Convenient synthesis of 2-alkynylbenzazoles through Sonogashira cross-coupling reaction between thioethers and terminal alkynes

Article abstract of DOI:10.1016/j.tetlet.2015.08.001

We describe herein the synthesis of 2-alkynylbenzoxazole and 2-alkynylbenzothiazole derivatives through the Sonogashira cross-coupling reaction of the corresponding thioethers and terminal alkynes under aerobic conditions, using CuI and Pd(dppf)Cl₂ as catalysts. The synthetic methodology allows the convenient cross-coupling of heteroaromatic substrates with a wide variety of aromatic and aliphatic alkynes, in moderate to good yields. The behavior of mercapto benzoxazoles and benzothiazoles were also investigated in the desulfitative Sonogashira cross-coupling reaction. It is noteworthy that the reaction occurred better under aerobic conditions rather than an inert atmosphere, although with increased amounts of the diyne side-product.

Full text of DOI:10.1016/j.tetlet.2015.08.001

Tetrahedron Letters 56 (2015) 5349–5352
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Convenient synthesis of 2-alkynylbenzazoles through Sonogashira
cross-coupling reaction between thioethers and terminal alkynes
Anca Paun a,y, Mihaela Matache a,y, Florina Enache b, Ioana Nicolau a, Codruta C. Paraschivescu a,
Petre Ionita a, Irina Zarafu a, Vasile I. Parvulescu a, , Gérald Guillaumet b,
⇑
⇑
a University of Bucharest, Faculty of Chemistry, 90-92 Panduri Street, RO-050663 Bucharest, Romania
b Institut de Chimie Organique et Analytique, Université d’Orléans, UMR CNRS 7311, BP 6759, 45067 Orléans Cedex 2, France
a r t i c l e i n f o
a b s t r a c t
Article history:
We describe herein the synthesis of 2-alkynylbenzoxazole and 2-alkynylbenzothiazole derivatives
through the Sonogashira cross-coupling reaction of the corresponding thioethers and terminal alkynes
under aerobic conditions, using CuI and Pd(dppf)Cl2 as catalysts. The synthetic methodology allows the
convenient cross-coupling of heteroaromatic substrates with a wide variety of aromatic and aliphatic
alkynes, in moderate to good yields. The behavior of mercapto benzoxazoles and benzothiazoles were
also investigated in the desulfitative Sonogashira cross-coupling reaction. It is noteworthy that the reac-
tion occurred better under aerobic conditions rather than an inert atmosphere, although with increased
amounts of the diyne side-product.
Received 23 April 2015
Revised 21 July 2015
Accepted 1 August 2015
Available online 6 August 2015
Keywords:
Sonogashira reaction
Benzoxazole
Heteroaromatic thioethers
Cross-coupling reactions
Palladium-catalysis
Ó 2015 Elsevier Ltd. All rights reserved.
