Facile One-Pot Transformation of Primary Alcohols into 3-Aryl- and 3-Alkyl-isoxazoles and -pyrazoles

Article abstract of DOI:10.1055/s-0039-1690102

Various primary alcohols were smoothly transformed into 3-aryl- and 3-alkylisoxazoles in good yields in one pot by successive treatment with PhI(OAc) ₂ in the presence of TEMPO, NH ₂ OH, and then NCS, followed by reaction with alkynes in the presence of Et ₃ N. Similarly, various primary alcohols were smoothly transformed into 3-aryl- and 3-alkylpyrazoles in good yields in one pot by successive treatment with PhI(OAc) ₂ in the presence of TEMPO, PhNHNH ₂, and then NCS and decyl methyl sulfide, followed by reaction with alkynes in the presence of Et ₃ N. Thus, both 3-aryl- and 3-alkylisoxazoles, and 3-aryl- and 3-alkylpyrazoles could be prepared from readily available primary alcohols in one pot under transition-metal-free conditions.

Full text of DOI:10.1055/s-0039-1690102

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2019, 51, A–M
paper
A
en
E. Kobayashi, H. Togo
Paper
Synthesis
Facile One-Pot Transformation of Primary Alcohols into 3-Aryl-
and 3-Alkyl-isoxazoles and -pyrazoles
O
Eiji Kobayashi
2
R3
4)
N
3) NCS
R
R2
Et3N
OH
Hideo Togo*
R1
R1
N
R3
isoxazoles
20 examples
up to 92% yield
2) NH2OH•HCl
K2CO3
Graduate School of Science, Chiba University, Yayoi-cho 1-33,
Inage-ku, Chiba 263-8522, Japan
togo@faculty.chiba-u.jp
1) DIB,
TEMPO
O
OH
R1
R1
H
widely available
primary alcohols
R4
2) NH2NH-R4
N
N
2
R
R3
4)
R2
3) NCS
CH3-S-C10H21
H
N
R1
Et3N
R4
R1
N
R3
pyrazoles
20 examples
up to 90% yield
Received: 09.05.2019
Accepted after revision: 06.06.2019
Published online: 18.06.2019
Numerous synthetic studies of isoxazoles and pyrazoles
have been carried out. The most typical and useful method
for the preparation of isoxazoles is the 1,3-dipolar cycload-
dition reaction of nitrile N-oxides with alkynes. Recent syn-
thetic studies of isoxazoles via nitrile N-oxides are:4 (1) The
preparation of 3-isopropylisoxazoles from isopropyloxime,
alkynes, NaCl, and Oxone®;4a (2) 3-(p-Phenylbenzyl)isoxaz-
oles from p-phenylbenzyl hydroximoyl fluorides, alkynes,
EtONa, and Ag2CO3;4b (3) 3-Substituted isoxazoles bearing a
phosphate group at the 4- or 5-position from halogenoxim-
es, bromovinyl phosphates, and NaHCO3;4c (4) 3-(Difluoro-
methyl)isoxazoles from difluoromethyl nitrile N-oxides and
alkynes;4d (5) 3-(-Amino)alkylisoxazoles from chloroxim-
es derived from -amino acids and alkynes;4e (6) 3,4,5-Tri-
substituted isoxazoles from -ketoamides and chloroximes
with N,N,N′,N′-tetramethylguanidine and Et3N;4f (7) 3-(Tri-
fluoromethyl)isoxazoles from (trifluoromethyl)hydroxi-
moyl bromide and alkynes with Et3N;4g (8) 3,4,5-Trisubsti-
tuted isoxazoles from aldoximes, alkynes, and (diacetoxyio-
do)benzene (PhI(OAc)2, DIB);4h and (9) 3,5-Disubstituted
isoxazoles from aldoximes, alkynes, and 3,5-(dimethyl)io-
dobenzene, and Oxone®.4i The preparation of isoxazoles
with transition metals was also reported recently, as fol-
lows:5 (1) The preparation of 3,5-disubstituted isoxazoles
from ynone O-methyl oximes in the presence of
Pd(O2CCF3)2 and CuCl2;5a,b (2) 3-(Difluoromethyl)- and 3-
DOI: 10.1055/s-0039-1690102; Art ID: ss-2019-f0261-op
Abstract Various primary alcohols were smoothly transformed into 3-
aryl- and 3-alkylisoxazoles in good yields in one pot by successive treat-
ment with PhI(OAc)2 in the presence of TEMPO, NH2OH, and then NCS,
followed by reaction with alkynes in the presence of Et3N. Similarly, var-
ious primary alcohols were smoothly transformed into 3-aryl- and 3-al-
kylpyrazoles in good yields in one pot by successive treatment with
PhI(OAc)2 in the presence of TEMPO, PhNHNH2, and then NCS and de-
cyl methyl sulfide, followed by reaction with alkynes in the presence of
Et3N. Thus, both 3-aryl- and 3-alkylisoxazoles, and 3-aryl- and 3-al-
kylpyrazoles could be prepared from readily available primary alcohols
in one pot under transition-metal-free conditions.
Key words isoxazole, pyrazole, alcohol, oxime, hydrazone, cycloaddi-
tion
Nitrogen-containing heterocyclic compounds are very
important and attractive due to their potent biological ac-
tivities.1 Among them, isoxazoles2 and pyrazoles3 are the
most important nitrogen-containing five-membered het-
eroaromatics, and they serve as units or cores of many
pharmaceuticals and agrochemicals. For example,
Valdecoxib,2d,f a 3-phenylisoxazole derivative, and Celecox-
ib,2e,f,3b a 3-arylpyrazole derivative, are nonsteroidal anti-in-
flammatory drugs (Figure 1).
(trifluoromethyl)isoxazoles
from
arylacetylenes,
(1)
CHF2CH2NH2 or CF3CH2NH2, and tert-butyl nitrite in the
presence of ZnBr2 and CuI;5c (3) 3,5-Disubstituted isoxaz-
oles from arylacetylenes and tert-butyl nitrite in the pres-
ence of Sc(OTf)3;5d (4) 3,5-Diarylisoxazoles from enone ox-
imes in the presence of Cu(OAc)2;5e and (5) 4-Borylated 3-
arylisoxazoles from ynone oximes and HB(OR)2 in the pres-
O
H2NO2S
(2)N
(3)
(1)
N
(2)
N
(3)
CF3
SO2NH2
Valdecoxib
(anti-inflammatory drug)
Celecoxib
(anti-inflammatory drug)
i
ence of PrAuTFA.5f Under transition-metal-free conditions,
the preparation of 3,5-disubstituted isoxazoles from ynones
Figure 1 Typical pharmaceuticals bearing 3-arylisoxazole or 3-arylpyr-
azole units
and TMSN3 was also reported.6
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–M
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
E. Kobayashi, H. Togo
Paper
Synthesis
On the other hand, recent synthetic studies on the
preparation of pyrazoles with hydrazines include:7 (1) The
preparation of 4-borylated pyrazoles from hydrazone with
B-chlorocatecolborane, Et3N, and Cu(OTf)2;7a (2) 3-Aryl-5-
(arylmethyl)pyrazoles from arylacetylenes and hydrazine in
the presence of CuI and Ru(bpy)3Cl2 under irradiation with
blue LED;7b (3) 5-Amino-1-aryl-3-methylpyrazoles from
arylhydrazines and -aminocrotononitrile under micro-
wave irradiation;7c (4) 5-Aryl-4-iodo-3-(trifluorometh-
yl)pyrazoles from hydrazones derived from CF3-ynones
with I2;7d (5) 5-Aryl-3-(trifluoromethyl)pyrazoles from
ynones and arylhydrazines in the presence of AgOTf;7e
(6) 4-Benzeneselenyl-3,5-diarylpyrazoles from chalcones,
arylhydrazines, and PhSeSePh in the presence of CuBr;7f
(7) 3,4,5-Trisubstituted pyrazoles from arylhydrazines and
1,3-diketones in the presence of Cu(NO3)2;7g and (8) 3-
Arylpyrazole-5-tetrafluoroborates from ynone trifluorobo-
rates and hydrazines.7h Moreover, the preparation of pyra-
zoles bearing ester groups from alkenes and -di-
azoesters;8a,b pyrazoles bearing amide groups from -ke-
toamides, hydrazonyl chlorides, and DMAP;8c and pyrazoles
bearing 1,5-cyclic group from hydrazones and -bromom-
alonate esters in the presence of [Ir(ppy)2dtbbpy]PF6 under
blue LED irradiation8d was also reported.
Here, as part of our continuing synthetic studies on ni-
trogen-containing heteroaromatics, such as isoxazoles, pyr-
azoles, oxazoles, quinolines,9 we would like to report a fac-
ile one-pot transformation of primary alcohols into 3-aryl-
and 3-alkylisoxazoles and -pyrazoles, as shown in Scheme 1
(II).
One of the most efficient precursors for the preparation
of both isoxazoles and pyrazoles are aldehydes, and one of
the most useful, safe, and promising methods for the prepa-
ration of aldehydes from widely available primary alcohols
is DIB oxidation in the presence of 2,2,6,6-tetrameth-
ylpiperidine 1-oxyl (TEMPO) as catalyst.10 Thi is because
most primary alcohols can be smoothly oxidized to alde-
hydes in good yields at room temperature with a TEMPO-
DIB system, and the oxidation can be carried out without
bad smell, as is the case using the Swern oxidation, and
without using explosive reagents, such as Dess–Martin re-
agent. Based on these considerations, first, the optimum re-
action conditions for the preparation of diethyl 3-(p-meth-
ylphenyl)isoxazole-4,5-dicarboxylate (4A) from p-methyl-
benzyl alcohol (1A) were examined (Table 1). p-
Methylbenzyl alcohol 1A (1.0 mmol) was treated with DIB
(1.1 equiv) in the presence of TEMPO (0.1 equiv) in CH2Cl2
(1.0 mL) at room temperature for 0.5 h (first step), and then
with NH2OH·HCl (1.5 equiv) and K2CO3 (0.75 equiv) at room
temperature for 18 h to form oxime 2A (second step). Under
We reported the one-pot preparation of 3,5-disubstitut-
ed isoxazoles through the reaction with terminal alkynes
and n-BuLi, and then with aldehydes and molecular iodine,
followed by the reaction with hydroxylamine; we also re-
ported the reaction of 3,5-disubstituted pyrazoles with ter-
minal alkynes and n-BuLi, and then with aldehydes and
molecular iodine, followed by the reaction with hydrazine,
respectively, by a successive treatment, as shown in Scheme
1 (I).9a
Table 1 Transformation of 4-Methylbenzyl Alcohol (1A) into
3-(4′-Methylphenyl)isoxazole (4A)
OH
1) DIB (1.1 equiv), TEMPO (0.1 equiv)
OH
(1st step)
(2nd step)
CH2Cl2, r.t, 0.5 h
N
2) NH2OH•HCl (1.5 equiv)
Me
Me
K2CO3 (0.75 equiv), r.t., 18 h
1A
2A
(1.0 mmol)
Previous work with alkynes and aldehydes9a
4) NH2OH, TBAI
O
N
O
R2
5) TsOH•H2O
3) NXS, DMF
Temp, Time
N
CO2Et
(3rd step)
R1
4) EtO2C
Et3N (1.5 equiv), r.t., 1 h
CO2Et
CO2Et
(1.5 equiv)
1) n-BuLi
Me
2) R2-CHO
3) I2, K2CO3
(4th step)
R2
O
4A
R1
H
R1
I)
Entry
NXS (equiv)
Temp, time
Yield 4A (%)
1a
2c
3c
4c
5d
6d
7d
8c
NCS (1.2)
NCS (1.2)
NCS (1.2)
NCS (1.2)
NCS (1.2)
NCS (1.5)
NBS (1.5)
NIS (1.5)
r.t., 1 h → 40 °C, 1 h
r.t., 1 h → 40 °C, 1 h
0 °C, 1 h → r.t., 3 h
–78 °C, 1 h → r.t., 3 h
0 °C, 1 h → r.t., 3 h
0°C, 1 h → r.t., 3 h
0 °C, 1 h → r.t., 3 h
0 °C, 1 h → r.t., 3 h
55 (16)b
62 (8)b
73 (10)b
72 (10)b
78
N
4) RNHNH2
R2
RN
R1
This work with primary alcohols and alkynes
2) NH2OH•HCl
3) NCS
R2
R2
4)
O
R2
R2
N
88
R1
0
1) oxidation
R1 CH2OH
II)
R
CH=O
0
widely available
2) NH2NHR
3) NCS
a DMF (0.1 mL) was not used in the third step of the reaction.
b Yield of oxime 2A.
