Rapid access to unsymmetrical tolanes and alkynones by sequentially palladium-catalyzed one-pot processes

Article abstract of DOI:10.1039/c6ob00483k

Alkynones as well as unsymmetrically substituted tolanes (diarylalkynes) can be rapidly generated in a one-pot fashion via sequential palladium catalysis. Terminal alkynes, formed in situ by protecting-group free palladium-catalyzed coupling of aryl iodides with ethynyl magnesium bromide, are subsequently transformed by Sonogashira coupling with aryl halides or aroyl chlorides to furnish unsymmetrically substituted alkynes in good to excellent yields.

Full text of DOI:10.1039/c6ob00483k

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Rapid access to unsymmetrical tolanes and
alkynones by sequentially palladium-catalyzed
Cite this: DOI: 10.1039/c6ob00483k
one-pot processes†‡
Received 2nd March 2016,
Accepted 14th March 2016
Alissa C. Götzinger and Thomas. J. J. Müller*
DOI: 10.1039/c6ob00483k
www.rsc.org/obc
Alkynones as well as unsymmetrically substituted tolanes (diaryl- considered as the precursor of the commonly employed TMS
alkynes) can be rapidly generated in a one-pot fashion via sequen- acetylene. Most advantageously, the reagent is easy to handle
tial palladium catalysis. Terminal alkynes, formed in situ by and the only side product is the corresponding magnesium
protecting-group free palladium-catalyzed coupling of aryl iodides halide. Therefore, a subsequent Sonogashira coupling could
with ethynyl magnesium bromide, are subsequently transformed be concatenated in a one-pot fashion with no further addition
by Sonogashira coupling with aryl halides or aroyl chlorides to of palladium catalyst.
furnish unsymmetrically substituted alkynes in good to excellent
yields.
Table 1 Sequentially Pd-catalyzed three-component synthesis of
alkynones 4 from aryl iodides 1, ethynyl magnesium bromide (2), and
aroyl chlorides 3
Unsymmetrically substituted alkynes are valuable building
blocks in heterocycle synthesis1 and, in their own right,
exhibit interesting properties for applications in molecular
electronics.2 The most common approach to this class of mole-
cules is the palladium-catalyzed coupling of aryl halides or
aroyl chlorides with terminal alkynes,3 which are usually syn-
thesized by Sonogashira coupling of a second aryl halide with
trimethylsilyl acetylene (TMS acetylene), followed by work up,
isolation, and desilylation. While several one-pot approaches
to unsymmetrically substituted tolanes, i.e. diarylalkynes, are
known, protected acetylene species such as TMS acetylene,4
propiolic acid,5 or methyl butynol6 are usually applied, fol-
lowed by in situ deprotection and coupling. No analogous one-
pot synthesis of alkynone derivatives has so far been published
to the best of our knowledge. We herein present a protecting-
group free, sequentially palladium-catalyzed multicomponent
approach7 towards alkynones8 and unsymmetrically substi-
tuted tolanes in a one-pot fashion.
Yield of
alkynone 4 (%)
Entry
Product
Aryl1
Aryl2
1
2
3
4
5
6
7
8
9
4a
4b
4c
4d
4e
4f
4g
4h
4i
4-MeOC6H4
4-MeOC6H4
3,4,5-(MeO)3C6H2
3,4,5-(MeO)3C6H2
Ph
4-Me2NC6H4
2-Naphthyl
4-Me2NC6H4
4-Me2NC6H4
Ph
Ph
4-Tol
Ph
2-Thienyl
Ph
Ph
Ph
4-F3CC6H4
4-NCC6H4
4-MeOC6H4
81
80
68
76
86
79
82
60
74
59
10
4j
In the conception of this novel one-pot approach we first
reasoned that intermediate terminal alkynes can be generated
in situ by a palladium-catalyzed Kumada-type coupling of aryl
iodides with ethynyl magnesium bromide originally presented
by Negishi and coworkers.9 Ethynyl magnesium bromide is a
commercially available activated acetylene species and can be
Institut für Organische Chemie und Makromolekulare Chemie, Heinrich-Heine-
Universität Düsseldorf, Universitätsstraße 1, D-40225 Düsseldorf, Germany.
E-mail: ThomasJJ.Mueller@uni-duesseldorf.de
†Dedicated to Prof. Dr Dieter Enders on the occasion of his 70th birthday.
‡Electronic supplementary information (ESI) available: Experimental details and
NMR spectra of compounds 4, 6, and 8. See DOI: 10.1039/c6ob00483k
Scheme 1 Pseudo-five component synthesis of 3,3’-(1,4-phenylene)bis
(1-phenylprop-2-yn-1-one) (4k) from 1,4-diiodobenzene (1a), ethynyl
magnesium bromide (2), and benzoyl chloride (3a).
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Indeed, this sequentially Pd-catalyzed reaction can be per- and a stoichiometric amount of triethylamine, followed by
formed within 2 h by first reacting aryl iodides 1 with ethynyl aqueous work up and simple flash chromatography. The
magnesium bromide (2) under modified Kumada conditions, Kumada-type alkynylation was originally performed by Negishi
followed by partial neutralization with substoichiometric et al. using tetrakis(triphenyl-phosphane)palladium(0).9 This
