Mechanistic studies on the Pd-catalyzed direct C-H arylation of 2-substituted thiophene derivatives with arylpalladium bipyridyl complexes

Article abstract of DOI:10.1002/asia.201101011

Direct C-H phenylation of 2-ethylthiophene and 2-chlorothiophene with PhPdI(bipy) complex to form either the corresponding 4-phenyl or 5-phenylthiophene derivative is studied under stoichiometric conditions using various Lewis acids as additives. It is sh

Full text of DOI:10.1002/asia.201101011

DOI: 10.1002/asia.201101011
À
Mechanistic Studies on the Pd-catalyzed Direct C H Arylation of 2-
Substituted Thiophene Derivatives with Arylpalladium Bipyridyl Complexes
Marc Steinmetz,[a] Kirika Ueda,[c] Stefan Grimme,*[b] Junichiro Yamaguchi,[c]
Sylvia Kirchberg,[a] Kenichiro Itami,*[a] and Armido Studer*[a]
À
À
Abstract: Direct C H phenylation of
2-ethylthiophene and 2-chlorothio-
corresponding cationic Pd complex
(PhPdbipy+) and that the counteranion
determines the regioselectivity. High-
level DFT calculations reveal that C C
bond formation occurs via a carbopal-
ladation pathway and not via electro-
philic palladation. These calculations
give some indications regarding the re-
gioselectivity of the thiophene aryla-
tion.
phene with PhPdIACHTUNGTRENNUNG(bipy) complex to
form either the corresponding 4-phenyl
or 5-phenylthiophene derivative is
studied under stoichiometric conditions
using various Lewis acids as additives.
It is shown that reactions occur via the
À
Keywords: catalysis · C H activa-
tion · cross-coupling · DFT calcula-
tions · palladium
À
Introduction
ment of specific reagents that allow highly regioselective C
H bond arylation of heteroarenes. The most difficult task is,
À
À
The development of synthetic methods for direct C H ary-
lation of arenes and heteroarenes is a highly active and
modern research area. In most cases transition metals have
of course, the direct C H arylation of intrinsically less reac-
À
tive C H bonds in a heteroarene. Along this line, we have
initiated a program towards Pd-catalyzed selective C(4)-ary-
lation of 2-substituted thiophene derivatives.[4] C H Aryla-
À
À
been used as catalysts to conduct such C C bond forming
reactions.[1–5] Heteroarenes occur as structural key entities in
many drugs and drug candidates. Importantly, the construc-
tion of 2-substituted thiophenes at the most reactive C(5)-
position is well established.[6] The C(4)-position in such sys-
tems can be addressed by installing an ortho-directing group
at C(5).[7,8] However, the directing groups need to be instal-
led and removed (if possible) after successful arylation and
that route is therefore economically not ideal.
À
tion of such arylated heteroarenes via direct C H arylation
offers economic advantages over the more traditional cross-
coupling approaches where both coupling partners, the het-
eroarene and also the arene, have to be prefunctionalized.
However, in contrast to the classical cross-coupling process-
es, where the reactive positions in both partners are prede-
termined by the location of their functional groups, the
À
direct C H arylation of heteroarenes poses a regiochemistry
problem if the heteroarene contains more than one aromatic
À
C H bond. An important goal in this field is the develop-
[a] M. Steinmetz, Dr. S. Kirchberg, Prof. Dr. K. Itami,
Prof. Dr. A. Studer
Westfꢀlische Wilhelms-Universitꢀt Mꢁnster
Organisch-Chemisches Institut
Corrensstrasse 40, 48149 Mꢁnster (Germany)
Fax : (+49)281-833-6523
E-mail: studer@uni-muenster.de
[b] Prof. Dr. S. Grimme
Mulliken Center for Theoretical Chemistry
University of Bonn
E-mail: grimme@thch.uni-bonn.de
We have developed two protocols that allow for selective
functionalization of thiophene at the 4-position via direct
[c] K. Ueda, Dr. J. Yamaguchi
Department of Chemistry
Graduate School of Science
Nagoya University
[4]
À
C H arylation. For example, 2-chlorothiophene reacted
with iodobenzene under the action of PdCl2/P
A
G
Ag2CO3 catalysis to give 2-chloro-4-phenylthiophene with
Chikusa, Nagoya 464-8602 (Japan)
Fax : (+81)52-788-6098
virtually complete regioselectivity [Eq. (1)].[4b] We also
[9]
found that 2-ethylthiophene reacted with PhB(OH)2 under
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201101011.
