Direct synthesis of pyrazoles from esters using tert-butoxide-assisted C-(C=O) coupling

Article abstract of DOI:10.1039/c5cc02020d

This paper describes the direct synthesis of pyrazoles from esters that comprises two sequential reactions: tert-butoxide-assisted C-C(=O) coupling reaction to yield β-ketonitrile or α,β-alkynone intermediates, and condensation by hydrazine addition. The method reported allows for easy control of the regioselectivity and structure of substituents at N-1, C-3, C-4 and/or C-5 positions.

Full text of DOI:10.1039/c5cc02020d

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Direct Synthesis of Pyrazoles from Esters using
tert-Butoxide-Assisted C-(C=O) Coupling
Cite this: DOI: 10.1039/x0xx00000x
Bo Ram Kim,a Gi Hyeon Sung,a Ki Eun Ryu,a Sang-Gyeong Lee,a Hyo Jae
Yoon,*b Dong-Soo Shin,c and Yong-Jin Yoon*a
Received 00th January 2012,
Accepted 00th January 2012
DOI: 10.1039/x0xx00000x
www.rsc.org/
This paper describes the direct synthesis of pyrazoles from expensive catalysts—and under mild conditions in fairly good
esters that comprises two sequential reactions: tert-butoxide- yields (24–86 % of overall yields).
R3
assisted C-C(=O) coupling reaction to yield
β-ketonitrile or
N
O
H2N
t
R3NHNH2
R2CH CN 2 KO B
α
,
β
-alkynone intermediates, and condensation by hydrazine
u
N
,
2
R2
R
-
R2
m no razo es
addition. The method reported allows for easy control of the
regioselectivity and structure of substituents at N-1, C-3, C-4
and/or C-5 positions.
R
CN
e on e
r
it il
O
-
5 A
i
l
py
R3
K
t
β
R
E
R1
O
s ers
t
N
R4
O
t
R4CCH 2 KO B
R3NHNH2
N
u
,
R
Pyrazole—1,2-azole that is
a
five-membered heterocycle
R4
none
R
-
su
s
tit
u e - or
α
3 5 Di
b
t
d
-
,
,
Alk
y
comprising adjacent two nitrogens and three carbons—is a key
structural motif for pharmaceutical and pesticide compounds.1
Pyrazole derivatives have been extensively studied in past few
decades as important heterocycles and still receive great
attention for biological properties2 such as antitumor,3 CNS
disorders,4 antimicrobial,5 anti-inflammatory6 and antiviral
activities.7 Pyrazole moiety is a core structure in a large variety of
leading drugs and pesticides: for example, Celebrex,8 Viagra,9
β
- r su
1 3 5 t i
s
u e
tit
razo es
l
py
b
t
d
,
,
Fig. 1 Newly designed synthetic strategies for synthesis of substituted pyrazoles.
To develop a method for the synthesis of pyrazoles from
esters, we utilized tert-butoxide-assisted C-(C=O) coupling
reaction. Previously, we developed synthetic methodologies that
use tert-butoxide for synthesis of amides, β-ketonitriles, α,β-
alkynones, and biscarbinols from esters.18 These methodologies
were particularly attractive in that reactions proceed under
ambient conditions in the presence of tert-butoxide that is easily
accessible and cheap, rather than transition metal catalysts that
are often prepared through tedious, multi-step reactions. The
proposed mechanism of the reactions involves the radical
cleavage of C-O bond in ester resulting from the reaction of ester
with tert-butoxide in technical grade of THF in air at room
temperature. Typically, two equivalents of tert-butoxide, relative
to an ester, is used for the reaction: two equivalents of tert-
butoxide is needed, presumably, to form superoxide anion
radical and then acyl radical species, which are important
intermediates for the C-(C=O) coupling reaction.18 In this study
we develop a novel strategy to transform directly esters to
pyrazoles in conjunction with condensation of ketone by
hydrazine (Fig. 1).
