On the directing effect of boronate groups in the lithiation of boronated thiophenes

Article abstract of DOI:10.1002/ejoc.201101764

An investigation of thiophene boronates has revealed the usefulness of a metalation reaction in the synthesis of various lithiated thiophene boronates, which were further converted to functionalized thiopheneboronic derivatives. The lithiation of 2- and 3-thienylboronic N-butyldiethanolamine (BDEA) esters with lithium diisopropylamide and lithium 2,2,6,6-tetramethylpiperidide showed that both boronated thiophenes were readily deprotonated. In the latter case, lithiation at the 2-position adjacent both to sulfur and the borocanyl group is thermodynamically favoured due to the significant stabilizing effect of the borocanyl group. Further derivatization with a range of electrophiles followed by hydrolysis afforded various 2-substituted 3-thiopheneboronic acids. Lithiation of the corresponding thiopheneboronic "ate" complexes of the type [ThB(OR)₃]Li revealed that the 2-thienyl derivatives could not be effectively deprotonated, whereas the "ate" complex, [3-ThB(OEt)₃]Li, was selectively lithiated with nBuLi at C-2. This points to a directing effect of the anionic boronate moiety. The resulting bimetallic species, [(2-Li-3-Th)B(OEt)₃]Li, underwent ring-closing dimerization upon heating to give, after subsequent hydrolysis, 4,8-dihydro-4,8-dihydroxy-p-diborino[2,3-b:5,6-b′]dithiophene - a cyclic diborinic acid. A computational study of the lithiation of boronated thiophenes and furans proved that boronation decreases ring-proton acidity. This effect is much stronger for the boronic "ate" complexes than for the corresponding neutral BDEA esters. Calculations of the transition states have shown that the specific directing effect of boronate groups in 3-thienyl derivatives is due to intramolecular oxygen-lithium coordination.

Full text of DOI:10.1002/ejoc.201101764

FULL PAPER
DOI: 10.1002/ejoc.201101764
On the Directing Effect of Boronate Groups in the Lithiation of Boronated
Thiophenes
Elena Borowska,[a] Krzysztof Durka,*[a] Sergiusz Lulin´ski,*[a] Janusz Serwatowski,[a] and
[b]
´
Krzysztof Wozniak
Keywords: Lithiation / Boron / Heterocycles / Bimetallic reagents / Ab initio calculations
An investigation of thiophene boronates has revealed the
usefulness of a metalation reaction in the synthesis of various
lithiated thiophene boronates, which were further converted
to functionalized thiopheneboronic derivatives. The lithiation
of 2- and 3-thienylboronic N-butyldiethanolamine (BDEA)
esters with lithium diisopropylamide and lithium 2,2,6,6-tet-
ramethylpiperidide showed that both boronated thiophenes
were readily deprotonated. In the latter case, lithiation at the
2-position adjacent both to sulfur and the borocanyl group is
thermodynamically favoured due to the significant stabiliz-
ing effect of the borocanyl group. Further derivatization with
a range of electrophiles followed by hydrolysis afforded vari-
ous 2-substituted 3-thiopheneboronic acids. Lithiation of the
corresponding thiopheneboronic “ate” complexes of the type
[ThB(OR)3]Li revealed that the 2-thienyl derivatives could
not be effectively deprotonated, whereas the “ate” complex,
[3-ThB(OEt)3]Li, was selectively lithiated with nBuLi at C-2.
This points to a directing effect of the anionic boronate moi-
ety. The resulting bimetallic species, [(2-Li-3-Th)B(OEt)3]Li,
underwent ring-closing dimerization upon heating to give,
after subsequent hydrolysis, 4,8-dihydro-4,8-dihydroxy-p-di-
borino[2,3-b:5,6-bЈ]dithiophene Ϫ a cyclic diborinic acid. A
computational study of the lithiation of boronated thiophenes
and furans proved that boronation decreases ring-proton
acidity. This effect is much stronger for the boronic “ate”
complexes than for the corresponding neutral BDEA esters.
Calculations of the transition states have shown that the spe-
cific directing effect of boronate groups in 3-thienyl deriva-
tives is due to intramolecular oxygen–lithium coordination.
their conversion into functionalized thiophene boronates. It
should be stressed that boronated thiophene derivatives are
widely used as building blocks in Suzuki–Miyaura cross-
coupling reactions that lead to a wide range of heterobiaryl
systems.[5] These include conducting polymers and lumines-
cent materials based on oligothiophene cores.[6] To the best
of our knowledge, our results show for the first time that
the lithiation of the aromatic ring is directed by boronate-
type groups.
Introduction
Arylboron compounds are important as versatile and
convenient reagents in modern organic synthesis. They are
intensively used in C–C and other cross-coupling reactions.
Their applications in analytical and materials chemistry
also seem promising.[1] Thus, it is highly desirable to de-
velop new synthetic strategies that lead to new function-
alized derivatives. Bimetallic lithium–boron aromatic rea-
gents are valuable intermediates, which can be readily con-
verted into functionalized arylboronic acids and esters,[2,3]
although they have attracted limited interest to date. How-
ever, results have been recently published and reviewed by
our group.[4] Despite a high demand for heteroarylboron
compounds in recent years, there are essentially no reports
devoted to the synthesis and reactions of heteroaryllithium–
boron aromatic derivatives. In this work, we report the gen-
eration of such compounds from thiophene boronates and
Results and Discussion
Lithiation of Thiopheneboronic BDEA Esters
The synthesis of thiopheneboronic azaesters 1b and 2b
was accomplished using a stepwise protocol, which involved
the lithiation of thiophene followed by transmetalation with
trialkylborate and quenching with ethereal HCl. The re-
sulting thiopheneboronic diethyl esters 1a and 2a were iso-
lated by fractional distillation and treated with N-butyl-
diethanolamine in Et2O to give crystalline products
(Scheme 1). The same protocol was successfully applied to
the synthesis of analogous furanboronic azaesters 3b and
4b. All products were obtained in high yields.
[a] Warsaw University of Technology, Faculty of Chemistry,
Department of Physical Chemistry,
Noakowskiego 3, 00-664 Warsaw, Poland
Fax: +4822-6282741
E-mail: kdurka@gmail.com
serek@ch.pw.edu.pl
[b] University of Warsaw, Department of Chemistry, Structural
Research Laboratory,
Pasteura 1, 02-093 Warsaw, Poland
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201101764.
2208
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 2208–2218

Lithiation of Boronated Thiophenes
lowed by hydrolysis gave thiophene-2,5-diboronic acid (1e)
[10]
1
in good yield as evidenced from its H NMR spectrum,
in which a singlet resonance of two thiophene ring protons
at 7.69 ppm indicates the regioselective formation of the
symmetrical structure.
The metalation of 2b with LDA occurred smoothly at ca.
–80 °C. Two isomeric products, 2c and 2d, could potentially
be formed due to proton abstraction at C-2 and C-5, respec-
tively. Based on previous results, we initially expected that
lithiation at C-2 would be disfavoured due to the steric hin-
drance and electron-donating properties of the adjacent
borocanyl moiety. To our surprise, the 2-lithiated intermedi-
ate 2c was formed exclusively as evidenced by the regioselec-
tive formation of a range of 2-substituted thiophene-3-
boronic acids 2e–2i upon treatment with electrophiles
(Scheme 3). The formation of thiophene-2,3-diboronic acid
(2i) was confirmed by single-crystal X-ray diffraction. To
the best of our knowledge, this is the first crystal structure
of an ortho-diboronic acid. The molecular structure of 2i is
shown in Figure 1 (a). One molecule of 2i is accompanied
by 1.5 molecules of H2O in the asymmetric part of the unit
cell. Both boronic acid groups are almost coplanar with the
aromatic ring. The C(1)- and C(2)-bound B(OH)2 groups
adopt exo–exo and endo–exo conformations, respectively.
