Catalytic C-H and C-S bond activation of thiophenes

Article abstract of DOI:10.1021/ol303136x

A new Pd-catalyzed reaction of thiophenes with alkynes via C-H and C-S bond activation has been developed. This provides a new approach to prepare sulfur-containing compounds. An interesting salt effect was observed, and the reaction's efficiency and selectivity depend not only on the type but also on the amount of the salt used.

Full text of DOI:10.1021/ol303136x

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Catalytic CꢀH and CꢀS Bond Activation
of Thiophenes
Jing Li, Huanan Huang, Weihong Liang, Qun Gao, and Zheng Duan*
College of Chemistry and Molecular Engineering, Zhengzhou University,
Zhengzhou 450001, P. R. China
*duanzheng@zzu.edu.cn
Received November 14, 2012
ABSTRACT
A new Pd-catalyzed reaction of thiophenes with alkynes via CꢀH and CꢀS bond activation has been developed. This provides a new approach to
prepare sulfur-containing compounds. An interesting salt effect was observed, and the reaction’s efficiency and selectivity depend not only on the
type but also on the amount of the salt used.
Carbonꢀsulfur bond activation of thiophene is an im-
portant reaction in the modern petroleum industry. Con-
siderable attention has been paid to this area, and the
representative examples are the insertion of a transition
metal into the CꢀS bond of thiophene-forming related
complexes, which provided deeper understanding of the
key step in hydrodesulfurization (HDS).1
Very recently, we have reported a catalytic method to
prepare sulfur-containing heterocycles via CꢀS bond acti-
vation and formation from bromothiophenes.2 This reac-
tion proceeds with high efficiency and regioselectivity, but
the presence of a reactive CꢀBr bond at the R position is
required. An alternative reaction via catalytic CꢀH
activation3 would provide an atom-economical approach
for this reaction. Herein, we report a palladium-catalyzed
activation of CꢀH and CꢀS bonds of thiophene and
their application in the preparation of sulfur-containing
compounds.
Inspired by the related R-CꢀH activation of thiophene,4
we investigated the palladium-catalyzed reaction between
thiophene 1a and alkyne 2a through CꢀH activation and
the brief screening of reaction conditions (summarized
(4) (a) Mitsuda, S.; Fujiwara, T.; Kimigafukuro, K.; Monguchi, D.;
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Hara, K.; Mori, A. Org. Lett. 2009, 11, 2297. (i) Mori, A.; Sugie, A. Bull.
Chem. Soc. Jpn. 2008, 81, 548. (j) Takahashi, M.; Masui, K.; Sekiguchi,
H.; Kobayashi, N.; Mori, A.; Funahashi, M.; Tamaoki, N. J. Am. Chem.
Soc. 2006, 128, 10930. (k) Kobayashi, K.; Sugie, A.; Takahashi, M.;
Masui, K.; Mori, A. Org. Lett. 2005, 7, 5083. (l) Masui, K.; Ikegami, H.;
Mori, A. J. Am. Chem. Soc. 2004, 126, 5074.
(1) (a) Wang, L. D.; He, W.; Yu, Z. K. Chem. Soc. Rev. 2013, 42, 599.
(b) Chen, J. B.; Angelici, R. J. Coord. Chem. Rev. 2000, 206, 63.
(c) Angelici, R. J. Organometallics 2001, 7, 1259. (d) Bianchini, C.; Meli,
A. Acc. Chem. Res. 1998, 31, 109. (e) Bianchini, C.; Meli, A. J. Chem.
Soc., Dalton Trans. 1996, 801.
(2) Huang, H. N.; Li, J.; Lescop, C.; Duan, Z. Org. Lett. 2011, 13,
5252.
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2012, 45, 788. (b) Schnuerch, M.; Dastbaravardeh, N.; Ghobrial, M.;
Mrozek, B.; Mihovilovic, M. D. Curr. Org. Chem. 2011, 15, 2694.
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r
10.1021/ol303136x
XXXX American Chemical Society