Zometapine,10
Tebufenpyrad.13 The condensation of hydrazine with 1,3-
dicarbonyl or
compounds,14 -ketonitriles,15 ynones16
Cyenopyrafen,11
Fenpyroximate,12
and
β
aminoalkenylnitriles17 is commonly used to synthesize pyrazole
derivatives. These methods, however, have drawbacks such as
low reactivity and poor regioselectivity of C-3, C-4, C-5 positions
of pyrazole, limited scope for starting compounds, use of
expensive/toxic reagents, harsh reaction conditions, and/or
multistep reactions with low yields.
Herein, we report a convenient and efficient protocol for
direct conversion of esters to regioselectively substituted
pyrazoles (Fig. 1). The central idea for the method reported is
based on a facile, room-temperature C-C(=O) coupling reaction
facilitated by tert-butoxide to form β−ketonitrile or α,β−alkynone
intermediates. Several sets of experiments with a wide range of
esters, nitriles, alkynes and hydrazines under various reaction
conditions showed that the method allows one to prepare highly
substituted pyrazoles in an economical way—i.e., without using
For preparing β-ketonitrile and α,β-alkynone from esters we
used the literature conditions: technical grade (containing ca. 0.2%
H2O) of THF under ambient conditions.18a To optimize the
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second step conditions—those for the reaction of β-ketonitrile or Table 1. Substrate scope for synthesis of 5-aminopyrazoles with
α,β-alkynone with hydrazine—we performed the cyclization of
β
-
cyanomethylenes
R2
N
e
2
p
ketonitrile in different conditions (Table S1 in the ESI). We
changed i) a type of hydrazine (NH2NH2·X; X=H2O or H2SO4), ii)
equivalent of hydrazine (1.5 – 3.0 equiv), and iii) solvent (THF,
EtOH, toluene or a mixture of THF and H2O). When solvent was
different between the first and the second reactions, the suitable
solvent for the second step was used after evaporating the first-
reaction solvent (THF). We monitored a reaction designed for
synthesis of 5-amino-3-phenyl-1H-pyrazole from ethyl benzoate
t
S
e
p
t
1
S
O
r. .
t
i
H SO
H2N
,
4
O
t
2 KO B R1CH CN
N
)
2
u
,
2
CN
R
THF
t
(
h
ii a R2NHNH2 fl
ec . r. .
re ux
t
,
)
O
Et
,
R
)
R1
R
R1
time
5-amino-
pyrazole
yield(%)b
entry
R
R1
H
R2
step 1
(min)
step 2
(h)
1
2
p-Cl-C6H5
p-Cl-C6H5
C6H5
H
35
35
30
30
35
35
35
0.7 77
1.2 53
1.3 61
0.8 55
0.6 80
0.6 78
via β-ketonitrile; and found that the reaction of β-ketonitrile with
CH3CH2
H
hydrazine hydrate either in THF, EtOH or toluene did not
proceed at all (Table S1). It was attributed to the basicity of the
reaction mixture: the use of acidic hydrazine sulfate, gave the
desired product in 65% overall and isolated yield (Table S1, entry
4). Once we increased the equivalent of hydrazine sulfate from
1.5 to 3.0 equiv (Table S1, entry 4-6), no significant change was
observed in reaction yield. To increase the solubility of hydrazine
sulfate, we tested a mixture of THF and H2O (THF:H2O=1:6, v/v);
unfortunately, this reaction resulted in decrease in the yield (34%)
(Table S1, entry 7).
3
C6H5CH2
H
4
C6H5
CH3CH2
H
5
(CH3)2CH
C6H5
H
H
H
H
H
H
H
6
H
7
C6H5
C6H5
24
58
56
37
42
8
C6H5
p-MeOC6H5 35
p-NO2C6H5 35
9
68
48
9
C6H5
10
C6H5
CH3
35
aEntries 1-6 used R2NHNH2·H2O; entries 7-9 used free R2NHNH2;
entry 10 used R2NHNH2·HCl.
bIsolated yield; and overall yield for the two sequential reactions in one-
The significant difference in the reaction yield between
hydrazine hydrate and hydrazine sulfate implies that the basicity
of the first-reaction mixture influences the second reaction (e.g.,
pot synthesis.
the solubility of hydrazine salt, and/or enolization of β-ketonitrile).
