Pseudo five-component synthesis of 2,5-di(hetero)arylthiophenes via a one-pot Sonogashira-Glaser cyclization sequence

Article abstract of DOI:10.3762/bjoc.7.174

Based upon a consecutive one-pot Sonogashira-Glaser coupling-cyclization sequence a variety of 2,5-di(hetero)arylthiophenes were synthesized in moderate to good yields. A single Pd/Cu-catalyst system, without further catalyst addition, and easily available, stable starting materials were used, resulting in a concise and highly efficient route for the synthesis of the title compounds. This novel pseudo five-component synthesis starting from iodo(hetero)arenes is particularly suitable as a direct access to well-defined thiophene oligomers, which are of peculiar interest in materials science.

Full text of DOI:10.3762/bjoc.7.174

Pseudo five-component synthesis of
2,5-di(hetero)arylthiophenes via a one-pot
Sonogashira–Glaser cyclization sequence
Dominik Urselmann, Dragutin Antovic and Thomas J. J. Müller*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2011, 7, 1499–1503.
Institut für Organische Chemie und Makromolekulare Chemie,
Heinrich-Heine-Universität Düsseldorf, Universitätsstr. 1, D-40225
Düsseldorf, Germany
doi:10.3762/bjoc.7.174
Received: 27 May 2011
Accepted: 10 October 2011
Published: 04 November 2011
Email:
Dominik Urselmann - Dominik.Urselmann@uni-duesseldorf.de;
Dragutin Antovic - Dragutin.Antovic@uni-duesseldorf.de;
Thomas J. J. Müller* - ThomasJJ.Mueller@uni-duesseldorf.de
This article is part of the Thematic Series "Multicomponent reactions".
Associate Editor: D. O'Hagan
* Corresponding author
© 2011 Urselmann et al; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
C–C coupling; copper; multicomponent reactions; palladium;
thiophenes
Abstract
Based upon a consecutive one-pot Sonogashira–Glaser coupling–cyclization sequence a variety of 2,5-di(hetero)arylthiophenes
were synthesized in moderate to good yields. A single Pd/Cu-catalyst system, without further catalyst addition, and easily available,
stable starting materials were used, resulting in a concise and highly efficient route for the synthesis of the title compounds. This
novel pseudo five-component synthesis starting from iodo(hetero)arenes is particularly suitable as a direct access to well-defined
thiophene oligomers, which are of peculiar interest in materials science.
Introduction
Over the past decades 2,5-di(hetero)aryl substituted thiophenes share the drawback of ultimately requiring two different halo-
[1,2] have constantly attracted a lot of interest, especially as genated (hetero)arenes and the separate conversion into an
charge-transport materials in electronic [3] and optoelectronic organometallic derivative in an additional step. From a prac-
[4-6] devices, but also in drug design as antitumor [7] or anti- tical point of view halogen–metal exchange, transmetalation
inflammatory agents [8] or in plaque imaging [9]. Most and isolation occasionally turns out to be tedious and in many
commonly the methodological access to these targets has been cases the use of polar functionality in the substrate is consider-
based upon Pd- or Ni-catalyzed coupling of dihalo thiophenes ably restricted.
with organometallic (hetero)aryl derivatives by virtue of Suzuki
[10] or Stille [11] coupling. Even though this strategy for In recent years interesting examples of palladium-catalyzed
the synthesis of symmetrical 2,5-diarylated thiophenes has direct C–H activation and arylation of (hetero)aromatics have
proven to be efficient and general, all of these synthetic routes been reported [12,13]. Although these procedures only employ
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Beilstein J. Org. Chem. 2011, 7, 1499–1503.
a single halogenated substrate and avoid the stoichiometric for- Results and Discussion
mation of organometallic intermediates the substrate scope is The conversion of 1,4-diaryl-1,3-butadiynes into 2,5-diarylthio-
limited to activated heteroaromatic C–H bonds. In addition, phenes by base-mediated cyclization with sodium sulfide or
sophisticated catalyst systems must be applied, and the effi- sodium hydrogen sulfide is a literature-known procedure [16-
ciency is also variable.
23]. Therefore, we reasoned that the concatenation of our
sequentially Pd/Cu-catalyzed Sonogashira–Glaser reaction [15]
Just recently we reported a very straightforward one-pot syn- with the sulfide-mediated cyclization should lead to a straight-
thesis of symmetric 1,4-di(hetero)arylated 1,3-butadiynes forward one-pot pseudo five-component synthesis of 2,5-
starting from (hetero)aryl iodides by virtue of a sequentially Pd/ di(hetero)arylthiophenes (Scheme 2).
