Oxidative biaryl coupling of thiophenes and thiazoles with arylboronic acids through palladium catalysis: Otherwise difficult C4-selective C-H arylation enabled by boronic acids

Article abstract of DOI:10.1002/anie.201007060

(Chemical Equation Presented) It adds up to 4! Thiophenes and thiazoles can be arylated in the 4- rather than the expected 5-position in a new C-H functionalization reaction (see scheme; TEMPO: 2,2,6,6-tetramethylpiperidine-N- oxyl). The boronic acid proved to be the key to achieving the otherwise difficult C4 selectivity. The method was applied to a concise synthesis of a key pharmacological structure with potential for treatment of Alzheimers disease.

Full text of DOI:10.1002/anie.201007060

DOI: 10.1002/anie.201007060
À
Oxidative C H Arylation
Oxidative Biaryl Coupling of Thiophenes and Thiazoles with
Arylboronic Acids through Palladium Catalysis: Otherwise Difficult
À
C4-Selective C H Arylation Enabled by Boronic Acids**
Sylvia Kirchberg, Satoshi Tani, Kirika Ueda, Junichiro Yamaguchi, Armido Studer,* and
Kenichiro Itami*
Heteroarenes equipped with aryl groups (heterobiaryls) are
often found in biologically active compounds, organic materi-
À
als, and pharmaceuticals. In recent years, the direct C H
arylation of heteroarenes catalyzed by a transition-metal
complex[1,2] has emerged as a practical alternative to the well-
established Pd-catalyzed cross-coupling reactions. Although
tremendous efforts in the synthetic community including our
groups[3–5] have culminated in a wealth of useful and highly
active catalysts,[2] considerable room remains for further
investigations. In particular, the development of a unique
catalytic system that can preferentially activate and arylate an
À
otherwise less reactive C H bond on heteroarenes is critically
important from both scientific and practical points of view.[6]
À
Scheme 1. Reagent-controlled regiodivergency in the Pd-catalyzed C H
arylation of thiophenes and thiazoles.
À
For example, the Pd-catalyzed arylation of C H bonds of
thiophenes with haloarenes is known to occur preferentially
at the positions a to the sulfur atom (C2 and/or C5) following
the typical reactivity profile of the thiophene ring (Scheme 1,
top reaction).[6,7] Except for very rare cases,[4,8] selective and
preferential arylation at the positions b to the sulfur atom (C3
and/or C4) does not take place. This is also true for the
arylation of thiazoles, and a catalytic system that can
preferentially arylate the least reactive C4 positions has not
been forthcoming.[6,9] We herein report that the Pd-catalyzed
difference between these two seemingly related Pd-catalyzed
direct arylation processes.
À
In early experiments, we found that the C H arylation of
2-ethylthiophene (1a) with phenylboronic acid (2a) took
place in the presence of 2,2,6,6-tetramethylpiperidine-N-oxyl
radical[11] (TEMPO), Pd(OAc)2, and 2,2’-bipyridyl (bipy) in
1,2-dichloroethane (DCE) at 808C (Table 1, entry 1). Very
surprisingly, we identified 2-ethyl-4-phenylthiophene (3aa) to
be the sole coupling product under these conditions (69%
yield). The corresponding C5-phenylation product (4aa) was
not identified.
À
oxidative C H arylation of thiophenes and thiazoles with
arylboronic acids manifests the otherwise difficult C4 regio-
selectivity (Scheme 1, bottom reaction).[10] The present find-
ing is significant not only because the regioselective outcome
is complementary to that of the arylation using haloarenes,[2]
but also because it demonstrates the remarkable mechanistic
Based on these promising initial results we decided to
further optimize the reaction conditions (Table 1). After we
had found that the bipy is necessary for the reaction to occur
(entry 2), we screened various nitrogen-based bidentate
ligands such as bipy derivatives (L1–L3), phenanthrolines
(L4–L6), and TMEDA (L7) in the reaction of 1a with 2a
(entries 3–9). Although L4 and L6 were found to be equally
effective ligands in terms of yield and regioselectivity, we
selected bipy as the standard ligand for subsequent experi-
ments in view of its efficiency, cost, and simplicity. With a,a,a-
trifluorotoluene as a solvent, a slightly higher yield (76%) was
obtained (entry 10) and the reaction also proceeded at lower
temperatures, remarkably even at room temperature
(entry 11). Replacing TEMPO with other oxidants such as
p-benzoquinone, (diacetoxyiodo)benzene, and copper(II)
[*] S. Kirchberg, Prof. Dr. A. Studer
Organisch-Chemisches Institut, Westfꢀlische Wilhelms-Universitꢀt
Corrensstrasse 40, 48149 Mꢁnster (Germany)
Fax: (+49)281-83-36523
E-mail: studer@uni-muenster.de
S. Tani, K. Ueda, Dr. J. Yamaguchi, Prof. Dr. K. Itami
Department of Chemistry, Graduate School of Science
Nagoya University, Chikusa, Nagoya 464-8602 (Japan)
Fax: (+81)52-788-6098
E-mail: itami@chem.nagoya-u.ac.jp
Homepage: http://synth.chem.nagoya-u.ac.jp
[**] This work was financially supported by a Grant-in-Aid for Scientific
Research from MEXT and JSPS (Japan). We thank Dr. Yasutomo
Segawa for his help in the X-ray crystal-structure analysis. S.K.
