Palladium-Catalyzed Carbonylative Four-Component Synthesis of Thiochromenones: The Advantages of a Reagent Capsule

Article abstract of DOI:10.1002/anie.201600953

Multicomponent reactions, especially those involving four or even more reagents, have been a long-standing challenge because of the issues associated with balancing reactivity, selectivity, and compatibility. Herein, we demonstrate how the use of a reagen

Full text of DOI:10.1002/anie.201600953

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201600953
German Edition: DOI: 10.1002/ange.201600953
Multicomponent Reactions
Palladium-Catalyzed Carbonylative Four-Component Synthesis of
Thiochromenones: The Advantages of a Reagent Capsule
Chaoren Shen, Anke Spannenberg, and Xiao-Feng Wu*
Abstract: Multicomponent reactions, especially those involv-
ing four or even more reagents, have been a long-standing
challenge because of the issues associated with balancing
reactivity, selectivity, and compatibility. Herein, we demon-
strate how the use of a reagent capsule provides straightforward
access to synthetically valuable thiochromenone derivatives by
a palladium-catalyzed carbonylative four-component reaction.
To the best of our knowledge, this is the first example of
applying a capsule to prevent catalyst poisoning and undesired
side reactions of the multicomponent reaction.
introduced to substantially minimize the inconvenience of
dispensing air- or moisture-sensitive compounds in the glove
box, enabling the bench-top storage of air- or moisture-
sensitive reagents,[6] and were selected as one of 2015ꢀs most
notable chemistry research advances.[7] This award proves the
enormous potential of reagent capsules in organic synthesis.
Therefore, based on our long-lasting interest in developing
highly efficient multicomponent reactions[8] and carbonyla-
tive syntheses of heterocycles,[9] we intended to take advant-
age of reagent capsules to overcome the barriers encountered
in the development of multicomponent reactions.
P
urification processes probably are the most time-consum-
Thiochromone, the thio homologue of the core constitu-
ent of the natural product class of flavones, constitutes the
skeleton of numerous biologically or pharmaceutically active
compounds.[10] Furthermore, the oxidized variants of thio-
chromen-4-ones are used as human cytomegalovirus protease
inhibitors[11] and photolabile protecting groups for phosphate
compounds.[12] Aside from various classical pathways entail-
ing cyclization by condensation or addition,[13] only a limited
number of transition-metal-catalyzed syntheses of thiochro-
mones have been reported.[14] The previously reported
methods generally suffer from drawbacks related to synthetic
efficiency, availability or diversity of the substrates, regiose-
lectivity, and functional-group compatibility. In theory, our
proposed carbonylative four-component one-pot reaction is
a fairly efficient pathway that provides the desired products
from commercially available odorless materials with a re-
duced number of manual operations (Scheme 1).[15] The
ing, cost-ineffective, and waste-producing manual operations
in modern organic synthesis. However, to improve compat-
ibility and to ensure that the consecutive reaction proceeds
smoothly, the purification of intermediates seems to be
inevitable. As an advancement of this conventional “stop-
and-go” synthetic approach, multistep one-pot strategies,
which are more compact, less time-consuming, and less waste-
generating, can dramatically improve synthetic efficiency.[1] In
this respect, significant progress has been achieved in the area
of multicomponent reactions (MCR),[2] as illustrated by
various examples of three-component reactions.[3] Upon
addition of further components, the balance between selec-
tivity and reactivity will become more subtle, and more
undesired side products may be formed. Furthermore, the
participation of transition-metal catalysts would further
complicate this scenario. The possibility of catalyst poisoning
and side reactions triggered by the catalyst must be taken into
consideration. Hence, straightforward MCRs with transition-
metal catalysts and four or even more reagents are still under
development and have remained an arduous challenge.[4]
As one of the most important inventions in pharmacy, the
use of capsules represents a reproducible method for the
precise and consistent dosing and delivery of medicines as
well as for maintaining the stability of pharmaceuticals.[5a,b] In
the meantime, capsules have also been applied within the
realm of energy and functional materials.[5c-e] Recently, simple
and practical techniques for reagent encapsulation were
Scheme 1. Retrosynthetic analysis of thiochromenones.
reaction is expected to proceed by a carbonylative Sonoga-
shira coupling followed by an aromatic nucleophilic substitu-
tion (SNAr)/conjugate addition tandem reaction. Quick and
irreversible poisoning of the transition-metal catalyst by the
sulfur species[16] and potential side reactions with sulfide or its
hydrate could pose problems that must not be neglected.
The initial investigation was carried out with 1-fluoro-2-
iodobenzene, phenylacetylene, and sodium sulfide nonahy-
drate as the substrates and a palladium catalyst under CO
atmosphere. After screening various reaction conditions,
including palladium precursors, ligands, solvents, and reaction
temperatures, the desired product could still not be detected
(Figure 1a). Upon analyzing the reaction mixture and isolat-
[*] M. Sc. C. Shen, Dr. A. Spannenberg, Prof. Dr. X.-F. Wu
Leibniz-Institut für Katalyse an der Universität Rostock e.V.