Cu-catalyzed [14] Sonogashira–Glaser process (Scheme 1) [15].
We first set out to identify an optimal cosolvent for all four
According to this general one-pot access to 1,4-di(hetero)aryl- steps taking advantage of the high yield Sonogashira–Glaser
1,3-butadiynes we reasoned that it should be possible to address coupling synthesis [15] of 1,4-diphenylbutadiyne starting
the butadiyne functionality towards heterocyclization, again in a from iodobenzene (1a) (Table 1). In addition, the final
one-pot fashion. Here, we communicate the first pseudo five- cyclization step to give 2,5-diphenylthiophene (2a) was
component synthesis of 2,5-di(hetero)arylthiophenes by virtue performed under microwave heating at 120 °C for a hold time
of a one-pot Sonogashira–Glaser cyclization sequence.
of 2 h.
Scheme 1: Concept of a Sonogashira–Glaser coupling sequence.
Scheme 2: Concept of a Sonogashira–Glaser cyclization synthesis of 2,5-di(hetero)arylthiophenes.
Table 1: Evaluation of different solvents.a
entry
solvent
cavity temperature [°C] (hold
time in the cyclization step)
conversionb (yield of 2a [%]c)
1
THF
120 (2 h)
120 (2 h)
120 (2 h)
120 (2 h)
90 (4 h)
complete (61)
complete (59)
complete (11)
complete (64)
complete (n. i.)d
complete (n. i.)d
2
1,4-dioxane
DMSO
DMF
3
4
5
DMF
6e
DMF
90 (8 h)
aReaction conditions: Iodobenzene (2 mmol) in degassed solvent (10 mL) was reacted for 1.5 h at rt with TMSA (3 mmol) in the presence of
PdCl2(PPh3)2 (0.04 mmol), CuI (0.08 mmol), and NEt3 (2 mmol). Then KF (3 mmol) and methanol (5 mL) were added and the reaction mixture was
stirred in the open reaction vessel at rt for 16 h. After the addition of Na2S·9H2O (3 mmol) and KOH (3 mmol) the sealed reaction vessel was heated
in a microwave oven. bConversion in the final step (monitored by TLC). cGiven yields refer to isolated and purified products. dn. i.: Not isolated. eThe
final step was performed in an oil bath at 90 °C for 8 h to achieve complete conversion.
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Beilstein J. Org. Chem. 2011, 7, 1499–1503.
The solvent screening revealed that THF (tetrahydrofuran) groups (2f) are tolerated as well. Furthermore, several different
(Table 1, entry 1), 1,4-dioxane (Table 1, entry 2), and DMF 5- and 6-membered S- and N-heteroaryl iodides give rise to the
(N,N-dimethylformamide) (Table 1, entry 4) are equally suit- formation of the corresponding 2,5-di(heteroaryl)thiophenes
able solvents giving rise to essentially comparable yields. (2j–2k and 2o) in good yields.
DMSO (dimethylsulfoxide) (Table 1, entry 3), however, turned
out to give inferior yields, resulting in an increased formation of Deviating from the general procedure, in the case of m-bromo-
byproducts already during the desilylation and the oxidative iodobenzene (1d) only 1 equiv of TMSA was added in order to
coupling step (as monitored by TLC). A lower reaction minimize a second alkynylation at the bromine position in the
temperature resulted in a prolonged reaction time under initial Sonogashira coupling step, which resulted in a moderate
microwave conditions to achieve complete conversion (Table 1, yield of the dibromo derivative (2d). Upon reaction of the
entry 5), whereas conductive heating at the same temperature m-iodo-nitrobenzene (1g) a concomitant reduction of the nitro
even doubled this reaction time (Table 1, entry 6). As a conse- groups to the amines was observed, giving rise to the dianilino
quence, DMF as a solvent and dielectric heating at 120 °C for thiophene 2g.
2 h in the final step were identified as the optimal settings for
the sequence.
Most interestingly, even the linear five-ring-containing deriva-
tives “PPTPP” (2n) and “T5” (2o), which are important charge-
With these optimized conditions in hand, the substrate scope transport molecules in materials science [3], were easily
of this novel pseudo five-component synthesis of 2,5- accessed in a one-pot procedure. Starting from the stable and
di(hetero)arylthiophenes was studied (Scheme 3). Starting from readily available aryliodides 1n and 1o, the presented new
(hetero)aryl iodide 1 all reactions were carried out on a 2 mmol methodology allowed the synthesis of both molecules in a
scale to give symmetrical 2,5-di(hetero)arylthiophenes 2 as quick, simple and economic one-pot reaction. Moreover, the
stable, crystalline solids (with the exception of 2b) in moderate usual preparation and isolation of boronic acids or even more
to good yield (Figure 1). The structural assignments of all thio- sensitive zinc organometallics was circumvented. In addition
phenes 2 were unambiguously supported by 1H and 13C NMR the use of the rather expensive diiodothiophene as a coupling
spectroscopy, mass spectrometry, and combustion analysis. Due partner was avoided [24-26]. “PPTPP” (2n) and “T5” (2o) were
to poor solubility no NMR spectra of compounds 2m, 2n and 2o readily purified by Soxhlet extraction.