N
R2
R2
4)
R2
RN
R1
c CH2Cl2 (1.0 mL) in the first step of the reaction and DMF (0.1 mL) in the
third step were used.
R2
d CH2Cl2 (2.0 mL) in the first step of the reaction and DMF (0.2 mL) in the
third step were used.
Scheme 1 One-pot preparation of isoxazoles and pyrazoles
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–M

C
E. Kobayashi, H. Togo
Paper
Synthesis
the present reaction procedure and conditions, oxime 2A
was obtained from p-methylbenzyl alcohol 1A in one pot,
quantitatively. The mixture was treated with NCS (1.2
equiv) in the absence or presence of DMF (0.1 mL) at room
temperature for 1 h, and then warmed to 40 °C for 1 h to
form the precursor of nitrile N-oxide (third step). This mix-
ture was further treated with diethyl acetylenedicarboxyl-
ate (1.5 equiv) and Et3N (1.5 equiv) at room temperature for
1 h (fourth step) to form isoxazole 4A in 55% and 62% yields,
respectively, together with oxime 2A in low yields (entries 1
and 2). Here, the addition of DMF was effective to increase
the solubility of oxime 2A. When NCS was added to the
mixture at 0 °C and –78 °C, and both reaction mixtures
were warmed to room temperature (third step), respective-
ly, under the same procedure and conditions, the yields of
isoxazole 4A were increased to 73% and 72%, together with
oxime 2A in 10% yield, respectively (entries 3 and 4).
Moreover, when the amounts of CH2Cl2 and DMF were
increased to 2.0 and 0.2 mL using 1.2 and 1.5 equiv of NCS
under the same procedure and conditions, the yields of
isoxazole 4A were increased to 78 and 88%, respectively (Ta-
ble 1, entries 5 and 6 in entries 3–6). Thus, entry 6 summa-
rizes the best result. When a gram-scale experiment with
8.0 mmol of p-methylbenzyl alcohol 1A was carried out un-
der the same procedure and conditions as those detailed in
entry 6, isoxazole 4A was obtained in 86% yield, as shown in
Scheme 2.
1) DIB (1.1 equiv), TEMPO (0.1 equiv)
CH2Cl2 (2.0 mL), r.t, Time
(1st step)
(2nd step)
OH
OH
R1
R1
N
2) NH2OH•HCl (1.5 equiv)
1
K2CO3 (0.75 equiv.), r.t., 18 h
2
(1.0 mmol)
3) NCS (1.5 equiv)
DMF (0.2 mL),
0 °C, 1 h
O
N
R2
(3rd step)
(4th step)
r.t., 3 h
R1
R3
4) R2
R3 (1.5 equiv)
Et3N (1.5 equiv), r.t., 1 h
4
Product, Yield, (1st step Time)
O
N
O
O
N
N
Me
CO2Et
CO2Et
CO2Et
Me
CO2Et
CO2Et
CO2Et
Me
4A 88% (0.5 h)
4B 70%b~d (1.0 h)
4C 92% (0.5 h)
86%a
O
N
O
N
O
N
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
MeO2C
MeO
4E 81% (0.5 h)
4F 80% (0.5 h)
4D 90% (0.5 h)
O
N
O
N
O
N
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
Cl
Ph
Ph
4G 85% (0.5 h)
4H 80% (0.5 h)
4I 84% (2.0 h)
O
N
O
N
O
N
CO2Et
CO2Et
CO2Et
Ph
n-C7H15
CO2Et
CO2Et
CO2Et
4J 66% (3.0 h)
4K 71% (3.0 h)
4L 73% (5.0 h)
On the other hand, when NBS and NIS instead of NCS
were used in the third reaction step under the same proce-
dure and conditions, no isoxazole 4A was obtained (Table 1,
entries 7 and 8, respectively). Thus, NCS played an import-
ant role in the formation of isoxazole 4A.11
O
N
O
N
O
N
CO2Et
CO2Et
CO2Et
Ph
CO2Et
CO2Et
CO2Et
4M 69% (3.0 h)
4N 52% (2.5 h)
4O 85% (1.5 h)
Based on those results, various benzylic alcohols (1.0
mmol), such as m-methylbenzyl alcohol (1B), o-methylben-
zyl alcohol (1C), p-methoxybenzyl alcohol (1D), benzyl al-
cohol (1E), p-(methoxycarbonyl)benzyl alcohol (1F), p-
chlorobenzyl alcohol (1G), p-phenylbenzyl alcohol (1H),
and 1-naphthalenemethanol (1I), were treated with DIB
(1.1 equiv) in the presence of TEMPO (0.1 equiv) in CH2Cl2
(2.0 mL) at room temperature for 0.5–2.0 h (first step), and
then with NH2OH·H2O (1.5 equiv) and K2CO3 (0.75 equiv) at
room temperature for 18 h to form oxime 2 (second step).
The mixtures were then treated with NCS (1.5 equiv) in the
presence of DMF (0.2 mL) at 0 °C for 1 h, and then warmed
to room temperature for 3 h (third step). The mixtures were
further treated with diethyl acetylenedicarboxylate (1.5
equiv) and Et3N (1.5 equiv) at room temperature for 1 h
(fourth step) to form diethyl 3-arylisoxazole-4,5-dicarbox-
ylates 4B–I in good yields, respectively, as shown in Scheme
2. Aliphatic primary alcohols, such as 3-phenylpropanol
(1J), 4-phenylbutanol (1K), 1-octanol (1L), cyclopen-
tanemethanol (1M), and 1-adamantanemethanol (1N),
were also smoothly transformed into the corresponding 3-
alkylisoxazole-4,5-dicarboxylates 4J–M in good yields, re-
spectively, and into diethyl 3-(1′-adamantyl)isoxazole-4,5-
O
N
O
N
O
N
CO2Et
CO2Me
Ph
CO2Et
CO2Me
Me
Me
4S 75%d,e (0.5 h)
4P 65% (6.0 h)
80% (0.5 h)
O
4Q
O
N
O
N
N
CO2Et
+
CO2Et
Me
Me
Me
60% + 15% (0.5 h)
4T 60%e,f (0.5 h)
4R
4R'
Scheme 2 Transformation of primary alcohols 1 into isoxazoles 4.
a Substrate 1A (8.0 mmol) was used. b NH2OH (2.0 equiv) and K2CO3
(1.0 equiv) were added at second step of the reaction. c Reaction was
carried out at 0 °C for 10 h at third step of the reaction and at 0 °C for
16 h at fourth step of the reaction. d After evaporation, CH2Cl2 (2.0 mL)
and DMF (0.2 mL) were added at the third step of the reaction. e Reac-
tion time at the fourth step of the reaction was 3 h. f 1-Octyne (10.0
equiv) was added at the fourth step of the reaction.
dicarboxylate (4N) in moderate yield, under the same pro-
cedure and conditions. Moreover, primary alcohols bearing
an olefinic group, such as cinnamyl alcohol 1O and 5-hex-
en-1-ol 1P, could be successfully converted into the corre-
sponding 3-alkenylisoxazoles 4O and 4P in good yields,
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–M

D
E. Kobayashi, H. Togo
Paper
Synthesis
keeping their olefinic groups. Other alkynes, such as di-
methyl acetylenedicarboxylate, ethyl propiolate, pheny-
lacetylene, and 1-octyne, instead of diethyl acetylenedicar-
boxylate could be also used under the same procedure and
conditions to form 3-(p-methylphenyl)isoxazole derivatives
4Q–T in good to moderate yields, respectively, together
with regioisomer 4R′ in 15% yield using ethyl propiolate.
The one-pot preparation of 1-phenyl-3-arylpyrazoles
was then studied. The optimum reaction conditions for the
preparation of diethyl 3-(p-methylphenyl)-1-phenylpyra-
zole-4,5-dicarboxylate (5A) from p-methylbenzyl alcohol
(1A) were studied. p-Methylbenzyl alcohol (1A; 1.0 mmol)
was treated with DIB (1.1 equiv) in the presence of TEMPO
(0.1 equiv) in CH2Cl2 (1.0 mL) at room temperature for 0.5 h
(first step), and then with NH2NHPh (1.1 equiv) at 60 °C for
3 h to form hydrazone 3A (second step). After the second
reaction step, the mixture was treated with NCS (1.5 equiv)
and dodecyl methyl sulfide (2.0 equiv) in CH2Cl2 (4.0 mL)
and DMF (0.5 mL) at –78 °C for 1 h and then warmed to
room temperature for 3 h to form hydrazonyl chloride
(third step),12 a precursor of nitrilimine. The mixture was
further treated with diethyl acetylenedicarboxylate (3.0
equiv) and Et3N (3.0 equiv) at room temperature for 1 h
(fourth step) to form diethyl 3-(p-methylphenyl)-1-phen-
ylpyrazole-4,5-dicarboxylate (5A) in 48% yield, as shown in
Table 2 (entry 1). When the solvent was removed after the
second reaction step, and the residue was treated in CH2Cl2
(5.0 mL) without or with DMF (0.5 mL) in the third reaction
step under the same procedure and conditions, pyrazole 5A
was generated in 72% and 82% yields, respectively (entries 2
and 3). Thus, the removal of the solvent after the second re-
action step and the addition of DMF in the third reaction
step are important to promote the formation of hydrazonyl
chloride and, therefore, to improve the yield of pyrazole 5A.
After optimizing the experimental conditions by changing
the amounts of CH2Cl2 and Et3N, it was found that the addi-
tion of CH2Cl2 (5.0 mL) in the third reaction step and Et3N
(1.5 equiv) in the fourth reaction step was best, giving pyra-
zole 5A in 82% yield (entry 5). When dodecyl methyl sulfide
was not used in the third reaction step under the same pro-
cedure and conditions as those summarized in entry 5, the
yield of pyrazole 5A decreased to 50% (entry 6). When a
gram-scale experiment with 8.0 mmol of p-methylbenzyl
alcohol 1A was carried out under the same procedure and
conditions as those of entry 5, pyrazole 5A was obtained in
83% yield, as shown in Scheme 3. When NBS and NIS in-
stead of NCS were used in the third reaction step under the
same procedure and conditions, pyrazole 5A was not ob-
tained at all (entries 7 and 8, respectively). Again, NCS
played an important role in the formation of pyrazole 5A.
