Utilizing an Encapsulated Solution of Reagents to Achieve the Four-Component Synthesis of (Benzo)Thiophene Derivatives

Article abstract of DOI:10.1002/adsc.201601343

Reagent capsules can help to resolve the compatibility problem of reagents in multicomponent processes. Herein we demonstrate a facile method for encapsulating smelly liquid chemicals and its application in a modular palladium-catalyzed carbonylative synthesis of multi-substituted thiophenes from terminal alkynes and aryl iodides as well as a palladium-catalyzed carbonylative synthesis of benzothiophene derivatives from aryl iodides and arylboronic acids. Here, the capsule plays a pivotal role in solving the issues on reaction condition incompatibilities and selectivity of multicomponent reactions as well as avoiding deactivation of the catalyst by releasing the reagents when the reaction temperature is raised. It greatly facilitates the development of highly-efficient multicomponent reactions and demonstrates a modular pathway to obtain functionalized molecules. (Figure presented.).

Full text of DOI:10.1002/adsc.201601343

COMMUNICATIONS
DOI: 10.1002/adsc.201601343
Utilizing an Encapsulated Solution of Reagents to Achieve the
Four-Component Synthesis of (Benzo)Thiophene Derivatives
Chaoren Shen,a Anke Spannenberg,a Matthias Auer,a and Xiao-Feng Wua,b,*
a
Leibniz-Institut fꢀr Katalyse an der Universitꢁt Rostock e.V., Albert-Einstein-Straße 29a, 18059 Rostock, Germany
Fax : (+49)-0381-1281-343; phone: (+49)-0381-1281-343; e-mail: xiao-feng.wu@catalysis.de
Department of Chemistry, Zhejiang Sci-Tech University, Xiasha Campus, Hangzhou 310018, Peopleꢂs Republic of China
b
Received: December 6, 2016; Revised: January 16, 2017; Published online: && &&, 0000
Supporting information for this article can be found under: http://dx.doi.org/10.1002/adsc.201601343.
Abstract: Reagent capsules can help to resolve the
compatibility problem of reagents in multicompo-
nent processes. Herein we demonstrate a facile
method for encapsulating smelly liquid chemicals
and its application in a modular palladium-cata-
lyzed carbonylative synthesis of multi-substituted
thiophenes from terminal alkynes and aryl iodides
as well as a palladium-catalyzed carbonylative syn-
thesis of benzothiophene derivatives from aryl io-
dides and arylboronic acids. Here, the capsule plays
a pivotal role in solving the issues on reaction con-
dition incompatibilities and selectivity of multicom-
ponent reactions as well as avoiding deactivation of
the catalyst by releasing the reagents when the re-
action temperature is raised. It greatly facilitates
the development of highly-efficient multicomponent
reactions and demonstrates a modular pathway to
obtain functionalized molecules.
free synthesis[3] and advancement of organic chemis-
try teaching in the undergraduate laboratory.[5] Due
to the fluidity of liquid chemicals and complexity of
making paraffin capsules, neither dispersion into par-
affin wax nor encapsulation by paraffin wax is the
suitable solution to make capsules containing liquid
chemicals. Recently a method of encapsulating liquid
chemicals by embedding the compounds in crystalline
matrices that form inclusion complexes of defined sto-
ichiometry has been reported.[6] It makes toxic or mal-
odorous liquid compounds easy to handle and dis-
pense while but guarantees the immediate release of
reagents in solution, but it always requires stoichio-
metric amounts of tetrakis(dimethoxyphenyl)adaman-
tane. Therefore we sought to achieve the facile encap-
sulation and controlled release of liquid chemicals
and excavate the potential of encapsulated liquid re-
agents in organic synthesis.
