Cyclization of 1,4-phenylenediacrylic acid with thionyl chloride and subsequent Suzuki-Miyaura reactions revisited. the products are benzo[1,2-b;5,6-b′]dithiophenes and not benzo[1,2-b;4,5-b′] dithiophenes

Article abstract of DOI:10.1002/adsc.201100668

The reaction of 1,4-phenylenediacrylic acid with thionyl chloride was reinvestigated. In earlier reports [Liebigs Ann. Chem. 1980, 1172; Heterocycles 1995, 41, 2691; Adv. Synth. Catal. 2009, 351, 2683] it was claimed that 3,7-dichlorobenzo[1,2-b;4,5-b′]dithiophenes were formed in these reactions. Herein, we provide unambiguous evidence that the assignment of these structures is wrong and that, in contrast, 3,6-dichlorobenzo[1,2-b;5,6-b′] dithiophenes are formed. As a consequence, the structures of these parent molecules and of numerous aryl-substituted derivatives prepared by Pd-catalyzed cross-coupling reactions have to be revised. As many of these dithiophenes were reported to show interesting optical, thermal and electronic properties, the theoretical explanations for these properties have to be reconsidered in the light of the corrected structures reported herein. Our structural assignments are based on X-ray crystal structure analyses of the parent molecules and on NMR spectroscopic studies of the first unsymmetrical derivatives. Besides, mechanistic investigations based on quantum chemical calculations have been carried out which support the formation of the 3,6-dichlorobenzo[1,2-b;5,6- b′]dithiophene isomers. Copyright

Full text of DOI:10.1002/adsc.201100668

UPDATES
DOI: 10.1002/adsc.201100668
Cyclization of 1,4-Phenylenediacrylic Acid with Thionyl
Chloride and Subsequent Suzuki–Miyaura Reactions Revisited.
The Products are Benzo[1,2-b;5,6-b’]dithiophenes and not
Benzo[1,2-b;4,5-b’]dithiophenes
Zahid Hassan,a Sebastian Reimann,a,b Kai Wittler,c Ralf Ludwig,b,c
Alexander Villinger,a and Peter Langera,b,*
a
Institut fꢀr Chemie, Universitꢁt Rostock, Albert Einstein Str. 3a, 18059 Rostock, Germany
E-mail: peter.langer@uni-rostock.de
Leibniz-Institut fꢀr Katalyse an der Universitꢁt Rostock e.V., Albert Einstein Str. 29a, 18059 Rostock, Germany
Institut fꢀr Chemie, Physikalische und Theoretische Chemie, Universitꢁt Rostock, Dr.-Lorenz-Weg 1, 18059 Rostock,
b
c
Germany
Received: August 24, 2011; Revised: November 15, 2011; Published online: February 23, 2012
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201100668.
Abstract: The reaction of 1,4-phenylenediacrylic
acid with thionyl chloride was reinvestigated. In
earlier reports [Liebigs Ann. Chem. 1980, 1172;
Heterocycles 1995, 41, 2691; Adv. Synth. Catal. 2009,
351, 2683] it was claimed that 3,7-dichloroben-
zo[1,2-b;4,5-b’]dithiophenes were formed in these
reactions. Herein, we provide unambiguous evi-
dence that the assignment of these structures is
wrong and that, in contrast, 3,6-dichlorobenzo[1,2-
b;5,6-b’]dithiophenes are formed. As a consequence,
the structures of these parent molecules and of nu-
merous aryl-substituted derivatives prepared by Pd-
catalyzed cross-coupling reactions have to be re-
vised. As many of these dithiophenes were reported
to show interesting optical, thermal and electronic
properties, the theoretical explanations for these
properties have to be reconsidered in the light of
the corrected structures reported herein. Our struc-
tural assignments are based on X-ray crystal struc-
ture analyses of the parent molecules and on NMR
spectroscopic studies of the first unsymmetrical de-
rivatives. Besides, mechanistic investigations based
on quantum chemical calculations have been car-
ried out which support the formation of the 3,6-di-
chlorobenzo[1,2-b;5,6-b’]dithiophene isomers.
Introduction
Benzo[b]thiophenes show a wide range of pharmaco-
logical activities, such as estrogen receptor modulat-
ing activity, tubulin binding activity, activity as MRP1,
angiogenesis and thrombin inhibitors, anti-inflamma-
tory activity, and antifungal activity.[1] More complex,
annulated thiophene derivatives often contain a low
singlet-triplet energy gap and are important core
structures of magnetic and electronic materials,[2] such
as organic ferromagnets, conductors, transistors, pho-
tovoltaic cells and organic light-emitting diodes
(OLEDs).[3] Therefore, the synthesis and properties of
rigid benzothiophene-fused aromatic compounds has
been extensively studied in recent years.
