Catalyst-Free Formal Thioboration to Synthesize Borylated Benzothiophenes and Dihydrothiophenes

Article abstract of DOI:10.1002/anie.201608090

The first ring-forming thioboration reaction of C?C π bonds is reported. This catalyst-free method proceeds in the presence of a commercially available external electrophilic boron source (B-chlorocatecholborane) in good to high yields. The method is scalable and tolerates a variety of functional groups that are intolerant of other major borylation methods. The resulting borylated benzothiophenes participate in a variety of in situ derivatization reactions, showcasing that these borylated intermediates do not need to be isolated prior to downstream functionalization. This methodology has been extended to the synthesis of borylated dihydrothiophenes. Mechanistic experiments suggest that the operative mechanistic pathway is through boron-induced activation of the alkyne followed by electrophilic cyclization, as opposed to S?B σ bond formation, providing a mechanistically distinct pathway to the thioboration of C?C π bonds.

Full text of DOI:10.1002/anie.201608090

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201608090
German Edition: DOI: 10.1002/ange.201608090
À
C C Activation
Catalyst-Free Formal Thioboration to Synthesize Borylated
Benzothiophenes and Dihydrothiophenes
Darius J. Faizi, Ashlee J. Davis, Fiach B. Meany, and Suzanne A. Blum*
À
Abstract: The first ring-forming thioboration reaction of C C
p bonds is reported. This catalyst-free method proceeds in the
presence of a commercially available external electrophilic
boron source (B-chlorocatecholborane) in good to high yields.
The method is scalable and tolerates a variety of functional
groups that are intolerant of other major borylation methods.
The resulting borylated benzothiophenes participate in a vari-
ety of in situ derivatization reactions, showcasing that these
borylated intermediates do not need to be isolated prior to
downstream functionalization. This methodology has been
extended to the synthesis of borylated dihydrothiophenes.
Mechanistic experiments suggest that the operative mechanistic
pathway is through boron-induced activation of the alkyne
À
followed by electrophilic cyclization, as opposed to S B
s bond formation, providing a mechanistically distinct path-
À
way to the thioboration of C C p bonds.
À
T
hioboration, the addition of sulfur and boron across C C p
bonds, holds promise as an efficient route to synthesize
functionalized thioethers.[1] This area of research has focused
Figure 1. a) Previously reported thioboration methods. b) This work
demonstrating formal thioboration. ClBcat=B-chlorocatecholborane.
À
on reagents containing B S s bonds that are capable of
adding in a direct fashion to p systems. In 2015, Bo,
À
Fernꢀndez, and Westcott demonstrated the ability of B S
s bonds from in-house synthesized reagents to add across
in synthesis, such knowledge would facilitate the development
À
Michael acceptors through boron activation of the carbonyl
of thioboration reactions by indicating when B S s bonds are
necessary and when such bonds can be avoided, aiming
instead for previously unknown carbophilic activation of the
À
oxygen (Figure 1a, top), but without generation of a B C
bond for downstream functionalization.[2] In 1993, Miyaura
À
À
and Suzuki developed a thioboration reaction of B S s bonds
C C p bond by boron with simultaneous attack by sulfur via
across alkynes.[3,4] This method similarly employed in-house
an AdE3 or AdE2 reaction mechanism (Figure 1b).[5,6] Herein
À
À
synthesized reagents containing B S s bonds, however it used
the first formal thioboration of C C p bonds is reported,
À
a carbophilic palladium catalyst to activate the C C p bond.
concurrently developing fundamental knowledge about guid-
ing principles of relative carbophilicity and thiophilicity. The
experiments were motivated by a broader study on gold-
Protodeboration and in situ Suzuki cross-coupling reactions
of these thioboration products were demonstrated, establish-
ing the utility of such synthetic intermediates (Figure 1a,
bottom).