As one of the powerful tools in organic synthesis,
the multicomponent reaction (MCR) can implement
the continuous construction of multiple bonds and
rapid generation of molecular complexity.[7] It pro-
vides an operationally effective and highly modular
approach to obtain structurally diverse molecules
through a process that combines three or more com-
ponents in a single reaction vessel without isolating
Keywords: carbonylation; encapsulated reagents;
heterocycles; multicomponent reactions; palladium
catalysis
Encapsulation is an ancient but important invention the intermediates or adding further reagents. Owing
originally for precise and consistent dosing and deliv- to the strict requirement of MCRs on reaction se-
ery of medicines as well as for maintaining the stabili- quential order,[7c] MCRs involving four or more re-
ty of pharmaceuticals.[1] Nowadays the application of agents are rather fewer than three-component reac-
encapsulation has been extended from pharmacy to tions.[8] Apart from interrupting the original sequence,
other realms,[2] for example, facilitating chemical re- the addition of further components may also make
search,[2a,b] and promoting the development of energy the balance between selectivity and reactivity more
and material technology.[2c–g] In organic synthesis, the subtle and elevate the probability of forming unde-
application and advantage of encapsulation are also sired side products. Moreover, the scenario would be
emerging. By dispersing or encapsulating solid chemi- further complicated with the participation of transi-
cals in paraffin wax, encapsulation helps to achieve tion metal catalysts. The concerns over side-reactions,
the benchtop storage and delivery of air- or moisture- deactivation of catalyst and incompatibilities of reac-
sensitive organometallic catalysts[3] and reagents.[4] It tion conditions between each step must be taken into
is expected to boost the popularization of glove-box- consideration. Reagent capsules might be one of the
Adv. Synth. Catal. 0000, 000, 0 – 0
1
ꢃ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÞÞ
These are not the final page numbers!

COMMUNICATIONS
asc.wiley-vch.de
Table 1. Selected results form the optimization of the reac-
latent pathways to eliminate the issue of side reac-
tions.[3] Based on our long-standing interest in devel-
oping highly efficient multicomponent reactions[9] and
carbonylative synthesis of heterocycles,[10] we envis-
aged utilizing the combination of carbonylation[11] and
Fiesselmann reaction[12] to achieve the four-compo-
nent synthesis of multisubstituted thiophenes.[13] Ethyl
3,5-diphenylthiophene-2-carboxylate was selected as
the exemplary product. By retrosynthetic analysis, the
thiophene ring is disassembled to four moieties, aryl
halides, carbon monoxide, phenylacetylene and ethyl
thioglycolate (Scheme 1). Considering that the Fies-
tion conditions.[a]
En- Variations from the standard
try conditions
Yield
[%][b]
1
2
3
4
–
65 (64)[c]
0
50
reagent capsule A without DBU
reagent capsule B[d]
EtOH in the reaction glass vial instead of in 17
the capsule
5
6
DBU in the reaction glass vial instead of in
the capsule
EtOH, ethyl thioglycolate and DBU without
encapsulation
0
0
64[e]
Scheme 1. Retrosynthetic analysis of ethyl 3,5-diphenylthio-
7
1.50 mmol reaction scale
phene-2-carboxylate.
[a]
Reaction scale: 0.50 mmol (1.0 equiv. 1a, 1.0 equiv. 2a).
The content of reagent capsule A is an EtOH (0.20 mL)
solution of ethyl thioglycolate (0.55 mmol) and DBU
(0.55 mmol).
Yields of isolated products are given.
With the reagent capsule A that had been stored on the
benchtop for two months.
The content of reagent capsule B is a THF (0.20 mL) so-
lution of ethyl thioglycolate (0.55 mmol) and DBU
(0.55 mmol).
The shell of capsule is made from a glass Pasteur pipette.
The content in one reagent capsule A is an EtOH
(0.60 mL) solution of ethyl thioglycolate (1.65 mmol) and
DBU (1.65 mmol). DBU=1,8-diazabicyclo[5.4.0]undec-
7-ene. THF=tetrahydrofuran.
selmann reaction of ethyl thioglycolate with an alky-
none intermediate would be the second step in this
four-component process and the potential coordina-
tion of ethyl thioglycolate with a transition metal,[14]
the foul-smelling ethyl thioglycolate liquid should be
encapsulated and released from the capsule when the
reaction temperature is raised. In order to predigest
the preparation of reagent capsule and adapt the cap-
sule to the liquid chemicals, the cheap and commer-
cially available glass shell[15] is chosen to replace the
paraffin capsule shell and capsule is sealed up with
paraffin wax (see the Supporting Information for de-
tails).