Miura and co-workers have recently reported the
synthesis of various 3,7-diarylbenzo[1,2-b;4,5-b’]di-
thiophenes[4] by two-fold Suzuki–Miyaura and Sono-
gashira cross-coupling reactions of 3,7-dichloroben-
zo[1,2-b;4,5-b’]dithiophenes. The latter compounds
were first prepared by Ried[5] and Karminski-
Zamola[6] and their co-workers by cyclization of 1,4-
phenylenediacrylic acid (1) with thionyl chloride and
subsequent addition of a nucleophile. The basic meth-
odology, the cyclization of thionyl chloride with cin-
namic acids to give benzophenones, was first reported
by Krubsack and Higa[7a] and later improved by Ried
and co-workers.[7b]
Keywords: catalysis; cyclization; dithiophenes; het-
erocycles; palladium; regioselectivity; structure re-
vision
During our studies related to regioselective cross-
coupling reactions of polyhalogenated heterocycles,
we reinvestigated the cyclization of 1 with thionyl
chloride. Herein, we provide unambiguous evidence
that several of the earlier reported structures, 3,7-di-
Adv. Synth. Catal. 2012, 354, 731 – 739
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Zahid Hassan et al.
UPDATES
1
chlorobenzo[1,2-b;4,5-b’]dithiophenes, are wrong and their product by H NMR, IR and mass spectroscopy
that, in contrast, 3,6-dichlorobenzo[1,2-b;5,6-b’]dithio- as well as by elemental analysis. They considered that,
phenes are formed. As a consequence, the structures alternatively, the isomeric 3,6-dichlorobenzo[1,2-b;5,6-
of numerous arylated dithiophenes prepared by Pd- b’]dithiophene 2 could have been formed. But they
catalyzed cross-coupling reactions of the parent decided that isomer 2ꢀ is more likely based on an
chlorinated derivatives have to be revised as well. analysis of the IR bands in the fingerprint region be-
Many of these products were reported to show inter- cause more reliable methods were not available at
esting optical, thermal and electronic properties. The that time. In 1995, Karminski-Zamola referred to the
theoretical explanations for these properties have to original report of 1980 and reported the employment
be carefully reconsidered in the light of the correct of anilines as the nucleophile and formation of 3,7-di-
structures reported herein. Indeed, our results are chlorobenzo[1,2-b;4,5-b’]dithiophene-diamides.
In
also important for the future design of related mole- 2009, Miura used n-butanol as the nucleophile and re-
cules and materials. Our structural assignments are ported the synthesis of diester 3’.[4] This product was
based on X-ray crystal structure analyses of the transformed into various symmetrical 3,6-diarylated
parent chlorinated dithiophenes and on NMR spec- benzo[1,2-b;5,6-b’]dithiophenes by two-fold Suzuki–
troscopic studies of unsymmetrical derivatives which Miyaura cross-coupling reactions. None of these struc-
were prepared for the first time. Besides, mechanistic tures reported were unambiguously confirmed by X-
studies based on quantum chemical calculations have ray crystal structure analyses or detailed NMR stud-
been carried out which are in agreement with the ob- ies.
served formation of 3,6-dichlorobenzo[1,2-b;5,6-b’]di-
thiophenes.
Our original plan was to study whether unsymmet-
rical benzo[1,2-b;4,5-b’]dithiophenes can be prepared
by mono-Suzuki reactions of 2’ and related molecules.
Therefore, we reinvestigated the work of Ried and
Miura and their co-workers. We have found that the
reaction of 1,4-phenylenediacrylic acid (1) with thio-
Results and Discussion
In 1980, Ried and Oremek reported[5] that the reac- nyl chloride (5 h, 1408C), in the presence of catalytic
tion of 1,4-phenylenediacrylic acid (1) with thionyl amounts of pyridine, and subsequent addition of
chloride, in the presence of catalytic amounts of pyri- methanol (2 h, reflux), following the conditions re-
dine, afforded the diacid dichloride A’ as a reactive ported by Ried,[5] afforded a yellow crystalline solid.
intermediate which was subsequently trapped with To our surprise, an X-ray crystal structure analysis re-
methanol as a nucleophile to give the 3,7-dichloroben- vealed that the product was 3,6-dichlorobenzo[1,2-
zo[1,2-b;4,5-b’]dithiophene 2’ (Scheme 1). In their b;5,6-b’]dithiophene 2 instead of the expected isomer-
original report,[5] Ried and co-workers characterized ic
3,7-dichlorobenzo[1,2-b;4,5-b’]dithiophene
2’
(Scheme 1, Figure 1).[8] To confirm that product 2’
does not simply represent a by-product which crystal-
lized in the presence of 2, special attention was given
to the work-up procedure. The crude product mixture
showed only one major spot by TLC which was isolat-
ed by chromatography and examined by NMR and
X-ray crystal structure analysis. The NMR data of the
crystals were identical with the rest of the material.
The moderate isolated yield of 2 (57%) can be ex-
Scheme 1. Synthesis of 2 and 3. Reaction conditions: 1)
SOCl2, pyridine, 5 h, 1408C; 2) ROH, 2 h, reflux.
