Palladium-catalyzed dehydrogenative coupling of cyclic enones with thiophenes: A rapid access to β-heteroarylated cyclic enones

Article abstract of DOI:10.1039/c8cc01059e

Dehydrogenative coupling of cyclic enones with heteroarenes has been a longstanding challenge because of the competitive ketone dehydrogenation and conjugated addition. Herein, a dehydrogenative coupling reaction of cyclic enones of different sizes with substituted thiophenes to construct β-thienyl cyclic enone compounds through palladium-catalyzed C-H functionalization under mild reaction conditions is reported. Simple substituted thiophenes with different functional groups can be directly introduced into cyclic enones with predominant regioselectivity at the α position of thiophene moieties and excellent functional group tolerance. Further molecular transformations of the coupling products to synthetically useful meta-heteroarylated phenol derivatives have also been demonstrated.

Full text of DOI:10.1039/c8cc01059e

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Palladium Catalyzed Dehydrogenative Coupling of Cyclic Enones
with Thiophenes: A Rapid Access to β-Heteroarylated Cyclic
Enones
Received 00th January 20xx,
Accepted 00th January 20xx
Zhen-Kang Wen,*,a Ting-Ting Songa, Yu-Fang Liua and Jian-Bin Chaob
DOI: 10.1039/x0xx00000x
www.rsc.org/
Dehydrogenative coupling of cyclic enones with heteroarenes has opposite position in the Pd(II)-cyclic enolate4c intermediate.
been a longstanding challenge because of competitive ketone Thus the establishment of catalytic reactions that involve Csp2-
dehydrogenation and conjugated addition. Reported herein is a
H
activation between cyclic enones and substituted
dehydrogenative coupling reaction of different size of cyclic heteroarenes through Heck coupling to provide 3-
enones with substituted thiophenes to construct β-thienyl cyclic (hetero)arylated cyclic enones remains great challenge.
enone compounds through palladium catalyzed C-H Despite the recent progress in palladium catalyzed Heck
functionalization under mild reaction conditions. Simple coupling of cyclic enones with arenes via arene C-H activation,
substituted thiophenes with different functional groups can be a large excess of arene (neat or more than 15 equivalents) as
directly introduced to cyclic enones with predominant regio- well as an acid reaction media and high temperature (above
selectivity at the α position of thiophene moieties and excellent 100oC) are typically required,8 which limits the practicality and
functional group tolerance. Further molecular transformations of utility of these approaches. Herein, we report a facile method
the coupling products to synthetically useful meta-heteroarylated for the synthesis of β-heteroarylated cyclic enones through
phenol derivatives are also demonstrated.
palladium-catalyzed cross-coupling strategy between different
size of cyclic enones and readily available thiophenes under
mild conditions, in which thiophene is used as a limiting
reagent (Scheme 1b). To the best of our knowledge, the direct
dehydrogenative cross-coupling between cyclic enones and
thiophenes has not been reported to date. In addition, the
derivatization of the prepared β-thienyl-substituted
The palladium catalyzed Fujiwara-Moritani-Heck1 coupling
through C-H functionalization represents an important class of
powerful C-C bond forming strategy in step and atom
economical manner. While significant progress has been
achieved for coupling reaction between linear terminal alkenes
2
and (hetero)arenes,
the direct coupling between cyclic
cyclohexenones
to
meta-substituted
phenols
was
enones and (hetero)arenes is hardly enabled to afford the
desired product 3-(hetero)arylated cyclic enones, which are of
great importance as structure motifs both in bioactive
molecules3 and in the synthesis of substituted phenols or
demonstrated, thus providing a complementary to the meta-
phenol preparation4c,9 which could not be accessible by typical
electrophilic substitution of phenol due to its strong directing
effect of hydroxyl group.
