Sterics versus electronics: Regioselective cross-coupling of polybrominated thiophenes

Article abstract of DOI:10.1002/ejoc.200701148

Methods for the regioselective cross-coupling of 2,3,5-tribromothiophene have been developed in which selective aryl-aryl coupling occurs at the 5-position with yields up to 63%. The difference in reactivity of the α- and β-positions then allows sequential regioselective couplings first at the 2-position, followed by the 3-position. Such regioselective cross-coupling allows unprecedented control in the generation of trifunctionalized thiophenes. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200701148

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200701148
Sterics versus Electronics: Regioselective Cross-Coupling of Polybrominated
Thiophenes
Chad M. Amb[a] and Seth C. Rasmussen*[a]
Keywords: Cross-coupling / Regioselectivity / Heterocycles / Homogeneous catalysis
Methods for the regioselective cross-coupling of 2,3,5-tribro-
mothiophene have been developed in which selective aryl–
aryl coupling occurs at the 5-position with yields up to 63%.
The difference in reactivity of the α- and β-positions then al-
lows sequential regioselective couplings first at the 2-posi-
tion, followed by the 3-position. Such regioselective cross-
coupling allows unprecedented control in the generation of
trifunctionalized thiophenes.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
multifunctional thiophenes can be seen in the elegant work
of Mori and co-workers,[14] who demonstrate coupling at
the α-hydrogen atom of brominated thiophenes with aryl
iodides, thus allowing cross-coupling while retaining the
bromo functionalities.
Introduction
Functionalized thiophenes have found extensive use as
precursors for materials,[1] natural products,[2] and pharma-
ceuticals.[3] Such functionalized thiophenes are commonly
generated from various halothiophenes, which can provide
access to the desired product through the application of
catalytic cross-coupling chemistry. However, as the desired
molecular architecture becomes more complex, it is impor-
tant to be able to control site-specific reactions, particu-
larily in use of polyhalogenated precursors that contain
multiple reactive centers. The most common approach to
regioselective coupling in polyhalogenated thiophenes is to
take advantage of the electronic differences between the α-
and β-positions of the thiophene ring.[4] As the α-positions
are significantly more reactive than the corresponding β-
positions (ca. 95:5),[5] selective cross-coupling at the 2-posi-
tion of 2,3- and 2,4-dihalothiophenes are common.[4,6] Ex-
amples of site selectivity in the cross-coupling of asymmet-
ric 3,4- or 2,5-dihalothiophenes, however, are very rare,[7]
and a general approach for achieving selectivity has not
been established.
In contrast, selective debrominations of asymmetric 2,5-
dibromothiophenes have been known since the 1930s,[8–13]
and the lack of selective cross-couplings has led to such
debrominations as the most commonly used approach in
syntheses of multifunctional thiophenes. As a result, most
syntheses are accomplished through combinations of bro-
mination, debromination, and cross-coupling, resulting in a
large number of synthetic steps. A recent approach to re-
duce the number of synthetic steps in the generation of
In reviewing known selective thiophene debrominations,
it can be seen that these are commonly accomplished by
metal/halogen exchange[13] followed by hydrolysis and that
the resulting selectivity is due to a combination of elec-
tronics and sterics. Metal/halogen exchange is thought to
follow an SN2 mechanism,[15] and thus the observed selec-
tivity is most often due to inductive effects of the functional
groups. For example, in 3-alkyl-2,5-dibromothiophenes[8–13]
(Table 1, Entries 1–7), the alkyl group enhances the electro-
positive nature of the 5-bromo group, favoring debromina-
tion at this position. Thus, selectivity is mainly due to elec-
tronics, and sterics only play a role when the alkyl group
becomes very bulky (i.e. tert-butyl, Entries 3, 7). In such
cases, the 2-position is favored as a result of steric re-
lease,[11,15c] where removal of strain between the tert-butyl
group and bromine atom overcomes the electronic prefer-
ence and steric shielding of the 2-position. If the size of the
incoming nucleophile is also increased (Entry 4), the steric
hindrance becomes too large for attack at the 2-position,
and selectivity reverts to the 5-position. The use of electro-
negative elements activates adjacent halogen atoms,[15] and
thus selectivity for both the 3-alkoxy and 3-bromo examples
(Entries 8–11) favors the 2-position. As before, sterics can
overcome electronics by increasing the nucleophile size, re-
sulting in a decrease or reversal in selectivity (Entries 9, 10).