Figure 1. ORTEP plot of 2
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Cyclization of 1,4-Phenylenediacrylic Acid with Thionyl Chloride and Subsequent Suzuki–Miyaura Reactions
plained by losses during the chromatographic purifi- possible. The aromatic protons Ha appear as a singlet
cation. The isomeric product 2’ was not formed which with the integration of two protons. However, this ob-
was confirmed by NMR measurements of the crude servation is compatible with both isomers 3 and 3’,
product (before chromatographic purification). The since no coupling between the two aromatic protons
1H NMR shifts of the aromatic protons of 2 and 2’ Ha is expected (the protons are equivalent)
were calculated by DFT computations (B3LYP level (Figure 2).
of theory using a 6-31G* basis set, see the Supporting
To solve the problem, we decided to transform the
Information). The calculated chemical shifts of both symmetrical product 3 to an unsymmetrical deriva-
isomers are very similar (0.22 ppm difference) and tive. The mono-Suzuki–Miyaura cross-coupling reac-
are, thus, not diagnostic for the structural assignment tion[9] of 3 (symmetrical substrate) with 1.2 equiva-
of the product by comparison of the calculated with lents of arylboronic acids 4a–c afforded the 3-aryl-6-
the experimental data.
chlorobenzo[1,2-b;5,6-b’]dithiophenes 5a–c in very
We also repeated the synthesis of diAHCTUNGRETG(NNUN butyl)ester 3’ good yields (Scheme 2, Table 1). The best yields were
which was reported by Miura in 2009.[4] The cycliza- obtained when Pd
tion of 1 with SOCl2 and subsequent reaction with n-
butanol (instead of methanol) again afforded a yellow
solid. The structure, which was unambiguously con-
firmed by X-ray crystal structure analysis, turned out
to be 3,6-dichlorobenzo[1,2-b;5,6-b’]dithiophene 3 in-
stead of 3,7-dichlorobenzo[1,2-b;4,5-b’]dithiophene 3’
(see the Supporting Information).[8] Because of the
importance of this finding, we aimed to obtain an ad-
ditional structural proof by NMR. The NMR data of
our product were identical with those reported by
ACHTNUGTNERN(NUG PPh3)4 (5 mol%) and K3PO4
Scheme 2. Synthesis of 5a–c. Reaction conditions: i,
3
Miura and co-workers. Due to the symmetrical struc-
tures of dithiophenes 3 and 3’, similar NMR data are
expected and a structural elucidation by NMR is not
(1.0 equiv.), ArB(OH)2 (1.2 equiv.), PdACHTNUTGRNEUGN(PPh3)4 (5 mol%),
K3PO4 (2.0 equiv.), dioxane, 1208C, 4 h.
Figure 2. 1H NMR spectrum of compound 3 in CDCl3 at 300 MHz.
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Zahid Hassan et al.
UPDATES
Table 1. Synthesis of 5a–c.
7.36 ppm with coupling constants of about 8.8 Hz
(Figure 3). These results are only compatible with the
structures of 3-aryl-6-chlorobenzo[1,2-b;5,6-b’]dithio-
phenes 5a–c, but not with the corresponding isomeric
3-aryl-8-chlorobenzo[1,2-b;4,5-b’]dithiophenes. In the
latter case, no significant coupling is possible for the
aromatic protons Ha and Hb. As a consequence, the
NMR experiments of 5a–c clearly confirm the struc-
ture of dichlorodithiophene 3 as well, as no change of
the aromatic core can be expected during the Suzuki
4
Ar
Yield [%] of 5[a]
a
b
c
2-MeO-5-F-C6H3
2-MeO-5-Cl-C6H3
2-(MeO)-C6H4
82
87
80
[a]
Yields of isolated compounds.
(1.5 equiv.) were used as the catalyst and base, respec- reactions.
tively. The reactions were carried out in dioxane
Due to the striking difference between our results
(1208C, 4 h). The arylboronic acids were chosen in and those reported earlier, the cyclization reaction of
1
the sense that their H NMR signals would not disturb 1 with thionyl chloride, pyridine and methanol or n-
the structure elucidation of the aromatic core struc- butanol was repeated five times under the original
ture (vide infra).
conditions and always the same result was observed
1
Inspection of the H NMR spectra of 5a–c clearly (formation of 2 and 3 as the main products, respec-
showed that the two aromatic protons Ha and Hb are, tively). The reaction was also carried out in the ab-
as expected, chemically different and resonate as sence of pyridine, but no significant change of the
characteristic doublets at approx. d=7.74 and product distribution was observed.
Figure 3. 1H NMR spectrum of 5b in CDCl3 at 300 MHz.
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Cyclization of 1,4-Phenylenediacrylic Acid with Thionyl Chloride and Subsequent Suzuki–Miyaura Reactions
Computations
cause the energetic difference between the two diaste-
reomers is low.
To get some rationalization of the observed selectivity
In analogy to the mechanistic studies of Krubsack
in favour of 3,6-dichlorobenzo[1,2-b;5,6-b’]dithio- et al. for trans-cinnamic acid, three possible paths for
phene A instead of 3,7-dichlorobenzo[1,2-b;4,5-b’]di- the transformation of ImA and ImA’ to A and A’ can
thiophene A’ (Scheme 1), the cyclization of 1 with be proposed, respectively (Scheme 4 and Scheme 5).
thionyl chloride was studied by density functional This includes a direct electrophilic substitution (path
theory calculations (DFT) at the B3LYP level of 1), or electrophilic substitution via intermediate
theory using a 6-31G* basis set. The DFT calculations ImBA which could be formed by 1,2-elimination of
show that isomer A is thermodynamically more stable hydrogen chloride (path 2), or rearrangement of inter-
than isomer A’ (by 5.5 kJmolÀ1, Table 3). However, mediate ImBA to episulfide ImA3 (path 3).