Based on those results, benzylic alcohols 1B–I were
treated with DIB (1.1 equiv) in the presence of TEMPO (0.1
equiv) in CH2Cl2 (1.0 mL) at room temperature for 0.5–2.0 h
(first step), and then with NH2NHPh (1.1 equiv) at 60 °C for
3 h to form hydrazones 3 (second step). After the removal of
Table 2 Transformation of 4-Methylbenzyl Alcohol 1A into
3-(4′-Methylphenyl)pyrazole 5A
OH
H
N
Ph
1) DIB (1.1 equiv), TEMPO (0.1 equiv)
N
CH2Cl21st, r.t, 0.5 h
(1st step)
Me
Me
2) NH2NH-Ph (1.1 equiv), 60 °C, 3 h
(2nd step)
1A
3A
(1.0 mmol)
Ph
3) evaporation:
N
N
4) NXS (1.5 equiv), CH3SC10H21 (2.0 equiv)
CH2Cl23rd:DMF
CO2Et
(3rd step)
–78 °C, 1 h
5) EtO2C
Et3N, r.t., 1 h
r.t., 3 h
CO2Et
Me
CO2Et(3.0 equiv)
(4th step)
5A
Entry CH2Cl21st (mL) CH2Cl23rd/DMF
(mL)
NXS Et3N
(equiv)
Yield 5A (%)
1a
2
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
4.0:0.5
5.0:0
NCS 3.0
NCS 3.0
NCS 3.0
NCS 3.0
NCS 1.5
NCS 1.5
NBS 1.5
48
72
82
76
82
50
0
3
5.0:0.5
4.0:0.5
5.0:0.5
5.0:0.5
5.0:0.5
5.0:0.5
4
5
6b
7
8
NIS
1.5
0
a After the second step of the reaction, solvent was not removed.
b Without CH3-S-C10H21 in the third step of the reaction.
the solvent, CH2Cl2 (5.0 mL) and DMF (0.5 mL) were added
to the residue, and the mixtures were treated with NCS (1.5
equiv) at –78 °C for 1 h, and then warmed to room tempera-
ture for 3 h (third step). The mixtures were then further
treated with diethyl acetylenedicarboxylate (3.0 equiv) and
Et3N (1.5 equiv) at room temperature for 1 h (fourth step) to
form diethyl 3-aryl-1-phenylpyrazole-4,5-dicarboxylates
5B–I in good yields, respectively, as shown in Scheme 3. Ali-
phatic primary alcohols 1J–N were also smoothly trans-
formed into the corresponding diethyl 3-alkyl-1-phen-
ylpyrazole-4,5-dicarboxylates 5J–M in good yields, and into
diethyl3-(1′-adamantyl)-1-phenylpyrazole-4,5-dicarboxyl-
ate (5N) in moderate yield, under the same procedure and
conditions. Furthermore, primary alcohols bearing an ole-
finic group, such as cinnamyl alcohol 1O and 5-hexen-1-ol
1P, could be also successfully transformed into the corre-
sponding 3-alkenylpyrazoles 5O and 5P in good yields,
keeping their olefinic groups. Other alkynes, such as di-
methyl acetylenedicarboxylate, ethyl propiolate, and phe-
nylacetylene, instead of diethyl acetylenedicarboxylate
could be also used under the same procedure and condi-
tions to form 3-(p-methylphenyl)-1-phenylpyrazole deriva-
tives 5Q–S in good to moderate yields, together with regio-
isomers 5R′ and 5S′ in 16% and 8% yields using ethyl propio-
late
and
phenylacetylene,
respectively.
When
benzylhydrazine was used instead of phenylhydrazine in
the second reaction step under the same procedure and
conditions, diethyl 1-benzyl-3-(p-methylphenyl)pyrazole-
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–M

E
E. Kobayashi, H. Togo
Paper
Synthesis
4,5-dicarboxylate (5U) was obtained in 50% yield. However,
when methylhydrazine and hydrazine were used instead of
phenylhydrazine under the same procedure and conditions,
diethyl 1-methyl-3-(p-methylphenyl)pyrazole-4,5-dicar-
boxylate and diethyl 3-(p-methylphenyl)pyrazole-4,5-di-
carboxylate, respectively, were not formed at all.
Unfortunately, the present methods could not be ap-
plied to N-Boc-protected L-prolinol due to the occurrence of
deprotection mediated by HCl formed with NCS in the third
reaction step. Additionally, the standard treatment of 3-hy-
1) DIB (1.1 equiv), TEMPO (0.1 equiv)
(1st step)
H
OH
CH2Cl2 (1.0 mL), r.t, Time
N
R4
R1
R1
N
2) NH2NH-R4 (1.1 equiv), 60 °C, 3 h
(2nd step)
1
3
(1.0 mmol)
3) evaporation:
R4
4) NCS (1.5 equiv), CH3SC10H21 (2.0 equiv)
CH2Cl2 : DMF = 10 : 1 (5.5 mL)
N
N
R2
(3rd step)
–78 °C, 1 h
r.t., 3 h
R1
R3
5) R2
R3 (3.0 equiv)
5
(4th step)
Et3N (1.5 equiv), r.t., 1 h
Product, Yield, (1st step Time)
Ph
Ph
Ph
N
N
N
N
N
N
Me
droxymethyl-1-methylindole,
3-(hydroxymethyl)ben-
CO2Et
CO2Et
CO2Et
Me
zothiophene, and 3-(hydroxymethyl)benzofuran gave the
corresponding 3-heteroarylisoxazoles and -pyrazoles to-
gether with their monochlorination products at the 2-posi-
tion of the heteroaryl groups by NCS, as mixtures in the
range of 32–40% yields.
CO2Et
CO2Et
CO2Et
Me
5A 82% (0.5 h)
5B 81%b,c (1.0 h)
5C 82% (0.5 h)
83%a
Ph
Ph
Ph
N
N
N
N
N
N
CO2Et
CO2Et
CO2Et
Once diethyl 3-arylisoxazole-4,5-dicarboxylates and di-
ethyl 3-arylpyrazole-4,5-dicarboxylates were formed, they
could be further transformed into other 3-arylisoxazole and
3-arylpyrazole derivatives. Thus, treatment of isoxazole de-
rivative 4A with hydrazine in ethanol at 90 °C for 6 h gave
bicyclic pyridazine derivative 4A–I in 96% yield, as shown in
Scheme 4, Equation 1. Treatment of isoxazole derivative 4A
with DIBAL in THF at temperatures from –78 to 20 °C gave
compound 4A–II in 84% yield (Eq. 2).
CO2Et
CO2Et
CO2Et
MeO2C
MeO
5E 90% (0.5 h)
5F 72% (0.5 h)
5D 88% (0.5 h)
Ph
Ph
Ph
N
N
N
N
N
N
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
Cl
Ph
Ph
5G 79% (0.5 h)
5H 71%d (0.5 h)
5I 75% (2.0 h)
Ph
Ph
Ph
N
N
N
N
N
N
CO2Et
CO2Et
CO2Et
Ph
n-C7H15
CO2Et
CO2Et
CO2Et
O
O
N
N
5J 71% (3.0 h)
5K 85% (3.0 h)
OH
5L 72% (5.0 h)
NH2NH2•H2O (7.5 equiv)
CO2Et
Ph
Ph
Ph
1)
N
EtOH (0.75 mL)
90 °C, 6 h
N
N
N
N
CO2Et
N
N
N
Me
Me
HO
CO2Et
CO2Et
CO2Et
4A
Ph
4A-I
96%
CO2Et
CO2Et
CO2Et
0.5 mmol
5M 79% (3.0 h)
5N 55%d (2.5 h)
5O 62% (1.5 h)
Ph
O
O
N
Ph
N
N
N
CO2Et
CH2OH
DIBAL-H (8.0 equiv)
THF (2.0 mL)
N
N
CO2Me
CO2Et
2)
CO2Et
CH2OH
Me
Me
CO2Me
–78 °C
20 °C, 18 h
CO2Et
5P 87% (6.0 h)
Me
4A-II
4A
5Q 69% (0.5 h)
84%
Ph
Ph
N
N
N
N
Ph
Ph
CO2Et
N
N
N
N
OH
+
NH2NH2•H2O (10 equiv)
CO2Et
CO2Et
Ph
Me
Me
3)
N
5R
5R'
61% + 16% (0.5 h)
EtOH (1.0 mL)
90 °C, 6 h
CO2Et
N
Me
Me
HO
Ph
Bn
5A
N
N
N
N
N
5A-I
N
Ph
CO2Et
CO2Et
5U 50%g,h (0.5 h)
76%
+
Ph
N
Ph
Ph
Me
Me
Me
N
N
N
58% + 8%e,f (0.5 h)
5S
5S'
LiAlH4 (2.5 equiv)
THF (2.0 mL)
CO2Et
CH2OH
4)
Scheme 3 Transformation of primary alcohols 1 into pyrazoles 5.
a Substrate 1A (8.0 mmol) was used. b NH2NHPh (1.5 equiv) was added
in the second step of the reaction. c Reaction was carried out at –78 °C
for 1 h and at 0 °C for 12 h in the third step of the reaction, and at 0 °C
for 24 h in the fourth step of the reaction. d CH2Cl2 (2.0 mL) was used as
a solvent in the first step of the reaction. e Reaction time for the fourth
step of the reaction was 3 h. f After evaporation, alkyne (15.0 equiv)
was added. g NH2NHBn·HCl (1.1 equiv) and Et3N (1.1 equiv) were added
instead of NH2NHPh in the second step of the reaction. h After addition
of Et3N (1.5 equiv) at r.t., NaH (3.0 equiv) was added in the fourth step
of the reaction.
CO2Et
CH2OH
Me
Me
0 °C
50 °C, 4 h
5A
5A-II
86%
Bn
N
NH
Pd(OH)2/C (25 mol%)
HCO2NH4 (2.5 equiv)
N
N
CO2Et
CO2Et
5)
HCO2H (6.0 mL)
80 °C, 24 h
CO2Et
CO2Et
Me
Me
5U
5U'
68%
Scheme 4 Derivatization of isoxazole 4 and pyrazoles 5
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–M

F
E. Kobayashi, H. Togo
Paper
Synthesis
The reactions of pyrazole derivative 5A with hydrazine
in ethanol at 90 °C for 6 h, and with LiAlH4 in THF at tem-
peratures from 0 to 50 °C also gave pyridazine derivative
5A–I and compound 5A–II in 76 and 86% yields, respective-
ly (Eq. 3 and 4). Debenzylation of pyrazole derivative 5U
with Pd(OH)2 and HCO2NH4 in HCO2H at 80 °C generated di-
ethyl N-free pyrazole 5U′ in 68% yield (Eq. 5).
The reaction pathways for the preparation of 3-aryl-
and 3-alkylisoxazoles and -pyrazoles from primary alcohols
are shown in Scheme 5 and Scheme 6, respectively.
lenedicarboxylate via a 1,3-dipolar cycloaddition to form
diethyl 3-aryl- and 3-alkylpyrazole-4,5-dicarboxylate 5, as
shown in Scheme 6.
In conclusion, 3-aryl- and 3-alkylisoxazoles could be ob-
tained efficiently from primary alcohols by successive
treatment with DIB in the presence of TEMPO, hydroxyl-
amine, and then NCS, followed by the reaction with alkynes
in the presence of Et3N. 3-Aryl- and 3-alkyl-1-phenylpyra-
zoles could be also obtained efficiently from primary alco-
hols by successive treatment with DIB in the presence of
TEMPO, phenylhydrazine, and then NCS in the presence of
decyl methyl sulfide, followed by reaction with alkynes in
the presence of Et3N. The chlorine atom derived from NCS
plays an important role in the formation of 1,3-dipolar pre-
cursors, nitrile N-oxide and nitrilimine, from oximes and
hydrazones, respectively. The present successive operations
will be useful for the one-pot preparation of 3-aryl- and 3-
alkylisoxazoles and -pyrazoles from readily available pri-
mary alcohols.
1) TEMPO-DIB
Oxidation
2) NH2OH•HCl
K2CO3
O
H
OH
R1
OH
R1
R1
N
1
2
a
Cl–
H
Cl
3) NCS
O
H
R1
O
H
R1
N+
R1
N
N+
H
O
Cl
d
b
c
CO2Et
O
O–
N+
N
CO2Et
4) Et3N
R1
(– HCl)
CO2Et
1,3-Dipolar
Cycloaddition
CO2Et
1H NMR spectra were measured with 400 MHz spectrometers. Chem-
ical shifts were recorded as follows: chemical shift in ppm from inter-
nal tetramethylsilane on the  scale, multiplicity (s = singlet; d = dou-
blet; t = triplet; q = quartet; sext = sextet; m = multiplet; br = broad),
coupling constant (Hz), integration, and assignment. 13C NMR spectra
were measured with 100 MHz spectrometers. Chemical shifts were
recorded in ppm from the solvent resonance employed as the internal
standard (CDCl3 at  = 77.0 ppm, or DMSO-d6 at  = 39.5 ppm). Char-
acteristic peaks in the infrared (IR) spectra are given in wavenumber
(cm–1). High-resolution mass spectra (HRMS) were recorded with
Thermo Fisher Scientific Exactive Orbitrap mass spectrometers. Melt-
ing points are uncorrected. Thin-layer chromatography (TLC) was
performed using 0.25 mm silica gel plates (60F254). The products
were purified by column chromatography on neutral silica gel 60N
(63–200 mesh).