[b]
[c]
[d]
[e]
The initial investigation was carried out with iodo-
benzene, phenylacetylene, reagent capsule containing
ethyl thioglycolate and a palladium catalyst under
a CO atmosphere. After investigation of the reaction
parameters, it was found that the desired product 3a
was obtained in 65% yield by using PdCl2(PPh3)2 with
the help of the encapsulated ethanol solution of ethyl
thioglycolate and DBU under 3 bar of CO in tetrahy-
drofuran solution[16] (Table 1). The molecular struc-
ture of product 3a was confirmed by X-ray diffraction
(Figure 1). With capsules that had been stored on the
benchtop for two months, the product 3a was still ob-
tained in 64% yield, indicating that prolonged expo-
sure to atmospheric oxygen and moisture does not
reduce the efficacy of the capsule (entry 1). DBU,
a stronger base than triethylamine, is crucial for the
cyclization of the alkynone intermediate with ethyl
thioglycolate (entry 2). Although ethanol can promote
the Fiesselmann cyclization (entry 3), unencapsulated
ethanol led to a significant diminution in the selectivi-
ty of the palladium-catalyzed carbonylative Sonoga-
shira reaction (entry 4) and the side-product 1,2-di-
phenylethyne overwhelmed the product 3a. Unencap-
Figure 1. ORTEP diagram of 3a.[17] Thermal ellipsoids set at
sulated DBU has a similar negative effect on the reac- 50% probability.
Adv. Synth. Catal. 0000, 000, 0 – 0
2
ꢃ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÞÞ
These are not the final page numbers!

COMMUNICATIONS
asc.wiley-vch.de
Table 3. Palladium-catalyzed four-component reaction of io-
tion (entry 5). When EtOH, ethyl thioglycolate and
DBU were all unencapsulated, neither the generation
of 1,2-diphenylethyne or 3a nor the conversion of 1a
was observed on GC (entry 6). This indicated that the
palladium catalyst might be deactivated by ethyl thio-
glycolate. By trimming a commercially-available glass
Pasteur pipette to make the shell of a capsule with
a larger volume, the reaction scale can be enlarged
(entry 7, see the Supporting Information for details).
With the optimized protocol in hand, we investigat-
ed the scope of substrates with a range of substituted
iodobenzenes (Table 2). Although the whole process
involves Pd-catalyzed carbonylative Sonogashira reac-
tion, 1,4-addition of thiol to alkynone and intramolec-
ular condensation, moderate to good yields were ach-
ieved with various substituted iodobenzenes. With
aryl iodides bearing electronically neutral groups (3b–
3f), para- and meta-substituted substrates (3b, 3c, 3e,
3f) can provided higher yields than the ortho-substi-
tuted substrate (3d). For both substrates with elec-
tron-donating groups on the para- and meta-position
of phenyl ring or on the fused ring (3g–3i) and sub-
strates with electron-withdrawing groups (3j–3m), the
protocol also gave the desired products in moderate
yields. Moreover nitro group, carboxylic ester and
dobenzene with substituted phenylacetylene derivatives.[a]
[a]
Reaction scale: 0.50 mmol (1.0 equiv. 1a, 1.0 equiv. 2).
Yields of isolated products are given. Reagent capsule A
is the encapsulated EtOH (0.20 mL) solution of ethyl
thioACTHNUTRGNEgUNG lycolate (0.55 mmol) and DBU (0.55 mmol).
thiophene ring were able to survive under these reac-
tion conditions (3n–3p).
Then phenylacetylenes with different substitution
patterns were tested as well (Table 3). Substituents in
the para, meta, or ortho position, including methyl,
methoxy, fluorine, and chlorine moieties, were all well
tolerated (3q–3x). Because of the low temperature for
carbonylation, there was no concern about the com-
patibility issue of a bromine substituent (3y). By em-
ploying 3-ethynylthiophene, the corresponding prod-
uct with the skeleton of 2,3’-bithiophene was con-
structed (3z). Compared to those of arylacetylenes,
the yield of the product from an alkylacetylene (3aa)
is relatively lower.
