Divergent synthesis and evaluation of inhibitory activities against cyclooxygenases-1 and -2 of natural withasomnines and analogues

Article abstract of DOI:10.1248/cpb.c12-00725

The divergent synthesis of natural withasomnines and analogues was achieved from 4-hydroxypyrazoles, which was prepared via alkaline hydrolysis of the Baeyer-Villiger oxidation products from 4-formylpyrazoles. Key steps of this synthesis are regioselective Claisen rearrangement of 4-allyloxypyrazoles and the Suzuki-Miyaura coupling of 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl trifluoromethanesulfonate and commercially available arylboronic acids. The Suzuki-Miyaura coupling at the final step of this strategy enabled facile access to natural withasomnines and their analogues. The biological activities of the twelve synthesized compounds against cyclooxygenases-1 and -2 (COX-1 and COX-2) were evaluated.

Full text of DOI:10.1248/cpb.c12-00725

1550
Regular Article
Chem. Pharm. Bull. 60(12) 1550–1560 (2012)
Vol. 60, No. 12
Divergent Synthesis and Evaluation of Inhibitory Activities against
Cyclooxygenases-1 and -2 of Natural Withasomnines and Analogues
,a
Yoshihide Usami,* Ryo Watanabe,a Yuiko Fujino,a Makio Shibano,b Chihiro Ishida,b
,a,c
Hiroki Yoneyama,a Shinya Harusawa,a and Hayato Ichikawa*
a Laboratory of Pharmaceutical Organic Chemistry, Osaka University of Pharmaceutical Sciences; b Laboratory
of Pharmacognosy, Osaka University of Pharmaceutical Sciences; 4–20–1 Nasahara, Takatsuki, Osaka 569–1094,
c
Japan: and College of Industrial Technology, Nihon University; 1–2–1 Izumi-cho, Narashino, Chiba 275–8575,
Japan. Received August 16, 2012; accepted September 7, 2012
The divergent synthesis of natural withasomnines and analogues was achieved from 4-hydroxypyrazoles,
which was prepared via alkaline hydrolysis of the Baeyer–Villiger oxidation products from 4-formylpyra-
zoles. Key steps of this synthesis are regioselective Claisen rearrangement of 4-allyloxypyrazoles and the
Suzuki–Miyaura coupling of 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl trifluoromethanesulfonate and com-
mercially available arylboronic acids. The Suzuki–Miyaura coupling at the final step of this strategy enabled
facile access to natural withasomnines and their analogues. The biological activities of the twelve synthesized
compounds against cyclooxygenases-1 and -2 (COX-1 and COX-2) were evaluated.
Key words 4-hydroxy-1H-pyrazole; withasomnine; Claisen rearrangement; Suzuki–Miyaura coupling;
microwave; cyclooxygenase inhibitory activity
Pyrazoles are important heterocyclic compounds that ex- 1c along with 1a from the root bark of Newbouldia laevis
hibit various biological activities, and extensive studies of SEEM (Bignoniaceae) were reported.20–22) The isolation of
the synthesis of substituted or functionalized pyrazoles have withasomnines from Elytraria acaulis (Acanthaceae)23) and
been conducted.1,2) Of the many available methods for the Discopodium penninervium (Solanaceae)24) was also reported
synthesis of the pyrazole ring, the reaction of hydrazines with in 2001 and 2008, respectively. Withasomnine 1a exhibited
1,3-dicarbonyl compounds is probably the most general and central nervous and circulatory system depressions, mild an-
versatile.3–7) In contrast, synthetic methods using the direct algesic activity,25,26) and TBL4, cyclooxygenase-1 (COX-1),
functionalization of pyrazoles have been little reported.
and COX-2 inhibitory activities.24) Because of these interest-
A binuclear platinum complex bearing C-4 alkylpyrazole ing biological activities, several reports of the synthesis of 1a
ligands was reported to exhibit remarkable anticancer activi- were disclosed.27–36) In the course of our synthetic studies of
ties against cisplatin-resistant human cancer cell lines.8,9) This small natural products and their analogues,37–42) we recently
has inspired us to examine the direct functionalization at the reported the divergent synthesis of withasomnines 1a–c and
C-4 position of pyrazoles. We recently reported the synthesis their analogues via 4-hydroxypyrazole intermediates in a
of 4-substituted pyrazoles via the Kumada–Tamao coupling,10) preliminary communication.43) We herein describe the details
the Suzuki–Miyaura coupling,11) the Heck reaction,12) as well of the divergent synthesis of natural 1a–c as well as nine
as the synthesis of 2H-indazoles via a double Sonogashira withasomnine analogues 1d–l, which were easily prepared by
coupling followed by Bergmann–Masamune cycloaromatiza- the Suzuki–Miyaura coupling of key intermediate 16. In this
tion reaction.13)
work, we focused on the use of 4-hydroxypyrazole intermedi-
4-Hydroxypyrazoles possess important and interesting ates followed by the Claisen rearrangement of their 4-O-allyl
biological activities, including the inhibition of several kinds ethers. Furthermore, the inhibitory activities of 1a–l against
of cytochrome P450 (CYP) enzymes and the induction of COX-1 and COX-2 were tested.
CYP2E1.14–18) It has been reported that 4-hydroxypyrazole
is a metabolite of pyrazole in mouse hepatic microsomes.
However, as far as we know, there are almost no reports of
Results and Discussion
4-Iodo-1-trityl-1H-pyrazole (4a) was prepared from com-
the synthesis of 4-hydroxypyrazoles. Therefore, our inter- mercially available pyrazole (2) via 4-iodo-1H-pyrazole (3)
est was directed to the development of a new method for the following our previous work10,12,13) (Chart 1). Compound 4a
synthesis of 4-hydroxy-1H-pyrazoles. Further, the synthesis of was treated with isopropylmagnesium chloride for halogen–
4-hydroxypyrazoles may lead to find novel biologically active metal exchange and after 1h, N,N-dimethylformamide (DMF)
substances.
Although the isolation of natural pyrazole alkaloids from
higher plants has been rarely reported, withasomnine (1a)
shown in Fig. 1 was originally isolated in 1966 from the root
bark of Withania somnifera (Solanaceae),19) which is widely
distributed in India and Africa. The plant is also known as
Achwagandha in Sanskrit or Indian ginseng and used as
folk medicine in India. In the 1990s, withasomnines 1b and
The authors declare no conflict of interest.
*To whom correspondence should be addressed. e-mail: usami@gly.oups.ac.jp;
Fig. 1. Structures of Natural Withasomnines 1a–c
© 2012 The Pharmaceutical Society of Japan

December 2012
1551
Chart 1. Synthesis of 4-Hydroxypyrazoles
Chart 2. Preparation of 1-Substituted-4-allyloxy-1H-pyrazoles 9c–h
was added to afford 4-formylpyrazole 5a.44) Aldehyde 5a was were performed in N,N-diethylaniline (DEA) as solvent
subsequently converted into allyl ether 9a via the following under microwave (MW) irradiation to afford 1-substituted
three steps in a simple one-pot procedure: 1) The Baeyer–Vil- 3-allyl-4-hydroxy-1H-pyrazole (10) and 1-substituted 5-allyl-
liger oxidation of 5a with 30% aq. hydrogen peroxide using 4-hydroxy-1H-pyrazole (11) (The numbering in the text was
catalytic 2-trifluoromethane-sulfonyloxyphenylselenic acid tentatively derived from that of 9). As summarized in Table 1,
(6), which was developed in our previous work,45) providing the results indicated a highly regioselective rearrangement at
formate 7a. 2) Alkaline hydrolysis of 7a with aq. NaOH under C5 to give 11 as the major product. The structures of all the
reflux afforded desired 4-hydroxy-1-trityl-1H-pyrazole (8a). 3) rearranged products were determined by nuclear Overhauser
Reaction of 8a with allyl bromide gave corresponding allyl effect spectroscopy (NOESY) analyses. Key NOESY correla-
ether 9a (75% overall yield from 5a), which could be used im- tions were observed in 10a and 11a as representative com-
mediately for the following Claisen rearrangement. Similarly, pounds (Fig. 2). Positive effect of MW irradiation could not be
1-benzyl-4-hydroxy-1H-pyrazole (8b) and allyl ether 9b were observed in this reaction (entries 1, 2) since entry 1 was car-
obtained in good yields from 5b.
ried out in a sealed tube with heating similarly to entry 2 in
The next crucial step in the total synthesis of 1 is the a sealed vessel for MW reaction. It was interesting that only
regioselective Claisen rearrangement of 4-allyloxy-1H- in the case of N-benzylpyrazole 9b (entry 3) was a very small
pyrazoles (9). The Claisen rearrangement of 3-substituted-5- amount of 3,5-diallyl-2-benzyl-4-hydroxy-2H-pyrazole (12,
allyloxypyrazoles was reported by Hori and colleagues46) and 2%) obtained along with major product 11b (92%). However
Hwang et al.47) independently, in which the allyl group was the separation of 11b and 12 was troublesome. Claisen rear-
rearranged toward C-4 exclusively resulting from the structure rangement of N-tosylpyrazole 9f (R=Ts) provided a significant
of the substrate, 3-substituted-5-allyloxypyrazoles. However, amount of minor rearranged product 10f (20%) along with 11f
allyl ethers 9 offer two possible routes for the Claisen rear- (65%) (entry 5). Entries on 9e (R=Boc) or 9h (R=Tf) are not
rangement. Thus, the Claisen rearrangement of 9 having vari- presented in Table 1 because desired products 10 or 11 could
ous N-1 protecting groups with control of regioselectivities is not be obtained. Boc group was removed thermolytically dur-
useful for the synthesis of withasomnine. In order to examine ing MW reaction in case of 9e.
the directionality of the rearrangement, five additional 4-allyl-
Although understanding of the rearrangement direction of 9
oxy-1H-pyrazoles 9d–h were prepared from 9c as shown in arising from various N-protecting groups remains incomplete,
Chart 2.
