Lewis base catalyzed synthesis of multisubstituted 4-sulfonyl-1 H-pyrazole involving a novel 1,3-sulfonyl shift

Article abstract of DOI:10.1021/ol401818m

A facile synthesis of highly substituted 4-sulfonyl-1H-pyrazoles from N-propargylic sulfonylhydrazone derivatives has been developed. Allenic sulfonamide formation and 1,3-sulfonyl shift were established to be the critical steps of this transformation.

Full text of DOI:10.1021/ol401818m

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Lewis Base Catalyzed Synthesis of
Multisubstituted 4‑Sulfonyl‑1H‑Pyrazole
Involving a Novel 1,3-Sulfonyl Shift
Yu Zhu, Wen-Ting Lu, Hong-Chao Sun, and Zhuang-Ping Zhan*
Department of Chemistry, College of Chemistry and Chemical Engineering,
Xiamen University, Xiamen 361005, Fujian, P. R. China
zpzhan@xmu.edu.cn
Received June 28, 2013
ABSTRACT
A facile synthesis of highly substituted 4-sulfonyl-1H-pyrazoles from N-propargylic sulfonylhydrazone derivatives has been developed. Allenic
sulfonamide formation and 1,3-sulfonyl shift were established to be the critical steps of this transformation.
Pyrazoles and their derivatives have been recognized as
important frameworks in pharmaceutical and agrochem-
ical science,1 and certain pyrazole derivatives including
Celebrex (selective COX-2 inhibition) and Zoniporide
(selective human NHE-1 inhibition) have been developed
into clinical drugs. Owing to the attractive medicinal
properties of pyrazoles, new approaches for the efficient
assembly of different pyrazoles have attracted great inter-
est. Efficient strategies have beendevelopedwiththe aim of
the preparation of diverse substitution pyrazoles.2 Con-
ventional approaches for the synthesis of compounds
containing pyrazole skeletons involve either the modifica-
tion of the pre-existing pyrazole precursors through the
introduction of new groups3 or synthesis of a new pyrazole
ring from creation of CÀN and CÀC bonds.4
(1) (a) Penning, T. D.; Talley, J. J.; Bertenshaw, S. R.; Carter, J. S.;
Collins, P. W.; Docter, S.; Graneto, M. J.; Lee, L. F.; Malecha, J. W.;
Miyashiro, J. M. J. Med. Chem. 1997, 40, 1347. (b) Guzman-Perez, A.;
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Day, W. W.; Hamanaka, E. S.; Kennedy, S. P.; Knight, D. R. Bioorg.
Med. Chem. Lett. 2001, 11, 803. (c) Chimenti, F.; Fioravanti, R.;
Bolasco, A.; Manna, F.; Chimenti, P.; Secci, D.; Befani, O.; Turini, P.;
Ortuso, F.; Alcaro, S. J. Med. Chem. 2007, 50, 425. (d) Okuno, S.; Saito,
A.; Hayashi, T.; Chan, P. H. J. Neurosci. 2004, 24, 7879. (e) Wasylyk, C.;
Zheng, H.; Castell, C.; Debussche, L.; Multon, M.-C.; Wasylyk, B.
Cancer Res. 2008, 68, 1275. (f) Wu, C.-H.; Hung, M.-S.; Song, J.-S.; Yeh,
T.-K.; Chou, M.-C.; Chu, C.-M.; Jan, J.-J.; Hsieh, M.-T.; Tseng, S.-L.;
Chang, C.-P. J. Med. Chem. 2009, 52, 4496. (g) Ivachtchenko, A. V.;
Golovina, E. S.; Kadieva, M. G.; Kysil, V. M.; Mitkin, O. D.; Tkachenko,
S. E.; Okun, I. M. J. Med. Chem. 2011, 54, 8161. (h) Ivachtchenko, A. V.;
Dmitriev, D. E.; Golovina, E. S.; Kadieva, M. G.; Koryakova, A. G.;
Kysil, V. M.; Mitkin, O. D.; Okun, I. M.; Tkachenko, S. E.; Vorobiev,
A. A. J. Med. Chem. 2010, 53, 5186. (i) Ivachtchenko, A. V.; Golovina,
E. S.; Kadieva, M. G.; Kysil, V. M.; Mitkin, O. D.; Vorobiev, A. A.;
Okun, I. Bioorg. Med. Chem. Lett. 2012, 22, 4273.
Previous studies from our group have reported a concise
approach to prepared N-propargylic N-sulfonylhydra-
zones through FeCl3-catalyzed nucleophilic substitution
(3) For recent examples, see: (a) Ye, M.; Edmunds, A. J.; Morris,
J. A.; Sale, D.; Zhang, Y.; Yu, J.-Q. Chem. Sci. 2013, 4, 2374. (b)
Goikhman, R.; Jacques, T. L.; Sames, D. J. Am. Chem. Soc. 2009, 131,
ꢁ
3042. (c) Grosse, S.; Pillard, C.; Massip, S.; Leger, J. M.; Jarry, C.;
Bourg, S.; Bernard, P.; Guillaumet, G. Chem.;Eur. J. 2012, 18, 14943.
(d) Yan, T.; Chen, L.; Bruneau, C.; Dixneuf, P. H.; Doucet, H. J. Org.
Chem. 2012, 77, 7659. (e) Pan, X.; Luo, Y.; Wu, J. J. Org. Chem. 2013, 78,
5756. (f) Ma, W.; Graczyk, K.; Ackermann, L. Org. Lett. 2012, 14, 6318.
(g) Mateos, C.; Mendiola, J.; Carpintero, M.; Mınguez, J. M. Org. Lett.
€
2010, 12, 4924. (h) Enders, D.; Grossmann, A.; Gieraths, B.; Duzdemir,
M.; Merkens, C. Org. Lett. 2012, 14, 4254.
(4) For recent examples, see: (a) Neumann, J. J.; Suri, M.; Glorius, F.
Angew. Chem., Int. Ed. 2010, 49, 7790. (b) Kinjo, R.; Donnadieu, B.;
Bertrand, G. Angew. Chem., Int. Ed. 2011, 50, 5560. (c) Hao, L.; Hong,
J. J.; Zhu, J.; Zhan, Z. P. Chem.;Eur. J. 2013, 19, 5715. (d) Wang, L.;
Yu, X.; Feng, X.; Bao, M. J. Org. Chem. 2013, 78, 1693. (e) Attanasi,
O. A.; Favi, G.; Geronikaki, A.; Mantellini, F.; Moscatelli, G.; Paparisva,
A. Org. Lett. 2013, 15, 2624. (f)Wang, H.;Zhao, Y. L.;Li, L.;Zhang, Z. W.;
Liu, Q. Adv. Synth. Catal. 2013, 355, 1540. (g) Wang, L.; Huang, J.; Gong,
X.; Wang, J. Chem.;Eur. J. 2013, 19, 7555. (h) Li, X.; He, L.; Chen, H.;
Wu, W.; Jiang, H. J. Org. Chem. 2013, 78, 3636. (i) Dissanayake, A. A.;
Odom, A. L. Chem. Commun. 2012, 48, 440.
(2) For reviews on the synthesis of pyrazole, see: (a) Fustero, S.;
ꢀ
ꢀ
ꢀ
Sainchez-Roselloi, M.; Barrio, P.; Simoin-Fuentes, A. Chem. Rev. 2011,
111, 6984. (b) Janin, Y. L. Chem. Rev. 2012, 112, 3924. (c) Dadiboyena,
S.; Nefzi, A. Eur. J. Med. Chem. 2011, 46, 5258. (d) Svete, J. ARKIVOC
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Makino, K.; Kim, H. S.; Kurasawa, Y. J. Heterocycl. Chem. 1998, 35,
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1999, 36, 321.
r
10.1021/ol401818m
XXXX American Chemical Society

of propargylic acetates with N-sulfonylhydrazones.6 The
N-propargylic substitution products underwent a copper-
(I)-catalyzed [3,3]-rearrangement affording (1E,3E)-2-sul-
fonyl-1,3-dienes (Scheme 1).6a As part of ongoing research
on N-propargylic sulfonylhydrazones, we herein report a
Lewis base catalyzed synthesis of 4-sulfonyl-1H-pyazoles
in moderate to good yields. Allenic sulfonamide formation
and 1,3-sulfonyl shift were established to be critical steps in
this transformation.
prolonged (Table 1, entry 13). Absence of catalyst led to
complete recovery of 1a (Table 1, entry 14). Thus, the most
suitable reaction conditions for the formation of 3a were
established (Table 1, entry 7).
Table 1. Screening for the Reaction Conditionsa
Scheme 1. Reaction of N-Propargylic Sulfonylhydrazones
catalyst
time
(h)
yieldb (%)
entry
(5 mol %)
solvent
DME
of 3a (2a)
1
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
PPh3
4
40
2
THF
4
52
3
PhMe
6
47
4
CH3CN
3
50
5
dioxane
1
15
6
VT:VNc = 3:1
VT:VN = 5:1
VT:VN = 100:1
VT:VN = 5:1
VT:VN = 5:1
VT:VN = 5:1
VT:VN = 5:1
VT:VN = 5:1
VT:VN = 5:1
3
76
7
3
78
8
4
56
9
4
60
10
11
12
13
14
DABCO
DBU
4
10
Recently, base-promoted construction of pyrroles,5a
oxazoles,5b and imidazoles5c from propargylic amides or
propargylic amines involving sulfonyl group shift have
been developed. Different from those transformations,
which introduced the sulfonyl group to the exocyclic alkyl
group of heterocycles,5 here we report a sulfonyl group
migration to the 4-position of 1H-pyrazole. The recent
studies indicate that pyrazole derivatives containing a sul-
fonyl substituent display a variety of biological activities.1gÀi
In our initial study, we decided to investigate the reac-
tion conditions that would improve the yield of 3a using 1a
as the reactant (Table 1). We treated the 1a in 1,2-dichlor-
oethane with 5 mol % of DMAP at 80 °C. The desired
product 3a was observed in 40% yield (Table 1, entry 1).
The reaction also took place in solvents such as THF
(52%), PhMe (47%), CH3CN (50%), and dioxane
(15%) (Table 1, entries 2, 3, 4, and 5). Subsequently, the
synthesisof pyrazolewas investigatedin the mixed solvents
of THF and NEt3 (Table 1, entries 6À8). The best mixture
volume ratio for THF and NEt3 was 5:1, which afforded
the product 3a in 78% yield (Table 1, entry 7). When Lewis
bases PPh3 or DABCO were utilized in the same mix-
solvent, the reaction proceeded to afford 3a in 60% and
10% yields respectively (Table 1, entries 9 and 10). Other
bases, such as DBU and Cs2CO3, were also screened but
failed to promote this transformation (Table 1, entries 11
and 12). However, the reaction occurred to afford 2a in
81% yield at room temperature for 0.5 h, and no desired
product 3a was detected after the reaction time was
4
trace
trace
0 (81)d
n.r.e
Cs2CO3
DMAP
4
0.5
4
a Reaction conditions: 1a (0.5 mmol), solvent (5 mL), 80 °C. b Iso-
lated yield. c Mixture volume ratio of THF and NEt3. d The reaction was
performed at room temperature. e n.r. = no reaction.
To broaden the scope of this reaction, we carried out the
reaction of the N-propargylic N-sulfonylhydrazone deri-
vatives 1 under the optimized conditions (summarized in
Table 2). The substrates 1a (R1 = 4-MeC6H4) and 1b
(R1 = Ph) gave the desired results, providing 3a and 3b in
78% and 64% yields, respectively(Table 2, entries 1 and 2).
The electron-donating N-sulfonylhydrazone 1c (R1
=
4-MeOC6H4) was also successfully employed in the reac-
tion to give product 3c in 61% yield (Table 2, entry 3). The
electron-deficient N-sulfonylhydrazone 1d (R1 =4-BrC6H4)
reacted smoothly affording the product 3d in 83% yield
(Table 2, entry 4). The results suggested that reactant 1e
(R1 = Me) failed to form 4-methylsulfonyl-1H-pyrazole
(3e) (Table 2, entry 5). Gratifyingly, reactants (1fÀk)
bearing a terminal alkyne group (R4 = H) successfully
afforded the desired products (3fÀk) in good isolated
yields in a short reaction time (Table 2, entries 6À11).
