Transition-Metal-Free Synthesis of Borylated Thiophenes via Formal Thioboration

Article abstract of DOI:10.1021/acs.orglett.8b02727

A simple, regiocontrolled, and transition-metal-free approach to access exclusively 3-borylated thiophene derivatives is reported. The commercially available B-chlorocatecholborane reagent (ClBcat) acts as a carbophilic Lewis acid to activate the alkyne i

Full text of DOI:10.1021/acs.orglett.8b02727

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Transition-Metal-Free Synthesis of Borylated Thiophenes via Formal
Thioboration
Hassen Bel Abed and Suzanne A. Blum*
Department of Chemistry, University of CaliforniaIrvine, Irvine, California 92617-2025, United States
S
* Supporting Information
ABSTRACT: A simple, regiocontrolled, and transition-metal-free approach to access exclusively 3-borylated thiophene
derivatives is reported. The commercially available B-chlorocatecholborane reagent (ClBcat) acts as a carbophilic Lewis acid to
activate the alkyne in readily synthesized (Z)-organylthioenyne substrates. This boron-induced activation initiates the formal
thioboration and subsequent sulfur dealkylation, leading to the formation of 3-borylated thiophenes in good yields. The
resulting borylated thiophenes are isolable as boronic esters (Bpin) and boronamides (Bdan). These borylated products are
amenable to diverse downstream functionalization reactions, i.e., C−C bond formation through cross-coupling, azidation,
bromination, and C−H activation.
orylated heteroaromatic rings are key building blocks for
accessing several derivatizations,1−8 especially for the
incompatible with specific substrates, i.e., those possessing
multiple halides or additional heterocyclic rings.
B
rapid generation of carbon−carbon bonds in preparation of
bioactive molecules.9−11 Among these heteroarenes, thio-
phene12−18 rings bearing boron groups have found widespread
applications in the synthesis of pharmaceutical drugs,19 such as
Bruton’s tyrosine kinase (BTK) inhibitor 1 and as fungicide
agrochemical20 Penthiopyrad 2. Furthermore, the combination
of thiophene and boron units has displayed promising
photophysical and redox properties21,22 in the development
of organic materials. Dithienoborepine (DTB) derivatives 3
have been introduced as functionalizable polycyclic π-electron
systems (Figure 1).23
The installment of a boron functionality as a transient group
into heteroarenes has been extensively explored, and several
methods have been developed24−27 such as Miyaura
borylation,28 sequential lithiation/borylation,29 or C−H
borylation.30,31 However, these methods require the use of
transition-metal catalysts, lack regioselectivity, and/or are
Aside from the established procedures requiring the use of
halide-containing thiophenes32 as precursors, the regioselective
borylation of thiophenes has remained limited to iridium-
catalyzed C−H borylation methods. Borylation at the α-
position of the thiophene has been reported to be
straightforward33 due to the high acidity of the C−H bonds
at that position; however, the current available strategies to
incorporate a boron group at the 3- and 4-positions in a
regioselective way have been restricted by the use of
nonremovable directing groups such as aldimines and
thiophene analogues presubstituted at the 2- and 5-positions34
preventing the functionalization of the heterocycle in an
efficient manner.
In a similar approach, the prior generation of a silica-
supported iridium complex allowed Sawamura to perform an
ester-directed borylation35 (Scheme 1a). It is noteworthy that,
to date, this is the only method leading to 3-borylated
thiophenes with at least one unsubstituted α-position in one
synthetic step. An additional technique described by Smith has
led to the boron-containing thiophenes through a sequential
iridium-catalyzed diborylation/monodeborylation route based
on the higher reactivity of the 2- and 5-positions for selective
iridium-catalyzed deborylation36 (Scheme 1b). This strategy
required the use of iridium catalysts over both steps of the
procedure.
Recently, we have reported borylative heterocycliza-
tions37−45 to access heteroaryl boronic ester analogues in a
Received: August 25, 2018
Figure 1. Synthetic importance of thiophene building blocks.
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02727
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
borylated thiophene 9. Boronic esters (Bpin)58 were chosen
for the potential direct derivatization of the boron group, and
boronamides (Bdan)59 were incorporated as masked boron
groups to allow us the option of functionalizing the thiophene
ring prior to boron-mediated transformations.
