Synthesis of internal alkynes through the Pd-catalyzed coupling of heteroaryl halides with terminal alkynes

Article abstract of DOI:10.1002/ejoc.201201689

Sonogashira-type cross-couplings of functionalized heterocyclic halides with terminal alkynes were performed efficiently at room temperature. The heteroaryl halides were easily prepared from the corresponding heterocyclic compounds. The catalytic system tolerated a very broad scope of substrates; oxazoles, thiazoles, and furans participate in this type of reaction for the first time. This reaction provides an efficient method for the direct functionalization of heterocycles. Sonogashira-type cross-coupling of functionalized heterocyclic halides with terminal alkynes are performed efficiently at room temperature. The catalytic system tolerates a very broad scope of substrates; oxazoles, thiazoles, and furans participate in this type of reaction for the first time. The reaction provides an efficient method for the direct functionalization of heterocycles. Copyright

Full text of DOI:10.1002/ejoc.201201689

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201201689
Synthesis of Internal Alkynes through the Pd-Catalyzed Coupling of
Heteroaryl Halides with Terminal Alkynes
Linhua Lu,[a] Hong Yan,[a] Peng Sun,[a] Yan Zhu,[a] Hailong Yang,[a] Defu Liu,[a]
Guangwei Rong,[a] and Jincheng Mao*[a]
Keywords: Synthetic methods / Cross-coupling / Alkynes / Heterocycles / Palladium / Halides
Sonogashira-type cross-couplings of functionalized heterocy- catalytic system tolerated a very broad scope of substrates;
clic halides with terminal alkynes were performed efficiently
at room temperature. The heteroaryl halides were easily pre-
pared from the corresponding heterocyclic compounds. The
oxazoles, thiazoles, and furans participate in this type of re-
action for the first time. This reaction provides an efficient
method for the direct functionalization of heterocycles.
well as by Lautens et al.,[8] and this system allowed the cou-
pling of heteroaryl bromides with various alkynes. However,
examples of efficient palladium catalyst systems for the
Sonogashira coupling of heteroaryl chlorides with various
alkynes are rare. In this paper, based on our interest in cou-
pling reactions,[9] we herein report our preliminary trials
and results. We describe here a high-yielding catalyst system
based on PdCl2(PPh3)2/Et3N/CuI for the Sonogashira cou-
pling of heteroaryl bromides and chlorides with terminal
alkynes 2 [Scheme 1, Equation (2)]. It is noteworthy that
these heteroaryl halides could be easily prepared from the
corresponding heterocyclic compounds.[10] Furthermore,
the substrate scope of this reaction is very broad, and het-
erocycles such as oxazoles, thiazoles, and furans are, for the
first time, shown to participate in this type of coupling reac-
tion.
Introduction
Substituted alkynes are recurring units in numerous nat-
ural products, bioactive molecules, and organic materials,[1]
and they are also versatile synthetic intermediates.[2] Among
them, alkynyl-substituted azoles have gained much atten-
tion owing to both industrial and academic values.[3] Over
the last several decades, Sonogashira coupling has become
one of the most widely used methods for the incorporation
of the alkynyl functional group into organic compounds.[4]
It enables the efficient coupling of an organic halide or
pseudohalide with a terminal alkyne, typically by using a
Pd catalyst together with a Cu co-catalyst. Aryl bromides
and aryl iodides are well known to undergo this coupling
reaction in the presence of suitable catalysts. Aryl alkynes
are easily prepared in this way; however, there are few ex-
amples of Sonogashira reactions to synthesize the het-
eroaryl alkynes. Fortunately, new synthetic methods to pre-
pare heteroaryl alkynes have been developed recently.[5]
A
significant step forward in the development of the Sonoga-
shira reaction to synthesize heteroaryl alkynes was achieved
by Chang et al. who treated various alkynyl bromides with
heterocyclic compounds in the presence of Pd(OAc)2
(2.5 mol-%), xantphos ligand (2.8 mol-%), and tBuOLi
(2 equiv.) at 100 °C to produce the coupling products in
good yields [Scheme 1, Equation (1)].[6] Apart from this
work, state-of-the-art catalysts are based on the Pd(PPh3)4/
Et3N/CuI system, which was described by Panek et al.[7] as
[a] Key Laboratory of Organic Synthesis of Jiangsu Province,
College of Chemistry, Chemical Engineering and Materials
Science, Soochow University,
Suzhou 215123, P. R. China
Fax: +86-512-65880403
E-mail: jcmao@suda.edu.cn
Homepage: http://chemistry.suda.edu.cn/en/index.aspx?
lanmuid=80&sublanmuid=636&id=194
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201689.
Scheme 1. Synthesis of 2-(2-phenylethynyl)benzo[d]thiazoles by dif-
ferent approaches.
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Synthesis of Internal Alkynes through the Pd-Catalyzed Coupling
the coupling products were obtained in yields of 87 and
76% under the standard conditions (Table 2, entries 2 and
3). Unfortunately, we observed the formation of the homo-
coupling dimer of 4-methoxyphenylacetylene, which led to
a decrease in the yield of the desired product. Relative to
aromatic alkynes with electron-donating groups, an aro-
matic alkyne with an electron-withdrawing group needed a
longer reaction time, and the yield of the product was 90%
(Table 2, entry 4). Interestingly, a 99% yield could be ob-
tained for 2-ethynylthiophene (Table 2, entry 5). Further-
more, the Sonogashira coupling reaction of 2-bromobenzo-
thiazole with aliphatic alkynes also gave good to excellent
results of 80–95%, whereas the reaction time should be ex-
tended to complete the coupling (Table 2, entries 6–13).
Therefore, one can conclude that Sonogashira coupling re-
actions of aromatic alkynes are more favorable than those
of aliphatic alkynes.
Results and Discussion
2-Bromobenzothiazole could be synthesized from benzo-
thiazole in one step in 82% yield.[10] Thus, initial studies
were carried out by treating 2-bromobenzothiazole with
phenylacetylene. In our initial screening of the reaction, two
catalytic systems were examined[11] (Table 1, entries 1 and
2), and the PdCl2(PPh3)2/CuI system gave better results
than PdCl2(PCy3)2 alone (Table 1, entry 2). The effects of
different solvents were then studied (Table 1, entries 3–5).
The results show that dimethylformamide (DMF) is well
suited for this reaction. Further experiments proved that
the yield of the product could reach 99% in less than 4 h.
Another control experiment was performed in the absence
of CuI, and the corresponding product was obtained in
67% yield (Table 1, entry 6). Obviously, CuI in combination
with PdCl2(PPh3)2 led to an enhancement in the catalytic
efficiency. However, when the copper loading was reduced
to 6 mol-%, a decrease in the yield of the desired product
was observed after increasing the reaction time (Table 1, en-
try 7). Furthermore, to our delight, when we reduced both
PdCl2(PPh3)2 to 2 mol-% and CuI to 7 mol-%, we achieved
a yield of 99% after 11 h at room temperature (Table 1, en-
try 8), and these conditions were deemed optimal.
Table 2. Scope of the Pd-catalyzed couplings of various terminal
alkynes with 2-bromobenzo[d]thiazole.[a]
Table 1. Screening of the catalytic conditions in the coupling of 2-
bromobenzo[d]thiazole with phenylacetylene.[a]
Entry Pd. cat. (mol-%)
Base
Solvent
T [°C]
/t [h]
Yield
[%][b]
1
2
3
4
5
6
7
8
PdCl2(PCy3)2 (3)
PdCl2(PPh3)2 (3)/CuI (10) Pr2NH
Cs2CO3 DMSO
120/24 trace
DMF
THF
120/24
r.t./10
r.t./10
r.t./4
r.t./43
r.t./24
62
85
73
Ͼ99
67
95
PdCl2(PPh3)2 (3)/CuI (10)
PdCl2(PPh3)2 (3)/CuI (10)
PdCl2(PPh3)2 (3)/CuI (10)
PdCl2(PPh3)2 (3)
PdCl2(PPh3)2 (3)/CuI (6)
PdCl2 (PPh3)2 (2)/CuI (7)
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
dioxane
DMF
DMF
DMF
DMF
r.t./11 Ͼ99
[a] Reaction conditions: 2-bromobenzo[d]thiazole (0.2 mmol),
phenylacetylene (0.4 mmol), base (0.4 mmol), solvent (1.5 mL), Ar.
[b] Isolated yield (based on 2-bromobenzo[d]thiazole).
With the optimized protocol in hand, the scope of the
coupling was investigated. Coupling reactions of 2-bromo-
benzothiazole with both aromatic and aliphatic alkynes fur-
nished the desired products in 76–99% isolated yields
(Table 2). We monitored the remaining amount of 2-bromo-
benzothiazole by TLC to control the reaction time at room
temperature. For aryl alkynes with electron-donating
[a] Reaction conditions: 2-bromobenzo[d]thiazole (0.2 mmol), alk-
yne (0.4 mmol), Et3N (0.4 mmol), DMF (1.5 mL), r.t., Ar. [b] Iso-
lated yield (based on 2-bromobenzo[d]thiazole, average of two
groups, the reaction time could be reduced to 4–5 h, and runs).
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L. Lu, H. Yan, P. Sun, Y. Zhu, H. Yang, D. Liu, G. Rong, J. Mao
SHORT COMMUNICATION
To extend the range of substrates further, we intended to tries 1–8). However, when 2-chlorobenzoxazoles were exam-
apply our method to a wide range of different halides, such ined as substrates, a longer reaction time and a higher tem-
as heteroaryl bromides and chlorides.[10] Table 3 shows the perature was needed, and decreased yields of the desired
experimental results performed under standard conditions. products were observed (44, 40%; Table 3, entries 9 and 10).