4
anilines for drug design. The reason is likely attributed to the
Scheme 1. Dehydrogenative coupling of cyclic enones with arenes
low reactivity of simple (hetero)arenes in the absene of
directing groups1,5, side reactions of cyclic enones during the
catalytic system such as ketone dehydrogenation6 and
conjugated addition7. In most cases the Pd(II)-enolate
intermediate, which was generated by migratory insertion of
aryl palladium species into conjugated enone olefin, prefers to
undergo hydrolysis rather than β-hydride elimination (Scheme
1a) because of the Pd and β-hydrogen atom were in the
a.School of Chemistry and Chemical Engineering, Shanxi University,Taiyuan 030006,
China. E-mail: zkwen@sxu.edu.cn
b.Scientific Instrument Center, Shanxi University, Taiyuan 030006, China.
c. Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
Our strategy focuses on developing an efficient catalytic
system for facie synthesis of 3-(hetero)arylated cyclic enones
This journal is © The Royal Society of Chemistry 20xx
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aConditions: The reaction was conducted with thiophene (0.25 mmol, 1 equiv),
cyclohexenone (0.75 mmol, 3 equiv), Pd(OAc)2 (0.025 mmol, 0.1 equiv), Ac-Gly-OH
(0.025 mmol, 0.1 equiv), Ag2CO3 (0.5 mmol, 2 equiv) in 1 mL solvent at 60 oC for 24
h. bIsolated yield. cAgOAc (4 equiv) as oxidant dAg2O (2 equiv) as oxidant, eCu(OAc)2
(4 equiv) as oxidant fDMSO (0.05 mL) was added as the minor cosolvent. HFIP =
1,1,1,3,3,3-Hexafluoro-2-propanol
from the corresponding cyclic enones and thiophenes. This
strategy avoids use of prefunctionalized aryl surrogates10 (aryl
halides, aryl boronic acids, aryl carboxylic acids) and thereby
enhances synthetic efficiency. To achieve the coupling of cyclic
enones and thiophenes, following challenges must be
considered. First, due to the absence of directing group, the
low reactivity of simple heteroarenes should be enhanced
using a sufficiently reactive palludium catalyst. Secondly, side
reactions such as homocoupling of thiophene11 and
overoxdiation of cyclic enones6,12 must be inhibited. Thus,
exploitation of a catalytic system via precise control over the
catalytic sequence is desired.
Polar solvents including DMSO, DMA, DMF led to trace of
product formation. Interestingly, neither thiophene
dimerization nor overoxidation side product was observed. A
brief examination of palladium catalysts revealed that 2a could
be isolated in 38% yield when PdCl2 was used (entry 10), while
use of more ionic Pd(TFA)2 was found much less effective
(entry 11). Oxidants survey showed that Ag2CO3 was suitable
oxidant for this reaction (entries 12-14). In order to improve
the reaction efficiency, the combination of PdCl2 with additives
in 1:2 ratio was examined. Pleasingly, AgSbF6 as additive could
afford 2a in 46% yield, other additives such as KPF6 or dibenzyl
phosphate resulted in a decreased yield (entries 15-17).
Finally, when using 0.05 mL DMSO as a minor cosolvent, the
yield of 2a increased up to 64%, which was expected to
stablize Pd (0) species and inhibit undesired inert palladium
black formation (entry 18). Control experiment revealed that
palladium catalyst and Ac-Gly-OH were crucial for this
coupling, and no reaction occurred in the absence of them (for
detailed optimization, see the Supporting Information). Thus,
the standard condition was established as following: the
mixture of thiophene (0.25 mmol), cyclohexenone (0.75
mmol), DMSO (0.05 mL), PdCl2 (0.1 equiv), Ac-Gly-OH (0.1
equiv), AgSbF6 (0.2 equiv), Ag2CO3 (2 equiv) in 5%
HFIP/dioxane (0.05 mL/1 mL) at 60 oC stirred for 24 h.
We commenced our investigation by screening various
reaction conditions for the envisioned dehydrogenative
coupling of cyclohexenone with thiophene 1a employing
Pd(OAc)2 as catalyst and Ag2CO3 as the oxidant. Given the
widely applicable ligand-induced acceleration5 in C-H
activation reactions, we envisage that the judicious choice of a
suitable ligand could promote direct coupling of cyclic enones
with thiophene through C-H activation. Note that the
combination of palladium catalyst with amino acid ligands has
been well established in the C-H bond functionalization
reactions.13 Gratifyingly, preliminary attempts using Ac-Gly-OH
in dioxane at 60 °C stirred for 24 h led to the coupling product
2a in 18% yield (Table 1, entry 1). A variety of solvents
screening revealed that additon of 5% mildly acidic HFIP in
dioxane provided the desired coupling product in 32% yield
(entries 2-9), although the role of HFIP was unclear. Other
single solvents such as THF and HFIP proved less effective.
