Rapid consecutive three-component coupling-Fiesselmann synthesis of luminescent 2,4-disubstituted thiophenes and oligothiophenes

Article abstract of DOI:10.1039/c2cc17548g

(Hetero)aroyl chlorides, alkynes, and ethyl 2-mercapto acetate can be reacted in a consecutive three-component synthesis to give 2,4-disubstituted thiophene 5-carboxylates in good to excellent yields. In the sense of a pseudo-five-component reaction highly blue luminescent symmetrical terthiophenes and a quinquethiophene can be synthesized in excellent yield.

Full text of DOI:10.1039/c2cc17548g

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COMMUNICATION
Rapid consecutive three-component coupling-Fiesselmann synthesis of
luminescent 2,4-disubstituted thiophenes and oligothiopheneswz
Marco Teiber and Thomas J. J. Muller*
¨
Received 2nd December 2011, Accepted 20th December 2011
DOI: 10.1039/c2cc17548g
(Hetero)aroyl chlorides, alkynes, and ethyl 2-mercapto acetate
can be reacted in a consecutive three-component synthesis to give
2,4-disubstituted thiophene 5-carboxylates in good to excellent
yields. In the sense of a pseudo-five-component reaction highly
blue luminescent symmetrical terthiophenes and a quinquethiophene
can be synthesized in excellent yield.
definitely restricts conjugative electronic communication in the
ground state this ligation mode might be particularly intriguing
in the excited electronic state or upon p- or n-doping of the native
oligomer by oxidation or reduction, respectively. A solution to
circumvent the difficult access to 2,4-difunctionalized thiophenes
is the de novo synthesis of the thiophene core by the Fiesselmann
synthesis.8 Here, we communicate the conception of a rapid
consecutive three-component synthesis of 2,4-disubstituted
thiophene 5-carboxylates, the elaboration of this principle into
a novel one-pot synthesis of ter- and quinquethiophenes and first
studies of the electronic properties.
Thiophenes and oligothiophenes constitute important scaffolds in
natural products,1 pharmaceutically active agents,2 and, most
importantly, as functional p-electron systems in organic materials
science.3 As a consequence, numerous applications of thiophene
based molecular entities have found entry as hole transport
materials in organic light-emitting diodes,4 organic field-effect
transistors,5 and organic photovoltaics.6 Furthermore, 2,5-ligated
oligothiophenes and polymers in linear and cyclic topologies are
important nanostructured models of one-dimensional conductive
molecular wires that can be imaged by scanning probe and atomic
force microscopies.7
In the past years we have established diversity-oriented synth-
eses of chromophores9 based upon Pd-catalyzed cross-coupling
as an entry to consecutive multi-component10 and domino11
reactions for accessing hetero- and carbocyclic frameworks.
The mild and catalytic conditions of the modified Sonogashira
alkynylation of acid chlorides to furnish alkynones12 as bifunc-
tional electrophiles and three-carbon building blocks are
perfectly suited for accessing five-, six- and seven-membered
heterocycles in a consecutive one-pot fashion. Therefore, the
retrosynthetic analysis of 2,4-disubstituted thiophene 5-carboxy-
lates 1 suggests a concatenation of our catalytic generation of
alkynone 2 from acid chloride 3 and terminal alkyne 4 with a
Fiesselmann cyclocondensation of ethyl mercapto acetate (5),13
to give 2,4-disubstituted thiophenes (Scheme 1).
Most oligothiophene syntheses are founded on the functiona-
lization and cross- or homocoupling of halo and organometallic
thiophenes in a stepwise approach. By virtue of the easily
accessible 2,5-difunctionalization this ligation motif has become
dominant (Fig. 1).
Whereas the 2,3- or 3,4-ligation leads to the implementation
of kinks into the oligothiophene backbone the 2,4-connectivity
of the thienyl cores, maintaining a linear arrangement, has
remained astoundingly unknown. Although the 2,4-connectivity
With respect to the compatibility with the alkynone forming
first step we decided to optimize the Fiesselmann cyclo-
condensation with alkynone 2a and ethyl mercapto acetate
(5) as substrates in THF as a solvent (Scheme 2, Table 1).