The reactant 1l (R4 = TMS) underwent protodesilylation
under these base cyclization conditions with the same
products 3f obtained in 47% yield (Table 2, entry 12).
No reaction of 1m (R3 = H) and 1n (R3 = C2H5) occurred
under normal conditions (Table 2, entries 13 and 14).
Unfortunately, the results suggested that internal alkynes
1o (R4 = n-C4H9) failed to form the corresponding
(5) (a) Xin, X.; Wang, D.; Li, X.; Wan, B. Angew. Chem., Int. Ed.
2012, 51, 1693. (b) Yu, X.; Xin, X.; Wan, B.; Li, X. J. Org. Chem. 2013,
78, 4895. (c) Jiang, Z.; Lu, P.; Wang, Y. Org. Lett. 2012, 14, 6266.
(6) (a) Zhu, Y.; Tang, H. T.; Zhan, Z. P. Adv. Synth. Catal. 2013, 355,
1291. (b) Zhan, Z.-p.; Yu, J.-l.; Liu, H.-j.; Cui, Y.-y.; Yang, R.-f.; Yang,
W.-z.; Li, J.-p. J. Org. Chem. 2006, 71, 8298.
pyrazole. Other internal alkynes 1p and 1q (R4
t-C4H9 and 1-cyclohexenal) afforded allenamides 2p and
2q as the major products (Table 2, entries 16 and 17).
=
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 2. DMAP-Catalyzed Formation of 4-Sulfonyl 1H-Pyrazolesa
a Reaction conditions: 1 (0.5 mmol), DMAP (0.025 mmol), solvent (5 mL), 80 °C. b Isolated yield. c n.r. = no reaction. d No future reactions occurred
by prolonging reaction time.
Electron-neutral, electron-deficient, and electron-rich
aromatic groups (R2 and R3) on 1r and 1tÀw were all
tolerated, and the desired products (3r and 3tÀw) were
obtained in moderate-to-good yields (50À91%, Table 2,
3a. Indeed, 2a completely converted into pyrazole 3a (97%
yield) under the standard conditions (Scheme 2, eq 1,
conditionc B). No reaction occurred was obtained at room
temperature without Lewis base, indicating that the alle-
namide formation and cyclization reactions were both
catalyzed by a single catalyst DMAP (Scheme 2, eq 1,
conditions A).
entries 18 and 20À23). The reaction of 1s (R2
=
2-OHC6H4) containing weakly acidic hydroxyl group
failed to afforded 3s (Table 2, entry 19). The substrates
1x and 1y bearing a fused ring or thiophene were also
suitable for the transformations (Table 2, entries 24 and 25).
Notably, starting from 1z, we could finally obtain a
symmetrical oligomer 3z containing two pyrazole rings
(Table 2, entry 26). However, when sulfonyl group on 1a
was replaced by an acetyl group, the reaction afforded
allenic N-acetylhydrazones only, and the subsequent
cyclization did not occur. It proved that migration of
the sulfonyl group played a critical role in cyclization. The
structure of 3w was unambiguously demonstrated by
X-ray diffraction analysis (see the Supporting Information).7
Attempts were made toprobe the mechanism (Scheme 2,
eq 1). In our previous study, allenic sulfonamide 2a was
obtained at room temperature (Table 1, entry 13). There-
fore, we assumed that 2a was the intermediate which led to
Scheme 2. Conversion of Allene to Pyrazole and Crossover
Experiment of 1f and 1ia
a n.r. = no reaction.
On the basis of the above experiments and related
reports,8,9 we propose the following mechanism (Scheme 3).
In the presence of base, the propargylic amide moiety of 1 is
transformed into the allenic sulfonamide intermediate 2.