Table 2. Synthesis of 5-acetamidopyrazoles
We thereby hypothesized that a better yield for the second
reaction may be achieved by neutralizing the first-step prior to
the addition of hydrazine sulfate. To find a suitable acid for
neutralization of the first-step mixture, four protic acids (H2SO4,
HCl, HNO3 and H3PO4) of different equivalents were evaluated;
Table S2 in the ESI summarizes the results. Among ten entries,
the reaction with one equivalent of sulfuric acid gave the best
result (Table S2, entry 1): 78% yield was achieved with one
equivalent of H2SO4 in 0.6 h. Hydrochloric acid (Table S2, entries
5 and 6) and nitric acid (Table S2, entries 7 and 8) gave the
same yield but required a longer reaction time or more
equivalents than sulfuric acid. When phosphoric acid as weak
acid was used, the yields were low (~60%; Table S2, entries 9
and 10). These observations allowed us to determine the final
R1
e
t
2a
p
S
e
t
1
S
p
N
R1NHNH2
c
re ux
A OH fl
,
O
t
O
c
A HN
u
,
2 KO B CH CN
3
N
CN
ec . r. .
THF t
R
h
t
,
)
R
Et
O
(
R
time
5-acetami-
dopyrazole
yield (%)a
entry
1
R
R1
H
step1 (min)
30
step 2 (h)
C6H5
15
53
2
3
4
(CH3)2CH
p-Cl-C6H5
C6H5
H
H
35
35
35
16
18
68
47
86
82
C6H5
aEntries 1-3 used R2NHNH2·H2O; entry 4 used free R2NHNH2.
bIsolated yield; and overall yield for the two sequence reactions in one-
pot synthesis.
optimum conditions for the synthesis of pyrazole via β-ketonitrile:
step 1) i) ester (1 equiv) / cyanomethylene (1 equiv) / KOtBu (2
equiv) / tech. THF / room temperature, ii) H2SO4 (1 equiv); step 2)
We further demonstrated the synthesis of 5-acetamido-3-
substituted-pyrazoles from aryl and aliphatic esters using excess
.
NH2NH2 H2O (1.5 equiv) / reflux.
amount of AcOH (Table 2). After forming
β
-ketonitrile by the
reaction of ester with acetonitrile in the presence of KOtBu, the
resulting -ketonitrile was reacted with hydrated or free
We next examined the substrate scope of esters,
cyanomethylenes and hydrazines. The reaction of aryl and
aliphatic esters with cyanomethylenes and then with hydrated or
free hydrazines under the optimum conditions gave the
corresponding 5-amino-4-alkyl-3-aryl (or alkyl) pyrazoles in 37-80%
(Table 1). Interestingly, this reaction offered the ability to control
the substituents at N-1, C-3 and/or C-4 and to introduce primary
amino group (-NH2) on C-5 position of pyrazole. It is noteworthy
that this is a one-pot synthesis without purification of the
β
hydrazines in acetic acid. The corresponding 5-acetamido-3-alkyl
(or aryl)pyrazoles were obtained in 47-86% yields in one-pot
synthesis (Table 2). In this reaction, acetic acid serves as: i)
acylation reagent for the amino group, ii) acid for neutralization
after the first step reaction, and iii) solvent for the second step
reaction. The method described in Table 2 is useful for one-pot
synthesis of 5-acetamidopyrazoles from esters via
β-ketonitriles.
intermediate, β-ketonitrile. We observed the lowest yield (37%;
The FT-IR, NMR and HR-MS established the structure of the
prepared pyrazole compounds. The IR spectrum of 5-
aminopyrazoles exhibited the absorption bands at 3434 - 3148
entry 9 in Table 1) for p-nitrophenyl-substituted hydrazine; it is
attributed to the decreased nucleophilicity of hydrazine for the
cyclization in the step 2.