4
R1
e
Scheme 5 Reaction pathway for isoxazoles
1) TEMPO-DIB
O
2) NH2NH-R4
3) evaporation
OH
Oxidation
NHR4
R1
R1
R1
N
H
a
1
3
S
C10H21
H3C
H
+
Cl
S+
4)
H3C
C10H21
H
Cl–
H
Cl
R1
NR4
NR4
H
N+
Cl
N
R1
R1
N+
NR4
h
g
f
R4
R4
CO2Et
CO2Et
N
N–
N+
Transformation of Primary Alcohols 1 into Diethyl 3-Aryl- or 3-Al-
kylisoxazole-4,5-dicarboxylates 4; Typical Procedure
N
CO2Et
5) Et3N
(– HCl)
R1
CO2Et
1,3-Dipolar
Cycloaddition
DIB (354.0 mg, 1.1 mmol) was added to a solution of p-methylbenzyl
alcohol 1A (122.2 mg, 1.0 mmol) and TEMPO (15.6 mg, 0.1 mmol) in
CH2Cl2 (2.0 mL). The mixture was stirred at r.t. under Ar atmosphere.
After 30 min, NH2OH·HCl (104.2 mg, 1.5 mmol) and K2CO3 (103.7 mg,
0.75 mmol) were added and the obtained mixture was stirred for 18 h
at r.t. Then, DMF (0.2 mL) and NCS (200.1 mg, 1.5 mmol) were added
to the solution at 0 °C. After 1 h, the reaction mixture was stirred for 3
h at r.t., then Et3N (209.1 L, 1.5 mmol) and diethyl acetylenedicar-
boxylate (238.5 L, 1.5 mmol) were added to the solution and the ob-
tained mixture was stirred for 1 h at r.t. The mixture was quenched
with sat. aq. NaHCO3 and extracted with CHCl3 (3 × 10.0 mL), and the
organic layer was dried over Na2SO4. After removal of the solvent,
purification by short column chromatography on silica gel (hexane/
EtOAc, 8:1)gavediethyl3-(p-methylphenyl)isoxazole-4,5-dicarboxyl-
ate 4A (266.9 mg, 88%).
5
R1
i
Scheme 6 Reaction pathway for pyrazoles
Primary alcohol 1 is smoothly oxidized to aldehyde a,
and this further reacts with hydroxylamine to form oxime
2. Oxime 2 reacts with NCS to form nitrile N-oxide e via the
dehydrochlorination of hydroximoyl chloride d. Once nitrile
N-oxide e is formed, it smoothly reacts with diethyl acety-
lenedicarboxylate via a 1,3-dipolar cycloaddition to form
diethyl 3-aryl- and 3-alkylisoxazole-4,5-dicarboxylate 4, as
shown in Scheme 5. Similarly, formed aldehyde a reacts
with hydrazine to give hydrazone 3. The latter reacts with
NCS in the presence of decyl methyl sulfide to form nitrili-
mine i through dehydrochlorination of hydrazonyl chloride
h. Once nitrilimine i is formed, it reacts with diethyl acety-
Diethyl 3-(p-Methylphenyl)isoxazole-4,5-dicarboxylate (4A)
Yield: 266.9 mg (88%); white solid; mp 45–46 °C (44–46 °C).9g,h
IR (neat): 2923, 1737, 1447, 1274, 826 cm–1
.
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–M

G
E. Kobayashi, H. Togo
Paper
Synthesis
1H NMR (400 MHz, CDCl3):  = 1.33 (t, J = 7.0 Hz, 3 H), 1.43 (t, J =
7.0 Hz, 3 H), 2.41 (s, 3 H), 4.38 (q, J = 7.0 Hz, 2 H), 4.47 (q, J = 7.0 Hz,
2 H), 7.27 (d, J = 8.2 Hz, 2 H), 7.60 (d, J = 8.2 Hz, 2 H).
13C NMR (100 MHz, CDCl3):  = 13.6, 13.7, 21.1, 62.1, 62.6, 115.9,
123.9, 127.7 (2C), 129.3 (2C), 140.7, 155.9, 159.1, 160.1, 161.3.
Diethyl 3-[p-(Methoxycarbonyl)phenyl]isoxazole-4,5-dicarboxyl-
ate (4F)
Yield: 277.9 mg (80%); colorless oil.
IR (neat): 2985, 1724, 1436, 1250, 1273, 1065, 720 cm–1
.
1H NMR (400 MHz, CDCl3):  = 1.31 (t, J = 7.3 Hz, 3 H), 1.44 (t, J =
7.3 Hz, 3 H), 3.96 (s, 3 H), 4.38 (q, J = 7.3 Hz, 2 H), 4.49 (q, J = 7.3 Hz,
2 H), 7.79 (d, J = 8.4 Hz, 2 H), 8.14 (d, J = 8.4 Hz, 2 H).
HRMS (APCI): m/z [M + H]+ calcd for C16H18O5N: 304.1179; found:
304.1176.
13C NMR (100 MHz, CDCl3):  = 13.8, 14.0, 52.4, 62.5, 63.0, 116.0,
128.3 (2C), 129.9 (2C), 131.2, 132.0, 156.0, 160.0, 160.5, 161.0, 166.3.
Diethyl 3-(m-Methylphenyl)isoxazole-4,5-dicarboxylate (4B)
Yield: 212.3 mg (70%); colorless oil.
IR (neat): 2984, 1734, 1445, 1304, 1069 cm–1
HRMS (APCI): m/z [M + H]+ calcd for C17H18O7N: 348.1077; found:
348.1078.
.
1H NMR (400 MHz, CDCl3):  = 1.32 (t, J = 7.2 Hz, 3 H), 1.43 (t, J =
7.2 Hz, 3 H), 2.41 (s, 3 H), 4.38 (q, J = 7.0 Hz, 2 H), 4.47 (q, J = 7.0 Hz,
2 H), 7.31 (d, J = 7.4 Hz, 1 H), 7.36 (t, J = 7.4 Hz, 1 H), 7.48 (d, J = 7.4 Hz,
1 H), 7.53 (s, 1 H).
13C NMR (100 MHz, CDCl3):  = 13.9, 14.0, 21.3, 62.3, 62.8, 116.2,
125.2, 126.9, 128.7, 128.7, 131.4, 138.6, 156.1, 159.3, 161.2, 161.4.
Diethyl 3-(p-Chlorophenyl)isoxazole-4,5-dicarboxylate (4G)
Yield: 275.2 mg (85%); yellow oil.
IR (neat): 2985, 1732, 1272, 1065, 731 cm–1
.
1H NMR (400 MHz, CDCl3):  = 1.33 (t, J = 7.2 Hz, 3 H), 1.43 (t, J =
7.2 Hz, 3 H), 4.38 (q, J = 7.2 Hz, 2 H), 4.48 (q, J = 7.2 Hz, 2 H), 7.46 (d,
J = 8.5 Hz, 2 H), 7.66 (d, J = 8.5 Hz, 2 H).
HRMS (APCI): m/z [M + H]+ calcd for C16H18O5N: 304.1179; found:
304.1177.
13C NMR (100 MHz, CDCl3):  = 13.8, 14.0, 62.5, 62.9, 115.7, 125.4,
129.1 (2C), 129.5 (2C), 136.9, 156.0, 159.9, 160.2, 161.1.
HRMS (APCI): m/z [M + H]+ calcd for C15H15O5NCl: 324.0633; found:
324.0628.
Diethyl 3-(o-Methylphenyl)isoxazole-4,5-dicarboxylate (4C)
Yield: 279.0 mg (92%); colorless oil.
IR (neat): 2984, 1733, 1463, 1304, 1065, 756 cm–1
.
1H NMR (400 MHz, CDCl3):  = 1.14 (t, J = 7.2 Hz, 3 H), 1.44 (t, J =
7.2 Hz, 3 H), 2.28 (s, 3 H), 4.2 (q, J = 7.2 Hz, 2 H), 4.50 (q, J = 7.2 Hz,
2 H), 7.24–7.31 (m, 3 H), 7.38 (dt, J = 8.2, 1.8 Hz, 2 H).
13C NMR (100 MHz, CDCl3):  = 13.6, 14.0, 19.9, 61.8, 62.9, 116.4,
125.6, 126.6, 129.6, 130.0, 130.3, 137.3, 156.3, 160.0, 160.3, 162.2.
Diethyl 3-(p-Biphenyl)isoxazole-4,5-dicarboxylate (4H)
Yield: 292.3 mg (80%); white solid; mp 79–80 °C (78–79 °C).9g,h
IR (neat): 2965, 1726, 1283, 1070, 733, 510 cm–1
.
1H NMR (400 MHz, CDCl3):  = 1.34 (t, J = 7.0 Hz, 3 H), 1.44 (t, J =
7.0 Hz, 3 H), 4.41 (q, J = 7.0 Hz, 2 H), 4.49 (q, J = 7.0 Hz, 2 H), 7.40 (t, J =
7.3 Hz, 1 H), 7.48 (t, J = 7.0 Hz, 2 H), 7.63 (d, J = 7.3 Hz, 2 H), 7.70 (d, J =
8.4 Hz, 2 H), 7.80 (d, J = 8.4 Hz, 2 H).
HRMS (APCI): m/z [M + H]+ calcd for C16H18O5N: 304.1179; found:
304.1178.
13C NMR (100 MHz, CDCl3):  = 13.9, 14.0, 62.5, 62.9, 125.8, 127.1
(2C), 127.5 (2C), 127.9, 128.6 (2C), 128.9 (2C), 140.0, 143.4, 156.1,
159.5, 160.9, 161.5.
Diethyl 3-(p-Methoxyphenyl)isoxazole-4,5-dicarboxylate (4D)
Yield: 287.4 mg (90%); yellow oil.
IR (neat): 2985, 1610, 1455, 1254, 1066, 753 cm–1
.
HRMS (APCI): m/z [M + H]+ calcd for C21H20O5N: 366.1336; found:
1H NMR (400 MHz, CDCl3):  = 1.33 (t, 3 H, J = 7.3 Hz), 1.43 (t, 3 H, J =
7.3 Hz), 3.86 (s, 3 H), 4.38 (q, 2 H, J = 7.3 Hz), 4.47 (q, 2 H, J = 7.3 Hz),
6.98 (d, 2 H, J = 8.8 Hz), 7.66 (d, 2 H, J = 8.8 Hz).
366.1335.
Diethyl 3-(Naphthalen-1′-yl)isoxazole-4,5-dicarboxylate (4I)
13C NMR (100 MHz, CDCl3):  = 13.9, 14.0, 55.3, 62.4, 62.8, 114.2 (2C),
Yield: 285.1 mg (84%); colorless oil.
IR (neat): 2983, 1732, 1300, 1095, 776 cm–1
.
115.9, 119.2, 129.6 (2C), 156.1, 159.2, 160.7, 161.4, 161.6.
HRMS (APCI): m/z [M + H]+ calcd for C16H18O6N: 320.1129; found:
320.1127.
1H NMR (400 MHz, CDCl3):  = 0.85 (t, J = 7.3 Hz, 3 H), 1.46 (t, J =
7.3 Hz, 3 H), 4.04 (q, J = 7.3 Hz, 2 H), 4.53 (q, J = 7.3 Hz, 2 H), 7.48–7.57
(m, 3 H), 7.61 (d, J = 7.7 Hz, 1 H), 7.79 (d, J = 7.7 Hz, 1 H), 7.92 (d, J =
7.7 Hz, 1 H), 7.99 (d, J = 8.2 Hz, 1 H).
Diethyl 3-Phenylisoxazole-4,5-dicarboxylate (4E)
13C NMR (100 MHz, CDCl3):  = 13.3, 14.0, 61.8, 63.0, 117.2, 124.5,
124.8, 124.9, 126.3, 127.0, 128.2, 128.4, 130.6, 133.4, 133.3, 156.3,
160.1, 160.2, 161.5.
HRMS (APCI): m/z [M + H]+ calcd for C19H18O5N: 340.1179; found:
340.1177.
