Cui-catalyzed coupling reactions of 4-iodopyrazoles and alcohols: Application toward withasomnine and Homologs

Article abstract of DOI:10.3390/molecules26113370

The direct 4-alkoxylation of 4-iodo-1H-pyrazoles with alcohols was achieved by a CuIcatalyzed coupling protocol. The optimal reaction conditions employed excess alcohol and potassium t-butoxide (2 equiv) in the presence of CuI (20 mol%) and 3,4,7,8-tetramethyl-1,10-phenanthroline (20 mol%) at 130 °C for 1 h under microwave irradiation. The present method was efficiently applied to the synthesis of withasomnine and its six- and seven-membered cyclic homologs.

Full text of DOI:10.3390/molecules26113370

molecules
Article
CuI-Catalyzed Coupling Reactions of 4-Iodopyrazoles and
Alcohols: Application toward Withasomnine and Homologs
Yoshihide Usami * , Yumika Kubo, Toshiki Takagaki, Nao Kuroiwa, Jun Ono, Kohei Nishikawa, Ayaka Nakamizu,
Yuya Tatsui, Shinya Harusawa, Noboru Hayama and Hiroki Yoneyama
Department of Pharmaceutical Organic Chemistry, Osaka University of Pharmaceutical Sciences,
4-20-1 Nasahara, Takatsuki, Osaka 569-1094, Japan; e12343@gap.oups.ac.jp (Y.K.); e16442@gap.oups.ac.jp (T.T.);
e16332@gap.oups.ac.jp (N.K.); e15439@gap.oups.ac.jp (J.O.); e15637@gap.oups.ac.jp (K.N.);
e14519@gap.oups.ac.jp (A.N.); e18902@gap.oups.ac.jp (Y.T.); harusawa@gly.oups.ac.jp (S.H.);
hayama@gly.oups.ac.jp (N.H.); yoneyama@gly.oups.ac.jp (H.Y.)
* Correspondence: usami@gly.oups.ac.jp; Tel.: +81-726-90-1087
Abstract: The direct 4-alkoxylation of 4-iodo-1H-pyrazoles with alcohols was achieved by a CuI-
catalyzed coupling protocol. The optimal reaction conditions employed excess alcohol and potassium
t-butoxide (2 equiv) in the presence of CuI (20 mol%) and 3,4,7,8-tetramethyl-1,10-phenanthroline
◦
(20 mol%) at 130 C for 1 h under microwave irradiation. The present method was efficiently applied
to the synthesis of withasomnine and its six- and seven-membered cyclic homologs.
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
Keywords: synthesis; 4-alkoxypyrazole; CuI; coupling reaction; microwave; withasomnine; homologue
ꢀꢁꢂꢃꢄꢅꢆ
Citation: Usami, Y.; Kubo, Y.;
Takagaki, T.; Kuroiwa, N.; Ono, J.;
Nishikawa, K.; Nakamizu, A.; Tatsui,
1. Introduction
Y.; Harusawa, S.; Hayama, N.; et al.
Owing to their diverse bioactivities, both natural and synthetic pyrazoles and pyrazole-
CuI-Catalyzed Coupling Reactions of
fused heterocycles have been widely exploited as pharmaceutical or pesticide active in-
4-Iodopyrazoles and Alcohols:
gredients [1–4]. Therefore, the efficient synthesis of substituted pyrazoles possessing
characteristic functionalities at specific positions is an important objective in organic and
medicinal chemistry, as well as in drug discovery. In this context, we recently reported
Application toward Withasomnine
and Homologs. Molecules 2021, 26,
3370. https://doi.org/10.3390/
molecules26113370
palladium- or copper-catalyzed C–N coupling reactions at the C-4 positions of pyrazoles [
Although metal-catalyzed C–O coupling reactions have been widely reported, owing to
their wide-ranging potentials [ 12], the direct C4-O-functionalization of pyrazoles has not
yet been studied satisfactorily [13 14] despite the important bioactivities that have been
5].
Academic Editor: Mohammad Alam
6–
,
Received: 10 May 2021
Accepted: 31 May 2021
Published: 2 June 2021
demonstrated for several 4-alkoxypyrazoles, as presented in Figure 1.
Publisher’s Note: MDPI stays neutral
with regard to jurisdictional claims in
published maps and institutional affil-
iations.
Copyright:
© 2021 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).
Figure 1. Bioactive 4-alkoxypyrazoles.
Molecules 2021, 26, 3370. https://doi.org/10.3390/molecules26113370
https://www.mdpi.com/journal/molecules

Molecules 2021, 26, 3370
2 of 13
4-Hyroxypyrazole, a metabolite of pyrazole, exhibits various biological activities such
as anti-inflammatory, antipyretic, antitumor, antifungal effects [15]. 4-Methoxy-, 4-ethoxy-
, 4-n-propoxy-, and 4-isopropoxypyrazoles have been reported to inhibit liver alcohol
dehydrogenase (LAD) in humans, rats, and horses [16]. In particular, 4-ethoxypyrazole
and 4-propyloxypyrazole have been recognized as a cytochrome P-450 inducer [17] and
cytochrome P450 2E1 inhibitor, respectively [18]. Two C4-O-functionalized pyrazoles have
been patented: 1-methyl-3,5-diphenyl-4-propoxypyrazole, as a fungicide [19], and the
alkyl (4-alkoxy-1-phenyl)pyrazolylcarboxylates, which possess antipyretic, sedative, anti-
inflammatory, and analgesic activities [20]. A compound bearing a 4-(2,4-difluorophenyl)oxy
group was revealed as a human dihydroorotate dehydrogenase (DHODH) inhibitor [21].
4-Allyloxy-1H-1-tritylpyrazole 4a (Scheme 1), derived from 4-iodopyrazole (
a key role as a versatile intermediate in our previous studies for the total synthesis of the
pyrazole alkaloid, withasomnine ( ) [22 23], and its six-membered homolog 11 23 27],
which were reported to exhibit COX-2 inhibitory activities [23 27 28]. Compound 4a was
also extensively utilized as an important intermediate for the construction of new pyrazole-
fused heterobicyclic molecules via ring-closing metathesis (RCM) (Scheme 1) [29 31].
However, the synthesis of compound 4a requires six steps from commercially available
pyrazole, through 4-iodopyrazole ( ), 4-iodo-1H-1-tritylpyrazole (2a), and aldehyde . If
direct O-allylation from could be realized, the synthesis of several synthetic targets would
be remarkably shortened. Thus, we focused our attention on the direct C–O coupling
reactions of , based on our prior report of the C–N couplings of 4-halopyrazoles [ ].
1), played
7
,
[ –
,
,
9
–
1
3
1
1
5
Herein, we disclose CuI-catalyzed coupling reactions of 4-iodo-1H-pyrazoles and alcohols.
Furthermore, the developed method was applied to improve the synthesis of withasomnine
and its homologs containing six- or seven-membered ring systems.
Scheme 1. Versatile intermediate 4-allyloxy-1H-tritylpyrazole (4a), developed in our previous works (adapt from refer-
ences [22–24,29–31]).
2. Results and Discussions
2.1. Investigation of 4-O-Allylation of 4-Iodopyrazole
Initially, we attempted the Pd(dba)2-catalyzed reaction between 2a and allyl alco-
hol (2 equivalent (equiv)) in the presence of tBuDavePhos as a ligand and potassium
tert-butoxide (tBuOK) as a base under the reaction conditions in our previous report [
5];
however, none of the desired coupling product was obtained (Table 1, entry 1). The
corresponding 4-bromo-1H-1-tritylpyrazole was not effective in the palladium-catalyzed
coupling reaction. Then, the CuI-catalyzed reaction between 4-iodo-1H-1-tritylpyrazole
2a and allyl alcohol was examined; the results are summarized in Table 1. All reac-
tions were performed using 2a (50 mg) in a solvent (2.0 mL). In the presence of ligand
2-isobutyroylcyclo-hexanone (L2) or 1,10-phenanthroline (L3) in N,N-dimethylformamide
(DMF) [5], reactions of 2a and allyl alcohol (2 equiv) did not afford 4a (entries 2 and
3, respectively). However, when allyl alcohol was used as a solvent for this reaction