With the optimized reaction conditions in hand, we attempted
the dehydrogenative coupling reactions of cyclic enones with
various substituted thiophenes (Scheme 2). Pleasingly, all
reactions proceeded smoothly to provide the coupling
products in moderate to high yields at α position of
thiophenes. 2-Methyl thiophene gave 68% yield of the
corresponding product 2b under the standard reaction
conditions. Interestingly, 3-Methyl thiophene gave an
inseparable mixture of 2ca and 2cb (83:17) in 70% yield
through the C-H functionalization of thiophene at the 5 and 2
position, while 3-methoxylthiophene afforded a single product
2d in 63% yield. It's noteworthy that various functional groups
Table 1. Optimization Conditionsa
entrya
1
catalyst
solvent
yieldb
18%
8%
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
dioxane
2
THF
3
DCE
5%
4
DMF
trace
trace
trace
8%
(
2e-2g, 2i, 2j) such as chloro, boromo, enolizable methyl
5
DMSO
ketones and esters were all tolerated under this catalytic
reaction conditions, thus offered a great potential for further
transformation of these products to more complicated
molecules. 2-Phenylthiophene also reacted successfully,
affording the corresponding product 2h in 75% yield. When
3,4-ethylenedioxythiophene was used to react with
cyclohexenone, the desired product 2k was obtained in 29%
yield. Benzothiophene was also suitable substrate in this
catalytic reaction conditions, gave the corresponding product
6
DMA
7
HFIP
8
HFIP/dioxane (1:1)
5% HFIP/dioxane
5% HFIP/dioxane
5% HFIP/dioxane
5% HFIP/dioxane
5% HFIP/dioxane
5% HFIP/dioxane
5% HFIP/dioxane
5% HFIP/dioxane
5% HFIP/dioxane
5% HFIP/dioxane
22%
32%
38%
<10%
23%
15%
<10%
33%
46%
20%
64%
9
10
11
12c
13d
14e
15
16
17
18f
Pd(TFA)2
PdCl2
PdCl2
(
2la, 2lb) with a mixture of α and β funtionalized isomers
PdCl2
(67:33) in 24% yield. Other heterocyclic analogues such as
furan and 2-methylfuran worked efficiently in this protocol,
affording the products at α-position of furans in moderate
PdCl2/ KPF6
PdCl2/AgSbF6
PdCl2/(BnO)2P(O)OH
PdCl2/AgSbF6
yields (2m, 2n). Furthermore, more steric hindered 2,4-
disubstituted thiophenes, which are untouched substrates in
14
previously reprorted thiophene functionalization reactions,
2 | J. Name., 2012, 00, 1-3
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were employed in this transformation and gave the products cross-coupling reaction. Moreover an intermolecular
2o 2r) in moderate to high yield, Moreover, when 3, 4- competition reaction between 2-methyl thiophene and 2-
disubstituted thiophenes were used, the mono- and di- chloro thiophene with cyclohexenone was also conducted
coupling cyclohexenone products (2s 2s' 2t 2t') were isolated under the standard reaction conditions (eq 3), the remarkable
(
-
,
,
,
in high yields. Finally, different size of cyclic enones such as difference of coupling product yields verified the reaction
cyclopentenone and cycloheptenone were suitable substrates efficiency was dependent on the electron properties of
to couple with thiophene or 2-phenylthiophene, providing the thiophenes, thus providing indirect support for thiophene C-H
desired coupling products in moderate yields (2u
,
2v
,
2w).
cleavage step was involved in the rate-determining step.
Based on these results, a plausible proposed catalytic
mechanism for the dehydrogenative coupling reaction was
described in Scheme 3. Starting with a thiophene and a Pd(II)
Scheme 2. Scope of the dehydrogenative coupling between substituted
thiophenes with cyclic enones
O
10 mol % PdCl2
O
catalyst, a thienyl-Pd(II) species
I can be formed (Step A).