Claisen rearrangements using 4-allyloxypyrazoles
electron-donating groups at N-1 tended to show preference for
the desired C5-rearrangements (entries 1−4).
9

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Vol. 60, No. 12
CH3CN contrarily provided only a small amount of 10a (16%)
(entry 13). The reaction solutions of 9 in DEA or CH3CN were
turned red under MW irradiations, but they were kept color-
less in DME or EtOH. The color change in DEA or CH3CN
may be allowed to presume the decomposition of the reaction
contents.
The transformation of 11a into 5,6-dihydro-4H-pyrrolo[1,2-
b]pyrazol-3-yl trifluoromethanesulfonate (16) is summarized
in Chart 3.48) The 4-hydroxyl group of 11a was converted
into triflate 13 (87%) using triflic anhydride as the functional
group for the subsequent Suzuki–Miyaura coupling. The
hydroboration–oxidation sequence of 13 with borane–dimeth-
Fig. 2. Selected NOEs in 10a and 11a
The preference for 11 in the Claisen rearrangement could ylsulfide complex resulted in desired alcohol 14 in 27–40%
be explained by the relative stabilities of two intermediates yields under various reaction conditions. Alternatively, the
(IMs), IM1 for 11 and IM2 for 10, as shown in Fig. 3. IM1 use of 9-BBN improved the yield of 14 to 87%. Alcohol 14
had opposite electric charges (δ+ and δ−) lying side by side was subsequently treated with p-toluenesulfonyl chloride and
at C4 and C5. Meanwhile, IM2 seemed less stable than IM1 triethylamine to give tosylate 15 in 93% yield. Detritylation
because the partially negative charge (δ−) on C3 neighbored of 15 under reflux in hydrochloric acid induced a spontaneous
the negative charge on N2 in IM2, causing a mismatch of the intramolecular SN2 reaction to furnish intermediate 16 in 40%
charge balance. In addition, electrons on the O-allyl group as yield.
well as all π electrons on the pyrazole ring could be forced to
participate in the rearrangement into 10.
The final step in the total synthesis of withasomnine 1a
is the Suzuki–Miyaura coupling of triflate 16 and phenyl-
N1-Tritylated pyrazole 11a (R=Tr) possessing an allylic side boronic acid. Various reaction conditions in DME–H2O to
chain at C5 was selected as the key intermediate for the total form 1a were examined as shown in Table 2. MW irradiation
synthesis of withasomnines owing to the easy removal of the shortened the reaction time remarkably (entry 2) compared to
trityl group in the acidic condition. Thus, the MW-assisted conventional reflux conditions (entry 1), affording 1a in the
Claisen rearrangement of 9a was further examined under similar low yields along with undesired 17. Changing ratio of
various conditions (Table 1, entries 7–13). (Reaction time of DME–H2O from 1:1 to 9:1 depressed the production of 17
entries 1–7 was determined by TLC monitoring consump- (entry 3). Although the DME–H2O solvent system was effec-
tion of 9.) Use of 1,2-dimethoxyethane (DME) as the solvent tive for the reaction as reported in the literature,35) the sole
under MW condition (200°C, 30min) afforded the desirable use of DME did not give 1a (entry 5). In an investigation of
rearrangement product 11a in 65% yield with recovery of the the effects of phase transfer catalyst on the reaction, we found
staring 9a (23%), contaminating 10a (1.4%) (entry 9). In ad- that the addition of 2eq of tetra-n-butylammonium bromide
dition, the MW reaction in DME or EtOH tended to suppress (TBAB) gave a slightly better yield (54%) (entry 7), whereas
formation of unfavorable 10a (entries 7–12), while the use of the addition of only one drop of trioctylmethylammonium
Table 1. Claisen Rearrangement of 4-Allyloxy-1H-pyrazoles
Product yieldb) (%)
Entrya)
Substrate
Solvent
Temp. (°C)
Time (min)
Recovery of 9
10
11
12
1c)
2
9a (R=Tr)
DEA
DEA
190
190
190
190
190
190
200
200
200
200
150
180
200
60
60
30
60
30
60
10
20
30
60
60
30
30
3
3
0
2
59
0
0
2
0
0
0
0
0
0
0
0
0
0
9a
61
92
84
65
68
53
53
65
59
13
51
0
3
9b (R=Bn)
9d (R=n-Bu)
9f (R=Ts)
9g (R=Ms)
DEA
4
DEA
5
DEA
20
6
DEA
Traced)
NDe)
ND
1.4
1.5
0
7
9a
9a
9a
9a
9a
9a
9a
DME
DME
DME
DME
DME
EtOH
CH3CN
35
40
23
27
84
43
0
8
9
10
11
12
13
2
16
a) All entries except 1 were carried out under MW irradiation. b) Isolated yield. c) Conventional heating in a sealed tube. d) Not isolated but observed in the crude 1H-NMR
spectrum. e) ND: not detected.

December 2012
1553
Fig. 3. Mechanism of Claisen Rearrangement from 9 to 10 and 11
Chart 3. Transformation of 11a into 16
chloride (TOMAC) showed a remarkable improvement, giving 3-hydroxyphenyl) and 1g (Ar=3-aminophenyl) showed potent
target compound 1a in 90% yield (entry 8). From entries 8–10, inhibitory activities against COX-1 and COX-2. Then the
the optimum reaction time for the Suzuki–Miyaura coupling IC50 values of them were determined by further experiments
under MW irradiation was determined to be 30min (entry 10). using aspirin as the positive control and results are summa-
Indeed, the reaction condition in entry 10 was applied to the rized in Table 4. Worth mentioning is that the COX-1 and
synthesis of other natural withasomnines and withasomnine COX-2 inhibitory activities of 1g were stronger than those
derivatives.
of aspirin. The presence of an amino group in 1g increased
The Suzuki–Miyaura coupling toward them was carried its potency by one order of magnitude for COX-1 and two
out. Results are summarized in Table 3. Remaining two natu- orders for COX-2 compared to 1b and 1d, both of which pos-
ral 1b and 1c could be prepared in good yields using 4-hy- sess a hydroxyl group. The COX-2 inhibitory activity (IC50:
droxyphenyl- and 4-methoxyphenylboronic acids, respectively 2.7×10−6 M) of 1g was almost four times as effective as its
(entries 2, 3). Further applications to unnatural withasomnine COX-1 inhibitory activity (IC50: 1.0×10−5 M). Compounds 1b
analogues 1d–l were also demonstrated via the reaction be- and 1d exhibited nearly two-fold higher selectivity for COX-1
tween 16 and various arylboronic acids (entries 4–12). The than COX-2, being similar to the selectivity of aspirin. Mean-
easy access to these analogues from the common intermediate while, the other nine compounds showed much lower inhibi-
16 proved to be an advantage of our synthetic method com- tory activities (IC50>10−3 M) against both enzymes.
pared to recent approaches by other research groups,35,36) since
all arylboronic acids appearing in Table 3 are commercially are capable of hydrogen bonding, on the aromatic ring of syn-
The results suggested that the presence of the groups, which
available.
thesized withasomnines increased their inhibitory activities
Since 1a was reported to exhibit minor inhibitory activ- against COX-1 and COX-2.49) These findings may stimulate
ity against COX-1 and COX-2 in the literature,24) synthesized the design of COX inhibiting drugs based on withasomnine
withasomnines 1a–l were applied to the preliminary in- derivatives.
hibitory assay against those enzymes. Among them, natural
compound 1b (Ar=4-hydroxyphenyl) and unnatural 1d (Ar=

1554
Vol. 60, No. 12
Table 2. Suzuki–Miyaura Coupling of 16 and Phenylboronic Acid to Withasomnine 1a
Entry
Catalyst/Ligand
DME/H2O
Additive
Condition
1a (yield, %)
17 (%)
1
2
Pd(OAc)2/PPh3
1/1
1/1
9/1
9/1
1/0
9/1
9/1
9/1
9/1
9/1
No
Reflux, 24h
20
24
29
42
0
77
71
0
Pd(OAc)2/PPh3
No
MW, 130°C, 1h
MW, 130°C, 1h
MW, 130°C, 1h
MW, 130°C, 1h
MW, 130°C, 1h
MW, 130°C, 1h
MW, 130°C, 1h
3
Pd(OAc)2/PPh3
No
4
Pd(dba)2/PPh3
No
No
0
5
Pd(OAc)2/PPh3
0
6
Pd(dba)2/P(o-tol)3
Pd(dba)2/P(C6H11)3
Pd(dba)2/P(C6H11)3
Pd(dba)2/P(C6H11)3
Pd(dba)2/P(C6H11)3
No
51
54
90
37a)
88
0
7
TBAB (2eq)
TOMAC (1 drop)
0
8
0
9
TOMAC (1 drop) MW, 130°C, 10min
TOMAC (1 drop) MW, 130°C, 30min
0
10
0
a) Starting material 16 was recovered in 55%.
Table 3. Suzuki–Miyaura Coupling of 16 and Arylboronic Acid to Table 4. Inhibitory Activities of Selected Withasomnines 1b, 1d, and 1g
Withasomnines 1a–l
against COX-1 and COX-2
IC50 (M)
Compound
COX-1
COX-2
1b
1d
1.1×10−4
1.1×10−4
1.0×10−5
4.6×10−5
2.4×10−4
2.3×10−4
2.7×10−6
8.4×10−5
1g
Aspirin
Entry
ArB(OH)2: Ar =
Phenyl
Product (yield, %)
1a)
2
1a (88)
1b (84)
1c (82)
1d (71)
1e (88)
1f (70)
1g (76)
1h (83)
1i (80)
1j (83)
1k (92)
1l (82)
that 1g exhibited the most potent activities against COX-1 and
COX-2.