Molecules 2021, 26, 3370
3 of 13
with L3 at 100 ◦C overnight, the desired C4-O-allylation product 4a was obtained in 51%
yield (entry 4). Next, microwave (MW) assistance was applied to reduce the reaction
time (entries 5–9). In these experiments, the reaction time was fixed at 1 h and the ligand
was changed to 3,4,7,8-tetramethyl-1,10-phenanthroline (L4). From entry 6, the optimum
◦
◦
reaction temperature was determined to be 130 C, giving 4a in 66% yield. At 160 C,
the reaction mixture turned black with a poor yield of 4a (16%, entry 8). In addition,
shortening the reaction time (30 min) or reducing the amount of CuI to 10 mol% afforded
4a in lower yields (entry 7:24%; entry 9:37%, respectively). Based on these results, the
optimum conditions obtained in entry 6 were applied in the following coupling reactions
of 4-iodopyrazoles with various alcohols.
Table 1. Optimization of CuI-catalyzed reaction between 4-iodo-1H-1-tritylpyrazole (2a) and allyl alcohol.
◦
Entry
Catalyst
Ligand a
Solvent
Temperature ( C)
Time
4a Yield, %
1 b,c
2 c
3 c
4
5
6
Pd(dba)2
CuI
L1
L2
L3
L3
L4
L4
L4
L4
L4
xylene
DMF
DMF
160 (MW)
100
30 min
overnight
overnight
overnight
1 h
1 h
30 min
1 h
0
0
0
51
31
66
24
16
37
CuI
CuI
CuI
CuI
CuI
CuI
CuI
100
100
allyl alcohol
allyl alcohol
allyl alcohol
allyl alcohol
allyl alcohol
allyl alcohol
100 (MW)
130 (MW)
130 (MW)
160 (MW)
130 (MW)
7
8
9 d
1 h
a.
. b. 10 mol% Pd(dba)2 was used, c. 2 equiv of allyl
alcohol was added, d. 10 mol% CuI was used.
2.2. C4-Alkoxylation of 4-iodopyrazole with Alcohols Using CuI-Catalyzed Coupling
To study the scope and limitations of this transformation, the CuI-catalyzed reactions
of iodopyrazoles
2 (50 mg) with various alcohols (2.0 mL, excess amount) were carried out
under the optimal conditions (Table 1, entry 6). The results are summarized in Table 2. The
reactions of 2a with linear short-chain primary alcohols (methanol, ethanol, and n-propanol)
afforded the corresponding products 4c, 4d, and 4e in moderate yields (61–76%, entries 1–3),
while the reaction with a longer-chain primary alcohol (n-butanol) resulted in a lower yield
(33%, entry 4). The reactions of 2a with branched primary alcohols (isobutyl and isoamyl
alcohols) provided 4i (45%) and 4k (37%), respectively (entries 7 and 9), but with secondary
isopropanol, gave 4g in only 9% yield (entry 5). The presence of sec- or tert-butyl groups
in the alcohol was not compatible with the present reaction conditions (entries 6 and 8),
probably due to steric hindrance. In contrast, the reactions with cyclic secondary alcohols
did proceed (entries 10, 11, and 12), but the respective isolated yields of the coupled
products 4l, 4m, and 4n were 59%, 18%, and 25%, respectively. In these reactions, 1.0 mL
of cyclic alcohol was used with respect to substrate 2a (50 mg); the high boiling points
(cyclobutanol: 123 ◦C/733 mmHg; cyclopentanol: 139–140 ◦C; cyclohexanol: 160–161 ◦C)
of these materials complicated product isolation by chromatography. Furthermore, when
2 equivalents of the cyclic alcohols and acetonitrile (2.0 mL) as a co-solvent were used,

Molecules 2021, 26, 3370
4 of 13
no coupled products could be detected. Although the reaction with benzyl alcohol (bp:
205 ◦C) was also difficult, the use of benzyl alcohol (1.0 mL) and toluene as a co-solvent
(1.0 mL) afforded the corresponding product (4o) in poor yield (12%, entry 13). With
phenols, no desired coupling products were obtained under various reaction conditions
(entries 14 and 15). In the case of p-methoxyphenol (entry 15), a detailed analysis of the
reaction mixture revealed a trace amount of 5,50-dimethoxy-2,20-biphenyldiol, which has
been reported to have radical scavenging or antibacterial activities [32,33]. The initially
formed dihydroxybiphenyls [34] might inhibit the attempted C–O coupling reaction.
Table 2. CuI-catalyzed coupling reaction between iodopyrazoles and various alcohols.
Entry
Substrate
R2OH
Product
Yield (%)
2a: R1 = Tr
R2 = Me
R2 = Et
4c: R1 = Tr, R2 = Me
4d: R1 = Tr, R2 = Et
1
2
3
4
5
6
7
8
9
61
76
64
33
9
0
45
0
37
59
18
25
12
0
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
R2 = n-Pr
4e: R1 = Tr, R2 = n-Pr
4f: R1 = Tr, R2 = n-Bu
4g: R1 = Tr, R2 = iPr
R2 = n-Bu
R2 = iPr
R2 = sec-Bu
R2 = iBu
4h: R1 = Tr, R2 = sec-Bu
4i: R1 = Tr, R2 = iBu
R2 = tert-Bu
R2 = isoamyl
R2 = cyclobutyl
R2 = cyclopentyl
R2 = cyclohexyl
R2 = Bn
4j: R1 = Tr, R2 = tert-Bu
4k: R1 = Tr, R2 = isoamyl
4l: R1 = Tr, R2 = cyclobutyl
4m: R1 = Tr, R2 = cyclopentyl
4n: R1 = Tr, R2 = cyclohexyl
4o: R1 = Tr, R2 = Bn
10 a
11 a
12 a
13 b
14
15 c
16 d
17
18
19
20 e
21
R2 = Ph
4p: R1 = Tr, R2 = Ph
R2 = p-MeOPh
R2 = allyl
4q: R1 = Tr, R2 = p-MeOPh
4a: R1 = Tr, R2 = allyl
4r: R1 = 1-propenyl, R2 = allyl
4s: R1 = R2 = allyl
0
66
65
58
64
0
2b: R1 = 1-propenyl
R2 = 1-propenyl
R2 = allyl
2c: R1 = allyl
2d: R1 = 3-butenyl
R2 = allyl
4t: R1 = 3-butenyl, R2 = allyl
4u: R1 = Tr, R2 = H
R2 = OH
2a
1
R2 = allyl
4v: R1 = H, R2 = allyl
0
a. 1.0 mL of cyclic alcohol was used, b. 1.0 mL of BnOH was used with toluene (1.0 mL) as co-solvent, c. Trace amount of 5,5’-dimethoxy-
2,2’-biphenyldiol was isolated, d. Table 1, entry 6, e. 2a was recovered (89%).
The direct introduction of the allyloxy group at the C4 position of N-alkenyl-4-iodo-
1H-pyrazoles (2b, 2c, 2d) by CuI-mediated reaction afforded the expected products 4r, 4s,
and 4t in moderate yields (entries 17–19). These products were subsequently applied in the
synthesis of withasomnine and its analogs (Scheme 2). Neither the C–O coupling reaction
of 2a with water nor of N-nonprotected iodopyrazole 1 with allyl alcohol was successful
(entries 20 and 21).
In preliminary experiments, the Pd(dba)2-catalyzed coupling of 2a with four types
of alcohols (methanol, ethanol, n-propanol, and tert-butyl alcohol) under the same condi-
tions as mentioned above was examined; however, these trials did not give the desired
coupling products, yielding only hydrogenated 1H-1-tritylpyrazole in 52, 63, 64, and 8%
yields, respectively.

Molecules 2021, 26, 3370
5 of 13
Scheme 2. Application to improved synthesis of withasomnine (7).
2.3. Application to Improved Synthesis of Withasomnine and Six- and Seven-Membered Cyclic Homologs
A modified synthesis of withasomnine and its homologs using the products described
above was performed to demonstrate the usefulness of the present method. The improved
synthesis of withasomnine (7) is summarized in Scheme 2. 4-Iodo-1H-pyrazole (1) was
treated with allyl bromide under basic conditions to give N-allylated compound 2c in
97% yield. The double bond in the N-allyl group in 2c was migrated by treatment with
a ruthenium hydride catalyst (RuClH(CO)(PPh3)3) to give an E/Z mixture of 2b in 96%
yield, which was transformed to 4r by CuI-catalyzed coupling, as described above (Table 2,
entry 17). The Claisen rearrangement of 4r gave (E/Z)-12 (87%), which was subsequently
O-triflated by treatment with trifluoromethanesulfonic anhydride (Tf2O) in the presence of
triethylamine at
−
20 ◦C to yield ring-closing metathesis (RCM) substrate 13 in 90% yield.
Treatment of 13 with Grubbs2nd catalyst in toluene at 100 ◦C under MW irradiation gave
the desired RCM product 14 in 0–58% yields with unsatisfied reproducibility.
Alternatively, CuI-assisted RCM [24
using MW-aided heating at 80 C for 1 h successfully afforded pyrrole-[1,2-b] pyrazole
14 (63%), which was immediately hydrogenated under a hydrogen gas atmosphere with
,
35] of 13 in CH2Cl2 under milder conditions
◦
Pd/C in MeOH to give penultimate product
to via a Suzuki-Miyaura coupling reaction has already been reported [22
approach constitutes a formal total synthesis of withasomnine (
6 in 90% yield. As the transformation from 6
7
,
23], the present
7
). The overall yield of 7
in this case was 24% over nine steps from commercially available pyrazole, whereas that
of our previous method was 8% in 13 steps. Therefore, the current synthesis realizes a
four-step reduction and nearly threefold improvement in overall yield [22,23].
The syntheses of the six-and seven-membered cyclic homologs 11 and 15 are sum-
marized in Scheme 3. The total yield of 11 was improved by ~1.6-fold over our former
synthesis based on the yields of transformations from
to 4s (Table 2, entry 18) [24]. Our synthesis of another withasomnine homolog, 15, previ-
ously achieved by Allin via radical cyclization [25 26], began with the transformation of
to 2d in 88% yield. Compound 2d was O-allylated using the present method to 4t, as
1 to 2c (seen in Scheme 2) and 2c
,
1
described previously (Table 2, entry 19). Then, 4t was rearranged into 16 (81% yield) under
MW-assisted heating, and subsequent O-triflation afforded 17 (83% yield). RCM substrate
17 was similarly cyclized to seven-membered intermediate 18 in 72% yield, which was then
subjected to Suzuki-Miyaura coupling with phenylboronic acid to afford 19 in 87% yield.
The synthesis of 15 was completed in 92% yield by the Pd-C-catalyzed hydrogenation of
19. An alternative route to 15 comprised the transformation of 1 to 4b in 52% yield via a
five-step process, and subsequent N-butenylation to give the common intermediate 4t in
69% yield. Therefore, the present route to 15 using the CuI-catalyzed coupling achieved a
1.6-fold increase in overall yield compared to the prior procedure.