The optimization study of the Fiesselmann thiophene synthesis
of compound 1a reveals that for caesium carbonate as a base low
temperatures in the Michael addition step give best results
(entries 4–6) and that ethanol favors the Michael addition
(entries 4–8). This can be rationalized assuming the kinetically
controlled formation of the Z-configured Michael adduct in the
Fig. 1 Modes of ligation in oligothiophenes.
Lehrstuhl fur Organische Chemie, Institut fur Organische Chemie und
¨
¨
Makromolekulare Chemie, Heinrich-Heine-Universitat Dusseldorf,
¨
¨
Universitatsstraße 1, D-40225, Dusseldorf, Germany.
¨
¨
E-mail: ThomasJJ.Mueller@uni-duesseldorf.de;
Fax: +49 0211 8114324; Tel: +49 0211 8112298
w Dedicated to Prof. Dr Klaus Hafner on the occasion of his 85th
birthday.
z Electronic supplementary information (ESI) available: Experimental
procedures and characterization of compounds 1 and 7. See DOI:
10.1039/c2cc17548g
Scheme 1 Retrosynthetic analysis of 2,4-disubstituted thiophene
5-carboxylates 1.
c
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Table 2 Three-component synthesis of 2,4-disubstituted thiophene
5-carboxylates 1a
2,4-Disubstituted
thiophene 5-
carboxylate 1
(Hetero)aroyl
Entry chloride 3
(yield after
isolation)
Scheme 2 Optimization of the Fiesselmann thiophene synthesis in
Alkyne 4
THF as a solvent.
1
R1 = p-MeOC6H4 R2 = Ph (4a)
(3a)
1a (97%)
Table 1 Optimization of the Michael addition–aldol condensation
sequence (Fiesselmann thiophene synthesis) to give thiophene 1a in
THF as a solventa
2
3
3a
R1 = p-NCC6H4
(3b)
R2 = p-tBuC6H4 (4b) 1b (91%)
4b 1c (88%)
4
R1 = p-MeC6H4
R2 = p-NCC6H4 (4c) 1d (68%)
Ethyl mercapto
acetate (5)
[equiv.]
T/1C
(Michael
addition)
(3c)
3c
3c
5
6
R2 = p-MeOC6H4 (4d) 1e (83%)
R2 = p-MeO2CC6H4 1f (89%)
(4e)
Entry
Base
Yield of 1a [%]
1
2
3
1.10
1.10
1.50
1.50
1.50
1.50
1.50
1.50
0
25
0
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
DBU
45
40
59
68
78
86
97
97
7
8
9
10
11
12
13
14
15
3c
3c
3c
3c
3c
R2 = p-FCC6H4 (4f) 1g (93%)
R2 = 2-pyridyl (4g)
1h (32%)
1i (50%)
1j (45%)
n
R2 = butyl (4h)
4b
5b
6b
7b
8b,c
0
R2 = SiMe3 (4i)
ꢀ18
ꢀ78
ꢀ78
25
R2 = ferrocenyl (4j) 1k (91%)
R1 = 2-thienyl (3d) 4a
1l (90%)
1m (93%)
1n (80%)
1o (94%)
3d
3c
3d
4b
R2 = 2-thienyl (4k)
4k
DBU
a
Reaction conditions: To a solution of 1.00 equiv. of alkynone 2a
(0.1 m in THF) 1.10 or 1.50 equiv. of ethyl mercapto acetate (5) were
added at T and the mixture was stirred at this temp. for 2.5 h;
1.02 equiv. of the base and 5.5 equiv. of anhydrous MgSO4 were added
a
Reaction conditions: 1.00 equiv. of (hetero)aroyl chlorides 3 (0.1 M in
THF), 1.10 equiv. of terminal alkynes 4, 0.02 equiv. of PdCl2(PPh3)2,
0.04 equiv. of CuI, and 1.05 equiv. of triethylamine; after stirring for
2 h at rt addition of 1 mL of ethanol, 1.20 equiv. of ethyl mercapto
acetate (5), and 1.5 equiv. of DBU, stirring at rt for 12–24 h.
b
at 25 1C and stirring was continued for 20 h. Prior to ethyl mercapto
acetate (5) 1 mL of ethanol was added to the solution of 2a in THF.
c
DBU was added directly after compound 5 to the reaction mixture.