4-Hydroxyphenyl
4-Methoxyphenyl
3-Hydroxyphenyl
2-Methylphenyl
3-Nitrophenyl
3
4
Experimental
5
General IR spectra were obtained with a JASCO FT/
IR-680 Plus spectrometer. High resolution (HR)-MS were de-
termined using a JEOL JMS-700 (2) mass spectrometer. NMR
spectra were recorded at 27°C on Varian UNITY INOVA-500
and Mercury-3000 spectrometers in CDCl3 with tetramethyl-
silane (TMS) as the internal reference. Melting points were
determined on a Yanagimoto micromelting point apparatus
MD-S3 and are uncorrected. Liquid column chromatography
was conducted over silica gel (SILICYCLE, Silia Flash F60,
mesh 230–400). Analytical TLC was performed on precoated
Merck glass plates (DC-Alufolien Kieselgel 60 F254) and com-
6
7
3-Aminophenyl
3,4-Methylenedioxyphenyl
4-Fluorophenyl
2-Thiophenyl
8
9
10
11
12
3-Thiophenyl
2-Furyl
a) The same reaction appeared in entry 10 in Table 2.
Conclusion
We have developed a novel method for the synthesis of pounds were visualized by spraying plates with an ethanol
4-hydroxy-1H-pyrazoles 8, which utilizes our previously de- solution of phosphomolybdic acid followed by heating. Dry
veloped Baeyer–Villiger oxidation reaction.
tetrahydrofuran (THF) was distilled over sodium benzophe-
We also found that the Claisen rearrangement of O-allyl de- none ketyl under nitrogen atmosphere. Microwave reactions
rivatives 9 gave 5-allyl-4-hydroxy-2H-pyrazoles in good yields were carried out with a Biotage Initiator®. A COX Fluorescent
with high regioselectivities. Our divergent synthesis was Activity Assay Kit was purchased from Cayman Chemical
completed with the Suzuki–Miyaura coupling of triflate ester (Ann Arbor, MI, U.S.A.).
of 4-hydroxypyrazole derivative 16 and various arylboronic
4-Formyl-1-trityl-1H-pyrazole 5a To a solution of 4a
acids, affording various natural and synthetic withasomnines (22.8g, 52.3mmol) in Et2O (120mL) and THF (240mL) was
1a–l. Diverging from intermediate 16 realized easy access added 2.0M isopropylmagnesium chloride in THF (31.5mL,
to various withasomnines. The COX-1 and COX-2 inhibitory 52.3mmol) at 0°C under nitrogen atmosphere. After stirring
activities of the synthesized compounds 1a–l were evaluated. for 1h, N,N-dimethylformamide (DMF) (14mL, 160mmol)
Among them, 1b, 1d, and 1g showed significant inhibitory was added and the reaction mixture was stirred for another
activities against both enzymes. Of particular interest was hour at room temperature (rt). After the reaction was quenched

December 2012
1555
by the addition of water, extraction was carried out with
4-Allyloxy-1-trityl-1H-pyrazole (9a) To a solution of 5a
CH2Cl2. The organic layer was washed with brine, dried over (7.2g, 21mmol) in CH2Cl2 (107mL) were added 30% H2O2
MgSO4, and filtered. The solvent was removed under reduced aq. (10.7mL, 94mmol) and 6 (746mg, 2.1mmol) at rt. After
pressure to give a crude residue that was subsequently purified stirring for 24h, 10% NaOH aq. (1.7mL) was added and the
by recrystallization to afford 5a (16.0g, 90%). 5a: Colorless reaction mixture was warmed at 50°C for 1.5h. Then, allyl
needles (CH2Cl2); mp 208–210°C; IR (KBr) νmax 1686 (C=O), bromide (2.5mL, 26mmol) was added at rt and the reaction
1
1546 (C=C), 1491 (C=C) cm−1; H-NMR (300MHz, CDCl3) mixture was stirred for 2h. After quenching the reaction
δ: 7.12–7.16 (m, 6H, Tr-H), 7.31–7.36 (m, 9H, Tr-H), 7.97 (s, with NH4Cl aq., extraction was carried out with EtOAc. The
1H, pyrazole-H), 8.12 (s, 1H, pyrazole-H), 9.83 (s, 1H, CHO); organic layer was washed with brine, dried over MgSO4, and
13C-NMR (75MHz, CDCl3) δ: 79.7, 122.8, 127.8, 128.0, 130.0, filtered. The solvent was removed under reduced pressure to
135.9, 140.6, 142.0, 184.3; HR-MS m/z Calcd for C23H19N2O give a crude residue that was subsequently purified by column
([M+H]+) 339.1498, Found 339.1503.
chromatography (hexane–EtOAc=3:1) to afford 9a (5.9g, 75%
1-Benzyl-4-formyl-1H-pyrazole (5b) Compound 5b was in 3 steps). 9a: White powder; mp 123–125°C; IR (KBr) νmax
prepared from 4b similarly except for purification proce- 1649, 1570, 1492 (C=C) cm−1; H-NMR (300MHz, CDCl3) δ:
1
dure (by column chromatography) in 75% yield. 5b: Oil; 4.34 (2H, ddd, J=5.6, 1.4, 1.6Hz, –OCH2CH=), 5.23 (1H, ddt,
IR (liquid film) νmax 1685 (C=O), 1543 (C=C), 1489 (C=C) J=10.6, 1.4, 1.4Hz, –CH=CHcisH), 5.32 (1H, ddt, J=17.2, 1.6,
1
cm−1; H-NMR (300MHz, CDCl3) δ: 5.34 (s, 2H, ArCH2Ph), 1.4Hz, –CH=CHtransH), 5.97 (1H, ddt, J=17.2, 10.6, 5.6Hz,
7.26–7.29 (2H, m, Ph-H), 7.36–7.41 (3H, m, Ph-H), 7.88 (1H, –CH=CH2), 7.03 (1H, s, pyrazole-H), 7.13–7.17 (6H, m, Tr-H),
s, pyrazole-H), 8.01 (1H, s, pyrazole-H), 9.84 (1H, s, CHO); 7.27–7.32 (9H, m, Tr-H), 7.42 (1H, s, pyrazole-H); 13C-NMR
13C-NMR (75MHz, CDCl3) δ: 56.6, 128.2, 128.7, 129.1, 132.5, (75MHz, CDCl3) δ: 72.4, 78.6, 117.9, 118.4, 127.6, 127.9, 128.1,
134.7, 139.4, 141.0, 184.0; HR-MS m/z Calcd for C11H11N2O 130.1, 133.2, 143.1, 144.1; HR-MS m/z Calcd for C25H22N2O
([M+H]+) 187.0872, Found 187.0868.
1-Benzyl-4-hydroxy-1H-pyrazole (8b) To a solution of
(M+) 366.1732, Found 366.1727.
1-Tritylpyrazol-4-yl Formate (7a) Colorless crystals
5b (200mg, 1.1mmol) in CH2Cl2 (6mL) were added 30% (CH2Cl2); mp 130–131°C; IR (KBr) νmax 1741 (C=O), 1577
H2O2 aq. (0.7mL, 6.2mmol) and 2-trifluoro-methanesulfonyl- (C=C) cm−1; 1H-NMR (500MHz, CDCl3) δ: 7.12–7.17 (6H,
phenylselenic acid (6) (46mg, 0.1mmol) at rt. After stirring m, Tr-H), 7.28–7.33 (9H, m, Tr-H), 7.55 (1H, d, J=0.7Hz,
for 24h, 10% NaOH aq. (0.7mL) was added to the reaction pyrazole-H), 7.67 (1H, d, J=0.7Hz, pyrazole-H), 8.15 (1H, s,
mixture containing 1-benzylpyrazol-4-yl formate (7b). The re- –OCOH); 13C-NMR (125MHz, CDCl3) δ: 79.2, 123.2, 127.6,
action mixture was warmed at 50°C for 1.5h. After the reac- 127.8, 127.9, 130.1, 130.8, 142.7, 157.4; HR-MS m/z Calcd for
tion was quenched with NH4Cl aq., extraction was carried out C23H18N2O2 (M+) 354.1368, Found 354.1364.
with EtOAc. The organic layer was washed with brine, dried
4-Hydroxy-1-trityl-1H-pyrazole (8a) Colorless crystals
over MgSO4, and filtered. The solvent was removed under re- (EtOAc); mp >300°C; IR (KBr) νmax 3137 (OH), 1608 (C=C)
1
duced pressure to give a crude residue that was subsequently cm−1; H-NMR (500MHz, CDCl3) δ: 7.06 (1H, d, J=0.9Hz,
purified by column chromatography (hexane–EtOAc=1:1) pyrazole-H), 7.13–7.17 (6H, m, Tr-H), 7.28–7.32 (9H, m, Tr-H),
to afford 8b (93mg, 61% in 2 steps). 8b: Colorless crystals 7.37 (1H, d, J=0.9Hz, pyrazole-H); 13C-NMR (125MHz,
(CH2Cl2); mp 84–86°C; IR (KBr) νmax 3735 (OH), 1584 (C=C) CDCl3) δ: 76.5 (s), 119.9 (d), 127.6 (d), 129.5 (d), 130.1 (d),
1
cm−1; H-NMR (300MHz, CDCl3) δ: 5.05 (2H, s, PhCH2Ar), 139.6 (s), 143.1 (s) (one of a doublet signal should be over-
6.90 (1H, s, pyrazole-H), 7.07–7.09 (2H, m, Ph-H), 7.08 (1H, lapped); HR-MS m/z Calcd for C22H18N2O (M+) 326.1219,
s, pyrazole-H), 7.22–7.25 (3 H, m, Ph-H), 8.80 (1H, brs, OH); Found 326.1412.
