Reagent-controlled oxidative aromatization in iodocyclization: Switchable access to dihydropyrazoles and pyrazoles

Article abstract of DOI:10.1021/ol101365x

(Equation Presented). Switchable access to dihydropyrazoles and pyrazoles has been developed from common hydrazides by reagent-controlled iodocyclization. Controlling the oxidative aromatization in iodocyclization for heterocycles is reported for the firs

Full text of DOI:10.1021/ol101365x

ORGANIC
LETTERS
2010
Vol. 12, No. 15
3506-3509
Reagent-Controlled Oxidative
Aromatization in Iodocyclization:
Switchable Access to Dihydropyrazoles
and Pyrazoles
Takashi Okitsu, Kana Sato, and Akimori Wada*
Department of Organic Chemistry for Life Science, Kobe Pharmaceutical UniVersity,
4-19-1, Motoyamakita-machi, Higashinada-ku, Kobe 658-8558, Japan
a-wada@kobepharma-u.ac.jp
Received June 14, 2010
ABSTRACT
Switchable access to dihydropyrazoles and pyrazoles has been developed from common hydrazides by reagent-controlled iodocyclization.
Controlling the oxidative aromatization in iodocyclization for heterocycles is reported for the first time, and this methodology maximally
utilizes the dual nature of iodine.
Pyrazoles and its derivatives have been recongnized as an
important framework in pharmaceutical science.1 For ex-
ample, Rimonabant (Acomplia) works as CB1 cannabinoid
receptor antagonist for the treatment of obesity.1a Celecoxib
(Celebrex) is used as an anti-inflammatory as a COX-2
inhibitor.1b Certain pyrazole derivatives possess antitumor1c
and antiviral activities.1d Due to the attractive medicinal
properties of the pyrazole skeleton, various efficient ap-
proaches have been developed for the preparation of these
compounds.2
Iodocyclization is one of the most attractive methods for
the construction of functionalized molecular architecture
because this reaction can create not only ring skeletons but
can also introduce the iodo functionality for further trans-
formations. In addition, iodinating reagents are relatively
inexpensive and are ideal for achieving environmentally
friendly reactions.3,4 During our iodocyclization project,5 we
thought of the iodocyclization of propargylic hydrazide 1a
for the synthesis of dihydropyrazole 2a (Table 1) since there
have been no reports for the iodocyclization of hydrazide as
(3) For reviews, see: (a) French, A. N.; Bissmire, S.; Wirth, T. Chem.
Soc. ReV. 2004, 33, 354–362. (b) Larock, R. C. Acetylene Chem. 2005,
51–99. (c) Togo, H.; Iida, S. Synlett 2006, 2159–2175. (d) Mphahlele, M. J.
Molecules 2009, 14, 4814–4837
.
(4) For selected papers on the iodocyclizations of alkynes, see: (a)
Fischer, D.; Tomeba, H.; Pahadi, N. K.; Patil, N. T.; Yamamoto, Y. Angew.
Chem., Int. Ed. 2007, 46, 4764–4766. (b) Worlikar, S. A.; Kesharwani, T.;
Yao, T.; Larock, R. C. J. Org. Chem. 2007, 72, 1347–1353. (c) Halim,
R. H.; Scammells, P. J.; Flynn, B. L. Org. Lett. 2008, 10, 1967–1970. (d)
Barluenga, J.; Palomas, D.; Rubio, E.; Gonza´lez, J. M. Org. Lett. 2007, 9,
2823–2826. (e) Garud, D. R.; Koketsu, M. Org. Lett. 2008, 10, 3319–3322.
(f) Bi, H.-P.; Guo, L.-N.; Duan, X.-H.; Gou, F.-R.; Huang, S.-H.; Liu, X.-
Y.; Liang, Y.-M. Org. Lett. 2007, 9, 397–400. (g) Barluenga, J.; Trincado,
M.; Rubio, E.; Gonza´lez, J. M. Angew. Chem., Int. Ed. 2006, 45, 3140–
3143. (h) Yue, D.; Yao, T.; Larock, R. C. J. Org. Chem. 2005, 70, 10292–
10296. (i) Barluenga, J.; Trincado, M.; Rubio, E.; Gonza´lez, J. M. Angew.
Chem., Int. Ed. 2003, 42, 2406–2409. (j) Yue, D.; Yao, T.; Larock, R. C.
J. Org. Chem. 2006, 71, 62–69. (k) Yao, T.; Larock, R. C. J. Org. Chem.
2005, 70, 1432–1437. (l) Yao, T.; Campo, M. A.; Larock, R. C. J. Org.
Chem. 2005, 70, 3511–3517. (m) Khan, Z. A.; Wirth, T. Org. Lett. 2009,
11, 229–231. (n) Zhang, X.; Larock, R. C. J. Am. Chem. Soc. 2005, 127,
12230–12231. (o) Barluenga, J.; Trincado, M.; Rubio, E.; Gonza´lez, J. M.
Angew. Chem., Int. Ed. 2003, 42, 2406–2409. (p) Mehta, S.; Waldo, J. P.;
(1) (a) Seltzman, H. H. Drug DeV. Res. 2009, 70, 601–615. (b) Bensen,
W. G. Pain 2003, 515–521. (c) Wasylyk, C.; Zheng, H.; Castell, C.;
Debussche, L.; Multon, M.-C.; Wasylyk, B. Cancer Res. 2008, 68, 1275–
1283. (d) Millis, D. L.; Weigel, J. P.; Moyers, T.; Buonomo, F. C. Vet.
Ther. 2002, 3, 453–464.
(2) (a) Nair, V.; Biju, A. T.; Mohanan, K.; Suresh, E. Org. Lett. 2006,
8, 2213–2216. (b) Nair, V.; Mathew, S. C.; Biju, A. T.; Suresh, E. Angew.
Chem., Int. Ed. 2007, 46, 2070–2073. (c) Cui, S.-L.; Wang, J.; Wang, Y.-
G. Org. Lett. 2008, 10, 13–16. (d) Basavaiah, D.; Roy, S. Org. Lett. 2008,
10, 1819–1822.
Larock, R. C. J. Org. Chem. 2009, 74, 1141–1147
.
(5) (a) Okitsu, T.; Nakazawa, D.; Taniguchi, R.; Wada, A. Org. Lett.
2008, 10, 4967–4970. (b) Okitsu, T.; Nakazawa, D.; Kobayashi, A.;
Mizohata, M.; In, Y.; Ishida, T.; Wada, A. Synlett 2010, 203–206.
10.1021/ol101365x  2010 American Chemical Society
Published on Web 07/08/2010