Yield: 234.3 mg (81%); colorless oil.
IR (neat): 2985, 1733, 1443, 1302, 1273, 1066, 694 cm–1
1H NMR (400 MHz, CDCl3):  = 1.31 (t, J = 7.3 Hz, 3 H), 1.43 (t, J =
7.3 Hz, 3 H), 4.37 (q, J = 7.3 Hz, 2 H), 4.48 (q, J = 7.3 Hz, 2 H), 7.45–7.53
(m, 3 H), 7.69–7.71 (m, 2 H).
.
13C NMR (100 MHz, CDCl3):  = 13.8, 14.0, 62.4, 62.8, 116.1, 127.0,
128.1 (2C), 128.8 (2C), 130.5, 156.0, 159.3, 161.1, 161.3.
Diethyl 2-(Phenethyl)isoxazole-4,5-dicarboxylate (4J)
Yield: 209.5 mg (66%); colorless oil.
IR (neat): 2983, 1726, 1269, 1196, 1098, 699 cm–1
HRMS (APCI): m/z [M + H]+ calcd for C15H16O5N: 290.1023; found:
290.1019.
.
1H NMR (400 MHz, CDCl3):  = 1.36 (t, J = 7.3 Hz, 3 H), 1.42 (t, J =
7.3 Hz, 3 H), 3.00–3.04 (m, 2 H), 3.16–3.20 (m, 2 H), 4.35 (q, J = 7.3 Hz,
2 H), 4.46 (q, J = 7.3 Hz, 2 H), 7.20–7.24 (m, 3 H), 7.28–7.32 (m, 2 H).
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–M

H
E. Kobayashi, H. Togo
Paper
Synthesis
13C NMR (100 MHz, CDCl3):  = 13.95, 14.00, 27.4, 33.9, 61.8, 62.9,
113.9, 126.3, 128.4 (2C), 128.5 (2C), 140.3, 156.8, 160.5, 161.2, 162.7.
HRMS (APCI): m/z [M + H]+ calcd for C17H20O5N: 318.1335; found:
318.1336.
1H NMR (400 MHz, CDCl3):  = 1.41 (t, J = 7.0 Hz, 3 H), 1.43 (t, J =
7.0 Hz, 3 H), 4.42 (q, J = 7.0 Hz, 2 H), 4.48 (q, J = 7.0 Hz, 2 H), 7.19 (d,
J = 14.6 Hz, 1 H), 7.33–7.42 (m, 3 H), 7.55 (d, J = 6.5 Hz, 2 H), 7.58 (d,
J = 14.6 Hz, 1 H).
13C NMR (100 MHz, CDCl3):  = 14.0 (2C), 62.0, 63.0, 112.8, 113.9,
127.4 (2C), 128.8 (2C), 129.4, 135.5, 137.6, 156.6, 159.4, 160.8, 160.9.
HRMS (APCI): m/z [M + H]+ calcd for C17H18O5N: 316.1179; found:
Diethyl 3-(3′-Phenylpropyl)isoxazole-4,5-dicarboxylate (4K)
Yield: 235.3 mg (71%); colorless oil.
316.1179.
IR (neat): 2983, 1728, 1269, 1196, 1098, 1030, 700 cm–1
.
1H NMR (400 MHz, CDCl3):  = 1.33 (t, J = 7.3 Hz, 3 H), 1.41 (t, J =
7.3 Hz, 3 H), 2.04 (quint, J = 7.3 Hz, 2 H), 2.71 (t, J = 7.3 Hz, 2 H), 2.90
(t, J = 7.3 Hz, 2 H), 4.33 (q, J = 7.3 Hz, 2 H), 4.45 (q, J = 7.3 Hz, 2 H),
7.18–7.21 (m, 3 H), 7.29 (q, J = 7.5 Hz, 2 H).
Diethyl 3-(4′-Penten-1′-yl)isoxazole-4,5-dicarboxylate (4P)
Yield: 182.9 mg (65%); yellow oil.
IR (neat): 3469, 2983, 1728, 1269, 1197, 1098, 1031 cm–1
.
13C NMR (100 MHz, CDCl3):  = 14.0 (2C), 25.0, 29.2, 35.2, 61.7, 62.9,
114.0, 126.0, 128.4 (2C), 128.5 (2C), 141.3, 156.9, 160.6, 161.1, 163.0.
HRMS (APCI): m/z [M + H]+ calcd for C18H22O5N: 332.1492; found:
332.1490.
1H NMR (400 MHz, CDCl3):  = 1.36 (t, J = 7.0 Hz, 3 H), 1.42 (t, J =
7.0 Hz, 3 H), 1.81 (quint, J = 7.7 Hz, 2 H), 2.15 (q, J = 7.7 Hz, 2 H), 2.87
(t, J = 7.7 Hz, 2 H), 4.36 (q, J = 7.0 Hz, 2 H), 4.46 (q, J = 7.0 Hz, 2 H),
4.99–5.08 (m, 2 H), 5.76–5.86 (m, 1 H).
13C NMR (100 MHz, CDCl3):  = 14.0 (2C), 24.9, 26.8, 33.1, 61.7, 62.9,
114.0, 115.4, 137.5, 156.9, 160.6, 161.1, 163.2.
HRMS (APCI): m/z [M + H]+ calcd for C14H20O5N: 282.1336; found:
Diethyl 3-(Heptyl)isoxazole-4,5-dicarboxylate (4L)
Yield: 227.3 mg (73%); yellow oil.
282.1334.
IR (neat): 2930, 1730, 1467, 1272, 1196, 1097, 1196, 768 cm–1
.
1H NMR (400 MHz, CDCl3):  = 0.88 (t, J = 7.5 Hz, 3 H), 1.26–1.40 (m,
8 H), 1.37 (t, J = 7.3 Hz, 3 H), 1.41 (t, J = 7.3 Hz, 3 H), 1.69 (quint, J =
7.5 Hz, 2 H), 2.85 (t, J = 7.5 Hz, 2 H), 4.36 (q, J = 7.3 Hz, 2 H), 4.45 (q, J =
7.3 Hz, 2 H).
Dimethyl 3-(p-Methylphenyl)isoxazole-4,5-dicarboxylate (4Q)
Yield: 220.2 mg (80%); white solid; mp 66–68 °C.
IR (neat): 2959, 1731, 1448, 1280, 1218, 1068, 820, 806 cm–1
.
13C NMR (100 MHz, CDCl3):  = 14.0 (3C), 22.6, 25.4, 27.7, 28.8, 29.1,
31.6, 61.7, 62.9, 114.0, 156.9, 160.7, 161.0, 163.4.
1H NMR (400 MHz, CDCl3):  = 2.41 (s, 3 H), 3.91 (s, 3 H), 4.02 (s, 3 H),
7.28 (d, J = 8.4 Hz, 2 H), 7.58 (d, J = 8.4 Hz, 2 H).
HRMS (APCI): m/z [M + H]+ calcd for C16H26O5N: 312.1805; found:
13C NMR (100 MHz, CDCl3):  = 21.4, 53.1, 53.3, 116.0, 123.9, 128.0
312.1801.
(2C), 129.6 (2C), 141.0, 156.5, 159.1, 161.2, 161.9.
HRMS (APCI): m/z [M + H]+ calcd for C14H14O5N: 276.0866; found:
276.0863.
Diethyl 3-(Cyclopentyl)isoxazole-4,5-dicarboxylate (4M)
Yield: 194.1 mg (69%); colorless oil.
IR (neat): 2963, 1730, 1267, 1098 cm–1
Ethyl 3-(p-Methylphenyl)isoxazole-5-carboxylate (4R)9g,9h,13
.
Yield: 138.8 mg (60%); white solid; mp 46–48 °C.
1H NMR (400 MHz, CDCl3):  = 1.36 (t, J = 7.3 Hz, 3 H), 1.41 (t, J =
7.3 Hz, 3 H), 1.62–1.73 (m, 2 H), 1.73–1.89 (m, 4 H), 2.02–2.11 (m,
2 H), 3.39 (quint, J = 7.7 Hz, 1 H), 4.36 (q, J = 7.3 Hz, 2 H), 4.44 (q, J =
7.3 Hz, 2 H).
IR (neat): 2980, 1729, 1445, 1278, 821, 509 cm–1
.
1H NMR (400 MHz, CDCl3):  = 1.44 (t, J = 7.0 Hz, 3 H), 2.41 (s, 3 H),
4.46 (q, J = 7.3 Hz, 2 H), 7.23 (s, 1 H), 7.29 (d, J = 8.2 Hz, 2 H), 7.73 (d,
J = 8.2 Hz, 2 H).
13C NMR (100 MHz, CDCl3):  = 13.9 (2C), 25.3 (2C), 31.2 (2C), 36.7,
61.7, 62.7, 114.4, 156.8, 160.6, 161.0, 166.3.
HRMS (APCI): m/z [M + H]+ calcd for C14H20O5N: 282.1336; found:
13C NMR (100 MHz, CDCl3):  = 14.2, 21.4, 62.3, 107.3, 125.1, 126.7
(2C), 129.7 (2C), 140.8, 156.9, 160.7, 162.8.
282.1333.
HRMS (APCI): m/z [M + H]+ calcd for C13H14O5: 232.0968; found:
232.0969.
Diethyl 3-(Adamantan-1′-yl)isoxazole-4,5-dicarboxylate (4N)
3-(p-Methylphenyl)-5-phenylisoxazole (4S)9g,9h
Yield: 180.7 mg (52%); white solid; mp 42–45 °C.
IR (neat): 2922, 2854, 1724, 1289, 1097, 1059, 848 cm–1
.
Yield: 176.5 mg (75%); white solid; mp 125–128 °C.
1H NMR (400 MHz, CDCl3):  = 1.38 (t, J = 7.3 Hz, 3 H), 1.39 (t, J =
7.3 Hz, 3 H), 1.73–1.80 (m, 6 H), 2.05–2.07 (m, 9 H), 4.40 (q, J = 7.3 Hz,
2 H), 4.41 (q, J = 7.3 Hz, 2 H).
IR (neat): 2915, 1445, 813, 761, 688, 528 cm–1
.
1H NMR (400 MHz, CDCl3):  = 2.42 (s, 3 H), 6.81 (s, 1 H), 7.29 (d, J =
8.0 Hz, 2 H), 7.43–7.52 (m, 3 H), 7.77 (d, J = 8.0 Hz, 2 H), 7.84 (d, J =
6.6 Hz, 2 H).
13C NMR (100 MHz, CDCl3):  = 13.9, 14.0, 28.0 (3C), 35.7, 36.3 (3C),
40.2 (3C), 62.3, 62.5, 116.4, 156.3, 158.4, 162.8, 168.6.
HRMS (APCI): m/z [M + H]+ calcd for C19H26O5N: 348.1806; found:
13C NMR (100 MHz, CDCl3):  = 21.4, 97.4, 125.8 (2C), 126.3, 126.7
(2C), 127.5, 129.0 (2C), 129.6 (2C), 130.1, 140.1, 162.9, 170.2.
348.1805.
HRMS (APCI): m/z [M + H]+ calcd for C16H14ON: 236.1070; found:
236.1070.
Diethyl (E)-3-(Styryl)isoxazole-4,5-dicarboxylate (4O)
Yield: 268.1 mg (85%); yellow oil.
5-Hexyl-3-(p-methylphenyl)isoxazole (4T)
IR (neat): 2984, 1728, 1274, 1101, 752 cm–1
.
Yield: 146.1 mg (60%); yellow oil.
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–M

I
E. Kobayashi, H. Togo
Paper
Synthesis
IR (neat): 3122, 2958, 2918, 1601, 1430, 911, 813, 723 cm–1
.
IR (neat): 2984, 1726, 1498, 1259, 1223, 756 cm–1
.
1H NMR (400 MHz, CDCl3):  = 0.90 (t, J = 7.3 Hz, 3 H), 1.30–1.44 (m,
6 H), 1.74 (quint, J = 7.3 Hz, 2 H), 2.40 (s, 3 H), 2.78 (t, J = 7.3 Hz, 2 H),
6.25 (s, 3 H), 7.25 (d, J = 8.2 Hz, 2 H), 7.68 (d, J = 8.2 Hz, 2 H).