Due to the success of utilizing sterics in selective debro-
minations, it should be reasonable to apply the same ap-
proach to regioselective cross-couplings of polybrominated
thiophenes. Sterics have a strong influence on the outcome
of heterocyclic cross-coupling reactions as both oxidative
addition and transmetalation steps require space around
the metal center.[4] For electronically comparable sites, pref-
[a] Department of Chemistry and Molecular Biology, North Da-
kota State University,
Fargo, ND 58105, USA
Fax: +1-701-231-8831
E-mail: seth.rasmussen@ndsu.edu
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Eur. J. Org. Chem. 2008, 801–804
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
801

C. M. Amb, S. C. Rasmussen
SHORT COMMUNICATION
Table 1. Selective debromination of 2,5-dibromothiophenes.[a]
was only ca. 2:1. In addition, a large amount of 2,2Ј-bithio-
phene (4), as well as the homocoupled 5, were also pro-
duced. This suggested that the reductive elimination of
product 2 was slow, and metathesis was able to occur be-
tween the 2-thienylzinc chloride and the (dibromothio-
phene)palladium complex.
Entry
R
RЈM
A
B
Ref.
[11]
[11]
[11]
[11]
[12]
[11]
[11]
[13]
[13]
[8]
1
2
3
4
5
6
7
8
9
ethyl
isopropyl
tert-butyl
tert-butyl
hexyl
isopropyl
tert-butyl
alkoxy[b]
alkoxy[b]
Br
BuLi
BuLi
BuLi
23
28
57
13
15
23
64
70
55
18
75
6
77
72
43
87
85
77
36
30
45
82
25
94
In the process of the study, a deeper literature search re-
vealed the reported cross-coupling of 1 in the presence of
Ni(PPh3)2Cl2 to give 85% of 2,[16] although no product
characterization was given. This did not seem consistent
with our initial results, as reductive elimination from the
more electron-rich Ni complexes are generally slower than
from the Pd analogues.[17] Indeed, it was found that the
claims could not be reproduced in our hands, with the Ni-
catalyzed coupling giving only 3% of 2 under the reported
conditions (Entry 2). As with the Pd results above, a large
amount of 4 was isolated, consistent with slow reductive
elimination. The isolation of an appreciable amount of 6
also indicated metathesis under these conditions, and
showed the Ni-based oxidative addition favored the 2- over
the 5-position of 1.
Increasing the scope of catalysts, [bis(phosphane)]palla-
dium complexes were then investigated. While Pd(dppe)Cl2
did not provide improvements, the application of Pd(dppf)-
Cl2 successfully resulted in both increased yields and re-
duced byproducts. This was presumably due to the in-
creased rate of reductive elimination as a result of the in-
creased bite angle of the dppf ligand.[18] Optimization of
these reaction conditions (Entry 9) gave a 63% yield of the
desired product 2, with the thienylzinc reagent giving
slightly higher yields than the thienyl Grignard reagent.
BuLi/TMEDA
EtMgCl
EtMgBr
EtMgBr
MeMgBr
tBuMgBr
MeMgBr
BuLi
10
11
12
[9]
Br
Br
[10]
Pd(PPh3)4/NaBH4
[a] Values given are ratios of selectivity. [b] alkoxy = O(C2H4O)2-
CH3.
erence is usually found for the more easily accessible posi-
tion, and if steric factors are large enough it may be pos-
sible to overcome reaction at an electronically more reactive
site. Hor and co-workers reported an excellent example of
this with the highly selective debromination of 2,3,5-tribro-
mothiophene (1) by oxidative addition of Pd(PPh3)4 fol-
–
lowed by BH4 reduction (Table 1, Entry 12).[10] Extending
this methodology to aryl–aryl cross-couplings, we then be-
gan investigation of the cross-coupling of 1.
