Efficient synthesis of novel 1,3-diyne-based sulfonamides using CuCl2/Et3N as a robust catalytic system

Article abstract of DOI:10.1080/17415993.2016.1263634

An efficient and practical synthesis of 1,3-diyne-based sulfonamides using CuCl₂/Et₃N as a catalytic system is disclosed. Mild reaction conditions, atom-economy and high yields (50–91%) make this method an attractive option for the preparation of 1,3-diyne-based sulfonamide derivatives.

Full text of DOI:10.1080/17415993.2016.1263634

Journal of Sulfur Chemistry
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Efficient synthesis of novel 1,3-diyne-based
sulfonamides using CuCl2/Et3N as a robust
catalytic system
Zohreh Mirjafary, Hamed Sadighian, Samira Piri & Hamid Saeidian
To cite this article: Zohreh Mirjafary, Hamed Sadighian, Samira Piri & Hamid Saeidian (2016):
Efficient synthesis of novel 1,3-diyne-based sulfonamides using CuCl2/Et3N as a robust catalytic
system, Journal of Sulfur Chemistry, DOI: 10.1080/17415993.2016.1263634
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Date: 26 December 2016, At: 08:00

JOURNAL OF SULFUR CHEMISTRY, 2016
http://dx.doi.org/10.1080/17415993.2016.1263634
Efficient synthesis of novel 1,3-diyne-based sulfonamides
using CuCl2/Et3N as a robust catalytic system
Zohreh Mirjafarya, Hamed Sadighianb, Samira Pirib and Hamid Saeidianb
aDepartment of Chemistry, Tehran Science and Research Branch, Islamic Azad University, Tehran, Iran;
bDepartment of Science, Payame Noor University (PNU), Tehran, Iran
ABSTRACT
ARTICLE HISTORY
Received 22 September 2016
Accepted 17 November 2016
An efficient and practical synthesis of 1,3-diyne-based sulfonamides
using CuCl2/Et3N as a catalytic system is disclosed. Mild reaction con-
ditions, atom-economy and high yields (50–91%) make this method
an attractive option for the preparation of 1,3-diyne-based sulfon-
amide derivatives.
KEYWORDS
1,3-Diyne;
N-propargylsulfonamides;
CuCl2; C–C coupling
Introduction
1,3-Diynes are versatile and valuable building block for a number of biologically and
pharmaceutically active compounds and for the material field due to the unique behav-
ior of acetylenes [1–9]. They can be converted into various structural entities, especially
substituted heterocyclic compounds such as furans, thiophenes, and pyrazoles with high
atom efficiency [10–14]. Moreover, sulfonamide derivatives are also well-known important
biological compounds which have attracted great attention for their interesting phar-
macological activity [15–18]. The marketed drugs containing sulfonamide motifs are
known to have many biological properties, including but not restricted to anti-diabetic,
antimicrobial, anti-epilepsy, and antibacterial activities.
Design and synthesis of novel molecular scaffolds with unique structural and biologi-
cal properties is always important and interesting. The most common strategy employed
in the synthesis of 1,3-diynes relies upon the oxidative Glaser–Eglinton coupling reaction
[19]. In recent years, several improvements and modifications have been introduced in this
CONTACT Zohreh Mirjafary
mirjafary@srbiau.ac.ir, zmirgafary@yahoo.com
Supplemental data for this article can be accessed here. http://dx.doi.org/10.1080/17415993.2016.1263634
© 2016 Informa UK Limited, trading as Taylor & Francis Group