13C NMR (100 MHz, CDCl3):  = 14.0, 21.3 (2C), 22.5, 26.7, 27.5, 28.7,
31.4, 98.6, 126.6 (2C), 129.5 (2C), 139.8, 162.2, 174.1.
1H NMR (400 MHz, CDCl3):  = 1.11 (t, J = 7.0 Hz, 3 H), 1.27 (t, J =
7.0 Hz, 3 H), 2.30 (s, 3 H), 4.16 (q, J = 7.0 Hz, 2 H), 4.36 (q, J = 7.0 Hz,
2 H), 7.19–7.27 (m, 2 H), 7.30 (d, J = 6.8 Hz, 1 H), 7.33 (t, J = 6.8 Hz,
1 H), 7.41–7.50 (m, 3 H), 7.57 (d, J = 6.8 Hz, 2 H).
13C NMR (100 MHz, CDCl3):  = 13.7 (2C), 20.1, 60.6, 62.6, 114.5, 124.0
(2C), 125.1 (2C), 128.7, 128.8, 129.2, 129.7 (2C), 130.2, 131.5, 137.3,
138.9, 153.0, 160.9, 162.0.
HRMS (APCI): m/z [M + H]+ calcd for C16H22ON: 244.1696; found:
244.1694.
HRMS (APCI): m/z [M + H]+ calcd for C22H23O4N2: 379.1652; found:
379.1652.
Transformation of Primary Alcohols 1 into 3-Aryl- and 3-Alkyl-1-
phenylpyrazole-4,5-dicarboxylates 5; Typical Procedure
Diethyl 3-(p-Methoxyphenyl)-(1H)-1-phenylpyrazole-4,5-dicar-
boxylate (5D)
DIB (354.0 mg, 1.1 mmol) was added to a solution of p-methylbenzyl
alcohol 1A (122.2 mg, 1.0 mmol) and TEMPO (15.6 mg, 0.1 mmol) in
CH2Cl2 (1.0 mL). The mixture was stirred at r.t. under Ar atomosphere.
After 30 min, phenylhydrazine (108.1 L, 1.1 mmol) was added and
the obtained mixture was stirred at 60 °C for 3 h. After removal of the
solvent under reduced pressure, CH2Cl2 (5.0 mL), DMF (0.5 mL), decyl
methyl sulfide (445.9 L, 2.0 mmol), and NCS (200.1 mg, 1.5 mmol)
were added at –78 °C. After being stirred for 1 h, the reaction mixture
was stirred at r.t. for 3 h, then Et3N (209.1 L, 1.5 mmol) and diethyl
acetylenedicarboxylate (477.0 L, 3.0 mmol) were added to the solu-
tion and the obtained mixture was stirred for 1 h at r.t. The reaction
was quenched with sat. aq. NaHCO3 and extracted with CHCl3
(3 × 10.0 mL), and the organic layer was dried over Na2SO4. After re-
moval of the solvent, purification by short column chromatography
on silica gel (hexane/EtOAc, 8:1) gave diethyl 3-(p-methylphenyl)-1-
phenylpyrazole-4,5-dicarboxylate 5A (310.3 mg, 82%).
Yield: 347.1 mg (88%); white solid; mp 78–80 °C.
IR (neat): 2979, 1729, 1715, 1498, 1234, 1111, 845, 763 cm–1
.
1H NMR (400 MHz, CDCl3):  = 1.24 (t, J = 7.0 Hz, 3 H), 1.29 (t, J =
7.0 Hz, 3 H), 3.85 (s, 3 H), 4.30 (q, J = 7.3 Hz, 4 H), 6.96 (d, J = 8.4 Hz,
2 H), 7.42–7.55 (m, 5 H), 7.72 (d, J = 8.4 Hz, 2 H).
13C NMR (100 MHz, CDCl3):  = 13.8, 14.0, 55.3, 61.1, 62.4, 113.5 (2C),
113.8, 123.9, 124.7 (2C), 129.0, 129.1 (2C), 130.2 (2C), 137.1, 139.1,
151.8, 160.1, 160.3, 163.0.
HRMS (APCI): m/z [M + H]+ calcd for C22H23O5N2: 395.1601; found:
395.1601.
Diethyl 1,3-Diphenyl-(1H)-pyrazole-4,5-dicarboxylate (5E)
Yield: 328.0 mg (90%); yellow solid; mp 51–54 °C (52–53 °C).13
IR (neat): 2987, 1717, 1497, 1262, 1230, 762, 630 cm–1
.
Diethyl 3-(p-Methylphenyl)-(1H)-1-phenylpyrazole-4,5-dicarbox-
ylate (5A)
1H NMR (400 MHz, CDCl3):  = 1.24 (t, J = 7.2 Hz, 3 H), 1.28 (t, J =
7.2 Hz, 3 H), 4.30 (q, J = 7.2 Hz, 2 H), 4.31 (q, J = 7.2 Hz, 2 H), 7.38–7.56
(m, 8 H), 7.73–7.77 (m, 2 H).
13C NMR (100 MHz, CDCl3):  = 13.7, 13.9, 61.1, 62.4, 114.2, 124.7
(2C), 128.0 (2C), 128.8 (2C), 129.0, 129.1 (2C), 131.4, 137.0, 139.1
(2C), 151.9, 160.1, 162.9.
Yield: 310.3 mg (82%); yellow solid; mp 50–53 °C (210–212 °C).13
IR (neat): 2982, 1714, 1498, 1231, 1111, 757, 690 cm–1
.
1H NMR (400 MHz, CDCl3):  = 1.24 (t, J = 7.3 Hz, 3 H), 1.29 (t, J =
7.3 Hz, 3 H), 2.39 (s, 3 H), 4.30 (q, J = 7.3 Hz, 4 H), 7.23 (d, J = 8.2 Hz,
2 H), 7.42–7.50 (m, 3 H), 7.52–7.55 (m, 2 H), 7.65 (d, J = 8.2 Hz, 2 H).
13C NMR (100 MHz, CDCl3):  = 13.8, 14.0, 21.3, 61.1, 62.4, 114.2,
124.8 (2C), 128.5, 128.7 (2C), 128.8 (2C), 129.0, 129.1 (2C), 136.9,
138.7, 139.2, 152.0, 160.2, 163.0.
HRMS (APCI): m/z [M + H]+ calcd for C21H21O4N2: 395.1495; found:
395.1495.
Diethyl 3-[p-(Methoxycarbonyl)phenyl]-(1H)-1-phenylpyrazole-
4,5-dicarboxylate (5F)
HRMS (APCI): m/z [M + H]+ calcd for C22H23O4N2: 379.1652; found:
379.1649.
Yield: 304.2 mg (72%); yellow solid; mp 90–92 °C.
IR (neat): 2989, 1721, 1267, 1229, 1100, 760, 692 cm–1
.
Diethyl 3-(m-Methylphenyl)-(1H)-1-phenylpyrazole-4,5-dicarbox-
ylate (5B)
1H NMR (400 MHz, CDCl3):  = 1.24 (t, J = 7.2 Hz, 3 H), 1.28 (t, J =
7.2 Hz, 3 H), 3.94 (s, 3 H), 4.31 (q, J = 7.2 Hz, 2 H), 4.32 (q, J = 7.2 Hz,
2 H), 7.45–7.56 (m, 5 H), 7.85 (d, J = 8.3 Hz, 2 H), 8.10 (d, J = 8.3 Hz,
2 H).
13C NMR (100 MHz, CDCl3):  = 13.7, 14.0, 52.2, 61.3, 62.5, 114.5,
124.7 (2C), 128.8 (2C), 129.2 (3C), 129.4 (2C), 130.2, 135.9, 137.4,
139.0, 150.8, 160.0, 162.7, 166.8.
Yield: 306.5 mg (81%); yellow oil.
IR (neat): 2983, 1727, 1498, 1221, 752 cm–1
.
1H NMR (400 MHz, CDCl3):  = 1.24 (t, J = 7.3 Hz, 3 H), 1.29 (t, J =
7.3 Hz, 3 H), 2.40 (s, 3 H), 4.31 (q, J = 7.3 Hz, 4 H), 7.22 (d, J = 8.2 Hz,
1 H), 7.31 (t, J = 7.7 Hz, 1 H), 7.43–7.57 (m, 7 H).
13C NMR (100 MHz, CDCl3):  = 13.7, 13.9, 21.4, 61.1, 62.3, 114.4,
124.8 (2C), 125.9, 128.0, 129.0, 129.1 (2C), 129.3, 129.6, 131.2, 136.8,
137.7, 139.1, 151.9, 160.1, 163.0.
HRMS (APCI): m/z [M + H]+ calcd for C23H23O6N2: 423.1550; found:
423.1548.
HRMS (APCI): m/z [M + H]+ calcd for C22H23O4N2: 379.1652; found:
379.1652.
Diethyl 3-(p-Chlorophenyl)-(1H)-1-phenylpyrazole-4,5-dicarbox-
ylate (5G)
Yield: 315.1 mg (79%); red solid; mp 85–88 °C.
IR (neat): 2984, 1733, 1703, 1497, 1265, 1230, 1177, 762 cm–1
Diethyl 3-(o-Methylphenyl)-(1H)-1-phenylpyrazole-4,5-dicarbox-
ylate (5C)
.
Yield: 310.3 mg (82%); yellow solid; mp 75–77 °C.
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–M

J
E. Kobayashi, H. Togo
Paper
Synthesis
1H NMR (400 MHz, CDCl3):  = 1.24 (t, J = 7.3 Hz, 3 H), 1.29 (t, J =
7.3 Hz, 3 H), 4.30 (q, J = 7.3 Hz, 2 H), 4.31 (q, J = 7.3 Hz, 2 H), 7.40 (d,
J = 8.6 Hz, 2 H), 7.44–7.55 (m, 5 H), 7.72 (d, J = 8.6 Hz, 2 H).
13C NMR (100 MHz, CDCl3):  = 13.7, 14.0, 61.2, 62.5, 113.9, 124.6
(2C), 128.3 (2C), 129.1 (2C), 129.9, 130.2 (2C), 134.9, 137.5, 138.9
(2C), 150.9, 160.1, 162.6.
1H NMR (400 MHz, CDCl3):  = 1.23 (t, J = 7.0 Hz, 3 H), 1.32 (t, J =
7.0 Hz, 3 H), 2.07 (quint, J = 7.7 Hz, 2 H), 2.74 (t, J = 7.7 Hz, 2 H), 2.98
(t, J = 7.7 Hz, 3 H), 4.29 (q, J = 7.0 Hz, 2 H), 4.31 (q, J = 7.0 Hz, 2 H),
7.15–7.23 (m, 3 H), 7.27 (t, J = 5.9 Hz, 2 H), 7.38–7.50 (m, 5 H).
13C NMR (100 MHz, CDCl3):  = 13.7, 14.2, 27.3, 30.6, 35.7, 60.5, 62.5,
112.7, 123.9 (2C), 125.7, 128.2 (2C), 128.5 (2C), 128.7, 129.2 (2C),
138.0, 138.9, 142.1, 154.8, 161.3, 162.4.
HRMS (APCI): m/z [M + H]+ calcd for C21H20ClO4N2: 399.1105; found:
399.1104.
HRMS (APCI): m/z [M + H]+ calcd for C24H27O4N2: 407.1966; found:
407.1964.
Diethyl 3-(p-Biphenyl)-(1H)-1-phenylpyrazole-4,5-dicarboxylate
(5H)
Diethyl 3-Heptyl-(1H)-1-phenylpyrazole-4,5-dicarboxylate (5L)
Yield: 312.8 mg (71%); yellow oil.
Yield: 278.3 mg (72%); yellow oil.
IR (neat): 2982, 1728, 1262, 1224, 753, 731, 692 cm–1
.
IR (neat): 2927, 2856, 1716, 1219, 1092 cm–1
.