Results and Discussion
The cross-coupling of 1 with various 2-metallated thio- Interestingly, the reactivity of the zinc reagent seemed to be
phenes (Table 2), was investigated using Pd(PPh3)4 as the modulated by its coordination environment, as these rea-
initial catalyst. While the desired 4,5-dibromo-2,2Ј-bithio- gents were more reactive in weakly coordinating diethyl
phene (2) was produced exclusively over the isomeric 3,5- ether than in the more strongly coordinating THF, and the
dibromo-2,2Ј-bithiophene, the yield was fairly low, and the addition of TMEDA further inhibited the zinc reagent’s re-
selectivity between 2 and the corresponding terthiophene 3 activity. Negishi and co-workers[19] also noted substantial
Table 2. Coupling of 1 with 2-metallated thiophenes.[a]
Entry
Catalyst
Equiv. of th-MX
MX[b]
Solvent
1
2
3
4
5
6
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Pd(PPh3)4
Ni(PPh3)2Cl2
Pd(dppe)Cl2
Pd(dppf)Cl2
Pd(dppf)Cl2
Pd(dppf)Cl2
Pd(dppf)Cl2
Pd(dppf)Cl2
Pd(dppf)Cl2
Pd(dppf)Cl2
Pd(dppf)Cl2
Pd(dppf)Cl2
Pd(dppf)Cl2
Pd(dppf)Cl2
1.5
2.0
1.5
1.5
1.5
1.5
1.5
1.2
1.2
1.2
1.2
1.5
1.2
1.2
ZnCl
MgBr
ZnCl
ZnCl
ZnCl
ZnCl
ZnCl
ZnCl
ZnCl
THF
THF
THF
THF
Et2O
44
55
51
6
tr
7
11
20
14
16
81
18
34
12
27
3
16
3
tr
27
31
21
21
7
15
6
48
47
86
tr
tr
tr
17
11
56
54
62
63
53
63
60
17
53
56
54
Ͻ10
Ͻ10
Ͻ10
Ͻ10
Ͻ10
Ͻ10
Ͻ10
Ͻ10
Ͻ10
Ͻ10
Ͻ10
Et2O/THF (1:1)
Et2O/THF (1:3)
THF
Et2O
THF/hexane (2:1)
THF
ZnCl
ZnCl(TMEDA)
MgBr
MgBr
MgBr
tr
THF
THF
Et2O
15
10
16
[a] Yields based on 1, except for 4, which is based on th-MX. tr = trace. [b] Arylzinc reagents formed from aryllithium precursors.
802 Eur. J. Org. Chem. 2008, 801–804
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Regioselective Cross-Coupling of Polybrominated Thiophenes
Table 3. Regioselective coupling of 1 with arylzinc chlorides.
detectable 2-coupled products due to reduced reactivity of
the arylzinc reagent and enhancement of the second oxidat-
ive addition, thus resulting in higher yields of the doubly
coupled triaryl byproducts. 2-Pyridylzinc chloride (Entry 8)
did not react, most likely a result of aggregation, making
the reagent insoluble in diethyl ether. Even the use of the
more reactive 2-pyridylmagnesium chloride resulted in only
a 6% yield of the desired 2,3-dibromo-5-(2-pyridyl)thio-
phene (15). The tendency for these reagents to aggregate
demonstrates a potential complication in the cross-coupling
of organozinc reagents containing strong coordinating
groups.
Lastly, the selectivity in the presence of other aryl halides
is also of significant interest. The use of (4-bromophenyl)-
zinc chloride gave 38% of the desired product 11 without
detectable coupling at the phenyl bromide. This further level
of selectivity could allow the stepwise construction of fairly
elaborate aryl systems.