13C-NMR (75MHz, CDCl3) δ: 56.1, 116.8, 127.4, 128.0, 128.2,
4-Allyloxy-1H-pyrazole (9c) To a solution of 9a (183mg,
128.7, 136.2, 141.8; HR-MS m/z Calcd for C10H10N2O (M+) 0.5mmol) in acetone (1mL) was added 1N HCl aq. (2mL,
174.0788, Found 174.0787. 2mmol). After stirring at 50°C for 30min, the reaction
4-Allyloxy-1-benzyl-1H-pyrazole (9b) To a solution of mixture was extracted with EtOAc. The organic layer was
8b (89mg, 0.5mmol) in 10% NaOH aq. (0.4mL, 1mmol) was washed with brine, dried over MgSO4, and filtered. The sol-
added allyl bromide (52µL, 0.6mmol) at rt and the reaction vent was removed under reduced pressure to give a crude
mixture was stirred for 2h. After the reaction was quenched residue that was subsequently purified by column chroma-
with NH4Cl aq., extraction was carried out with EtOAc. The tography (hexane–EtOAc=3:1) to afford 9c (48mg, 78%).
organic layer was washed with brine, dried over MgSO4, and 9c: White powder; mp 40−42°C; IR (KBr) νmax 3308 (NH)
1
filtered. The solvent was removed under reduced pressure to cm−1; H-NMR (300MHz, CDCl3) δ: 4.42 (2H, ddd, J=5.6,
give a crude residue that was subsequently purified by column 1.5, 1.2Hz, –OCH2CH=), 5.27 (1H, ddt, J=10.5, 1.5, 1.2Hz,
chromatography (hexane–EtOAc=4:1) to afford 9b (107mg, –CH=CHH), 5.38 (1H, dq, J=17.4, 1.5Hz, –CH=CHH), 6.02
99%). 9b: Yellow oil; IR (liquid film) νmax 3032 (C–H), 1649 (1H, ddt, J=17.4, 10.5, 5.6Hz, –OCH2CH=CH2), 7.30 (2H, s,
1
(C=C) cm−1; H-NMR (300MHz, CDCl3) δ: 4.36 (2H, ddd, pyrazole-H), 11.10 (1H, brs, NH); 13C-NMR (75MHz, CDCl3)
J=5.4, 1.6, 1.5Hz, –OCH2CH=), 5.18 (2H, s, ArCH2Ph), 5.24 δ: 72.6, 117.9, 120.8, 120.8, 133.2, 145.0; HR-MS m/z Calcd for
(1H, dtd, J=10.5, 1.5, 1.5Hz, –CH=CHH), 5.35 (1H, dtd, C6H8N2O (M+) 124.0637, Found 124.0634.
J=17.3, 1.6, 1.5Hz, –CH=CHH), 5.98 (1H, ddt, J=17.3, 10.5,
Synthesis of 4-Allyloxy-1H-pyrazoles (9d–9h) Gen-
5.4Hz, –CH2CH=CH2), 7.04 (1H, d, J=0.6Hz, pyrazole-H), eral To a solution of 9c (62mg, 0.5mmol) in 10% NaOH aq.
7.18 (2H, m, Ph-H), 7.26–7.36 (4H, m, Ph-H, pyrazole-H); (0.4mL, 1mmol) was added n-butylbromide (110µL, 1mmol)
13C-NMR (75MHz, CDCl3) δ: 56.5, 72.4, 115.0, 117.8, 127.4, at rt and the reaction mixture was stirred for 12h. After the
127.4, 127.9, 128.7, 133.2, 136.6, 145.6; HR-MS m/z Calcd for reaction was quenched with NH4Cl aq., extraction was carried
C13H14N2O (M+) 214.1106, Found 214.1104.
out with EtOAc. The organic layer was washed with brine,

1556
Vol. 60, No. 12
dried over MgSO4, and filtered. The solvent was removed chromatography (hexane–EtOAc=2:1) to afford 11b (197mg,
under reduced pressure to give a crude residue that was subse- 92%) and 12 (4.0mg, 2%).
quently purified by column chromatography (hexane–EtOAc=
4:1) to afford 9d (118mg, 85%).
10a: White powder; mp 88–90°C; IR (KBr) νmax 3031
1
(OH), 1638, 1584 (C=C) cm−1; H-NMR (500MHz, CDCl3)
9d: White powder; mp 120°C; IR (KBr) νmax 1648 δ: 3.43 (2H, ddd, J=6.4, 1.7, 1.4Hz, ArCH2CH=), 5.13 (1H,
(C=C) cm−1; 1H-NMR (300MHz, CDCl3) δ: 0.93 (3H, ddt, J=10.1, 1.8, 1.4Hz, –CH=CHH), 5.18 (1H, ddt, J=17.2,
t, J=7.4Hz, –NCH2CH2CH2CH3), 1.31 (2H, tq, J=7.4, 1.8, 1.7Hz, –CH=CHH), 6.02 (1H, ddt, J=17.2, 10.1, 6.4Hz,
7.5Hz, –OCH2CH2CH2CH3), 1.80 (2H, tt J=7.5, 7.4Hz, –CH2CH=CH2), 6.95 (1H, s, pyrazole-H), 7.14–7.18 (6H, m,
–NCH2CH2CH2CH3), 4.01 (2H, t, J=7.4Hz, –NCH2CH2–), Tr-H), 7.27–7.30 (9H, m, Tr-H); 13C-NMR (125MHz, CDCl3)
4.40 (2H, ddd, J=5.6, 1.6, 1.4Hz, –OCH2CH=CH2), 5.27 (1H, δ: 30.5 (t), 78.1 (s), 116.3 (t), 120.5 (d), 127.5 (d), 127.6 (d),
ddt, J=10.5, 1.5, 1.4Hz, –CH=CHcisH), 5.38 (1H, ddt, J=17.3, 130.1(d), 135.8 (d), 138.0 (s), 138.3 (s), 143.3 (s); HR-MS m/z
1.6, 1.5Hz, –CH=CHtransH), 6.02 (1H, ddt, J=17.3, 10.5, Calcd for C25H22N2O (M+) 366.1732, Found 366.1728.
5.6Hz, –CH2CH=CH2), 7.07 (1H, s, pyrazole-H), 7.23 (1H, s,
11a: White powder; mp 120–121°C; IR (KBr) νmax 3436
1
pyrazole-H); 13C-NMR (75MHz, CDCl3) δ: 13.6, 19.8, 32.3, (OH), 1644, 1597 (C=C) cm−1; H-NMR (500MHz, CDCl3)
52.5, 72.6, 114.9, 117.9, 126.8, 133.4, 145.1; HR-MS m/z Calcd δ: 2.84 (2H, brd, J=6.3Hz, Ar-CH2CH=), 4.07 (1H, brs,
for C10H16N2O (M+) 180.1263, Found 180.1264.
OH), 4.94 (1H, dd, J=10.5, 1.4Hz, –CH=CHH), 4.97 (1H,
9e: Oil; IR (liquid film) νmax 1595 (C=C) cm−1; H-NMR dd, J=17.2, 1.4Hz, –CH=CHH), 5.07 (1H, ddt, J=17.2, 10.5,
(300MHz, CDCl3) δ: 1.64 (9H, s, –O–t-Bu), 4.44 (2H, d, 6.3Hz, –CH2CH=CH2), 7.13–7.15 (6H, m, Tr-H), 7.28 (1H, s,
J=5.4Hz, –OCH2CH=), 5.31 (1H, d, J=10.7Hz, –CH=CHH), pyrazole-H), 7.26–7.31 (9H, m, Tr-H); 13C-NMR (125MHz,
5.41 (1H, d, J=17.3Hz, –CH=CHH), 6.01 (1H, ddt, J=17.3, CDCl3) δ: 31.5 (t), 78.4 (s), 117.2 (t), 125.9 (s), 127.3 (d), 127.6
10.7, 5.4Hz, –CH2CH=CH2), 7.52 (1H, s, pyrazole-H), 7.63 (d), 130.0 (d), 132.9 (d), 141.2 (s), 143.0 (s); HR-MS m/z Calcd
(1H, s, pyrazole-H); 13C-NMR (75MHz, CDCl3) δ: 27.1, 27.6, for C25H22N2O (M+) 366.1732, Found 366.1729.
1
72.0, 84.8, 112.6, 118.0, 132.2, 134.9, 146.5; HRMS m/z Calcd
11b: Yellow powder; mp 75–78°C; IR (KBr) νmax 3111 (OH),
1
for C11H16N2O3 (M+) 224.1161, Found 224.1166.