Most interestingly, upon choosing thiophene-2,5-dicarbonyl
dichloride (6) as a coupling partner the symmetrical terthio-
phenes 7a and 7b, and even the symmetrical quinquethiophene
7c can be prepared in a one-pot fashion and in the sense of a
pseudo-five-component reaction in good yields (Scheme 4).14
The yield of oligothiophenes 7 was improved by lowering the
reaction temperature to 0 1C in the terminal Michael addition–
cyclocondensation step. Furthermore Pd(PPh3)4 was used as a
precatalyst. With respect to the overall yields of this one-pot
sequence ranging from 74–84% an average yield of 94–97% per
step appears to be quite efficient.
sense of ethanol assisted anti-addition of ethyl mercapto acetate
(5) to alkynone 2a. For a successful terminating aldol condensation
a Z-configured Michael adduct as an intermediate is mandatory.
In the cyclocondensation step DBU as a base is superior to caesium
carbonate (entries 7 and 8). The use of other bases such as NEt3 or
NEt(iPr)2 did not furnish thiophene 1a. For DBU as a base the
variation of the temperature in the aldol condensation step did not
affect the yield.
After reaction of (hetero)aroyl chlorides 3 and terminal
alkynes 4 in THF under modified Sonogashira conditions
for 2 h at room temperature forming alkynones 2, ethanol,
ethyl mercapto acetate (5), and DBU were subsequently added
to the reaction mixture at room temp. and stirring was
continued for 12–24 h to give after isolation and flash chromato-
graphy on silica gel the analytically pure thiophene derivatives 1
in good to excellent yields (Scheme 3, Table 2).
Our primary interest in the electronic properties of oligothio-
phenes 7 led us to investigate the electronic spectra of symmetrical
thiophenes 7a and 7b and quinquethiophene 7c. Expectedly, the
According to our alkynone synthesis under modified
Sonogashira conditions12 the substituent pattern in the 2,4-
disubstituted thiophene 5-carboxylates 1 can be varied for R1
and R2 from electron deficient to electron rich, from aromatic,
heteroaromatic, and sterically demanding for R1 to even
organometallic and alkyl for R2.
Scheme 3 Consecutive three-component Sonogashira alkynylation–
Fiesselmann cyclocondensation synthesis of 2,4-disubstituted thiophene
5-carboxylates 1.
Scheme 4 Consecutive pseudo-five-component Sonogashira alkynyl-
ation–Fiesselmann cyclocondensation synthesis of symmetrical
terthiophenes 7a and 7b and quinquethiophene 7c.
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 2080–2082 2081

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Fig. 2 Solution (left) and solid state luminescence of quinquethio-
phene 7c (upon irradiation at lexc = 366 nm).
electronic absorption spectra display broad and intense longest
wavelength absorption bands in the near UV between 307 nm
(7a) and 344 nm (7c) (see ESIz for complete data sets). Most
interestingly all representatives reveal strong blue luminescence in
solution with emission maxima at 445 nm (Fig. 2, left). The
symmetrical terthiophenes 7a and 7b and quinquethiophene 7c
exhibit Stokes shifts ranging from 6600 cmꢀ1 (7c) to 10 100 cmꢀ1
(7a). In addition the fluorescence efficiency is quite high as
reflected by fluorescence quantum yields Ff ranging between
8 and 11%. The solid state emissions as determined from solids
and drop cast films are red shifted and appear with greenish
luminescence between 481 (film) and 512 nm (solid) for
oligothiophene 7c (Fig. 2, right).