Table 2. Palladium-catalyzed four-component reaction of
phenylacetylene with substituted iodobenzenes.[a]
The reaction was further extended to a number of
ethyl 3,5-diphenylthiophene-2-carboxylates with sub-
stituents on both phenyl rings (Table 4). Moderated
to good yields (3ab–3af) displayed the facility brought
about by the reagent capsule in a rapid synthesis of
highly functionalized molecules. This method was also
able to be applied in synthesis of oligothiophene
(3ag).
After adjusting the components of capsule, the cap-
sule of ethyl thioglycolate was further applied in the
preparation of a benzothiophene derivative (Table 5).
With the aid of an encapsulated DMSO solution of
ethyl thioglycolate, the four-component synthesis of
ethyl 3-([1,1’-biphenyl]-4-yl)benzo[b]thiophene-2-car-
boxylate[18] was achieved as well. The structure of
product 6 was also determined by X-ray diffraction.[17]
To our delight, when the reaction scale was amplified
5 times, the yield was not significantly affected
[a]
Reaction scale: 0.50 mmol (1.0 equiv. 1, 1.0 equiv. 2a).
Yields of isolated products are given. The content of re-
agent capsule A is the encapsulated EtOH (0.20 mL) so-
lution of ethyl thioglycolate (0.55 mmol) and DBU
(0.55 mmol).
Adv. Synth. Catal. 0000, 000, 0 – 0
3
ꢃ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÞÞ
These are not the final page numbers!

COMMUNICATIONS
asc.wiley-vch.de
Table 4. Synthesis of ethyl 3,5-diarylthiophene-2-carboxy-
late.[a]
Table 5. Synthesis of ethyl 3-([1,1’-biphenyl]-4-yl)benzo[b]-
G
thiophene-2-carboxylate in the presence of reagent cap-
AHCTUNGTRENNUNG
sule.[a]
En-
try
Variations from the standard
conditions
Yield
[%]
1
2
3
–
59 (56)[b]
40
0
reagent capsule D[c]
DMSO in the reaction glass vial instead
of in the capsule
4
unencapsulated ethyl thioglycolate and
DMSO
0
[a]
Unless otherwise stated, reaction scale: 0.50 mmol
(1.0 equiv. 4, 1.1 equiv. 5). Yields of isolated products are
given. The content of reagent capsule C is a DMSO
(0.20 mL) solution of ethyl thioglycolate (0.55 mmol).
Reaction scale: 2.50 mmol (1.0 equiv. 4, 1.1 equiv. 5). The
shell of capsule is made from a glass Pasteur pipette. Re-
agent capsule C is a DMSO (0.6 mL) solution of thiogly-
colate (2.75 mmol).
[b]
[c]
The content of reagent capsule D is a 1,4-dioxane
(0.20 mL) solution of ethyl thioglycolate (0.55 mmol).
DMSO=dimethyl sulfoxide.
[a]
Reaction scale: 0.50 mmol (1.0 equiv. 1, 1.0 equiv. 2).
Yields of isolated products are given. Reagent capsule A
is the encapsulated EtOH (0.20 mL) solution of ethyl
thioACHTUNGTRENNUNGglycolate (0.55 mmol) and DBU (0.55 mmol).
Experimental Section
(entry 1). When polar DMSO was replaced by non- General Procedure
polar 1,4-dioxane, the aromatic nucleophilic substitu-
A 12-mL Wheatonꢄ vial was charged with PdCl2(PPh3)2
tion (SNAr) turned to be sluggish (entry 2). Although
DMSO can promote the SNAr, unencapsulated
DMSO made the undesired Suzuki cross-coupling
dominant and no desired product was generated
(entry 3). Similar to the scenario in the synthesis of
ethyl 3,5-diphenylthiophene-2-carboxylate, no product
(7.1 mg, 0.01 mmol, 2 mol%), one reagent capsule A [encap-
sulated EtOH (0.20 mL) solution of ethyl thioglycolate
(0.55 mmol) and DBU (0.55 mmol)] and a magnetic stirring
bar (Supporting Information, Figure S11). Then under
argon, a THF (2 mL) solution of iodobenzene (0.5 mmol),
alkyne (0.5 mmol) and triethylamine (1.5 mmol) mixture
or diaryl ketone intermediate was detected when both was injected by syringe (Supporting Information, Fig-
ure S12). The vial (or several vials) was (were) placed in an
alloy plate, which was transferred into a 300 mL autoclave
of the 4560 series from Parr Instrumentsꢄ under an argonr
atmosphere. After flushing the autoclave three times with
CO, a pressure of 3 bar CO was adjusted at ambient temper-
ature. The reaction was performed at 408C (Note: avoid
temperature rising too fast causing overheating above 458C)
for 14 h. Then the temperature was elevated to 808C for
10 h. After the reaction had finished, the autoclave was
cooled down to room temperature and the pressure was re-
leased carefully. The reaction mixture was diluted with ace-
tone (ca. 10 mL) and passed through a pad of Celiteꢄ once
under reduced pressure. The filter cake was washed with ad-
ditional acetone (ca. 15 mL). The filtrate was then collected
and filtered through a pad of Celiteꢄ once more. After evap-
ethyl thioglycolate and DMSO were unencapsulated
(entry 4).