in Table 1). The presence of organic oxidant did not
provide any desired product (Table 1, entries 1ꢀ2). Similar
results were observed with Mn(OAc)2, CuCl2 or CuBr2
(entries 3ꢀ5). To our delight, in the presence of K2S2O8
(entry 6), 3aa was isolated in 32% yield. A better result was
obtained with Cu(OAc)2 (entry 7, 36%). Cu(OAc)2 was
chosen as the oxidant for further optimizations. Solvent
is crucial to this reaction. In the presence of Pd(OAc)2
(10 mol %) and Cu(OAc)2 (75 mol %), 3aa was isolated in
∼30% yield when toluene (entry 7), DMF (entry 8) or
dioxane (entry 10) was the solvent, while no reaction
occurred in DMSO (entry 9). A better result was obtained
when the reaction was performed in the mixture of tolueneꢀ
DMF (64%, entry 12). The yield could be improved to
72% at elevated temperature (entry 14), and the reaction
conditions of entry 14 were chosen as optimized conditions
for further investigations. Various 2-arylthiophenes 1 and
alkynes 2 were investigated, and the results are shown in
Table 2. This reaction is compatible with both electron rich
(entries 6, 7, 11, 12) and electron deficient (entries 8, 9, 10, 13)
arylthiophenes and proceeded smoothly with alkynes
through two CꢀH bonds and one CꢀS bond activation.
The structure of 3ad was confirmed by X-ray crystal
analysis (see SI). The crystal structure shows that one
CꢀS bond of thiophene was cleaved. The carbon fragment
was captured by two alkynes and formed the fulvene
moiety. The sulfur part was trapped by one alkyne and a
neighboring sp2-carbon through Csp2ꢀH activation (see SI
for proposed mechanism). The carbon and sulfur moieties
are cis to each other, which is inconsistent with our
previous results.2 Noticeably, reactions of 2-(ortho-substi-
tuted aryl)-thiophenes 1h, 1i and 1j with alkyne 2a also
proceeded efficiently to give the corresponding products
in good yields (entries 11ꢀ13). Interestingly, although
Table 1. Optimization of Reaction Conditionsa
entry
solvent
Toluene
oxidant
Phl(OAc)2
yield (%)
1
N.R.
trace
trace
N.R.
N.R.
32
2
Toluene
BQ
3
Toluene
Mn(OAc)2 4H2O
3
4
Toluene
CuBr2
CuCl2
K2S2O8
5
Toluene
6
Toluene
7
Toluene
Cu(OAc)2 H2O
36
3
8
DMF
Cu(OAc)2 H2O
28
3
9
DMSO
Cu(OAc)2 H2O
N.R.
30
3
10
11
12
13
14b
1,4-Dioxane
TolueneꢀDMF(20:1)
TolueneꢀDMF(9:1)
TolueneꢀDMF(5:1)
TolueneꢀDMF(9:1)
Cu(OAc)2 H2O
3
Cu(OAc)2 H2O
63
3
Cu(OAc)2 H2O
64
3
Cu(OAc)2 H2O
48
3
Cu(OAc)2 H2O
72
3
a Reaction conditions (unless otherwise specified): 1a (0.5 mmol), 2a
(1.5 mmol), Pd(OAc)2 (10 mol %), Cu(OAc)2 H2O (75 mol %), solvent
3
(5 mL), 120 °C, under air, 24 h. b 140 °C
Table 2. Reactions of 2-Arylthiophenes with Alkynesa
entry
arylthiophene
1a (Ar = Ph)
alkyne
yield (%)e
3aa (72)
1
2a (Ar0 = Ph)
2b
3
1a
2b (Ar0 = p-MeꢀPh)
3ab (56)
1a
2c (Ar0 = p-OMeꢀPh)
3ac (52)
4
5c
1a
2d (Ar0 = p-FꢀPh)
3ad (46)
1b (Ar = 1-Naphthyl)
1c (Ar = p-MeꢀPh)
1d (Ar = p-OMeꢀPh)
1e (Ar = p-FꢀPh)
1f (Ar = p-CNꢀPh)
1g (Ar = p-AcetylꢀPh)
1h (Ar = o-MeꢀPh)
1i (Ar = o-OMeꢀPh)
1j (Ar = o-FꢀPh)
2a
2a
2a
2a
2a
2a
2a
2a
2a
3ba (63)
6
3ca (R0 = Me, 62)
3da (R0 = OMe, 48)
3ea (R0 = F, 69)
3fa (R0 = CN, 30)
3ga (R0 = Acetyl, 45)
3ha (R = Me, 60)
3ia (R = OMe, 50)
3ja (R = F, 61)
7
8
9d
10
11
12c
13
a Reaction conditions (unless otherwise specified): 1 (0.5 mmol), 2 (1.5 mmol), Pd(OAc)2 (10 mol %), Cu(OAc)2 H2O (75 mol %), TolueneꢀDMF
3
(5 mL, 9:1), air, 140 °C, 24 h. b TolueneꢀDMF(5 mL,1:1). c 1,4-DioxaneꢀDMF (5 mL, 9:1). d Benzoic acid (0.5 mmol) was added. e R = R0 = H (unless
otherwise specified).
B
Org. Lett., Vol. XX, No. XX, XXXX