In contrast, formal thioboration, wherein the equivalents
of boron and sulfur add across a C C p bond, is underex-
plored, despite the potential advantages of employing com-
mercially available boron reagents as opposed to the thiobo-
ration reagents requiring synthesis, and the plausibility of
avoiding a palladium catalyst as previously required in the
direct thioboration of alkynes.[3,4] Although little is known
about the thiophilicity versus carbophilicity of boron reagents
catalyzed and catalyst-free oxyboration and aminoboration
[7–10]
À
À
(B O and B N addition) reactions in our research group.
This catalyst-free thioboration method generates borylated
benzothiophene derivatives, a heterocyclic scaffold found in
a variety of bioactive molecules and pharmaceuticals, such as
raloxifene and sertaconazole (Figure 2).[11–13] These borylated
benzothiophenes can then be further elaborated using the
wide range of established boron functionalization chemis-
try.[14–16] This reaction employs a commercial boron reagent,
À
À
B-chlorocatecholborane (ClBcat), removing the need for B S
s bond formation in starting materials or in intermediates and
making the reaction mechanistically distinct for thioboration.
Primary competing strategies for the synthesis of bory-
lated benzothiophenes include lithiation/electrophilic trap-
ping[17,18] and transition metal-catalyzed borylation of the
benzothiophene core.[19,20] The formal thioboration strategy
described herein provides complementary functional group
[*] D. J. Faizi, A. J. Davis, F. B. Meany, Prof. Dr. S. A. Blum
Department of Chemistry, University of California, Irvine
Irvine, CA 92697 (USA)
E-mail: blums@uci.edu
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201608090.
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Table 1: Synthesis of borylated benzothiophenes via the formal thiobo-
ration reaction.[a]
Figure 2. Two bioactive molecules that contain a benzothiophene core
(in red). Raloxifene is used in the treatment of osteoporosis, and
sertoconazole is used to treat skin infection.
tolerance to these other borylation methods, and also
furnishes the benzothiophene core in the same synthetic
step. Alternative routes to borylated benzothiophenes, in
contrast, require separate steps for borylation and generation
of the benzothiophene core.
We hypothesized that 2-alkynylthioanisoles (1) would
react upon treatment with ClBcat to yield thioboration
products 2 (Table 1). After initial identification of successful
reactivity, reaction conditions were optimized. Examination
of the equiv of ClBcat (1.0–1.4 equiv) identified 1.4 equiv as
the optimal value at 1.3m concentration in substrate 1 as
1
determined by H NMR spectroscopy relative to 1,3,5-triiso-
propylbenzene as an internal standard. Transesterification of
2 to the more air and moisture stable pinacolboronic ester (3)
provided bench-stable organoboron building blocks. The use
of ClBpin as an alternative electrophilic boron reagent, which
would theoretically provide direct access to the desired
pinacolboronic ester 3 from 1, was not evaluated because of
its instability above À358C and its difficulty of synthesis.[21]
The functional group compatibility of the thioboration
reaction was next examined (Table 1). Esters, aryl and alkyl
halides, amines and cyano groups, an O-silyl protecting group,
and several heterocycles tolerated the thioboration reaction
conditions in good yields. Functional groups that were
incompatible with the thioboration reaction included pyri-
dinyl and alcohol (in both cases, only starting material was
[a] Yield is that of the isolated product. 1H NMR yields were determined
using mesitylene as an internal standard in [D8]toluene, and are listed in
parentheses. [b] Required 24 h.
1
observed by H NMR spectroscopy, consistent with reaction
inhibition by the heteroatom lone pairs). Consistent with the
need to favor carbophilicity and avoid competing hetero-
atomphilicity of boron in the formal thioboration reaction,
amide-containing compound 3p required 24 h rather than the
standard 4 h to reach complete conversion (70% isolated
yield at 24 h vs. 25% isolated yield at 4 h). The slower
reactivity was attributed to competitive coordination of the
amide to boron. Notably, functional groups that cannot be
tolerated by existing methods of borylation of benzothio-
phenes (i.e., lithiation/electrophilic trapping or Pd-catalyzed
Miyaura borylation)[17–20] were tolerated by these thiobora-
tion reaction conditions (e.g., substrates 3 f–3h, 3j, 3m, 3n).