thanks the International Research Training Group Mꢁnster/Nagoya
for support. K.U. thanks JSPS for a predoctoral fellowship.
chloride resulted in
a much lower reaction efficiency
(entries 12–14). Higher concentrations of 1a in a,a,a-
trifluorotoluene resulted in higher yields while the high
regioselectivity was maintained (entries 15 and 16). Reducing
the catalyst loading to 5 or 2 mol% Pd(OAc)2 led to a slight
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201007060.
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À
Table 1: Pd-catalyzed C H arylation of 2-ethylthiophene (1a) with
phenylboronic acid (2a).[a]
Entry
Ligand
Oxidant
Solvent
Yield [%][b]
3aa/4aa
1
2
3
4
5
6
7
8
bipy
–
L1
L2
L3
L4
L5
L6
L7
bipy
bipy
bipy
bipy
bipy
bipy
bipy
bipy
bipy
bipy
bipy
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
BQ
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
69
<1
55
51
41
65
25
72
7
76
40
16
2
>99:1
n.d.[e]
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
92:8
>99:1
>99:1
96:4
98:2
90:10
99:1
9
10
DCE
C6H5CF3
C6H5CF3
C6H5CF3
C6H5CF3
DCE
C6H5CF3
C6H5CF3
C6H5CF3
C6H5CF3
C6H5CF3
C6H5CF3
11[c]
12[d]
13[d]
14
PhI(OAc)2
CuCl2
1
15[f]
16[g]
17[g,h]
18[g,i]
19[j,k]
20[j,l]
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
84
88 (81)
76
63
81
34
99:1
99:1
99:1
99:1
96:4
[a] Conditions: 1a (1 equiv), 2a (4 equiv), Pd(OAc)2 (10 mol%), ligand
(10 mol%), oxidant (4 equiv), solvent (0.25m of 1a), 808C, 12 h. BQ=p-
benzoquinone. [b] Yields were determined by GC analysis. The number in
parenthesis for entry 16 is the yield of isolated product. [c] The reaction
was carried out at room temperature. [d] 0.63m of 1a. [e] Not
determined. [f] 0.83m of 1a. [g] 2.5m of 1a. [h] 5 mol% Pd(OAc)2/bipy
was used. [i] 2 mol% Pd(OAc)2/bipy was used; the reaction time was
24 h. [j] 1.25m of 1a. [k] 2 equiv of TEMPO was used. [l] 2 equiv of 2a was
used.
Scheme 2. Scope of thiophene and boronic acid coupling partners;
yield of the isolated product and regioselectivity (in brackets) are
given. [a] 1.25m of 1 in DCE. [b] 3,6-Diphenylated product was
obtained in 19% yield.
We next investigated whether also other heteroarenes
undergo highly regioselective arylation. Although furans and
indoles reacted with arylboronic acids under the optimized
conditions, these heteroarenes manifested low reactivity
(<20% yield) and the preferred reaction sites turned out to
be the C2 positions. However, we were pleased to find that the
C4-selective arylation of 2-phenylthiazole (5) occurred with
PhB(OH)2 (2a) using Pd(OAc)2/bipy/TEMPO to give the
coupling product 6a in 43% yield with good regioselectivity
(C4/C5 = 87:13). After optimization we found that regiose-
lective C4-arylation of 5 is best conducted in dimethylacet-
amide (1.25m) with phenanthroline (L4) as the ligand at
1008C for 48 h. Various arylboronic acids 2 were reacted with
5 under these conditions to afford the C4-arylated thiazoles 6
in good yields and regioselectivity (selected examples are
shown in Scheme 3).[13] To the best of our knowledge, these
decrease in the yield without affecting the regioselectivity
(entries 17 and 18). Lowering the amount of TEMPO to
2 equiv (entry 19) did not affect the yield, but decreasing the
amount of 2a led to lower yield and slightly lower regiose-
lectivity (entry 20).
Under optimized reaction conditions (see Scheme 2), the
scope with respect to thiophenes 1 and arylboronic acids 2 was
investigated. As shown in Scheme 2 the optimized reaction
conditions can be applied to a wide variety of substrates. A
range of thiophene derivatives including 2-substituted (1a–
1e), 3-substituted (1 f), and 2,3-disubstituted thiophenes (1g
and 1h) as well as thiophene-containing fused arenes (1i and
À
1j) underwent C H bond arylation with very high regiose-
lectivity (93 to > 99%) at the position b to the sulfur atoms
(C4 for 2-substituted thiophenes).[12]
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not responsible for the C4 regioselectivity but rather plays its
primary role as an oxidant in the PdII/Pd0 redox catalytic
cycle.[11]
To shed more light onto the mechanism, we next inves-
tigated the reactions of bipy-bound PhPdOAc complex 7,[14]
which could be produced within a catalytic cycle from
[(bipy)Pd(OAc)2] and 2a by transmetalation (Scheme 4).
Very surprisingly, we found that the “wrong” C5-arylated
isomer 4aa was preferentially formed when 7 (1 equiv) was
treated with 2-ethylthiophene (1a; 10 equiv) in DCE at 808C
(3aa/4aa = 22:78, 50% combined yield). At this point, we
became aware of the possibility that boronic acids might play
a secondary role in catalysis for switching the regiochemical
outcome (C5 to C4). In line with such an assumption, we
observed complete recovery of the C4 regioselectivity when a
“spectator” arylboronic acid such as o-CF3C6H4B(OH)2 (8)[15]
was added in the reaction of 7 with 1a (3aa/4aa = 71:29 (with
1 equiv of 8) and 92:8 (with 2 equiv of 8)). These results
clearly showed the essential role of excess boronic acids in
achieving the otherwise difficult C4 regioselectivity.
Scheme 3. C4-selective arylation of 2-phenylthiazole (5); yield of the
isolated product and regioselectivity (in brackets) are given.
are the first examples of C4-selective arylation of thiazoles
catalyzed by a transition-metal complex.[6,9]
To determine the mechanism of C4-selective arylation of
thiophenes and thiazoles, we carried out several control
experiments (Scheme 4). The focal point in this study was to
Based on these results, we propose a possible mechanism
for the Pd-catalyzed C4-selective oxidative arylation of
thiophenes and thiazoles with arylboronic acids (Scheme 5);
1) transmetalation of [(bipy)Pd(OAc)2] (A) with ArB(OH)2
followed by acetate abstraction from the resulting intermedi-
À
ate B with ArB(OH)2 generates a cationic Ar Pd species C
having a boronate [ArB(OH)2OAc]À as the counteranion;
2) nucleophilic attack of thiophene/thiazole to C (at the most
nucleophilic C5 position) leads to cationic intermediate D;
3) aryl-group migration from Pd to the C4 position provides
intermediate E; 4) deprotonation of E eventually produces
C4-arylated product 3 and the Pd0 species F; and 5) oxidation
of F by two equivalents of TEMPO and subsequent ligand
exchange with HOAc regenerates A to close the catalytic
cycle.
In this mechanistic proposal, the reversal in the regiose-
lectivity caused by the arylboronic acid could be explained as
follows: the acetate anion that is expelled from reaction of B
to give C is trapped by the excess arylboronic acid to generate
the boronate [ArB(OH)2OAc]À. Since this boronate is less
basic than the free acetate anion, the deprotonation of
intermediate D would become significantly slower, thereby
allowing the aryl group on Pd to irreversibly migrate onto the
C4 position of thiophene/thiazole to give E. In the absence of
excess ArB(OH)2, the deprotonation from D (where X =
OAc) would become the major pathway to afford diaryl-
palladium intermediate G, which should then provide the C5-
arylated product 4 by reductive elimination. The control
experiments shown in Scheme 4 are all in agreement with this
mechanistic scenario. It should be noted that cationic
intermediates similar to D have been often considered in
Scheme 4. Roles of TEMPO and arylboronic acid.
identify the critical elements (TEMPO or arylboronic acids)
responsible for the unique C4 regioselectivity. In the first set
of experiments, TEMPO was excluded from the reaction
mixture. When the mixture of 2-ethylthiophene (1a),
PhB(OH)2 (2a), Pd(OAc)2, and bipy in DCE was heated at
808C for 12 h (molar ratio, 1a/2a/Pd(OAc)2/bipy = 1:4:1:1),
3aa and 4aa were produced in 25% combined yield with high
C4 regioselectivity (3aa/4aa = 98:2). The low yield resulted
from the competing formation of biphenyl as a result of the
homocoupling of 2a. Assuming that a high 1a/Pd ratio might
be important in suppressing the formation of biphenyl in the
actual catalytic reactions, we increased the 1a/Pd ratio to 10:1.