product,2 but the crystal structure of 5a clearly indicated
a trans-carbothiolation, and the fulvene moiety is located
trans to sulfur. Promoted by these expected and unex-
pected results, we decided to investigate this palladium
catalyzed reaction of 1k with 2a in depth. After many
efforts, the yield of this reaction could not be improved. In
order to check the effect of the products on the catalyst,
controlled reactions were carried out. When the reaction
was carried out in the presence of 28 or 56 mg of the
mixture of 4a and 5a, 24 or 48 mg of the mixed 4a and 5a
was isolated (entries 2, 3), respectively. These results
indicated that our catalytic system could be deactivated
by the formation of products. The research on the relation-
ship between catalyst, 4a and 5a is underway in our group.
Our attempts to maintain the activity of catalyst by adding
different ligands was also unsuccessful (see SI). Then our
attentions were shifted to salt effects, which might change
the reactivity and/or selectivity of this thiophene activation
process. LiCl was chosen as the additive first.6 In the
presence of 25 mol % of LiCl (Table 3, entry 4), besides
the major product 4a, a new product 6a was isolated, and
the formation of 5a was not observed. The structure of 6a
was determined by X-ray crystal analysis (Figure 2).
Table 3. Reactions of 1k with 2a in the Presence of Additivesa
entry
additive
None
product
yieldb
1
2
3
4
5
6
7
8
9
10
4aþ5a
4aþ5a
4aþ5a
4aþ6a
4aþ6a
4aþ6a
6a
29%(4a/5a = 3:1)c
24 mg
4aþ5a (28 mg)
4aþ5a (56 mg)
LiCl (25 mol %)
LiCl (50 mol %)
LiCl (75 mol %)
LiCl (100 mol %)
LiCl (125 mol %)
NiCl2 (25 mol %)
NiCl2 (50 mol %)
48 mg
12%(4a) þ 5%(6a)
21%(4a) þ 10%(6a)
trace (4a) þ 15%(6a)
trace
none
N.R.
4aþ5a
4aþ5aþ6a
29%(4a/5a = 7:1)b
28%(4a/5a = 20:1)b þ
trace (6a)
11
NiCl2 (75 mol %)
4aþ6a
trace
a Recation conditions: 1k (0.5 mmol), 2a (1.5 mmol), Pd(OAc)2
(10 mol %), Cu(OAc)2 H2O (75 mol %), Toluene-1.4-dioxane(5 mL,
3
v:v = 1:1), 100 °C, 24 h, under air. b Isolated yield. c Ratio was
determined by 1H NMR.
thiophene 1h has two types of CꢀH bonds at ortho
positions of the aryl group, only the ortho-Csp2ꢀH bond
was activated and product from ortho-Csp3ꢀH activation
was not observed. Next, we started to investigate the
possibility of forming a CꢀS bond with a sp3-carbon
through more stable Csp3ꢀH bond activation.5
Our initial studies focused on the use of thiophene 1k.
Under modified conditions (100 °C, toluene-dioxane =
1:1, see SI for the optimizations of reaction conditions),
thiophene 1k reacted smoothly with 2a and a mixture of
two products was isolated (Table 3, entry 1). After careful
separations and recrystallizations, the two composites, 4a
and 5a, were isolated partially from this mixture. The ratio
of these two compounds was determined by the 1H NMR
Figure 1. Molecular structure of 5a.
of the crude reaction mixture. As expected, one ortho-Csp3
-
To our surprise, this1, 2-diorganothio-substitued alkene
6a was formed with high stereoselectivity and only cis-
thiolation product was obtained. It should be mentioned
that the fulvene moiety is located trans to sulfur also
(Figure 2). When 50 mol % of LiCl was added (Table 3,
entry 5), higher yields of 4a and 6a were obtained in almost
same chemoselectivity as entry 4 and 4a was the major
product. When the amount of LiCl was increased to 75 mol
%, the reaction proceeded with higher chemoselectivity, 6a
was obtained as major product, and only trace amount of
4a was observed (entry 6). However, the activity of catalyst
H bond was activated and provided the desired 4a. The
structure of 5a was confirmed by X-ray crystal analysis
(Figure 1). The formation of 5a is quite surprising. Until
now, only cis-carbothiolations of alkynes were observed
with our Pd-catalyzed CꢀS bond activation of thiophenes
and the captured fragments are cis-fused in the final
(5) (a) Ramirez, T. A.; Zhao, B.; Shi, Y. Chem. Soc. Rev. 2012, 41,
931. (b) Li, H.; Li, B.-J.; Shi, Z.-J. Catal. Sci. Technol. 2011, 1, 191.
(c) Zhang, S.-Y.; Zhang, F.-M.; Tu, Y.-Q. Chem. Soc. Rev. 2011, 40,
1937. (d) Bellina, F.; Rossi, R. Chem. Rev. 2010, 110, 1082. (e) Giri, R.;
Shi, B.-F.; Engle, K. M.; Maugel, N.; Yu, J.-Q. Chem. Soc. Rev. 2009, 38,
3242. (f) Chen, X.; Engle, K. M.; Wang, D.-H.; Yu, J.-Q. Angew. Chem.,
Int. Ed. 2009, 48, 5094.
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Org. Lett., Vol. XX, No. XX, XXXX
C