In summary, a facile method of encapsulating liquid
chemicals and an efficient four-component synthetic
pathway to (benzo)thiophene derivatives that taking
full advantage of encapsulated liquid reagents has
been developed. The capsule plays a pivotal role in
solving the issues on reaction conditions incompatibil-
ities and selectivity of MCR as well as avoiding deac-
tivation of the catalyst. It greatly facilitates the devel-
opment of a highly-efficient multicomponent reaction
and demonstrates a modular pathway to obtain func-
tionalized molecules, which has the potential in readi-
ly preparing drug and material candidates.
Adv. Synth. Catal. 0000, 000, 0 – 0
4
ꢃ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÞÞ
These are not the final page numbers!

COMMUNICATIONS
asc.wiley-vch.de
oration of the solvent the residue was adsorbed on silica gel
and the crude product was purified by column chromatogra-
phy using n-pentane/AcOEt as eluent.
Orru, Angew. Chem. Int. Ed. 2011, 50, 6234–6246;
Angew. Chem. 2011, 123, 6358–6371; b) A. Dçmling, W.
Wang, K. Wang, Chem. Rev. 2012, 112, 3083–3135; c) S.
Brauch, S. S. van Berkela, B. Westermann, Chem. Soc.
Rev. 2013, 42, 4948–4962; d) B. H. Rotstein, S. Zaretsky,
V. Rai, A. K. Yudin, Chem. Rev. 2014, 114, 8323–8359;
e) C. Allais, J.-M. Grassot, J. Rodriguez, T. Constan-
tieux, Chem. Rev. 2014, 114, 10829–10868; f) R. C.
Cioc, E. Ruijter, R. V. A. Orru, Green Chem. 2014, 16,
2958–2975; g) T. Zarganes-Tzitzikas, A. L. Chandgude,
A. Dçmling, Chem. Rec. 2015, 15, 981–996; h) L. Levi,
T. J. J. Mꢀller, Chem. Soc. Rev. 2016, 45, 2825–2846;
i) A. Galvꢅn, F. J. FaÇanꢅs, F. Rodrꢆguez, Eur. J. Inorg.
Chem. 2016, 1306–1313; j) C. Shen, X.-F. Wu, Chem.
Eur. J. 2017, 23, DOI: 10.1002/chem.201603623.
Acknowledgements
We thank the China Scholarship Council (CSC) for financial
support to C.S. (201406230040) and the analytical department
of the Leibniz Institute for Catalysis at the University of Ro-
stock for their excellent technical and analytical support.
Thanks also go to Prof. Matthias Beller for his generous sup-
port on chemicals.
[8] For selected very recent examples of three-component
reactions, see: a) K. Yeung, R. E. Ruscoe, J. Rae, A. P.
Pulis, D. J. Procter, Angew. Chem. Int. Ed. 2016, 55,
11912–11916; Angew. Chem. 2016, 128, 12091–12095;
b) J. A. Boerth, J. R. Hummel, J. A. Ellman, Angew.
Chem. Int. Ed. 2016, 55, 12650–12654; Angew. Chem.
2016, 128, 12840–12844; c) R. Y. Liu, Y. Yang, S. L.