Thus, this thioboration reaction provided access to borylated
benzothiophenes that had limited accessibility through tradi-
tional methods. A crystal structure confirmed the regioselec-
tivity of the thioboration method (Figure 3).
Figure 3. X-ray crystallographic structure of 3d, with the thermal
ellipsoids shown at 50% probability (B, blue; C, gray; S, yellow; O,
red).
We hypothesized that the catalyst-free conditions of the
formal thioboration reaction would provide minimal inter-
ference to downstream functionalization conditions due to
the absence of residual metal salts. Indeed, synthetic inter-
mediate 2a participated in a wide range of C-B s-bond
functionalization reactions without the need for the addi-
tional synthetic manipulations of boron ligand exchange from
catechol to pinacol or the requirement to isolate any boron-
containing compound (Scheme 1).
In addition to its good functional group tolerance, the
thioboration reaction was scalable. Alkynylthioanisole 1d
underwent smooth thioboration at the 2.0 g scale to generate
3d in 69% yield (Table 1).
2
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À
sulfur rather than the C C p bond, forming activated
intermediate 9 (Scheme 2, top). Demethylation furnishes
À
thioboric ester 10; subsequent B S bond addition across the
alkyne yields product 2, which is a known pathway for several
[29–32]
À
other B X s bond addition reactions.
In order to
examine the thiophilicity of ClBcat toward 1a at ambient
temperature, the initial reaction mixture was evaluated by
1
NMR spectroscopy in [D8]toluene. H and 11B NMR spectra
obtained at t = 0 at ambient temperature showed no evidence
of sulfur coordination to boron as judged by persistence
resonances corresponding to starting material 1a and ClBcat
and the absence of other resonances. This result provided an
early indication of the lack of thiophilicity of this reagent, but
did not rule out sulfur-boron coordination or activation
leading to possible reaction intermediates, which was next
investigated.
If demethylation were occurring first, through activated
À
sulfonium intermediate 9 and B S bond containing 10, then
Scheme 1. In situ functionalization without isolation of organoboron
intermediates: direct access to downstream products.
a no-alkyne control would demethylate at the same rate (or
faster, but not slower) than the thioboration reaction
proceeds (4 h at 1008C). Treatment of o-iodothioanisole 14,
however, under these conditions resulted in no reaction:
> 95% of the starting material remained after 4 h as
determined by 1H NMR spectroscopy using mesitylene as
an internal standard, with no demethylated product 15
observed [Eq. (1)]. Moreover, by 11B NMR spectroscopy,
À
Oxidative workup of the C B bond furnished 1-benzo-
thiophene-3(2H)-one derivative 4, a heterocyclic motif that
has been examined as a donor–acceptor chromophore,[22] in
73% yield from 1a. Rhodium-catalyzed conjugate addition to
methyl vinyl ketone furnished product 5 in 71% yield over
two steps.[23,24] Subjecting intermediate 2a to two different
Suzuki conditions[15,25] produced products 6 and 7 in 65% and
56% yield over two steps, respectively. Trifluoromethylation
using a modification of a procedure developed by Sanford[26]
furnished 8 in 37% yield over two steps. Albeit in low yield,
this reaction provided access to 3-trifluoromethylated benzo-
thiophenes, which have limited alternative synthetic
routes.[27,28] These in situ reactions illustrate strategies for
efficiently generating the heterocyclic core and functionaliz-
ing at the 3-position in one pot.
only the ClBcat peak at d = 28.6 ppm was detected, suggesting
that the sulfur was not significantly coordinating to ClBcat,
even after extended reaction times. This lack of chemical shift
change in the 11B NMR spectrum also ruled out formation of
detectable amounts of sulfur-based borenium species.[33,34]
This mechanistic control reaction demonstrated that deme-
thylation of 1 is too slow relative to the timescale of the
overall thioboration reaction (4 h) to be a step in the
operative pathway and therefore ruled out the thiophilic
activation pathway.