a nitrogen nucleophile toward alkynes.6 In addition, prop-
argylic hydrazide 1 could be easily prepared in only one step
by the Mitsunobu reaction of diisopropyl azodicarboxylate
with propargylic alcohol or N-alkylation of hydrazide with
corresponding bromide (Scheme 1).7
Table 2. Product Switch in Iodocyclization of 1a
Scheme 1. Preparation of the Precursors in Iodocyclization
Table 1. Optimization for the Iodocyclization of 1aa
temp time
2a
3a
entry
[I+] (equiv)
additive
(°C)
(min) (%) (%)
1
2
3
4
5
6
7
I(coll)2PF6 (2)
I(coll)2PF6(2)
I(coll)2PF6 (1.5) none
NIS (2.5)
NIS (2.5)
NIS (3)
ICl (2.5)
BF3·OEt2
none
rt
rt
rt
0
0
0
30
30
20
180
30
10
17
85
82
19
0
44
0
0
none
7
BF3·OEt2
BF3·OEt2
NaHCO3
72
84
48
0
8
rt
30
a Reaction was performed in CH2Cl2 (0.1 M) under Ar atmosphere.
b Equivalent of additive is the same as that of [I+]. c Isolated yield after
purification by column chromatography.
a Condition A: I(coll)2PF6 (2 equiv), CH2Cl2 (0.1 M), rt, 30 min.
Condition B: NIS (3 equiv), BF3·OEt2 (3 equiv), CH2Cl2 (0.1 M), 0 °C, 10
min. b Isolated yield after purification by column chromatography. c Four
equivalents of NIS and BF3·OEt2 were used. d Two and a half equivalents
of NIS and BF3·OEt2 were used. e Four equivalents of I(coll)2PF6 was used.
f Six equivalents of NIS and BF3·OEt2 were used.
First, we chose the combination of bis(2,4,6-collidine)-
iodonium(I) hexafluorophosphate [I(coll)2PF6]8 and BF3·OEt2
as reaction conditions because this worked well in our
previous studies.5 As a result, we obtained desired product
2a and unprecedented pyrazole 3a, which would be formed
by oxidative aromatization of 2a (Table 1, entry 1). Iodi-
nating reagents possess two natures: one is the ability to
iodinate and the other is the ability to oxidize. Therefore,
further oxidized products have sometimes been obtained
during the iodocyclization process and such occasions
depended on the nature of the cyclized products formed
initially.9 Nevertheless, there has been only one report of
the control of such overoxidation by the conditions of
iodocyclization.10 We expected that we might achieve
switchable access to dihydropyrazole 2 and pyrazole 3 from
common hydrazide 1 by reagent control if the conditions
(6) Transition metal-catalyzed cyclization of hydrazides, see: (a) Yang,
Q.; Jiang, X.; Ma, S. Chem.sEur. J. 2007, 13, 9310–9316. (b) Cheng, X.;
Ma, S. Angew. Chem., Int. Ed. 2008, 47, 4581–4583. (c) Shu, W.; Yang,
Q.; Jia, G.; Ma, S. Tetrahedron 2008, 64, 11159–11166.
(9) (a) Zhang, X.; Campo, M. A.; Yao, T.; Larock, R. C. Org. Lett.
2005, 7, 763–766. (b) Likhar, P. R.; Subhas, M. S.; Roy, S.; Kantam, M. L.;
Sridhar, B.; Seth, R. K.; Biswas, S. Org. Biomol. Chem. 2009, 7, 85–93.
(10) During the preparation of this manuscript, the first report of
controlling the oxidative aromatization for carbocycles appeared: Crone,
B.; Kirsch, S. F.; Umland, K.-D. Angew. Chem., Int. Ed. 2010, 49, 4661–
4664.
(7) (a) Mitsunobu, O.; Yamada, M.; Mukaiyama, T. Bull. Chem. Soc.
Jpn. 1967, 40, 935–939. (b) Rabjone, N. Org. Synth. 1948, 28, 375–377.
(8) Homsi, F.; Robin, S.; Rousseau, G. Org. Synth. 2000, 77, 206–211.
Org. Lett., Vol. 12, No. 15, 2010
3507