The endo-oriented OH group is engaged in a strong intra-
molecular hydrogen bond with O(2) with an O(2)···O(3) dis-
tance of 2.633(1) Å. Classical hydrogen bonded, centrosym-
metric B(OH)2···2(HO)B dimers[11] are not present in the
structure of 2i. Instead, several other supramolecular motifs
were formed. The most basic of which involves intermo-
lecular O(1)–H(1)···O(4) bridges that give rise to molecular
chains parallel to the [110] or [1–10] directions. Two adja-
cent antiparallel chains are connected through water mole-
cules to form a double chain (Figure 1, b). The 3D supra-
molecular structure is reinforced by additional lateral H-
bonding interactions.
Scheme 1. The synthesis of 1b–4b.
We have previously shown that halogenated phenylbor-
onic azaesters are metalated cleanly using nonnucleophilic
bases, such as lithium dialkylamides, whereas alkyllithiums
can be problematic as boron alkylation occurs to some ex-
tent.[7] Thus, deprotonative lithiation of 1b proceeded read-
ily at C-5 using either lithium diisopropylamide (LDA) or
lithium 2,2,6,6-tetramethylpiperidide (LTMP) at ca. –80 °C
(internal temperature), and the resulting bimetallic species,
1c, was carboxylated by saturation with CO2 at ca. –100 °C.
The addition of pinacol and hydrolysis afforded 2-(5Ј-
carboxy-2Ј-thienyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
(1d) in 76% yield (Scheme 2). The structural formulation of
1
1d was based on its H NMR spectrum, in which two dou-
blets with a coupling constant of J = 3.5 Hz appear in the
aromatic region. Such a value is typical of 3-H,4-H cou-
pling in thiophene derivatives.[8] When the lithiation was
performed at a slightly higher temperature using a dry ice/
acetone bath (internal temperature ca. –70 °C), 1d was iso-
lated in a much lower yield (ca. 25%). This suggests that 1c
is thermally unstable. However, it can be effectively trapped
using an internal electrophile. Thus, in situ lithiation/
boronation[9] of 1b with LDA/B(OiPr)3 at ca. –65 °C fol-
Scheme 3. Lithiation of 2b and the regioselective formation of 2-
substituted thiophene-3-boronic acids 2e–2i.
When the lithiation of 2b was performed with the steri-
cally more demanding base LTMP followed by boronation
and hydrolysis, a mixture of isomeric thiophenediboronic
Scheme 2. Lithiation of 1b.
Eur. J. Org. Chem. 2012, 2208–2218
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2209

K. Durka, S. Lulin´ski et al.
FULL PAPER
tween the thiophene ring protons J3-H,5-H = 1.0 Hz.[8] These
results indicate that the lithiation of 2b with LTMP is kinet-
ically favoured at C-5 and the resulting bimetallic derivative
2d shows a strong tendency to form a thermodynamically
more stable 2-lithio isomer 2c.
Equilibration experiments were performed to assess the
relative basicities of 1c and 2c with respect to 2-thienyl-
lithium. When a solution of 1 equiv. of 1c (prepared from
1b and LDA/THF at –80 °C) was treated with 1 equiv. of
thiophene followed by the addition of (EtO)3B and hydroly-
sis, thiophene-2-boronic acid (almost 2 equiv.) was obtained
as the sole product (Scheme 5). This indicates that the com-
plete reprotonation of 1c with thiophene occurred to give a
mixture of 1b and 2-thienyllithium, the latter being trans-
metalated with (EtO)3B to produce the corresponding “ate”
complex. Aqueous acidic hydrolysis of both boronated thio-
phenes provided thiophene-2-boronic acid. A similar ex-
periment was carried out with 2c in combination with thio-
phene. In this case, after the addition of (EtO)3B and hy-
drolysis, diboronic acid 2i was isolated as the main product,
which was contaminated with only a small amount of thio-
phene-2-boronic (ca. 9%) and thiophene-3-boronic (ca.
9%) acids. To summarize this point, 1c seems to be more
basic than 2-thienyllithium, which can be rationalized in
terms of the σ-donor properties of the borocanyl group,
which result in the decreased acidity of the thiophene ring
in 1b with respect to the parent thiophene. This effect
should be even more pronounced for the 2b/thiophene pair
as the borocanyl group is closer to the deprotonation site.
The increased stability of 2c is thus somewhat confusing
but it can be reasonably explained by assuming extra stabili-
zation due to the intramolecular chelation of the lithium
atom by one or two oxygen atom(s) from the borocanyl
moiety. To the best of our knowledge, this is the first clear
evidence of the activating and ortho-directing effect of the
boronic ester group in aromatic lithiation. It should be
noted that related intramolecular Li–F coordination has
been invoked in the ortho-lithiation of BF3 complexes of
N,N-dimethylanilines.[12]
Figure 1. (a) Labelling of atoms and visualization of their atomic
displacement parameters at the 50% probability level in 2i. (b)
Fragments of the crystal lattice of 2i showing the hydrogen-bonded
double chain formed between diboronic acid and water. Hydrogen
bonds are shown as dashed lines.
acids was formed. The main product, 2i, was contaminated
with a significant proportion of thiophene-2,4-diboronic
acid (2j, ca. 30%). In situ lithiation/boronation of 2b with
LTMP/B(OiPr)3 at ca. –80 °C followed by hydrolysis gave
2j with only ca. 6% 2i (Scheme 4). Compound 2j was sub-
sequently converted into the isomerically pure bis(pinacol)
1
ester 2k whose structure was confirmed by its H NMR
spectrum, which showed two separate singlets from non-
equivalent BPinacol groups as well as two doublets in the
aromatic region with a long-range coupling constant be-
Scheme 4. Lithiation/in situ boronation of 2b.
Scheme 5. Acid–base equilibration between thiophene and 1c–2c.
2210
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 2208–2218

Lithiation of Boronated Thiophenes
Surprisingly, it was even possible to obtain thiophene- Et2O/THF (ca. 3:1) at –70 °C. Quenching with B(OR)3 and
2,3,5-triboronic acid (2l, isolated as the trihydrate) by a hydrolysis gave a mixture of diboronic acid 2i (ca. 60%) and
double in situ lithiation/boronation of 2b with LDA/ 3-thiopheneboronic acid (ca. 40%). The lithiation of 6b was
B(OiPr)3 (Scheme 6). It should be stressed that the second more effective as the crude reaction mixture contained ca.
lithiation must involve proton abstraction from the di- 75% 2i and only 25% 3-thiopheneboronic acid. Similarly,
boronated intermediates, which are strongly electronically the carboxylation of 6b-Li resulted in the formation of 2e.
deactivated due the presence of the anionic boronate moi- The extent of the lithiation of 6b was not improved even
ety. Nevertheless, the reaction occurred readily, and 2l was when a large excess of nBuLi (1.5 equiv.) was used. Surpris-
formed in good yield.
ingly, the related “ate” complex 6a could not be metalated.
Unlike 6b and 6c, 6a underwent extensive boron alkylation
as evidenced by the formation of dibutyl(methoxy)borane
and tributylborane as the major products. The lithiation of
6b and 6c seems to proceed via the intermediate prelithi-
ation complex formed between nBuLi and one (or two) oxy-
–
gen atoms of the B(OR)3 group. Thus, this is a specific
example of a complex-induced proximity effect (CIPE)
mechanism,[15] which involves the anionic boronate as the
directing group in the aromatic lithiation. In addition, we
have attempted to perform the lithiation of the analogous
“ate” complex 3-FuB(OEt)3Li. Unfortunately, it was totally
unreactive, which is in accordance with the similar behav-
iour of related 4b.
Scheme 6. Synthesis of 2l.
Unfortunately, furanboronic azaesters 3b and 4b were
not susceptible to metalation even using an in situ protocol
that involved lithiation/boronation with LTMP/B(OiPr)3 at
room temperature. This is consistent with the much weaker
acidity of furan (pKa 35.6) with respect to thiophene (pKa
= 33.0) measured in tetrahydrofuran (THF).[13] LTMP is
sufficiently basic to deprotonate furan (LTMP pKa
=
37.3),[13] but boronation decreases the acidity of the furan
ring. Thus, the proton transfer step becomes kinetically and
thermodynamically suppressed. Hence, we were unable to
observe the anticipated directing effect (apparently thermo-
dynamic in nature) of the borocanyl moiety during the at-
tempted lithiation of 4b.