1637 (C=C) cm−1; H-NMR (500MHz, CDCl3) δ: 3.23 (2H,
1
9f: Oil; IR (liquid film) νmax 1589 (C=C) cm−1; H-NMR ddd, J=5.9, 1.6, 1.4Hz, –OCH2CH=), 4.96 (1H, ddt, J=17.1,
(300MHz, CDCl3) δ: 2.42 (3H, s, ArCH3), 4.40 (2H, d, 1.6Hz, –CH=CHH), 5.02 (1H, ddt, J=10.3, 1.6, 1.4Hz, –CH=
J=5.4Hz, –OCH2CH=), 5.31 (1H, dd, J=10.4, 1.4Hz, –CH= CHH), 5.17 (2H, s, ArCH2Ph) 5.72 (1H, ddt, J=10.3, 17.1,
CHH) 5.38 (1H, dd, J=17.3, 1.4Hz, –CH=CHH), 5.96 (1H, 5.9Hz, –CH2CH=CH2), 6.99–7.02 (2H, m, Ph-H), 7.14 (1H, s,
ddt, J=17.3, 10.4, 5.4Hz, –CH2CH=CH2), 7.32 (2H, d, pyrazole-3-H), 7.20–7.27 (3H, m, Ph-H), 7.68 (1H, brs, OH);
J=8.3Hz, Ph-H), 7.52 (1H, s, pyrazole-H), 7.64 (1H, s, pyra- 13C-NMR (125MHz, CDCl3) δ: 27.0 (t), 53.6 (t), 116.5 (t), 126.6
zole-H), 7.85 (2H, d, J=8.3Hz, Ph-H); 13C-NMR (75MHz, (d), 127.6 (d), 127.9 (d), 128.6 (d), 133.5 (d), 136.9 (s), 139.1 (s)
CDCl3) δ: 21.6, 72.3, 113.6, 118.6, 127.8, 129.9, 132.0, 133.9, (a singlet carbon should be overlapped with a benzyl methine
136.8, 145.6, 146.9; HR-MS m/z Calcd for C13H14N2O3S (M+) at 126.6ppm since a signal at 126.6ppm correlated with CH2
278.0725, Found 278.0719.
at 3.23ppm in the HMBC spectrum); HR-MS m/z Calcd for
1
9g: Oil; IR (liquid film) νmax 1590 (C=C) cm−1; H-NMR C13H14N2O (M+) 214.1106, Found 214.1100.
(300MHz, CDCl3) δ: 3.26 (3H, s, –SO2CH3), 4.45 (2H, ddd,
3,5-Diallyl-2-benzyl-4-hydroxy-2H-pyrazole (12) White
J=5.4, 1.4, 1.3Hz, –OCH2CH=), 5.34 (1H, ddt, J=10.5, 1.4, powder; mp 55–58°C; IR (KBr) νmax 3079 (OH), 1639 (C=
1
1.3Hz, –CH=CHH), 5.42 (1H, ddt, J=17.4, 1.4, 1.3Hz, –CH= C) cm−1; H-NMR (500MHz, CDCl3) δ: 3.23 (2H, dt, J=6.0,
CHH), 6.00 (1H, ddt, J=17.4, 10.5, 5.4Hz, –CH2CH=CH2), 1.6Hz, –OCH2CH=), 3.44 (2H, dt, J=6.4, 1.6Hz, –OCH2CH=
7.59 (1H, s, pyrazole-H), 7.63 (1H, s, pyrazole-H); 13C-NMR ), 3.84 (1H, brs, OH), 5.03 (1H, ddt, J=17.1, 1.7, 1.6Hz,
(75MHz, CDCl3) δ: 40.9, 72.5, 113.4, 118.8, 132.1, 136.8, –CH=CHH), 5.08 (1H, ddt, J=10.1, 1.7, 1.6Hz, –CH=CHH),
146.7; HR-MS m/z Calcd for C7H10N2O3S (M+) 202.0412, 5.15 (1H, ddt, J=10.1, 1.8, 1.6Hz, –CH=CHH), 5.18 (2H, s,
Found 202.0414.
ArCH2Ph), 5.22 (1H, ddt, J=17.2, 1.8, 1.6Hz, –CH=CHH),
9h: Oil; IR (liquid film) νmax 1644 (C=C) cm−1; H-NMR 5.77 (1H, ddt, J=17.1, 10.1, 6.0Hz, –CH2CH=CH2), 6.06 (1H,
(300MHz, CDCl3) δ: 4.49 (2H, ddd, J=5.7, 1.5, 1.4Hz, ddt, J=17.2, 10.1, 6.4Hz, –CH2CH=CH2), 7.02–7.05 (2H, m,
–OCH2CH=), 5.37 (1H, dtd, J=10.4, 1.4, 1.3Hz, –CH=CHH), Ph-H), 7.23–7.31 (3H, m, Ph-H); 13C-NMR (125MHz, CDCl3)
5.43 (1H, dtd, J=17.3, 1.5, 1.3Hz, –CH=CHH), 5.99 (1H, ddt, δ: 27.5 (t), 30.5 (t), 53.6 (t), 116.3 (t), 116.8 (t), 126.5 (d), 127.5
J=17.3, 10.4, 5.7Hz, –CH2CH=CH2), 7.55 (1H, s, pyrazole-H), (d), 127.9, 128.6 (d), 133.4 (d), 135.6 (d), 136.6 (s), 137.3 (s),
7.81 (1H, s, pyrazole-H); 13C-NMR (75MHz, CDCl3) δ: 72.6, 137.5(s); HR-MS m/z Calcd for C16H18N2O (M+) 254.1419,
112.5, 114.4, 119.0 (q, JC–F=323.6Hz), 119.1, 131.4, 141.1, 148.2; Found 254.1418.
1
HR-MS m/z Calcd for C7H7F3N2O3S (M+) 256.0129, Found
256.0120.
10d: Oil; IR (liquid film) νmax 3081 (OH), 1639 (C=
C) cm−1; 1H-NMR (500MHz, CDCl3) δ: 0.88 (3H, t,
Claisen Rearrangement of 4-Allyloxy-1H-pyrazoles 9 J=7.6Hz, –NCH2CH2CH2CH3), 1.27 (2H, tq, J=7.7,
General Procedure under Microwave Irradiation (Table 1 7.6Hz, –NCH2CH2CH2CH3), 1.71 (2H, tt, J=7.7, 7.6Hz,
Entry 3) A sealed vial containing a solution of 9b (214mg, –NCH2CH2CH2CH3), 3.38 (2H, dt, J=6.0, 1.6Hz, ArCH2CH=
1.0mmol) in DEA (2.0mL) was heated at 190°C for 30min ), 3.91 (2H, t, J=7.6Hz, NCH2CH2CH2CH3), 5.02 (1H,
under microwave irradiation. After the reaction was quenched ddt, J=17.3, 1.6Hz, –CH=CHH), 5.08 (1H, ddt, J=10.0,
with NH4Cl aq., extraction was carried out with EtOAc. The 1.6Hz, –CH=CHH), 5.85 (1H, ddt, J=17.3, 10.0, 6.0Hz,
organic layer was washed with brine, dried over MgSO4, and –CH2CH=CH2), 7.07 (1H, s, pyrazole-3-H), 8.23 (1H, brs,
filtered. The solvent was removed under reduced pressure to OH); 13C-NMR (125MHz, CDCl3) δ: 13.6 (q), 19.8 (t), 27.0 (t),
give a crude residue that was subsequently purified by column 32.3 (t), 49.3 (t), 116.2 (t), 126.1 (s), 127.2 (d), 133.9 (d), 138.5

December 2012
1557
(s); HR-MS m/z Calcd for C10H16N2O (M+) 180.1262, Found CH2Cl2. The organic layer was washed with brine, dried over
180.1260.
MgSO4, and filtered. The solvent was removed under reduced
11d: Oil; IR (liquid film) νmax 3340 (OH) cm−1; pressure to give a crude residue that was subsequently purified
1H-NMR (500MHz, CDCl3) δ: 0.92 (3H, t, J=7.6Hz, by column chromatography (hexane–EtOAc=6:1) to afford 13
–NCH2CH2CH2CH3), 1.31 (2H, tq, J=7.6, 7.6Hz, (217mg, 87%). 13: White powder; mp 58–59°C; IR (KBr) νmax
1
–NCH2CH2CH2CH3),
1.76
(2H,
tt,
J=7.6,
7.3Hz, 1648 (C=C) cm−1; H-NMR (300MHz, CDCl3) δ: 3.43 (2H,
–NCH2CH2CH2CH3) 3.41 (2H, ddd, J=6.5, 1.6, 1.4Hz, ddd, J=6.4, 1.6, 1.6Hz, ArCH2–), 5.07 (1H, ddt, J=10.3, 1.6,
ArCH2CH=), 3.94 (2H, t, J=7.3Hz, NCH2CH2CH2CH3), 5.15 1.6Hz, –C=CHH), 5.08 (1H, ddt, J=16.9, 1.6, 1.6Hz, –C=
(1H, ddt, J=10.1, 1.8, 1.4Hz, –CH=CHH), 5.21 (1H, ddt, CHH), 5.91 (1H, ddt, J=16.9, 10.3, 6.4Hz, –CH=C), 7.11–7.15
J=17.2, 1.8, 1.6Hz, –CH=CHH), 6.04 (1H, ddt, J=17.2, 10.1, (6H, m, Tr-H), 7.29–7.34 (9H, m, Tr-H), 7.35 (1H, s, pyrazole-
6.5Hz, –CH2CH=CH2), 7.03 (1H, s, pyrazole-5-H); 13C-NMR 5-H); 13C-NMR (75MHz, CDCl3) δ: 29.7 (t), 79.4 (s), 116.6 (t),
1
(125MHz, CDCl3) δ: 13.6 (q), 19.8 (t), 30.3(t), 32.5 (t), 52.2 (t), 118.6 (q, JC–F=321.2Hz), 125.1 (d), 127.8 (d), 128.0 (d), 130.0
116.4 (t), 116.9 (d), 135.6 (d), 137.0 (s), 138.5 (s); HR-MS m/z (d), 130.4 (s), 133.7 (d), 142.1 (s), 142.3 (s); HR-MS m/z Calcd
Calcd for C10H16N2O (M+) 180.1262, Found 180.1258.
for C26H21F3N2O3S (M+) 498.1225, Found 498.1224.
10f: Brown powder; mp 120–122°C; IR (KBr) νmax 1643
3-(3-Hydroxy)propyl-4-trifluoromethanesulfonyloxy-2-
(C=C), 3133 (OH) cm−1; 1H-NMR (500MHz, CDCl3) δ: trityl-2H-pyrazole (14) To a solution of 13 (498mg, 1mmol)
2.40 (3H, s, ArCH3), 3.72 (2H, d, J=6.3Hz, ArCH2CH=), in THF (1mL) was added 9-BBN (244mg, 1mmol) at 0°C.