the thermodynamic stability is unlikely to be the
The energies of the open-chain intermediates ImA,
reason for the selectivity of the reaction because the ImBA, ImA3 were compared with the energies of
reaction is irreversible. Therefore, possible mechanis- their rotamers ImA’, ImBA’, ImA3’, respectively. In
tic intermediates were studied by DFT calculations. general, the rotamers, in which the aromatic carbon
The calculations were carried out for analogues of the atom C-6 is more close to the sulfur atom, are slightly
mechanistic intermediates suggested by Krubsack energetically favoured (by 0.8 kJmolÀ1–2.1 kJmolÀ1).
et al. for the reaction of trans-cinnamic acid with thio- In addition, position 6 of the arene moiety has
nyl chloride.[7a]
a higher electron density as compared to position 4.
À
We assumed that the two cyclization reactions of Based on these calculations, the sulfur atom of the S
diacrylate 1 occur sequentially and not at the same Cl moiety is expected to preferentially attack at
time. Thus, the first cyclization of 1 with thionyl chlo- carbon C-6 (Table 2). In addition, we computed the
ride afforded the planar intermediate 1A which reacts energies of the cationic cyclic intermediates ImA1,
with a second equivalent of thionyl chloride to give ImA1’, ImA2 and ImA2’ (Table 3). Interestingly, in-
the rotamers ImA and ImA’ (Scheme 3). In principle, termediate ImA1 is considerably more stable than
two diastereomers can be formed for each rotamer. ImA1’ (by 16.15 kJmolÀ1). Likewise, ImA2 is more
However, only one diastereomer was considered be- stable than ImA2’ (by 12.63 kJmolÀ1). The calcula-
Table 2. Energies of the optimized structures, the energy differences between the conformers, natural (NBO) charges and
distances (S-C) of ImA, ImA’, ImBA, ImBA’, ImA3, ImA3’ calculated at the B3LYP/6-31G* level for optimized structures.
Intermediate
ImA
ImA’
ImBA
ImBA’
ImA3
ImA3’
Energy [a.u.]
DE [kJmolÀ1]
Charge [a.u.]
À4167.66135
À0.785129
À0.21715
À0.20714
0.33445
4167.66105
À3706.85652
À1.28786
À0.19426
À0.19969
0.33339
À3706.85603
À3706.85263
À2.06798
À0.20603
À0.19660
0.31805
À3706.85185
C-6
C-4
S
C-6
C-4
À0.19980
À0.22368
0.33571
3.89695
3.31937
À0.19107
À0.20087
0.33321
4.33132
3.26222
À0.18995
À0.20846
0.32131
4.13341
3.22313
À
r
A
3.33400
3.87239
3.24921
4.35374
3.20363
4.17400
Scheme 3. Formation of ImA and ImA’.
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Zahid Hassan et al.
UPDATES
Scheme 4. Proposed mechanism for the formation of 3,8-dichlorobenzo[1,2-b;4,5-b’]dithiophene A’.
Scheme 5. Proposed mechanism for the formation of 3,8-dichlorobenzo[1,2-b;5,6-b’]dithiophene A.
Table 3. Energies of the optimized structures, the energy differences between the conformers of ImA1, ImA1’, ImA2, ImA2’,
A and A’ calculated at the B3LYP/6-31G* level for optimized structures.
Intermediate
ImA1
ImA1’
ImA2
ImA2’
A
A’
Energy [a.u].
À3707.16569
À16.15168
À3707.15954
À3246.38173
À12.6282
À3246.37692
À3246.10058
À5.5161
À3246.09848
DE [kJmolÀ1]
tions rationalize the fact that isomer A instead of A’ hols and provided evidence that the earlier reported
is formed.
structures,
3,7-dichlorobenzo[1,2-b;4,5-b’]dithio-
phenes, are wrong and that, in contrast, 3,6-dichloro-
benzo[1,2-b;5,6-b’]dithiophenes are formed. The first
report related to the reaction of 1 with SOCl2, pub-
lished by Ried et al. and using methanol as a trapping
Conclusions
We have reinvestigated the cyclization of 1,4-pheny- agent, provided a wrong structural assignment of die-
ACHTUNGTRENNUNG
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Cyclization of 1,4-Phenylenediacrylic Acid with Thionyl Chloride and Subsequent Suzuki–Miyaura Reactions
Zamola reported the use of anilines as the nucleo- pected to be important for the future design of relat-
phile and the formation of 3,7-dichlorobenzo[1,2- ed molecules and materials.
b;4,5-b’]dithiophene-diamides.[6] The authors refer to
the original report of 1980, but unfortunately did not
provide an unambiguous structural proof. In 2009, Experimental Section
Miura et al. referred to the work of 1995, again with-
out providing an unambigious structural proof, and General Procedure for the Synthesis of 2 and 3
thus misinterpreted the structure of diester 3 which
Thionyl chloride (6 mL, 80 mmol) was added portionwise to
they believed would be 3’.[4] As a consequence, the
a
mixture of 1,4-phenylene-diacrylic acid (1) (2.00 g,
structures of a variety of symmetrical arylated diben-
zothiophenes, prepared from 3 by Suzuki–Miyaura
cross-coupling reactions, were not correctly assigned.