Lithiation of Lithium Thienyl(trialkoxy)borates
We next embarked on a study of the deprotonative lithi-
ation of lithium thienyl(trialkoxy)borates. They were ob-
tained simply by treatment of thienyllithiums with a trialk-
ylborate and used in the key step without isolation. It has
been shown previously that selected lithiated lithium phen-
yl(trialkoxy)borates can easily be obtained by halogen–lith-
ium exchange from brominated or iodinated precursors.[3]
However, lithium 2-thienyl(trialkoxy)borates 5a–c [2-
ThB(OR)3Li, R = Me, Et, iPr] are resistant against depro-
tonation using lithium amide bases even at room tempera-
ture (Scheme 7). Furthermore, the internal electrophile
B(OiPr)3 was employed to shift the assumed equilibrium to
the product side but this approach also failed. No reaction
was also observed with nBuLi as the metalating agent,
whereas related lithium 2-thienylcarboxylate can be depro-
tonated at C-3 or C-5 with nBuLi or LDA, respectively.[14]
In a simple generalization, this decreased reactivity can be
rationalized in terms of the weaker acidity of aryl(trialk-
oxy)borates due to the strong electron-donating properties
Scheme 7. Synthesis and lithiation of thiopheneboronic “ate” com-
plexes.
We have investigated the thermal behaviour of 6b-Li.
Thus, 6b was treated with 1.1 equiv. of nBuLi and warmed
to room temperature. Hydrolysis and subsequent workup
afforded the cyclic diborinic acid 4,8-dihydro-4,8-di-
hydroxy-p-diborino[2,3-b:5,6-bЈ]dithiophene (7) in low yield
(Scheme 8). This compound is apparently formed by the
ring-closing dimerization of 6b-Li, which involves the
–
of the anionic trialkoxyborate moiety, B(OR)3 . A different
situation was observed in the case of lithium 3-thienyl(tri-
alkoxy)borates 6a–c, R = Me, Et and iPr, respectively,
which are also unreactive towards lithium dialkylamides.
Surprisingly, 6c was lithiated with nBuLi (1.2 equiv.) in Scheme 8. The formation of 7.
Eur. J. Org. Chem. 2012, 2208–2218
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2211

K. Durka, S. Lulin´ski et al.
FULL PAPER
nucleophilic attack of the carbanionic centres at C-2 on the Table 1. Deprotonation energies (ΔE) of the boronated thiophene
and furan derivatives. The positions of the boron-containing func-
tional group BR3 and the deprotonation site are assigned according
to the scheme.
boron atoms at C-3Ј of the partner molecule. The question
of whether the process is preceded by the dissociation of
–
anionic B(OR)3 group to give the Lewis acidic B(OR)2
group remains open.
Computational Studies
In order to obtain more information about possible de-
protonation mechanisms of the studied thiophene “ate”
complexes and azaesters, computational studies of the lithi-
ated thiophene boronates as well as the appropriate transi-
tion states have been performed. Directed lithiation reac-
tions are often supposed to proceed according to the CIPE
mechanism,[15] where the directing group (e.g. amide, carb-
amate) brings the base close to the acidic hydrogen atom
by precomplexation of the lithium atom. However, other
effects should also be considered, particularly the increased/
decreased acidity of the hydrogen atoms in the neighbour-
hood of the electron-withdrawing/donating groups or aro-
matic ring heteroatoms (e.g. sulfur). In the initial calcula-
tions, we compared the acidities of selected protons by cal-
culating their deprotonation energies.
Substrate
ΔE [kJmol–1]
2
3
4
5
Thiophene
1640
“aza”
1713
“ate”
1995
1681
“aza”
1725
1673
1731
“aza”
2010
“ate”
1701
1753
“aza”
–
–
1b
1722
1737
1979
2001
–
1729
1743
1690
1700
1948
1945
–
1703
1713
2b
5b
6b
Furan
3b
4b
13 and 15 kJmol–1, respectively. Nevertheless, according to
Deprotonation Energies
the experimental results, 6b can only be lithiated in the vi-
cinity of the B(OEt)3 group, which suggests that a potent
The deprotonation energies of hydrogen atoms can be
determined by calculating the heterolytic proton dissoci-
ation energies (AH = A– + H+). Such an approach has been
successfully applied in studies on the substituent additive
effects on acidity in a series of oligofluorobenzenes and oli-
gochlorobenzenes.[16] The calculations were performed at
the B3LYP[17]/aug-cc-pVDZ[18] level of theory. It should be
stressed that the values for the deprotonation energies do
not correspond to the real energies of lithiation and are
used only to compare the acidity levels of selected protons.
As expected, 2-H and 5-H are the most acidic and, there-
fore, more susceptible to abstraction (Table 1). It is well
–
directing effect of this substituent should be considered in
the metalation process. To summarize this point, the proton
abstraction from thiophene and furan rings is disfavoured
upon boronation (from a kinetic point of view), and this
effect strongly depends on the position and type of
boronate group.
Lithiation of Thiopheneboronic BDEA Esters – Transition
State Calculations
We next turned our attention to the lithiation reaction
known that thiophene is significantly more acidic than mechanism. There are several possible reaction pathways
furan. Indeed, the energy difference of proton abstraction for metalation with nBuLi and LDA. In the two most com-
in these two compounds from C-2 and C-3 are 41 and mon and frequently considered pathways, deprotonation
38 kJmol–1, respectively. These differences are less pro- occurs by dimeric ([nBuLi·2THF]2, [LDA·2THF]2) or mo-
nounced in the case of the “ate” and “aza” derivatives. For nomeric bases (nBuLi·3THF, LDA·3THF). Intensive stud-
instance, proton abstraction from C-2 in 2b costs ies of benzene deprotonation by nBuLi/tetramethylethyl-
12 kJmol–1 less energy than that in the corresponding posi- enediamine and nBuLi/(R,R)-trans-N,N,NЈ,NЈ-tetrameth-
tion in 4b. As a result of the strong electron-donating effect ylcyclohexanediamine conducted by Collum[19] and
–
of the B(OEt)3 group and the negative charge of the mole- Strohmann,[20] respectively, concluded that the mechanisms
cule, the deprotonation energies of boronate derivatives 5b that proceed via monomer- and dimer-based transition
and 6b are systematically larger in comparison with their states shows similar energy barriers. We decided to investi-
azaester analogues 1b and 2b. This is consistent with the gate the reactions using a monomer-based approach.
experimental results as only 6b (and its analogue 6c) was
Metalation of 1b and 2b proceeded with monomeric
effectively deprotonated at C-2 with nBuLi, whereas aza- LDA·3THF. Collum et al.[21] have shown that this form
esters 1b and 2b were more reactive and were lithiated with dominates in the in situ prepared LDA solution in THF.
less basic lithium dialkylamides.
The intermediate prelithiated complexes are similar in ener-
The presence of the boronate or borocanyl group de- gies to the reactants. The kinetically controlled regioselec-
creases the acidity of the neighbouring protons. As ex- tivity of the lithiation of 2b is dominated by the strong acti-
pected, this effect is significantly larger for the anionic vating effect of the sulfur atom together with a significant
boronates. For example, the differences between the ener- contribution of the steric effect of the borocanyl group. We
gies of proton abstraction at C-2 and C-5 in 2b and 6b are found that the disolvated structure of 2b–2Li is the most
2212
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 2208–2218

Lithiation of Boronated Thiophenes
stable in the 2b-Li series (Table 2). However, calculations of
the transition state structures show that the formation of
the 2b-5Li isomer is kinetically more favoured. The energy
barrier for lithiation at C-5 is 45.1 kJmol–1, whereas the
formation of the [2b-5Li]‡ transition state requires
55.5 kJmol–1 (Figure 2). The transition state structures of
[2b-2Li]‡ and [2b-5Li]‡ are depicted in Figure 3 (a and b).
This finding is in agreement with the calculated relative de-
protonation energies at C-2 and C-5 (Table 1). For sterically
more demanding bases, such as LTMP, lithiation at C-5
could be even more favoured. Indeed, experiments showed
that the lithiation of 2b with LTMP followed by boronation
with B(OiPr)3 and hydrolysis led to the preferential forma-
tion of 2j.