6-Substituted heteroaryl halides with electron-withdrawing Also, 2-bromobenzofurans proceed smoothly by using this
groups needed shorter reaction times than heteroaryl hal- sequence (Table 3, entries 11–13). X-ray structural analysis
ides with electron-donating groups, but both afforded good proved the structure of 4g (Figure 1). 5-Bromo-2-bromo-
to excellent yields of the products (80–99%; Table 3, en- benzofuran was then involved to test the regioselectivity of
the reaction, and the bromine in the 5-position remained
intact under these gentle conditions, which demonstrates
Table 3. Scope of the Pd-catalyzed couplings of various heteroaryl
that our catalytic system is regiospecific for substrates of
halides with phenylacetylene.[a]
this type. Furthermore, 2-bromothiazole was transformed
into the desired product in 77% yield at 40 °C (Table 3, en-
try 14). From an experimental point of view, it is found that
the coupling products of heteroaryl bromides were obtained
in good yields within shorter reaction times, and the cou-
pling reactions of heteroaryl chlorides were conducted with
moderate results because of their poor reactivity, which can
be attributed to the greater strength of the C–Cl bond.[12]
Finally, the couplings of bromides of indole and benzo[d]-
imidazole were fruitless, and many sides reactions occurred,
which was indicated by TLC. This may be attributed to the
influence of the secondary amine from the heterocyclic mo-
lecules. Further research is underway.
Figure 1. X-ray crystal structure of product 4g.
To test the reactivity of 2-bromobenzothiazole further,
an experiment involving the reaction of 2-bromobenzothi-
azole with phenylpropiolic acid was carried out. As shown
in Scheme 2, under the optimized conditions, the desired
heteroaryl alkyne was obtained in 96% yield, which broad-
ened the scope of our method.
[a] Reaction conditions: Heteroaryl halide (0.2 mmol), phenyl-
acetylene (0.4 mmol), Et3N (0.4 mmol), DMF (1.5 mL), r.t. to
40 °C, Ar. [b] Isolated yield (based on heteroaryl halide, average of
two runs).
Scheme 2. Pd-catalyzed coupling of 1a with phenylpropiolic acid.
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Synthesis of Internal Alkynes through the Pd-Catalyzed Coupling
acetate, dried with anhydrous Na2SO4, filtered, and concentrated
under vacuum. The residue was purified by flash column
chromatography (petroleum ether or petroleum ether/ethyl acetate)
to afford the corresponding coupling products.
In addition, when using 2,5-dibromobenzofuran as a
substrate, to our surprise, another undesired product could
be obtained after a prolonged reaction time. As shown in
Scheme 3, we finally achieved a 56% yield of 6a. Interest-
ingly, this compounds showed strong blue fluorescence
(357, 364 nm) in solution (ΦF = 0.49, 0.51). It cannot only
be used as a potential fluorescent material but also apply
to industrial production.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental details, fluorescence experiments, characteriza-
tion data of the products, and copies of the HRMS and NMR
spectra for the products.
Acknowledgments
The authors are grateful to grants from the International S&T Co-
operation Program of Jiangsu Province (BZ2010048), the Scientific
Research Foundation for the Returned Overseas Chinese Scholars,
the Chinese State Education Ministry, the Priority Academic Pro-
gram Development of Jiangsu Higher Education Institutions, and
the Key Laboratory of Organic Synthesis of Jiangsu Province.
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Conclusions
In summary, we have developed an effective and promis-
ing Pd/Cu co-catalyzed system for the coupling of het-
eroaryl halides, including heteroaryl bromides and chlor-
ides, with various alkynes. Furthermore, these heteroaryl
halides were easily prepared from the corresponding hetero-
cyclic compounds. Notably, for the first time, it was shown
that the substrate scope of the reaction was very broad and
included oxazoles, thiazoles, and furans, which offers an im-
portant advance in the direct functionalization of heterocy-
cles. Practical application of the products is underway in
our laboratory. Thus, these products are potentially useful
in the synthesis of biologically active molecules. Further in-
vestigations in this direction are in progress.
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Experimental Section
General Procedure for Pd-Catalyzed Coupling between Heteroaryl
Halides and Terminal Alkynes: A mixture of the heteroaryl halide
(0.2 mmol), terminal alkyne (0.4 mmol), Et3N (0.4 mmol),
PdCl2(PPh3)2 (2 mol-%), CuI (7 mol-%), and DMF (1.5 mL) in a
Schlenk tube was stirred under an argon atmosphere at room tem-
perature to 40 °C for the desired time until complete consumption
of the starting material (monitored by TLC). The mixture was then
poured into ethyl acetate, washed with water, extracted with ethyl
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L. Lu, H. Yan, P. Sun, Y. Zhu, H. Yang, D. Liu, G. Rong, J. Mao
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SHORT COMMUNICATION
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114, 4350–4386; Angew. Chem. Int. Ed. 2002, 41, 4176–4211.
Received: December 14, 2012
Published Online: February 6, 2013
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