10 mol % Ac-Gly-OH
S
2.0 equiv Ag2CO3
S
+
Subsequently, migratory insertion of the produced thienyl-
Pd(II) into conjugated enone olefin would afford a thiophene
based Pd-enolate intermediate II (Step B), which should
R
20 mol % AgSbF6
DMSO ( 0.05 mL )
5% HFIP/dioxane
60 °C, 24 h
n
n
R
1a-t
2a-t
O
O
O
O
O
O
Cl
S
O
S
Cl
S
S
S
S
S
+
undergo a rapid isomerization (II, IIA, IIB) for the facile syn β-
O
2b 68%
[ b ]
hydride elimination (Step C) to give the desired coupling
product III and restore Pd(0) (Step D). Finally, with a suitable
oxidant the active Pd(II) could be regenerated to complete the
cytalytic cycle (Step E).
2a 64%
2ca
2cb
2d
2e 59%
O
63%
O
2ca : 2cb = 83:17 70%
O
O
O
Br
S
S
O
S
O
S
S
2f 57%
2g 67%
O
2i 44% [ c ]
]
2j 60% [ c
2h 75%
S
O
O
S
O
O
O
O
O
Scheme 3. Proposed Mechanism
+
O
2m 42%
2la
2la : 2lb = 67 : 33, 24%
2n 56%
2k 29%
2lb
O
O
O
O
S
S
S
S
2q 53%
2p 96%
2r 50%
2o 85%
O
O
O
O
O
O
S
S
S
S
2s 45%
2t
41%
2t 45%
2s
46%
O
O
O
S
S
S
2u, 28%
2v, 43%
2w, 42%
aReaction condition: Thiophene homologues (0.25 mmol), 2-cyclohexen-1-
one (0.75 mmol, 3 equiv), PdCl2 (0.025 mmol), Ac-Gly-OH (0.025 mmol), Ag2CO3
(0.5 mmol), AgSbF6 (0.05 mmol), DMSO (0.05 mL), HFIP (0.05 mL), dioxane (1 mL),
60 oC, 24 h. bAgSbF6 was not added. c0.5 equiv Ac-Gly-OH were used, HFIP (0.5
mL)/dioxane (0.5 mL) instead of HFIP (0.05 mL)/dioxane (1 mL), 110
℃.
To demonstrate the utility of this transformation,
derivatization reactions of the coupling products to meta-
phenols were consequently conducted by using a phosphine
To examine the potential use of current method in organic
synthesis, mmol scale-up reactions between 2-
a
2
methylthiophen or 2-methylfuran and cyclohexenone were
performed (eq 1), the direct cross-coupling products were
isolated in 76% yield and 48% yield respectively.
Scheme 4. Application of palladium catatlyzed dehydrogenation reactions in
the synthesis of meta-thiophene substituted phenols.
aReaction condition: Pd(TFA)2 (10 mol%), silver trifluoroacetate (2.0 equiv),
triisopropylphosphane (20 mol%) and substrate 2 (0.15 mmol) were stirred in 1,4-
dioxane (0.75 mL) at 120 °C for 36 h.
To gain further insight into the mechanism of palladium
catalyzed cross-coupling of cyclohexenone with thiophene, an
intermolecular kinetic isotope effect (KIE) experiment was
performed under the standard reaction conditions (eq 2). As a
result, a significant KIE value (kH/kD = 4) was observed, thus
suggesting the thiophene C–H bond cleavage is probably
involved in the rate-determining step of this dehydrogenative
based electron rich palladium catalyst, and the representative
results are shown in Scheme 4. We are pleased to observe that
β-heteroarylated cylcohexenones with different electron
properties worked well and gave the desired meta-phenol
derivatives in moderate to high yields. It's noteworthy that
when the reaction is performed under Stahl's conditions
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4c
Lett. 2012, 14, 1760; e) N. Kuhl, M. N. Hopkinson, J. Wencel-
Delord, F. Glorius, Angew. Chem. Int. Ed. 2012, 51, 10236; e) Y. H.
