventional); m.p.: 145–147 °C;
1H NMR (400 MHz, CDCl3): d = 3.69 (d, 1H, 2J = 18 Hz,
H4a), 4.09 (d, 1H, 2J = 18 Hz, H4b), 7.09 (dd, 2H, H–Ar),
7.64 (dd, 2H, H–Ar) ppm; 13C NMR (100 MHz, CDCl3):
d = 43.6 (C4), 93.7 (q, 2J = 32 Hz, C5), 116.1 (d,
3-Ethyl-1-(pentafluorophenyl)-5-(trichloromethyl)-4,5-
dihydro-5-hydroxy-1H-pyrazole (5c, C12H8Cl3F5N2O)
Yield 93 %; m.p.: 75–77 °C; 1H NMR (400 MHz, CDCl3):
d = 1.19 (t, 3H, H8), 2.42 (q, 2H, H7), 3.25 (d, 1H,
2
2J = 20 Hz, H4a), 3.74 (d, 1H, J = 20 Hz, H4b) ppm;
1
2J = 23 Hz, CAr), 122.6 (q, J = 283 Hz, CF3), 126.8 (d,
13C NMR (100 MHz, CDCl3): d = 10.6 (CH3), 23.2
(CH2), 48.1 (C4), 101.4 (C5), 103.4 (CCl3), 145.8, 142.8,
138.9, 136.4, 114.8 (PhF5), 156.1 (C3) ppm; MS (EI,
70 eV): m/z (%) = 396 (M ? H?, 1), 380 (M? – OH, 1),
279 (M? – CCl3, 100).
4J = 3 Hz, C Ar), 128.0 (d, 3J = 8 Hz, CAr), 136.5, 139.0,
140.3, 142.8, 146.1, 147.7 (PhF5), 148.9 (C3), 163.9 (d,
1J = 251 Hz, CAr) ppm; MS (EI, 70 eV): m/z (%) = 414
(M?, 20), 319 (10), 247 (10), 152 (10).
3-(2-Methylpropyl)-1-(pentafluorophenyl)-5-
(trifluoromethyl)-4,5-dihydro-5-hydroxy-1H-pyrazole
(4l, C14H12F8N2O)
1-(Pentafluorophenyl)-3-propyl-5-(trichloromethyl)-4,5-
dihydro-5-hydroxy-1H-pyrazole (5d, C13H10Cl3F5N2O)
Yield 94 %; m.p.: 106–108 °C; 1H NMR (400 MHz,
CDCl3): d = 0.99 (t, 3H, H9), 1.64 (q, 2H, H8), 2.36 (t,
2H, H7), 3.25 (d, 1H, 2J = 20 Hz, H4a), 3.72 (d, 1H,
2J = 20 Hz, H4b) ppm; 13C NMR (100 MHz, CDCl3):
d = 13.5 (CH3), 19.8 (CH2), 31.6 (CH2), 48.3 (C4), 101.4
(C5), 103.4 (CCl3), 148.6, 142.9, 140.3, 139.0, 136.5, 117.2
(PhF5), 155.0 (C3) ppm; MS (EI, 70 eV): m/z (%) = 410
(M?, 1), 364 (100), 358 (63), 293 (M? – CCl3, 20), 83 (2).
Yield 79 %; oil; 1H NMR (400 MHz, CDCl3): d = 0.98 (d,
6H, CH3), 1.92–1.95 (m, 1H, CH), 2.26 (d, 2H, CH2), 3.02 (d,
1H, 2J = 18 Hz, H4a), 3.37 (d, 1H, 2J = 18 Hz, H4b) ppm;
13C NMR (100 MHz, CDCl3): d = 22.1 (CH3), 22.2 (CH3),
26.5 (CH2), 38.4 (CH), 45.4 (C4), 92.9 (q, 2J = 32 Hz, C5),
1
122.7 (q, J = 283 Hz, CF3), 153.8, 148.7, 143.9, 139.1,
135.0, 132.6 (PhF5), 154 (C3) ppm; MS (EI, 70 eV): m/
z (%) = 376 (M?, 43), 317 (51), 307 (100), 181 (26).