Molecules 2021, 26, 3370
6 of 13
Scheme 3. Synthesis of withasomnine six- and seven-membered cyclic homologs 11 and 15.
3. Conclusions
In this study, a range of 4-alkoxy-1H-pyrazoles was synthesized using the CuI-
catalyzed coupling reaction of 4-iodopyrazoles with an excess amount of alcohol. Im-
proved syntheses of withasomnine and its homologs were achieved using the products
obtained with the present method. The current withasomnine synthetic route was reduced
by four steps with a threefold-improvement in the overall yield compared to our previous
report [22,23]. However, reducing the amounts of catalysts, ligands, and alcohols will be
required to increase the practicality of this reaction in the future.
4. Materials and Methods
4.1. General Information
◦
NMR spectra were recorded at 27 C on Agilent 400- and 600-MR-DD2 spectrometers
(Agilent Tech., Inc., Santa Clara, CA, USA) in CDCl3 with tetramethylsilane (TMS) as an in-
ternal standard. HRMS was performed using a JEOL JMS-700 (2) mass spectrometer (JEOL,
Tokyo, Japan). Melting points were determined using a Yanagimoto micromelting point
apparatus (Yamagimoto, Kyoto, Japan) and were uncorrected. Liquid column chromatog-
raphy was conducted using silica gel (Fuji Silysia FL-60D). Analytical TLC was performed
on precoated Merck glass plates (silica gel 60 F254), and compounds were detected by dip-
ping the plates in an ethanol solution of phosphomolybdic acid, followed by heating. All
microwave-aided reactions were performed using a Biotage Initiator® (Biotage, Uppsala,
Sweden). Allyl alcohol, n-propanol, isobutyl alcohol, cyclobutanol, cyclopentanol, cyclohex-
anol, Phenol, p-methoxyphenol, allylbromide, and Pd(dba)2, were purchased from Tokyo
Chemical Industry (TCI) Co. (Tokyo, Japan). t-BuOK, CuI, 1,10-phenanthroline (L3), 3,4,7,8-
tetramethyl-1,10-phenanthroline (L4), isopropanol, tert-butanol, isoamyl alcohol, toluene,
cesium acetate, trifluoromethanesulfonic anhydride, and triethylamine were purchased

Molecules 2021, 26, 3370
7 of 13
from Nacalai Tesque, Inc. (Kyoto, Japan). Dry xylene, dry DMF, n-butanol, sec-butanol, and
1,2-dimethoxyethane, were purchased from FUJIFILM Wako Pure Chemical Co. (Osaka,
Japan). tBuDavePhos (L1), 2-isobutyrylcyclohexanone (L2), RuClH(CO)(PPh3)3, Grubbs2nd
,
and XPhos were purchased from Sigma-Aldrich Co. LLC (St. Louis, MO, USA).
1H- and 13C-NMR spectra of all new compounds with compound 15 are provided in
Supplementary Materials as Figures S1–S48.
4.2. CuI-Catalyzed Coupling Reactions of 4-iodo-1H-1-tritylpyrazole with Alcohols (Tables 1 and 2)
General procedure (Table 1, entry 6): To a solution of 2a (50.0 mg, 0.12 mmol) in allyl
alcohol (2.0 mL, 29 mmol) in a microwave vial (0.5–2.0 mL) were added 3,4,7,8-tetramethyl-
1,10-phenanthroline (5.8 mg, 0.026 mmol, 20 mol%), CuI (4.4 mg, 0.023 mmol, 20 mol%),
and tBuOK (28.8 mg, 0.2◦6 mmol, 2.0 equiv). The mixture was stirred to make a solution,
sealed, and heated at 130 C for 1 h under MW irradiation. The cooled mixture was checked
by TLC (hexane/AcOEt = 8:1), quenched by the addition of saturated (sat.) aqueous (aq.)
NH4Cl (1 mL), and extracted with dichloromethane (CH2Cl2; 1.0 mL × 3). The combined
organic layers were dried over MgSO4, filtered, and evaporated to give a crude residue
that was purified by silica gel column chromatography (eluent:hexane/AcOEt = 20:1) to
afford previously reported 4a (27.9 mg, 66%).
4a: known [22,23]
4-Methoxy-1H-1-tritylpyrazole (4c): Colorless needles (CH2Cl2); mp 149–152 ◦C; 1H-
NMR (400 MHz, CDCl3):
δ 7.40 (1H, s, pyrazole-H), 7.32–7.28 (9H, m, Tr-H), 7.18–7.14 (6H,
m, Tr-H), 7.01 (1H, s, pyrazole-H), 3.68 (3H, s, 4-OMe); 13C-NMR (100 MHz, CDCl3):
δ
145.7, 143.2, 130.1, 127.6, 127.4, 127.2, 117.2, 78.6, 58.7; HREIMS m/z calculated (calcd) for
C23H20N2O (M+) 340.1575, found 340.1577.
4-Ethoxy-1H-1-tritylpyrazole (4d): Colorless needles (CH2Cl2); mp 141–144 ◦C; 1H-
NMR (400 MHz, CDCl3):
δ 7.40 (1H, s, pyrazole-H), 7.01 (1H, s, pyrazole-H), 7.31–7.28 (9H,
m, Tr-H), 7.18–7.14 (6H, m, Tr-H), 3.87 (2H, q J = 6.6 Hz, -OCH2CH3), 1.32 (3H, t, J = 6.6 Hz,
CH2CH3); 13C-NMR (100 MHz, CDCl3):
δ 144.4, 143.2, 130.1, 127.8, 127.6, 127.6, 117.9, 78.6,
67.1, 14.9; HREIMS m/z calcd for C24H22N2O (M+) 354.1732, found 354.1735.
4-n-Propyloxy-1H-1-tritylpyrazole (4e): Colorless needles (CH2Cl2); mp 118–120 ◦C;
1H-NMR (400 MHz, CDCl3):
δ, 7.40 (1H, s, pyrazole-H), 7.30–7.27 (9H, m, Tr-H), 7.18–7.14
(6H, m, Tr-H), 7.01 (1H, s, pyrazole-H), 3.76 (2H, t, J = 6.6 Hz, -OCH2CH2-), 1.72 (2H, qt,
J = 7.4, 6.6 Hz, -CH2CH2CH3), 0.97 (3H, t, J = 7.4 Hz, -CH2CH3); 13C-NMR (100 MHz,
CDCl3):
δ 144.6, 143.2, 130.1, 127.8, 127.61, 127.59, 117.7, 78.5, 73.1, 22.7, 10.4; HREIMS m/z
calcd for C25H24N2O (M+) 368.1889, found 368.1889.
4-n-Butoxy-1H-1-tritylpyrazole (4f): Colorless needles (CH2Cl2); mp 127–130 ◦C; 1H-
NMR (400 MHz, CDCl3):
δ 7.40 (1H, s, pyrazole-H), 7.31–7.28 (9H, m, Tr-H), 7.18–7.14 (6H,
m, Tr-H), 7.01 (1H, s, pyrazole-H), 3.80 (2H, q J = 6.6 Hz, -OCH2CH2-), 1.68 (2H, quint,
J = 6.7 Hz, -CH2CH2CH2-), 1.42 (2H, sext, J = 6.6 Hz, -CH2CH2CH3), 0.93 (3H, t, J = 6.7 Hz,
-CH2CH3); 13C-NMR (100 MHz, CDCl3):
δ 144.7, 143.2, 130.1, 127.8, 127.6, 127.6, 117.7, 78.5,
71.3, 31.4, 19.1, 13.9; HREIMS m/z calcd for C26H26N2O (M+) 382.2035, foun◦d 382.2040.
1
4-Isopropyloxy-1H-1-tritylpyrazole (4g): White powder; mp 91–93 C; H-NMR
(400 MHz, CDCl3):
δ 7.39 (1H, d, J = 1.0 Hz, pyrazole-H), 7.31–7.28 (9H, m, Tr-H), 7.18–7.14
(6H, m, Tr-H), 7.02 (1H, d, J = 0.7 Hz, pyrazole-H), 4.12 (1H, sept, J = 6.1 Hz, -OCH(CH3)2),
1.26 (6H, d, J = 6.1 Hz, -CH(CH3)2); 13C-NMR (100 MHz, CDCl3):
δ 143.2, 142.7, 130.1,
129.2, 127.6, 119.8, 78.6, 74.0, 21.9; HREIMS m/z calcd for C25H24N2O (M+) 368.1889, found
368.1885.
◦
4-Isobutoxy-1H-1-tritylpyrazole (4i): White powder; mp 95–98 C; 1H-NMR (400 MHz
,
CDCl3):
(1H, s, pyrazole-H), 3.56 (2H, d, J = 6.7 Hz, -OCH2CH-), 1.99 (1H, nonet, J = 6.7 Hz, -
CH2CH(CH3)2), 0.96 (6H, d, J = 6.7 Hz, -CH(CH3)2); 13C-NMR (100 MHz, CDCl3):
144.8,
δ 7.40 (1H, s, pyrazole-H), 7.30–7.28 (9H, m, Tr-H), 7.18–7.14 (6H, m, Tr-H), 7.02
δ
143.2, 130.1, 127.8, 127.65, 127.61, 127.58, 117.6, 78.5, 78.0, 28.4, 19.1; HREIMS m/z calcd for
C26H26N2O (M+) 382.2035, found 382.2040.