Scheme 1. Current Strategies for the Borylation of
Thiophenes
Moreover, the nature of the substitutionally labile R2
attached to the sulfur atom of 7a was studied. The use of a
dodecyl group attached to the sulfur atom led to 8a and the
corresponding boronic acid pinacol ester 9a-Bpin after SN2
dealkylation by chloride, but the chromatographic purification
did not afford pure product due to coelution with the
byproduct 1-chlorododecane (Table 1, entry 1). The
a
Table 1. Effect of the Sulfur Substituents
regiocontrolled manner through carbophilic activation of C−C
π bonds46−52 by using the commercially available B-
chlorocatecholborane (ClBcat) via a cyclization−dealkylation
sequence. This strategy enabled construction of borylated 5-
and 6-membered heteroaromatic rings that were primed for
accessing the rich downstream functionalization chemistry of
boron, including cross-coupling reactions. We now report an
extension of this strategy to the transition-metal-free synthesis
of borylated thiophenes via formal thioboration (Scheme 1c).
This reaction exclusively produces the 3-borylated regioisomer,
in complement to alternative borylation strategies, and does
not require a transition metal.
(Z)-Organylthioenyne analogues are efficient starting
materials due to their straightforward preparation from readily
available alkynes. A sequential route involving a copper-
catalyzed heterocoupling53 of alkynes 4 with 2-methylbut-3-yn-
2-ol 5 followed by cleavage under basic conditions54 of the
buta-1,3-diyne derivatives 6 and subsequent hydrothiola-
tion55−57 allowed access to monosubstituted (Z)-organylth-
ioenynes 7 in moderate-to-good yields (Scheme 2). This
procedure was applied to the majority of the substrates.
b
c
entry
R2
time
boron group
yield (%)
d
1
2
3
4
5
6
7
C12H25
Bn
n-Bu
n-Bu
Me
2 h
2 h
2 h
Bpin
Bpin
Bpin
Bdan
Bpin
Bdan
Bpin
−
0
40
45
69
56
16 h
2 h
16 h
2 h
Me
Me
e
53
a
b
See SI for details. Reaction time for the boron-interconversion step.
Yield of isolated product. Coelution with 1-chlorododecane.
equiv of 1-bromobutane was used as additive.
c
d
e
1
introduction of a benzyl group did not deliver the expected
product 9a, but gave a trisubstituted thiophene with no boron
group60 (Table 1, entry 2). The isolation of 9a was possible by
R2 = n-Bu leading to the Bpin and Bdan derivatives in
moderate yields as an initial result (Table 1, entries 3−4).
Finally, the replacement of n-Bu by a methyl group as an R2
substitution enabled the improvement of the yield of 9a-Bpin
to 69% and 9a-Bdan to 56% (Table 1, entries 5 and 6). This
difference in yield may have been caused by noninnocence of
the 1-chloroalkane byproducts generated during the deal-
kylation step; the 1-chlorobutane (bp 77−78 °C, from R2 = n-
Bu) remained in solution for the boron-interconversion step,
but the chloromethane (bp −24 °C, from R2 = Me) evaporated
prior to the isolation procedure. A higher halide analogue 1-
bromobutane (bp 100−104 °C) was selected as an additive in
order to examine the potential influence of these dealkylation
products. A decrease in yield was observed for the synthesis of
9a-Bpin in the presence of 1-bromobutane (added to the
reaction, Table 1, entry 7) and supported the noninnocent role
of the byproducts from the sulfur dealkylation.
We then focused on the robustness of this methodology with
different substitutions as well as its tolerance toward relevant
functional groups for further derivatizations. A substrate scope
was initiated starting from diversely substituted (Z)-organylth-
ioenyne derivatives 7 with R2 = methyl. The technique was
applied to the monosubstituted substrate 7b and gave the
envisioned borylated thiophene 9b with no group attached at
the 5-position in 73% yield for the Bpin product and 49% for
Scheme 2. Synthesis of (Z)-Organylthioenyne Substrates
Our initial investigation was performed with disubstituted 7a
as a model substrate due to ease of the reaction analysis by 1H
NMR spectroscopy (synthesized via Cu-catalyzed homocou-
pling of phenylacetylene followed by hydrothiolation; see
Supporting Information (SI) for reaction conditions). This
investigation permitted identification of 1.5 equiv of ClBcat
reagent as optimal to complete the conversion to 8a after 2 h
in toluene at 100 °C. Two types of boron interconversions
were explored in order to facilitate the isolation of the resulting
B
DOI: 10.1021/acs.orglett.8b02727
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Letter
the Bdan analogue (Scheme 3). It is interesting to mention
that the reaction time leading to the nonisolated boronic ester
the presence of three competing unsubstituted and more
reactive C−H bonds.