oxidative PdACHTNUGRTENUNG(OAc)2/bipyridyl catalysis using 2,2,6,6-tetrame-
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thylpiperidine-N-oxyl radical (TEMPO)[10,11] as an oxidant
with excellent regioselectivity and high yield to the corre-
sponding C(4)-phenylated thiophene [Eq. (2)].[4c] Very re-
cently, Bach and co-workers also published on Pd-catalyzed
oxidative coupling of 3-substituted thiophenes with aryl bor-
onic acids at the C(4)-position.[12]
therefore assumed that the basicity of the counteranion gen-
À
erated during C H arylation must be responsible for the re-
giochemical outcome of the direct thiophene arylation.
To further support this assumption, we decided to study
the effect of a series of counteranions with different basicity
on the regioselectivity of the phenylation of 1. To this end,
we reacted 2-ethylthiophene (1, 3 equiv) with PhPdI(2,2’-
bipy) complex 6 (1 equiv)[14] in the presence of an additive
(2 equiv) in DCE at 808C for 14–15 hours (Table 1).
Herein we report mechanistic studies on the C(4)-selectiv-
À
ity of the direct C H arylation of thiophene with arylpalla-
dium bipyridyl complexes. Moreover, we will present high-
level density functional theory (DFT) calculations to sup-
port our experimental findings.
Table 1. Effect of the counteranion on the C(4)/C(5) selectivity.
Results and Discussion
Effect of the Counteranion in Cationic PhPd Bipyridyl
Complexes on the C(4)/C(5) Selectivity.
Additive
t [h]
Yield [%][a]
Ratio (2:3)[a]
Ph2 [%][b]
As a first test reaction, we chose the phenylation of 2-ethyl-
thiophene (1) to give 2-ethyl-4-phenylthiophene (C(4)-prod-
uct 2) and/or its regioisomeric congener, 2-ethyl-5-phenyl-
thiophene (C(5)-product 3).
AgPF6
AgPF6
Ag2CO3
AgOAc
AgOTf
14
14
14
14
14
15
15
15
74
78[c]
19
67
91
74
41
17
97:3
97:3
18:82
10:90
99:1
96:4
96:4
97:3
<1
<1
36
15
10
1
We prepared Pd complex 4[13] and studied the direct phe-
nylation of 2-ethylthiophene in 1,2-dichloroethane (DCE) at
808C for 12 hours, mimicking the conditions applied under
catalysis [see Equation (2)]. Surprisingly, we found that re-
action of 1 with Pd complex 4 (10 mol%) afforded the C(5)-
regioisomer as the major product (C(4)/C(5)=22:78,
Scheme 1). Note that the catalytic process delivered the
Cu
Sc(OTf)3
BF3/Et2O
ACHTNUGRTNE(NUGN BF4)2/6H2O
G
4
13
[a] The yield and the selectivity were determined by GC and 1H NMR
spectroscopy. [b] The yield was determined based on the amount of Pd
complex used. [c] 5 Equivalents of 2-ethylthiophene were used.
With AgPF6 as an additive, phenylation occurred in 74%
yield with high C(4)-selectivity (97:3). The yield slightly im-
proved to 78% upon increasing the amount of 1. Biphenyl,
which was observed in all other experiments, was not identi-
fied in these two reactions. With Ag2CO3 a lower yield was
observed. Importantly, the regioselectivity was reversed
(C(5)/C(4)=82:18). A similar C(5)-selectivity was obtained
with AgOAc as an additive (90:10). The use of AgOTf re-
sulted in an excellent C(4)-selectivity (99:1). Other non-
silver-containing Lewis acids such as Cu
AHCTUNGTRENNUNG
ACHTNUGTNERN(UGN BF4)2/6H2O, Sc-
Scheme 1. Effect of free arylboronic acid on the regioselectivity.
ty. In the absence of any additive, no reaction took place.
Based on these experiments we conclude that C(4)-selectivi-
ty is obtained for Lewis acids leading to non-basic anions
C(4)-phenylated product with high regioselectivity. The dif-
ference to the arylation shown in equation 2 was the ab-
sence of any free arylboronic acid. We have previously com-
municated that TEMPO used in the catalytic process did
not influence the regioselectivity.[4c] Repeating the same ex-
periment in the presence of 2-CF3C6H4B(OH)2 (10 mol%),
an arylboronic acid that does not undergo any transmetala-
tion, led to the inversed regioselectivity also noted in cataly-
sis (C(4)/C(5)=71:29). It was obvious that the free arylbor-
onic acid affected the regioselectivity. It is important to
mention that in the experiments run under catalytic condi-
tions, we always used a large excess of the arylboronic acid.
We previously suggested that the free arylboronic acid is
able to sequester the acetate anion deriving from 4 to gener-
ate a borate complex of the type ArylB(OH)2OAcÀ, which
is, as compared to the acetate anion, certainly less basis. We
À
À
(PF6 , OTfÀ, BF4 , and BF3IÀ), whereas C(5)-selectivity is
achieved for additives providing basic counteranions (car-
bonate and acetate).
To check whether electronic effects exerted by the sub-
strate influence the regioselectivity, we also studied the phe-
nylation of 2-chlorothiophene (7) with complex 6 under stoi-
chiometric conditions (Table 2). Reactions were conducted
in DCE at 808C and various additives were tested. In com-
parison to the more electron-rich 2-ethylthiophene, reac-
tions with 7 gave rise to low yields. The more electron-defi-
cient thiophene 7 also revealed the strong counteranion
effect on the regioselectivity observed for 1. Hence, with ad-
ditives leading to basic counteranions such as AgOAc and
Ag2CO3 high C(5)-selectivity was obtained. Additives lead-
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Direct C H Arylation of 2-Substituted Thiophene Derivatives
Table 2. Regioselective phenylation of 2-chlorothiophene with 6.
was in agreement with the experimental results discussed
above that showed the necessity for activation of the Pd
complex by an Ag-, Cu-, Sc-, or B-based Lewis acid. The
calculations showed that the cationic Pd complex generated
after acetate or iodide abstraction from PhPdXbipy (4, 6)
first forms a cationic p-complex with thiophene. The Pd
thereby interacts with C(2) and C(3) of thiophene
(Figure 1). The C(3)-reaction pathway then passes a transi-
tion state (TS, +3.7 kcalmolÀ1) in which the Pd is bound to
C(2) of thiophene via a s-complex to end up as new cationic
p-type complex (intermediate) with thiophene where Pd
binds to S and C(2) of thiophene. This intermediate is slight-
ly higher in energy (+1.9 kcalmolÀ1). As an important
Additive
t [h]
Yield [%][a]
Ratio (8:9)[a]
Ph2 [%][b]
AgPF6
15
16
16
15
16
15
15
17
14
21
13
19
6
>99:1
6:94
7:93
>99:1
>99:1
>99:1
>99:1
19
22
15
31
8
Ag2CO3
AgOAc
AgOTf
Cu
Sc(OTf)3
BF3/Et2O
ACHTUNGTRENNUNG(BF4)2/6H2O
G
8
20
5
À
result, we found that the subsequent C C bond-forming re-
[a] The yield and the selectivity were determined by GC. [b] The yield
was determined based on the amount of Pd complex used.
action is a carbopalladation (TS=+16.7 kcalmolÀ1) to give
the C(3)-phenylated thiophene where the Pd remains bound
to the C(2) atom of the thiophene as a s-complex (+4.3 kcal
molÀ1). The complex is further stabilized via interaction of
Pd with the phenyl substituent.
ing to non-basic counteranions provided regioisomer 8 as
the major compound with perfect regioselectivity.
To gain more insight into the mechanism, we then investi-
gated the Pd-catalyzed direct thiophene phenylation by
computational chemistry.
Electrophilic palladation,[2] which is often suggested to
occur in direct arene C H arylation reactions, can be ruled
out. Contrary to a previous supposition, a carbopalladation
À
À
pathway needs to be taken into consideration for the C H
Analysis of the Mechanism by DFT Calculations.
arylation of thiophenes.[18] The reaction pathway leading to
the C(2)-phenylated Pd intermediate also follows a similar
mechanism (see Figure 1). The precomplex that undergoes
the carbopalladation is in that case a Pd p-complex in which
Pd binds to C(3) and C(4) of the thiophene (+4.4 kcal
molÀ1). The transition state for the subsequent C(2)-carbo-
palladation is 2.0 kcalmolÀ1 higher in energy as compared to
the TS for the C(3)-carbopalladation.
DFT calculations were performed with two different disper-
sion-corrected density functionals, which yield qualitatively
the same picture. However, for the discussion only the re-
sults including corrections to (relative) free reaction ener-
gies at the B2PLYP-D3/QZVPP//TPSS-D3/TZVP[15–17] level
in kcalmolÀ1 were used (Figure 1). As a model reaction,
phenylation of thiophene with the cationic PhPdbipy com-
plex was investigated. To simplify the system, calculations
were conducted on unsubstituted thiophene.
À
To conclude the theoretical part, we can state that C C
bond formation occurs via a carbopalladation and that the
C(3)-arylated intermediate is formed as the major isomer.
Importantly, carbopalladation of thiophene with the cationic
PhPdbipy complex is endothermic (+4.3 kcalmolÀ1). There-
fore, reversibility must be considered to explain the follow-
up chemistry (aromatization). Interestingly, both carbopalla-
dation intermediates have the same energy.
Calculations clearly revealed that dissociation of the ace-
À
tate from the [PdACHTUNGTRENNUNG(bipy)(Ph)OAc] complex preceded the C
C bond-forming event. Hence, the reactive complex in these
phenylations must be the cationic PhPdbipy species. This
Since selectivity depended on the base/counteranion (see
above), it is obvious that the deprotonation/rearomatization
step must be included in the discussion on the regiochemical
outcome of our thiophene arylation reactions. Unfortunate-
ly, due to the complexity of the system, we were not able to
adequately analyze the deprotonation step using computa-
tional chemistry.
Considering the experimental and theoretical findings we
noted that in the presence of weak bases as counteranions
of the cationic Pd complex, the regioselectivity deduced
from the calculations for the initial carbopalladation is well
reflected by the isomer ratio for the two regioisomeric phe-
nylated product thiophenes obtained in the experiment.
Therefore, we assume that both carbopalladation isomers
must further react with similar rates to the corresponding
phenylated thiophenes (Scheme 2). The mechanism for the
rearomatization with weakly basic counteranions is currently
not fully understood. However, in the presence of a stronger
Figure 1. Calculated relative free energy (DG353) at the B2PLYP-D3/
QZVPP level for the reaction of thiophene with the cationic PhPdbipy
complex in kcalmolÀ1. The structures shown represent the corresponding
stationary points on each potential energy surface (PES).
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stronger bases as counteranions, such as acetate or carbon-
ate, deprotonation becomes the regioselectivity-determining
step and the isomer ratio set in the preequilibrium, assuming
the carbopalladation as a reversible step, is not important
for the regioselectivity.
Experimental Section
Computational Details
All calculations were carried out with the TURBOMOLE 6.3 program
package.[19] The geometry optimizations were performed with the TPSS
density functional[16] together with the Ahlrichsꢃ type triple-z basis set
def2-TZVP.[17] For the single-point calculations the double hybrid func-
tional B2PLYP[15] and the large quadruple-z basis set def2-QZVPP[17]
were employed. In the case of the TPSS calculations, the resolutions of
identity (RI-J) approximation[20] were applied. For the DFT part of
B2PLYP the RI-JK approximation[21] was adapted and for the perturba-
tive part the RI approximation[22] was used as well. All auxiliary basis
sets were taken from the TURBOMOLE basis set library.[23] In all calcu-
lations the recently developed DFT-D3[24] together with the Becke–John-
son (BJ) damping function[25] was added, as indicated by the appended
“-D3” to the functional name. Furthermore, to simulate solvent effects,
COSMO was used in all calculations with a dielectric constant of e=
10.125 (DCE). The harmonic vibrational frequencies were obtained as
numerical derivatives of analytically calculated gradients employing a
modified version of the program SNF11.[26] This was done at the TPSS
level only, and the derived DG353 values were also used for B2PLYP. In
the case of the product with the phenyl group in position 3, the first and
second transition states exhibit an imaginary frequency of 46 cmÀ1 and
343 cmÀ1, respectively, and are thus characterized as first-order transition
states. This also holds for the route leading to the product with a phenyl
group in position 2. Here, the corresponding imaginary frequencies for
the first and second maxima are 23.33 cmÀ1 and 352.32 cmÀ1, respectively.
Scheme 2. Postulated mechanism.
base, we assume that the minor C(5)-phenylated carbopalla-
dation complex gets selectively deprotonated in a fast pro-
cess, whereas the major C(4)-phenylated Pd complex is de-
protonated much slower. Assuming the initial carbopallada-
tion as a reversible step (see above) and the deprotonation
of the initially formed major C(4)-phenylated Pd complex as
a high-energy reaction pathway, the minor C(5)-isomer can
be selectively further transformed into the C(5)-phenylated
thiophene, as observed in the experiment. Thus, by switch-
ing from a weak to a stronger base as a counteranion of the
Pd complex, we currently assume a change in the regio-
chemistry-determining step from the carbopalladation in the
former to the aromatization step in the latter case.
Typical Procedure for the Stoichiometric Reactions
Pd complex 6 (47 mg, 0.1 mmol, 1.0 equiv), 2-ethylthiophene 1 (34 mL,
0.3 mmol, 3 equiv), and silver trifluoromethanesulfonate (52 mg,
0.2 mmol, 2.0 equiv) were dissolved in DCE (0.4 mL) and stirred in a
sealed tube at 808C for 14 h. The mixture was filtrated over silica gel
(eluent: EtOAc, 50 mL), and the volatiles were removed under reduced
pressure. Analysis by GC gave a yield of 91% by using undecane as an
internal standard, and the ratio of isomers was found to be 2/3=99:1.
Conclusions
Acknowledgements
À
We showed that the direct C H arylation of 2-ethylthio-
phene or 2-chlorothiophene with PhPdIbipy complex 6
under stoichiometric conditions either delivers the C(4)-phe-
nylated thiophene or its C(5)-congener depending on the
additive used. Reactions occur via the cationic PdPhbipy
complex, and the regioselectivity is determined by the coun-
teranion of the Pd complex. For counteranions that are
We thank the DFG and the JSPS for supporting our research within the
framework of the IRTG Mꢁnster/Nagoya.
À
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À
weak bases, such as OTfÀ and BF4 , the C(4)-phenylated
À
[2] Catalytic C H bond arylation of aromatics and heteroaromatics. For
product was formed with excellent regioselectivity. Howev-
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forded the C(5)-phenylated thiophene. DFT calculations re-
vealed that the cationic Pd complex 6 is the reactive species,
which reacts via a carbopalladation to give the C(4)-phenyl
Pd complex as the major intermediate. The experimentally
observed selectivities are well reflected by the regioselectivi-
ties calculated for the initial carbopalladation reaction
under “base-free” conditions. However, in the presence of
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Received: December 15, 2011
Published online: && &&, 0000
Chem. Asian J. 2012, 00, 0 – 0
ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
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These are not the final page numbers! ÞÞ

FULL PAPERS
À
C H Arylation
Marc Steinmetz, Kirika Ueda,
Stefan Grimme,* Junichiro Yamaguchi,
Sylvia Kirchberg, Kenichiro Itami,*
Armido Studer*
&&& — &&&
Mechanistic Studies on the Pd-cata-
lyzed Direct C H Arylation of 2-
Substituted Thiophene Derivatives
with Arylpalladium Bipyridyl
Complexes
The counteranion does the job! Reac-
tions of 2-substituted thiophenes with
cationic PhPdbipy complexes afforded
either the corresponding C(4) or C(5)-
phenylated thiophene derivatives
depending on the counteranion pres-
ent. DFT calculations revealed that
reactions occur via carbopalladation
and not via electrophilic palladation.
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www.chemasianj.org
ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 0000, 00, 0 – 0
ÝÝ These are not the final page numbers!