Very recently, the synthesis of dialkylated 3,7-dichlor-
9.16 mmol) and a catalytic amount of pyridine (0.2 mL). The
reaction mixture was heated for 5 h at 1408C. Upon cooling,
the product solidified and the excess of thionyl chloride was
removed under reduced pressure to give a greenish solid.
This solid was dissolved in 50 mL of benzene and to the so-
lution 10 mL of methanol were added. The mixture was
heated at reflux for 2 h to give crude 2. The same procedure
was applied using n-butanol to give the crude butyl ester 3.
The residue was purified by flash column chromatography
(silica gel, heptanes/ethyl acetate=9:1). The spectroscopic
data of 3 are identical with those reported in the litera-
ture.[4]
2,8-Bis(methoxycarbonyl)-3,6-dichlorobenzo[1,2-b;5,6-
b’]dithiophene (2): Starting with 1 (2.00 g, 9.16 mmol),
SOCl2 (6 mL, 80 mmol), pyridine (0.2 mL), 2 was isolated as
a yellow crystalline solid; yield: 1.94 g (57%); mp 147–
Figure 4. Dialkylated 3,7-dichlorobenzo[1,2-b;4,5-b’]dithio-
phene 6 reported by Miura.
1
1498C. H NMR (300 MHz, CDCl3): d=3.93 (s, 6H, OCH3),
7.95 (s, 2H, Ar); 13C NMR (75.5 MHz, CDCl3): d=52.7
(OCH3), 121.3 (CH), 126.2, 128.5, 133.1, 137.0, 160.7 (C); IR
(KBr): v=3434, 2960, 2842, 1727 (s), 1650, 1643, 1633, 6113,
1509, 1434 (m), 1322, 1306, 1250, 1238, 1010, 1090, 1038 (s),
973, 940, 910, 817, 759, 736, 611 cmÀ1 (m); GC-MS (EI,
70 eV): m/z (%)=374 (M+, 2ꢄ35Cl, 100), 343 (89), 315 (43),
256 (29); HR-MS (EI, 70 eV): m/z=373.9274, calcd. for
C14H8Cl2O4S2 (2ꢄ35Cl) [M]+: 373.9276. The spectroscopic
data are identical with those previously reported.[5]
2,7-Bis(butoxycarbonyl)-3,6-dichlorobenzo[1,2-b;5,6-b’]di-
thiophene (3): Starting with 1 (2.00 g, 9.16 mmol), SOCl2
(6 mL, 80 mmol) and pyridine (0.2 mL), 3 was obtained as
a yellow crystalline solid; yield: 2.73 g (65%); mp 95–978C.
1H NMR (300 MHz, CDCl3): d=0.94 (t, J=7.3 Hz, 6H,
CH3), 1.39–1.46 (m, 4H, CH2), 1.68–1.77 (m, 4H, CH2), 4.34
(t, J=6.5 Hz, 4H, OCH2), 7.91 (s, 2H, Ar); 13C NMR
(75.5 MHz, CDCl3): d=13.7 (CH3), 19.2, 30.6 (CH2), 65.9
(OCH2), 121.2 (CH), 126.2, 128.2, 132.9, 137.1, 160.8 (C); IR
(KBr): v=3418, 2956, 2931, 2872 (s), 2736 (w) 1726, 1708,
1510, 1494 (s), 1476, 1406, 1380, 1301 (m), 1235, 1211, 1095,
1082, 1060, 1045, 1017, 964 (s), 932, 850, 804, 756 (m), 756,
734, 715 cmÀ1 (s); GC-MS (EI, 70 eV): m/z (%)=458 (M+,
2ꢄ35Cl, 100), 346 (78), 329 (41), 257 (33); HR-MS (EI,
70 eV): m/z=458.0171, calcd. for C20H20Cl2O4S2 (2ꢄ35Cl)
[M]+: 458.0280.
obenzo[1,2-b;4,5-b’]dithiophene 6 has been reported
by Miura (Figure 4).[10] In this case, only the forma-
tion of product 6 is possible because two aromatic po-
sitions are blocked by the alkyl groups.
The formation of benzo[b]thiophenes starting from
3-phenylpropanoic acid with thionyl chloride and
a small amount of pyridine was mechanistically dis-
cussed by Krubsack et al. in 1975.[7a] Based on his in-
vestigations we carried out quantum chemical calcula-
tions for several possible mechanistic intermediates.
The calculations support the experimental findings
and indicate that the formation of 3,6-dichloroben-
zo[1,2-b;5,6-b’]dithiophenes is considerably more fa-
vored than the formation of 3,7-dichlorobenzo[1,2-
b;4,5-b’]dithiophenes.
The misinterpretation of the structures of many
benzo[1,2-b;5,6-b’]dithiophenes by several authors is
presumably based on the fact that all of them relied
on previously published reports without providing an
independent unambiguous structural proof, such as an
X-ray crystal structure analysis, 2D NMR or prepara-
tion of non-symmetrical derivatives. Several of the
3,6-dichlorobenzo[1,2-b;5,6-b’]dithiophenes,
which
were earlier misinterpretated as 3,7-dichloroben-
zo[1,2-b;4,5-b’]dithiophenes, show extremely interest-
ing optical, thermal and electronic properties.[4] Theo-
retical explanations for these properties and compari-
sons with other molecules were provided by the au-
thors. These theories and models have to be reconsid-
ered in the light of the correct structures reported
General Procedure for Suzuki–Miyaura Reactions
A
Pd
1,4-dioxane solution (5 mL) of K3PO4 (2.0 equiv.),
(PPh3)4 (5 mol%) and arylboronic acids (1.0–1.2 equiv.)