amounts of triethylammonium chloride and coupling with catalyst, however, gave only traces of alkynone in the sub-
aroyl chlorides 3 in the presence of catalytic amounts of CuI sequent Sonogashira coupling with aroyl chlorides. Changing
the palladium species to bis(triphenylphosphane)palladium(II)
dichloride required a slightly higher temperature for the initial
alkynylation but gave good yields in the concluding alkynone
formation.8a,b As a result, 10 alkynones 4 were obtained in
good to very good yields (Table 1).
Table 2 Sequentially Pd-catalyzed three-component synthesis of di-
arylalkynes 6 from aryl iodides 1, ethynyl magnesium bromide (2), and
aryl halides 5
A quick access is also offered to push–pull substituted
derivatives 1i and 1j, thus establishing a quick entry to hetero-
cycles with interesting photophysical properties.10 By employ-
ing 1,4-diiodobenzene (1a) as aryl iodide component,
bisalkynone derivative 4k can be easily accessed (Scheme 1).
Employing a second aryl halide 5 in the Sonogashira
coupling step gives access to diarylalkynes 6 (Table 2). The
Sonogashira coupling with aryl iodides 5a–f proceeds at room
temperature within 1.5 h. Activated aryl bromide 5g bearing a
cyano group can also be employed by using slightly elevated
temperature and prolonged reaction time. Eight diarylalkynes
6 were synthesized by this one-pot sequence in good to excel-
lent yields (Table 2). Upon using Pd(PPh3)4 as a Pd source,
lower yields of product 6a (64%) were obtained in comparison
to Pd(PPh3)2Cl2 as a catalyst, which gave compound 6a in 81%
yield (Table 2, entry 1).
Yield of
diarylalkyne 6 (%)
Entry Product Aryl1
Aryl2
X
1
2
3
4
5
6
7
8
6a
6b
6c
6d
6e
6f
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
Ph
4-Me2NC6H4 4-F3CC6H4
4-F3CC6H4
4-ClC6H4
4-ClC6H4
4-BrC6H4
Ph
I
I
I
I
I
I
I
81
86
78
80
83
66
67
4-Pyridyl
1-Naphthyl
Ph
4-NCC6H4
6g
6h
4-MeOC6H4
Br 64
By employing p- and m-diiodobenzene 1a and 1b as starting
materials, the corresponding bis(arylethynyl)benzene deriva-
tives 2i and 2j are easily accessible (Scheme 2) via a pseudo-
five component reaction with a respective yield of 91%
and 97% per bond formation. These types of conjugated oligo-
(phenyleneethynylenes) are of potential interest as molecular
wires11 or in the preparation of cruciform fluorophores.12
In addition, arylethynyl phenothiazine derivatives 2k and 2l
can be readily prepared. These compounds have aroused par-
ticular interest for the corrosion protection of metal surfaces.13
It is noteworthy to mention that the pervious multi-step
approach required several days for performing the concluding
Sonogashira coupling. By using the Kumada–Sonogashira
methodology, the overall reaction time can be shortened to
two hours starting from 10-hexyl-3-iodo-10H-phenothiazine
(Scheme 3).
Scheme 2 Pseudo-five component synthesis of bis(arylethynyl)
benzene compounds 6i and 6j.
Finally, an addition extension of the methodology to three
Pd-catalyzed steps in a one-pot fashion is also possible. When
Scheme 3 Synthesis of arylethynyl phenothiazine derivatives 6k and 6l.
Scheme 4 Four-component synthesis of 4’-((4-methoxyphenyl)ethynyl)-[1,1’-biphenyl]-4-carbonitrile (8) by a sequentially Pd-catalyzed Kumada–
Sonogashira–Suzuki process.
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4-bromo-1-iodobenzene (1c) is employed in the second step,
the carbon–bromine bond becomes available for a concluding
Pd-catalyzed Suzuki coupling with 4-cyanophenylpinacol-
boronic ester (7), furnishing biaryl-substituted alkyne 8 in
moderate yield (Scheme 4) in the sense of a sequentially cata-
lyzed four-component Kumada–Sonogashira–Suzuki process
with 77% yield per coupling. The conditions for the terminal
Suzuki coupling step were adapted from related Sonogashira–
cyclocondensation–Suzuki sequences.14
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Conclusions
In summary, we have disclosed a convenient and versatile
sequentially palladium-catalyzed synthesis of unsymmetrically
substituted alkynes. The modular nature of the process, the
readily available starting materials, the omission of protecting
groups for the ethynyl arene formation, the mild reaction con-
ditions, and the short reaction times open a quick and
straightforward access to a large variety of disubstituted
alkynes in a one-pot fashion. Moreover, the palladium catalyst
is employed in a sequential fashion, catalyzing two or even
three different subsequent cross-coupling reactions without
any further addition. The extension of the reaction sequence
to one-pot syntheses of heterocycles and further sequences is
currently underway.
7 (a) T. J. J. Müller, Top. Organomet. Chem., 2006, 19, 149–
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