Table 4. Reactions of 1l with 2aa
entry
additive
product
isolated yield (%)
1
2
3
None
LiCl
4bþ5b
4bþ6b
4bþ6b
4b/5b (31, 4:1b)
4b(15) þ 6b(20)
4b(28) þ 6b(trace)
NiCl2
a Reaction conditions: 1l (0.5 mmol), 2a (1.5 mmol). b Ratio was
Figure 2. Molecular structure of 6a.
determined by 1H NMR.
was suppressed with overloaded LiCl (entries 7, 8). Since
there are several reports on the formations cis-1,2-diorga-
nothio-substitued alkenes with Ni catalyzed reactions
between sulfur containing compounds and alkynes,7 NiCl2
was examined as additive. It was observed that the pre-
sence of 25 or 50 mol % of NiCl2 was not useful for the
formation of 6a. To our delight, without altering the
efficiency, the presence of NiCl2 can improve the chemo-
selective formation of 4a dramatically and the ratio of
4a:5a was increased from 3:1 (entry 1) to 7:1 (entry 9) and
20:1 (entry 10), respectively.
Similarly, when thiophene 1l was used, a mixture of 4b
and 5b, in a molar ratio of 4:1 was isolated in a total 31%
yield (Table 4, entry 1). In the presence of 50 mol % of
LiCl, 4b and 6b were isolated in 15 and 20% yields,
respectively, while the formation of 5b was not observed
(entry 2). When NiCl2 was added (entry 3), 4b was isolated
in 28% yield, with trace amount of 6b.
In the presence of NiCl2 (50 mol %), only 4c was formed
in 33% yield from the reaction of thiophene 1k with alkyne
2d (eq 1). The structure of 4c was examined via X-ray
crystallography. As expected, a new ortho-Csp3ꢀS bond
was formed (Figure 3).
Figure 3. Molecular structure of 4c.
In summary, we have found a new palladium catalyzed
reaction of simple thiophenes with alkynes through a
domino type CꢀH and CꢀS bond activation. Compared
with our previous results, no reactive R-CꢀBr bond is
needed. During the research with Csp3ꢀH bond activation,
an interesting salt effect was observed. The reaction’s
efficiency and selectivity depend not only on the type but
also the amount of the salt used. Further investigation on
the scope and the mechanism of this reaction is in progress.
From these results, it can be seen that: (a) the chemose-
lective formation of Csp3ꢀS type product 4 can be achieved
with the presence of right amount of NiCl2 through CꢀS
and Csp3ꢀH bond activation; (b) the presence of suitable
amount of LiCl will favor the formation of cis-diorga-
nothio-substitued alkene 6, and an unexpected cis-to-trans
isomerization of the cleaved carbon and sulfur fragment
was observed also; (c) overloaded additive will reduce the
reaction’s efficiency; (d) the selective formation of5 isstill a
challenge. The reaction mechanism is proposed in the
Supporting Information.
Acknowledgment. We gratefully acknowledge the Na-
tional Natural Science Foundation of China (No.
21072179) for financial support.
Supporting Information Available. Experimental pro-
cedures, characterization data of compounds, and crys-
tallographic data (CIF). This material is available free of
charge via the Internet at http://pubs.acs.org.
(7) (a) Inami, T.; Baba, Y.; Kurahashi, T.; Matsubara, S. Org. Lett.
2011, 13, 1912. (b) Ananikov, V. P.; Gayduk, K. A.; Orlov, N. V.;
Beletskaya, I. P.; Khrustalev, V. N.; Antipin, M. Y. Chem.;Eur. J.
2010, 16, 2063. (c) Ananikov, V. P.; Gayduk, K. A.; Starikova, Z. A.;
Beletskaya, I. P. Organometallics 2010, 29, 5098.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX