Copper-catalyzed one-pot synthesis of tetrasubstituted pyrazoles from sulfonyl azides, terminal alkynes, and hydrazonoyl chlorides

Article abstract of DOI:10.1016/j.tetlet.2012.01.083

Ketenimine intermediates generated by the addition of copper acetylides to sulfonyl azides are trapped by nitrile imines (generated from hydrazonoyl chlorides and triethylamine) to afford tetrasubstituted pyrazoles in moderate to good yields.

Full text of DOI:10.1016/j.tetlet.2012.01.083

Tetrahedron Letters 53 (2012) 1889–1890
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Copper-catalyzed one-pot synthesis of tetrasubstituted pyrazoles
from sulfonyl azides, terminal alkynes, and hydrazonoyl chlorides
⇑
Issa Yavari , Manijeh Nematpour, Sima Yavari, Fatemeh Sadeghizadeh
Department of Chemistry, Tarbiat Modares University, PO Box 14115-175, Tehran, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
Ketenimine intermediates generated by the addition of copper acetylides to sulfonyl azides are trapped
by nitrile imines (generated from hydrazonoyl chlorides and triethylamine) to afford tetrasubstituted
pyrazoles in moderate to good yields.
Received 14 November 2011
Revised 24 December 2011
Accepted 20 January 2012
Available online 28 January 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Hydrazonoyl chloride
Pyrazole
Copper iodide
Tosyl azide
Ketenimine
Nitrile imine
The activity of the central carbon atom of ketenimines toward
various nucleophiles1–3 has led to their application in the construc-
tion of heterocycles. Among several methods leading to the
generation of ketenimines, the copper-catalyzed azide-alkyne
cycloaddition has attracted significant attention because of its mild
conditions.4,5 The in situ generated ketenimine intermediates can
be trapped by various nucleophiles.6–11 Applying this strategy,
Wang and co-workers12 used hydrazones to trap in situ generated
ketenimines and obtained linear addition products. This strategy
was extended to sulfonamidopyrazole in the presence of a Lewis
acid and an oxidant. This Letter, prompted us to describe our re-
sults on the direct one-pot synthesis of tetrasubstituted pyrazoles
using hydrazonoyl chlorides as the trapping agent.
The in situ generated ketenimine intermediate 1 reacts with ni-
trile imine13–15 derivative 2, generated from a hydrazonoyl chlo-
ride 3 and Et3N, to give the desired tetrasubstituted pyrazole 4 in
moderate to good yields (Scheme 1).16
Several catalysts including CuI, CuBr, CuCl, Cu2O, and copper
powder were tested with CuI giving the best results. Among the
solvents screened, N,N-dimethylformamide (DMF) proved to be
the best. Thus, the optimized reaction conditions were 10 mol %
of CuI, 1 mmol of alkyne 5, 1.2 mmol of sulfonyl azide 6, and
1 mmol of hydrazonoyl chloride in DMF at room temperature.
Phenylacetylene readily participates in the formation of pyra-
zole derivatives in good yields (Scheme 1). Aliphatic acetylenes
served as low-yielding substrates compared to phenylacetylene.
Aromatic and aliphatic sulfonyl azides reacted efficiently with 5
and the corresponding products 4a–n were obtained in good
yields.
The structures of compounds 4a–n were deduced from their IR,
1H NMR, and 13C NMR spectra. For example, the 1H NMR spectrum
of 4b exhibited two singlets for the methyl (d 2.43) and NH (d 8.73)
protons, along with multiplets for the aromatic protons. The 1H-
decoupled 13C NMR spectrum of 4b showed 20 distinct resonances
which confirmed the proposed structure. The NMR spectra of 4a
and 4c–n were similar to those for 4b except for the aliphatic
and aryl moieties, which exhibited characteristic resonances in
appropriate regions of the spectra.
A mechanistic rationalization for the reaction is given in
Scheme 2. The initial event is the formation of the yellow copper
acetylide 7 from 5 and CuI, which undergoes a 1,3-dipolar cycload-
dition with sulfonyl azide 6, to generate triazole 8. This intermedi-
ate is converted into the ketenimine derivative 1, which undergoes
a [3+2] dipolar cycloaddition with nitrile imine 2 to afford 9. Final-
ly, intermediate 9 is converted into the product pyrazole 4 via a
1,3-H shift.
In summary, we have reported a sequential transformation
involving ketenimine intermediates (generated by the addition of
copper acetylides to sulfonyl azides) and nitrile imine intermedi-
ates (derived from hydrazonoyl chlorides and Et3N), which repre-
sents a new route for the synthesis of tetrasubstituted pyrazoles.
The present method may be considered as a practical route for
the synthesis of functionalized pyrazoles which may show poten-
tial for further synthetic manipulations.
⇑
Corresponding author. Tel.: +98 21 82883465; fax: +98 21 82883455.
E-mail address: yavarisa@modares.ac.ir (I. Yavari).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2012.01.083

1890
I. Yavari et al. / Tetrahedron Letters 53 (2012) 1889–1890
R
Cu
5
CuI (10 mol%), Et3N
DMF, rt, 6 h
C
N
O
O
R"
R
N
R
S
O
O
N
Ph
S
R'
1
R'
N3
6
NH
O
O
S
Cl
N
Ph
R"
N
Ph
Et3N
N
H
N
R'
R"
2
3
4
R'
Entry
R
Product
R"
Yield (%)
p-tolyl
p-tolyl
4a
4b
4c
4d
4e
4f
91
87
81
90
85
83
84
80
79
69
66
68
65
60
p-tolyl
Ph
1
Ph
2
Ph
p-tolyl
Me
3
Ph
p-tolyl
Ph
4-ClC6H4
4-ClC6H4
4-ClC6H4
4
Ph
5
Ph
Me
6
Ph
4g
4h
4i
7
Ph
p-tolyl
Ph
Ph
8
Ph
Ph
9
Ph
Me
Ph
4j
10
11
12
13
14
n-Bu
n-Bu
n-Pr
n-Pr
n-Pr
Ph
p-tolyl
4k
4l
p-tolyl
p-tolyl
p-tolyl
Me
4-ClC6H4
4-ClC6H4
4m
4n
Ph
Ph
Scheme 1. Synthesis of compounds 4.
5. Tornøe, C. W.; Christensen, C.; Meldal, M. J. Org. Chem. 2002, 67, 3057.
6. Bae, I.; Han, H.; Chang, S. J. Am. Chem. Soc. 2005, 127, 2038.
7. Yoo, E. J.; Bae, I.; Cho, S. H.; Han, H.; Chang, S. Org. Lett. 2006, 8, 1347.
8. Cho, S. H.; Chang, S. Angew. Chem., Int. Ed. 2008, 47, 2836.
9. Shang, Y. J.; Ju, K.; He, X. W.; Hu, J. S.; Yu, S. Y.; Zhang, M.; Liao, K. S.; Wang, L. F.;
Zhang, P. J. Org. Chem. 2010, 75, 5743.
R
Cu
R'-N3
6
_
CuI
N2
5
R
Cu
N
N
R'
N
10. Wang, J.; Wang, J. J.; Zhu, Y. X.; Lu, P.; Wang, Y. G. Chem. Commun. 2011, 47,
3275.
8
7
11. Yavari, I.; Ahmadian, S.; Ghazanfarpur, M.; Solgi, Y. Tetrahedron Lett. 2011, 52,
668.
12. Li, Y.; Hong, D.; Zhu, Y.; Lu, P.; Wang, Y. Tetrahedron 2011, 67, 8086.
13. Smith, M. B.; March, J. March’s Advanced Organic Chemistry: Reactions,
Mechanisms, and Structure, 6th ed.; John Wiley & Sons, Inc., 2007. p 1189.
14. Foti, F.; Grassi, G.; Risitano, F. Tetrahedron Lett. 1999, 40, 2605.
15. Yildirim, M.; Dürüst, Y. Tetrahedron 2011, 67, 3209.
3
Et3N
R"
N
Ph
16. General procedure for the synthesis of compounds 4: The corresponding
N
hydrazonoyl chloride
3 (1 mmol) and Et3N (1.2 mmol) were dissolved in
R"
R
N
DMF (3 mL) and stirred for 10 min. Next, a mixture of the sulfonyl azide 6,
(1.2 mmol), alkyne 5 (1 mmol), CuI (0.1 mmol), and Et3N (1 mmol) in DMF
(2 mL) was added with stirring at room temperature under N2 atmosphere.
After completion of the reaction [about 6 h; TLC (EtOAc/hexane, 1:5)
monitoring], the mixture was diluted with CH2Cl2 (2 mL) and aqueous
NH4Cl solution (3 mL), stirred for 30 min, and the layers separated. The
aqueous layer was extracted with CH2Cl2 (3 Â 3 mL) and the combined
organic fractions dried (Na2SO4) and concentrated under reduced pressure.
The residue was purified by flash column chromatography [silica gel (230–
400 mesh; Merck), hexane/EtOAc, 5:1] to give the product. The spectroscopic
data for compounds 4a, 4g, 4h, and 4i were similar to those reported by
Wang.12
Cu
R
H2O
2
4
N
Ph
C
C NR'
[3+2] cycloaddition
Cu
NR'
9
1
Scheme 2. A plausible mechanism for the formation of compounds 4.
N1-[3-(4-Methylphenyl)-1,4-diphenyl-1H-pyrazol-5-yl]-1-benzenesulfonamide
Supplementary data
(4b): Yellow solid, mp: 219–221 °C; yield: 0.40 g (87%). IR (KBr) (m
max, cmÀ1):
3738, 3431, 1595, 1507, 1255, 1110. 1H NMR (500 MHz, CDCl3): dH = 2.43
(3H, s, Me), 6.97 (1H, t, 3J = 7.2 Hz, Ar), 7.11–7.18 (5H, m, Ph), 7.25–7.30 (5H, m,
Ph), 7.36 (2H, t, 3J = 7.2 Hz, Ar), 7.48 (2H, t, 3J = 7.3 Hz, Ar), 7.68 (2H, t,
3J = 7.3 Hz, Ar), 7.92 (2H, d, 3J = 8.0 Hz, Ar), 8.73 (1H, s, NH). 13C NMR
(125.7 MHz, CDCl3): dC = 21.3 (Me), 113.4 (C), 120.9 (2 CH), 121.6 (C), 122.0
(CH), 125.4 (2 CH), 126.0 (C), 128.7 (2 CH), 128.8 (CH), 128.9 (2 CH), 129.0 (2
CH), 129.1 (C), 129.2 (2 CH), 129.3 (CH), 129.5 (2 CH), 131.9 (2 CH), 133.3 (C),
138.1 (C), 143.8 (C), 148.9 (C). MS: m/z (%) = 465 (M+, 10), 309 (25), 257 (21),
157 (40), 141 (100), 91 (50), 77 (55). Anal. Calcd for C28H23N3O2S (465.12): C,
72.23; H, 4.98; N, 9.03%. Found: C, 72.53; H, 5.05; N, 9.09%.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2012.01.083.
References and notes
1. Krow, G. R. Angew. Chem., Int. Ed. Engl. 1971, 10, 435.
2. Lu, P.; Wang, Y. G. Synlett 2010, 165.
3. Yoo, E. J.; Chang, S. Curr. Org. Chem. 2009, 13, 1766.
4. Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B. Angew. Chem., Int. Ed.
2002, 41, 2596.