Divergent synthesis of withasomnines via synthesis of 4-hydroxy-1H- pyrazoles and Claisen rearrangement of their 4-O-allylethers

Article abstract of DOI:10.1016/j.tetlet.2011.06.061

4-Hydroxypyrazoles were synthesized by the alkaline hydrolysis of the Baeyer-Villiger oxidation products of 4-formylpyrazoles. This new synthesis of 4-hydroxypyrazoles was applied to the divergent synthesis of withasomnine alkaloids in a unique strategy, for which the key steps included the regioselective Claisen rearrangement of their 4-O-allyl-4-hydroxy-1H-pyrazoles and a Suzuki coupling of 4-trifluoromethanesulfonyloxy-1H-pyrazoles and arylboronic acids.

Full text of DOI:10.1016/j.tetlet.2011.06.061

Tetrahedron Letters 52 (2011) 4448–4451
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Divergent synthesis of withasomnines via synthesis of 4-hydroxy-1H-
pyrazoles and Claisen rearrangement of their 4-O-allylethers
Hayato Ichikawa a,b, , Ryo Watanabe a, Yuiko Fujino a, Yoshihide Usami a,
⇑
⇑
a Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka 569 1094, Japan
b College of Industrial Technology, Nihon University, 1-2-1 Izumi-cho, Narashino, Chiba 275 8575, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
4-Hydroxypyrazoles were synthesized by the alkaline hydrolysis of the Baeyer–Villiger oxidation prod-
ucts of 4-formylpyrazoles. This new synthesis of 4-hydroxypyrazoles was applied to the divergent
synthesis of withasomnine alkaloids in a unique strategy, for which the key steps included the regiose-
lective Claisen rearrangement of their 4-O-allyl-4-hydroxy-1H-pyrazoles and a Suzuki coupling of 4-trif-
luoromethanesulfonyloxy-1H-pyrazoles and arylboronic acids.
Received 16 May 2011
Revised 8 June 2011
Accepted 17 June 2011
Available online 23 June 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Withasomnine
Pyrazole
Claisen rearrangement
Suzuki coupling
Withasomnine (1) was originally isolated in 1966 from the root
bark of Withania somnifera (Solanaceae), which is distributed
around India and Africa ( Fig. 1).1 Withasomnine 1 exhibited a
depression of the CNS and circulatory systems, a mild analgesic
effect, and the inhibition of TBL4, COX-1 and COX-2.2 There have
been several reports of the synthesis of 1.3 Recently, Harrity et al.
reported the divergent synthesis of 1–3 via a key step involving
sydnone-alkynylboronate cycloaddition.3f
Pyrazoles are important heterocyclic compounds that take part
in various kinds of bioactivities.4 The synthesis of substituted or
functionalized pyrazoles has been studied extensively. However,
most pyrazoles are made up of a pyrazole ring from the condensa-
tion of 1,3-diketones and hydrazines and/or the 2+3 cycloaddition.
The synthetic challenge of the direct functionalization of pyrazoles
has been scarcely reported. Our interest is the direct functionaliza-
tion of pyrazoles at C-4, since the novel binuclear platinum complex
bearing C-4 alkylpyrazoles as ligands has exhibited an enhanced
anticancer activity against cisplatin-resistant human cancer cell
lines.5 We have reported the cross coupling reaction of halopyraz-
oles to produce 4-arylpyrazoles, 4-vinylpyrazoles and 2H-inda-
zoles.6 The study of 4-substituted pyrazoles heightened our
interest in the synthesis of 4-hydroxypyrazoles. Almost no report
exists on the synthesis of 4-hydroxypyrazoles despite its impor-
tance and interesting bioactivities such as the inhibition of several
kinds of CYP-enzymes and the induction of CYP2E1. Therefore, the
establishment of a synthetic method to produce 4-hydroxypyrazole
would be significant to synthetic organic chemistry.
In the course of continuous study into the total synthesis of
small, natural products and their analogues,7 our group began
work on the divergent synthesis of withasomnines 1–3. Herein is
a description of that study based on the synthesis of 4-hydroxypy-
razoles following the Claisen rearrangement of 4-O-allyl ether.
1-Substituted-4-iodopyrazoles 6 prepared from pyrazole (4) via
4-iodopyrazole (5), as with previous work,6a,d were reacted with
isopropylmagnesium chloride for halogen-metal exchange
(Scheme 1). After 1 h, N,N-dimethylformamide (DMF) was added
to the reaction mixture as a formylating reagent to afford 4-form-
ylpyrazoles 7. Baeyer–Villiger oxidation of 7b with 30% aqueous
hydrogen peroxide using catalytic 2-trifluoromethansulfonylben-
⇑
Corresponding authors.
E-mail address: ichikawa.hayato64@nihon-u.ac.jp (H. Ichikawa).
Figure 1. Withasomnines.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.06.061

H. Ichikawa et al. / Tetrahedron Letters 52 (2011) 4448–4451
4449
Scheme 1. The synthesis of 4-hydroxy-1-substitutedpyrazoles 10 and allyl ether 11.
zeneseleninic acid (8), which was developed in previous work,8
gave a reaction mixture containing formates 9. The following alka-
line hydrolysis of the mixture with aqueous NaOH under reflux
afforded the desired 4-hydroxypyrazoles 10b in a 61% yield in
two steps. The resulting 10b was reacted with allyl bromide to give
allyl ether 11b in a 99% yield. Similarly, 7a was applied to the one-
pot sequence oxidation-hydrolysis-O-allylation to give allyl ether
11a via 9a and 10a in a 75% yield in three steps. At this point, more
analogues, 11d–f, were also prepared from 11a via deprotected 11c
shown in Scheme 2, using for examination of regioselectivity in the
following Claisen rearrangement.
Previously, regioselectivity of the Claisen rearrangement on 3-
substituted-5-hydroxypyrazoles was reported by Hori9 and
Hwang,10 independently. But in this case, 4-allyloxypyrazoles
11 had two possibilities for a regioselective Claisen rearrange-
ment. It seemed efficient to control regioselectivity in the Clais-
en rearrangement of 11 depending on the protective group at
the 1-position (N1) of pyrazole. The results of a Claisen rear-
rangement of various 4-allyloxypyrazoles 11 under microwave
irradiation are summarized in Table 1. All entries exhibited a
high preference toward the C5-allylated product 12 contrary to
Scheme 2. The synthesis of various 4-allyloxy-1-substituted pyrazoles.
our prediction. It was interesting that only in the case of 11b
was a small amount of 3,5-diallyl-1-benzyl-5-hydroxypyrazole
(14) obtained along with the major product 12b. The structures
of all rearranged products 12–14 were determined by NOESY
analysis.
Table 1
Claisen rearrangement of 4-allyoxypyrazoles 11a
Entry
R
Time (min)
Yieldc (%)
12
13
14
1
Tr (11a)
Tr (11a)
Bn (11b)
n-Bu (11d)
Ts (11e)
Ms (11f)
60
60
30
60
30
60
61
59
92
84
65
68
3
3
0
2
0
0
2
0
0
0
2
3b
4
5
6
20
Trace
a
B
C
MW irradiation took place under a sealed vessel.
With conventional heating.
Isolated yield, MW: microwave, DEA: diethylaniline, a = Tr, b = Bn, c = H, d = n-Bu, e = Ts, f = Ms.

4450
H. Ichikawa et al. / Tetrahedron Letters 52 (2011) 4448–4451
Scheme 4. Divergent synthesis of 1–3.
9-BBN and gave 16 in an 87% yield. The resultant 16 was treated
with p-toluenesulfonylchloride and triethylamine to give tosylate
17 in
a 93% yield, which was then cyclized into 3-trif-
luoromethanesulfonyloxy-5,6-dihydro-4H-pyrroro[1,2-b]pyrazole
18 in a 40% yield under acidic reflux (Scheme 3).
The final step in this total synthesis of 1 is the Suzuki coupling
between triflate 18 and phenylboronic acid. Various reaction con-
ditions were examined and the results are summarized in Table
2. Using 1,2-dimethoxyethane (DME)–H2O as a solvent was found
to be effective, similar to Harrity’s work.3f Reaction time was short-
ened to 30 min under microwave irradiation at 130 °C, as shown in
the literature. The remaining two natural withasomnines 2 and 3
could also be prepared using commercially available 4-methoxy-
phenyl- and 4-hydroxyphenylboronic acids, respectively (Scheme
4). At this point, our divergent synthesis of natural withasomnines
has been achieved.
In conclusion, 4-hydroxypyrazoles have been synthesized in a
sequence of reactions: halogen-metal exchange of 4-iodopyraz-
oles–formylation–Baeyer–Villiger oxidationÀalkaline hydrolysis.
And a Claisen rearrangement of O-allyl-4-hydroxypyrazoles gave
5-allyl-4-hydroxypyrazoles in good yield and high regioselec-
tively. Our divergent total synthesis of withasomnines was com-
pleted using a Suzuki coupling between a 4-triflyloxypyrazole
derivative and various arylboronic acids and afforded three nat-
ural alkaloids.
Scheme 3. Cyclization to 18 from the Claisen rearrangement products 12a.
It seems that the C4–C5 bond of 11 has a double bond
character. Therefore, the rearrangement took place regioselec-
tively to produce 12. However, the minor rearrangement prod-
ucts, 3-allyl-4-hydroxypyrazoles 13 might be afforded when 11
have an electron-withdrawing group such as the tosyl group
(11e) at N1. Because the C3–C4 bond of 11e has more double
bond character than that of 11a and b. Therefore, 13e is ob-
tained from the rearrangement of 11e in 20% yield (Table 1,
entry 5).
Based on the facility of removal of the protective group on N1,
12a was selected as a substrate for the total synthesis of withasom-
nines. The Claisen rearrangement product 12a was converted into
15 in a usual way. The transformation of an allyl side chain in 15
was examined by
a hydroboration–oxidation sequence with
Table 2
Synthesis of withasomnine 1 via Suzuki coupling of 18 and PhB(OH)2
Entry
Pd catalyst/ligand
DME/H2O
Condition
1(%)
19(%)
1
2
3
4
5
6
7
Pd(OAc)2/PPh3
Pd(OAc)2/PPh3
Pd(OAc)2/PPh3
Pd(dba)2/PPh3
Pd(OAc)2/PPh3
Pd(OAc)2/PPh3
Pd(dba)2/P(o-tol)3
1/1
1/1
9/1
9/1
1/0
9/1
9/1
9/1
9/1
9/1
9/1
Reflux, 24 h
20
24
29
42
0
31
51
54
90
37c
88
77
71
0
0
0
0
0
0
0
MW, 130 °C, 1 h
MW, 130 °C, 1 h
MW, 130 °C, 1 h
MW, 130 °C, 1 h
MW, 130 °C, 1 h
MW, 130 °C, 1 h
MW, 130 °C, 1 h
MW, 130 °C, 1 h
MW, 130 °C, 10 min
MW, 130 °C, 30 min
8a
9b
10b
11b
Pd(dba)2/P(C6H11
Pd(dba)2/P(C6H11
Pd(dba)2/P(C6H11
Pd(dba)2/P(C6H11
)
)
)
)
3
3
3
3
0
0
a
b
c
Reaction in the presence of tetra-n-butylammonium bromide (TBAB).
Reaction in the presence of trioctylmethylammonium chloride (TOMAC).
Compound 18 was recovered in 55% yield.

H. Ichikawa et al. / Tetrahedron Letters 52 (2011) 4448–4451
4451
Staples, R. J.; Odom, R. L. Adv. Synth. Catal. 2009, 351, 2013–2023; (f) Foster, R.
S.; Huang, J.; Vivat, J. F.; Brown, L. D.; Harrity, J. P. A. Org. Biomol. Chem. 2009, 7,
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Acknowledgments
We are grateful to Ms. Mihoyo Fujitake of this University for MS
measurement and Professor Masao Arimoto, who retired from this
University in 2009, for continuous encouragement. This work was
supported in part by a Grant-in-Aid for the ‘High-Tech Research
Center’ Project for Private Universities: matching fund subsidy
from MEXT (Ministry of Education, Culture, Sports, Science, and
Technology), 2006–2009, Japan and the Lonza Japan Award 2008
in Synthetic Organic Chemistry, Japan to H.I.
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