Buchwald, Angew. Chem. Int. Ed. 2016, 55, 14077–
14080; Angew. Chem. 2016, 128, 14283–14286. For se-
lected recent examples of four-component reactions,
see: d) T. Flagstad, M. T. Petersen, T. E. Nielsen, An-
gew.Chem. Int. Ed. 2015, 54, 8395–8397; Angew.Chem.
2015, 127, 8515–8517; e) G. Martinez-Ariza, M. Ayaz,
S. A. Roberts, W. A. Rabanal-Leon, R. Arratia-Perez,
C. Hulme, Angew. Chem. Int. Ed. 2015, 54, 11672–
11676; Angew. Chem. 2015, 127, 11838–11842.
[9] a) L. He, H. Li, H. Neumann, M. Beller, X.-F. Wu, An-
gew.Chem. Int. Ed. 2014, 53, 1420–1424; Angew. Chem.
2014, 126, 1444–1448; b) K. Natte, H. Neumann, X.-F.
Wu, Catal. Sci. Technol. 2015, 5, 4474–4480; c) C. Shen,
A. Spannenberg, X.-F. Wu, Angew. Chem. Int. Ed.
2016, 55, 5067–5070; Angew. Chem. 2016, 128, 5151–
5154.
References
[1] a) F. A. B. Mothes, French Patent 9690, 1834; b) M. I.
Wilbert, Am. J. Pharm. 1913, 85, 559–572; c) Encyclo-
pedia of Pharmaceutical Technology, Vol. 7, (Eds.: J.
Swarbrick, J. C. Boylan), Informa Healthcare, London,
1998, pp 304–306.
[2] For selected examples about the application of capsules
in various fields, see: a) T. Iwasawa, R. J. Hooley, J. Re-
bek Jr, Science 2007, 317, 493–496; b) Y. Inokuma, S.
Yoshioka, J. Ariyoshi, T. Arai, Y. Hitora, K. Takada, S.
Matsunaga, K. Rissanen, M. Fujita, Nature 2013, 495,
461–466; inflaming retarding of lithium batteries: c) M.
Baginska, B. J. Blaiszik, R. J. Merriman, N. R. Sottos,
J. S. Moore, S. R. White, Adv. Energy Mater. 2012, 2,
583–590; d) T. Yim, M.-S. Park, S.-G. Woo, H.-K.
Kwon, J.-K. Yoo, Y. S. Jung, K. J. Kim, J.-S. Yu, Y.-J.
Kim, Nano Lett. 2015, 15, 5059–5067; self-healing mate-
rials: e) M. D. Hager, P. Greil, C. Leyens, S. van der Z-
waag, U. S. Schubert, Adv. Mater. 2010, 22, 5424–5430;
triggered release of loads: f) W.-C. Liao, M. Riutin,
W. J. Parak, I. Willner, ACS Nano 2016, 10, 8683–8689;
application in self-propelled motors: g) J. Guo, S. Moo,
H. Wang, M. Pumera, Chem. Commun. 2014, 50,
15849–15851.
[3] a) Y. Fang, Y. Liu, Y. Ke, C. Guo, N. Zhu, X. Mi, Z.
Ma, Y. Hu, Appl. Catal. A 2002, 235, 33–38; b) D. F.
Taber, K. J. Frankowski, J. Org. Chem. 2003, 68, 6047–
6048; c) A. C. Sather, H. G. Lee, J. R. Colombe, A.
Zhang, S. L. Buchwald, Nature 2015, 524, 208–211;
d) T. T. Nguyen, M. J. Koh, X. Shen, F. Romiti, R. R.
Schrock, A. H. Hoveyda, Science 2016, 352, 569–575;
e) J. E. Dander, N. A. Weires, N. K. Garg, Org. Lett.
2016, 18, 3934–3936; f) L. Ondi, G. M. Nagy, J. B.
Czirok, A. Bucsai, G. E. Frater, Org. Process Res. Dev.
2016, 20, 1709–1716.
[10] a) J. Chen, K. Natte, A. Spannenberg, H. Neumann, P.
Langer, M. Beller, X.-F. Wu, Angew. Chem. Int. Ed.
2014, 53, 7579–7583; Angew. Chem. 2014, 126, 7709–
7713; b) F. Zhu, Y. Li, Z. Wang, X.-F. Wu, Angew.