3-(1-Methylethyl)-1-(pentafluorophenyl)-5-
(trichloromethyl)-4,5-dihydro-5-hydroxy-1H-pyrazole
(5e, C13H10Cl3F5N2O)
3-(4-Methylphenyl)-1-(pentafluorophenyl)-5-
(trifluoromethyl)-4,5-dihydro-5-hydroxy-1H-pyrazole
(4m, C17H10F8N2O)
Yield 90 %; m.p.: 123–125 °C; 1H NMR (400 MHz,
CDCl3): d = 1.19 (d, 6H, 2 CH3), 2.69 (m, 1H, H7),
Yield 58 %; m.p.: 120–123 °C; 1H NMR (400 MHz,
2
CDCl3): d = 2.37 (s, 3H, CH3), 3.47 (d, 1H, J = 18 Hz,
H4a), 3.75 (d, 1H, J = 18 Hz, H4b), 7.19 (d, 2H, H–Ar),
2
2
2
3.26 (d, 1H, J = 18 Hz, H4a), 3.73 (d, 1H, J = 20 Hz,
H4b) ppm; 13C NMR (100 MHz, CDCl3): d = 19.9 (CH3),
20.0 (CH3), 29.6 (CH), 46.4 (C4), 101.4 (C5), 103.5
(CCl3), 148.2, 146.4, 145.6, 138.9, 136.4, 117.2 (PhF5),
159.6 (C3) ppm; MS (EI, 70 eV): m/z (%) = 365 (M? – i-Pr,
20), 293 (M? – CCl3,100), 83 (5).
7.50 (d, 2H, H–Ar) ppm; 13C NMR (100 MHz, CDCl3):
d = 21.5 (CH3), 43.5 (C4), 93.5 (q, 2J = 23 Hz, C5),
122.6 (q, J = 283 Hz, CF3), 149.0, 145.6, 142.1, 137.7,
1
135.2, 132.3 (PhF5), 140.6, 129.5, 127.6, 126.0 (PhMe),
150.2 (C3) ppm; MS (EI, 70 eV): m/z (%) = 410 (M?, 48),
392 (100), 341 (37), 181 (10).
3-Butyl-1-(pentafluorophenyl)-5-(trichloromethyl)-4,5-
dihydro-5-hydroxy-1H-pyrazole (5f, C14H12Cl3F5N2O)
Yield 73 %; m.p.: 59–61 °C; 1H NMR (400 MHz, CDCl3):
d = 0.94 (t, 3H, H10), 1.41 (s, 2H, H9), 1.58 (q, 2H, H8),
1-(Pentafluorophenyl)-5-(trichloromethyl)-4,5-dihydro-5-
hydroxy-1H-pyrazole (5a, C10H4Cl3F5N2O)
Yield 88 %; m.p.: 125–127 °C; 1H NMR (400 MHz,
2
2
2.38 (t, 2H, H7), 3.25 (d, 1H, J = 20 Hz, H4a), 3.74 (d,
CDCl3): d = 3.33 (d, 1H, J = 19 Hz, H4a), 3.81 (d, 1H,
1H, 2J = 20 Hz, H4b) ppm; 13C NMR (100 MHz,
(CD3)2CO): d = 15.0 (CH3), 23.8, 29.2, 32.6 (CH2), 49.1
(C4), 103.5 (C5), 106.0 (CCl3), 148.3, 144.3, 141.8, 138.2,
2J = 19 Hz, H4b), 6.99 (s, 1H, H-3) ppm; 13C NMR
(100 MHz, CDCl3): d = 49.7 (C4), 101.6 (C5), 103.2
(CCl3), 138.9, 136.4, 130.9, 130.9, 128.8, 116.7 (PhF5),
123

Evaluation of the synthesis
1049
`
578426/2008-0) and the Fundac¸a˜o de Amparo a Pesquisa do Estado
do Rio Grande do Sul—FAPERGS (PRONEX/Proc. 10/0037-8;
ARD/Proc. 11/1777-6) for the financial support. The fellowships from
CNPq (M.A.P.M., N.Z., H.G.B., D.N.M., M.R.B.M., M.Z.), CAPES
(L.B., C.P.F.), and FAPERGS are also acknowledged.