Three main mechanistic pathways were considered for the
thioboration reaction (Scheme 2). The first route was through
thiophilic activation of 1 via coordination of ClBcat to the
Next, two pathways were considered in which the ClBcat
À
acts as a carbophilic Lewis acid by activating the C C p
system.[34] The first is through a haloboration/cyclization
pathway proceeding through a chloroboration reaction anal-
ogous to that reported for alkynes,[30] generating intermediate
11 (Scheme 2, middle). This chloroboration product then
undergoes cyclization to form sulfonium 12. This mechanism
was probed by using a substrate without sulfur [Eq. (2)].
À
Chloroboration of alkynes with other reagents containing B
À
Scheme 2. Three possible mechanistic pathways: B S s bond forma-
tion (top), haloboration (middle), and alkyne activation by ClBcat
(bottom).
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Cl bonds is thermodynamically downhill;[30,35] we therefore
hypothesize that the chloroborated products in this system
would be observable. Treatment of diphenylacetylene 16,
which is the no-sulfur analogue of substrate 1b, under the
otherwise standard thioboration conditions resulted in no
synthesis of borylated dihydrothiophenes via both demethy-
lation and deacylation pathways. Mechanistic studies docu-
mented an unusual pathway for thioboration reactions in
À
which an S B s bond is not formed. This thioboration
reaction demonstrates a strategy for harnessing the carbo-
philic reactivity of boron without concurrent thiophilicity. We
envision that this knowledge gained about the thiophilic
versus carbophilic reactivity available to boron reagents can
be used as a guiding principle for the design of catalyst-free
direct or formal boron-element addition reactions.
1
reaction by H (> 95% 16 remaining using mesitylene as an
internal standard) or 11B NMR spectroscopy (only signal
detected at d = 28.6 ppm, corresponding to unreacted ClBcat)
in 4 h. This demonstrated that chloroboration product 17 did
not form, and thus is an unlikely operative pathway in this
thioboration reaction.
On the basis of these mechanistic experiments, a role for
boron as a carbophilic Lewis acid in this cyclization is
proposed, plausibly through an AdE2/AdE3 mechanism[5,6]
(Scheme 2, bottom). Subsequent attack by the sulfur via
transition state 13 generates sulfonium intermediate 12.
Demethylation furnishes borylated benzothiophene 2. Nota-
Acknowledgements
This work was supported by
a grant from the NIH
(1R01GM098512-01), by the University of California,
Irvine, and by an Allergan Foundation Graduate Fellowship
to D.J.F.
À
bly, this proposed pathway has no productive B S coordina-
tion.
À
Having established the feasibility of this thioboration
reaction, we hypothesized that this method could be extended
towards the synthesis of dihydrothiophenes, a class of
compounds that are useful toward anti-HIV therapeutics[36]
and in agricultural products.[37] Subjecting alkynyl thioether
18 to the standard thioboration reaction conditions furnished
the desired cyclic thioether 20a, which was transesterified to
the bench-stable pinacolboronic ester 21a in 60% overall
yield [Eq. (3)]. This additional substrate class established that
the thioboration reaction did not require the entropic
assistance of a rigid backbone or the enthalpic assistance of
a gain of aromaticity to proceed.
Keywords: boron · C C activation · cyclization · sulfur ·
sulfur heterocycles
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À
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Revised: September 22, 2016
Published online: && &&, &&&&
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À
C C Activation
D. J. Faizi, A. J. Davis, F. B. Meany,
S. A. Blum*
&&&& — &&&&
Catalyst-Free Formal Thioboration to
Synthesize Borylated Benzothiophenes
and Dihydrothiophenes
Borylative cyclizations: The first ring-
do not need to be isolated prior to
downstream functionalization. Mecha-
nistic experiments suggest a boron-
induced activation of the alkyne followed
by electrophilic cyclization.
À
forming thioboration reaction of C C p
bonds is reported. The resulting borylated
benzothiophenes participate in a variety
of in situ derivatization reactions, show-
casing that these borylated intermediates
6
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