Introduction
exhibit good compatibility with various transformations. Due to
the continued interest in developing new organic molecules with
Transition metal-catalyzed carbon–carbon cross-coupling reac-
tions have revolutionized the art and practice of organic synthesis
in the last two decades.1 The development of generalized mild
reaction conditions, high functional group tolerance and broad
availability of the starting materials have contributed to the grow-
ing success of palladium-catalyzed carbon–carbon bond formation
methods.2 The cross-coupling reactions usually occur between
organometallic or boronic reagents and organic halides (mostly
iodides and bromides, rarely chlorides) or pseudohalides (e.g., tri-
flates) as electrophilic partners.1b The variety of the electrophilic
partner has been extensively screened and, recently, protocols
involving sulfur compounds as electrophiles were reported as
convenient alternatives to halides.3 Notably, this holds true in
the cross-coupling of heteroaromatics which has not been devel-
oped to its full extent due to the limited availability of the corre-
sponding heteroaromatic halides. Heteroaryl thioethers have
been less explored as substrates in coupling reactions (i.e.,
Suzuki4 or Stille5) although they are stable, readily accessible and
biological relevance6 and functional materials containing ethyny-
lene-bridged
p
-conjugated systems,7 the Sonogashira reaction
has proved to be an excellent tool for the synthesis of alkyne
heteroaromatic motifs. The literature reported on the
Sonogashira reaction has witnessed tremendous development in
terms of the examined electrophilic substrates, catalysts, solvents
and bases, demonstrating its utility in various fields of chemistry.8
We therefore focused our attention on extending the scope of the
Sonogashira cross-coupling by using heteroaromatic methylth-
ioethers as electrophilic partners, which have been less explored
in alkynylation procedures via Sonogashira conditions.3,9 In this
work we report a new and convenient method for the preparation
of 2-alkynyl benzoxazoles and 2-alkynyl benzothiazoles (Fig. 1)
through the aerobic, copper(I)-promoted, palladium-catalyzed
desulfitative Sonogashira coupling of (2-methylthio)benzazoles
with terminal alkynes. Interest in the synthesis of compounds con-
taining the benzoxazole10a–c and benzothiazole10d,e moieties has
lately increased due to their presence in recently discovered
biologically active molecules, which act as natural antibiotics,
modulators for various receptors and antitumor compounds. This
is also apparent from the growing number of publications
reporting the direct oxidative coupling in position 2 of such
benzazoles using various reaction conditions.11
⇑
Corresponding authors. Tel./fax: +40 21 410 0241.
E-mail addresses: vasile.parvulescu@g.unibuc.ro (V.I. Parvulescu), gerald.
guillaumet@univ-orleans.fr (G. Guillaumet).
y
These authors contributed equally to this work.
http://dx.doi.org/10.1016/j.tetlet.2015.08.001
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.

5350
A. Paun et al. / Tetrahedron Letters 56 (2015) 5349–5352
R2
R1
a wide variety of substituted acetylenes (Table 2). Reasonable to
good yields were obtained in each case and varied according to
the nature of the alkyne partner. In the case of aryl acetylenes with
electron-donating substituents (2b–g), the yields differed accord-
ing to the position of the substituent on the benzene ring. The fol-
lowing pattern was observed: para-substituted aryl acetylenes
gave the lowest yields (60% for 3b and 52% for 3e) followed by
the meta-substituted (73% for 3c and 62% for 3f) and ortho-substi-
tuted (92% for 3d and 90% for 3g) arylalkynes. Excellent yields were
obtained for compounds 3d and 3g, and was consistent with stud-
ies performed in classical Sonogashira cross-coupling reactions17
which showed that bulky substituents in the ortho position of
the aryl ring of the alkyne enhance the cross-coupling reaction
rate. When aryl acetylenes with electron-withdrawing sub-
stituents were used, the overall yields of the cross-coupling reac-
tion were significantly lower than those involving electron-rich
alkynes (Table 2). However, using this protocol we were able to
prepare new ethylene bridged benzoxazole compounds containing
electron-withdrawing-substituted aryl rings (see ESI for the spec-
tra of new compounds). In this series, it was also noted that for
the para-substituted acetylenes, fluorine-substituted coupling pro-
duct 3h was obtained in higher yields than the cyano-substituted
product 3j and the trifluoromethyl derivative 3k, respectively. As
far as the meta-substituted acetylenes were concerned, we
observed that the yields of the resultant products 3i and 3l were
lower than the corresponding para-substituted arylalkynes (3i vs
3h), which was in contrast to the electron-donating substituted
arylalkynes (3c vs 3b and 3f vs 3e). Use of aliphatic alkynes in
the cross-coupling reaction18 led to very good yields using only
1.5 equiv of the alkyne (Table 2, entries 12 and 13).
An attempt (Scheme 1) to selectively perform the cross-
coupling reaction of compound 1h with phenylacetylene via the
classical Sonogashira protocol (under inert atmosphere at room
temperature) surprisingly yielded the 2-alkynylated product 5,
with preservation of the bromine substituent (see ESI). The main
side-product was found to be diphenyl-1,3-butadiyne. Although
the obtained yield was modest, one can note that by performing
the reaction at room temperature, 2-alkynylated-5-bromobenzox-
azole could selectively be obtained, thus, allowing the possibility to
further increase the molecular diversity through reactions of the
C–Br bond.