Chem. Int. Ed. 2016, 55, 14151–14154; Angew. Chem.
2016, 128, 14357–14360.
[11] For related reviews on carbonylation, see: a) X.-F. Wu,
H. Neumann, M. Beller, Chem. Soc. Rev. 2011, 40,
4986–5009; b) Q. Liu, H. Zhang, A. Lei, Angew. Chem.
Int. Ed. 2011, 50, 10788–10799; Angew. Chem. 2011,
123, 10978–10989; c) X.-F. Wu, H. Neumann, M. Beller,
ChemSusChem 2013, 6, 229–241; d) X.-F. Wu, H. Neu-
mann, M. Beller, Chem. Rev. 2013, 113, 1–35; e) B. Ga-
briele, R. Mancuso, G. Salerno, Eur. J. Org. Chem.
2012, 6825–6839. For selected recent examples on mul-
ticomponent carbonylative processes for preparing het-
erocycles, see: f) B. Gabriele, L. Veltri, R. Mancuso, C.
Carfagna, Adv. Synth. Catal. 2014, 356, 2547–2558;
g) R. Mancuso, I. Ziccarelli, D. Armentano, N. Marino,
S. V. Giofrꢇ, B. Gabriele, J. Org. Chem. 2014, 79, 3506–
3518; h) L. Veltri, R. Mancuso, A. Altomare, B. Gabri-
ele, ChemCatChem 2015, 7, 2206–2213; i) L. Veltri, G.
Grasso, R. Rizzi, R. Mancuso, B. Gabriele, Asian J.
Org. Chem. 2016, 5, 560–567; j) M. Feng, B. Tang, H.-
[4] a) D. F. Taber, C. G. Nelson, J. Org. Chem. 2006, 71,
8973–8974; b) H. Huang, C. G. Nelson, D. F. Taber, Tet-
rahedron Lett. 2010, 51, 3545–3546.
[5] D. F. Taber, K. J. Frankowski, J. Chem. Educ. 2006, 83,
283–284.
[6] A. Schwenger, W. Frey, C. Richert, Angew. Chem. Int.
Ed. 2016, 55, 13706–13709; Angew. Chem. 2016, 128,
13910–13913.
[7] For selected recent reviews on MCRs and catalytic
MCRs, see: a) E. Ruijter, R. Scheffelaar, R. V. A.
Adv. Synth. Catal. 0000, 000, 0 – 0
5
ꢃ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÞÞ
These are not the final page numbers!

COMMUNICATIONS
asc.wiley-vch.de
X. Xu, X. Jiang, Org. Lett. 2016, 18, 4352–4355;
k) G. M. Torres, J. S. Quesnel, D. Bijou, B. A. Arndtsen,
J. Am. Chem. Soc. 2016, 138, 7315–7324.
[15] A 0.35-mL glass insert with flat bottom purchased from
Sigma–Aldrich.
[16] Those solvents that dissolve paraffin wax such as di-
chloromethane and toluene must be avoided when
chosing solvents for reactions containing paraffin cap-
sules.
[17] CCDC 1518303 (3a), CCDC 1518302 (3g), CCDC
1518301 (3k), CCDC 1518304 (3w) and CCDC 1518305
(6) contain the supplementary crystallographic data for
this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
[12] a) H. Fiesselmann, P. Schipprak, Chem. Ber. 1954, 87,
835–841; b) H. Fiesselmann, P. Schipprak, L. Zeitler,
Chem. Ber. 1954, 87, 841–848; c) H. Fiesselmann, G.
Pfeiffer, Chem. Ber. 1954, 87, 848–856; d) H. Fiessel-
mann, P. Schipprak, Chem. Ber. 1956, 89, 1897–1902;
e) H. Fiesselmann, F. Thoma, Chem. Ber. 1956, 89,
1907–1912; f) M. Teiber, T. J. J. Mꢀller, Chem.
Commun. 2012, 48, 2080–2082; g) M. Teiber, S. Giebel-
er, T. Lessing, T. J. J. Mꢀller, Org. Biomol. Chem. 2013,
11, 3541–3552.
[18] For selected examples on preparing 2,3-disubstituted
benzothiophenes, see: a) B. Gabriele, R. Mancuso, E.