Zhang, B. F. Shi, J. Q. Yu, J. Am. Chem. Soc. 2009, 131, 5072.
where an electrophilic palladium catalyst was employed, no
phenol products were observed. Interestingly, the chloro and
enolizable methyl ketone substituted thiophene moieties were
also tolerated in this transformation, which provides a
straightforward route for further elaboration of complicated
phenol molecules.
6
For reviews and selected examples of Pd-catalyzed direct
dehydrogenation of ketone, see: a) J. Muzart, Eur. J. Org. Chem.
2010, 3779; b) W. Gao, Z. He, Y. Qian, J. Zhao, Y. Huang, Chem.
Sci. 2012, 3, 883; c) T. Diao, T. J. Wadzinski, S. S. Stahl, Chem. Sci.
2012, 3, 887; d) T. Diao, S. S. Stahl, J. Am. Chem. Soc. 2011, 133,
14566; e) Y. Shvo, A. H. I. Arisha, J. Org. Chem. 1998, 63, 5640.
In conclusion, we have developed palladium catalyzed
dehydrogenative cross-coupling of cyclic enones with
thiophenes to prepare β-thienyl cyclic enone molecules.
Remarkable regioselectivity and high functional group
compatability were achieved. The resulting β-thienyl
cyclohexenone compounds could be derivatized to useful
meta-heteroarylated phenol derivatives. We expect that these
dehydrogenative cross-coupling processes will provide new
routes to construct meta-heteroarylated phenol scaffolds with
omnipotent uses in synthetic and medicinal applications.
This work was financially supported by the National Natural
Science Foundation of China (21502106, 21601111) and the
National Natural Science Foundation for Young Scientists of
Shanxi Province (201701D221028). We are also very grateful
for the test platform provided by Scientific Instrument Center
of Shanxi University.
7
a) A. B. Weinstein, J. A. Ellman, Org. Lett. 2016, 18, 3294; b) X.
Y. Shi, C. J. Li, Org. lett. 2013, 15, 1476; c) J. A. Jordan-Hore, J. N.
Sanderson, A. L. Lee, Org. Lett. 2012, 14, 2508; d) A. L.
Gottumukkala, K. Matcha, M. Lutz, J. G. de Vries, A. J. Minnaard,
Chem. Eur. J. 2012, 18, 6907; e) K. Kikushima, J. C. Holder, M.
Gatti, B. M. Stoltz, J. Am. Chem. Soc. 2011, 133, 6902; f) S. H. Lin,
X. Y. Lu, Org. Lett. 2010, 12, 2536; g) T. Nishitaka, Y. Yamamoto,
N. Miyaura, Chem. Lett. 2007, 36, 1442; h) F. Gini, B. Hessen, A. J.
Minnaard, Org. Lett. 2005, 7, 5309; i) T. Nishikata, Y. Yamamoto,
N. Miyaura, Angew. Chem., Int. Ed. 2003, 42, 2768.
8
2015, 7, 1270; b) N. Gigant, J.-E. Bäckvall, Chem. Eur. J. 2014, 20,
5890; c) Y. Moon, D. Kwon, S. Hong, Angew. Chem. Int. Ed. 2012
51, 11333.
a) L. G. Y. Chung, N. A. B. Juwaini, J. Seayad, ChemCatChem
,
9
a) Y. F. Liang, S. Song, L. S. Ai, X. W. Li, N. Jiao, Green Chem.,
2016, 18, 6462; b) J. W. Zhang, Q. Q. Jiang, D. J. Yang, X. M. Zhao,
Y. L. Dong, R. H. Liu, Chem. Sci., 2015, 6, 4674.
10 For selected examples by using prefunctionalized aryl
surrogates, see: a) S. E. Walker, J. Boehnke, P. E. Glen, S. Levey, L.
Patrick, J. A. Jordan- Hore, A. L. Lee, Org. Lett. 2013, 15, 1886; b)
A. L. Gottumukkala, J. F. Teichert, D. Heijnen, N. Eisink, S. van
Dijk, C. Ferrer, A. van den Hoogenband, A. J. Minnaardb, J. Org.
Chem. 2011, 76, 3498; c) Y. Fall, H. Doucet, M. Santelli,
Tetrahedron 2009, 65, 489; d) K. S. Yoo, C. H. Yoon, K. W. Jung, J.