We further investigated the coupling reaction of 2-mercapto-
benzoxazole with alkynes, beginning with the reaction between
2-mercaptobenzoxazole 6a and alkyne 2a (Table 3). Attempts
to utilize the reaction conditions reported by Tatibouet and
co-workers19 (Table 3, entry 1) gave the coupling product 3a in
X
N
R
X = O: R2=H, R1=H, MeO, F, Cl
X = S: R1=R2=H; R1=H, R2=EtO;
R1=Cl, R2=H
R = H, electron-donating group,
electron-withdrawing group
Figure 1. Structure of the synthesized compounds.
Results and discussions
To the best of our knowledge, use of 2-(thioether)benzoxazoles
or 2-mercaptobenzoxazole derivatives in the Sonogashira coupling
reaction has not been reported.11,12 Thus, our work began with an
exploration of the reaction conditions for the model coupling of (2-
methylthio)benzoxazole 1a13 with phenylacetylene 2a, in presence
of copper(I) iodide, using Pd(dppf)Cl2 as the palladium source
(Table 1), which was in line with previous reports using this cat-
alytic system with various heteroaromatics.9b Solvents, bases,
alkyne equivalents as well as temperature and reaction times
were varied in order to find the optimum reaction conditions for
the preparation of compound 3a (Table 1). Since most classical
Sonogashira conditions use polar solvents,8a,9b,c we initially
utilized THF and 1,4-dioxane, under an inert atmosphere (entries
1 and 2), with very poor results (traces of 3a using THF and 32%
yield using 1,4-dioxane). The coupling reaction was found to
provide better yields (47%) when toluene was used (entry 5).
Performing the same reactions under aerobic conditions (entries
3 and 6) significantly increased the yield of 3a. This result
suggested that oxygen was not innocent in this reaction. A
possible role could be to preserve the effective oxidation state of
the catalyst in order to enhance the reaction yield.14 Further stud-
ies to elucidate this aspect are currently in progress.
The highest yields for the coupling reaction were obtained after
24 h in refluxing 1,4-dioxane or toluene (Table 1, entries 4 and 7).
The Sonogashira coupling reaction was found to be influenced by
the base used,15 and among the investigated bases, triethylamine
led to the best results for this particular substrate. In addition,
the amount of the alkyne was screened, which showed that three
equivalents of alkyne in 1,4-dioxane or toluene gave similar results
(Table 1, entries 4 and 7).
Expectedly, all reactions gave the homocoupling side-product,
1,4-diphenyl-1,3-butadiyne, as a combined result of the aerobic
atmosphere,16 and the excess alkyne. A larger amount of the acet-
ylene was thus required for effective cross-coupling to occur.
Having established the optimum reaction conditions (Table 1,
entry 7), we further investigated the scope of our reaction using
Table 1
Optimization of the cross-coupling reaction conditions between 2-(methylthio)benzoxazole 1a and phenylacetylene 2a
Pd(dppf)Cl2 10 mol%
O
N
CuI 20 mol%
O
N
+
S
base, solvent, air
1a
2a
3a
Entry
Solvent
Temp (°C)
Equivalents of 2a
Co-catalyst
Base
Reaction time (h)
Yields (%)
1a
2a
3
THF
66
2
2
2
3
2
2
3
3.5
3
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
—
TEA
TEA
TEA
TEA
TEA
TEA
TEA
TEA
6
6
6
24
6
Traces
32
52
69
47
67
72
70
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
Toluene
Toluene
Toluene
Toluene
DMF
100
100
100
110
110
110
110
130
130
106
4
5a
6
6
7
8
9
10
11
24
24
24
24
24
TEA
Cs2CO3
Piperidine
Traces
Traces
Traces
DMF
—
2
2
a
Reaction performed under Ar.

A. Paun et al. / Tetrahedron Letters 56 (2015) 5349–5352
5351
Table 2
Cross-coupling reactions between methylthioethers 1a–g and phenylacetylenes 2a–n
Pd(dppf)Cl2 10 mol%
R2
R1
R2
R1
X
N
1a-g
CuI 20 mol%
X
N
3b-s
R3
2a-n
R3
+
S
TEA, toluene, reflux, air
Entry
Reactant
X
R1
R2
Alkyne
R3
Alkyne equiv
Reaction time (h)
Producta
Yieldsb (%)
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1c
1d
1e
1f
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
S
H
H
H
H
H
H
H
H
H
H
H
H
H
MeO
F
Cl
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
2b
2c
2d
2e
2f
2g
2h
2i
4-Me-C6H4
3-Me-C6H4
2-Me-C6H4
4-MeO-C6H4
3-MeO-C6H4
2-MeO-C6H4
4-F-C6H4
3-F-C6H4
4-CN-C6H4
4-CF3-C6H4
3-Cl-C6H4
C5H11
C6H11
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
1.5/2/3
1.5/2/3
1.5/3
2/3
3
3
3
3
1.5/2/3
3
1.5/2/3
1.5
1.5
3
3
3
24/24/24
24/48/24
24/24
24/24
24
24
24
24
36/36/24
24
36/36/24
24
24
24
24
24
24
24
24
3b11a
3c11e
3d11c
3e11a
3f
57/59/60
30/57/73
27/92
47/52
62
90
56
45
14/17/29
19
48/52/54
62
77
75
67
—
53
60
40
3g
3h11f
3i
9
2j
2k
2l
3j
10
11
12
13
14
15
16
17
18
19
3k11c
3l
2m
2n
2a
2a
2a
2a
2a
2a
3m11e
3n
3o11d
3p
c
—
3
3
3
3q12
3r
S
S
EtO
H
1g
Cl
3s12
a
b
c
The spectral analysis of the reported compounds were identical with those described in the indicated references.
Yield after purification by flash column chromatography.
Degradation indicated by TLC.
Table 3
Optimization of the cross-coupling reaction conditions between 2-mercaptobenzoxazole 6a and phenylacetylene 2a
PdL 5 mol%
O
O
N
CuI 50 mol%
S
+
TEA
N
H
6a
2a
3a
Entry
Ligand (L)
Additive (equiv)
Solvent/temp (°C)
Atmosphere
Reaction time (h)
Alkyne equiv
Yielda (%)
1
2
3
4
5
(PPh3)4
(PPh3)4
(PPh3)4
(PPh3)4
(dppf)Cl2
CuTC (0.1)
CuTC (3)
CuMeSal (0.5)
CuMeSal (1)
CuMeSal (1)
DMF/130
1,4-Dioxane/100
DMF/25
DMF/130
DMF/130
Ar
Ar
Ar
air
air
2
1
3
1
1.5
1.2
3
3
3
15
Traces
24
50
60
24
a
Yield after purification by flash column chromatography.
low yield (15%). Use of 1,4-dioxane as solvent and 3 equiv of Cu(I)
thiophene-2-carboxylate (CuTC) did not furnish any product
(Table 3, entry 2) and attempts to perform the reaction in toluene
failed due to the low solubility of the substrate. However,
replacement of catalytic CuTC with one equivalent of Cu(I)-3-
methylsalycilate (CuMeSal) along with performing the reaction
under air and increasing the alkyne equivalents had a positive
effect (Table 3, entries 3 and 4). Finally, optimum results were
obtained when Pd(PPh3)4 was replaced by Pd(dppf)Cl2, yielding
the desired product in 60% yield (Table 3, entry 5) (see ESI for
experimental procedure).
Encouraged by these results, we attempted the cross-coupling
reactions of compounds 6b–e with phenylacetylene 2a (Table 4,
entries 1–4). We observed that successful coupling was only
achieved for methoxy-substituted benzoxazole 6b (Table 4, entry
1), proceeding in modest yield (30%), while for fluorine derivative
6c (Table 4, entry 2) only traces of the product were observed by
TLC. No coupling product was detected for the chlorine and bro-
mine derivatives 6d and 6e (Table 4, entries 3 and 4).
using the optimized reaction conditions. Gratifyingly, we obtained
very good results for the coupling reactions of 1b (75%, Table 2,
entry 14) and 1c (67%, Table 2, entry 15). However, for halogenated
methylthiobenzoxazoles 1d and 1h, we observed that the
chloroderivative 1d yielded only degradation products (Table 2,
entry 16), while the brominated analog 1h gave compound 4 in
54% yield (Scheme 1). Increasing the alkyne equivalents did not
improve the coupling reaction yield.
To further broaden the scope of the alkynylation procedure, we
also examined the use of 2-(methylthio)benzothiazoles 1e–g as
substrates (Table 2, entries 17–19). The yields of the cross-coupling
reactions were similar to their corresponding benzoxazole deriva-
tives for compounds 3q (53%) and 3r (60%), while the chlorine pro-
duct 3s was obtained in 40% yield, which was higher than its
benzoxazole derivative which was not formed (see ESI for the spec-
tral analysis of the compounds).
Finally, we used 2-mercaptobenzothiazoles 6f–h (Table 4,
entries 5–7) as substrates in the reaction with phenylacetylene
2a. Very good yields were obtained for compounds 3q (70%) and
3r (75%) while 3s was obtained in a lower yield (38%). We observed
enhanced reactivity compared to their corresponding mercapto-
benzoxazole derivatives (Table 4, entries 5 and 7 vs Table 1, entry
7 and Table 2, entry 16) as well as to their corresponding
Therefore, we transformed the mercaptobenzoxazoles 6b–e
into their corresponding methylthioethers 1b–d,h (see Table 2,
entries 14–16 for compounds 1b–d and Scheme 1 for compound
1h) and performed the coupling reactions with phenylacetylene

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A. Paun et al. / Tetrahedron Letters 56 (2015) 5349–5352
Table 4
Supplementary data
Cross-coupling reactions between compounds 6b–h and phenylacetylene 2a
Supplementary data (experimental procedures for the cross-
coupling reactions as well as 1H, 13C NMR and HRMS spectra of
the new compounds are described) associated with this article
can be found, in the online version, at http://dx.doi.org/10.1016/j.
tetlet.2015.08.001.
Pd(dppf)Cl2 5 mol%
R2
R1
R2
R1
CuI 50 mol%
X
X
N
S
+
CuMeSal, TEA, DMF
reflux, 24 h
N
H
6b-h
2a
R1
3o,p,q-s
Entry Reactant
X
R2
Alkyne equiv Producta Yieldb (%)
11d
References and notes
1
2
3
4
5
6
7
6b
6c
6d
6e
6f
O
O
O
O
S
MeO
F
Cl
Br
H
H
H
H
H
H
H
EtO
H
3
3
3
3
3
3
3
3o
3p
—
30
Traces
—
—
70
1. (a)Metal-Catalyzed Cross-Coupling Reactions; de Meijere, A., Diederich, F., Eds.,
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—
12
12
3q
3r
3s
6g
6h
S
S
75
38
Cl
a
The spectral analysis of the reported compounds were identical with those
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b
Yield after purification by flash column chromatography.
2a
Pd(dppf)Cl2 10 mol%
CuI 20 mol%
O
3 eq.
3 eq. TEA, toluene
air, reflux, 24 h
N
4 (54%)
O
N
S
Br
1h
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O
2a
Pd(PPh3)4 5 mol%
CuI 10 mol%
1.5 eq.
N
Br
TEA/THF 2/1 v/v
Ar, rt, 24 h
5 (25%)
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Scheme 1. Cross-coupling reactions between 5-bromo-2-(methylthio)benzoxazole
1h and phenylacetylene 2a.