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In conclusion we have developed an efficient and rapid
three-component synthesis of 2,4-disubstituted thiophene
5-carboxylates in the sense of a consecutive Sonogashira–
Fiesselmann sequence. This one-pot synthesis was also success-
fully transposed as a pseudo-five-component reaction for the
preparation of symmetrical terthiophenes and a quinquethio-
phene. All oligothiophenes luminesce with emission of intense
blue light in solution and green light from the solid. With this
straightforward diversity-oriented access to luminescent oligothio-
phenes in hand the stage is now set for the development of tunable
materials, which can be organized by esterification. Oligomeri-
zation studies under mild enzymatic conditions and more detailed
photophysical investigations are currently underway.
¨
T. J. J. Muller, Chem. Soc. Rev., 2007, 36, 1095; T. J. J. Muller,
¨
Targets Heterocycl. Syst., 2006, 10, 54.
¨
11 J. Schonhaber and T. J. J. Muller, Org. Biomol. Chem., 2011,
¨
¨
9, 6196; J. Scho
2010, 12, 4122; D. M. D’Souza, A. Kiel, D. P. Herten and T. J.
J. Muller, Chem.–Eur. J., 2008, 14, 529; D. M. D’Souza,
¨
¨
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¨
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¨
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¨
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¨
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¨
13 For Fiesselmann thiophene syntheses from alkynones, see D. Obrecht,
F. Gerber, D. Sprenger and T. Masquelin, Helv. Chim. Acta, 1997,
80, 531; M. T. Herrero, I. Tellitu, E. Dominguez, S. Hernandez,
I. Moreno and R. SanMartin, Tetrahedron, 2002, 58, 8581.
The support of this work by CLIB graduate cluster (scholarship
for M. T.) and the Fonds der Chemischen Industrie is gratefully
acknowledged. The authors also cordially thank B. Sc. Lisa-Maria
14 Synthesis of quinquethiophene 7c: Pd(PPh3)4 (92 mg, 0.08 mmol),
CuI (30 mg, 0.16 mmol), and dry THF (15 mL) were successively
placed in the reaction vessel under nitrogen at room temp. After
the addition of 2-ethynyl thiophene (4k) (324 mg, 3.00 mmol),
bisacidchloride 6 (209 mg, 1.00 mmol), and triethylamine (314 mL,
2.20 mmol) the reaction mixture was stirred at room temp. for 4 h.
Then, ethanol (2 mL), ethyl 2-mercapto acetate (5) (364 mL,
2.50 mmol), and DBU (506 mL, 3.50 mmol) were successively
added at 0 1C and the solution was stirred at 0 1C for 24 h. After
workup and purification 423 mg (76%) of the analytically pure
quinquethiophene 7c was obtained as a yellow solid, mp 141 1C.
1H NMR (500 MHz, CDCl3): d 1.37 (t, 3J = 7.1 Hz, 6H),
4.35 (q, 3J = 7.1 Hz, 4H), 7.07 (dd, 3J = 3.7, 5.0 Hz, 2H), 7.33
(dd, 3J = 2.3, 7.4 Hz, 4H), 7.35 (s, 2H), 7.61 (s, 2H); 13C NMR
(125 MHz, CDCl3): d 14.7 (CH3), 61.7 (CH2), 124.7 (Cquat), 125.9
(CH), 126.8 (CH), 127.5 (CH), 128.6 (CH), 129.7 (CH), 136.2
(Cquart), 137.7 (Cquart), 140.6 (Cquat), 141.7 (Cquat), 162.2 (Cquat);
MALDI MS: m/z (%) = 556 ([M+], 100); anal. calcd. for
C26H20O4S5 (556.8): C 56.09, H 3.62%; found: C 56.10, H 3.48%.
Kavallar and B. Sc. Timo Lessing (both University of Dusseldorf)
¨
for experimental assistance.
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2082 Chem. Commun., 2012, 48, 2080–2082
This journal is The Royal Society of Chemistry 2012