2
Z. MIRJAFARY ET AL.
Scheme 1. General pathway for synthesis of 1,3-diyne-based sulfonamide derivatives 3.
coupling reaction for the synthesis of different 1,3-diyne derivatives from terminal alkynes
and other substrates [20–24]. However, to the best of our knowledge, there is no report
for the fabrication of 1,3-diynes containing the sulfonamide group. Taking these factors
into consideration, we were interested in developing a method that provides facile access
to 1,3-diyne-based sulfonamide derivatives. The synthesis of the title compounds is based
on employing N-propargylsulfonamides as cheap acetylene derivatives which can be pre-
pared easily from commercial available arylsulfonyl chlorides, aromatic/aliphatic amines,
and propargyl bromide (Scheme1).
Result and discussion
The starting sulfonamides bearing alkynes 2 are readily prepared in house. Treatment of
para-toluene sulfonyl chloride with amine in pyridine at room temperature for 2 h gave the
corresponding sulfonamide in excellent yields (>85%). The N-propargylsulfonamides 2
were then prepared in high yields (>78%) by the treatment of the synthesized sulfonamide
with propargylbromide in the presence of K2CO3 in refluxing acetonitrile for 8 h.
Preliminary investigation of the model reaction (N-propargylsulfonamide 2 (N-benzyl-
N-tosylprop-2-yn-1-amine)) showed that the coupling reaction did not proceed in the
absence of catalyst and base after 18 h (Table 1, Entry 1), while good results were obtained
in the presence of copper (II) catalysts. CuCl2 was more efficient than other Cu(II) salts
(Table 1, Entries 2 and 4). Trace amount of the desired product was obtained in the pres-
ence of CuCl (Table 1, Entry 3). Upon optimization of amount of catalyst, we found that
5 mol% of the catalyst could effectively catalyze the reaction for synthesis of the desired
product (Table 1, Entry 5). Using more than 5 mol% CuCl2 was ineffective at improv-
ing the yield of the reaction. Our experiment showed that the presence of CuCl2 along
with base is required to achieve the coupling of 2 and no reaction was observed when the
coupling was performed with Cu(II) alone (Table 1, Entry 6). It is known that the base

JOURNAL OF SULFUR CHEMISTRY
3
Table 1. Optimization of the model reaction for synthesis of 1,3-diyne-based sulfonamide derivatives.a
Entry
Catalyst (mol%)
Base
Solvent
Temp (°C)
Yield (%)b
1
2
3
4
5
6
7
8
None
Cu(OAc)2 (10)
CuCl (10)
CuCl2 (10)
CuCl2 (5)
CuCl2 (5)
CuCl2 (5)
CuCl2 (5)
CuCl2 (5)
CuCl2 (5)
CuCl2 (5)
CuCl2 (5)
CuCl2 (5)
CuCl2 (5)
CuCl2 (5)
CuCl2 (5)
CuCl2 (5)
None
Et3N
Et3N
Et3N
Et3N
None
K2CO3
pyridine
Et2NH
piperidine