Two reasonable pathways accounting for the 1,3-sulfonyl
(7) CCDC 943608 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from the
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
Org. Lett., Vol. XX, No. XX, XXXX
C

shift and formation of 7 are shown. In path I, Lewis base
facilitates the sulfonyl dissociation, and then intermolec-
ular addition occurs to afford intermediate 7. In path II,
nucleophilic addition of Lewis base B such as DMAP to
the terminal sp2 carbon atom of allene pushs electron
density into the sulfonamide moiety to afford transition
state 4, then the NÀS bond is broken which allows the 1,3-
sulfonyl shift and generates transition state 6, and then
electron transfer affords 7. R,β-Unsaturated imine 7
undergoes intramolecular Michael addition providing
zwitterionic species 8. Finally, 8 rearranges to pyrolyze
3 via a 1,3-H shift and electron transfer.
Scheme 3. Proposed Mechanism
In order to establish whether the shift of the sulfonyl group
occurred in an intramolecular or intermolecular pathway,
we performed a crossover experiment between equimolar
amounts of reactants 1f and 1i which yields the correspond-
ing products 3f and 3i in 82% and 83% yields, respectively,
and the crossover products 3g and 3h were not detected
(Scheme 2, eq 2, determined by HPLC). This result clearly
indicated that migration of the sulfonyl group proceeds in an
intramolecular manner. Therefore, path II might be the
possible pathway envisioned for this 1,3-sulfonyl migration.
In summary, a facile approach for the synthesis of highly
substituted multisubstituted 4-sulfonyl-1H-pyrazole from
N-propargylic N-sulfonylhydrazone derivatives has been de-
veloped. A key feature of the reaction is the straightforward
introduction of sulfonyl group to the 4-position of
1H-pyrazole. Studies aiming at exploring mechanistic
aspects of this reaction and developing further transforma-
tions of N-propargylic N-sulfonylhydrazone derivatives
are ongoing.
(8) For reviews and recent examples of Lewis base catalysis, see: (a)
Denmark, S. E.; Beutner, G. L. Angew. Chem., Int. Ed. 2008, 47, 1560.
(b) Heinrich, M. R.; Klisa, H. S.; Mayr, H.; Steglich, W.; Zipse, H.
Angew. Chem., Int. Ed. 2003, 42, 4826. (c) Yoshida, M.; Saito, K.;
Fujino, Y.; Doi, T. Chem. Commun. 2012, 48, 11796. (d) Dadwal, M.;
Mobin, S. M.; Namboothiri, I. N. Org. Biomol. Chem. 2006, 4, 2525. (e)
Hills, I. D.; Fu, G. C. Angew. Chem., Int. Ed. 2003, 42, 3921. (f) Yoshida,
M.; Fujino, Y.; Saito, K.; Doi, T. Tetrahedron 2011, 67, 9993.
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M.; Duong, H. M.; Bolanos, E.; Wudl, F. Org. Lett. 2005, 7, 783. (b)
Yeom, H. S.; So, E.; Shin, S. Chem.;Eur. J. 2011, 17, 1764. (c)
Nakamura, I.; Yamagishi, U.; Song, D.; Konta, S.; Yamamoto, Y.
Angew. Chem., Int. Ed. 2007, 119, 2284. (d) Nakamura, I.; Yamagishi,
U.; Song, D.; Konta, S.; Yamamoto, Y. Chem.;Asian J. 2008, 3, 285.
(e) Prasad, B.; Adepu, R.; Sandra, S.; Rambabu, D.; Krishna, G. R.;
Reddy, C. M.; Deora, G. S.; Misra, P.; Pal, M. Chem. Commun. 2012, 48,
10434. (f) DeKorver, K. A.; Johnson, W. L.; Zhang, Y.; Hsung, R. P.; Dai,
H.; Deng, J.; Lohse, A. G.; Zhang, Y.-S. J. Org. Chem. 2011, 76, 5092. (g)
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Acknowledgment. Financial support from the National
Natural Science Foundation of China (No. 21072159 and
21272190) and PCSIRT at Xiamen University is gratefully
acknowledged.
Supporting Information Available. Experimental pro-
cedures and characterization of compounds 3aÀk,rÀz
and 2a,p,q. This material is available free of charge via the
Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX