Palladium-catalyzed desulfurative Sonogashira cross-coupling reaction of 3-cyano assisted thioamide-type quinolone derivatives with alkynes

Article abstract of DOI:10.1039/c5ra06337j

A Pd-catalyzed Cu-mediated desulfurative Sonogashira cross-coupling reaction of thioamide-type quinolone derivatives was proposed for the construction of C_sp²-C_sp bonds. Alkynylated quinoline derivatives can be easily synt

Full text of DOI:10.1039/c5ra06337j

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Palladium-catalyzed desulfurative Sonogashira
cross-coupling reaction of 3-cyano assisted
thioamide-type quinolone derivatives with alkynes†
Cite this: RSC Adv., 2015, 5, 48558
a
a
a
a
You Wu, Yongning Xing, Jie Wang, Qi Sun, Weiqi Konga and Franck Suzenetb
Received 9th April 2015
Accepted 21st May 2015
*
DOI: 10.1039/c5ra06337j
www.rsc.org/advances
A
Pd-catalyzed Cu-mediated desulfurative Sonogashira cross- 2(1H)-pyrazinones.6 It was demonstrated for the rst time that
coupling reaction of thioamide-type quinolone derivatives was the cleavage of C–S from the resin without prior oxidation of the
proposed for the construction of Csp2–Csp bonds. Alkynylated quin- sulfur linker can be realized with the Sonogashira alkynylation
oline derivatives can be easily synthesized in moderate to excellent of C–S with alkynes in the presence of aryl chloride. The scope of
yields. The mechanism and effect of the 3-cyano on the reaction were this novel reaction was then extended to pyrimidine function-
also discussed.
alized-disuldes.7
¨
Encouraged by Kappe's work, Tatibouet reported the desul-
furative alkynylations of 1,3-oxazolidine-2-thiones (OZTs) and
1,3-oxazoline-2-thiones (OXTs) with bases (Scheme 1a, X ¼ O).8
This method was also used in the total synthesis of natural
products with anti-tumor activity.9 Hintermann reported a base-
free reaction system for the coupling reactions of 2-mercapto-
1,3-pyrimidine and alkynes (Scheme 1b), and this method was
scoped to 1,3-thiazoline-2-thiones (Scheme 1a, X ¼ S).10
However, the succeeded Sonogashira reactions were only used
to substrates of which the latent free thiol functionality linked
next to two heteroatoms (marked with red in Scheme 1), such as
O, S and N. To the best of our knowledge, Sonogashira coupling
reaction of thioamide-type quinolone derivatives with alkynes
has not been explored.
A transition metal-catalyzed Sonogashira reaction for the
formation of Csp2–Csp bond is an indispensible tool for targeted
and parallel synthesis of heterocyclic compounds.1 Tradition-
ally, all of these cross-coupling reactions employ aryl halides,
aryl triates, aryl tosylates and aryl sulfonates as electrophilic
coupling partners to perform the cross-coupling with nucleo-
philic organometallic reagents to produce new C–C bonds.
However, the limited stability and/or accessibility of the corre-
sponding heteroaromatic derivatives is somewhat problematic.
In 2000, Liebeskind and Srogl reported a new efficient Pd-
catalyzed cross-coupling reaction of thiol ester and thioether
species.2 Later, Kappe and co-workers demonstrated that the
use of non-basic Liebeskind–Srogl conditions was not only
applicable to thiol esters and thioethers as substrates, but could
also be extended to latent free thiol group-containing substrates
including pyrimidinethiones3 and cyclic thio-amides.4 Consid-
ering the wide distribution of C–S bonds in natural products,
pesticides and drugs, their transformation via metal-catalyzed
coupling reaction have become more and more important in
organic chemistry.5
Considering the limitation of the scope of the substrates, we
inferred that the coordination of the heteroatoms on the
substrates, such as oxaline, thiazoline and pyrimidine, to the
Pd(0) catalyst could stabilize the Pd(0)-substrate complex to
Van der Eycken and co-workers reported an unprecedented
microwave-assisted desulfurative Sonogashira cross-coupling
protocol for the alkynylation of the C-3 of phenylsulfanylated-
aState Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical
Sciences, Peking University, Beijing 100191, PR China. E-mail: sunqi@bjmu.edu.cn;
Fax: +86 10 8280 1571; Tel: +86 10 8280 1504
b
´
Institut of Organic and Analytical Chemistry, University of Orleans UMR-CNRS 7311,
´
rue de chartres, BP 6759, 45067 Orleans Cedex 2, France
† Electronic supplementary information (ESI) available. See DOI:
Scheme 1 Desulfurative Sonogashira cross-coupling reactions.