Table 2. Lithiation energies (ΔE) for thiophene and furan
boronates. The positions of the boron-containing functional group
BR3 and the lithium atom are assigned according to the scheme.
Substrate
Li agent
ΔE [kJmol–1]
2
3
4
5
Thiophene
Thiophene
nBuLi
LDA
LDA
LDA
nBuLi
nBuLi
LDA
LDA
–115.5
–23.2
“aza”
–27.4
“ate”
–76.1
“aza”
13.4
–82.8
9.5
23.1
“aza”
–69.1
“ate”
16.9
–
–
–
–
1b
2b
5b
6b
3b
4b
34.0
31.5
–33.3
–49.2
27.0
30.3
–6.5
–6.8
–61.9
–47.9
7.3
Figure 3. Calculated transition structures of (a) [2b-2Li]‡, (b) [2b-
5Li]‡ and (c) [6b-2Li]‡. Hydrogen atoms are omitted for clarity.
–
Boron-containing functional group “ate” = B(OEt)3 ; “aza” =
“aza”
7.8
B(OCH2CH2)2NBu.
Figure 2. Reaction pathways for the lithiation of 2b with LDA at (a) C-2, (b) C-4 and (c) C-5. [B3LYP/6-31+G(d)].
Eur. J. Org. Chem. 2012, 2208–2218
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2213

K. Durka, S. Lulin´ski et al.
–
FULL PAPER
Theoretical calculations show that the borocanyl group ortho-stabilizing effect of the B(OEt)3 group has been con-
activates the metalation process by the chelation effect, firmed by the hypothetical lithiation of 2-thienyl(tri-
which involves intramolecular Li–O coordination and re- ethoxy)borate (5b). The 5b-3Li derivative is slightly more
sults in the increased stability of 2b-2Li compared to 2b- stable than 5b-5Li (the difference between the isomers is
5Li. Moreover, if one compares the metalation of unsubsti- 7.2 kJmol–1). However, due to the strong electron-donating
tuted thiophene and 2b, one can conclude that the forma- effect of the B(OEt)3– group, the aromatic ring acidity in 5b
tion of 2b-2Li is also more favoured in this case. The activa- is too low to effect proton abstraction. To summarize, the
ting effect of the borocanyl group was observed even in the lithiation of anionic boronate derivatives occurs when both
–
presence of an additional B(OR)3 group. Thus, the lithi- sufficient acidity and the boronate-group-effected stabiliza-
ation energy of diboronic complex 2b-5B (formed upon in tion criteria are fulfilled.
situ metalation of 2b) is 11.6 kJmol–1 lower than the met-
alation of the analogous borocanyl-free 2-thienyl(triiso-
propoxy)borate (5c, Figure 4). This is consistent with the
formation of the triboronic acid 2l upon in situ double li-
thiation/boronation of 2b. We believe that a plausible
mechanism for this process is similar to that described for
2b. The first lithiation yields 2b-5Li, which is immediately
boronated, and the consecutive lithiation of the resulting
mixed diboronic complex 2b-5B would occur analogously
as proposed for the formation of 2b-2Li.
Figure 5. Reaction pathways for the lithiation of 6b with nBuLi at
(a) C-2, (b) C4 and (c) C-5 [B3LYP/6-31+G(d)].
Figure 4. Comparison of lithiation of 5c and 2b-5B.
Conclusions
Because of their weaker acidity and the endoenergetic
We have developed a new method for the efficient genera-
tion of synthetically useful lithiated thiophene boronates,
which were successfully employed in the synthesis of a
range functionalized thiopheneboronic derivatives includ-
ing hitherto unknown 2,3- and 2,4-thiophenediboronic ac-
effects of lithiation, the furan derivatives 3b and 4b are re-
sistant to metalation with LDA.
Lithiation of Lithium Thienyl(trialkoxy)borates –
Transition State Calculations
According to the CIPE model,[15] deprotonation at the ids and 2,3,5-thiophenetriboronic acid. This was comple-
positions adjacent to the boronate functional group should mented by the isolation of the thiophene-based diborinic
be preceded by the association of 6b with the lithiating rea- acid 7. The formation of 2,3-thiophenediboronic acid was
gent. The formation of the prelithiation complex from 6b confirmed by single-crystal X-ray diffraction. The signifi-
and nBuLi·3THF requires only 1.0 kJmol–1. The product cant activating effect of the borocanyl and anionic
–
of lithiation at C-2 (6b-2Li) is 26.9 and 28.2 kJmol–1 more B(OR)3 groups was found to operate in the lithiation of 3-
stable than the C-4- (6b-4Li) and C-5-lithiated (6b-5Li) de- thienyl derivatives. Theoretical calculations revealed that
rivatives, respectively (Table 2). Moreover, transition state the proton abstraction from the thiophene and furan rings
calculations indicate that 2-lithiation exhibits a very low re- is disfavoured upon boronation. However, this is counter-
action barrier of 22.1 kJmol–1 for deprotonation with balanced by the substantial chelation effect that involves
nBuLi (Figure 5). The geometry of the [6b-2Li]‡ transition intramolecular lithium–oxygen coordination, which results
state structure is depicted in part c of Figure 3. Lithiations in the increased stability of 3-boronated 2-lithiothiophenes
at C-4 and C-5 require considerably higher activation ener- compared to their regioisomeric counterparts. Calculations
gies (96.8 and 91.8 kJmol–1, respectively), which totally pre- showed that despite the fairly strong σ-donor properties of
clude the reaction. In the series of boronate derivatives, the the borocanyl function, the basicity of the 2-lithiothiophene
2214
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 2208–2218

Lithiation of Boronated Thiophenes
6-Butyl-2-(2Ј-furyl)-1,3,6,2-dioxazaborocane (3b): 2-(Diethoxy-
boryl)furan 3a was obtained as described for 1a starting with furan
(13.6 g, 0.2 mol). The lithiation step was performed at 0 °C; yield
31 g (92%), b.p. 48–52 °C (2 Torr). Compound 3b was prepared as
described for 1b starting with 3a (17.0 g, 0.1 mol); yield 21 g (89%),
that bears this group at the 3-position is even lower than
that of the parent compound by 4.2 kJmol–1, which corre-
sponds to the difference of the lithiation energies of 2b and
thiophene. This can be compared with the experimental
value of ca. 7 kJmol–1 roughly estimated based on the dis-
tribution of the products of the equilibration reaction
(Scheme 5). We are currently studying the lithiation of other
aryl and heteroaryl boronates. Specifically, we will try to
find whether the directing effect of boronate-type groups
will be observed in such systems.
1
m.p. 119–121 °C. H NMR (CDCl3, 400 MHz): δ = 7.42 (m, 1 H,
Fu), 6.46 (d, J = 3.0 Hz, 2 H, Fu), 6.21 (m, 1 H, Fu), 3.98 (m, 4
H, CH2O), 2.94 (m,
NCH2CH2CH2CH3), 1.43 (m, 2 H, NCH2CH2CH2CH3), 1.09 (m,
H, NCH2CH2CH2CH3), 0.76 (t, 7.0 Hz, H,
4
H, CH2N), 2.40 (m,
2
H,
2
J
=
3
NCH2CH2CH2CH3) ppm. 13C NMR (CDCl3, 100.6 MHz): δ =
143.9, 115.6, 109.0, 62.5, 58.0, 56.8, 26.3, 19.9, 13.4 ppm. 11B NMR
(CDCl3, 64.16 MHz): δ = 10 ppm. C12H20BNO3 (237.10): calcd. C
60.79, H 8.50, N 5.91; found C 60.72, H 8.75, N 5.92.
Experimental Section
General Comments: All reactions involving air- and moisture-sensi-
tive reagents were carried out under an argon atmosphere. Et2O
and THF were stored over sodium wire before use. The NMR
chemical shifts are given relative to Me4Si using the known chemi-
cal shifts of residual proton (1H) or carbon (13C) solvent reso-
nances. In the 13C NMR spectra, the resonances of boron-bound
carbon atoms were not observed in most cases due to their broad-
ening by the quadrupolar boron nucleus.