2 | J. Name., 2012, 00, 1-3
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cm-1 (multi-peaks were observed due to tautomerism of 5- resulting mixture was extracted with organic solvent (see the ESI
aminopyrazoles)19 corresponding to -NH2 and -NH functional for detailed procedures). The intention for the partial purification
groups. For 5-acetamidopyrazole the IR absorption bands of -NH was to neutralize the reaction mixture without using strong acid.
(3248 - 3100 cm-1) and C=O (1663 - 1617 cm-1) were detected, Indeed, the addition of hydrazine hydrate to the first-reaction
indicative of the presence of amide carbonyl group. The NMR mixture, which was partially purified by adding H2O at 5oC
and HR-MS spectra were also consistent with the proposed following extraction with ethyl acetate, at room temperature gave
structures (see the ESI for detailed analytical data).
3-methyl-5-phenyl-1H-pyrazole in an increased yield (54%; Table
Table 3. Optimization of reaction conditions for synthesis of 3-methyl- 3, entry 6). Increasing reaction temperature for refluxing in the
5-phenyl-1H-pyrazole
reaction gave a similar yield (58%; Table 3, entry 7) but reaction
time was much shorter (5 min) than that (720 min) for the
reaction at room temperature. Based on the preliminary
experiments, we were able to determine the final optimum
conditions for the synthesis of pyrazole via α,β-alkynone
intermediate: step 1) i) ester (1 equiv) / alkyne (1 equiv) / KOtBu
t
u
i
)
2 KO B PhCCH
,
H
O
O
N
.
NH2NH2 H
2O
ec .
m n r. .
THF
t
(
h
5
,
)
i
t
,
Ph
N
H3C
OEt
H3C
m n
ii H SO
5
,
4
ti
i
,
)
2
on
on
di
on
Ph
C
ti
B
on
CH3
C
di
A
equiv
of
H2SO4
condition
A
o
product
(2 equiv) / tech. THF / ambient temperature (17 - 19 C), and ii)
entry
yield(%)a
B
extraction of reaction mixture with H2O and EtOAc; step 2)
.
b
NH2NH2 H2O (1.5 equiv) / reflux.
1
2
3
4
5
6
7
-
r.t.
r.t., 10 min
r.t., 10 min
-
Table 4. Substrate scope for synthesis of 3,5-disubstitued- or 1,3,5-
1
1
1
1
-
r.t.
11
31
24
18
54
58
5 oC
5 oC
5 oC
H2O/EtOAcc
H2O/EtOAcc
5 oC, 360 min
25 oC, 60 min
reflux, 10 min
25 oC, 720 min
reflux, 5 min
trisubstituted pyrazoles from esters
S
2a
e
p
e
t
1
S
p
t
t
R2
N
u
2 KO B
,
R1
O
O
R2NHNH2
R1CCH
5 o
C
ec .
,
)
N
R
t
R
r
e u
x
OE
fl
THF
t
(
h
R
R1
-
e
e
o
o
:
ar
a
ur ca on
l
p
ifi ti
M
M
th d A
P
ti
ifi ti
:
ure ur ca on
th d B
P
aIsolated yield; and overall yield for two sequential reactions.
p
bDecomposition of α,β
was observed on TLC monitoring. Partial purification method: when
the first reaction was finished, it was quenched by adding water (10
-
alkynone intermediate (4-phenylbut-3-yn-2-one)
c
Conditions
Method Ab
Method Bc
R1
R2
o
entry
R
mL), and then stirred for 1 min under 5 C. The reaction mixture was
pyrazole
yield
pyrazole
yield
time
time
(min)c
(min)d
further extracted with cold EtOAc (10 mL × 2), and organic layer was
separated. Hydrazine hydrate was then added to the organic layer for
the second reaction (see the ESI for details).