U
was stirred at 110–1208C for 4 h. After cooling to 208C,
H2O was added. The organic and the aqueous layers were
separated and the latter was extracted with CH2Cl2 (15ꢄ
3 mL). The combined organic layers were dried (Na2SO4),
herein. In addition, the results reported herein are ex- filtered and the filtrate was concentrated under vacuum.
Adv. Synth. Catal. 2012, 354, 731 – 739
ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
737

Zahid Hassan et al.
UPDATES
The residue was purified by column chromatography (flash
silica gel, heptanes/dichloromethane=1:1).
2,7-Bis(butoxycarbonyl)-3-(5-fluoro-2-methoxyphenyl)-6-
chlorobenzo[1,2-b;5,6-b’]dithiophene (5a): Starting with 3
(200 mg, 0.43 mmol), 5-fluoro-2-methoxyphenylboronic acid
1.7 Hz, 1H), 7.34–7.39 (m, 2H), 7.71 (d, J=8.8 Hz, 1H);
13C NMR (75.5 MHz, CDCl3): d=13.7, 13.8 (CH3), 19.1,
19.2 (CH2), 30.5, 30.6 (CH2), 55.8 (OCH3), 65.5, 65.7
(OCH2), 110.9, 120.2, 120.5 (CH), 123.2, 125.2 (CH), 128.2
(C), 129.9 (CH), 130.1 (C), 130.9 (CH), 133.0, 134.1, 136.1,
140.2, 140.7, 157.1, 161.0, 162.2; IR (KBr): v=2957, 2930,
2872, 1716, 1698 (s), 1547, 1531, 1501, 1486, 1462, 1413,
1337, 1311 (m), 1274, 1228, 1175, 1123, 1114, 1071 (s) 906,
875, 727 cmÀ1 (s); GC-MS (EI, 70 eV): m/z (%)=530 (M+,
35Cl, 100), 457 (49), 443 (33), 381 (37), 325 (21); HR-MS
(EI, 70 eV): m/z=530.0981, calcd. for C27H27ClO5S2 (35Cl)
[M]+: 530.0982.
4a (1.2 equiv., 88 mg, 0.53 mmol), PdACHTNURTGNE(UNG PPh3)4 (25 mg,
5 mol%), K3PO4 (2.0 equiv., 185 mg, 0.85 mmol), and 1,4-di-
oxane (5 mL), 5a was isolated as a white solid; yield: 195 mg
(82%); mp 108–1108C. 1H NMR (300 MHz, CDCl3): d=
0.79 (t, J=7.3 Hz, 3H, CH3), 0.92 (t, J=7.3 Hz, 3H, CH3),
1.11–1.38 (m, 2H), 1.40–1.48 (m, 4H), 1.66–1.74 (m, 2H),
3.61 (s, 3H, OCH3), 4.10 (t, J=6.3 Hz, 2H), 4.31 (t, J=
6.3 Hz, 2H), 6.86–6.95 (m, 2H), 7.04–7.10 (td, J=8.1,
3.1 Hz, 1H), 7.36 (d, J=8.8 Hz, 1H), 7.74 (d, J=8.8 Hz,
1H); 19F NMR (282.4 MHz, CDCl3): d=À124.0; 13C NMR
(75.5 MHz, CDCl3): d=13.3, 13.7 (CH3), 19.0, 19.2 (CH2),
30.5, 30.6 (CH2), 56.1 (OCH3), 65.4, 65.7 (OCH2), 111.9 (d,
Calculations
Geometry optimizations have been carried out using the
11,12]
Gaussian 09
G
program package. We used the B3LYP
method including the Becke-3-parameter gradient corrected
exchange functional combined with the gradient-corrected
correlation LYP functional by Lee, Yang and Parr and the
6–31G* basis sets to calculate the structures of the com-
pounds. No imaginary frequencies were found indicating
that all geometries represent at least local minimum struc-
tures on the potential energy surface. Additionally we calcu-
lated the natural atomic charges by applying the NBO pro-
gram as implemented in Gaussian 09. All calculations have
been carried out on the HPC-Cluster in Rostock.
J
J
F,C =8.3 Hz, CH), 115.9 (d, JF,C =22.5 Hz, CH), 117.9 (d,
F,C =23.6 Hz, CH), 120.5, 122.5 (CH), 124.6 (d, JF,C =8.2 Hz,
CH), 128.2, 130.5, 133.0, 134.2, 136.3, 139.2, 139.8, 153.5 (C),
156.1 (d, JF,C =237.7 Hz, CF), 161.0, 162.0; IR (KBr): v=
2958, 2932, 1872, 2836, 1718, 1697 (s), 1493, 1463, 1414,
1334, 1311 (m), 1273, 1255, 1227, 1206, 1180, 1155, 1125,
1085, 1069, 1029 (s), 992, 940, 907, 877 (m), 807, 757,
729 cmÀ1 (s); GC-MS (EI, 70 eV): m/z (%)=548 (M+, 35Cl,
97), 475 (48), 461 (41), 447 (13) 405 (32), 391 (22), 381 (34),
359 (31), 325 (21); HR-MS (EI, 70 eV): m/z=548.8890,
calcd. for C27H26ClFO5S2 (35Cl) [M]+: 548.0889.