6-Butyl-2-(3Ј-furyl)-1,3,6,2-dioxazaborocane (4b): 3-(Diethoxy-
boryl)furan 4a was obtained as described for 2a starting with 3-
bromofuran (29.4 g, 0.2 mol); yield 30 g (90%), b.p. 50–53 °C (2
Torr). Compound 4b was prepared as described for 1b starting with
4a (17.0 g, 0.1 mol); yield 21.5 g (91%), m.p. 126–128 °C. 1H NMR
(CDCl3, 400 MHz): δ = 7.33 (m, 2 H, Fu), 6.31 (dd, J = 1.5, 1.0 Hz,
1 H, Fu), 3.97 (m, 4 H, CH2O), 2.92 (m, 4 H, CH2N), 2.42 (m, 2
H, NCH2CH2CH2CH3), 1.46 (m, 2 H, NCH2CH2CH2CH3), 1.13
6-Butyl-2-(2Ј-thienyl)-1,3,6,2-dioxazaborocane (1b): A solution of
thiophene (84 g, 1 mol) in THF (100 mL) was added to stirred solu-
tion of nBuLi (10 m, 100 mL, 1 mol) in THF (1.0 L) at –70 °C. The
lithiate was stirred for 1 h at –70 °C followed by the dropwise ad-
dition of (EtO)3B (153 g, 1.05 mol). The mixture was stirred for 1 h
and then quenched with ethereal HCl (1 L, 1.0 mol). The resultant
suspension was filtered under argon and concentrated. The residue
was distilled under reduced pressure. The fraction of 2-(dieth-
oxyboryl)thiophene (1a) was collected, b.p. 85–90 °C (2 Torr); yield
167 g (91%). A solution of N-butyldiethanolamine (80.5 g, 0.5 mol)
in diethyl ether (100 mL) was added to a stirred solution of 1a
(92.0 g, 0.5 mol) in Et2O (200 mL). A white crystalline precipitate
was formed rapidly, and the resulting suspension was stirred for
1 h at room temperature and cooled to –50 °C. The mixture was
concentrated under reduced pressure. The crystalline product was
collected by filtration, washed with Et2O (2ϫ20 mL) and dried to
give 1b; yield 118 g (93%), m.p. 121–122 °C. 1H NMR (CDCl3,
400 MHz): δ = 7.36 (dd, J = 5.0, 1.0 Hz, 1 H, Th), 7.19 (dd, J =
3.0, 1.0 Hz, 1 H, Th), 7.07 (dd, J = 5.0, 1.0 Hz, 1 H, Th), 4.09 (m,
(m,
2 H, NCH2CH2CH2CH3), 0.80 (t, J = 7.0 Hz, 3 H,
NCH2CH2CH2CH3) ppm. 13C NMR (CDCl3, 100.6 MHz): δ =
146.3, 141.9, 113.4, 62.4, 59.2, 56.9, 26.6, 20.0, 13.5 ppm. 11B NMR
(CDCl3, 64.16 MHz): δ = 10 ppm. C12H20BNO3 (237.10): calcd. C
60.79, H 8.50, N 5.91; found C 60.86, H 8.61, N 5.97.
2-(5Ј-Carboxy-2Ј-thienyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
(1d): A solution of 1b (5.06 g, 20 mmol) in THF (20 mL) was added
to a stirred solution of LDA freshly prepared from diisopropyl-
amine (2.2 g, 22 mmol) and nBuLi (10 m, 2.2 mL, 15 mmol) in THF
(30 mL) at –80 °C. After ca. 30 min stirring at ca. –80 °C (internal
temperature), the mixture containing the lithiate was carboxylated
by passing a stream of dried gaseous CO2 through it with rapid
stirring. After saturation, a solution of pinacol (2.36 g, 20 mmol)
in Et2O (10 mL) was added. The mixture was left to warm to ca.
0 °C to evaporate the excess CO2 followed by careful hydrolysis
with aqueous sulfuric acid (1.5 m, 50 mL). The organic phase was
separated and concentrated under reduced pressure. The crude
product was washed with water (3ϫ10 mL) and hexane (10 mL)
to give 1d as a white powder; yield 3.8 g (76%), m.p. 172–174 °C.
1H NMR ([D6]acetone, 400 MHz): δ = 7.81 (d, J = 3.5 Hz, 1 H,
Th), 7.56 (d, J = 3.5 Hz, 1 H, Th), 1.33 (s, 12 H, Me) ppm. 13C
NMR ([D6]acetone, 100.6 MHz): δ = 162.9, 141.1, 138.0, 134.8,
85.3, 25.0 ppm. 11B NMR ([D6]acetone, 64.16 MHz): δ = 29 ppm.
C11H15BO4S (254.11): calcd. C 51.99, H 5.95; found C 51.75, H
5.66.
4
H, CH2O), 3.01 (m,
NCH2CH2CH2CH3), 1.48 (m, 2 H, NCH2CH2CH2CH3), 1.14 (m,
H, NCH2CH2CH2CH3), 0.81 (t, 7.0 Hz, H,
4 H, CH2N), 2.40 (m, 2 H,
2
J
=
3
NCH2CH2CH2CH3) ppm. 13C NMR (CDCl3, 100.6 MHz): δ =
131.1, 127.6, 127.5, 62.7, 59.1, 56.9, 26.7, 20.1, 13.6 ppm. 11B NMR
(CDCl3, 64.16 MHz): δ = 11 ppm. C12H20BNO2S (253.17): calcd.
C 56.93, H 7.96, N 5.53; found C 56.85, H 7.84, N 5.52.
6-Butyl-2-(3Ј-thienyl)-1,3,6,2-dioxazaborocane (2b): 3-(Diethoxy-
boryl)thiophene (2a) was obtained as described for 1a starting
with 3-bromothiophene (163 g, 1.0 mol) and using Et2O as the sol-
vent; yield 163 g (89%), b.p. 88–92 °C (2 Torr). Compound 2b was
Thiophene-2,5-diboronic Acid (1e): A solution of LDA freshly pre-
pared from diisopropylamine (2.2 g, 22 mmol) and nBuLi (10 m,
2.2 mL, 22 mmol) in THF (30 mL) was added to a stirred solution
of 1b (5.06 g, 20 mmol) in THF (20 mL) containing B(OiPr)3 (4.5 g,
24 mmol) at –70 °C. The mixture was stirred for 30 min at –75 °C
prepared as described for 1b starting with 2a (92.0 g, 0.5 mol); yield
1
115 g (91%), m.p. 120–121 °C. H NMR (CDCl3, 400 MHz): δ = and then hydrolyzed with 2 m aqueous H2SO4 (10 mL). The aque-
7.41 (dd, J = 3.0, 1.0 Hz, 1 H, Th), 7.23 (dd, J = 5.0, 3.0 Hz, 1 H,
Th), 7.41 (dd, J = 5.0, 1.0 Hz, 1 H, Ph), 4.09 (m, 4 H, CH2O), 2.99 (2ϫ15 mL). The extracts were added to the organic phase, which
(m, 4 H, CH2N), 2.34 (m, 2 H, NCH2CH2CH2CH3), 1.47 (m, 2 H, was concentrated under reduced pressure. The solid residue was
ous phase was separated and extracted with diethyl ether
NCH2CH2CH2CH3), 1.13 (m, 2 H, NCH2CH2CH2CH3), 0.81 (t, collected by filtration and washed with water (2ϫ10 mL) and tolu-
J = 7.0 Hz, 3 H, NCH2CH2CH2CH3) ppm. 13C NMR (CDCl3, ene (10 mL). Drying in vacuo afforded 1e as a white powder; yield
100.6 MHz): δ = 131.9, 129.4, 124.2, 62.7, 59.1, 57.1, 26.7, 20.1, 3.0 g (72%), m.p.
13.7 ppm. 11B NMR (CDCl3, 64.16 MHz):
= 10 ppm. 400 MHz): δ = 7.69 (s, 2 H, Th), 7.41 [broad, 4 H, B(OH)2], 3.20
Ͼ
375 °C (dec.). 1H NMR ([D6]acetone,
δ
C12H20BNO2S (253.17): calcd. C 56.93, H 7.96, N 5.53; found C
56.71, H 7.93, N 5.57.
[broad, 4 H, H2O] ppm. 11B NMR ([D6]acetone, 64.16 MHz): δ =
27 ppm.
Eur. J. Org. Chem. 2012, 2208–2218
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2215

K. Durka, S. Lulin´ski et al.
FULL PAPER
2-Carboxythiophene-3-boronic Acid (2e): A solution of 2b (5.06 g,
20 mmol) in THF (20 mL) was added to a stirred solution of LDA
freshly prepared from diisopropylamine (2.2 g, 22 mmol) and
nBuLi (10 m, 2.2 mL, 15 mmol) in THF (30 mL) at –75 °C. After
ca. 30 min stirring at ca. –80 °C (internal temperature), the mixture
containing 2c was carboxylated by passing a stream of dried gas-
eous CO2 through it with rapid stirring. The mixture was left to
warm to ca. 0 °C to evaporate the excess CO2 followed by a careful
hydrolysis with aqueous sulfuric acid (1.5 m, 50 mL). The organic
phase was separated and concentrated under reduced pressure. The
crude product was washed with water (3ϫ10 mL) and acetone
(10 mL) to give 2e as a white powder; yield 3.0 g (72%), m.p. 196–
ene (10 mL). Drying in vacuo afforded 2h as a pale yellow powder;
yield 2.2 g (70%), m.p. 220–222 °C (dec.). H NMR ([D6]acetone,
1
400 MHz): δ = 10.27 (s, 1 H, CHO), 8.22 [br., 2 H, B(OH)2], 7.96
(d, J = 5.0 Hz, 1 H, Th), 7.60 (d, J = 5.0 Hz, 1 H, Th) ppm. 13C
NMR ([D6]acetone, 100.6 MHz):
δ = 186.5, 150.2, 136.9,
135.0 ppm. 11B NMR ([D6]acetone, 64.16 MHz): δ = 27 ppm.
C5H5BO3S (155.97): calcd. C 38.50, H 3.23; found C 38.75, H 3.02.
Thiophene-2,3-diboronic Acid (2i): A solution of 2c (obtained as
described as part of the synthesis of 2e) was quenched with B(OEt)3
(3.2 g, 22 mmol). The mixture was stirred for 30 min at –75 °C and
then hydrolyzed with 2 m aqueous H2SO4 (10 mL). The water phase
was separated and extracted with diethyl ether (2ϫ15 mL). The
extracts were added to the organic phase, which was concentrated
under reduced pressure. The solid residue was collected by filtration
and washed with water (2ϫ10 mL) and toluene (10 mL). Drying
in vacuo afforded 2i as a white powder; yield 3.4 g (85%), m.p.
1
197 °C (dec.). H NMR ([D6]DMSO, 400 MHz): δ = 8.60 [broad,
3 H, COOH + B(OH)2], 7.76 (d, J = 5.0 Hz, 1 H, Th), 7.32 (d, J
= 5.0 Hz, 1 H, Th) ppm. 13C{1H} NMR ([D6]DMSO, 100.6 MHz):
δ = 166.2, 145.1, 138.3, 135.0, 132.1 ppm. 11B NMR ([D6]DMSO,
64.16 MHz): δ = 28 ppm. C5H5BO4S (171.97): calcd. C 34.92, H
2.93; found C 34.76, H 2.74.
1
121–122 °C (dec.). H NMR ([D6]acetone, 400 MHz): δ = 8.28 [s,
2 H, B(OH)2], 8.18 [s, 2 H, B(OH)2], 7.65 (m, 2 H, Th), 3.21 (s, 3
H, H2O) ppm. 13C{1H} NMR ([D6]acetone, 100.6 MHz): δ = 136.7,
130.8 ppm. 11B NMR ([D6]acetone, 64.16 MHz): δ = 27 ppm.
C4H6B2O4S·1.5H2O (198.80): calcd. C 25.31, H 4.25; found C
25.05, H 4.20.
2-(2Ј-Iodo-3Ј-thienyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2f):
A solution of 2c (obtained as described as part of the synthesis of
2e) was quenched with a solution of I2 (5.1 g, 22 mmol) in THF
(20 mL) at –90 °C. The mixture was stirred for 30 min at –75 °C
and then hydrolyzed with 2 m aqueous H2SO4 (10 mL). The water
phase was separated and extracted with diethyl ether (2ϫ15 mL).
The extracts were added to the organic phase, which was washed
with 10 wt.-% aqueous Na2S2O5 (20 mL) and concentrated under
reduced pressure. The residue was treated with pinacol (2.36 g,
20 mmol) in Et2O (20 mL). The resulting solution was washed with
water and concentrated. The crude product was recrystallized from
hexane (10 mL) to give 2f as almost colourless crystals; yield 3.4 g
Bis(pinacol)thiophene-2,4-diboronate (2k): A solution of LTMP
freshly prepared from 2,2,6,6-tetramethylpiperidine (3.1 g,
22 mmol) and nBuLi (10 m, 2.2 mL, 22 mmol) in THF (30 mL) was
added to a stirred solution of 2b (5.06 g, 20 mmol) in THF (20 mL)
containing B(OiPr)3 (4.5 g, 24 mmol) at –75 °C. Hydrolysis and
workup was performed as described for 2b and afforded thiophene-
2,4-diboronic acid (2j) contaminated with ca. 6% 2i; yield 3.0 g.
Compound 2j was converted into the corresponding bis(pinacol)
ester 2k by treatment with pinacol (2.0 g) in acetone (10 mL). The
resulting solution was evaporated, and the crude product was
recrystallized from hexane (20 mL) to give 2k; yield 4.1 g (72%).
1H NMR ([D6]acetone, 400 MHz): δ = 8.14 (d, J = 1.0 Hz, 1 H,
Th), 8.00 (d, J = 1.0 Hz, 1 H, Th), 1.33 (s, 12 H, BPin), 1.31 (s, 12
H, BPin) ppm. 13C{1H} NMR ([D6]acetone, 100.6 MHz): δ =
143.3, 142.9, 84.0, 83.6, 24.8, 24.7 ppm. 11B NMR ([D6]acetone,
64.16 MHz): δ = 27 ppm. C16H26B2O4S (336.06): calcd. C 57.18, H
7.80; found C 56.98, H 7.68.
1
(51%), m.p. 78–80 °C. H NMR (CDCl3, 400 MHz): δ = 7.35 (d,
J = 5.0 Hz, 1 H, Th), 7.09 (d, J = 5.0 Hz, 1 H, Th), 1.35 (s, 12 H,
Me) ppm. 13C NMR (CDCl3, 100.6 MHz): δ = 134.1, 131.1, 84.5,
84.0, 24.5 ppm. 11B NMR (CDCl3, 64.16 MHz): δ = 27 ppm.
C10H14BIO2S (336.00): calcd. C 35.75, H 4.20; found C 35.42, H
3.98.
2-(2Ј-tert-Butylcarboxamido-3Ј-thienyl)-4,4,5,5-tetramethyl-1,3,2-di-
oxaborolane (2g): A solution of 2c (obtained as described as part
of the synthesis of 2e) was quenched with a solution of tBuNCO
(2.2 g, 22 mmol) in THF (20 mL) at –90 °C. The mixture was
stirred for 30 min at –75 °C and then hydrolyzed with 2 m aqueous
H2SO4 (10 mL). The water phase was separated and extracted with
diethyl ether (2ϫ15 mL). The extracts were added to the organic
phase, which was concentrated under reduced pressure. The residue
was treated with pinacol (2.36 g, 20 mmol) in Et2O (20 mL). The
resulting solution was washed with water and concentrated. The
crude product was recrystallized from hexane (10 mL) to give 2g
as almost colourless crystals; yield 3.8 g (62%), m.p. 101–103 °C.
1H NMR (CDCl3, 400 MHz): δ = 7.35 (d, J = 5.0 Hz, 1 H, Th),
7.09 (d, J = 5.0 Hz, 1 H, Th), 1.35 (s, 12 H, Me) ppm. 13C NMR
(CDCl3, 100.6 MHz): δ = 161.4, 153.3, 135.9, 128.4, 84.9, 51.9,
28.7, 24.8 ppm. 11B NMR (CDCl3, 64.16 MHz): δ = 26 ppm.