(%)e
(%)e
f
1
2
CH3
C6H9
H
H
3/80
5/60
31
51
3/10
5/10
72
59
(CH3)2CH C6H5
We also investigated the synthesis of pyrazoles from esters
via α,β-alkynones. To search optimal conditions for the reaction
(in particular for the neutralization-step and the second-step
involving α,β-alkynones and hydrazine), ethyl acetate was
reacted with phenylacetylene in the presence of KOtBu in
technical THF under ambient conditions, and then with hydrazine
hydrate under various conditions. Table 3 summarizes the
results. The desired product, 3-methyl-5-phenyl-1H-pyrazole
was not obtained without neutralization process (Table 3, entry
1); it was due to the decomposition of 4-phenylbut-3-yn-2-one
(confirmed by TLC monitoring). Alternatively, the first-reaction
mixture was neutralized by one equivalent of sulfuric acid, and
then reacted with hydrazine hydrate (Table 3, entry 2); the
product begun to form but the yield was low (11%). We changed
the temperature in neutralization process (Condition A in Table
3), or the reaction time and/or temperature (Condition B in Table
3) for the cyclization by addition of hydrazine (Table 3, entries 3 -
5); however the yields were still low (18 - 31%). We assumed
CH3(CH2)5-
C6H4
3
(CH3)2CH
H
5/60
27
5/10
44
4
5
6
C6H5(CH2)2 C6H5
H
H
H
5/20
5/60
5/30
38
28
28
5/10
5/5
56
50
47
g
c-C6H11
C6H5
CH3(CH2)6 C6H5
5/5
3-(C5H4N)-
C6H5
7
H
5/25
11
5/5
8
CH2CH2
8
CH3
C6H5
C6H5 3/240 46
2/120 24
aEntries 1-7 used R2NHNH2·H2O; entry 8 used free R2NHNH2.
bMethod A (partial purification): when the first reaction was finished,
H2O (10 mL) was added to the reaction mixture and then stirred at 1
o
min under 5 C followed by extraction with cold EtOAc (10 mL × 2),
organic layer was separated. Hydrazine (1.5 equiv.) was then added and
c
refluxed. Method B (pure purification): Pure α,β
for the second reaction. dTime: the step 1/the step 2. eIsolated yield; and
-
alkynones were used
f
g
overall yield for the two sequence reaction. Cyclohex-1-en-1-yl. c-
C6H11: Cyclohexyl.
We examined the substrate scope under the optimal
conditions. 3,5-Disubstituted- or 1,3,5-trisubstituted pyrazoles
were obtained from various esters, alkynes and hydrazines in 27-
51% overall yields (Table 4, Method A, except entry 7). We did
not test aryl esters; the previous work demonstrated that the
reaction of aryl esters with tert-butoxide affords over-addition
that the low reaction yields result from the low stability of α,β
alkynone intermediates that are decomposed by the addition of
sulfuric acid. Thus, we performed the cyclization of α,β
-
-
alkynones without neutralization process and after partial
purification—water was added to quench the first reaction at the
point where α,β-alkynone intermediate forms maximally, and the
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product, biscarbinols, and not α,β-alkynone.18a We further (4) (a) F. Chimenti, R. Fioravanti, A. Bolasco, F. Manna, P. Chimenti, D.
investigated whether yields of the cyclization of α,β-alkynones
could be improved upon complete isolation of α,β-alkynone
intermediates. Eight pyrazoles were obtained from aliphatic
esters by Method B (using pure α,β-alkynones) in 24-72% overall
yields. In most of reactions, the yields by the Method B were
Secci, O. Befani, P. Turini, F. Ortuso, S. Alcaro, J. Med. Chem. 2007,
50, 425; (b) J. Elguero, P. Goya, N. Jagerovic, A. M. S. Silva,
Targets Heterocycl. Syst. 2002,
6, 52; (c) Comprehensive
Heterocyclic Chemistry II, A. R. Katrizky, C. W. Rees, E. F. V.
Scriven, Eds.; Pergamon: Oxford, 1996, 5.
higher than those by the Method A except for the use of ethyl 3- (5) S. Bondock, W. Fadaly, M. A. Metwally, Eur. J. Med. Chem. 2010,
(pyridin-3-yl)propanoate as a starting compound (Table 4, entry 45, 3692.