Molecules 2021, 26, 3370
8 of 13
◦
4-Isoamyloxy-1H-1-tritylpyrazole (4k): White powder; mp 77–75 C; 1H-NMR (400 MHz
,
CDCl3): 7.40 (1H, s, pyrazole-H), 7.31–7.29 (9H, m, Tr-H), 7.18–7.14 (6H, m, Tr-H), 7.01
δ
(1H, s, pyrazole-H), 3.83 (2H, q, J = 6.6 Hz, -OCH2CH2-), 1.76 (1H, nonet, J = 6.7 Hz,
-CH2CH(CH3)2), 1.58 (2H, q, J = 6.7 Hz, -CH2CH2CH-), 0.92 (6H, d, J = 6.7 Hz, -CH (CH3)2);
13C-NMR (100 MHz, CDCl3):
δ 22.6, 24.8, 38.1, 70.0, 78.6, 117.8, 127.6, 127.7, 127.8, 130.1,
143.2, 144.6; HREIMS m/z calcd for C26H26N2O (M+) 396.2201, found 396.2201.
4-Cyclobutyloxy-1H-1-tritylpyrazole (4l): White powder; mp 119–121 ◦C; 1H-NMR
(
400 MHz, CDCl3):
Tr-H), 6.95 (1H, br s, pyrazole-H), 4.40–4.33 (1H, m, -OCH(CH2)2-), 2.31–2.33 (2H, m), 2.13–
2.03 (2H, m), 1.81–1.73 (1H, m), 1.62–1.52 (1H, m); 13C-NMR (100 MHz, CDCl3):
143.2,
δ 7.34 (1H, br s, pyrazole-H), 7.31–7.28 (9H, m, Tr-H), 7.17–7.12 (6H, m,
δ
142.4, 130.1, 128.3, 127.6, 118.6, 78.6, 74.4, 30.3, 12.6; HREIMS m/z calcd for C26H24N2O
(M+) 380.1889, found 380.1890.
◦
4-Cyclopentyloxy-1H-1-tritylpyrazole (4m): White powder; mp 104–106 C; 1H-NMR
(400 MHz, CDCl3):
δ 7.37 (1H, d, J = 0.6 Hz, pyrazole-H), 7.37–7.28 (9H, m, Tr-H), 7.17–7.12
(6H, m, Tr-H), 6.98 (1H, d, J = 0.8 Hz, pyrazole-H), 4.44–4.42 (1H, m, -OCH(CH2)2-), 1.82–
1.74 (4H, m), 1.72–1.56 (2H, m); 13C-NMR (100 MHz, CDCl3):
δ 143.2, 130.1, 128.7, 127.8,
127.7, 127.6, 119.0, 83.1, 78.5, 32.6, 23.8; HREIMS m/z calcd for C27H26N2O (M+) 394.2045,
found 394.2043.
4-Cyclohexyloxy-1H-1-tritylpyrazole (4n): White powder; mp 132–135 ◦C; 1H-NMR
(400 MHz, CDCl3):
δ 7.39 (1H, s, pyrazole-H), 7.31–7.28 (9H, m, Tr-H), 7.17–7.12 (6H, m,
Tr-H), 7.03 (1H, s, pyrazole-H), 3.78–3.83 (1H, m, -OCH(CH2)2-), 1.95–1.92 (2H, m), 1.57–1.51
(2H, m), 1.48–1.38 (2H, m) 1.32–1.23 (2H, m); 13C-NMR (100 MHz, CDCl3):
δ 143.2, 142.5,
130.1, 129.5, 127.6, 120.1, 79.6, 78.6, 31.8, 25.6, 23.6; HREIMS m/z calcd for C28H28N2O (M+)
408.2202, found 408.2201.
◦
4-Benzyloxy-1H-1-tritylpyrazole (4o): White powder; mp 154–156 C; 1H-NMR (400 MHz
,
CDCl3):
δ 7.44 (1H, s, pyrazole-H), 7.35–7.28 (14H, m, Tr-H, Ph-H), 7.15–7.12 (6H, m, Tr-H,
Ph-H), 7.02 (1H, s, pyrazole-H), 4.86 (2H, br s, -OCH2Ph); 13C-NMR (100 MHz, CDCl3):
δ
144.1, 143.1, 136.7, 130.1, 128.5, 128.0, 127.8, 127.6, 118.7, 78.6, 73.7; HREIMS m/z calcd for
C29H24N2O (M+) 416.1889, found 416.1889.
(E/Z)-4-(Allyloxy)-1-(prop-1-en-1-yl)-1H-pyrazole (4r): Colorless oil; 1H-NMR (400 MHz
,
CDCl3):
δ 7.38 (0.1H, s, pyrazole-H), 7.32 (0.7H, br s, pyrazole-H), 7.28 (0.3H, d, J = 0.6
Hz, pyrazole-H), 7.23 (0.7H, d, J = 0.8 Hz, pyrazole-H), 6.74 (0.7H, dq, J = 14.2, 0.7 Hz,
(E)-NCH=CHCH3), 6.68 (0.3H, dq, J = 9.4, 0.7 Hz, (Z)-NCH=CHCH3), 6.08–5.97 (1H,
m, -OCH2CH=CH2), 5.85 (0.7H, dq, J = 14.2, 7.0 Hz, (E)-NCH=CHCH3), 5.40 (1H, br d,
J = 17.2 Hz, -CH=CHH), 5.29 (1H, br d, J = 9.4 Hz, -CH=CHH), 5.26 (0.3H, dq, J = 9.4, 7.9,
(Z)-NCH=CHCH3), 4.44 (0.6H, dt, J = 5.5, 1.2Hz, -OCH2CH=CH2), 4.42 (1.4H, dt, J = 5.5,
1.5 Hz, -OCH2CH=CH2), 1.95 (0.9H, dd, J = 7.4, 1.8 Hz, (Z)-NCH=CHCH3), 1.81 (2.1H,
dd, J = 7.1, 0.6 Hz, (E) -NCH=CHCH3); 13C-NMR (100 MHz, CDCl3):
δ 146.0, 133.1, 133.0,
128.8, 128.72, 127.67, 127.65, 118.1, 115.0, 111.8, 111.1, 72.55, 72.47„ 14.7, 12.8 (3 carbons are
overlapped); HREIMS m/z calcd for C9H12N2O (M+) 164.0950, found 164.0949.
4s: known [24]
4-Allyloxy-1-(3-buten-1-yl)pyrazole (4t): Colorless oil; 1H-NMR (400 MHz, CDCl3):
δ
7.24 (1H, d, J =1.2 Hz, pyrazole-H), 7.08 (1H, d, J =1.0 Hz, pyrazole-H), 6.01 (1H, ddt,
J = 17.2, 10.5, 5.5 Hz, -OCH2CH=CH2), 5.74 (1H, ddt, J = 17.2, 10.4, 6.8 Hz, -CH2CH=CH2),
5.38 (1H, dq, J = 17.2, 1.6 Hz, -CH2CH=CHH), 5.28 (1H, dq, J = 10.4, 1.4 Hz,-CH2CH=CHH),
5.04–5.10 (2H, overlapped, 2 × -CH=CHH), 4.40 (2H, dt, J = 5.4, 1.5 Hz, -OCH2CH=), 4.07
(2H, t, J = 7.1 Hz, NCH2CH2-), 2.57 (2H, qt, J = 7.0, 1.2 Hz, -CH2CH2CH=CH2); 13C-NMR
(100 MHz, CDCl3): δ144.9, 134.1, 133.3, 127.0, 117.8, 117.4, 115.0, 72.5, 52.1, 34.5; HREIMS
m/z calcd for C10H14N2O (M+) 178.1106, Found 178.1105.
4.3. Modified Synthesis of Withasomnine, (Scheme 2)
4.3.1. Synthesis of 1-allyl-4-iodo-1H-pyrazole (2c)
To a solution of 4-iodopyrazole
1 (500.0 mg, 2.6 mmol) in acetone (5 mL), 20% NaOH
aq. (0.5 mL, 1.5 equiv) was added with stirring followed by allyl bromide (0.2 mL, 3.9 mmol
,