This approach afforded the multiply substituted thiophene
9j in 76% yield, combining an arene group, an aliphatic chain,
and a boronic ester without using transition-metal-mediated
transformations. While aryl and heteroaryl groups were able to
undergo formal thioboration and boron interconversion in
good yields, the introduction of a cycloalkenyl effected the
borylative heterocyclization and 9k was not obtained from 7k
with R2 = Me. Nevertheless, the use of (Z)-organylthioenyne
7k-Bu bearing a n-butyl group allowed the access to 9k in low
yield, showing the effect of the substituent R2 on the
accessibility of the product 9.
Scheme 3. Regioselective Synthesis of 3-Borylated
a
Thiophenes
Next, the diverse utility of borylated heterocycles 9 was
showcased through a range of regiocontrolled functionaliza-
tions that aimed to generate important building blocks for
possible late-stage modifications (Figure 2). The formation of
Figure 2. Functionalization of borylated thiophenes 9.
a carbon−carbon bond was achieved by a Suzuki cross-
coupling reaction between 9b-Bpin and 4-iodotoluene under
microwave conditions to give 10a in 80% yield. The
conversion of the boronic ester group of 9b-Bpin into an
amine surrogate azide was conducted via a copper-catalyzed
azidation with TMSN3 and CuCl leading to 10b in 77%
yield.62 The interconversion into a brominated derivative 10c
was performed with a stoichiometric amount of CuBr2 in 71%
yield.63 The derivatization of the 5-position was also explored
and resulted in the direct α-borylation of 9b-Bpin with HBpin
under iridium catalysis at room temperature to afford 10d in
38% yield (Figure 2; see SI for reaction conditions). This
demonstrated ability to derivatize through both C−H
activation and cross-coupling strategies makes these building
blocks potential partners in the synthesis of hexaarylbenzenes
(HABs).64,65
In conclusion, we have reported a simple method to access
3-borylated thiophene derivatives via formal thioboration.
Substrates are readily available, no transition-metal catalyst is
required, and the borylative heterocyclization/dealkylation
sequence proceeds with the commercially available reagent
ClBcat. Borylated thiophene products with one of the α-
positions unsubstituted were synthesized to emphasize the
exclusive formation of one regioisomer without a directing
group, in contrast to previous iridium-catalyzed methods to
borylated thiophenes. These reactions proceed via a different
mechanism and distinct bond disconnections, creating a
complementary synthetic toolkit for generating this important
heterocyclic product class. Moreover, a study of potential
a
Yields of the isolated product are quoted as an average over at least
b
c
two experiments. Reaction on 1.4 mmol scale. Formation of 8 was
performed at 120 °C.
8b (18 h) was longer than that for 8a (2 h) as observed by 1H
NMR spectroscopy in our preliminary study. The incorpo-
ration of a methyl group at the para-position of the phenyl in
the starting material 7c led to generation of product 9c in 69%
yield. In contrast, ortho analogue 7d afforded 9d in 29% yield,
showing the effects of sterics around the reactive alkyne. The
formal thioboration proceeded in good yields with substrates
containing electron-donating groups; 9e was synthesized in
69% yield. Halides were tolerated as represented with the
chlorinated 9f (56%) and lower-yielding brominated 9g (10%)
derivatives but required a higher reaction temperature to
complete the initial borylative heterocyclization to 8f,g. Such
halide substitutions provided the potential for orthogonal X/B
reactivity on the resulting thiophenes.
It was also possible to synthesize borylated heterocycle 9h
with electron-withdrawing groups such as the trifluoromethyl
attached to the aryl component, but in lower yield. The
procedure allowed unique access to the mono-borylated
dithiophene product 9i, an interesting building block for the
synthesis of oligothiophenes61 in 25% yield with complete
regioselectivity. Product 9i would not be a candidate for
synthesis via alternative, previously published methods due to
C
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downstream applications of 9 has been conducted and has
shown the versatility of this method toward various
functionalization reactions. This methodology thus represents
a unique approach to synthesize 3-borylated thiophenes
without transition metals, and the range of potential
applications provides additional research opportunities for
the regiocontrolled and rapid synthesis of novel thiophene-
based products.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b02727.
■
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: blums@uci.edu.
ORCID
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ACKNOWLEDGMENTS
■
We thank the National Science Foundation (CHE-1665202)
and the University of California, Irvine (UCI) for funding.
H.B.A. thanks Ms. Kim N. Tu and Ms. Adena Issaian (UCI)
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