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
H2O
H2O/EtOH
DMF
benzene
THF
toluene
toluene
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
25
110
0
31
trace
93
91
0
12
53
51
37
9
10
11
12
13
14
15
16
17
0
trace
29
82
20
trace
84
aReaction conditions: Solvent (3 mL), N-propargylsulfonamides 2 (1 mmol), Base (1 mmol), and reaction time 18 h.
bIsolated yields after column chromatography.
plays a vital role in the reaction: deprotonation of the presumed copper (II)-coordinated
N-propargylsulfonamide 2 (Scheme 3). Triethylamine was more effective than other
organic or inorganic bases (Table 1, Entries 7–10). We then continued to optimize the
model reaction by examining the efficiency of polar and nonpolar solvents. It was found
that the reaction proceeded in a nonpolar solvent such as toluene with good yield. The
yields decreased when the reaction was carried out in other solvents (Table 1, Entries
11–15). The effect of temperature was also studied by carrying out the model reaction at
room temperature, 80°C and 110°C. It was observed that the yield increased as the reaction
temperature was raised to 80°C. Therefore, the optimal condition for the reaction involves
CuCl2 (5 mol%)/Et3N (1 mmol), N-propargylsulfonamide 2 (1 mmol) in toluene (3 mL) at
80°C under an air/O2 atmosphere for 18 hours (Table 1, Entry 5).
In order to prove the applicability of the optimized reaction condition for the syn-
thesis of various 1,3-diynes bearing a sulfonamide group, we examined various com-
bination of substrates. As shown in Scheme 2, the catalytic oxidative homocoupling of
N-propargylsulfonamides 2, containing aromatic and aliphatic substituents, proceeded
readily to afford the corresponding 1,3-diyne-based sulfonamide derivatives 3a–h in
50–91% yields.
1
The structure of the products was confirmed by H NMR, 13C NMR and elemental
1
(CHN) analysis (Supplementary material). The H NMR spectra of the products do not
exhibit an alkynyl proton and the intensity of the terminal alkynyl carbon in the 13C
1
NMR increased on going from the alkyne to the diyne. The H NMR and 13C NMR
1
spectra of the product clearly indicated the formation of 3g. The H NMR spectrum
of 3g consisted of a triplet line at δ = 0.94 ppm (J = 7.2 Hz) for the methyl protons,
two multiplet lines at δ = 1.33–1.38 and 1.49–1.54 ppm for the two methylene groups,
a triplet line at δ = 3.14 ppm (J = 7.2 Hz) for the methylene protons (CH2–N), a broad
singlet at δ = 4.17 ppm for the methylene connected to the alkyne group, two multi-
plets at δ = 7.48–7.52 and 7.57–7.60 ppm and a doublet at δ = 7.82 ppm (J = 7.6 Hz) for

4
Z. MIRJAFARY ET AL.
Scheme 2. Efficient synthesis of 1,3-diyne-based sulfonamides.
Scheme 3. Proposed mechanism for formation of 1,3-diyne-based sulfonamides 3a–h.
1
the aromatic protons. The H-decoupled 13C NMR spectrum of 3g showed 11 distinct
resonances which is in agreement with the proposed structure.
A possible reaction mechanism to account for the formation of substituted 1,3-diyne-
based sulfonamide derivatives using catalytic amount of CuCl2 and Et3N is proposed in
Scheme 3. The reaction starts with the coordination of the N-propargylsulfonamide 2 to Cu
(II), leading to deprotonation of 2 with the assistance of Et3N to form copper acetylide I as
the key intermediate [25]. Subsequently another alkynyl unit is attached to I and reductive
elimination occurs to assemble the desired product [11,26]. The need for only a catalytic
amount of the Cu (II) indicates that Cu (I) to Cu (II) regeneration by molecular oxygen
occurs during the reaction [27].
Conclusion
In summary, this paper describes an efficient and practical protocol for the synthesis of 1,3-
diyne-based sulfonamides through oxidative dimerization of N-propargylsulfonamides.

JOURNAL OF SULFUR CHEMISTRY
5
We established catalytic conditions for the copper(II) salt-mediated coupling reaction of
N-propargylsulfonamides in contrast to existing stoichiometric systems. The advantages
of the method are the commercially available or easily accessible starting materials, the
simplicity and excellent yields.
Experimental
General information
All the chemicals required for the synthesis of the 1,3-diyne-based sulfonamide derivatives
3 were purchased from Sigma-Aldrich (St. Louis, MO, USA), Fluka (Neu-Ulm, Germany)
and Merck (Darmstadt, Germany companies and were used as received. The all synthesized
compounds 3 gave satisfactory spectroscopic data. A Bruker (DRX-400 Avance) NMR
1
was used to record the H NMR and 13C NMR spectra. All NMR spectra were deter-
mined in CDCl3 at ambient temperature. All the reactions are monitored by thin layer
chromatography carried out on silica gel with ultraviolet light and iodine, as detecting
agents.
General procedure for the synthesis of 1,3-diyne-based sulfonamides 3a–h
A solution of the N-propargylsulfonamide 2 (1.0 mmol), CuCl2 (0.05 mmol, 5 mol%), Et3N
(1 mmol) and toluene (3.0 mL) in 10 mL round-bottomed flask was heated at 80°C under
air atmosphere for 18 h. The resulting Mixture was poured into H2O (5 mL), and extracted
with CH2Cl2 (3 × 5 mL). The organic layer was dried over Na2SO4 and evaporated under
reduced pressure. The residue was subjected to column chromatography (EtOAc/hexane
1:4) on silica gel to obtain pure products.
Spectra data of 1,3-diyne-based sulfonamides 3a–h
1
Compound 3a: H NMR (400 MHz, CDCl3): δ = 2.44 (s, 6H), 4.01 (s, 4H), 4.30 (s,
4H), 7.11–7.32 (m, 14H), 7.80 (d, J = 8.4 Hz, 4H) ppm; 13C NMR (100 MHz, CDCl3):
δ = 21.67, 36.24, 50.23, 69.57, 71.62, 127.84, 128.36, 128.74, 128.84, 129.66, 134.59, 135.62,
144.00 ppm. Anal. Calcd for C34H32N2O4S2: C, 68.43; H, 5.40; N, 4.69. Found: C, 68.35;
1
H; 5.48. N, 4.73. Compound 3b: H NMR (400 MHz, CDCl3): δ = 1.49 (d, J = 6.8 Hz,
6H), 2.48 (s, 6H), 3.63 (d, J = 18.4 Hz, 2H), 4.26 (d, J = 18.4 Hz, 2H), 5.26 (q, J = 6.8 Hz,
2H), 7.30–7.37 (m, 14H), 7.87 (d, J = 8.4 Hz, 4H) ppm; 13C NMR (100 MHz, CDCl3):
δ = 16.89, 21.64, 33.19, 55.80, 68.48, 74.81, 127.54, 127.55, 128.05,128.59, 129.65, 137.70,
139.04, 143.69 ppm. Anal. Calcd for C36H36N2O4S2: C, 69.20; H, 5.81; N, 4.48. Found:
1
C, 69.36; H; 5.75. N, 4.56. Compound 3c: H NMR (400 MHz, CDCl3): δ = 2.43 (s,
6H), 4.52 (s, 4H), 7.20–7.36 (m, 14H), 7.52 (d, J = 8 Hz, 4H) ppm; 13C NMR (100 MHz,
CDCl3): δ = 21.64, 41.89, 69.53, 73.46, 127.99, 128.29, 128.37, 129.21, 129.38, 135.31,
139.33, 143.96 ppm. Anal. Calcd for C32H28N2O4S2: C, 67.58; H, 4.96; N, 4.93. Found:
C, 67.39; H; 5.07. N, 4.86. Compound 3d: 1H NMR (400 MHz, CDCl3): δ = 4.01 (s, 4H),
4.34 (s, 4H), 7.32–7.42 (m, 10H), 7.55–7.66 (m, 6H), 7.91–7.94 (m, 4H) ppm; 13C NMR
(100 MHz, CDCl3): δ = 36.26, 50.24, 69.57, 71.44, 127.77, 128.43, 128.78, 128.87, 129.08,
133.09, 134.45, 138.63 ppm. Anal. Calcd for C32H28N2O4S2: C, 67.58; H, 4.96; N, 4.93.

