Regioselective oxidative coupling reactions of 3-substituted thiophenes with arylboronic acids

Article abstract of DOI:10.1021/ol201292v

Under optimized conditions, 3-substituted thiophenes (EWG = COOEt, PO(OEt)₂) undergo a facile and regioselective oxidative coupling reaction at carbon atom C4. The reactions were performed with various aryl boronic acids as nucleophiles in the presence of silver oxide (2.0 equiv), cesium trifluoroacetate (tfa) (1.0 equiv), benzoquinone (BQ) (0.5 equiv), and catalytic amounts of Pd(tfa)₂ (10 mol %) employing trifluoroacetic acid (TFA) as the solvent.

Full text of DOI:10.1021/ol201292v

ORGANIC
LETTERS
2011
Vol. 13, No. 14
3640–3643
Regioselective Oxidative Coupling
Reactions of 3-Substituted Thiophenes
with Arylboronic Acids
Ingo Schnapperelle, Stefan Breitenlechner,* and Thorsten Bach*
Lehrstuhl fu€r Organische Chemie I and Catalysis Research Center, Technische
€
Universitat Munchen, Lichtenbergstr. 4, 85747 Garching, Germany
€
thorsten.bach@ch.tum.de; stefan.breitenlechner@tum.de
Received May 13, 2011
ABSTRACT
Under optimized conditions, 3-substituted thiophenes (EWG = COOEt, PO(OEt)2) undergo a facile and regioselective oxidative coupling reaction at
carbon atom C4. The reactions were performed with various aryl boronic acids as nucleophiles in the presence of silver oxide (2.0 equiv), cesium
trifluoroacetate (tfa) (1.0 equiv), benzoquinone (BQ) (0.5 equiv), and catalytic amounts of Pd(tfa)2 (10 mol %) employing trifluoroacetic acid (TFA) as
the solvent.
There have been significant efforts in recent years to
realize Pd-catalyzed cross-coupling reactions with the
conventionally used nucleophiles (e.g., organoboron re-
agents, organostannanes, organosilanes) by CH-activa-
tion, i.e. by employing arenes instead of haloarenes as
reaction partners.1 In order to achieve this goal, oxidative
conditions are required and a plethora of methods have
been described for this purpose, which need to be fine-
tuned for the respective substrates. Mechanistically, oxi-
dative coupling is different from conventional cross-cou-
pling because the initial step is an electrophilic attack at the
arene by Pd(II) but not a nucleophilic attack by Pd(0). In
this respect, previously elaborated and established parameters
to predict the regioselectivity of cross-coupling reactions at
heterocyclic substrates2 are not valid in these reactions but
have tobe investigated.3 Based on our experience with five-
membered heterocycles4 we have started a research pro-
gram, which aims to elucidate and categorize important
regioselectivity features of oxidative coupling reactions.5
One substrate class, which we have started to look at more
closely, are thiophenes. In this respect, it was of particular
interest to us to achieve a substitution in the 3- or 4-position
as the 2- and 5-position of thiophenes can be readily
addressed by electrophilic aromatic substitution chemistry6
or by conventional cross-coupling reactions.7 A recently
published manuscript on the regioselectivity of oxidative
coupling reactions with boronic acids at 2-substituted
(1) Reviews: (a) Sun, C.-L.; Li, B.-J.; Shi, Z.-J. Chem. Commun. 2010,
46, 677–685. (b) Chen, X.; Engle, K.; Wang, D.-H.; Yu, J.-Q. Angew.
Chem., Int. Ed. 2009, 48, 5094–5115. (c) Ackermann, L.; Vicente, R.;
Kapdi, A. Angew. Chem., Int. Ed. 2009, 48, 9792–9826.
€
(4) Examples: (a) Bach, T.; Kruger, L. Tetrahedron Lett. 1998, 39,
1729–1732. (b) Bach, T.; Heuser, S. J. Org. Chem. 2002, 67, 5789–5795.
(c) Schroter, S.; Bach, T. Synlett 2005, 1957–1959. (d) Gross, S.; Heuser,
€
(2) Reviews: (a) Roger, J.; Gottumukkala, A. L.; Doucet, H. Chem-
CatChem 2010, 2, 20–40. (b) Wang, J.-R.; Manabe, K. Synthesis 2009,
1405–1427. (c) Fairlamb, I. J. S. Chem. Soc. Rev. 2007, 36, 1036–1045.
S.; Ammer, C.; Heckmann, G.; Bach, T. Synthesis 2011, 199–206.
(5) For recent publications addressing the issue of regioselectivity in
Pd(II)-mediated reactions at hetarenes, see: (a) Bellina, F.; Calandri, C.;
Cauteruccio, S.; Rossi, R. Tetrahedron 2007, 63, 1970–1980. (b) Stuart,
D. R.; Villemure, E.; Fagnou, K. J. Am. Chem. Soc. 2007, 129, 12072–
12073. (c) Zhao, J.; Huang, L.; Cheng, K.; Zhang, Y. Tetrahedron Lett.
2009, 50, 2758–2761. (d) Liang, Z.; Yao, B.; Zhang, Y. Org. Lett. 2010,
12, 3185–3187. (e) Lapointe, D.; Markiewicz, T.; Whipp, C. J.; Toderian,
A.; Fagnou, K. J. Org. Chem. 2011, 76, 749–759.
€
(d) Schroter, S.; Stock, C.; Bach, T. Tetrahedron 2005, 61, 2245–2267.
(3) For recent publications on Pd-catalyzed oxidative coupling reac-
tions at heterocycles, see: (a) Yang, S.-D.; Sun, C.-L.; Fang, Z.; Li, B.-J.;
Li, Y.-Z.; Shi, Z.-J. Angew. Chem., Int. Ed. 2008, 47, 1473–1476. (b)
Zhao, J.; Zhang, Y.; Cheng, K. J. Org. Chem. 2008, 73, 7428–7431. (c)
€
Kirchberg, S.; Frohlich, R.; Studer, A. Angew. Chem., Int. Ed. 2009, 48,
4235–4238. (d) Liu, B.; Qin, X.; Li, K.; Li, X.; Guo, Q.; Lan, J.; You, J.
Chem.;Eur. J. 2010, 16, 11836–11839. (e) Ranjit, S.; Liu, X. Chem.;
Eur. J. 2011, 17, 1105–1108.
(6) Review: Schatz, J. In Science of Synthesis, Vol. 9; Maas, G., Ed.;
Thieme: Stuttgart, 2001; pp 287ꢀ392.
r
10.1021/ol201292v
Published on Web 06/21/2011
2011 American Chemical Society

thiophenes (vide infra)8 prompts us to disclose our results
on the oxidative coupling of 3-substituted thiophenes.
For our own study, the 3-substituted thiophene 1 was
chosen as a test substrate. In preliminary oxidative cou-
pling experiments it showed superior behavior as com-
pared to 3-methylthiophene. In addition, the activated
methylene group allows for further reactions (vide infra).
A screening for optimal reaction conditions was per-
formed. Some of the results are listed in Table 1. The
choice of benzoquinone (BQ) as a ligand and trifluoro-
acetic acid (TFA) as a solvent was inspired by previous
experiments.3a,12 Among possible palladium sources, pal-
ladium trifluoroacetate (Pd(tfa)2) was the most efficient
when silver(I) oxide was used as the oxidant (entries 1ꢀ5).
It was subsequently found that cesium is slightly better
than potassium in promoting the reaction. With the same
oxidant (Ag2O), the reaction was almost complete after
26 h in the presence of Cs2CO3 (entry 9) while it required
48 h to go to completion with K2CO3 (entry 4). Regard-
ing the oxidant, silver(I) fluoride (entry 8) was approxi-
mately as effective as silver(I) oxide whereas other silver
sources were inferior (entries 6, 7). In the absence of a
silver oxidant, the reaction proceeded very slowly and
nonselectively (entry 10). Without a palladium catalyst
only traces of product could be obtained (entry 11).
Although the benefit of Cs2CO3 was marginal when using
silver(I) oxide, for nonbasic silver sources (e.g., AgOTf or
AgBF4) yield and regioselectivity dropped dramatically
without its addition.
It was found that the slightly more expensive cesium
trifluoroacetate Cs(tfa) was for preparative purposes bet-
ter suited as a cesium source than Cs2CO3, because there is
no CO2 evolution when dissolving it in TFA. With this
minor modification the optimized conditions of entry 9
wereapplied toa numberofarylboronicacids, which could
be successfully coupled at the C4 position of thiophene 1
(Scheme 1). In general, the reaction proceeded well for a
number of phenylboronic acids, which exhibit weak or no
donor or acceptor substituents in the para-position
(products 2a, 2d, 2e, 2h). It appears as if the acceptor-
substituted boronic acids fail to deliver the aryl residue to
the palladium while the donor-substituted boronic acids
are sensitive toward hydrolysis. Typically, anisylboronic
acid underwent hydro-deborylation while nitro-substi-
tuted and trifluoromethyl-substituted phenylboronic acids
reacted sluggishly (<30% conversion after 24 h). Hetar-
ylboronic acids have not yet been tested. Steric hindrance
was not an issue with ortho-substituted boronic acids
(product 2b) and 1-naphthylboronic acid (product 2f)
both reacting well. Mesitylboronic acid, however, failed
to produce any coupling products.
Table 1. Screening Different Conditions for Oxidative Cross-
Couplinga
Ag(I)
time convb yieldb
entry
Pd catalyst
PdCl2
source
(h)
(%)
(%)
rrc
1
Ag2O
48
48
48
48
48
26
26
26
26
26
26
22
65
69
99
96
71
74
91
90
27
<5
8
40
40
81
72
38
45
66
76
16
<5
n.d.
2
PdCl2(PPh3)2 Ag2O
97/3
99/1
95/5
93/7
84/16
88/12
92/8
93/7
59/41
n.d.
3
Pd(OAc)2
Pd(tfa)2
Pd2(dba)3
Pd(tfa)2
Pd(tfa)2
Pd(tfa)2
Pd(tfa)2
Pd(tfa)2
;
Ag2O
Ag2O
Ag2O
AgOTf
AgBF4
AgF
4
5
6d
7d
8d
9d
10d
11d
Ag2O
;
Ag2O
a Reaction conditions: Pd catalyst (0.1 equiv), Ag(I) source (3.0 equiv),
phenylboronic acid (2.0 equiv), BQ (0.5 equiv), K2CO3 (1.0 equiv), TFA
(c = 0.2 M). b Conversion and yields were determined by GC using
n-undecane as an internal standard. c The ratio of regioisomers was
determined by GC. d Cs2CO3 (1.0 equiv) was used instead of K2CO3.
Previous studies regarding a CꢀC bond formation at
thiophenes with aryl boronic acids were conducted by
Demir et al., Shi et al., and Studer et al. The first group
employed Mn(OAc)3 as a promoter to achieve a selective
C2-arylation by a radical type pathway.9 The Shi group
employed oxidative coupling conditions (O2, Pd(OAc)2,
Cu(OAc)2 in TFA) and observed a regioselective reaction
atC2 of benzothiophene.3a TheStudergroup madeuseofa
strong 2-pyridine directing group at C2 to facilitate an
arylation at C3 under Rh10 or Pd catalysis11 employing
2,2,6,6,tetramethylpiperidine-N-oxyl (TEMPO) as the oxi-
dant. In the most recent contribution by Studer, Itami
et al.8 2-substituted thiophenes were shown to react at
C4 when using TEMPO as the oxidant and a catalyst
combination of Pd(OAc)2 and 2,20-bipyridine (bipy).
Benzothiophene reacted at C3 under these conditions
and 3-methoxythiophene at C4.
The regioisomeric ratio (rr) (C4-substituted product vs
regioisomers at C2/C5) was determined by 1H NMR
integration of the respective methylene protons of the
acetate. Given the high reactivity of thiophenes toward
electrophilic substitution at carbon atoms C2/C5, the
regioselectivity outcome is surprising. In line with the
earlier findings of Studer, Itami et al.8 it might be
(7) For regioselective Suzuki cross-coupling reactions on thiophenes,
see: (a) Pereira, R.; Iglesias, B.; de Lera, A. R. Tetrahedron 2001, 57,
ꢀ
ꢀ
7871–7881. (b) ^ang, T. T.; ^ang, T. T.; Rasool, N.; Villinger, A.; Reinke,
H.; Fischer, C.; Langer, P. Adv. Synth. Catal. 2009, 351, 1595–1609.
(8) Kirchberg, S.; Tani, S.; Ueda, K.; Yamaguchi, J.; Studer, A.;
Itami, K. Angew. Chem., Int. Ed. 2011, 50, 2387–2391.
€
(9) (a) Demir, A. S.; Reis, O.; Emrullahoglu, M. J. Org. Chem. 2003,
68, 578–580. (b) Demir, A. S.; Findik, H.; Saygili, N.; Subasi, N. T.
Tetrahedron 2010, 66, 1308–1312.
(10) Vogler, T.; Studer, A. Org. Lett. 2008, 10, 129–131.
(11) Kirchberg, S.; Vogler, T.; Studer, A. Synlett 2008, 2841–2845.
(12) Chen, X.; Goodhue, C. E.; Yu, J.-Q. J. Am. Chem. Soc. 2006,
128, 12634–12635.
Org. Lett., Vol. 13, No. 14, 2011
3641

Scheme 1. 4-Substituted Thiophenes 2 Obtained by Reaction of
Different Boronic Acids with Ethyl 2-(Thiophen-3-yl)acetate
(1)a
Scheme 2. Regioselectivity in the Oxidative Coupling Reaction
of Substrate 3 with Phenylboronic Acid
went to completion under standard conditions in 24 h
delivering the respective products 8 in good yields and with
high regioselectivity (Scheme 3).
Scheme 3. Reaction of Boronic Acids with Diethyl (Thiophen-3-
ylmethyl)phosphonate (7) Providing 4-Substituted Thiophenes 8
a The regioisomeric ratio (rr) is given in brackets.
conceivable that the primary reaction of Pd(II) occurs at
C5 but thearylgroupisdelivered intra-orintermolecularly
to the C4 carbon atom. This hypothesis is supported by the
reaction of 2,4-disubstituted thiophene 3, which upon
reaction with phenylboronic acid gave three products
4ꢀ6 the relative ratio of which varied depending on the
equivalents of boronic acid being used (Scheme 2). The
reactions were run for 24 h (ca. 70% conversion), and
product analysis was performed by 1H NMR integration.
The results were further validated by GC/MS analysis.
When 1 equiv of phenylboronic acid was used, the major
product was C5-substituted product 4. The C3-substituted
product 5 was formed in minor amounts presumably due
to the fact that electrophilic palladium attack at the thiophene
occurs at C5 but not at C2. With 2 equiv of phenylboronic
acid, double substitution (product 6) prevailed but the
major monosubstituted product was still product 4.
a Reaction was carried out for 36 h instead of 24 h.
Insearchfor other 3-substituted thiophenes, whichcarry
anelectron-withdrawing group atthe methylene bridge, we
turned to the readily available13 phosphonate 7. Gratify-
ingly, this compound showed to be even better suited to
oxidative coupling reactions than acetate 1. Reactions
The phosponates are more stable under the oxidative
conditions than acetates 1 and 2. In cases, in which the
reaction was not complete after 24 h (e.g., product 8f),
further stirring led to complete conversion resulting in
higher yields. The reaction with para-chloroboronic acid
worked sluggishly with substrate 1 but gave a good yield in
the reaction with phosphonate 2.
(13) Lukovskaya, E. V.; Bobyleva, A. A.; Fedorova, O. A.; Fedorov,
Yu. V.; Anisimov, A. V.; Didane, Y.; Brisset, H.; Fages, F. Russ. Chem.
Bull. 2009, 58, 1509–1515.
3642
Org. Lett., Vol. 13, No. 14, 2011

It appears too early to draw further mechanistic conclu-
sions, and further studies are warranted. Given the low reac-
tivity of other 3-substituted thiophenes, it appears as if there is
an activating/directing effect by the electron-withdrawing
groups COOEt and PO(OEt)2. As mentioned previously,
3-methylthiophene reacted sluggishly under the conditions
applied to substrates 1 and 7 whereas 3-ethynylthiopene did
not undergo oxidative coupling reactions at all.
performed with benzaldehyde (Scheme 4) as the electro-
phile employing sodium hydride as the base and 1,2-
dimethoxyethane (DME) as the solvent. The reaction
proceeded smoothly delivering the respective olefins 9 in
good yields and with perfect diastereoselectivity. Related
products synthesized from aromatic aldehydes are known
to undergo photocyclization to obtain naphtho[1,2-b]
thiophenes.14
In summary, we could show that acetate 1 and phos-
phonate 7 are suitable substrates for regioselective oxi-
dative cross-coupling reactions with several boronic
acids. Yields are moderate to high, and the regioselec-
tivity in favor of an attack at C-4 is close to perfect in
most cases. The effect of the two groups COOEt and
PO(OEt)2 on the regioselectivity of oxidative coupling
reactions needs to be further studied. In addition, the
question, at what stage does the aryl transfer from the
boronic acid to palladium occur, will be addressed in
further experiments.
Scheme 4. Olefination Reaction Performed with Benzaldehyde
and Phosphonates 8
Acknowledgment. I.S. gratefully acknowledges support
by the TUM Graduate School.
In order to demonstrate that the intermediate phospho-
nates 8 can be employed for further reactions at the
activated methylene group a short study was undertaken
regarding a possible olefination reaction.14 Reactions were
Supporting Information Available. Representative ex-
perimental procedures and spectral data for all new
compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
(14) Tedjamulia, M. L.; Stuart, J. G.; Tominaga, Y.; Castle, R. N.;
Lee, M. L. J. Heterocycl. Chem. 1984, 21, 1215–1219.
Org. Lett., Vol. 13, No. 14, 2011
3643