Highly efficient copper- and palladium-free one-pot coupling of alkynes with sodium carboxylate salts using cyanuric and magnesium chlorides

Article abstract of DOI:10.1055/s-0030-1260336

A facile and highly efficient copper- and palladium-free procedure for the one-pot synthesis of ynones via coupling of sodium carboxylate salts with alkynes is described. In this method, cross-coupling of terminal alkynes with a mixture of structurally diverse sodium carboxylate salts, cyanuric chloride and triethylamine in the presence of magnesium chloride furnishes the corresponding ynones in good to excellent yields at room temperature. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0030-1260336

2562
LETTER
Highly Efficient Copper- and Palladium-Free One-Pot Coupling of Alkynes
with Sodium Carboxylate Salts Using Cyanuric and Magnesium Chlorides
One-Pot Coupling of
A
o
lkynes
w
ith
h
SodiumCar
a
mlts mad Navid Soltani Rad,* Somayeh Behrouz*
Department of Chemistry, Shiraz University of Technology, Shiraz 71555-313, Iran
Fax +98(711)7354520; E-mail: soltani@sutech.ac.ir; E-mail: behrouz@sutech.ac.ir
Received 31 July 2011
This paper is dedicated to Prof. Dr. Jalil Moghadasi, founder of Shiraz University of Technology.
boxylic acids compared with acid chlorides, the one-pot
Abstract: A facile and highly efficient copper- and palladium-free
procedure for the one-pot synthesis of ynones via coupling of sodi-
um carboxylate salts with alkynes is described. In this method,
cross-coupling of terminal alkynes with a mixture of structurally di-
coupling reaction of carboxylic acids with alkynes would
seem to be a suitable and attractive strategy. However, to
the best of our knowledge, there have been no reports on
verse sodium carboxylate salts, cyanuric chloride and triethylamine this type of approach. In this context, the application of
in the presence of magnesium chloride furnishes the corresponding
ynones in good to excellent yields at room temperature.
carboxylic salts is normally preferred due to their ease of
handling, higher nucleophilicity, simpler work-up, and
Key words: one-pot synthesis, alkyne, cyanuric chloride, sodium
carboxylate salt, ynone
cleaner reactions compared to carboxylic acids.
Cyanuric chloride (2,4,6-trichloro-1,3,5-triazine; TCT) is
a stable, nonvolatile, inexpensive, and safe reagent that
has been used extensively in many organic transforma-
tions.22 Recently, we have reported the application of cy-
anuric chloride as a useful and efficient reagent for the
synthesis of sulfonamides from amine-derived sulfonate
salts23a and also the N-acylation of sulfonamides from
carboxylic acids.23b In a continuation of our interest in
discovering new applications for cyanuric chloride in or-
ganic synthesis, now we report a very mild and highly ef-
ficient copper- and palladium-free protocol for the one-
pot synthesis of ynones by direct coupling of alkynes with
sodium carboxylate salts using cyanuric chloride, triethyl-
amine and magnesium chloride in acetonitrile at room
temperature (Scheme 1).