6
Z. MIRJAFARY ET AL.
Found: C, 67.66; H, 4.88; N, 5.02. Compound 3e: 1H NMR (400 MHz, CDCl3): δ = 1.50 (d,
J = 7.2 Hz, 6H), 3.63 (d, J = 18.4 Hz, 2H), 4.24 (d, J = 18.4 Hz, 2H), 5.26 (q, J = 6.8 Hz,
2H), 7.20–7.37 (m, 10H), 7.54–7.74 (m, 6H), 7.98 (d, J = 8.8 Hz, 4H) ppm; 13C NMR
(100 MHz, CDCl3): δ = 16.96, 33.26, 55.94, 68.52, 74.67, 127.48, 127.53, 128.11, 128.63,
129.06, 132.88, 138.91, 140.64 ppm. Anal. Calcd for C34H32N2O4S2: C, 68.43; H, 5.40;
N, 4.69. Found: C, 68.51; H; 5.32. N, 4.78. Compound 3f: 1H NMR (400 MHz, CDCl3):
δ = 4.53 (s, 4H), 7.19–7.23 (m, 4H), 7.34–7.38 (m, 6H), 7.41–7.54 (m, 4H), 7.56–7.65 (m,
6H) ppm; 13C NMR (100 MHz, CDCl3): δ = 41.95, 69.57, 73.31, 127.95, 128.30, 128.49,
128.74, 129.24, 133.09, 138.23, 139.23 ppm. Anal. Calcd for C30H24N2O4S2: C, 66.65; H,
1
4.47; N, 5.18. Found: C, 66.49; H; 4.57. N, 5.25. Compound 3g: H NMR (400 MHz,
CDCl3): δ = 0.94 (t, J = 7.2 Hz, 6H), 1.33–1.38 (m, 4H), 1.49–1.54 (m, 4H), 3.14 (t,
J = 7.2 Hz, 4H), 4.18 (s, 4H), 7.48–7.52 (m, 4H), 7.57–7.60 (t, J = 7.20 Hz, 2H), 7.82 (d,
J = 7.6 Hz, 4H) ppm; 13C NMR (100 MHz, CDCl3): δ = 13.67, 19.69, 29.47, 36.84, 46.37,
69.11, 71.76, 127.57, 128.94, 132.85, 138.57 ppm. Anal. Calcd for C26H32N2O4S2: C, 62.37;
H, 6.44; N, 5.60. Found: C, 62.24; H, 6.58; N, 5.69. Compound 3h: 1H NMR (400 MHz,
CDCl3): δ = 2.44 (s, 6H), 4.48 (s, 4H), 7.05–7.09 (m, 4H), 7.26 (d, J = 8 Hz, 4H), 7.45–7.47
(m, 4H), 7.50 (d, J = 8 Hz, 4H) ppm; 13C NMR (100 MHz, CDCl3): δ = 21.67, 41.66,
69.64, 73.24, 122.36, 127.94, 129.55, 128.83, 132.41, 134.85, 138.24, 144.3 ppm. Anal. Calcd
for C32H26Br2N2O4S2: C, 52.90; H, 3.61; N, 3.86. Found: C, 52.79; H; 3.70. N, 3.96.
Acknowledgements
We would like to acknowledge to Mr Biglari for NMR spectral support.
Disclosure statement
No potential conflict of interest was reported by the authors.
References
[1] Stang PJ, Diederich F, editors. Modern acetylene chemistry. Weinheim: VCH; 1995.
[2] Turlington M, Du Y, Ostrum SG, et al. From highly enantioselective catalytic reaction of
1,3-diynes with aldehydes to facile asymmetric synthesis of polycyclic compounds. J Am Chem
Soc. 2011;133:11780–11794.
[3] Diederich F, Stang PJ, Tykwinski RR. Acetylene chemistry: chemistry, biology and material
science. Weinheim: Wiley-VCH Verlag GmbH & Co. KGaA; 2005.
[4] Shun ALKS, Tykwinski RR. Synthesis of naturally occurring polyynes. Angew Chem Int Ed.
2006;45:1034–1057.
[5] Bettanin L, Botteselle GV, Godoi M, et al. Green synthesis of 1,3-diynes from terminal
acetylenes under solvent-free conditions. Green Chem Lett Rev. 2014;7:105–112.
[6] Wang J, Shen Y, Kessel S, et al. Self-assembly made durable: water-repellent materials formed
by cross-linking fullerene derivatives. Angew Chem Int Ed. 2009;48:2166–2170.
[7] Shainyan BA, Ushakova IV. N,Nꢀ-(hexa-2,4-diyne-1,6-diyl)bis(trifluoromethanesulfonamide).
Russian J Org Chem. 2014;50:1835–1836.
[8] Karmakar R, Mamidipalli P, Yun SY, et al. Alder-Ene reactions of arynes. Org Lett.
2013;15:1938–1941.
[9] Brauer MCN, Filho RAWN, Westermann B, et al. Synthesis of antibacterial 1,3-diyne-linked
peptoids from an Ugi-4CR/Glaser coupling approach. Org Chem. 2015;11:25–30.
[10] Shi W, Lei A. 1,3-Diyne chemistry: synthesis and derivations. Tetrahedron Lett. 2014;55:
2763–2772.

JOURNAL OF SULFUR CHEMISTRY
7
[11] Siemsen P, Livingston RC, Diederich F. Acetylenic coupling: a powerful tool in molecular
construction. Angew Chem Int Ed. 2000;39:2632–2657.
[12] Gupta S, Agarwal PK, Saifuddin M, et al. Hydro-amination/-amidation of 1,3-diynes with
indoles/azoles/amides under modified Ullmann conditions: stereo- and regio-selective syn-
thesis of N-alkenynes via N–H bond activation. Tetrahedron Lett. 2011;52:5752–5757.
[13] Gholami M, Tykwinski RR. Oligomeric and polymeric systems with a cross-conjugated
π-framework. Chem Rev. 2006;106:4997–5027.
[14] Wang L, Yu X, Feng X, et al. Synthesis of 3,5-disubstituted pyrazoles via cope-type hydroami-
nation of 1,3-dialkynes. J Org Chem. 2013;78:1693–1698.
[15] Shen CH, Wang YF, Kovalevsky AY, et al. Amprenavir complexes with HIV-1 protease and its
drug-resistant mutants altering hydrophobic clusters. FEBS J. 2010;277:3699–3714.
[16] Sławinski J, Szafranski K, Vullo D, et al. Carbonic anhydrase inhibitors. Synthesis of hete-
rocyclic 4-substituted pyridine-3-sulfonamide derivatives and their inhibition of the human
cytosolic isozymes I and II and transmembrane tumor-associated isozymes IX and XII. Eur J
Med Chem. 2013;69:701–710.
[17] Kwon Y, Song J, Lee H, et al. Design, synthesis, and biological activity of sulfonamide analogues
of antofine and cryptopleurine as potent and orally active antitumor agents. J Med Chem.
2015;58:7749–7762.
[18] Johnson BK, Colvin CJ, Needle DB, et al. The carbonic anhydrase inhibitor ethoxzolamide
inhibits the mycobacterium tuberculosis PhoPR regulon and Esx-1 secretion and attenuates
virulence. Antimicrob Agents Chemother. 2015;59:4436–4445.
[19] Sindhu KS, Anilkumar G. Recent advances and applications of Glaser coupling employing
greener protocols. RSC Adv. 2014;4:27867–27887.
[20] Wang D, Li J, Li N, et al. An efficient approach to homocoupling of terminal alkynes: solvent-
free synthesis of 1,3-diynes using catalytic Cu(Ii) and base. Green Chem. 2010;12:45–48.
[21] Eglinton G, Galbraith AR. Cyclic diynes. Chem Ind. 1956;737–738.
[22] Balaraman K, Kesavan V. Efficient copper(II) acetate catalyzed homo- and heterocoupling of
terminal alkynes at ambient conditions. Synthesis. 2010;2010:3461–3466.
[23] Gao HY, Wagner H, Zhong D, et al. Glaser coupling at metal surfaces. Angew Chem Int Ed.
2013;52:4024–4028.
[24] Merkul E, Urselmann D, Müller TJ. Consecutive one-pot sonogashira-glaser coupling sequence
- direct preparation of symmetrical diynes by sequential Pd/Cu catalysis. Eur J Org Chem.
2011;2011:238–242.
[25] Li YN, Wang JL, He LN. Copper(II) chloride-catalyzed Glaser oxidative coupling reaction in
polyethylene glycol. Tetrahedron Lett. 2011;52:3485–3488.
[26] Yin W, He C, Chen M, et al. Nickel-catalyzed oxidative coupling reactions of two different
terminal alkynes using O2 as the oxidant at room temperature: facile syntheses of unsymmetric
1,3-diynes. Org Lett. 2009;11:709–712.
[27] Lu XL, Zhang YH, Luo CC, et al. Efficient and recyclable reaction system for the homocoupling
of terminal acetylenes. Synth Commun. 2006;36:2503–2511.