130.6, 120.5 (PhF5), 156.8 (C3) ppm; MS (EI, 70 eV):
m/z (%) = 406 (M? – OH, 1), 264 (100), 257 (1).
3-(3-Methylbutyl)-1-(pentafluorophenyl)-5-
(trichloromethyl)-4,5-dihydro-5-hydroxy-1H-pyrazole
(5g, C15H14Cl3F5N2O)
Yield 80 %; m.p.: 91–93 °C; 1H NMR (400 MHz, CDCl3):
d = 0.93 (d, 6H, 2 CH3), 1.50 (m, 2H, H8), 1.54 (m, 1H,
H9), 2.37 (d, 2H, H7), 3.25 (d, 1H, 2J = 18 Hz, H4a), 3.74
(d, 1H, 2J = 20 Hz, H4b) ppm; 13C NMR (100 MHz,
(CD3)2CO): d = 23.5, 23.6 (CH3), 29.3, 29.3 (CH2), 36.9
(CH), 49.7 (C4), 103.6 (C5), 106.0 (CCl3), 144.3, 141.8,
140.6, 138.2, 133.8, 120.5 (PhF5), 156.9 (C3) ppm; MS
(EI, 70 eV): m/z (%) = 320 (M? – CCl3, 10), 304 (5), 278
(5), 264 (100), 97 (15).
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Yield 89 %; m.p.: 113–115 °C; 1H NMR (400 MHz,
2
CDCl3): d = 3.66 (d, 1H, J = 18 Hz, H4a), 4.09 (d, 1H,
2J = 18 Hz, H4b), 7.35 (d, 2H, H–Ar), 7.55 (d, 2H, H–Ar)
ppm; 13C NMR (100 MHz, CDCl3): d = 46.2 (C4), 102.8
(CCl3), 106.9 (C5), 148.1, 145.5, 143.1, 140.5, 138.9, 116.8
(PhF5), 136.0, 129.2, 127.3, 102.1 (PhCl), 149.1 (C3) ppm;
MS (EI, 70 eV): m/z (%) = 443 (M? – Cl, 40), 409 (100),
373 (10), 344 (1).
3-(4-Bromophenyl)-1-(pentafluorophenyl)-5-
(trichloromethyl)-4,5-dihydro-5-hydroxy-1H-pyrazole
(5j, C16H7BrCl3F5N2O)
Yield 90 %; m.p.: 113–115 °C; 1H NMR (400 MHz,
2
CDCl3): d = 3.69 (d, 1H, J = 18 Hz, H4a), 4.10 (d, 1H,
2J = 18 Hz, H4b), 7.50 (m, 4H, H–Ar) ppm; 13C NMR
(100 MHz, CDCl3): d = 46.2 (C4), 102.8 (CCl3), 106.9
(C5), 148.0, 145.6, 143.1, 140.5, 138.9, 116.8 (PhF5),
136.0, 129.0, 127.3, 102.1 (PhBr), 151.4 (C3) ppm; MS
(EI, 70 eV): m/z (%) = 505 (M? – OH, 1), 367 (75), 338
(1), 298 (100).
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(trichloromethyl)-4,5-dihydro-5-hydroxy-1H-pyrazole
(5k, C16H7Cl3F6N2O)
Yield 78 %; m.p.: 134–136 °C; 1H NMR (400 MHz,
2
CDCl3): d = 3.69 (d, 1H, J = 18 Hz, H4a), 4.12 (d, 1H,
2J = 18 Hz, H4b), 7.50 (s, 4H, H–Ar) ppm; 13C NMR
(100 MHz, (CD3)2CO): d = 47.5 (C4), 104.3 (C5), 105.4
(CCl3), 145.7, 141.8, 140.7, 136.9, 119.9, 108.9 (PhF5),
167.7, 151.3, 130.1, 117.6, 105.4, 104.2 (PhF), 164.2 (C3)
ppm; MS (EI, 70 eV): m/z (%) = 346 (M? – CCl3, 30),
345 (100), 295 (1), 83 (5).
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(2008) Chem Rev 108:2015
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