were tuned.11 To achieve our strategy, we elaborated the
reaction conditions, and found that I(coll)2PF6 as the iodi-
nating reagent at room temperature afforded dihydropyrazole
2a in 85% yield (entry 2). In contrast, the combination of
N-iodosuccinimide (NIS) and BF3·OEt2 at 0 °C gave pyrazole
3a in 84% yield (entry 6), as the sole product.12 In this study,
other Lewis acids were not tried because BF3·OEt2 was the
inexpensive and easy handling reagent. Among the carbamate
groups, isopropyloxycarbonyl was the most suitable for both
iodocyclization conditions (data was not shown).
Scheme 3. Possible Reaction Mechanism
These clear results encouraged us to examine the scope
of usable substrates (Table 2). In almost cases, dihydropy-
razole 2 and pyrazole 3 were selectively produced from
propargylic hydrazide 1. For the substituents on alkynes,
various aryl and heteroaryl groups were successful while the
p-nitrophenyl group was not suitable as a substrate (entries
1-7). Vinylic and alkyl substituted alkynes were also
applicable under these reaction conditions and afforded the
cyclized products in moderate to good yields except for 3j,
due to the unstability of formed iodonium ion (entries 8 and
9). The iodocyclizations also allowed for the presence of
substitution at the propargylic position (entry 10). Further-
more, double-iodocyclizations were achieved by using twice
the quantity of reagents to obtain 2l and 3l which contained
three connected heterocycles (entry 11).
To better understand the reaction mechanism, we treated
dihydropyrazole 2a with the combined reagent NIS/BF3·OEt2
to give pyrazole 3a in 67% yield (Scheme 2). The treatment
of 2a with the N-bromosuccinimide (NBS)/BF3·OEt2 com-
bination instead of NIS afforded 4-bromopyrazole 4a as a
major product accompanied with 3a. 4a was individually
prepared from 1a with NBS/BF3·OEt2 system in 49% yield.
These results indicated that pyrazole 3 was formed via
electrophilic addition of halonium ion to dihydropyrazole 2.
Although 2a was exposed to BF3·OEt2 alone as a control
experiment, the reaction did not proceed at all.
(Scheme 3). The 5-endo cyclization of iodonium ion A
formed by electrophilic addition of I+ to alkyne 1 gives
dihydropyrazole 2. When a more acidic condition, the NIS/
BF3·OEt2 system, is employed, more reactive I+ source might
caused further iodination at an enecarbamate group to
produce iodonium ion B. The ring-opening of B followed
by the elimination of HI from acyl hydrazonium ion C
affords pyrazolium ion D. Pyrazole 3 would be formed by
hydrolysis at the less hindered carbamate group of D. The
position of the carbamate group for 3 was unambiguously
1
assigned by H-15N HMBC NMR spectra (see Supporting
Information).
As described above, the iodo functionality can create
diversity by metal-catalyzed cross-coupling. For example,
we applied dihydropyrazole 2a toward palladium-catalyzed
Scheme 4. Transformation of 2a and 3a
Scheme 2
.
Halonium Ion-Induced Oxidative Aromatization of
2a
On the basis of the outcomes of these reactions, we
proposed a reaction mechanism for the iodocyclization
(11) Stepwise iodocyclizations/aromatizations, see: (a) Knight, D. W.;
Redfern, A. L.; Gilmore, J. Chem. Commun. 1998, 2207–2208. (b) Knight,
D. W.; Redfern, A. L.; Gilmore, J. J. Chem. Soc., Perkin Trans. 1 2002,
622–628. (c) Knight, D. W.; Rost, H. C.; Sharland, C. M.; Singkhonrat, L.
Tetrahedron Lett. 2007, 48, 7906–7910. (d) Schumacher, R. F.; Rosa´rio,
A. R.; Souza, A. C. G.; Menezes, P. H.; Zeni, G. Org. Lett. 2010, 12, 1952–
1955.
(12) Synthesis of 4-iodopyrazoles, see: (a) Waldo, J. P.; Mehta, S.;
Larock, R. C. J. Org. Chem. 2008, 73, 6666–6670. (b) Felding, J.;
Kristensen, J.; Bjerregaard, T.; Sander, L.; Vedsø, P.; Begtrup, M. J. Org.
Chem. 1999, 64, 4196–4198.
3508
Org. Lett., Vol. 12, No. 15, 2010