1H NMR (400 MHz, CDCl3):  = 1.25 (t, J = 7.0 Hz, 3 H), 1.31 (t, J =
7.0 Hz, 3 H), 4.32 (q, J = 7.0 Hz, 2 H), 4.33 (q, J = 7.0 Hz, 2 H), 7.36 (dt,
J = 8.2, 1.4 Hz, 1 H), 7.44–7.52 (m, 5 H), 7.54–7.57 (m, 2 H), 7.64 (d, J =
8.2 Hz, 2 H), 7.66 (d, J = 8.2 Hz, 2 H),7.86 (d, J = 8.2 Hz, 2 H).
1H NMR (400 MHz, CDCl3):  = 0.88 (t, J = 7.3 Hz, 3 H), 1.23 (t, J =
7.3 Hz, 3 H), 1.26–1.44 (m, 11 H), 1.72 (quint, J = 7.9 Hz, 2 H), 2.91 (t,
J = 7.9 Hz, 2 H), 4.30 (q, J = 7.3 Hz, 2 H), 4.31 (q, J = 7.3 Hz, 2 H), 7.38–
7.50 (m, 5 H).
13C NMR (100 MHz, CDCl3):  = 13.7, 14.0, 61.2, 62.4, 114.2, 124.7
(2C), 126.8 (2C), 127.1 (2C), 127.4, 128.7 (2C), 129.0, 129.1 (2C), 129.2
(2C), 130.3, 137.1, 139.1, 140.6, 141.5, 151.6, 160.1, 162.9.
13C NMR (100 MHz, CDCl3):  = 13.8, 14.1, 14.2, 22.6, 27.6, 29.1, 29.2,
29.5, 31.8, 60.5, 62.5, 112.7, 123.9 (2C), 128.7, 129.2 (2C), 137.9,
139.0, 155.4, 161.3, 162.5.
HRMS (APCI): m/z [M + H]+ calcd for C27H25O4N2: 441.1810; found:
HRMS (APCI): m/z [M + H]+ calcd for C22H31O4N2: 387.2279; found:
441.1807.
387.2275.
Diethyl3-(Naphthalen-1′-yl)-(1H)-1-phenylpyrazole-4,5-dicarbox-
Diethyl 3-Cyclopentyl-(1H)-1-phenylpyrazole-4,5-dicarboxylate
ylate (5I)
(5M)
Yield: 310.9 mg (75%); red oil.
Yield: 281.6 mg (79%); yellow oil.
IR (neat): 2984, 1731, 1217, 1095, 909, 752, 731 cm–1
.
IR (neat): 2959, 1715, 1504, 1219, 1095, 756 cm–1
.
1H NMR (400 MHz, CDCl3):  = 0.78 (t, J = 7.3 Hz, 3 H), 1.29 (t, J =
7.3 Hz, 3 H), 3.98 (q, J = 7.3 Hz, 2 H), 4.39 (q, J = 7.3 Hz, 2 H), 7.43–7.55
(m, 6 H), 7.60–7.64 (m, 3 H), 7.85–7.93 (m, 3 H).
13C NMR (100 MHz, CDCl3):  = 13.3, 13.8, 60.6, 62.7, 115.7, 124.2
(2C), 124.9, 125.7 (2C), 126.2, 128.1 (2C), 129.0, 129.2 (3C), 129.6,
132.3, 133.4, 137.5, 139.0, 151.8, 160.7, 162.0.
1H NMR (400 MHz, CDCl3):  = 1.23 (t, J = 7.3 Hz, 3 H), 1.34 (t, J =
7.3 Hz, 3 H), 1.65–1.73 (m, 2 H), 1.76–1.93 (m, 4 H), 2.04–2.12 (m,
2 H), 3.60 (quint, J = 8.6 Hz, 1 H), 4.30 (q, J = 7.3 Hz, 2 H), 4.31 (q, J =
7.3 Hz, 2 H), 7.37–7.50 (m, 5 H).
13C NMR (100 MHz, CDCl3):  = 13.7, 14.1, 25.4 (2C), 32.1, 38.0 (2C),
60.4, 62.4, 112.7, 123.9 (2C), 128.5, 129.1 (2C), 137.8, 139.1, 158.2,
161.4, 162.6.
HRMS (APCI): m/z [M + H]+ calcd for C25H23O4N2: 415.1653; found:
415.1650.
HRMS (APCI): m/z [M + H]+ calcd for C20H25O4N2: 357.1809; found:
357.1807.
Diethyl 2-Phenethyl-(1H)-1-phenylpyrazole-4,5-dicarboxylate (5J)
Diethyl 3-(Adamantan-1′-yl)-(1H)-1-phenylpyrazole-4,5-dicarbox-
ylate (5N)
Yield: 278.6 mg (71%); yellow oil.
IR (neat): 2981, 1713, 1503, 1249, 1224, 1159, 692 cm–1
.
Yield: 232.4 mg (55%); white solid; mp 58–60 °C.
1H NMR (400 MHz, CDCl3):  = 1.24 (t, J = 7.0 Hz, 3 H), 1.35 (t, J =
7.0 Hz, 3 H), 3.04 (t, J = 7.9 Hz, 2 H), 3.24 (t, J = 7.9 Hz, 3 H), 4.31 (q, J =
7.0 Hz, 2 H), 4.33 (q, J = 7.0 Hz, 2 H), 7.19–7.24 (m, 1 H), 7.28–7.31 (m,
4 H), 7.40–7.50 (m, 5 H).
13C NMR (100 MHz, CDCl3):  = 13.8, 14.2, 29.8, 35.3, 60.6, 62.6, 112.7,
123.9 (2C), 125.9, 128.3 (2C), 128.5 (2C), 128.8, 129.3 (2C), 138.1,
138.9, 141.7, 154.3, 161.2, 162.4.
IR (neat): 2903, 2850, 1724, 1503, 1221, 1098, 757 cm–1
.
1H NMR (400 MHz, CDCl3):  = 1.19 (t, J = 7.3 Hz, 3 H), 1.37 (t, J =
7.3 Hz, 3 H), 1.74–1.81 (m, 6 H), 2.06 (m, 3 H), 2.13–2.14 (m, 6 H),
4.23 (q, J = 7.3 Hz, 2 H), 4.35 (q, J = 7.3 Hz, 2 H), 7.38–7.45 (m, 5 H).
13C NMR (100 MHz, CDCl3):  = 13.7, 14.1, 28.5 (3C), 35.8, 36.7 (3C),
40.7 (3C), 61.2, 61.9, 114.8, 125.0 (2C), 128.6, 128.9 (2C), 135.9, 139.5,
159.6, 160.1, 164.4.
HRMS (APCI): m/z [M + H]+ calcd for C23H25O4N2: 393.1809; found:
393.1807.
HRMS (APCI): m/z [M + H]+ calcd for C25H31O4N2: 423.2279; found:
4223.2278.
Diethyl1-Phenyl-3-(3′-phenylpropyl)-(1H)-pyrazole-4,5-dicarbox-
ylate (5K)
Diethyl (E)-(1H)-1-Phenyl-3-styrylpyrazole-4,5-dicarboxylate (5O)
Yield: 345.5 mg (85%); yellow oil.
Yield: 242.1 mg (62%); red oil.
IR (neat): 2981, 1714, 1504, 1249, 1220, 1095, 755, 692 cm–1
.
IR (neat): 2981, 1714, 1499, 1217, 1096, 750, 692 cm–1
.
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–M

K
E. Kobayashi, H. Togo
Paper
Synthesis
1H NMR (400 MHz, CDCl3):  = 1.24 (t, J = 7.0 Hz, 3 H), 1.39 (t, J =
7.0 Hz, 3 H), 4.31 (q, J = 7.0 Hz, 2 H), 4.37 (q, J = 7.0 Hz, 2 H), 7.30 (d,
J = 7.3 Hz, 1 H), 7.36 (t, J = 7.3 Hz, 2 H), 7.43–7.51 (m, 3 H), 7.55–7.58
(m, 4 H), 7.63 (d, J = 15.0 Hz, 1 H), 7.59 (d, J = 15.0 Hz, 1 H).
13C NMR (100 MHz, CDCl3):  = 13.8, 14.2, 60.8, 62.6, 112.7, 117.2,
124.2 (2C), 127.0 (2C), 128.2, 128.6 (2C), 129.1, 129.3 (2C), 133.0,
136.8, 138.2, 139.0, 150.3, 160.9, 162.4.
13C NMR (100 MHz, CDCl3):  = 21.3, 105.0, 125.3 (2C), 125.7 (2C),
127.3, 128.2, 128.4 (2C), 128.7 (2C), 128.9 (2C), 129.3 (2C), 130.2,
130.6, 137.7, 140.1, 144.2, 152.0.
HRMS (APCI): m/z [M + H]+ calcd for C22H19N2: 311.1543; found:
311.1540.
Diethyl (1H)-1-Benzyl-3-(p-methylphenyl)pyrazole-4,5-dicarbox-
ylate (5U)
HRMS (APCI): m/z [M + H]+ calcd for C23H23O4N2: 391.1653; found:
391.1652.
Yield: 196.3 mg (50%); orange oil.
IR (neat): 2982, 1720, 1242, 1091, 725 cm–1
.
Diethyl 3-(4′-Penten-1′-yl)-(1H)-1-phenylpyrazole-4,5-dicarboxyl-
ate (5P)
1H NMR (400 MHz, CDCl3):  = 1.29 (t, J = 7.3 Hz, 3 H), 1.29 (t, J =
7.3 Hz, 3 H), 2.38 (s, 3 H), 4.29 (q, J = 7.3 Hz, 2 H), 4.30 (q, J = 7.3 Hz,
2 H), 5.69 (s, 2 H), 7.21 (d, J = 8.2 Hz, 2 H), 7.26–7.33 (m, 5 H), 7.60 (d,
J = 8.2 Hz, 2 H).
Yield: 310.1 mg (87%); red oil.
IR (neat): 2981, 1715, 1504, 1220, 1094, 755 cm–1
.
1H NMR (400 MHz, CDCl3):  = 1.24 (t, J = 7.3 Hz, 3 H), 1.34 (t, J =
7.3 Hz, 3 H), 1.83 (quint, J = 7.7 Hz, 2 H), 2.18 (q, J = 6.6 Hz, 2 H), 2.94
(t, J = 7.7 Hz, 2 H), 4.31 (q, J = 7.3 Hz, 2 H), 4.31 (q, J = 7.3 Hz, 2 H), 4.98
(ddd, J = 17.0, 2.0, 1.6 Hz, 1 H), 5.05 (ddd, J = 17.0, 2.0, 1.6 Hz, 1 H),
5.81–5.91 (m, 1 H), 7.38–7.52 (m, 5 H).
13C NMR (100 MHz, CDCl3):  = 13.8, 14.2, 27.1, 28.3, 33.6, 60.5, 62.6,
112.7, 114.8, 123.9 (2C), 128.7, 129.2 (2C), 138.0, 138.4, 138.9, 155.0,
161.3, 162.5.
13C NMR (100 MHz, CDCl3):  = 13.9, 14.0, 21.3, 55.2, 61.4, 61.8, 115.8,
127.7 (2C), 127.8 (2C), 127.9, 128.6 (2C), 128.8, 129.1 (2C), 133.1,
136.1, 138.5, 149.3, 159.3, 164.4.
HRMS (APCI): m/z [M + H]+ calcd for C23H25O4N2: 393.1809; found:
393.1807.
Preparation of 3′-(p-Methylphenyl)isoxazolo[4′,5′-d]pyridazine-
3,6-diol (4A-I)
HRMS (APCI): m/z [M + H]+ calcd for C20H25O4N2: 357.1809; found:
357.1807.
Hydrazine monohydrate (187.8 L, 7.5 mmol) was added to a solution
of 4A (151.6 mg, 0.5 mmol) in EtOH (0.75 mL). The mixture was
stirred for 6 h at 90 °C, then filtration of the reaction mixture gave 3′-
(p-methylphenyl)isoxazolo[4′,5%-d]pyridazine-3,6-diol 4A-I (120.4
mg, 99%).
Dimethyl (1H)-1-Phenyl-3-(p-methylphenyl)pyrazole-4,5-dicar-
boxylate (5Q)
Yield: 241.8 mg (69%); white solid; mp 78–80 °C (65–67 °C).14
3′-(p-Methylphenyl)isoxazolo[4′,5′-d]pyridazine-3,6-diol (4A-I)
IR (neat): 2951, 1729, 1499, 1263, 1228, 759 cm–1
.
White solid; mp 245–255 °C.
1H NMR (400 MHz, CDCl3):  = 2.40 (s, 3 H), 3.83 (s, 3 H), 3.86 (s, 3 H),
7.24 (d, J = 8.2 Hz, 2 H), 7.43–7.55 (m, 5 H), 7.65 (d, J = 8.2 Hz, 2 H).
IR (neat): 3168 (br), 2587 (br), 1577, 1104, 820 cm–1
.
1H NMR (400 MHz, DMSO-d6):  {tautomeric isomer 6%} = {2.32 (s,
3 H)}, 2.38 (s, 3 H), {7.13 (d, J = 8.2 Hz, 2 H)}, 7.33 (d, J = 8.2 Hz, 2 H),
{8.02 (d, J = 8.2 Hz, 2 H)}, 8.36 (d, J = 8.2 Hz, 2 H).
13C NMR (100 MHz, DMSO-d6):  = 21.1, 112.2, 124.7, 129.0 (2C),
129.1 (2C), 140.3, 151.8, 156.7, 159.2, 164.2.
13C NMR (100 MHz, CDCl3):  = 21.3, 52.1, 53.1, 53.4, 114.0, 124.5
(2C), 128.4, 128.6 (2C), 128.9, 129.0, 129.1 (2C), 136.7, 138.8, 139.0,
151.9, 160.6, 163.4.
HRMS (APCI): m/z [M + H]+ calcd for C20H19O4N2: 351.1340; found:
351.1339.
HRMS (ESI): m/z [M + H]+ calcd for C12H10O3N3: 243.0717; found:
243.0717.
Ethyl (1H)-1-Phenyl-3-(p-methylphenylpyrazole-5-carboxylate
(5R)
Preparation of 4,5-Di(hydroxymethyl)-3-(p-methylphenyl)isoxaz-
Yield: 186.9 mg (61%); orange solid; mp 62–64 °C.
ole (4A-II)
IR (neat): 2982, 1726, 1230, 1103, 762 cm–1
.
To a solution of 4A (151.6 mg, 0.5 mmol) in THF (2.0 mL) was added
DIBAL-H (3.88 mL, 4.0 mmol) at –78 °C, and the resulting mixture
was stirred at 20 °C for 18 h. The reaction was quenched with ice and
then sat. aq. NH4Cl. The obtained mixture was filtered and washed
with EtOAc, and the filtrate was extracted with EtOAc (3 × 10.0 mL).
The organic layer was washed with brine and dried over Na2SO4. After
removal of the solvent, purification by short column chromatography
on silica gel (hexane/EtOAc, 1:3) gave 4,5-di(hydroxymethyl)-3-(p-
methylphenyl)isoxazole 4A-II (92.1 mg, 84%).
1H NMR (400 MHz, CDCl3):  = 1.27 (t, J = 7.3 Hz, 3 H), 2.38 (s, 3 H),
4.26 (q, J = 7.3 Hz, 2 H), 7.23 (d, J = 8.2 Hz, 2 H), 7.26 (s, 1 H), 7.42–7.52
(m, 5 H), 7.77 (d, J = 8.2 Hz, 2 H).
13C NMR (100 MHz, CDCl3):  = 14.0, 21.3, 61.1, 109.2, 125.7 (2C),
126.1 (2C), 128.5 (2C), 128.6, 129.3, 129.4 (2C), 134.5, 138.2, 140.4,
151.5, 159.1.
HRMS (APCI): m/z [M + H]+ calcd for C19H19O2N2: 307.1440; found:
307.1438.
(1H)-1,5-Diphenyl-3-(p-methylphenyl)pyrazole (5S)15,16
4,5-Di(hydroxymethyl)-3-(p-methylphenyl)isoxazole (4A-II)
Yield: 92.1 mg (84%); white solid; mp 99–101 °C.
Yield: 180.0 mg (58%); orange solid; mp 122–124 °C (126–
128 °C)16a,16c
IR (neat): 3221 (br), 2356, 1428, 998, 675 cm–1
.
IR (neat): 1499, 1485, 816, 758, 689 cm–1
.
1H NMR (400 MHz, CDCl3):  = 2.41 (s, 3 H), 2.72 (br t, J = 5.7 Hz, 1 H),
3.32 (br t, J = 5.7 Hz, 1 H), 4.66 (d, J = 5.7 Hz, 2 H), 4.84 (d, J = 5.7 Hz,
2 H), 7.28 (d, J = 8.2 Hz, 2 H), 7.57 (d, J = 8.2 Hz, 2 H).
1H NMR (400 MHz, CDCl3):  = 2.39 (s, 3 H), 6.80 (s, 1 H), 7.24 (d, J =
8.4 Hz, 2 H), 7.28–7.39 (m, 10 H), 7.82 (d, J = 8.2 Hz, 2 H).
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–M

L
E. Kobayashi, H. Togo
Paper
Synthesis
13C NMR (100 MHz, CDCl3):  = 21.4, 54.0, 55.7, 114.7, 125.5, 128.2
(2C), 129.6 (2C), 140.1, 162.3, 169.3.
HRMS (APCI): m/z [M + H]+ calcd for C12H14O3N: 220.0968; found:
dried over Na2SO4. After removal of the solvent, purification by short
column chromatography on silica gel (hexane/EtOAc, 4:1) gave dieth-
yl 3-phenyl-1H-pyrazole-4,5-dicarboxylate 5U′ (104.3 mg, 68%).
220.0968.
Diethyl 3-(p-Methylphenyl)-1H-pyrazole-4,5-dicarboxylate 5U′
Yield: 102.8 mg (68%); white solid; mp 81–83 °C.
Preparation of 3-(p-Methylphenyl)-(1H)-1-phenylpyrazolo[4,5-
d]pyridazine-3,6-diol (5A-I)
IR (neat): 2980 (br), 1720, 1291, 1069 cm–1
.
Hydrazine monohydrate (250.6 L, 10.0 mmol) was added to a solu-
tion of 5A (189.2 mg, 0.5 mmol) in EtOH (0.75 mL) and the mixture
was stirred at 90 °C for 6 h. Filtration of the reaction mixture gave 3-
(p-methylphenyl)-(1H)-1-phenylpyrazolo[4,5-d]pyridazine-3,6-diol
5A-I (120.97 mg, 76%).
1H NMR (400 MHz, CDCl3):  = 1.29 (t, J = 7.3 Hz, 3 H), 1.41 (t, J =
7.3 Hz, 3 H), 2.40 (s, 3 H), 4.31 (q, J = 7.3 Hz, 2 H), 4.42 (q, J = 7.3 Hz,
2 H), 7.26 (d, J = 8.2 Hz, 2 H), 7.51 (d, J = 8.2 Hz, 2 H), 10.47 (br, 1 H).
13C NMR (100 MHz, CDCl3):  = 13.9 (2C), 21.3, 61.3, 61.4, 112.9,
125.4, 127.84 (2C), 127.94, 128.6, 129.3 (2C), 139.5, 160.9, 163.9.
HRMS (APCI): m/z [M + H]+ calcd for C16H19O4N2: 303.1339; found:
303.1336.
3′-(p-Methylphenyl)-(1′H)-1′-phenylpyrazolo[4,5-d]pyridazine-
3,6-diol (5A-I)
Yield: 121.0 mg (76%); white solid; mp >300 °C.
IR (neat): 3187 (br), 2359 (br), 1456, 1331, 770, 708 cm–1
.
Funding Information
1H NMR (400 MHz, DMSO-d6):  = 2.34 (s, 3 H), 7.24 (d, J = 8.2 Hz,
2 H), 7.38–7.48 (m, 3 H), 7.64 (d, J = 7.0 Hz, 2 H), 8.32 (d, J = 8.2 Hz,
2 H).
Financial support in the form of a Grant-in-Aid for Scientific Research
(No. 15K05418) from the Ministry of Education, Culture, Sports, Sci-
ence, and Technology in Japan is acknowledged.
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13C NMR (100 MHz, DMSO-d6):  = 21.0, 114.6, 126.4 (2C), 127.7,
127.8 (2C), 128.6 (2C), 128.8 (2C), 129.1, 136.6, 137.8, 139.5, 148.5,
151.6, 156.9.
Supporting Information
HRMS (ESI): m/z [M + H]+ calcd for C18H15O2N4: 319.1190; found:
319.1187.
Supporting information for this article is available online at
https://doi.org/10.1055/s-0039-1690102.
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4,5-Di(hydroxymethyl)-3-(p-methylphenyl)-(1H)-1-phenylpyra-
zole (5A-II)
References
To a solution of 5A (189.2 mg, 0.5 mmol) in THF (2.0 mL) was added
LiAlH4 (47.5 mg, 1.25 mmol) at 0 °C and the resulting mixture was
stirred at 50 °C for 4 h. The reaction was quenched with ice and then
sat. aq. NH4Cl. The mixture was extracted with EtOAc (3 × 10.0 mL)
and the organic layer was washed with brine and dried over Na2SO4.
Purification by short column chromatography on silica gel (hex-
ane/EtOAc, 1:3) gave 4,5-di(hydroxymethyl)-3-(p-methylphenyl)-
(1H)-1-phenylpyrazole 5A-II (125.8 mg, 86%).
(1) Katritzky, A. R.; Ramsden, C. A.; Scriven, E. F. V.; Taylor, R. J. K.
Comprehensive Heterocyclic Chemistry III; Elsevier: Amsterdam,
2008.
(2) Isoxazoles: (a) Giomi, D.; Cordero, F. M.; Machetti, F. Five-Mem-
bered Rings with Two Heteroatoms, each with their Fused Carbo-
cyclic Derivatives, In Comprehensive Heterocyclic Chemistry III,
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J. K., Ed.; Elsevier: Amsterdam, 2008, Chap. 4.03, 365–485.
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Ramsden, C. A.; Scriven, E. F. V.; Taylor, R. J. K., Ed.; Elsevier:
Amsterdam, 2008, Chap. 6.01, 1–141. Review for pyrazoles:
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4,5-Di(hydroxymethyl)-3-(p-methylphenyl)-(1H)-1-phenylpyra-
zole (5A-II)
Yield: 126.6 mg (86%); white solid; mp 155–157 °C.
IR (neat): 3269 (br), 2366, 1500, 1013, 1000, 764 cm–1
1H NMR (400 MHz, CDCl3):  = 2.22 (br, 1 H), 2.40 (s, 3 H), 2.96 (br,
1 H), 4.72 (br d, J = 5.0 Hz, 2 H), 4.84 (br d, J = 2.5 Hz, 2 H), 7.26 (d, J =
7.9 Hz, 2 H), 7.41 (t, J = 7.3 Hz, 1 H), 7.50 (t, J = 7.3 Hz, 2 H), 7.58 (d, J =
7.9 Hz, 2 H), 7.63 (d, J = 7.3 Hz, 2 H).
13C NMR (100 MHz, CDCl3):  = 21.3, 54.4, 55.7, 118.3, 124.9 (2C),
128.1 (3C), 129.3 (4C), 129.8, 138.0, 139.1, 142.0, 151.1.
HRMS (APCI): m/z [M + H]+ calcd for C18H19O2N2: 295.1441; found:
295.1438.
.
Preparation of Diethyl 3-(p-Methylphenyl)-1H-pyrazole-4,5-dicar-
boxylate (5U′)
To a solution of 5U (189.2 mg, 0.5 mmol) in formic acid (5.0 mL) were
added HCO2NH4 (78.8 mg, 1.25 mmol) and Pd(OH)2 on carbon (87.0
mg, 20 wt%) and the resulting mixture was stirred at 80 °C for 24 h.
After filtration through Celite, the filtrate was concentrated. The resi-
due was dissolved in EtOAc and the obtained mixture was washed
with aqueous NaHCO3, water, and brine, and the organic layer was
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