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Lett. 2014, 16, 4488–4491; (b) Matsuyama, N.; Hirano, K.; Satoh, T.; Miura, M.
Org. Lett. 2009, 11, 4156–4159; (c) Matsuyama, N.; Kitahara, M.; Hirano, K.;
Satoh, T.; Miura, M. Org. Lett. 2010, 12, 2358–2361; (d) Kim, S. H.; Yoon, J.;
Chang, S. Org. Lett. 2011, 13, 1474–1477; (e) Kim, J.; Kang, D.; Yoo, E. J.; Lee, P.
H. Eur J. Org. Chem. 2013, 35, 7902–7906; (f) Ackermann, L.; Kornhaass, C.; Zhu,
Y. J. Org. Lett. 2012, 14, 1824–1826.
12. Sonogashira coupling using 2-halobenzothiazole was reported for example in
Lu, L.; Yan, H.; Sun, P.; Zhu, Y.; Yang, H.; Liu, D.; Rong, G.; Mao, J. Eur. J. Org.
Chem. 2013, 1644–1648.
13. Compounds 1 were synthesized from commercial 2-mercaptobenzoxazoles as
previously described in Melzig, L.; Metzger, A.; Knochel, P. J. Org. Chem. 2010,
75, 2131–2133.
14. Neatu, F.; Li, Z.; Richards, R.; Toullec, P. Y.; Genet, J. P.; Dumbuya, K.; Gottfried,
J. M.; Steinruck, H. P.; Parvulescu, V. I.; Michelet, V. Chem. Eur. J. 2008, 14,
9412–9418.
15. Tougerti, A.; Negri, S.; Jutand, A. Chem. Eur. J. 2007, 13, 666–676.
16. Tsuji, J. Palladium Reagents and Catalysts—New Perspectives for the 21st Century;
John Wiley & Sons: New York, 2004.
Conclusions
In conclusion, we have shown that benzoxazole and benzothia-
zole methylthioethers can be efficiently used as electrophilic sub-
strates in the Sonogashira reaction, enlarging, thus, the variety of
alternative reagents that can be used in cross-couplings.4,5,9 The
reactions with terminal alkynes were performed using palladium
and copper(I)-catalysis under aerobic conditions. The synthetic
approach allowed preparation of 2-alkynyl benzoxazole deriva-
tives containing aliphatic and substituted electron-donating and
electron-withdrawing aromatic moieties in moderate to good
yields. In addition, the reactions proceeded well when various ben-
zothiazole methylthioethers, as well as mercaptobenzothiazoles
were used, providing the coupling products in very good yields.
Moreover, the mercaptobenzothiazoles appear to perform better
than the corresponding mercaptobenzoxazoles. Our work showed
that the reaction proceeded better under aerobic conditions rather
than an inert atmosphere. Use of 5-bromo-2-(methylthio)benzox-
azole in our aerobic coupling conditions occurred with concomi-
tant C–Br and C–S coupling of the alkyne. Surprisingly, the C–S
cross-coupling reaction occurred selectively under an inert atmo-
sphere, at room temperature, albeit in modest yield, allowing the
possibility to further functionalize the benzoxazole core using
the C–Br bond and therefore, extending the scope of the reaction.
17. Schilz, M.; Plenio, H. J. Org. Chem. 2012, 77, 2798–2807.
Acknowledgment
18. Studies on Sonogashira cross-coupling reactions using 2-halobenzothiazoles
suggest a higher reactivity of the aryl alkynes than aliphatic alkynes using the
same amount of the alkyne under an inert atmosphere, see Ref. 12.
19. Silva, S.; Sylla, B.; Suzenet, F.; Tatibouet, A.; Rauter, A. P.; Rollin, P. Org. Lett.
2008, 10, 853–856.
Financial support by the National Research Council (CNCS) of
Romania,
project
PNII-ID-PCE-2011-3-0408
is
gratefully
acknowledged.