Molecules 2021, 26, 3370
9 of 13
1.5 equiv). The reaction mixture was stirred at room temperature for 1 h. After checking by
TLC (hexane/AcOEt = 2:1), sat. aq. NH4Cl (5 mL) was added to the reaction mixture to
quench the reaction. The mixture was extracted with CH2Cl2 (10 mL
×
3) and the combined
organic layers were washed with brine (5 mL 2), dried over MgSO4, and filtered. The
×
solvent was removed under reduced pressure to give a crude residue that was purified
by silica gel column chromatography (eluent:hexane/AcOEt = 2:1) to afford 2c (566.2 mg,
1
96%): colorless oil; H-NMR (400 MHz, CDCl3):
δ 7.53 (1H, s, pyrazole-H), 7.45 (1H, s,
pyrazole-H), 6.00 (1H, ddt, J = 17.1, 10.2, 6.1 Hz, -NHCH2CH=CH2), 5.30 (1H, dq, J = 10.2,
1.2 Hz, -CH2CH=CHH), 5.26 (1H, dq, J = 17.1, 1.4 Hz, -CH2CH=CHH), 4.75 (2H, dt, J = 6.3,
1.4 Hz, -NCH2CH=CH2); 13C-NMR (100 MHz, CDCl3)
δ 144.4, 133.4, 132.2, 119.3, 56.2, 55.1;
HREIMS m/z calcd for C6H7N2I (M+) 233.9654, found 233.9653.
4.3.2. Synthesis of (E/Z)-4-iodo-1-(prop-1-en-1-yl)-1H-pyrazole (2b)
To a MW vial containing a solution of 2c (571.5 mg, 2.4 mmol) in toluene (2 mL)
was added the ruthenium hydride catalyst, RuClH(CO)(PPh3)3 (116.3 mg, 0.12 mmol,
5 mol%). The reaction mixture in the sealed vial was heated at 160 ◦C for 10 min under
MW irradiation. After removal of the solvent from the mixture, the residue was purified
by silica gel column chromatography (eluent:hexane/AcOEt = 10:1) to afford 2b (546.6 mg,
1
96%) as a colorless oil: H-NMR (400 MHz, CDCl3):
δ 7.62 (0.2H, s, pyrazole-H), 7.61 (0.2H,
s, pyrazole-H), 7.58 (0.8H, s, pyrazole-H), 7.55 (0.8H, s, pyrazole-H), 6.80 (0.8H, dq, J = 14.0
,
1.6 Hz, -CHE=CHCH3), 6.76 (0.2H, dq, J = 9.2, 1.8 Hz, -CHZ=CHCH3), 6.04 (0.8H, dq,
J = 13.8, 7.0 Hz, -CH=CHECH3), 5,45 (0.2H, br quint, J = 7.3 Hz, -CH=CHZCH3), 1.94 (0.4H,
dd, J = 7.4, 1.8 Hz, -CH=CHCH3), 1.82 (2.6H, dd, J = 6.9, 1.8 Hz, -CH=CHCH3); 13C-NMR
(100 MHz, CDCl3):
δ 145.0, 144.8, 134.0, 133.8, 133.6, 131.3, 128.7, 128.5, 128.4, 127.4, 126.7,
116.7, 114.1, 57.6, 57.4, 14.7, 12.9; HREIMS m/z calcd for C6H7N2I (M+) 233.9654, found
233.9652.
4.3.3. Synthesis of (E/Z)-5-allyl-1-(prop-1-en-1-yl)-1H-pyrazol-4-yl
trifluoromethane-sulfonate (12)
A solution of 4r (418.9 mg, 2.6 mmol) in 1,2-dimethoxethane (DME, 2 mL) in a sealed
◦
vial was heated at 180 C for 30 min under MW irradiation. The reaction mixture was
concentrated directly under reduced pressure to give a crude residue that was purified by
silica gel column chromatography (eluent:hexane/AcOEt = 2:1) to give (E/Z)-12 (364.3 mg,
1
87%) as a colorless oil. H-NMR (400 MHz, CDCl3):
δ 7.30 (0.3H, s, pyrazole-H), 7.24 (0.7H,
s, pyrazole-H), 6.62 (0.7H, dd, J = 13.7, 1.6 Hz, (E)-NCH=CHCH3), 6.50 (0.3H, dd, J = 8.7
,
1.6 Hz, (Z)-NCH=CHCH3), 6.15 (0.7H, dq, J = 13.9, 6.9 Hz, (E)-CH=CHCH3), 5.83–5.94
(1H, m, -CH2CH=CH2), 5.54 (0.3H, dq, J = 8.7, 7.4 Hz, (Z)-CH=CHCH3), 5.12–5.17 (1H, m,
-CH2CH=CHH), 5.00 (1H, br, -OH), 5.04 (1H, ddd, J = 17.0, 7.2, 1.1 Hz, -CH2CH=CHH),
3.43 (1.4H, d, J = 5.7 Hz, -CH2CH=CH2), 3.38 (0.6H, d, J = 6.1 Hz, -CH2CH=CH2), 1.87
(0.9H, dd, J = 7.2, 1.4 Hz, -CH=CHCH3), 1.80 (2.1H, dd, J = 6.9, 1.2 Hz, -CH=CHCH3);
13C-NMR (100 MHz, CDCl3):
δ 139.2, 138.8, 133.5, 133.3, 129. 4, 129.1, 126.9, 125.8, 124.8,
124.6, 123.4, 116.7, 116.5, 114.8, 27.0, 26.5, 15.1, 12.9; HREIMS m/z calcd for C9H12N2O (M+)
164.0950, found 164.0949.
4.3.4. Synthesis of (E/Z)-5-allyl-1-(prop-1-en-1-yl)-1H-pyrazol-4-yl
trifluoromethanesulfonate (13)
To a solution of 12 (264.7 mg, 1.6 mmol) in CH2Cl2 (4 mL) was added triethylamine
◦
(0.3 mL, 2.4 mmol, 1.5 equiv) at
−
20 C with stirring. After stirring for 10 min, Tf2O (0.4 mL,
2.4 mmol, 1.5 equiv) was added dropwise to the reaction mixture. After stirring at room
temperature for another 1 h, the reaction was quenched by the addition of sat. aq. NH4Cl
(5 mL) and extracted with CH2Cl2 (5 mL
with brine (5 mL 2), dried over MgSO4, filtered, and evaporated. The obtained residue
was purified by silica gel column chromatography (eluent:hexane/AcOEt = 2:1) to give 13
(430.4 mg, 90%) as an (E/Z) mixture. (Z)-13: Colorless oil; 1H-NMR (600 MHz, CDCl3):
7.58 (1H, s, pyrazole-H), 6.54 (1H, dq, J = 8.8, 1.8 Hz, -CH=CHCH3), 5.79 (1H, ddt, J = 17.0,
×
3). The combined organic layers were washed
×
δ