Indeed, under these conditions, C4-selective arylation oc-
curred with higher yield (62% yield based on Pd). These
TEMPO-free experiments clearly indicate that TEMPO is
À
the Pd-catalyzed C H arylation of thiophenes and thiazoles
with haloarenes. As these reactions are typically conducted
under basic conditions, the direct deprotonation pathway
from D should be rapid and thereby manifest C5 regioselec-
tivity.
À
Finally, we applied our regioselective C H arylation
reaction to the synthesis of the pharmacologically important
structure 14 (Scheme 6).[16] Merck recently discovered that 4-
Angew. Chem. Int. Ed. 2011, 50, 2387 –2391
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Communications
of methyl acetate to furnish b-amino ester 11 after a
deprotection/protection sequence. This aminoester was
then treated with CbzNHC( S)NHMe[20] in the presence
=
of EDCI to afford thiophene-appended iminopyrimidi-
none 12. Applying our Pd(OAc)2/bipy/TEMPO catalysis
to the reaction of 12 and phenylboronic acid afforded the
desired 4-phenylthiophene derivative 13 in 60% yield
with virtually complete regioselectivity. It is important to
mention that this reaction tolerates the sensitive guani-
dine moiety. Finally, removal of the Cbz group in 13
afforded 14 in 82% yield. We believe that the late-stage
À
C H functionalization presented herein will find use in
the rapid generation of molecular libraries related to the
structure of 14.
In summary, we have developed a new method for
À
the C4-selective C H arylation of thiophenes and
thiazoles with arylboronic acids under Pd/TEMPO
catalysis. The reactions presented herein mostly occurred
in high yields and excellent regioselectivities. Mechanis-
tic studies revealed that the presence of excess boronic
acid is the key in achieving the otherwise difficult C4
regioselectivity. Furthermore, we applied our arylation
methodology to a concise synthesis of the key pharma-
cological structure 14, which has potential for treatment
of Alzheimerꢀs disease. The previously inaccessible
regioselectivity and the previously unrecognized regiocontrol
elements that have been uncovered in this study should
provide tremendous opportunities for these important pro-
cesses. Further work is in progress to bolster the proposed
mechanism of the C4-selective arylation of thiophenes/
thiazoles; we are examining the role of arylboronic acids by
supplemental experimentation and computational work.
À
Scheme 5. Proposed catalytic cycle for Pd/TEMPO-mediated C H arylation of
thiophenes and thiazoles with arylboronic acids.
arylated thiophenes such as SCH-785532 belong to a class of
small-molecule inhibitors of b-secretase (BACE), which are
potential drug candidates for treatment of Alzheimerꢀs
disease. Prominent structural features of these pharmacolog-
ically interesting compounds are an iminopyrimidinone
moiety and a 4-arylthiophene unit.
In our enantioselective synthesis of the core framework
14, commercially available 2-acetylthiophene (9) was con-
verted to the corresponding chiral sulfinyl imine 10[17] using
Ellmanꢀs Ti-mediated condensation reaction (Scheme 6).[18]
The imine 10 formed was reacted with the titanium enolate[19]
Received: November 10, 2010
Published online: January 31, 2011
À
Keywords: boronic acids · C H arylation · palladium ·
regioselectivity · thiazoles · thiophenes
.
À
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À
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Scheme 6. Application of the C4-selective thiophene arylation to the
synthesis of 14. Conditions: a) (R)-tBuSONH2, Ti(OEt)4, THF, 708C.
=
b) 1) H2C C(OLi)OMe, TiCl(OiPr)3, THF, À788C; 2) Me3SiCl, MeOH,
=
RT; 3) Me3SiCHN2, MeOH/CH2Cl2, RT. c) CbzNHC( S)NHMe, EDCI
(N-(3-dimethylaminopropyl)-N-ethylcarbodiimide), iPr2NEt, DMF, RT.
d) PhB(OH)2, Pd(OAc)2, bipy, TEMPO, C6H5CF3, 808C. e) Pd/C,
CF3CO2H.
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À
[7] For Pd-catalyzed C H arylation of thiophenes with haloarenes,
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À
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Angew. Chem. Int. Ed. 2011, 50, 2387 –2391
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