10.1039/c5ra06337j
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facilitate the oxidative addition procedure, therefore making
At the beginning of our study, we chose the desulfurative
the cross-coupled products easier to be produced. To simply coupling of 3-cyano-6-methyl-2-mercaptoquinoline 3a with
testify the supposition, we employed 2-mercaptoquinoline (R0 ¼ phenylacetylene 4a in the presence of the Pd catalyst, Cu addi-
H, Scheme 1c), which could not provide a heteroatom to coor- tive, CuI and base as a model system to optimize the reaction
dinate to the Pd(0) catalyst, as the substrate to perform the condition. As shown in Table 1, no reaction occurred without
desulfurative Sonogashira reaction with phenylacetylene. As the Pd catalyst (Table 1, entry 1). Among all Pd catalysts
expected, it failed to afford the desired alkynylated product. In including Pd(PPh3)2Cl2, Pd(MeCN)2Cl2, Pd(dba)2, PdCl2,
2011, Sun and co-workers reported a C–H bond activation Pd(OAc)2, Pd2(dba)3 and Pd(PPh3)4, Pd(PPh3)4 gave the highest
protocol using cyano as a directing group.11 A mechanism of the yield under same conditions (Table 1, entries 2–8). No desired
stabilizing effect of the coordination between the p-electrons of product was obtained without the Cu additive, indicating it was
the cyano group and the Pd(0) species was proposed. Inspired essential for the reaction (Table 1, entry 10). CuTC is the
by this work, we designed a 3-cyano-substituted substrate to optimal Cu additive for this transformation, which gave the
attempt the desulfurative Sonogashira cross-coupling reaction. expected product in 68% yield (Table 1, entry 9). Reducing the
To our delight, the desired coupling product was isolated in amount of CuI from 1 equiv. to 0.5 equiv. resulted in the same
good yield when 3-cyano-6-methyl-2-mercaptoquinoline 3a was yield. However, a considerable decline of the yield was observed
used as the substrate. As a continuing study of the desulfurative in the absence of CuI, indicating that appropriate amount CuI
Sonogashira cross-coupling reaction, in the present work, we was necessary for the reaction (Table 1, entries 9, 11 and 12). No
presented a Pd-catalyzed Sonogashira cross-coupling reaction desired products were obtained without base and only trace
of 3-CN assisted thioamide-type quinolone derivatives with product was obtained without solvent, indicating that they were
alkynes (Scheme 1c, R0 ¼ CN).
necessary for the reaction and could signicantly affect the
Table 1 Optimization of reaction conditionsa
Entry
Pd (cat.)
“Cu” (1 equiv.)
CuI
Baseb
Solv.
Time (h)
Yieldc (%)
1
2
3
4
5
6
7
8
—
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
CuTc
—
CuTc
CuTc
CuTc
CuTc
CuTc
CuTc
CuTc
CuTc
CuTc
CuTc
CuTc
1 equiv.
1 equiv.
1 equiv.
1 equiv.
1 equiv.
1 equiv.
1 equiv.
1 equiv.
1 equiv.
1 equiv.
0.5 equiv.
—
0.5 equiv.
0.5 equiv.
0.5 equiv.
0.5 equiv.
0.5 equiv.
0.5 equiv.
0.5 equiv.
0.5 equiv.
0.5 equiv.
0.5 equiv.
0.5 equiv.
0.5 equiv.
0.5 equiv.
0.5 equiv.
0.5 equiv.
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Pyridine
TMG
K2CO3
Cs2CO3
NaOH
—
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
5
0
Pd(PPh3)2Cl2
Pd(MeCN)2Cl2
Pd(dba)2
PdCl2
48
28
41
24
57
30
64
68
0
Pd(OAc)2
Pd2(dba)3
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
68
50
0
0
11
60
Trace
0
14
17
6
70
Trace
68
70
75
41
THF
THF
DMF
MeCN
CH2Cl2
Dioxane
—
Dioxane
Dioxane
Dioxane
Dioxane
CuTc
CuTc
CuTc
CuTc
CuTc
CuTc
10
15
48
a
Conditions: 3a (0.5 mmol), 4a (3 equiv.), Pd (Cat.) (0.05 equiv.), “Cu” (1 equiv.), CuI, base (3 mL) and solv. (3 mL) were mixed and heated at 110 ꢀC
under argon atmosphere. Amount of base: TMG (2.5 equiv.), K2CO3 (2.5 equiv.), Cs2CO3 (2.5 equiv.) and NaOH (2.5 equiv.). c Isolated yields.
b
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Table 3 Substrate scope of terminal alkynes 4ab
reaction (Table 1, entries 18 and 23). Among the bases tested,
including Et3N, pyridine, N,N,N0,N0-tetramethylguanidine
(TMG), K2CO3, Cs2CO3 and NaOH, Et3N gave the highest yield
(Table 1, entries 11 and 13–17). Among all the solvents tested,
including THF, DMF, MeCN, CH2Cl2 and dioxane, dioxane gave
the highest yield (Table 1, entries 11 and 19–22). The screening
of the reaction time indicates that 15 h reaction time is the most
suitable to afford the highest yield of product 5aa. A highest
yield of 75% was obtained under the optimized conditions as
shown (Table 1, entry 26).
The substrate scope of thioamide-type quinolones 3 was then
examined under the optimized conditions (Table 2). It is clear
that a variety of 3-cyano-2-mercaptoquinolines 3 derivatives can
be converted to the desired desulfurative coupling products
5aa–5fa in good yields ranging from 64% to 75%. The reaction
can also tolerate well to electron-donating groups such as
methyl (5aa, 5ea, 5fa) and methoxy (5da) and electron-
withdrawing groups such as uorine (5ca).
Next, reactions of 3a with various aromatic and aliphatic
terminal alkynes were investigated. As shown in Table 3, the
reactions with both electron-rich (4b–4e) and electron-poor (4f–
4h) aromatic terminal alkynes afforded the corresponding
products 5ab–5ah in good yields ranging from 68% to 78%. The
reaction with the heteroaryl alkynes afforded the desired
products 5ai and 5aj in moderate 46% and 48% yields, respec-
tively. The reactions with aliphatic alkynes 4k and 4m gave the
desulfurative coupling products 5ak and 5am in moderate
yields of 48% and 56%, respectively, while that with 4l gener-
ated the desired product 5al in good yield 78%, possibly due to
the steric effect caused by hindering the addition of electro-
philes to the C–C triple bond of the product.10,12
a
Conditions: 3a (0.5 mmol), 4 (3 equiv.), Pd(PPh3)4 (5 mol%), CuTC
(1 equiv.), CuI (0.5 equiv.), Et3N (3 mL) and dioxane (3 mL) were
mixed and heated at 110 ꢀC under argon atmosphere for 15 h.
b
Isolated yields.
Table 4 Reaction of 6a with different terminal alkynes 4ab
The focus of the study was then shied to screening other
substrates applicable to this method that could afford the
desired products in higher yields. The reactions of 2-mercapto-3-
pyrazine carbonitrile 6a with alkynes occurred highly efficiently
(Table 4). The reactions of 6a with electron-rich and electron-
Table 2 Substrate scope of 3-cyano-2-mercaptoquinolines 3ab
a
a
Conditions: 3 (0.5 mmol), 4a (3 equiv.), Pd(PPh3)4 (5 mol%), CuTC
Conditions: 6a (0.5 mmol), 4 (3 equiv.), Pd(PPh3)4 (5 mol%), CuTC
(1 equiv.), CuI (0.5 equiv.), Et3N (3 mL) and dioxane (3 mL) were
(1 equiv.), CuI (0.5 equiv.), Et3N (3 mL) and dioxane (3 mL) were
mixed and heated at 110 ꢀC under argon atmosphere for 15 h.
mixed and heated at 110 ꢀC under argon atmosphere for 15 h.
b
b
Isolated yields.
Isolated yields.