Am. Chem. Soc. 2006, 128, 16384; e) X. Lu, S. Lin, J. Org. Chem.
2005, 70, 9651; f) D. Tanaka, A. G. Myers, Org. Lett. 2004, 6, 433;
g) T. R. Krishna, N. Jayaraman, Tetrahedron 2004, 60, 10325; h) T.
Notes and references
1
a) C. G. Jia, T. Kitamura, Y. Fujiwara, Acc. Chem. Res. 2001,
34, 633; b) C. G. Jia, D. P. Piao, J. Oyamada, W. J. Lu, T. Kitamura,
Y. Fujiwara, Science 2000, 287, 1992; c) C. G. Jia, W. J. Lu, T
Kitamura, Y. Fujiwara, Org. Lett. 1999, 1, 2097; d) Y. Fujiwara, I.
Moritani, S. Danno, R. Asano, S. Teranishi, J. Am. Chem. Soc.
1969, 91, 7166; e) I. Moritani, Y. Fujiwara, Tetrahedron Lett.
1967, 8, 1119.
Nishikata, Y. Yamamoto, N. Miyaura, Angew. Chem. Int. Ed. 2003
42, 2768.
,
2
For selected reviews and examples, see: a) L. H. Zhou, W. J.
11 a) Y. D. Yang, J. B. Lan, J. S. You, Chem. Rev., 2017, 117, 8787;
b) N. N. Li, Y. L. Zhang, S. Mao, Y. R. Gao, D. D. Guo, Y. Q. Wang,
Org. Lett., 2014, 16, 2732; c) K. Masui, H. Ikegami, A. Mori, J. Am.
Chem. Soc., 2004, 126, 5074.
12 a) D. Pun, T. Diao, S. S. Stahl, J. Am. Chem. Soc. 2013, 135,
8213; b) Z. X. Huang, G. B. Dong, J. Am. Chem. Soc. 2013, 135,
17747; c) Y. Izawa, D. Pun, S. S. Stahl, Science 2011, 333, 209.
Lu, Chem. Eur. J. 2014, 20, 634; b) S. I. Kozhushkov, L. Ackermann,
Chem. Sci. 2013, 4, 886; c) P. B. Arockiam, C. Bruneau, P. H.
Dixneuf, Chem. Rev. 2012, 112, 5879; d) J. Le Bras, J. Muzart,
Chem. Rev. 2011, 111, 1170; e) T. Satoh, M. Miura, Chem. Eur. J.
2010, 16, 11212; f) M. Dams, D. E. De Vos, S. Celen, P. A. Jacobs,
Angew. Chem. Int. Ed. 2003, 42, 3512; g) T. Yokota, M. Tani, S.
Sakaguchi, Y. Ishii, J. Am. Chem. Soc. 2003, 125, 1476.
13 a) K. M. Engle, D. H. Wang, J. Q. Yu, J. Am. Chem. Soc. 2010
,
3
a) S. Radomkit, A. H. Hoveyda, Angew. Chem. Int. Ed. 2014,
132, 14137; b) Y. Lu, D. H. Wang, K. M. Engle, J. Q. Yu, J. Am.
Chem. Soc. 2010, 132, 5916; c) D. H. Wang, K. M. Engle, B. F. Shi,
J. Q. Yu, Science 2010, 327, 315; d) X. Wang, Y. Lu, H. X. Dai, J. Q.
Yu, J. Am. Chem. Soc. 2010, 132, 12203; e) Z. K. Wen, Y. H. Xu, T.
P. Loh, Chem. Sci., 2013, 4, 4520; f) Q. J. Liang, C. Yang, F. F.
53, 3387; b) P. Kwiatkowski, K. Dudziński, D. Łyżwa, Org. Lett.
2011, 13, 3624; c) S. Kehrli, D. Martin, D. Rix, M. Mauduit, A.
Alexakis, Chem. Eur. J. 2010, 16, 9890; d) I. H. Chen, L. Yin, W.
Itano, M. Kanai, M. Shibasaki, J. Am. Chem. Soc. 2009, 131,
11664; e) M. E. Jimenez, K. Bush, J. Pawlik, L. Sower, J. W.