Ynones are versatile substrates in organic and medicinal
chemistry due to their occurrence in a wide variety of bio-
active molecules and natural products.1 Additionally, they
have been extensively used as key synthetic intermediates
for the construction of numerous biologically active het-
erocyclic compounds.2 In the light of their wide applica-
tions, various synthetic approaches for the preparation of
ynones have been developed. Common routes to the syn-
thesis of ynones include (i) the a-oxidation of an alkyne,3
(ii) the oxidation of propergylic alcohol derivatives4 and/
or the direct oxidative nucleophilic addition of an alde-
hyde to a vanadium acetylide,5 (iii) the palladium-cata-
lyzed cross-coupling reaction of terminal alkynes,6 or
metalated derivatives,7 with organic halides in the pres-
ence of CO, and (iv) the palladium-catalyzed coupling re-
action of carboxylic acid derivatives as a source of CO
and terminal alkynes8 or metal acetylides.9 From a syn-
thetic point of view, the use of very toxic CO as well as
expensive palladium catalysts and oxidizing reagents, has
limited the applicability of these approaches. Alternative
methods to access ynones are the reaction of alkynyl orga-
nometallic reagents such as silver,10 copper,1b,11 sodium,12
lithium,13 cadmium,14 zinc,15 indium,4b silicon,16 thalli-
um,17 or tin18 with acid chlorides. The reaction of alkynes
with acid chlorides in the presence of metal salts such as
copper(I) salts19 and zinc bromide20 have also been report-
ed. In addition, coupling of carboxylic acids with a large
excess of acetylenic Grignard reagent also led to low
yields of ynones. 21 Although some of these methods pos-
sess synthetic value, working with harmful acid chlorides
is still a critical problem. In the light of wide diversity and
availability, ease of handling, and lower toxicity of car-
O
TCT, Et3N, MgCl2
R1CO Na
+
R2
R1
2
MeCN, r.t., 1–2 h
Cl
R2
R1, R2 = alkyl, aryl
TCT:
N
N
Cl
N
Cl
Scheme 1 Coupling of alkynes with sodium carboxylate salts using
cyanuric chloride and magnesium chloride
In order to optimize the reaction conditions, we initially
chose the reaction of phenyl acetylene with a mixture of
sodium benzoate, cyanuric chloride, triethylamine, and
magnesium chloride as a model reaction to afford 1,3-
diphenylprop-2-yn-1-one. We screened a variety of sol-
vents and examined their effect on reaction times and
yields; the results are summarized in Table 1. Anhydrous
acetonitrile (entry 1) was found to be the most appropriate
solvent and was therefore used for all subsequent reac-
tions. A moderate yield of 1,3-diphenylprop-2-yn-1-one
was obtained when acetone (Table 1, entry 2) was tested.
Moreover, by using dimethyl sulfoxide (DMSO) or N,N-
SYNLETT 2011, No. 17, pp 2562–2566
x
x
.x
x
.2
0
1
1
Advanced online publication: 27.09.2011
DOI: 10.1055/s-0030-1260336; Art ID: B14511ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
One-Pot Coupling of Alkynes with Sodium Carboxylate Salts
2563
dimethylformamide (DMF) as solvent (Table 1, entries 6 The choice of the Lewis acid was of great significance for
and 7), the coupling of sodium benzoate with phenyl acet- the progress of the reaction. We evaluated the potency of
ylene was completely blocked, in spite of prolonging the several Lewis acids on the model reaction (Table 3). In
reaction time to 18 h. The inefficiencies of these solvents the absence of Lewis acid, the reaction resulted in a low
can presumably be attributed to their tendency to react yield. However, with magnesium chloride (Table 3, entry
with cyanuric chloride.22 Other solvents were compatible 2), the reaction progressed remarkably smoothly and af-
with the reaction, however, lower yields of the corre- forded a near-quantitative yield in a short reaction time.
sponding product were obtained (Table 1, entries 3–5).
The use of tin(II) chloride, silver nitrate, or lithium car-
bonate (Table 3, entries 5, 6, and 8) also afforded good
yields of the product.
Table 1 Solvent Variation
O
Therefore, magnesium chloride was selected for use, not
only because of its success in processing the reaction, but
also because it is inexpensive, readily available, stable,
and easy to handle. The other tested Lewis acids (Table 3,
entries 3, 4 and 7) did not promote the reaction to the same
extent as magnesium chloride. Moreover, the use of cop-
per(I) iodide (entry 7) caused alkyne–alkyne homocou-
pling, which, in turn, made the separation of products
cumbersome.
TCT, Et3N, MgCl2
PhCO2Na
+
Ph
Ph
solvent, r.t.
Ph
Entry
Solventa
Time (h)
Yield (%)b
1
2
3
4
5
6
7
MeCN
acetone
toluene
CH2Cl2
CHCl3
DMSO
DMF
1
3
95
76
10
12
12
18
18
25
Having recognized the effect of magnesium chloride in
promoting the reaction, the amount of magnesium chlo-
ride used was investigated and optimized (Table 4). It was
found that the best result was obtained when an equimolar
amount of magnesium chloride was employed (entry 5).