Albert-Einstein-Strasse 29a, 18059 Rostock (Germany)
Prof. Dr. X.-F. Wu
Department of Chemistry
Zhejiang Sci-Tech University, Xiasha Campus
Hangzhou 310018 (P.R. China)
E-mail: xiao-feng.wu@catalysis.de
Supporting information for this article can be found under http://dx.
doi.org/10.1002/anie.201600953.
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product, but only side product bis(2-phenylvinyl)sulfide, was
generated (entry 2). Reducing the ligand loading or replacing
tBu3P with other monodentate phosphine ligands decreased
the yield (entries 3–5). Among various solvents, MeCN
proved to be the most suitable medium (entries 6–9). Several
other commonly applied inorganic and organic bases were not
able to achieve higher yields than NEt3 (entries 10–13). For
the leaving group, fluorine showed better reactivity in the
SNAr process than the chlorine, bromine, and methoxy
counterparts (entries 14–16).[19] Notably, when Mo(CO)6 was
used as a non-gaseous CO precursor, the desired product was
still formed in moderate yield (entry 17).[20]
With the optimized reaction conditions in hand, we
examined the scope of the reaction with a range of acetylenes
(Table 2). As the process combines three reactions, the
substitution and electronic effects are difficult to be clearly
attributed. With most substituted phenylacetylenes with
electronically neutral or electron-donating or -withdrawing
groups (3b–3i and 3k), moderate to good yields were
achieved. On the other hand, the yields obtained with
phenylacetylene derivatives with a strongly electron-with-
drawing group (EWG) in the para position (3j), an EWG in
the ortho position (3l), or two EWGs (3m) were lower.
Moderate yields of the desired products can also be achieved
with aliphatic alkynes (3n and 3o). Notably, when ethynyl-
Figure 1. a) Desired thiochromenone synthesis. b) Addition reaction
between Na2S·9H2O and phenyl acetylene.
ing a side product, we found that the inhibitory effect of the
sodium sulfide nonahydrate is not only due to the widely
recognized poisoning of transition-metal catalysts by sulfide
anions,[17] but also to the addition of sodium sulfide non-
ahydrate to phenyl acetylene.[18] The side reaction can rapidly
(usually < 6 h) consume all phenylacetylene at low temper-
ature (40–908C) and give a mixture of the cis/cis and cis/trans
isomers of bis(2-phenylvinyl)sulfide (Figure 1b).
To address the challenges of the four-component carbon-
ylative synthesis of thiochromenones and overcome the
problems associated with the use of sodium sulfide non-
ahydrate, a paraffin wax capsule for the controlled release
of Na2S·9H2O was conceived and prepared. After investigat-
ing various reaction parameters, we finally succeeded in
isolating the desired thiochromenone product in 68% yield
using the capsule containing Na2S·9H2O in combination
with Pd(OAc)2/tBu3P under 5 bar CO with a time-con-
trolled temperature regulator (Table 1). Conversely, when
Na2S·9H2O was employed without the capsule, no desired
Table 2: Palladium-catalyzed four-component reaction of 1-fluoro-2-
iodobenzene with various acetylenes.[a]
Table 1: Selected results of the optimization of the reaction conditions.[a]
3a, 68%
3e, 64%
3b, 73%
3 f, 56%
3c, 71%
3g, 58%
3d, 62%
3h, 69%
Entry Variations from the standard conditions
Yield
[%][b]
1
2
3
4
5
–
68
0
58
45
6
Na2S·9H2O without a paraffin wax capsule
tBu3P·HBF4 (6 mol%) instead of tBu3P·HBF4 (8 mol%)
nBuPAd2 instead of tBu3P·HBF4
PdCl2(PPh3)2 (2.5 mol%) instead of Pd(OAc)2 and
tBu3P·HBF4
6
7
8
DMF instead of MeCN
DMA instead of MeCN
toluene instead of MeCN
DMSO instead of MeCN
K2CO3 (2.0 equiv) instead of NEt3
Cs2CO3 (2.0 equiv) instead of NEt3
DIPEA instead of NEt3
29
33
0
0
10
0
22
0
51
32
28
3i, 55%
3j, 48%
3n, 34%
3k, 60%
3o, 36%
3l, 47%
9
10
11
12
13
14
15
16
17
3m, 51%
3p, 45%[b]
DBU instead of NEt3
1-chloro-2-iodobenzene instead of 1a
1-bromo-2-iodobenzene instead of 1a
1-iodo-2-methoxybenzene instead of 1a
Mo(CO)6 (1.0 equiv) in a sealed tube instead of 5 bar CO 55
in an autoclave
3q, 0%
3r, 0%
3i[c]
[a] Reaction scale: 0.50 mmol. [b] Yields of isolated products are given.