Molecules 2021, 26, 3370
10 of 13
10.0, 5.9 Hz, -CH2CH=CH2), 5.71 (1H, dq, J = 8.8, 7.3 Hz, -CH=CHCH3), 5.17 (1H, br dq,
J = 10.3, 1.8 Hz, -CH2CH=CHH), 5.06 (1H, br dq, J = 17.0, 1.8 Hz, -CH2CH=CHH), 3.42 (2H,
dt, J = 6.1, 1.6 Hz, -CH2CH=CH2), 1.87 (3H, dd, J = 7.4, 1.8 Hz, -CH=CHCH3); 13C-NMR
(100 MHz, CDCl3):
118.2, 27.2, 12.9; HREIMS m/z calcd for C10H11F3N2O3S (M+) 296.0442, found 296.0443.
(E)-13: colorless oil; 1H-NMR (600 MHz, CDCl3):
7.58 (1H, s, pyrazole-H), 6.54 (1H, dq,
δ 132.4, 131.4, 131.2, 130.9, 124.4, 123.9, 118.7 (q, J = 321.43 Hz, -CF3),
δ
J = 8.8, 1.8 Hz, -CH=CHCH3), 5.79 (1H, ddt, J = 17.0, 10.0, 5.9 Hz, -CH2CH=CH2), 5.83 (1H,
dq, J = 8.8, 7.3 Hz, -CH=CHCH3), 5.21 (1H, br dq, J = 10.3, 1.7 Hz, -CH2CH=CHH) 5.06
(1H, br dq, J = 17.0, 1.8 Hz, -CH2CH=CHH), 3.47 (2H, dt, J = 5.9, 1.8 Hz, -CH2CH=CH2),
1.84 (3H, dd, J = 7.0, 1.9 Hz, -CH=CHCH3); 13C-NMR (100 MHz, CDCl3):
δ 131.6 131.4,
131.0, 130.9, 124.3, 118.7 (q, J = 321.3Hz, -CF3), 118.3, 117.9, 26.7, 15.0; HREIMS m/z calcd
for C10H11F3N2O3S (M+) 296.0442, found 296.0443.
4.3.5. Synthesis of 4H-pyrrolo [1,2-b]pyrazol-3-yl trifluoromethanesulfonate (14)
To a solution of 13 (50.0 mg, 0.17 mmol) in CH2Cl2 (2 mL) were added Grubbs2nd
catalyst (7.1 mg, 0.0085 mmol, 5 mol%) and CuI (0.8 mg, 0.0042 mmol, 2.5 mol%). The
sealed reaction mixture was heated at 80 ◦C for 1 h under MW irradiation. The solvent
was removed from the mixture under reduced pressure to give a crude material that was
purified by silica gel column chromatography (eluent:hexane/AcOEt = 4:1) to afford 14
(27.0 mg, 63%). 14: Colorless oil; 1H-NMR (400 MHz, CDCl3):
δ
7.55 (1H, s, pyrazole-H),
7.21 (1H, dt, 4.1, 2.2 Hz, -CH2CH=CH-), 6.08 (1H, m, -CH2CH=CH-), 3.55 (2H, br t, J =
2.3 Hz, ArCH2CH=CH-); 13C-NMR (100 MHz, CDCl3):
δ 135.0, 134.0, 130.0, 129.0, 118.6
(q, J = 322.0 Hz, -CF3), 118.4, 30.3; HREIMS m/z calcd for C7H5F3N2O3S (M+) 253.9973,
found 253.9977.
4.3.6. Synthesis of 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl trifluoromethanesulfonate (6)
To a solution 14 (50.0 mg, 0.20 mmol) in MeOH (5 mL) was added Pd/C (5.00 mg,
10 mol%). The mixture was stirred for 24 h at room temperature under hydrogen gas at
1 atm. After removal of Pd/C by filtration, the solvent was evaporated to give a crude mix-
ture that was purified by silica gel column chromatography (eluent:hexane/AcOEt = 8:1
)
to afford 6 (45.6 mg, 90%) [22,23].
4.4. Synthesis of Withasomnine Homolog 15 (Scheme 3)
4.4.1. Synthesis of 1-allyl-4-iodo-1H-pyrazole (2d)
To a solution of
1 (300.0 mg, 1.5 mmol) in acetone (9 mL) was added 20% NaOH
aq. (6 mL, excess) with stirring, followed by allyl bromide (0.3 mL, 3.0 mmol), and the
reaction mixture was stirred at rt for 1 h. After quenching with sat. aq. NH4Cl (10 mL), the
mixture was extracted with CH2Cl2 (20 mL
×
3), and the combined organic layers were
washed with brine (5 mL × 2), dried over MgSO4, and filtered. The solvent was removed
under reduced pressure to give a crude residue that was purified by silica gel column
chromatography (eluent:hexane/AcOEt = 3:1) to afford 2d (373.9 mg, 88%). 2d: Colorless
oil;1 H-NMR (400 MHz, CDCl3):
δ 7.50 (1H, s, pyrazole-H), 7.42 (1H, s, pyrazole-H), 5.72
(1H, ddt, J = 17.4, 9.9, 7.0 Hz, -CH2CH=CH2), 5.08 (1H, br d, J = 17. 4 Hz, -CH=CHH),
5.08 (1H, br d, J = 9.9 Hz, -CH=CHH), 4.18 (2H, t, J = 7.0 Hz, NHCH2CH2-), 2.60 (2H, br q,
J = 7.0 Hz, -CH2CH2CH=); 13C-NMR (100 MHz, CDCl3)
δ 144.2, 133.7, 133.5, 117.9, 55.6,
52.0, 34.5 (one aromatic or olefinic carbon signal is overlapped); HREIMS m/z calcd for
C7H9N2I (M+) 247.9810, found 247.9810.
4.4.2. Synthesis of 5-allyl-1-(but-3-en-1-yl)-4-hydroxy-1H-pyrazole (16)
A solution of 4t (81.8 mg, 0.46 mmol) in DME (2 mL) in a sealed vial was heated
at 200 oC for 1 h under MW irradiation. The reaction mixture was concentrated directly
under reduced pressure to give a crude residue that was purified by silica gel column
chromatography (eluent:hexane/AcOEt = 2:1) to give 16 (70.0 mg, 81%). 16: Colorless oil;
1H-NMR (400 MHz, CDCl3):
δ 7.12 (1H, s, pyrazole-H), 6.91 (1H, br s, -OH), 5.87 (1H, ddt,

Molecules 2021, 26, 3370
11 of 13
J = 17.0, 10.0, 5. 8 Hz, -OCH2CH=CH2), 5.71 (1H, ddt, J = 17.0, 10.4, 7.0, -CH2CH=CH2),
5.11 (1H, dq, J = 10.2, 1.4 Hz, -CH=CHH), 5.01–5.07 (3H, overlapped. 3
×
-CH=CHH),
3.98 (2H, t, J = 7.4 Hz, NCH2CH2-), 3.39 (2H, dt, J = 5.8, 1.5 Hz, ArCH2CH=), 2.49 (2H,
br q, J = 7. 2 Hz, -CH2CH2CH=); 13C-NMR (100 MHz, CDCl3):
δ 138.3, 134.1, 133.7, 127.6,
126.0, 116.6, 116.4, 48.9, 34.5, 27.0; HREIMS m/z calcd for C10H14N2O (M+) 178.1106, Found
178.1104.
4.4.3. Synthesis of 5-allyl-1-(but-3-en-1-yl)-1H-pyrazol-4-yl trifluoromethanesulfonate (17
To a solution of 16 (70.0 mg, 0.39 mmol) in CH2Cl2 (10 mL) was added triethylamine
(0.06 mL, 0.43 mmol, 1.1 equiv) at
20 ◦C with stirring. After stirring for 10 min, Tf2O
0.1 mL, 0.6 mmol, 1.5 equiv) was added dropwise to the reaction mixture. After stirring at
room temperature for another 1 h, the reaction was quenched by the addition of sat. aq.
NH4Cl (5 mL) and extracted with CH2Cl2 (10 mL 3). The combined organic layers were
washed with brine (5 mL 2), dried over MgSO4, filtered, and concentrated. The obtained
residue was purified by silica gel column chromatography (eluent:hexane/AcOEt = 2:1)
to give 17 (100.6 mg, 83%). 17: Colorless oil; 1H-NMR (400 MHz, CDCl3):
7.48 (1H, s,
pyrazole-H), 5.88–5.67 (2H, overlapped, 2 -CH2CH=CH2), 5.20 (1H, dq, J = 10.2, 1.2 Hz,
-CH=CHH), 5.12–5.03 (3H, overlapped. 3 -CH=CHH), 4.06 (2H, t, J = 7.3 Hz, NCH2CH2-),
3.44 (2H, dt, J = 5.8, 1.6 Hz, ArCH2CH=), 2.57 (2H, br q, J = 7. 4 Hz, -CH2CH2CH=);
)
−
(
×
×
δ
×
×
13C-NMR (100 MHz, CDCl3):
δ 133.2, 131.5, 130.6, 129.7, 118.4 (q, JC-F = 321.2 Hz), 117.8,
117.7, 100.5, 49.4, 33.8, 26.9; HREIMS m/z calcd for C11H13F3N2O3S (M+) 310.0599, Found
310.0598.
4.4.4. Synthesis of 7,8-dihydro-4H-pyrazolo[1,5-a]azepin-3-yl trifluoromethanesulfonate (18)
To a solution of 17 (99.1 mg, 0.32 mmol) in CH2Cl2 (2 mL) were added Grubbs2nd
catalyst (13 mg, 0.016 mmol, 5 mol%) and CuI (1.0 mg, 0.005 mmol, 2.5 mol%). The sealed
reaction mixture was heated at 80 ◦C for 1 h under MW irradiation. Solvent was removed
under reduced pressure to give a crude mixture that was purified by silica gel column
chromatography (eluent:hexane/AcOEt = 4:1) to afford 18 (65.1 mg, 72%). 18: Amorphous
◦
1
solid; mp 72–75 C; H-NMR (400 MHz, CDCl3):
(2H, m, 2 -CH=CHCH2-), 4.46 (2H, dd, J = 5.6, 4.5 Hz, NCH2CH2-), 3.47–3.45 (2H, m,
ArCH2CH=), 2.49–2.45 (2H, m, -CH2CH2CH=); 13C-NMR (100 MHz, CDCl3):
134.0, 129.8,
δ 7.38 (1H, s, pyrazole-H), 5.77–5.70
×
δ
129.16, 129.12, 122.4, 118.6 (q, JC-F = 321.2 Hz), 50.9, 27.8, 21.7; HREIMS m/z calcd for
C9H9F3N2O3S (M+) 282.0286, found 282.0282.
4.4.5. Synthesis of 3-phenyl-7,8-dihydro-4H-pyrazolo[1,5-a]azepine (19)
To a solution of 18 (54.7 mg, 0.19 mmol) in DME/H2O = 9:1 (5 mL) in a MW vial were
added XPhos (9.2 mg, 0.019 mmol, 10 mol%), Pd(dba)2 (11.0 mg, 0.019 mmol, 10 mol%), ce-
sium carbonate (126.4 mg, 0.38 mmol, 2.0 eq.), and phenylboronic acid (50.0 mg, 0.41 mmol
,
2.0 eq.). The sealed vial was heated under MW irradiation at 130 ◦C for 1 h. The cooled
reaction mixture was quenched with sat. aq. NH4Cl solution (40 mL) and extracted with
CH2Cl2 (10 mL
×
3). The combined organic layers were dried over MgSO4, filtered, and the
solvent was removed under reduced pressure to give a crude residue that was purified by
silica gel column chromatography (eluent:hexane/AcOEt = 2:1) to afford 19 (35.4 mg, 87%).
19: Oil; 1H-NMR (400 MHz, CDCl3):
δ
7.49 (1H, s, pyrazole-H), 7.42–7.34 (2H, m, Ph-H),
7.34–7.26 (3H, m, Ph-H), 5.73–5.56 (2H, m, -NCH2CH=CH-, -CH=CHCH2-), 4.54–4.51 (m,
2H), 3.61–3.59 (2H, m), 2.50–2.46 (2H, m); 13C-NMR (100 MHz, CDCl3):
138.9, 136.8,
δ
133.6, 129.1, 128.9, 128.6, 128.2, 126.3, 123.8, 120.7, 49.5, 28.4, 23.1; HREIMS m/z calcd for
C14H14N2 (M+) 210.1157, found 210.1156.
4.4.6. Synthesis of 3-phenyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepine (15)
To a solution of 19 (3.0 mg, 0.014 mmol) in MeOH (10 mL) was added Pd/C (0.2 mg
10 mol%). The mixture was stirred overnight at room temperature under hydrogen gas
at 1 atm. After removal of Pd/C by filtration, the solvent was evaporated to give a crude
,

Molecules 2021, 26, 3370
12 of 13
residue that was purified by column chromatography (eluent:hexane/AcOEt = 4:1) to
afford 15 (2.8 mg, 92%). 15: δ 7.44 (1H, s, pyrazole-H),
1H-NMR (400 MHz, CDCl3):
7.37–7.42 (2H, m, Ph-H), 7.33–7.25 (3H, m, Ph-H), 4.35–4.30 (2H, m, -NCH2CH2-), 2.91–2.86
1
(2H, m, ArCH2CH2-), 1.93–1.86 (2H, m), 1.86–1.80 (2H, m), 1.74–1.67 (2H, m); lit. H-NMR
(400 MHz, CDCl3):
-NCH2CH2-), 2.89–2.86 (2H, m, ArCH2CH2-) 1.89–1.79 (4H, m), 1.75–1.67 (2H, m) [26];
13C-NMR (100 MHz, CDCl3):
140.7, 136.6, 134.1, 128.6, 128.3, 126.1, 121.0, 53.4, 31.0,
δ 7.43 (1H, s, pyrazole-H), 7.40–7.26 (5H, m, Ph-H), 4.33–4.31 (2H, m,
δ
28.0, 26.8, 24.4; lit. 13C-NMR (100 MHz, CDCl3):
δ 140.7, 136.5, 134.1, 128.5, 128.3, 126.1,
121.0, 53.3, 30.9, 28.0, 26.8, 24.4; HREIMS m/z calcd for C14H16N2 (M+) 212.1313, found
212.1312 [26].
4.4.7. Synthesis of 4t from 4b
To a solution of 4b (48.6 mg, 0.39 mmol) in acetone (1 mL) was added 20% NaOH aq.
(0.12 mg, 1.5 eq.) with stirring, followed by 1-bromo-3-butene (0.08 mL, 0.08 mmol, 2 eq.).
◦
The reaction mixture was heated at 80 C for 10 min under MW irradiation. After addition
of sat. aq. NH4Cl (1 mL) to the reaction mixture, it was extracted with CH2Cl2 (10 mL
×
3)
and the combined organic layers were washed with brine (5 mL 2), dried over MgSO4,
×
and filtered. The solvent was removed under reduced pressure to give a crude residue that
was purified by silica gel column chromatography (eluent:hexane/AcOEt = 3:1) to afford
4t (48.1 mg, 69%).
1
Supplementary Materials: Figures S1–S48: H- and 13C-NMR spectra of compounds 2c
, 2d, 4c, 4d,
4e, 4f, 4g, 4i, 4k, 4l, 4m, 4n, 4o, 4r, 4s, 4t, and 12–19.
Author Contributions: Y.U. conceived and designed experiments. Y.K., N.K., T.T., J.O., K.N., A.N.
and Y.T. performed experimental work. N.H., S.H. and H.Y. made discussions and suggestions on
this work and wrote the manuscript with Y.U. All authors have read and agreed to the published
version of the manuscript.
Funding: This research received no external funding.
Acknowledgments: We thank K. Minoura and Fujitake for the NMR and MS measurements, respec-
tively. K. Sumimoto of our laboratory is also appreciated for providing inspiration and suggestions
on the improved synthesis of withasomnine at an early stage.
Conflicts of Interest: The authors declare no conflict of interest.
Sample Availability: Samples of the compounds are not available from the authors.
References
1.
2.
3.
Fustero, S.; Sánchez-Roselló, M.; Barrio, P.; Simón-Fuentes, A. From 2000 to Mid-2010: A fruitful decade for the synthesis of
pyrazoles. Chem. Rev. 2011, 111, 6984–7034. [CrossRef]
Ansari, A.; Ali, A.; Asif, M.; Shamsuzzaman, S. Review: Biologically active pyrazole derivatives. New J. Chem. 2017, 41, 16–41.
[CrossRef]
Karrouchi, K.; Radi, S.; Ramli, Y.; Taoufik, J.; Mabkhot, Y.N.; Al-Aizari, F.A.; Ansar, M. Synthesis and pharmacological activities of
pyrazole derivatives: A review. Molecules 2018, 23, 134. [CrossRef]
4.
5.
Brown, A.W. Recent developments in the chemistry of pyrazoles. Adv. Heterocycl. Chem. 2018, 126, 55–107.
Usami, Y.; Tatsui, Y.; Yoneyama, H.; Harusawa, S. C4-Alkylamination of C4-halo-1H-1-tritylpyrazoles using Pd(dba)2 or CuI.
Molecules 2020, 25, 4634. [CrossRef]
6.
7.
8.
9.
Ray, R.; Hartwig, J.F. Oxalohydrazide ligands for copper-catalyzed C O coupling reactions with high turnover numbers. Angew.
Chem. Int. Ed. 2020, 133, 8284–8292. [CrossRef]
Vijeta, A.; Casadevall, C.; Roy, S.; Reisner, E. Visible-light promoted C-O bond formation with an integrated carbon nitride–nickel
heterogeneous photocatalyst. Angew. Chem. Int. Ed. 2021, 60, 8494–8499. [CrossRef] [PubMed]
−
Vorogushin, A.V.; Huang, X.; Buchwald, S.L. Use of tunable ligands allows for intermolecular Pd-catalyzed C O Bond formation.
−
J. Am. Chem. Soc. 2005, 127, 8146–8149. [CrossRef] [PubMed]
Maiti, D.; Buchwald, S.L. Orthogonal Cu- and Pd-based catalyst system for the O- and N-arylation of aminophenols. J. Am. Chem.
Soc. 2009, 131, 17423–17429. [CrossRef] [PubMed]
10. Zhang, H.; Ruiz-Castillo, P.; Buchwald, S.L. Palladium-catalyzed C-O cross-coupling of primary alcohols. Org. Lett. 2018, 20,
1580–1583. [CrossRef] [PubMed]

Molecules 2021, 26, 3370
13 of 13
11. Gowrisankar, S.; Sergeev, A.G.; Anbarasan, P.; Spannenberg, A.; Neumann, H.; Beller, M. A general and efficient catalyst for
palladium-catalyzed C
[CrossRef]
−
O coupling reactions of aryl halides with primary alcohols. J. Am. Chem. Soc. 2010, 132, 11592–11598.
12. Maiti, D.; Buchwald, S.L. Cu-catalyzed arylation of phenols: Synthesis of sterically hindered and heteroaryl diaryl ethers. J. Org.
Chem. 2010, 75, 1791–1794. [CrossRef] [PubMed]
13. Nayak, M.; Batra, S. Copper-Catalyzed Cascade Reactions of Substituted 4-Iodopyrazolecarbaldehydes with 1,2-Phenylenediamines
and 2-Aminophenols. Adv. Synth. Catal. 2020, 352, 3431–3437. [CrossRef]
14. Wong, D.M.; Li, J.; Chen, Q.H.; Han, Q.; Mutunga, J.M.; Wysinski, A.; Anderson, T.D. Select small core structure carbamates
exhibit high contact toxicity to “carbamate-resistant” strain malaria mosquitoes, Anopheles gambiae (Akron). PLoS ONE 2012, 7,
e46712. [CrossRef] [PubMed]
15. MacDonald, E.; Ihalainen, E.; Pispa, J.P. Pharmacological and toxicological properties of by 4-hydroxypyrazole, a metabolite of
pyrazole. Acta Pharmacol. Toxicol. 1981, 48, 418–423. [CrossRef] [PubMed]
16. Cornell, N.W.; Hansch, C.; Kim, K.H.; Henegar, K. The inhibition of alcohol dehydrogenase in vitro and in isolated hepatocytes
by 4-substituted pyrazoles. Arch. Biochem. Biophys. 1983, 227, 81–90. [CrossRef]
17. Sinclair, J.; Cornell, N.W.; Zaitlin, L.; Hansch, C. Induction of cytochrome P-450 by alcohols and 4-substituted pyrazoles:
Comparison of structure-activity relationships. Biochem. Pharmacol. 1986, 35, 707–710. [CrossRef]
18. Jones, J.P.; Joswig-Jones, C.A.; Hebner, M.; Chu, Y.; Koop, D.R. The effects of nitrogen-heme-iron coordination on substrate
affinities for cytochrome P450 2E1. Chem. Biol. Interact. 2011, 193, 50–56. [CrossRef] [PubMed]
19. Walworth, B.L. Fungicidal Use of 4-alkoxypyrazoles. U.S. (1976) Patent No. US 4000301 A 19761228, 14 November 1975.
20. Matsuo, J.; Takaya, M.; Maki, Y. 1-Phenyl-4-alkoxypyrazole-5-carboxylic Acid Esters. Jpn. Kokai Tokkyo Koho (1972) Patent No.
JP 47042665 A, 16 December 1972.
21. Munier-Lehmann, H.; Lucas-Hourani, M.; Guillou, S.; Helynck, O.; Zanghi, G.; Noel, A.; Tangy, F.; Vidalain, P.O.; Janin, Y.L.
Original 2-(3-Alkoxy-1H-pyrazol-1-yl)pyrimidine derivatives as inhibitors of human dihydroorotate dehydrogenase (DHODH). J.
Med. Chem. 2015, 58, 860–877. [CrossRef]
22. Ichikawa, H.; Watanabe, R.; Fujino, Y.; Usami, Y. Divergent synthesis of withasomnines via synthesis of 4-hydroxy-1H-pyrazoles
and Claisen rearrangement of their 4-O-allylethers. Tetrahedron Lett. 2011, 52, 4448–4451. [CrossRef]
23. Usami, Y.; Watanabe, R.; Fujino, Y.; Shibano, M.; Ishida, C.; Yoneyama, H.; Harusawa, S.; Ichikawa, H. Divergent synthesis and
evaluation of inhibitory activities against Cyclooxygenases-1 and
2012, 60, 1550–1560. [CrossRef]
−
2 of natural withasomnines and analogues. Chem. Pharm. Bull.
24. Usami, Y.; Tatsui, Y.; Sumimoto, K.; Miyamoto, A.; Koito, N.; Yoneyama, H.; Harusawa, S. 3-Trifluoromethansulfonyloxy-4,7-
dihidropyrazolopyridine via ring-closing metathesis: Synthesis and transformation to withasomnine homologs. Heterocycles 2021
103, 284–299. [CrossRef]
,
25. Allin, S.M.; Barton, W.R.S.; Bowman, W.R.; McInally, T. Radical cyclisation onto pyrazoles: Synthesis of withasomnine. Tetrahedron
Lett. 2002, 43, 4191–4193. [CrossRef]
26. Allin, S.M.; Barton, W.R.S.; Russell Bowman, W.; Bridge (née Mann), E.; Elsegood, M.R.J.; McInally, T.; McKee, V. Bu3SnH-
mediated radical cyclisation onto azoles. Tetrahedron 2008, 64, 7745–7758. [CrossRef]
27. Xia, T.; Hu, Z.; Ji, W.; Zhang, S.; Shi, H.; Liu, C.; Pang, B.; Liu, G.; Liao, X. Synthesis of withasomnine and pyrazole derivatives via
intramolecular dehydrogenative cyclization, as well as biological evaluation of withasomnine-based scaffolds. Org. Chem. Front.
2018, 5, 850–854. [CrossRef]
28. Wube, A.A.; Wenzig, E.M.; Gibbons, S.; Asres, K.; Bauer, R.; Bucar, F. Constituents of the stem bark of Discopodium penninervium
and their LTB4 and COX-1 and -2 inhibitory activities. PhytoChemistry 2008, 69, 982–987. [CrossRef]
29. Usami, Y.; Kohno, A.; Yoneyama, H.; Harusawa, S. Synthesis of dihydrooxepino[3,2-c]pyrazoles via Claisen rearrangement and
ring-closing metathesis from 4-allyloxy-1H-pyrazoles. Molecules 2018, 23, 592. [CrossRef]
30. Usami, Y.; Sumimoto, K.; Kishima, A.; Tatsui, Y.; Yoneyama, H.; Harusawa, S. Synthesis of dihydropyrano[3,2-c]pyrazoles via
double bond migration and ring-closing metathesis. Molecules 2019, 24, 296. [CrossRef]
31. Usami, Y.; Tsujiuchi, Y.; Machiya, Y.; Chiba, A.; Ikawa, T.; Yoneyama, H.; Harusawa, S. Synthetic challenges in the construction of
8- to 10-Membered pyrazole-fused rings via ring-closing metathesis. Heterocycles 2020, 101, 496–511. [CrossRef]
32. Kadoma, Y.; Murakami, Y.; Ogiwara, T.; Machino, M.; Yokoe, I.; Fujisawa, S. Radical-scavenging activity and cytotoxicity of
p-methoxyphenol and p-cresol dimers. Molecules 2010, 15, 1103–1112. [CrossRef]
33. Li, X.B.; Chen, G.Y.; Liu, R.J.; Zheng, C.J.; Song, X.M.; Han, C.R. A new biphenyl derivative from the mangrove endophytic
fungus Phomopsis longicolla HL-2232. Nat. Prod. Res. 2017, 31, 2264–2267. [CrossRef] [PubMed]
34. Allen, S.E.; Walvoord, R.R.; Padilla-Salinas, R.; Kozlowski, M.C. Aerobic copper-catalyzed organic reactions. Chem. Rev. 2013, 113,
6234–6458. [CrossRef] [PubMed]
35. Kamal, F.; Colombel-Rouen, S.; Dumas, A.; Guégan, J.P.; Roisnel, T.; Dorcet, V.; Baslé, O.; Rouen, M.; Mauduit, M. Activation of
olefin metathesis complexes containing unsymmetrical unsaturated N-heterocyclic carbenes by copper and gold transmetalation.
Chem. Commun. 2019, 55, 11583–11586. [CrossRef] [PubMed]