C15H24BNO3S (309.23): calcd. C 58.23, H 7.82, N 4.53; found C
58.40, H 7.66, N 4.46.
Thiophene-2,3,5-triboronic Acid (2l): A solution of LDA freshly pre-
pared from diisopropylamine (5.05 g, 50 mmol) and nBuLi (10 m,
5.0 mL, 50 mmol) in THF (60 mL) was added to a stirred solution
of 2b (5.06 g, 20 mmol) in THF (20 mL) containing B(OiPr)3 (4.5 g,
24 mmol) at –75 °C. The mixture was warmed to room temperature
and then cooled to 0 °C and hydrolyzed with 2 m aqueous H2SO4
(30 mL). The water phase was separated and extracted with diethyl
ether (2ϫ15 mL). The extracts were added to the organic phase,
which was concentrated under reduced pressure. The solid residue
was collected by filtration and washed with water (2ϫ10 mL). Dry-
ing in vacuo afforded 2l as a white powder. The product was ob-
1
tained as a trihydrate; yield 4.1 g (71%), m.p. Ͼ 395 °C (dec.). H
NMR ([D6]acetone, 400 MHz): δ = 8.26 [s, 2 H, B(OH)2], 8.12 (s,
1 H, Th), 8.10 [s, 2 H, B(OH)2], 7.35 [s, 2 H, B(OH)2], 3.15 (s, H2O)
ppm. 13C{1H} NMR ([D6]acetone, 100.6 MHz): δ = 145.7 ppm. 11
B
NMR ([D6]acetone, 64.16 MHz): δ = 27 ppm. C4H7B3O6S·3H2O
(287.65): calcd. C 17.82, H 4.86; found C 17.51, H 5.00.
2-Formylthiophene-3-boronic Acid (2h): A solution of 2c (obtained
as described as part of the synthesis of 2e) was quenched with
DMF (2.2 g, 30 mmol). The mixture was stirred for 30 min at
–75 °C and then hydrolyzed with 2 m aqueous H2SO4 (10 mL). The
water phase was separated and extracted with diethyl ether
(2ϫ15 mL). The extracts were added to the organic phase, which
was concentrated under reduced pressure. The solid residue was
collected by filtration and washed with water (2ϫ10 mL) and tolu-
4,8-Dihydro-4,8-dihydroxy-p-diborino[2,3-b:5,6-bЈ]dithiophene (7): A
solution of 3-bromothiophene (9.2 g, 50 mmol) in Et2O (20 mL)
was added to the stirred solution of nBuLi (10 m, 5 mL, 50 mmol)
in Et2O (50 mL) at –70 °C. The resulting white suspension was
stirred for 30 min before the addition of (EtO)3B (7.3 g, 50 mmol).
The white suspension was diluted with THF to give an almost clear
2216
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 2208–2218

Lithiation of Boronated Thiophenes
colourless solution. A solution of nBuLi (10 m, 5 mL, 50 mmol) in
pentane (20 mL) was added at –70 °C. The resulting mixture was
warmed to room temperature with stirring then cooled to ca. 0 °C
and hydrolyzed with 2 m aqueous H2SO4 (10 mL). The water phase
was separated and extracted with diethyl ether (2ϫ15 mL). The
extracts were added to the organic phase, which was concentrated
under reduced pressure. The solid residue was collected by filtration
and washed with water (2ϫ10 mL) and Et2O (2ϫ5 mL). Drying
in vacuo afforded 7 as a greyish powder; yield 0.5 g (18%), m.p.
aug-cc-pVDZ method and –7.6 kJmol–1 for the MP2/6-31+G(d)
method]. The minima were confirmed by vibrational frequency cal-
culations [B3LYP/6-31+G(d)] within harmonic approximation (no
imaginary frequencies). In the optimization processes, no symmetry
constraints were applied. Deprotonation energies were calculated
according to the equation:
AH = A– + H+; ΔE = EAH – EA–
In these computations, the B3LYP/aug-cc-pVDZ level of theory
was used starting from geometries optimized with the 6-31+G(d)
basis set. To optimize the structures of transition states, a synchro-
nous transit-guided quasi-Newton approach (qst3) was applied. In
this method three input structures were needed: one corresponded
to substrates, one to products and one is an estimation of the tran-
sition state. To verify the structures of the transition states, fre-
quency calculations were carried out at the B3LYP/6-31+G(d) level
of theory. One imaginary frequency was found in all cases.
1
160–162 °C (dec.). H NMR ([D6]acetone, 400 MHz): δ = 9.31 [s,
2 H, BOH], 7.79 (d, J = 4.5 Hz, 1 H, Th), 7.73 (d, J = 4.5 Hz, 1
H, Th) ppm. 13C{1H} NMR ([D6]acetone, 100.6 MHz): δ = 133.1,
132.8 ppm. 11B NMR ([D6]acetone, 64.16 MHz): δ = 36 ppm.
C8H6B2O2S2 (219.89): calcd. C 43.70, H 2.75; found C 43.21, H
2.98.
X-ray Data: The single-crystal XRD analysis of 2i was performed
with a Bruker AXS Kappa APEX II Ultra diffractometer with TXS
rotating anode (Mo-Kα radiation, λ = 0.71073 Å) and multilayer
optics and equipped with an Oxford Cryosystems nitrogen gas-flow
attachment. The data collection strategy was optimized and moni-
tored using the appropriate algorithms applied in the APEX2 pro-
gram package.[22] Data reduction and analysis were carried out
with the APEX2 suit of programs (integration was performed with
SAINT).[23] The data were corrected for Lorentz and polarization
effects. The multiscan absorption correction, scaling and merging
of reflection data were performed with SORTAV.[24] All structures
were solved by direct methods using SHELXS-97[25] and refined
using SHELXL-97.[25] The refinement was based on F2 for all re-
flections except those with very negative F2. All non-hydrogen
atoms were refined anisotropically.
Supporting Information (see footnote on the first page of this arti-
1
cle): Copies of the H and 13C NMR spectra of new compounds,
selected single-crystal XRD data for 2i and detailed results of the
computational studies.
Acknowledgments
This work was supported by the Narodowe Centrum Nauki
(National Science Centre) in the framework of project 2011/01/N/
ST5/05592. The authors thank the Interdisciplinary Centre for
Mathematical and Computational Modelling in Warsaw for pro-
viding computational facilities (G33-14). K. W. thanks the Founda-
tion for Polish Science for financial support within the “Mistrz”
programme. The support of the Aldrich Chemical Co., Milwaukee,
WI, U.S.A. through continuous donation of chemicals and equip-
ment is gratefully acknowledged.
CCDC-834903 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif. C8H18B4O11S2, molecular weight 397.60 a.u.; T =
100(2) K; monoclinic space group C2/c; unit cell dimensions, a =
11.088(1) Å, b = 11.845(1) Å, c = 13.283(1) Å, α = 90°, β =
104.72(1)°, γ = 90°, V = 1687.4(2) Å3; Z = 4; dcalc = 1.565 gcm–3;
absorption coefficient μ = 0.368 mm–1; F(000) = 824; crystal size:
0.15ϫ0.05ϫ0.05 mm3; θ range for data collection: 2.56°–38.93°;
index ranges: –18 Ͻ h Ͻ 17, –18 Ͻ k Ͻ 20, –20 Ͻ l Ͻ 22; reflections
collected: 18494/unique: 4770 (Rint = 0.0224); absorption correc-
tion: multiscan; refinement method: full-matrix least-squares on F2;
goodness-of-fit on F2, GooF = 1.002; data/restraints/parameters
[1] D. G. Hall, Boronic Acids, 1st ed., Wiley-VCH, Weinheim, Ger-
many, 2005.
[2] a) Y. Yamamoto, T. Seko, H. Nemoto, J. Org. Chem. 1989, 54,
4734–4736; b) P. Vedsø, P. H. Olesen, T. Hoeg-Jensen, Synlett
2004, 892–894; c) G. A. Molander, N. M. Ellis, J. Org. Chem.
2006, 71, 7491–7493; d) M. Dabrowski, P. Kurach, S. Lulin´ski,
˛
J. Serwatowski, Appl. Organomet. Chem. 2007, 21, 234–238.
[3] a) Q. Jiang, M. Ryan, P. Zhichkin, J. Org. Chem. 2007, 72,
6618–6620; b) P. Kurach, S. Lulin´ski, J. Serwatowski, Eur. J.