2,7-Bis(butoxycarbonyl)-3-(5-chloro-2-methoxyphenyl)-6-
chlorobenzo[1,2-b;5,6-b’]dithiophene (5b): Starting with 3
(200 mg, 0.43 mmol), 5-chloro-2-methoxyphenylboronic acid
Acknowledgements
4b (1.2 equiv., 96 mg, 0.51 mmol), PdACHTNURTGNE(UNG PPh3)4 (25 mg,
5 mol%), K3PO4 (2.0 equiv., 185 mg, 0.85 mmol), and 1,4-di-
oxane (5 mL), 5b was isolated as a light green solid; yield:
211 mg (87%); mp 77–998C. 1H NMR (300 MHz, CDCl3):
d=0.81 (t, J=7.3 Hz, 3H, CH3), 0.93 (t, J=7.3 Hz, 3H,
CH3), 1.14–1.21 (m, 2H), 1.38–1.42 (m, 4H), 1.44–1.48 (m,
2H), 3.60 (s, 3H, OCH3), 4.13 (t, J=6.5 Hz, 2H), 4.32 (t, J=
6.5 Hz, 2H), 6.88 (d, J=8.8 1H), 7.16 (d, J=2.6 Hz, 1H),
7.30–7.36 (m, 2H), 7.73 (d, J=8.8 Hz, 1H); 13C NMR
(75.5 MHz, CDCl3): d=13.7, 13.8 (CH3), 19.1, 19.2 (CH2),
30.5, 30.6 (CH2), 55.8 (OCH3), 65.5, 65.7 (OCH2), 112.1,
120.5, 122.5 (CH), 124.9, 125.3, 125.4, 128.2 (C), 129.6, 130.6
(CH), 130.7, 133.0, 134.2, 136.3, 138.9, 139.8, 155.9, 161.0,
162.0 (C); IR (KBr): v=2974, 2961, 2930, 2911, 2825, 1721,
1686 (s), 1675, 1663, 1582, 1561 (w), 1481, 1479, 1461, 1411,
1403, 1338, 1334 (m), 1289, 1261, 1251, 1182, 1134, 1127,
1025 (s), 802, 769, 684, 667 cmÀ1 (s); GC-MS (EI, 70 eV): m/
z (%)=564 (M+, 35Cl, 100), 491 (24), 477 (36), 463 (11), 421
(31), 381 (37) 325 (24); HR-MS (EI, 70 eV): m/z=564.0594,
calcd. for C27H26Cl2O5S2 (35Cl) [M]+: 564.0593.
We gratefully acknowledge the University of Rostock (schol-
arship of the interdisciplinary faculty of the University of Ro-
stock/Dept.LLM for S. R.), the State of Mecklenburg-Vor-
pommern and the Deutsche Forschungsgemeinschaft for fi-
nancial support.
References
[1] a) S.-J. Jeong, R. Higuchi, T. Miyamoto, M. Ono, M.
Kuwano, S. F. Mawatari, J. Nat. Prod. 2002, 65, 1344;
b) T. R. Kelly, Y. Fu, J. T. Sieglen, H. de Silva, Org.
Lett. 2000, 2, 2351.
[2] a) F. Garnier, Angew. Chem. 1989, 101, 529; Angew.
Chem. Int. Ed. Engl. 1989, 28, 513; b) F. Garnier, A.
Yassar, R. Hajlaoui, G. Horowitz, F. Deloffre, B.
Servet, S. Ries, P. Alnot, J. Am. Chem. Soc. 1993, 115,
8716; c) F. Garnier, R. Hajlaoui, A. Yassar, P. Srivasta-
va, Science 1994, 265, 1684; d) A. Dodabalapur, L.
Torsi, H. E. Katz, Science 1995, 268, 270; e) A. Doda-
balapur, L. J. Rothberg, A. W. P. Fung, H. E. Katz, Sci-
ence 1996, 272, 1462.
[3] For recent reviews: a) H. E. Katz, Z. Bao, S. L. Gilat,
Acc. Chem. Res. 2001, 34, 359; b) K. Takimiya, Y.
Kunugi, T. Otsubo, Chem. Lett. 2007, 36, 578; c) A. R.
Murphy, J. M. J. Frechet, Chem. Rev. 2007, 107, 1066;
d) B. S. Ong, Y. Wu, Y. Li, P. Liu, H. Pan, Chem. Eur. J.
2008, 14, 4766; e) S. Allard, M. Forster, B. Souharce, H.
Thiem, U. Schert, Angew. Chem. 2008, 120, 4138;
2,7-Bis(butoxycarbonyl)-3-(2-methoxyphenyl)-6-chloro-
benzo[1,2-b;5,6-b’]dithiophene (5c): Starting with 3 (200 mg,
0.43 mmol), 2-methoxyphenylboronic acid 4c (1.2 equiv.,
78 mg, 0.52 mmol), PdACTHNUTRGEN(UNG PPh3)4 (25 mg, 5 mol%), K3PO4
(2.0 equiv. 185 mg, 0.85 mmol), and 1,4-dioxane (5 mL), 5c
was isolated as a light green highly viscous oil; yield: 180 mg
1
(80%). H NMR (300 MHz, CDCl3): d=0.79 (t, J=7.3 Hz,
3H, CH3), 0.92 (t, J=7.3 Hz, 3H, CH3), 1.11–1.20 (m, 2H),
1.40–1.46 (m, 4H), 1.66–1.74 (m, 2H), 3.61 (s, 3H, OCH3),
4.10 (t, J=6.3 Hz, 2H), 4.31 (t, J=6.5 Hz, 2H), 6.95 (d, J=
8.3, 1H), 7.01 (td, J=7.4, 1.2 Hz, 1H), 7.17 (dd, J=7.4,
738
asc.wiley-vch.de
ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2012, 354, 731 – 739

Cyclization of 1,4-Phenylenediacrylic Acid with Thionyl Chloride and Subsequent Suzuki–Miyaura Reactions
Angew. Chem. Int. Ed. 2008, 47, 4070; f) J. Chen, A. Y.
Cao, Acc. Chem. Res. 2009, 42, 1709.
[10] J. Kumagai, K. Hirano, T. Satoh, S. Seki, M. Miura, J.
Phys. Chem. B: 2011, 115, 8446.
[4] M. Miyasaka, K. Hirano, T. Satoh, M. Miura, Adv.
[11] M. S. Simon, J. B. Rogers, W. Saenger, J. Z. Gougoutas,
Synth. Catal. 2009, 351, 2683.
J. Am. Chem. Soc. 1967, 89, 5838.
[5] W. Ried, G. Oremek, Liebigs Ann. Chem. 1980, 1172.
[6] M. Malesevic, G. Karminski-Zamola, M. Bajic, D. W.
Boykin, Heterocycles 1995, 41, 2691.
[7] a) T. Higa, A. J. Krubsack, J. Org. Chem. 1975, 40,
3037; the use of catalytic amounts of pyridine resulted
in a decrease of the reaction time: b) W. Ried, G.
Oremek, B. Ocakcioglu, Liebigs Ann. Chem. 1980,
1424.
[8] For reviews, see: a) N. Miyaura, A. Suzuki, Chem. Rev.
1995, 95, 2457; b) A. Suzuki, J. Organomet. Chem.
1999, 576, 147; c) N. Miyaura, in: Advances in Metal-
Organic Chemistry, (Ed.: L. S. Liebeskind), JAI,
London, 1998, Vol. 6, pp 187–243; d) A. Suzuki, in:
Metal-Catalyzed Cross-Coupling Reactions, (Eds.: F.
Diederich, P. J. Stang), Wiley-VCH, New York, 1998;
Chapter 2; e) S. P. Stanforth, Tetrahedron 1998, 54, 263.
[9] CCDC 852979 (2) and CCDC 852980 (3) contain all
crystallographic details of this publication. These data
can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif or can be ordered from the following
address: Cambridge Crystallographic Data Centre, 12
Union Road, Cambridge CB21EZ, U.K.; Fax: (+44)-
1223-336-033; or deposit@ccdc.cam.ac.uk.
[12] a) M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scu-
seria, M. A. Robb, J. R. Cheeseman, G. Scalmani, V.
Barone, B. Mennucci, G. A. Petersson, H. Nakatsuji,
M. Caricato, X. Li, H. P. Hratchian, A. F. Izmaylov, J.
Bloino, G. Zheng, J. L. Sonnenberg, M. Hada, M.
Ehara, K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida,
T. Nakajima, Y. Honda, O. Kitao, H. Nakai, T. Vreven,
J. A. Montgomery, Jr., J. E. Peralta, F. Ogliaro, M.
Bearpark, J. J. Heyd, E. Brothers, K. N. Kudin, V. N.
Staroverov, R. Kobayashi, J. Normand, K. Raghava-
chari, A. Rendell, J. C. Burant, S. S. Iyengar, J. Tomasi,
M. Cossi, N. Rega, N. J. Millam, M. Klene, J. E. Knox,
J. B. Cross, V. Bakken, C. Adamo, J. Jaramillo, R. Gom-
perts, R. E. Stratmann, O. Yazyev, A. J. Austin, R.
Cammi, C. Pomelli, J. W. Ochterski, R. L. Martin, K.
Morokuma, V. G. Zakrzewski, G. A. Voth, P. Salvador,
J. J. Dannenberg, S. Dapprich, A. D. Daniels, ꢅ. Farkas,
J. B. Foresman, J. V. Ortiz, J. Cioslowski, D. J. Fox,
Gaussian 09, Revision A.1, Gaussian, Inc., Wallingford
CT, 2009; b) A.-D. Becke, J. Chem. Phys. 1993, 98,
5648; c) C. Lee, W. Yang, R. G. Parr, Phys. Rev. B:
1988, 37, 785; d) E. D. Glendening, A. E. Reed, J. E.
Carpenter, F. Weinhold, NBO Version 3.1.
Adv. Synth. Catal. 2012, 354, 731 – 739
ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
739