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poor aryl terminal alkynes produced the desired products in
good to excellent yields ranging from 66% to 93% (Table 4, 7aa,
7ab, 7ad and 7af). In addition, the reactions with aliphatic
terminal alkynes gave the corresponding products in good to
excellent yields ranging from 64% to 91% (Table 4, 7ak, 7al and
7am). The disparity among the yields of 7ak, 7al and 7am once
again suggests the signicant inuence of steric hindrance on
the yields of the products. Unexpectedly, the reaction of 3-cyano-
2-mercaptopyridine 6b failed to afford the desired product 7ba.
The signicant difference between the results of 2-mercap-
toquinoline and 3-cyano-2-mercaptoquinolines 3 was evidence
that the cyano group crucially facilitated the reaction. Further-
more, a series of experiments were conducted to further verify
the effect of the 3-cyano group on the reaction. As mentioned
above, the cross-coupling of 3-cyano-2-mercaptoquinoline
3b with phenylacetylene 4a produced the corresponding desul-
furative Sonogashira product 5ba in 70% yield (Table 2), while
the reaction of 2-mercaptoquinoline 8a with 4a, as shown in
Table 5, failed to afford the desired product under the same
conditions (Table 5, entry 1). The desired product 9b was iso-
lated in a considerably lower yield of 16% with 3-methyl-2-
mercaptoquinoline 8b instead as the substrate (Table 5,
entry 2). Likewise, the reaction of 2-mercaptopyrazine 8c affor-
ded the desired product 9c in 20% yield (Table 5, entry 3).
However, the reaction of 3-cyano-2-mercaptopyrazine 6a
produced the corresponding product 7aa in a signicantly
higher yield of 88% (Table 4). It was worth mentioning that no
Scheme 2 Proposed reaction mechanism.
desired product was isolated with methyl 3-mercapto-2-
pyrazine-2-carboxylate 8d as the substrate. Since the ester
group was an electron-withdrawing group, similar to cyano
group, it could be inferred that it was the stabilizing coordina-
tion effect of the 3-cyano group, other than electron-
withdrawing effect, that crucially facilitated the desulfurative
Sonogashira cross-coupling reaction.
Based on the mechanism previously reported4 and the
discussion above, we proposed a possible mechanism of the
critical effect of the 3-cyano group on the reaction (Scheme 2). In
the proposed mechanism we highlight the effect of 3-cyano group
in transition state C. To a great extent, the reaction undergoes the
traditional Liebeskind–Srogl catalytic recycle. Once transition
state B8,12 is formed, the activated Pd(0) species coordinates both
to the p-electrons of the triple bond of the cyano group and the
pyridine ring to produce a stable transition state C,11,13,14 making
the oxidative addition of the C–S bond to Pd(0) much easier. This
step signicantly facilitates the reaction. The transmetalation of
C and D leads to the formation of transition state F.8,12 The nal
product G is afforded by the reductive elimination of Pd, and the
Pd(0) species returns to the catalytic recycle.
Table 5 Verification experiments of the effect of 3-cyano groupa
Entry
1
Substrates 8
Products 9
Yieldsb (%)
Conclusions
0
In summary, we have successfully achieved an efficient 3-cyano
assisted desulfurative Sonogashira cross-coupling reaction of
thioamide-type quinolone derivatives with Pd(PPh3)4 as the
catalyst, readily accessible CuTC and CuI as the additives and
cheap Et3N as base. This method can be simply conducted and
provide corresponding desulfurative Sonogashira cross-
coupling products in moderate to excellent yields. A variety of
electron-donating and electron-withdrawing substituent groups
are well tolerated. Furthermore, the signicant effect of the
3-cyano group, attached next to the thioamide fragment of the
substrates, on the Csp2–Csp formation was investigated. Further
work on detailed mechanism and extending the application of
this method is ongoing in our lab.
2
3
16
20
4
0
Acknowledgements
a
Conditions: 8 (0.5 mmol), 4a (3 equiv.), Pd(PPh3)4 (5 mol%), CuTC (1
equiv.), CuI (0.5 equiv.), Et3N (3 mL) and dioxane (3 mL) were heated
at 110 ꢀC under argon atmosphere for 15 h. b Isolated yields.
The project is supported by the funds of National Natural
Science Foundation of China (NSFC 21272009). We thank
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Professor Ning Jiao (Peking University) for his review and
comments.
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48562 | RSC Adv., 2015, 5, 48558–48562
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