Ad=adamantyl, DBU=1,8-diazabicyclo[5.4.0]undec-7-ene,
DIPEA=N,N-diisopropylethylamine, DMA=N,N-dimethylacetamide,
DMF=N,N-dimethylformamide, DMSO=dimethylsulfoxide.
[a] Reaction scale: 0.50 mmol (1.1 equiv 1a, 1.0 equiv 2). Yields of
isolated products are given. [b] Ethynyltrimethylsilane was employed.
[c] Molecular structure of 3i.[22] Thermal ellipsoids set at 30% proba-
bility; hydrogen atoms omitted for clarity.
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Table 4: Palladium-catalyzed four-component reaction of substituted
1-fluoro-2-iodobenzenes and substituted phenylacetylene derivatives.[a]
trimethylsilane was employed, owing to the water contained
within Na2S·9H2O, the product was further hydrolyzed, and
4H-thiochromen-4-one was generated as the final product
(3p). Functionalized terminal alkynes, such as propargyl
alcohol and propargyl benzoate (3q and 3r), failed to
generate the corresponding thiochromenones, which may be
due to the isomerization of propargyl alcohol and propargyl
benzoate catalyzed by the palladium catalyst.[21]
ortho-Fluoroiodobenzenes with different substitution pat-
terns were tested as well (Table 3). Substituents in the para,
meta, or ortho position, including methyl, fluorine, and
chlorine moieties, were all well tolerated (3s–3x). The
decreased yield of 3u is due to the steric hindrance of the
methyl group during nucleophilic substitution.
Furthermore, several disubstituted 2-aryl-4H-thiochro-
men-4-ones were prepared by this new method. Starting
from commercially available substituted phenylacetylenes
and substituted 1-fluoro-2-iodobenzenes, moderate to good
yields were achieved under the standard reaction conditions
(Table 4).
3z, 69%
3aa, 61%
3ad, 66%
3ab, 64%
3ae, 57%
3ac, 50%
[a] Reaction scale: 0.50 mmol (1.1 equiv 1, 1.0 equiv 2). Yields of isolated
products are given.
The preparation of 3-iodo-2-phenyl-4H-thiochromen-4-
one, a derivative of our product, was carried out as well. In the
presence of iodine and cerium(IV) ammonium nitrate
(CAN), the desired compound was isolated in 91% yield
(Scheme 2). This product is ready for further derivatization by
transition-metal-catalyzed coupling reactions, and the
obtained 2,3-disubstituted thiochromenones have potential
applications in pharmaceutical lead optimization.[23]
In summary, an efficient palladium-catalyzed carbonyla-
tive method for preparing thiochromenones in a four-compo-
nent reaction that makes use of an reagent capsule has been
developed. The reagent capsule was essential to solving
problems related to the poisoning of the transition-metal
Scheme 2. Top: Synthesis of 3-iodo-2-phenyl-4H-thiochromen-4-one.
The yield is that of isolated 4. Bottom: Molecular structure of 4;[22]
hydrogen atoms omitted for clarity.
Table 3: Palladium-catalyzed four-component reaction of substituted
1-fluoro-2-iodobenzenes with phenylacetylene.[a]
catalyst as well as the compatibility of the various reagents in
the one-pot process. It also helped to reduce the total number
of manual operations, rendering the purification of inter-
mediates unnecessary, and greatly facilitated the develop-
ment of a highly efficient, environmentally friendly multi-
component reaction. To the best of our knowledge, this is the
first example of applying a reagent capsule for preventing
catalyst poisoning and undesired side reactions in a multi-
component reaction.
3s, 75%
3v, 57%
3t, 69%
3w, 54%
3u, 47%
3x, 60%
Acknowledgements
We thank the China Scholarship Council (CSC) for financial
support (to C.S., 201406230040). Financial support from the
NSFC (21472174) and the Zhejiang Natural Science Fund for
Distinguished Young Scholars (LR16B020002) is greatly
appreciated. We also thank the analytical department of the
Leibniz Institute for Catalysis at the University of Rostock for
their excellent technical and analytical support. We also thank
Dr. Raffaella Ferraccioli for her valuable suggestions and
Prof. Matthias Beller for general support.
3y, 61%
3s[b]
[a] Reaction scale: 0.50 mmol (1.1 equiv 1, 1.0 equiv 2). Yields of isolated
products are given. [b] Molecular structure of 3s.[22] Thermal ellipsoids
set at 30% probability; hydrogen atoms omitted for clarity.
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Keywords: carbonylation · multicomponent reactions ·
palladium catalysis · thiochromenones
How to cite: Angew. Chem. Int. Ed. 2016, 55, 5067–5070
Angew. Chem. 2016, 128, 5151–5154
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Received: January 27, 2016
Published online: March 17, 2016
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