To demonstrate the power of the new regioselective
methods, they were applied to the synthesis of the known
compound 4Ј-bromo-5-methyl-2,2Ј;5Ј,2"-terthiophene (16)[20]
from thiophene (Scheme 1). By the new methods, the total
number of steps was reduced from six to three, and the
overall yield increased from 15 to 43%. Efficient cross
coupling (68%) of a third aryl group was then achieved
using Ni(dppp)Cl2 to give the trifunctionalized 3Ј-(4-meth-
oxyphenyl)-5-methyl-2,2Ј;5Ј,2"-terthiophene (17) with an
overall yield of 29%.
[a] Yields in parentheses determined by NMR spectroscopy after
initial chromatography (purity ca. 90%). Analytically pure samples
required additional recrystallization in these cases, resulting in re-
duced isolated yields.
coordination effects as a result of both solvent and coordi-
nating salts.
In order to determine the scope of the regioselective
cross-coupling of 1, a variety of arylzinc chlorides were then
investigated (Table 3). As can be seen, the donating or with-
drawing effects of the aryl groups have a significant effect
on the yields. The lack of regioisomer 3,5-dibromo-2,2Ј-bi-
thiophene (13) in Table 2 suggests that either oxidative ad-
dition was completely selective at the 5-position, or reaction
at both the 2- or 5-position was occurring in some ratio
and the relative reactivities of products 2 and 13 resulted in
selective consumption of 13. The second possibility agrees
well with the prior debromination results, and selective con-
version of 13 to the terthiophene 3 would explain the ab-
sence of this isomer in the recovered byproducts. This con-
clusion is also supported by the isolation of 3,5-dibromo-2-
Scheme 1. Sequential regioselective couplings.
(4-methoxyphenyl)thiophene (14, ca. 6.3%) and greatly re- Conclusions
duced triaryl production (Ͻ5%) in the preparation of 9,
Regioselective cross-coupling methods have been devel-
which indicates the p-methoxy group is electron-donating
enough to limit oxidative addition to 14. From this data, it
can be approximated that the selectivity between the 5- vs.
2-position of 1 is ca. 9:1. The slightly less donating 5-meth-
ylthiophene also resulted in the detection of both isomers
formed from the initial coupling in a ca. 12:1 ratio. Interest-
ingly, the minor isomer was not detected in the production
of 8, indicating that the cross-conjugated alkoxy unit had
a smaller electronic effect than the fully conjugated alkyl
group.
oped in which initial coupling occurs selectively (ca. 1:10)
at the 5-position of 1 with isolated yields of up to 63%. The
difference in reactivity of the α- and β-positions then allows
sequential regioselective couplings first at the 2-position,
followed by the 3-position. Such regioselective cross-coup-
ling allows unprecedented control in the generation of tri-
functionalized thiophenes.
Experimental Section
In contrast, the coupling of arylzinc reagents with elec-
General Procedure for the Regioselective Cross-Coupling of 1: To a
tron-withdrawing groups gave less desired product and no diethyl ether solution (50 mL) of arylzinc chloride (6.0 mmol) was
Eur. J. Org. Chem. 2008, 801–804
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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803

C. M. Amb, S. C. Rasmussen
SHORT COMMUNICATION
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added 2,3,5-tribromothiophene (1.60 g, 5.0 mmol) and Pd(dppf)Cl2
(0.10 g, 2.5 mol-%). The resulting mixture was stirred at room tem-
perature overnight, poured into 150 mL of satd. NH4Cl, and ex-
tracted with diethyl ether (3ϫ150 mL). The combined organic
phases were dried with MgSO4, filtered, and purified by silica gel
chromatography. Compounds 7, 8, 10 and 13 exhibit similar po-
larities to their byproducts, and thus additional recrystallization
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[8]
Supporting Information (see footnote on the first page of this arti-
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[9]
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Received: December 5, 2007
Published Online: January 7, 2008
804
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