Using less than an equimolar amount of magnesium chlo-
ride also led to the formation of product, however, longer
reaction times were required and lower yields were ob-
tained (Table 4, entries 1–4).
50
44
NRc
NRc
a Anhydrous solvent.
b Isolated yield.
c No reaction.
Table 3 Lewis Acid Variation
The effect of various organic and inorganic bases on the
model reaction was also investigated (Table 2). As shown,
among the examined bases, triethylamine (entry 4) proved
to be the most efficient base for cross-coupling of sodium
benzoate with phenyl acetylene; other bases were not as
effective and, although they provided the product in mod-
erate to good yields, they required longer reaction times.
O
TCT, Et3N, Lewis acid
PhCO2Na
+
Ph
Ph
MeCN, r.t.
Ph
Entry
Lewis acid
none
Time (h)
Yield (%)a
1
2
3
4
5
6
7
8
7
1
5
5
2
2
5
2
45
95
68
75
82
80
56
83
MgCl2
ZnCl2
AlCl3
Table 2 Base Variation
O
TCT, base, MgCl2
PhCO2Na
+
Ph
Ph
MeCN, r.t.
Ph
SnCl2
Entry
Base
Time (h)
Yield (%)a
AgNO3
CuI
1
2
3
4
5
6
7
K2CO3
DBU
8
3
3
1
5
5
7
62
76
74
95
78
83
74
Li2CO3
DBN
a Isolated yield.
Et3N
The use of more than an equimolar amount of magnesium
chloride had no distinguishable effect on progress of the
model reaction (Table 4, entry 6).
DABCO
DMAP
pyridine
Applying carboxylic acids instead of the corresponded so-
dium salts under the optimized conditions afforded lower
yields of the desired ynones even after long reaction
times.24 As an example, the coupling of benzoic acid with
a Isolated yield.
Synlett 2011, No. 17, 2562–2566 © Thieme Stuttgart · New York

2564
M. N. Soltani Rad, S. Behrouz
LETTER
Table 5 Investigation of Reaction Scope (continued)
Table 4 Variation in the Amount of Magnesium Chloride
O
Entry
Producta
Time (h) Yield (%)b
TCT, Et3N, MgCl2 (x mol%)
PhCO2Na
+
Ph
Ph
MeCN, r.t.
O
Ph
68g
1.5
2
88
86
85
Entry
MgCl2 (x mol%) Time (h)
Yield (%)a
Cl
1
2
3
4
5
6
20
40
4
68
72
83
90
95
95
O
3.5
3
76b,20b
60
MeO
80
2
O
100
120
1
88b
1.5
1
OMe
a Isolated yield.
O
phenyl acetylene was carried out in 63% yield, after
seven hours.
98b,c,g,20b
108g,20b
118f,20b
128b,f
1
95
94
89
88
86
83
68
O2N
O2N
To explore the scope of this method, the optimized reac-
tion conditions were applied to the coupling of a variety
of structurally diverse alkynes and sodium carboxylate
salts (Table 5). From the results detailed in Table 5, it is
clear that this method is highly efficient and useful for so-
dium benzoate derivatives with either electron-donating
or electron-withdrawing substituents on the aryl residue.
It is noteworthy that heteroaryl sodium carboxylate salts
such as thiophene and furan derivatives were completely
converted into the corresponding ynones in excellent
yields (Table 5, entries 11 and 12).
O
1
O
S
1.3
1.3
1.5
1.5
1.5
O
Table 5 Investigation of Reaction Scope
O
Entry
Producta
Time (h) Yield (%)b
O
18b,c,f,g,20
1
1
1
95
92
90
O
138b,f,20b
O
O
28c,20a
O
148f
36b,8c,20a
O
158f
OMe
O
46b,8g,20b
2
2
91
90
a All products were characterized by 1H and 13C NMR, IR, CHN and
MS analyses.
b Isolated yield.
O
58g,20
Moreover, the coupling reaction of phenyl acetylene with
aliphatic sodium carboxylate salts furnished the desired
Cl
Synlett 2011, No. 17, 2562–2566 © Thieme Stuttgart · New York

LETTER
One-Pot Coupling of Alkynes with Sodium Carboxylate Salts
2565
product in good yields (Table 4, entries 13–15). To further
evaluate the utility of this coupling reaction, the coupling
of aliphatic terminal alkynes with sodium carboxylate
salts were also evaluated.
References and Notes
(1) (a) Mead, D.; Asato, A. E.; Denny, M.; Liu, R. S. H.;
Hanzawa, Y.; Taguchi, T.; Yamada, A.; Kobayashi, N.;
Hosoda, A.; Kobayashi, Y. Tetrahedron Lett. 1987, 28, 259.
(b) Chowdhury, C.; Kundu, N. G. Tetrahedron 1999, 55,
7011. (c) Quesnelle, C. A.; Gill, P.; Dodier, M.; St. Laurent,
D.; Serrano-Wu, M.; Marinier, A.; Martel, A.; Mazzucco,
C. E.; Stickle, T. M.; Barrett, J. F.; Vyas, D. M.;
To our delight, excellent yields of the corresponding
ynones were attained when aliphatic terminal alkynes
were coupled with sodium carboxylate salts using this
method (Table 4, entries 4, 5, and 7).
Balasubramanian, B. N. Bioorg. Med. Chem. Lett. 2003, 13,
519.
Mechanistically, we believe that this reaction proceeds via
an initial SnAr-type reaction between the carboxylate an-
ion and cyanuric chloride, affording the active carboxy-
late-cyanuric ester (Scheme 2). Indeed, in agreement with
reports in the literature,25 the ready formation of the cor-
responding active ester was observed during the early
stages of the reaction. The alkynes then react with active
carboxylate-cyanuric esters in the presence of magnesium
chloride and triethylamine to provide the corresponding
ynones.
(2) (a) Hojo, M.; Omita, K.; Hosomi, A. Tetrahedron Lett. 1993,
34, 485. (b) Arcadi, A.; Marenelli, F.; Rossi, E. Tetrahedron
1999, 55, 13233. (c) Kelin, A. V.; Sromek, A. W.;
Gevorgyan, V. J. Am. Chem. Soc. 2001, 123, 2074.
(d) Jeevnandan, A.; Narkunan, K.; Ling, Y. J. Org. Chem.
2001, 66, 6014. (e) Grotjahn, D. B.; Van, S.; Combs, D.;
Lev, D. A.; Schneider, C.; Rideout, M.; Meyer, C.;
Hernandez, G.; Mejorado, L. J. Org. Chem. 2002, 67, 9200.
(f) Karpov, A. S.; Muller, T. J. Org. Lett. 2003, 5, 3451.
(3) (a) Muzart, J.; Piva, O. Tetrahedron Lett. 1988, 29, 2321.
(b) Shaw, J. E.; Sherry, J. J. Tetrahedron Lett. 1971, 4379.
(c) Sheats, W. B.; Olli, L. K.; Stout, R.; Lundeen, J. T.;
Justus, R.; Nigh, W. G. J. Org. Chem. 1979, 44, 4075.
(4) (a) Maeda, Y.; Kakiuchi, N.; Matsumura, S.; Nishimura, T.;
Kawamura, T.; Uemura, S. J. Org. Chem. 2002, 67, 6718;
and references therein. (b) Augé, J.; Lubin-Germain, N.;
Seghrouchni, L. Tetrahedron Lett. 2003, 44, 819.
(5) (a) Corey, E. J.; Kyler, K.; Raju, N. Tetrahedron Lett. 1984,
25, 5115. (b) Campestrini, S.; Furia, F. D.; Modena, G.
J. Org. Chem. 1990, 55, 3658. (c) Hirao, T.; Misu, D.;
Agawa, T. Tetrahedron Lett. 1986, 27, 933.
O
Cl
N
O
N
R1
O
3 R1CO Na
N
N
+
O
N
N
O
2
– NaCl
R1
O
Cl
Cl
R1
OH
O
(6) (a) Mohamed Ahmed, M. S.; Mori, A. Org. Lett. 2003, 5,
3057; and all references therein. (b) Liang, B.; Huang, M.;
You, Z.; Xiong, Z.; Lu, K.; Fathi, R.; Chen, J.; Yang, Z.