Peterson, S. R. Gilbertson, Bioorg. Med. Chem. Lett. 2008, 18,
4215; f) F. J. Moreno-Dorado, F. M. Guerra, F. J. Aladro, J. M.
Bustamante, Z. D. Jorge, G. M. Massanet, Tetrahedron 1999, 55,
6997.
Meng, B. Jiang, Y. H. Xu, T. P. Loh, Angew. Chem. Int. Ed. 2017
56, 5091.
,
14 For selected examples, see: a) B. J. Gorsline, L. Wang, P. Ren,
B. P. Carrow, J. Am. Chem. Soc. 2017, 139, 9605; b) T. Morita, T.
Satoh, M. Miura, Org. Lett. 2015, 17, 4384; c) A. Vasseur, C.
For recent examples, see: a) T. Boibessot, C. P. Zschiedrich, A.
4
Laugel, D. Harakat, J. Muzart, J. Le. Bras, Eur. J. Org. Chem. 2015
,
Lebeau, D. Bénimèlis, C. Dunyach-Rémy, J. P. Lavigne, H.
Szurmant, Z. Benfodda, P. Meffre, J. Med. Chem. 2016, 59, 8830;
b) T. Diao, D. Pun, S. S. Stahl, J. Am. Chem. Soc. 2013, 135, 8205;
c) Y. Izawa, C. Zheng, S. S. Stahl, Angew. Chem. Int. Ed. 2013, 52,
3672; d) M. O. Simon, S. A. Girard, C. J. Li, Angew. Chem. Int. Ed.
2012, 51, 7537; e) S. Quideau, D. Deffieux, C. Douat-Casassus, L.
Pouységu, Angew. Chem. Int. Ed. 2011, 50, 586.
944; d) C. Y. He, C. Z. Wu, Y. L. Zhu, X. G. Zhang, Chem. Sci., 2014
,
5, 1317; e) Y. P. Shang, X. M. Jie, J. Zhou, P. Hu, S. J. Huang, W. P.
Su, Angew. Chem. Int. Ed. 2013, 52, 1299; f) C.Y. He, Z. Wang, C.
Z. Wu, F. L. Qing, X. G. Zhang, Chem. Sci., 2013, 4, 3508; g) Y. X.
Zhang, Z. J. Li, Z. Q. Liu, Org. Lett., 2012, 14, 226; h) A. Vasseur, J.
Muzart, J. Le. Bras, Chem. Eur. J. 2011, 17, 12556; i) C. Y. He, S. L.
Fan, X. G. Zhang, J. Am. Chem. Soc. 2010, 132, 12850; j) P. H. Xi, F.
Yang, S. Qin, D. B. Zhao, J. B. Lan, G. Gao, C. W. Hu, J. S. You, J.
Am. Chem. Soc. 2010, 132, 132, 1822; k) A. Maehara, H. Tsurugi,
T. Satoh, M. Miura, Org. Lett. 2008, 10, 1159.
5
a) P. Wang, P. Verma, G. Q. Xia, J. Shi, J. X. Qiao, S. W. Tao, P.
T. W. Cheng, M. A. Poss, M. E. Farmer, K. S. Yeung, J. Q. Yu,
Nature 2017, 551, 489; b) J. F. Hartwig, M. A. Larsen, ACS Cent.
Sci. 2016, 2, 281; c) C.-H. Ying, S. B. Yan, W. L. Duan, Org. Lett.
2014, 16, 500; d) A. Kubota, M. H. Emmert, M. S. Sanford, Org.
4 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/C8CC01059E
Journal Name
COMMUNICATION
Palladium Catalyzed Dehydrogenative Coupling of Cyclic Enones with Thiophenes: A
Rapid Access to β-Heteroarylated Cyclic Enones
Zhen-Kang Wen,*,a Ting-Ting Songa, Yu-Fang Liua and Jian-Bin Chaob
A dehydrogenative coupling reaction of cyclic enones with thiophenes to construct β-thienyl cyclic enone compounds
through palladium catalyzed C-H functionalization is reported herein. Further molecular transformations of the coupling
products to synthetically useful meta-heteroarylated phenol derivatives are also demonstrated.
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