5.09 (1H, dd, J=17.2, 1.4Hz, –CH=CHH), 5.11 (1H, dd, After stirring for 2h at rt, MeOH (5mL) was added at 0°C to
J=10.3, 1.4Hz, –CH=CHH), 5.93 (1H, ddt, J=17.2, 10.3, quench the reaction. Then, 10% NaOH aq. (0.4mL, 1mmol)
6.3Hz, –CH2CH=CH2), 7.27 (2H, d, J=8.4Hz, Ph-H), 7.42 and 30% H2O2 aq. (0.42mL, 3.7mmol) were added at 0°C.
(1H, s, pyrazole-H), 7.77 (2H, d, J=8.4Hz, Ph-H); 13C-NMR After stirring at rt for 20h, the reaction was quenched with
(125MHz, CDCl3) δ: 21.6, 28.0, 117.4, 127.8, 128.4, 129.9, NH4Cl aq. and extraction was carried out with CH2Cl2. The
133.2, 134.5, 136.6, 141.2, 145.5; HR-MS m/z Calcd for organic layer was washed with brine, dried over MgSO4, and
C13H14N2O3S (M+) 278.0725, Found 278.0720.
filtered. The solvent was removed under reduced pressure to
11f: White powder; mp 138–139°C; IR (KBr) νmax 3133 give a crude residue that was subsequently purified by column
1
(OH), 1644, 1598 (C=C) cm−1; H-NMR (500MHz, CDCl3) chromatography (hexane–EtOAc=3:1) to afford 14 (449mg,
δ: 2.41 (3H, s, ArCH3), 3.39 (2H, ddd, J=6.6, 1.5, 1.4Hz, 87%). 14: Colorless oil; IR (liquid film) νmax 3376 (OH),
1
ArCH2CH=), 5.13 (1H, ddt, J=17.4, 1.5Hz, –CH=CHH), 1495 (C=C) cm−1; H-NMR (300MHz, CDCl3) δ: 1.85 (2H,
5.14 (1H, ddt, J=9.8, 1.5, 1.4Hz, –CH=CHH), 5.93 (1H, ddt, tt, J=6.2, 6.9Hz, –CH2CH2CH2OH), 2.75 (2H, t, J=6.9Hz,
J=17.4, 9.8, 6.6Hz, –CH2CH=CH2), 7.29 (2H, brd, J=8.5Hz, –CH2CH2CH2OH), 3.52 (2H, t, J=6.2Hz, –CH2CH2CH2OH),
Ph-H), 7.60 (1H, s, pyrazole-5-H), 7.82 (2H, brd, J=8.5Hz, 7.10–7.13 (6H, m, Tr-H), 7.28–7.33 (9H, m, Tr-H), 7.40 (1H,
Ph-H); 13C-NMR (125MHz, CDCl3) δ: 21.7 (q), 30.4 (t), 116.6 s, pyrazole-H); 13C-NMR (75MHz, CDCl3) δ: 21.5, 30.3,
(t), 117.7 (d), 127.8 (d), 130.0 (d), 133.5 (d), 134.2 (s), 141.8 (s), 61.6, 79.5, 118.5 (q, JC–F=321.3Hz), 125.0, 127.9, 128.0, 129.9,
145.4 (s), 147.7 (s); HR-MS m/z Calcd for C13H14N2O3S (M+) 130.1, 142.1, 143.7; HR-MS m/z Calcd for C26H23F3N2O4S (M+)
278.0725, Found 278.0722.
516.1331, Found 516.1334.
11g: Oil; IR (liquid film) νmax 3375 (OH), 1642, 1595
3-(3-Toluenesulfonyloxy)propyl-4-trifluoromethanesulfo-
(C=C), cm−1; 1H-NMR (500MHz, CDCl3) δ: 3.13 (3H, s, nyloxy-2-trityl-2H-pyrazole (15) To a solution of 14 (124
–SO2CH3), 3.48 (2H, ddd, J=6.5, 1.5, 1.4Hz, ArCH2CH=), mg, 0.24mmol) in CH2Cl2 (2mL) with triethylamine (70µL,
5.20 (1H, ddt, J=10.7, 1.7, 1.5Hz, –CH=CHH), 5.23 (1H, ddt, 0.48mmol) was added p-toluenesulfonylchloride (97mg,
J=17.2, 1.7, 1.4Hz, –CH=CHH), 5.96 (1H, ddt, J=17.2, 10.7, 0.48mmol) at rt. After stirring for 24h, the reaction was
6.5Hz, –CH2CH=CH2), 7.61 (1H, s, pyrazole-H); 13C-NMR quenched with NH4Cl aq. and extraction was carried out
(125MHz, CDCl3) δ: 28.4, 36.6, 117.6, 127.1, 130.4, 133.2, with CH2Cl2. The organic layer was washed with brine, dried
137.5; HR-MS m/z Calcd for C7H10N2O3S (M+) 202.0412, over MgSO4, and filtered. The solvent was removed under re-
Found 202.0414.
duced pressure to give a crude residue that was subsequently
Procedure for Heating in a Sealed Tube (Table 1 Entry purified by column chromatography (hexane–EtOAc=3:1)
1) A sealed tube containing a solution of 9a (4.0g, 11mmol) to afford 15 (150mg, 93%). 15: Colorless needles (CH2Cl2);
in DEA (44mL) was heated at 190°C for 1h in an oil bath. mp 66–70°C; IR (KBr) νmax 1598 (C=C), 1492 (C=C) cm−1;
After the reaction was quenched with NH4Cl aq., extraction 1H-NMR (300MHz, CDCl3) δ: 2.00 (2H, tt, J=6.8, 7.1Hz,
was carried out with EtOAc. The organic layer was washed –CH2CH2CH2OTs), 2.40 (3H, s, ArCH3), 2.66 (2H, t, J=7.1Hz,
with brine, dried over MgSO4, and filtered. The solvent was –CH2CH2CH2OTs), 4.03 (2H, t, J=6.8Hz, –CH2CH2CH2OTs),
removed under reduced pressure to give a crude residue 7.05–7.12 (6H, m, Ar-H), 7.25–7.36 (12H, m, Ar-H), 7.72–7.75
that was subsequently purified by column chromatography (2H, m, Ar-H); 13C-NMR (75MHz, CDCl3) δ: 20.8, 21.5, 26.9,
1
(hexane–EtOAc=2:1) to afford 3-allyl-4-hydroxy-2-trityl-2H- 69.5, 79.4, 118.5 (q, JC–F=321.3Hz), 125.0, 125.1, 127.1, 127.7,
pyrazole (11a) (2.36g, 59%) and 3-allyl-4-hydroxy-1-trityl-1H- 127.75, 127.80, 128.0, 129.7, 129.9, 133.0, 142.16, 142.23, 144.6;
pyrazole (10a) (120mg, 3%).
3-Allyl-4-trifluoromethanesulfonyloxy-2-trityl-2H-pyra- 670.1417.
HR-MS m/z Calcd for C33H29F3N2O6S2 (M+) 670.1419, Found
zole (13) To a solution of 11a (183mg, 0.5mmol) in CH2Cl2
5,6-Dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl
Trifluoro-
(2mL) with triethylamine (90µL, 0.6mmol) was added tri- methanesulfonate (16) To
a
solution of 15 (150mg,
fluoromethanesulfonic anhydride (100µL, 0.6mmol) at −20°C. 0.22mmol) in EtOH (2mL) was added 1N HCl aq. (4mL,
After stirring for 30min at that temperature, the reaction was 4mmol). After stirring for 18h at 80°C, the reaction was
quenched with NH4Cl aq. and extraction was carried out with quenched with NaHCO3 aq. and extraction was carried out

1558
Vol. 60, No. 12
with CH2Cl2. The organic layer was washed with brine, dried –CH2CH2CH2–), 3.07 (2H, t, J=7.7Hz, ArCH2CH2–), 3.82
over MgSO4, and filtered. The solvent was removed under (3H, s, –OCH3), 4.17 (2H, t, J=7.2Hz, –NCH2CH2–), 6.92 (2H,
reduced pressure to give a crude residue that was subse- d, J=8.4Hz, Ph-H), 7.37 (2H, d, J=8.4Hz, Ph-H), 7.74 (1H, s,
quently purified by column chromatography (CH2Cl2) to af- pyrazole-H); 13C-NMR (75MHz, CDCl3) δ: 23.7, 26.4, 47.5,
ford 16 (23mg, 40%). 16: Colorless oil; IR (liquid film) νmax 55.3, 114.3, 115.0, 126.1, 126.2, 140.6, 141.9, 157.7; HR-MS m/z
1
1541 (C=C) cm−1; H-NMR (300MHz, CDCl3) δ: 2.65 (2H, Calcd for C13H14N2O (M+) 214.1106, Found 214.1106.
tt, J=7.7, 7.4Hz, –CH2), 3.00 (2H, t, J=7.7Hz, –CH2), 4.17
1d: Colorless crystals (CH2Cl2); mp 162–165°C; IR
(2H, t, J=7.4Hz, –CH2), 7.45 (1H, s, pyrazole-H); 13C-NMR (KBr) νmax 3079 (OH), 1593 (C=C), 1504 (C=C) cm−1;
1
(75MHz, CDCl3) δ: 22.4, 25.6, 48.7, 118.5 (q, JC–F=321.3Hz), 1H-NMR (300MHz, CD3OD) δ: 2.71 (2H, quint, J=7.2Hz,
127.3, 134.6, 136.7; HR-MS m/z Calcd for C7H7F3N2O3S (M+) –CH2CH2CH2–), 3.11 (2H, t, J=7.2Hz, ArCH2CH2–), 4.14 (2H,
256.0129, Found 256.0132.