J. Org. Chem. 2005, 70, 6097.
R2
Et3N, MgCl2
3
+
3
N
N
R1
R2
HO
N
OH
(7) (a) Goure, W. F.; Wright, M. E.; Davis, P. D.; Labadie, S. S.;
Stille, J. K. J. Am. Chem. Soc. 1984, 106, 6417. (b) Grisp,
G. T.; Scott, W. J.; Stille, J. K. J. Am. Chem. Soc. 1984, 106,
7500. (c) Arcadi, A.; Cacchi, S.; Marinelli, F.; Ace, P.;
Sanzi, G. Synlett 1995, 823.
(8) (a) Palimkar, S. S.; Harish Kumar, P.; Jogdand, N. R.;
Daniel, T.; Lahoti, R. J.; Srinivasan, K. V. Tetrahedron Lett.
2006, 47, 5527. (b) Alonso, D. A.; Nájera, C.; Pacheco,
M. C. J. Org. Chem. 2004, 69, 1615. (c) Chen, L.; Li, C.-J.
Org. Lett. 2004, 6, 3151. (d) Cox, R. J.; Ritson, D. J.; Dane,
T. A.; Berge, J.; Charmant, J. P. H.; Kantacha, A. Chem.
Commun. 2005, 1037. (e) Likhar, P. R.; Subhas, M. S.; Roy,
M.; Roy, S.; Kantam, M. L. Helv. Chim. Acta 2008, 91, 259.
(f) Chen, J.-Y.; Lin, T.-C.; Chen, S.-C.; Chen, A.-J.; Mou,
C.-Y.; Tsai, F.-Y. Tetrahedron 2009, 65, 10134.
Scheme 2 A plausible mechanism for coupling of alkynes with
sodium carboxylate salts using cyanuric chloride
In summary, we have developed a mild and simple, one-
pot, copper- and palladium-free synthetic protocol for the
preparation of ynones via coupling of various, structurally
diverse sodium carboxylate salts and terminal alkynes us-
ing cyanuric chloride in the presence of magnesium chlo-
ride and triethylamine in anhydrous acetonitrile.26 Using
this method, various ynones were obtained in good to ex-
cellent yields and in short reaction times. Moreover, the
use of sodium carboxylate salts as starting material over-
comes the problems usually associated with handling tox-
ic and corrosive acid chlorides. No expensive catalysts
were consumed in this method. This present approach can
be considered as a useful protocol for large-scale synthe-
sis of ynones, which are significant precursors for access-
ing a large number of heterocyclic compounds.
(g) Bakherad, M.; Keivanloo, A.; Bahramian, B.; Rajaie, M.
Tetrahedron Lett. 2010, 51, 33.
(9) (a) Tohda, Y.; Sonogashira, K.; Hagihara, N. Synthesis 1977,
777. (b) Verkruijsse, H. D.; Heus-Kloos, Y. A.; Brandsma,
L. J. Organomet. Chem. 1988, 338, 289. (c) Logue, M. W.;
Teng, K. J. Org. Chem. 1982, 47, 2549. (d) Wakamatsu, T.;
Okuda, Y.; Oshima, K.; Nozaki, H. Bull. Chem. Soc. Jpn.
1985, 58, 2425. (e) Pérez, I.; Sestelo, J. P.; Sarandeses, L. A.
J. Am. Chem. Soc. 2001, 123, 4155. (f) Kakusawa, N.;
Yamaguchi, K.; Kurita, J.; Tsuchiya, T. Tetrahedron Lett.
2000, 41, 4143.
Acknowledgment
The authors wish to thank Shiraz University of Technology research
council for partial support of this work.
(10) Davis, R. B.; Scheiber, D. H. J. Am. Chem. Soc. 1956, 78,
1675.
(11) (a) Normant, J. F. Synthesis 1972, 63. (b) Logue, M. W.;
Moore, G. L. J. Org. Chem. 1975, 40, 131.
(12) Fontaine, M.; Chauvelier, J.; Barchewitz, P. Bull. Soc. Chim.
Fr. 1962, 2145.
Synlett 2011, No. 17, 2562–2566 © Thieme Stuttgart · New York

2566
M. N. Soltani Rad, S. Behrouz
LETTER
(13) Compagnon, P. L.; Grosjean, B.; Lacour, M. Bull. Soc.
Chim. Fr. 1975, 779.
Behrouz, S. Synthesis 2010, 2599.
(24) Similar reaction conditions were employed for carboxylic
acid, except that Et3N (6.6 equiv) was employed
(25) (a) Venkataraman, K.; Wagle, D. R. Tetrahedron Lett. 1979,
3037. (b) Bandgar, B. P.; Pandit, S. S. Tetrahedron Lett.
2002, 43, 3413. (c) Kaminski, Z. J.; Paneth, P.; Rudzinski, J.
J. Org. Chem. 1998, 63, 4248. (d) Rayle, H. L.; Fellmeth, L.
Org. Process Res. Dev. 1999, 3, 172.
(26) General procedure for coupling of alkynes with sodium
carboxylate salts using cyanuric chloride: To a solution of
sodium carboxylate salt (3.3 mmol) in anhydrous MeCN (5
mL), was added TCT (1 mmol) and the reaction mixture was
stirred at r.t. for 10 min. A solution of the appropriate alkyne
(3 mmol), Et3N (3.3 mmol) and MgCl2 (3.3 mmol) in
anhydrous MeCN (5 mL) was added and the solution was
stirred for a further 50–110 min (until TLC indicated
completion of the reaction, see Table 5). The solution was
filtered and the solvent was evaporated under vacuum. The
remaining foam was then diluted in CHCl3 (50 mL) and
subsequently washed with H2O (2 × 50 mL). The organic
layer was dried (Na2SO4) and evaporated. The crude product
was purified by short column chromatography on silica gel
(n-hexane–EtOAc, 20:1).
(14) Yashina, O. G.; Zarva, T. V.; Vereshchagin, L. I. Zh. Org.
Khim. 1967, 3, 219; Chem. Abstr. 1967, 66, 94664.
(15) Vereshchagin, L. I.; Yashina, O. G.; Zarva, T. V. Zh. Org.
Khim. 1966, 2, 1895; Chem. Abstr. 1967, 66, 46070p.
(16) (a) Utimoto, K.; Tanaka, M.; Kitai, M.; Nozaki, H.
Tetrahedron Lett. 1978, 2301. (b) Birkofer, L.; Ritter, A.;
Uhlenbrauck, H. Chem. Ber. 1963, 96, 3280. (c) Walton,
D. R. M.; Waugh, F. J. Organomet. Chem. 1972, 37, 45.
(d) Gallagher, W. P.; Maleczka, R. E. Jr. J. Org. Chem.
2003, 68, 6775.
(17) Markó, I. E.; Southern, J. M. J. Org. Chem. 1990, 55, 3368.
(18) Himbert, G. Angew. Chem., Int. Ed. Engl. 1979, 18, 405.
(19) Chowdhury, C.; Kundu, N. G. Tetrahedron Lett. 1996, 37,
7323.
(20) (a) Lee, K. Y.; Lee, M. J.; Kim, J. N. Tetrahedron 2005, 61,
8705. (b) Keivanloo, A.; Bakherad, M.; Bahramian, B.;
Baratnia, S. Tetrahedron Lett. 2011, 52, 1498.
(21) Dishart, K. T.; Levine, R. J. Am. Chem. Soc. 1956, 78, 2268.
(22) Blotny, G. Tetrahedron 2006, 62, 9507; and all references
cited therein.
(23) (a) Soltani Rad, M. N.; Khalafi-Nezhad, A.; Asrari, Z.;
Behrouz, S.; Amini, Z.; Behrouz, M. Synthesis 2009, 3983.
(b) Soltani Rad, M. N.; Khalafi-Nezhad, A.; Asrari, Z.;
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