7), and for the use of free hydrazine (Table 4, entry 8). The high (6) F. F. Barsoum, A. S. Girgis, Eur. J. Med. Chem. 2009, 44, 2172.
yields by the Method B are accounted for by the low stability of (7) M. Abdel-Aziz, A. El-Din, G. Abuo-Rahma, A. A. Hassan, Eur. J.
α,β-alkynone intermediates in the basic and ambient conditions.
Med. Chem. 2009, 44, 3480.
We observed the lowest yield (8%) for ethyl 3-(pyridin-3- (8) T. D. Penning, J. J. Talley, S. R. Bertenshaw, S. J. Carter, P. W.
yl)propanoate (Table 4, entry 7 by Method B); it was due to the
decomposition of the corresponding α,β-alkynone intermediate
(confirmed by TLC monitoring).
Collins, S. Docter, M. J. Graneto, L. F. Lee, J. W. Malecha, J. M.
Miyashiro, R. S. Rogers, D. J. Rogier, S. S. Yu, G. D. Anderson, E. G.
Burton, J. N. Cogburn, S. A. Gregory, C. M. Koboldt, W. E. Perkins,
K. Seibert, A. W. Veenhuizen, Y. Y. Zhang, P. C. Isakson, J. Med.
Chem. 1997, 40, 1347.
Conclusions
(9) (a) N. K. Terrett, A. S. Bell, D. Brown, P. Ellis, Bioorg. Med. Chem.
In conclusion, this study demonstrates the synthesis of pyrazoles
Lett. 1996,
Hughes, P. C. Levett, A. K. Pearce, P. M. Searle, G. Ward, A. S. Wood,
Org. Proc. Res. Dev. 2000, , 17.
6, 1819; (b) D. J. Dale, P. J. Dunn, C. Golightly, M. L.
starting from esters, using tert-butoxide-assisted C-(C=O)
coupling and hydrazine cyclization via
alkynones. The synthetic method reported here offers an
opportunity to prepare conveniently and efficiently
β-ketonitriles or α,β-
4
(10) H. A. De Wald, S. Lobbestael, B. P. H. Poschel, J. Med. Chem. 1981,
24, 982.
regioselectively functionalized pyrazoles in two sequential
reactions; many of pyrazoles are prepared in one-pot synthesis
(and/or under mild conditions). 5-Aminopyrazoles (ten examples),
5-acetoamidopyrazoles (four examples), and 3,5-disubstituted-
or 1,3,5-trisubstituted pyrazoles (nine examples) are synthesized
(11) H. Murakami, S. Masuzawa, S. Takii, T. Ito, Jpn. Patent
2012802003, 2003.
(12) M. Kim, C. Sim, D. Shin, E. Suh, K. Cho, Crop Prot. 2006, 25, 542.
(13) D. Marcic, Exp. Appl. Acarol. 2005, 36, 177.
(14) (a) S. Peruncheralathan, T. A. Khan, H. Ila, H. Junjappa, J. Org.
Chem. 2005, 70, 10030; (b) M. V. Patel, R. Bell, S. Majest, R. Henry,
T. Kolasa, J. Org. Chem. 2004, 69, 7058; (c) L. Knorr, Ber. Dtsch.
Chem. Ges. 1883, 16, 2587; (d) R. H. Wiley, H. P. E., Org. Synth.
1951, 31, 43; (e) A. N. Kost, I. I. Grandberg, Adv. Heterocycl. Chem.
from esters via
β-ketonitrile or α,β-alkynone intermediates in
moderate to good yields.
The synthetic method reported has three useful features: i) it
allows one to control readily the regioselectivity and structure of
substituents—particularly those at N-1, C-3, C-4 and/or C-5
positions; ii) it avoids use of transition metal catalysts that are
often expensive, and/or difficult to access; and iii) it starts from
esters—a wide variety of ester derivatives are commercially
available, or easily accessible by straightforward synthetic
pathways. The reported method would be applicable in synthetic,
medicinal and industrial chemistry.
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aDepartment of Chemistry & Research Institute of Natural Science,
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E-mail: yjyoon@gnu.ac.kr
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