Lupinacci, L. Veltri, G. Salerno, C. Carfagna, J. Org.
Chem. 2011, 76, 8277–8286; b) V. Guilarte, M. A.
Fernꢅndez-Rodrꢆguez, P. Garcꢆa-Garcꢆa, E. Hernando,
R. Sanz, Org. Lett. 2011, 13, 5100–5103; c) M. Kuhn,
F. C. Falk, J. Paradies, Org. Lett. 2011, 13, 4100–4103;
d) D. Yang, K. Yan, W. Wei, L. Tian, Q. Li, J. You, H.
Wang, RSC Adv. 2014, 4, 48547–48553; e) K. Yan, D.
Yang, M. Zhang, W. Wei, Y. Liu, L. Tian, H. Wang,
Synlett 2015, 26, 1890–1894; f) D. Wan, Y. Yang, X. Liu,
M. Li, S. Zhao, J. You, Eur. J. Org. Chem. 2016, 55–59;
g) Y. Nakamura, T. Ukita, Org. Lett. 2002, 4, 2317–
2320; h) K. Inamoto, Y. Arai, K. Hiroya, T. Doi, Chem.
Commun. 2008, 5529–5531; i) T. Inami, Y. Baba, T. Kur-
ahashi, S. Matsubara, Org. Lett. 2011, 13, 1912–1915;
j) A. Acharya, S. V. Kumar, H. Ila, Chem. Eur. J. 2015,
21, 17116–17125; k) X. Wang, T. Gensch, F. Glorius,
Org. Chem. Front. 2016, 3, 1619–1623; l) Y. Masuya, M.
Tobisu, N. Chatani, Org. Lett. 2016, 18, 4312–4315.
[13] <For examples on the rapid construction of multi-sub-
stituted thiophenes, see: a) B. Gabriele, G. Salerno, A.
Fazio, Org. Lett. 2000, 2, 351–352; b) T. Okazawa, T.
Satoh, M. Miura, M. Nomura, J. Am. Chem. Soc. 2002,
124, 5286–5287; c) M. Shindo, Y. Yoshimura, M. Haya-
shi, H. Soejima, T. Yoshikawa, K. Matsumoto, K. Shish-
ido, Org. Lett. 2007, 9, 1963–1966; d) S. Yanagisawa, K.
Ueda, H. Sekizawa, K. Itami, J. Am. Chem. Soc. 2009,
131, 14622–14623; e) L. K. Ransborg, Ł. Albrecht, C. F.
Weise, J. R. Bak, K. A. Jørgensen, Org. Lett. 2012, 14,
724–727; f) B. Gabriele, R. Mancuso, L. Veltri, V. Mal-
tese, G. Salerno, J. Org. Chem. 2012, 77, 9905–9909;
g) D. Kurandina, V. Gevorgyan, Org. Lett. 2016, 18,
1804–1807; h) J.-Y. Son, J. Kim, S. H. Han, S. H. Kim,
P. H. Lee, Org. Lett. 2016, 18, 5408–5411; i) W. W. Tan,
N. Yoshikai, J. Org. Chem. 2016, 81, 5566–5573.
[14] a) J. J. Draney, Jr., M. Cefola, J. Am. Chem. Soc. 1954,
76, 1975–1977; b) L. T. Talyor, R. P. Cassity, Inorg.
Nucl. Chem. Lett. 1969, 5, 441–444; c) M. Al-Hashimi,
A. C. Sullivan, J. R. H. Wilson, J. Mol. Catal. A: Chem.
2007, 273, 298–302.
Adv. Synth. Catal. 0000, 000, 0 – 0
6
ꢃ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÞÞ
These are not the final page numbers!

COMMUNICATIONS
Utilizing an Encapsulated Solution of Reagents to Achieve
the Four-Component Synthesis of (Benzo)Thiophene
Derivatives
7
Adv. Synth. Catal. 2017, 359, 1 – 7
Chaoren Shen, Anke Spannenberg, Matthias Auer,
Xiao-Feng Wu*
Adv. Synth. Catal. 0000, 000, 0 – 0
7
ꢃ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÞÞ
These are not the final page numbers!