coupling reactions such as Suzuki-Miyaura cross-coupling,13
Heck reaction,14 and Sonogashira cross-coupling15 to achieve
C-C bond formation in high yields (Scheme 4). In addition,
pyrazole 3a was also able to use in subsequent reaction to
afford 8 in moderate yield. These results indicated that C-I
bond of both 2 and 3 was available for the assembly of
carbon-unit.
including potent functionalization may provide a powerful
tool for drug discovery and other fields. Studies of the details
of the mechanism and the scope of substrates are currently
in progress.
Acknowledgment. We thank Dr. Makiko Sugiura (Kobe
Pharmaceutical University) for help with the 15N NMR
measurements. This work was supported by a Grant-in-Aid
for Encouragement of Young Scientists from the Ministry
of Education, Culture, Sports, Science and Technology and
by a grant from the Science Research Promotion Fund of
the Japanese Private School Promotion Foundation.
In summary, this work represents a switchable access to
dihydropyrazoles and pyrazoles from the common hy-
drazides. Controlling the oxidative aromatization in iodocy-
clization for heterocycles is reported for the first time and
this methodology maximally utilizes the dual nature of
iodine. The concept of our methodology would be adaptable
for other substrates. Moreover, the flexible synthetic strategy
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for the substrates and
products. This material is available free of charge via the
Internet at http://pubs.acs.org.
(13) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457–2483.
(14) Heck, R. F. Org. React. 1982, 27, 345–390.
(15) Sonogashira, K. J. Organomet. Chem. 2002, 653, 46–49.
OL101365X
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3509