t, J=7.5Hz, –NCH2CH2–), 4.73 (1H, s, –OH), 6.68 (1H, brd,
Suzuki–Miyaura Coupling of 16 and Arylboronic Acids J=7.8Hz, Ph-H), 6.94 (1H, s, Ph-H), 6.65 (1H, d, J=7.8Hz,
into Withasomnines 1a–l
Ph-H), 7.19 (1H, t, J=7.8Hz, Ph-H), 7.76 (1H, s, pyrazole-H);
Suzuki–Miyaura Coupling by Conventional Heating 13C-NMR (75MHz, CD3OD) δ: 23.0, 25.6, 46.7, 111.1, 112.2,
(Table 2 Entry 1) To a solution of 16 (48mg, 0.19mmol) 114.9, 115.8, 129, 133.7, 139.8, 142.7, 156.7; HR-MS m/z Calcd
in 1,2-diethoxyethane (DME) (1.0mL) and H2O (1.0mL) for C12H12N2O (M+) 200.0949, Found 200.0947.
were added phenylboronic acid (46mg, 0.38mmol), Pd(dba)2
1e: Colorless crystals (CH2Cl2); mp 84–85°C; IR (KBr)
(3.0mg, 10mol%), tricyclohexylphosphine (20mg, 40mol%), νmax 1551 (C=C), 1484 (C=C) cm−1; 1H-NMR (300MHz,
and NaCO3 (40mg, 0.38mmol). The reaction mixture was CDCl3) δ: 2.37 (3H, s, ArCH3), 2.66 (2H, tt, J=7.4, 7.2Hz,
heated at 100°C for 24h with stirring. Then, the reaction mix- –CH2CH2CH2–), 2.93 (2H, t, J=7.4Hz, ArCH2CH2–), 4.21
ture was extracted with EtOAc. The organic layer was washed (2H, t, J=7.2Hz, –NCH2CH2–), 7.15–7.28 (4H, m, Ph-H), 7.60
with brine, dried over MgSO4, and filtered. The solvent was (1H, s, pyrazole-H); 13C-NMR (75MHz, CDCl3) δ: 20.9, 23.6,
removed under reduced pressure to give a crude residue 26.5, 47.7, 115.1, 125.8, 126.5, 129.3, 130.5, 132.8, 135.6, 143.1,
that was subsequently purified by column chromatography 143.7; HR-MS m/z Calcd for C13H14N2 (M+) 198.1157, Found
(CH2Cl2–Et2O=1:1) to afford 1a (7.0mg, 20%).
General Procedure for Suzuki–Miyaura Coupling
198.1153.
1f: Colorless crystals (CH2Cl2); mp 130–132°C; IR
under Microwave Irradiation (Table 2 Entry 10=Table 3 (KBr) νmax 1583 (C=C), 1560 (C=C), 1525 (NO2) cm−1;
Entry 1) To a solution of 16 (10.3mg, 0.04mmol) in DME 1H-NMR (300MHz, CDCl3) δ: 2.74 (2H, tt, J=7.2, 6.9Hz,
(1.8mL) and H2O (0.2mL) in a vial for microwave irradiator –CH2CH2CH2–), 3.16 (2H, t, J=6.9Hz, ArCH2CH2–), 4.22
were added phenylboronic acid (9.8mg, 0.08mmol), Pd(dba)2 (2H, t, J=7.2Hz, –NCH2CH2–), 7.51 (1H, t, J=8.1Hz, Ph-H),
(2.3mg, 10mol%), tricyclohexylphosphine (4.6mg, 40mol%), 7.75 (1H, ddd, J=8.1, 1.5, 0.9Hz, Ph-H), 7.88 (1H, br s, pyra-
Na2CO3 (9.5mg, 0.086mmol), and TOMAC (1 drop, 8mg). zole-H), 8.02 (1H, ddd, J=8.1, 2.4, 0.9Hz, Ph-H), 8.25 (1H,
The reaction vial was filled with nitrogen gas, sealed, and then dd, J=2.4, 1.5Hz, Ph-H); 13C-NMR (75MHz, CDCl3) δ: 23.9,
heated at 130°C for 30min under microwave irradiation. After 26.3, 47.7, 113.4, 119.3, 120.2, 129.7, 130.5, 135.2, 141.0, 143.4,
cooling, the reaction mixture was extracted with EtOAc. The 148.7; HR-MS m/z Calcd for C12H11N3O2 (M+) 229.0851, Found
organic layer was washed with brine, dried over MgSO4, and 229.0849.
filtered. The solvent was removed under reduced pressure to
1g: Colorless crystals (CH2Cl2); mp 145–148°C; IR
give a crude residue that was subsequently purified by column (KBr) νmax 3433 (NH2), 1608 (C=C), 1587 (C=C) cm−1;
chromatography (CH2Cl2–Et2O=1:1) to afford 1a (6.5mg, 1H-NMR (300MHz, CDCl3) δ: 2.66 (2H, quint, J=7.4Hz,
88%).
–CH2CH2CH2–), 3.07 (2H, t, J=7.4Hz, ArCH2CH2–), 4.15
1a: Colorless crystals (CH2Cl2); mp 112–113°C (lit.1b) (2H, t, J=7.34Hz, –NCH2CH2–), 6.54 (1H, brd, J=7.8Hz,
117–118°C); IR (KBr) νmax 1606 (C=C), 1501 (C=C) cm−1; Ph-H), 6.78 (1H, brs, Ph-H), 6.85 (1H, brd, J=7.8Hz, Ph-H),
1H-NMR (300MHz, CDCl3) δ: 2.69 (2H, tt, J=7.7, 7.2Hz, 7.14 (1H, t, J=7.8Hz, Ph-H), 7.77 (1H, s, pyrazole-H);
–CH2CH2CH2–), 3.10 (2H, t, J=7.7Hz, ArCH2CH2–), 4.18 (2H, 13C-NMR (75MHz, CDCl3) δ: 23.8, 26.3, 47.5, 111.6, 112.6,
t, J=7.2Hz, –NCH2CH2–), 7.16–7.47 (5H, m, Ph-H), 7.82 (1H, 115.3, 115.6, 129.7, 134.3, 140.9, 142.6, 146.7; HR-MS m/z
s, pyrazole-H); 13C-NMR (75MHz, CDCl3) δ: 23.8, 26.4, 47.6, Calcd for C12H13N3 (M+) 199.1109, Found 199.1113.
115.3, 125.0, 125.6, 128.8, 133.4, 140.9, 142.6; HR-MS m/z
1h: Colorless crystals (CH2Cl2); mp 90–93°C; IR
Calcd for C12H12N2 (M+) 184.1000, Found 184.0998.
(KBr) νmax 1573 (C=C), 1502 (C=C), 1488 (C=C) cm−1;
1b: Colorless crystals (CH2Cl2); mp 225–229°C; IR (KBr) 1H-NMR (300MHz, CDCl3) δ: 2.67 (2H, quint, J=7.2Hz,
νmax 3401 (OH), 1570 (C=C), 1515 (C=C) cm−1; 1H-NMR –CH2CH2CH2–), 3.05 (2H, t, J=7.2Hz, ArCH2CH2–), 3.82
(300MHz, CDCl3–CD3OD=1:1) δ: 2.53 (2H, tt, J=7.5, 7.2Hz, (3H, s, –OCH3), 4.16 (2H, t, J=7.2Hz, –NCH2CH2–), 5.95
–CH2CH2CH2–), 2.90 (2H, t, J=7.2Hz, ArCH2CH2–), 3.16 (2H, s, –OCH2O–), 6.81 (2H, d, J=8.1Hz, Ph-H), 6.90 (1H, d,
(1H, brs, –OH), 3.96 (2H, t, J=7.5Hz, –NCH2CH2–), 6.65 J=8.1Hz, Ph-H), 6.92 (1H, s, Ph-H), 7.71 (1H, s, pyrazole-H);
(2H, d, J=8.3Hz, Ph-H), 7.12 (2H, d, J=8.3Hz, Ph-H), 7.51 13C-NMR (75MHz, CDCl3) δ: 23.7, 26.4, 47.5, 100.9, 105.8,
(1H, s, pyrazole-H); 13C-NMR (75MHz, CDCl3–CD3OD= 108.7, 115.2, 118.2, 127.6, 140.6, 142.1, 145.5, 148.0; HR-MS
1:1) δ: 22.9, 25.7, 46.7, 115.0, 115.0, 124.0, 125.7, 139.4, 141.9, m/z Calcd for C13H12N2O2 (M+) 228.0899, Found 228.0900.
154.7; HR-MS m/z Calcd for C12H12N2O (M+) 200.0949, Found
200.0955.
1i: Colorless crystals (CH2Cl2); mp 92–95°C; IR
(KBr) νmax 1567 (C=C), 1508 (C=C), 1509 (C=C) cm−1;
1c: Colorless crystals (CH2Cl2); mp 124–128°C; IR 1H-NMR (300MHz, CDCl3) δ: 2.69 (2H, quint, J=7.2Hz,
(KBr) νmax 1577 (C=C), 1565 (C=C), 1509 (C=C) cm−1; –CH2CH2CH2–), 3.07 (2H, t, J=7.2Hz, ArCH2CH2–), 4.17
1H-NMR (300MHz, CDCl3) δ: 2.68 (2H, tt, J=7.7, 7.2Hz, (2H, t, J=7.2Hz, –NCH2CH2–), 7.05 (2H, br t, J=8.7Hz, H-3′,

December 2012
1559
Chemistry,” Vol. 2, ed. by Alvarez-Builla J., Vaquero J. J., Barluen-
ga J., Wiley-VCH Verlag, Weinheim, Germany, 2011, pp. 651–678.