Org. Chem. 2008, 3171–3178.
[4] T. Klis´, S. Lulin´ski, J. Serwatowski, Curr. Org. Chem. 2010, 14,
4770/14/164; final R indices [IϾ2σ(I)]: R1 = 0.0300, wR2 = 0.0814;
2549–2566.
2
R indices (all data): R1 = 0.0365, wR2 = 0.0793; weight: 1/[σ2(Fo
)
[5] J. J. Li, G. W. Gribble, Palladium in Heterocyclic Chemistry,
2nd ed., Elsevier, Oxford, 2006, vol. 26, pp. 261–272.
[6] a) M. Jayakannan, J. L. J. van Dongen, R. A. J. Janssen, Mac-
romolecules 2001, 34, 5386–5393; b) H. Mori, K. Takano, T.
Endo, Macromolecules 2009, 42, 7342–7352; c) D. Tuncel, M.
Artar, S. B. Hanay, J. Polym. Sci. Polym. Chem. Ed. 2010, 48,
4894–4899.
+ (0.0775P)2 + 0.28P], where P = [max(Fo2,0) + 2Fc ]/3; largest
diffraction peak and hole: 0.626 and –0.251 eÅ–3. The carbon and
sulfur atoms were disordered and, therefore, modelled as two partly
occupied sites (the occupancy ratio of 3:2). The difference Fourier
map through the B(1)–C(1)–C(2) plane is shown in Figure S1 in
the Supporting Information.
2
[7] a) K. Durka, P. Kurach, S. Lulin´ski, J. Serwatowski, Eur. J.
Org. Chem. 2009, 4325–4332; b) K. Durka, R. Kamin´ski, S.
Lulin´ski, J. Serwatowski, K. Woz´niak, Phys. Chem. Chem.
Phys. 2010, 12, 13126–13136.
[8] S. Gronowitz (Ed.), Thiophene and Its Derivatives, part IV,
Wiley-InterScience, 1991, vol. 44, pp. 55–56.
[9] a) T. D. Krizan, J. C. Martin, J. Am. Chem. Soc. 1983, 105,
6155–6157; b) S. Caron, J. M. Hawkins, J. Org. Chem. 1998,
63, 2054–2055; c) J. Kristensen, M. Lysén, P. Vedsø, M. Beg-
trup, Org. Lett. 2001, 3, 1435–1437; d) S. Lulin´ski, J. Serwatow-
ski, A. Zaczek, Eur. J. Org. Chem. 2006, 5167–5173.
[10] I. G. C. Coutts, H. R. Goldschmid, O. C. Musgrave, N. C. Oli-
ver, J. Chem. Soc. C 1970, 3, 488–493.
Computational Details: All geometry optimizations and frequency
calculations were carried out with the Gaussian 03 suite of pro-
grams[26] and the Becke-style three-parameter density functional
method using the Lee–Yang–Parr correlation functional (B3LYP)
was applied.[17] The 6-31+G(d)[27] basis sets were used to calculate
the optimal geometries of “ate” complexes, azaesters and their lithi-
ated derivatives. To establish the outcome of the quantum-chemical
method, we performed additional calculations for 2b at the MP2[28]
/
6-31+G(d) and B3LYP/aug-cc-pVDZ[18] levels of theory and ob-
tained similar values of the lithiation energies at C-5 [–6.8 kJmol–1
for the B3LYP/6-31+G(d) method, –7.9 kJmol–1 for the B3LYP/
Eur. J. Org. Chem. 2012, 2208–2218
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2217

K. Durka, S. Lulin´ski et al.
[23] SAINT, 7.68A, Bruker AXS Inc., Madison, 2010.
FULL PAPER
[11]
See, for example: a) S. J. Rettig, J. Trotter, Can. J. Chem. 1977,
55, 3071–3075; b) M. Pilkington, J. D. Wallis, S. Larsen, J.
Chem. Soc., Chem. Commun. 1995, 1499–1500; c) P. R. Parry,
C. Wang, A. S. Batsanov, M. R. Bryce, B. Tarbit, J. Org. Chem.
2002, 67, 7541–7543.
[24] a) R. H. J. Blessing, Appl. Crystallogr. 1989, 22, 396–397; b)
R. H. J. Blessing, Acta Crystallogr., Sect. A 1995, 51, 33–38.
[25] G. M. Sheldrick, Acta Crystallogr., Sect. A 2008, 64, 112–122.
[26] M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria,
M. A. Robb, J. R. Cheeseman, J. J. A. Montgomery, T. Vreven,
K. N. Kudin, J. C. Burant, J. M. Millam, S. S. Iyengar, J. Tom-
asi, V. Barone, N. Mennucci, M. Cossi, G. Scalmani, N. Rega,
G. A. Petersson, H. Nakatsuji, M. Hada, M. Ehara, K. Toyota,
R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda,
O. Kitao, H. Nakai, M. Klene, X Li, J. E. Knox, H. P. Hratch-
ian, 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, P. Y. Ayala, K. Morokuma, G. Voth,
P. Salvador, J. J. Dannenberg, V. G. Zakrzewski, S. Dapprich,
A. D. Daniels, M. C. Strain, O. Farkas, D. K. Malick, A. D.
Rabuck, K. Raghavachari, J. B. Foresman, J. V. Ortiz, Q. Cui,
A. G. Baboul, S. Clifford, J. Cioslowski, B. B. Stefanov, G. Liu,
A. Liashenko, P. Piskorz, I. Komaromi, R. L. Martin, D. J.
Fox, T. Keith, M. A. Al-Laham, C. Y. Peng, A. Nanayakkara,
M. Challacombe, P. M. W. Gill, B. Johnson, W. Chen, M. W.
Wong, C. Gonzalez, J. A. Pople, Gaussian 03, revision C.02,
Gaussian Inc., Wallingford, CT, 2004.
[12]
S. V. Kessar, P. Singh, K. N. Singh, P. V. Bharatam, A. K.
Sharma, S. Lata, A. Kaur, Angew. Chem. 2008, 120, 4781; An-
gew. Chem. Int. Ed. 2008, 47, 4703–4706.
[13]
[14]
R. R. Fraser, T. S. Mansour, S. Savard, Can. J. Chem. 1985, 63,
3505–3509.
a) A. J. Carpenter, D. J. Chadwick, Tetrahedron Lett. 1985, 26,
1777–1781; b) D. W. Knight, A. P. Nott, J. Chem. Soc. Perkin
Trans. 1 1983, 791–794.
[15]
[16]
M. C. Whisler, S. McNeal, V. Snieckus, P. Beak, Angew. Chem.
2004, 116, 2256; Angew. Chem. Int. Ed. 2004, 43, 2206–2225.
I. Hyla-Kryspin, S. Grimme, H. H. Büker, N. M. M. Nibber-
ing, F. Cottet, M. Schlosser, Chem. Eur. J. 2005, 11, 1251–1256.
[17] a) D. Becke, Phys. Rev. A 1988, 38, 3098–3100; b) C. Lee, W.
Yang, R. G. Parr, Phys. Rev. B 1988, 37, 785–789.
[18] T. H. Dunning, J. Chem. Phys. 1989, 90, 1007–1023.
[19] D. Hoffmann, D. B. Collum, J. Am. Chem. Soc. 1998, 120,
5810–5811.
[20] C. Strohmann, V. H. Gessner, J. Am. Chem. Soc. 2008, 130,
[27] R. Krishnan, J. S. Binkley, R. Seeger, J. A. Pople, J. Chem.
Phys. 1980, 72, 650–654.
[28] C. Møller, M. S. Plesset, Pure Appl. Chem. 1934, 618–622.
11719–11725.
[21] A. C. Hoepker, L. Gupta, Y. Ma, M. F. Faggin, D. B. Collum,
J. Am. Chem. Soc. 2011, 133, 7135–7151.
[22] APEX2, 2010.3-0, Bruker AXS Inc., Madison, 2010.
Received: December 7, 2011
Published Online: February 24, 2012
2218
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 2208–2218