could be recorded, yet, the assignment of the molecular struc-
ture is supported by mass spectrometry and combustion Upon reaction of N-Boc-3-iodoindole (1p) a complete cleavage
analysis.
of the protection group and the formation of several byproducts
were observed leading to a significantly lower isolated yield of
The scope of this new one-pot pseudo five-component Sono- the corresponding thiophene 2p.
gashira–Glaser cyclization synthesis of symmetrical 2,5-
di(hetero)arylthiophenes 2 is fairly broad with respect to the Conclusion
applied (hetero)aryl iodides 1. The product analysis of the target In summary we have developed an economical and efficient
structures 2 reveals that aryl substituents can be electroneutral one-pot sequence for transforming (hetero)aryl iodides into
(2a and 2l–2n), electron-rich (2b, 2c, 2f, 2k, 2o, 2p) as well as symmetrical 2,5-di(hetero)arylthiophenes based upon an initial
electron-poor (2d, 2e and 2h–2j). Substituents in ortho- (2b), sequentially Pd/Cu-catalyzed Sonogashira–Glaser process fol-
meta- (2c–2g,) and para-positions (2h, 2i) are tolerated. Even lowed by a subsequent sulfide-mediated cyclization. A broad
bulky bi- or tricyclic substrates are transformed without any range of functional groups is tolerated and the iodo substrates
complications (2l–2p). Polar substituents such as hydroxy are either commercially available or easily accessible. This
Scheme 3: Pseudo five-component Sonogashira–Glaser cyclization synthesis of symmetrical 2,5-di(hetero)arylthiophenes 2.
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Beilstein J. Org. Chem. 2011, 7, 1499–1503.
Figure 1: Symmetrical 2,5-di(hetero)arylthiophenes 2 synthesized via the one-pot pseudo five-component Sonogashira–Glaser cyclization sequence
(yields refer to 0.5 equiv of (hetero)aryl iodide). aOnly one equiv of TMSA was applied in the Sonogashira step. bAccording to elemental analysis com-
pound 2f was obtained with 25% hydrate. cm-Iodo nitrobenzene (1g) was applied as a starting material. dAccording to elemental analysis, compound
2j was obtained as a bishydrochloride. eN-Boc 3-iodo indole (1p) was applied as a starting material.
strikingly simple methodology is highly practical and leads to a (0.55 mL, 4.00 mmol) the solution was stirred at rt for 1.5 h.
straightforward protocol for the preparation of the title com- Then KF (174 mg, 3.00 mmol), and methanol (5.00 mL) were
pounds. Studies addressing more-sophisticated 2,5-disubsti- subsequently added and the reaction mixture was stirred under
tuted thiophenes for surface modification and also mesoporous aerobic atmosphere in the opened reaction vessel overnight at rt.
hybrid materials are currently underway.
After the addition of sodium sulfide nonahydrate (960 mg,
4 mmol), potassium hydroxide (224 mg, 4 mmol), and methanol
(5 mL) the vessel was heated to 120 °C under microwave irradi-
Experimental
2c: An 80 mL microwave reaction vessel, equipped with a ation for 2 h. After cooling to rt the mixture was adsorbed on
rubber septum, was charged with 1-iodo-3-methoxybenzene neutral aluminium oxide and filtered through a short plug of
(1c) (468 mg, 2.00 mmol), PdCl2(PPh3)2 (28 mg, 0.04 mmol, neutral aluminium oxide with THF as an eluent. The solvents
2 mol %), CuI (16 mg, 0.08 mmol, 4 mol %), and degassed were removed in vacuo and the residue was adsorbed on
DMF (10.0 mL). The reaction mixture was flushed for 10 min Celite® and purified by column chromatography on silica gel
with nitrogen by using a cannula. After addition of trimethyl- (hexane) to give 215 mg (0.72 mmol, 72 %) of 2c as a light-
silylacetylene (0.43 mL, 3.00 mmol) and dry triethylamine yellow solid. Rf 0.35 (n-hexane/ethyl acetate 10:1); mp 73 °C;
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Beilstein J. Org. Chem. 2011, 7, 1499–1503.
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