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Yakugaku Zasshi, 127 (Suppl. 2), 51 (2007).
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2247–2252 (2006).
11) Ichikawa H., Nishioka M., Arimoto M., Usami Y., Heterocycles, 81,
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H-5′), 7.39 (2H, brdd, J=8.7, 5.4Hz, H-2′, H-6′), 7.76 (1H, s,
pyrazole-H); 13C-NMR (75MHz, CDCl3) δ: 23.7, 26.4, 47.6,
2
3
114.5, 115.6 (d, JC–F=21.8Hz), 126.4 (d, JC–F=8.0Hz), 129.5,
1
140.8, 142.4, 161.0 (d, JC–F=244.4Hz); HR-MS m/z Calcd for
C12H11FN2 (M+) 202.0906, Found 202.0908.
1j: Colorless crystals (CH2Cl2); mp 82–85°C; IR (KBr) νmax
1
1593 (C=C), 1498 (C=C) cm−1; H-NMR (300MHz, CDCl3)
δ: 2.68 (2H, tt, J=7.7, 7.2Hz, –CH2CH2CH2–), 3.03 (2H, t,
J=7.7Hz, ArCH2CH2–), 3.82 (3H, s, –OCH3), 4.17 (2H, t,
J=7.2Hz, –NCH2CH2–), 6.98–7.04 (2H, m, thienyl-H), 7.14
(1H, dd, J=5.1, 1.5Hz, thienyl-H), 7.71 (1H, s, pyrazole-H);
13C-NMR (75MHz, CDCl3) δ: 23.2, 26.3, 47.8, 109.9, 121.3,
122.2, 127.5, 136.0, 140.8, 142.5; HR-MS m/z Calcd for
C10H10N2S (M+) 190.0565, Found 190.0557.
1k: Colorless crystals (CH2Cl2); mp 62–64°C; IR (KBr) νmax
1
1595 (C=C), 1493 (C=C) cm−1; H-NMR (300MHz, CDCl3)
δ: 2.69 (2H, quint, J=7.2Hz, –CH2CH2CH2–), 3.06 (2H, t,
J=7.2Hz, ArCH2CH2–), 4.17 (2H, t, J=7.2Hz, –NCH2CH2–),
7.14 (1H, dd, J=3.0, 1.2Hz, thienyl-H), 7.21 (1H, dd, J=5.1,
1.2Hz, thienyl-H), 7.35 (1H, dd, J=5.1, 3.0Hz, thienyl-H),7.73 14) Penning T. D., Talley J. J., Bertenshaw S. R., Carter J. S., Collins P.
(1H, s, pyrazole-H); 13C-NMR (75MHz, CDCl3) δ: 23.3, 26.4,
W., Docter S., Graneto M. J., Lee L. F., Malecha J. W., Miyashiro J.
M., Rogers R. S., Rogier D. J., Yu S. S., AndersonGD, Burton E. G.,
Cogburn J. N., Gregory S. A., Koboldt C. M., Perkins W. E., Seibert
K., Veenhuizen A. W., Zhang Y. Y., Isakson P. C., J. Med. Chem.,
47.7, 111.3, 117.2, 125.7, 125.9, 134.0, 141.1, 142.6; HR-MS m/z
Calcd for C10H10N2S (M+) 190.0565, Found 190.0559.
1l: Oil; IR (liq. film) νmax 1660 (C=C), 1548 (C=C) cm−1;
40, 1347–1365 (1997).
1H-NMR (300MHz, CDCl3) δ: 2.66 (2H, m, –CH2CH2CH2–),
15) Maynadier M., Basile I., Gary-Bobo M., Drug Discov. Today, 14,
3.04 (2H, m, ArCH2CH2–), 4.16 (2H, t, J=7.2Hz,
–NCH2CH2–), 6.21 (1H, dd, J=3.3, 0.9Hz, furyl-H), 6.41 (1H,
192–197 (2009).
16) Tolf B.-R., Piechaczek J., Dahlbom R., Theorell H., Åkeson Å.,
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dd, J=3.3, 1.8Hz, furyl-H), 7.35 (1H, dd, J=1.8, 0.9Hz, furyl-
H), 7.72 (1H, s, pyrazole-H); 13C-NMR (75MHz, CDCl3) δ:
23.1, 26.3, 47.7, 76.6, 102.5, 111.0, 140.0, 140.3, 142.4, 148.8;
HR-MS m/z Calcd for C10H10N2O (M+) 174.0780, Found
174.0787.
(1990).
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Pharmazie, 26, 361–364 (1971).
5,6-Dihydro-5-hydroxy-4H-pyrrolo[1,2-b]pyrazole (17)
Colorless crystals (CH2Cl2); mp 137–140°C; IR (KBr) νmax
1
3042 (OH), 1604 (C=C) cm−1; H-NMR (500MHz, CDCl3)
δ: 2.55 (2H, m, –CH2CH2CH2–), 2.84 (2H, brt, J=7.3Hz,
ArCH2CH2–), 4.05 (2H, brdd, J=7.3, 7.1Hz, –NCH2CH2–),
7.17 (1H, s, pyrazole-H); 13C-NMR (125MHz, CDCl3) δ: 21.9
(t), 26.4 (t), 48.1 (t), 131.8 (s), 132.6 (d), 134.4 (s); HR-MS m/z
Calcd for C6H8N2O (M+) 124.0637, Found 124.0634.
Biological Assay50) The biological assay for the inhibitory
activity of 1a–l against COX-1 and COX-2 was carried out
with a COX Fluorescent Activity Assay Kit (Cayman Chemi-
cal) following the instructions included in the kit.
26) Zubek A., Pharmazie, 24, 382–384 (1969).
27) Morimoto A., Noda K., Watanabe T., Takasugi H., Tetrahedron
Lett., 9, 5707–5710 (1968).
28) Onaka T., Tetrahedron Lett., 9, 5711–5714 (1968).
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(1982).
30) Ranganathan D., Bamezai S., Synth. Commun., 15, 259–265 (1985).
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Acknowledgments We are grateful to Ms. M. Fujitake of
this University for MS measurement and Professor M. Ari-
moto for continuous encouragement. We also thank Y. Suzuki
and M. Ohno of our laboratory for technical support. This
work was supported in part by a Grant-in-Aid for the “High-
Tech Research Center” Project for Private Universities: match-
ing fund subsidy from MEXT (Ministry of Education, Cul-
ture, Sports, Science and Technology), 2006–2009, Japan and
the Lonza Japan Award 2009 in Synthetic Organic Chemistry,
Japan to H. I.
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Experiment: To
a
solution of 1-benzyl-1H-pyrazole (316mg,
2.0mmol) in CCl4 (2.0mL) were added acetic anhydride (0.95mL,
10mmol) and SnCl2 (4.13g, 10mmol) at tR. After stirring overnight
under reflux, the reaction mixture was treated with water and
extracted with CH2Cl2. The organic layer was washed with brine,
dried over MgSO4, and filtered. The solvent was removed under
reduced pressure to give a crude residue that was subsequently
purified by column chromatography (hexane–EtOAc=2:1) to afford
4-acetyl-1H-1-benzylpyrazole (95.0mg, 22%). 4-Acetyl-1H-1-ben-
zylpyrazole: Yellow oil; IR (liquid film) νmax 1757 (C=O), 1561
1
(C=C) cm−1; H-NMR (300 MHz, CDCl3): δ: 2.41 (3H, s, CH3CO–),
5.31 (2H, s, PhCH2Ar), 7.24–7.28 (2H, m, Ph-H), 7.34–7.39 (3
H, m, Ph-H), 7.85 (1H, s, pyrazole-H), 7.94 (1H, s, pyrazole-H);
13C-NMR (75MHz, CDCl3): δ: 20.7, 56.6, 120.0, 127.6, 128.1, 128.7,
130.2, 132.3, 136.0, 167.6; HR-MS m/z Calcd for C12H12N2O2 (M+)
216.0899, Found 216.0894.
44) Our early effort of the Friedel–Crafts acylation of 1-benzyl-1H- 45) Ichikawa H., Usami Y., Arimoto M., Tetrahedron Lett., 46, 8665–
pyrazole with acetylchloride or acetic anhydride in the presence
of various kinds of metal chloride as Lewis acid catalyst was not
successful. One hopeful example was the reaction with acetic an-
hydride (2.0eq) carried out in the presence of tin chloride (5.0eq)
under refluxing CCl4 overnight to produce desired 4-acetylated
product in 22% yield as shown below. However, this reaction is
impractical due to the low chemical yield and the use of a large
amount of toxic tin chloride. These disappointing results in our
earlier efforts pushed us to examine alternative methods for the
synthesis of 4-acylated-1H-pyrazoles.
8668 (2005).
46) Sugiura S., Ohno S., Hori M., Yakugaku Zasshi, 101, 271–274
(1981).
47) Hwang K.-J., Yu C.-M., Gong Y.-D., Park K.-H., Heterocycles, 36,
1375–1380 (1993).
48) The Suzuki–Miyaura coupling of 13 and phenylboronic acid did not
give the desired product under various conditions but yielded 11a in
our earlier examination.
49) Sawyer J. S., Beight D. W., Britt K. S., Anderson B. D., Campbell
R. M., Goodson T. Jr., Herron D. K., Li H.-Y., McMillen W. T.,
Mort N., Parsons S., Smith E. C. R., Wagner J. R., Yan L., Zhang F.,
Yingling J. M., Bioorg. Med. Chem. Lett., 14, 3581–3584 (2004).
50) Sato I., Kofujita H., Tsuda S., J. Vet. Med. Sci., 69, 709–712 (2007).