Transition-Metal-Free Synthesis of Heterobiaryls through 1,2-Migration of Boronate Complex

Article abstract of DOI:10.1002/chem.201904761

The synthesis of a diverse range of heterobiaryls has been achieved by a transition-metal-free sp²–sp² cross-coupling strategy using lithiated heterocycle, aryl or heteroaryl boronic ester and an electrophilic halogen source. The construction of heterobiaryls was carried out through electrophilic activation of the aryl–heteroaryl boronate complex, which triggered 1,2-migration from boron to the carbon atom. Subsequent oxidation of the intermediate boronic ester afforded heterobiaryls in good yield. A comprehensive ¹¹B NMR study has been conducted to support the mechanism. The cross coupling between two nucleophilic cross coupling partners without transition metals reveals a reliable manifold to procure heterobiaryls in good yields. Various heterocycles like furan, thiophene, benzofuran, benzothiophene, and indole are well tolerated. Finally, we have successfully demonstrated the gram scale synthesis of the intermediates for an anticancer drug and OLED material using our methodology.

Full text of DOI:10.1002/chem.201904761

A Journal of
Accepted Article
Title: Transition Metal Free Synthesis of Heterobiaryls Through 1,2-
Migration of Boronate Complex
Authors: Santanu Panda, Swagata Paul, Kanak Kanti Das, and Samir
Manna
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Transition Metal Free Synthesis of Heterobiaryls Through 1,2-
Migration of Boronate Complex
Swagata Paul‡, Kanak Kanti Das‡, Samir Manna‡ and Santanu Panda*
Abstract: The synthesis of a diverse range of heterobiaryl has been
achieved via a transition metal free sp2-sp2 cross coupling strategy
using lithiated heterocycle, aryl or heteroaryl boronic ester and an
electrophilic halogen source. The construction of heterobiaryls was
carried out through electrophilic activation of the aryl-heteroaryl
boronate complex which triggered 1,2-migration from boron to the
carbon atom. Subsequent oxidation of the intermediate boronic ester
afforded heterobiaryls in good yield. A comprehensive 11B NMR study
has been conducted to support the mechanism. The cross coupling
between two nucleophilic cross coupling partners without transition
metals reveals a reliable manifold to procure heterobiaryls in good
yields. Various heterocycles like furan, thiophene, benzofuran,
benzothiophene, and indole are well tolerated. Finally, we have
successfully demonstrated the gram scale synthesis of the
intermediates for anticancer drug and OLED material using our
methodology.
The coupling of two aryl rings for the synthesis of biaryls is an
important reaction and hence found applications in a myriad of
syntheses and functionalization of bioactive molecules, natural
products and useful materials.1 Besides, biaryls and heterobiaryls are
abundant in many marketed drugs2 like recently approved drug for
cancer rucaparib, raloxifene3 (Scheme 1a), agrochemical products4,
and in light harvesting materials.5 Transition metals have been
extensively used for aryl-aryl cross coupling to access biaryls and
heterobiaryls. One of the pioneering work is Suzuki coupling, which is
a palladium catalyzed cross coupling reaction between aryl halide as
an electrophilic coupling partner and organoboronate ester as a
nucleophilic coupling partner (Scheme 1b).6 Recent analysis of
important methodologies applied in medicinal chemistry ranked
Suzuki-Miyuara coupling after amide coupling.7 Other well-
documented cross coupling methods varying nucleophilic coupling
partners are Stille coupling,8 Negishi coupling,9 Kumada coupling,10
Hiyama-Denmark coupling,11 and transition metal catalyzed C-H
activation.12 Similar to the Grignard reagents, Organolithiums are
important reagents in organic synthesis.13 Pioneering studies by
Murahashi group demonstrated the palladium catalyzed cross
coupling of organolithiums with vinyl halides.14 Recently Feringa
group reported cross coupling of aryl halide with organolithium
reagents using palladium NHC based complex to access biaryls and
heterobiaryls (Scheme 1b).15 However, most of these current methods
rely upon the cross coupling between an electrophilic and nucleophilic
coupling partners. Therefore, the development of cross coupling using
two nucleophilic coupling partners represent a more ideal approach.
C-H arylation using aryl boron compounds was reported for the
successful synthesis of biaryls.16 However, such reactions were
conducted in the presence of directing groups, transition metals and
[a]
S. Paul, K. K. Das, Samir Manna and Dr. Santanu Panda
Indian Institute of Technology
under drastic conditions17. In parallel with the biaryl synthesis using
transition metal, there are reports without transition metals18 for their
benign toxicity, cost effectiveness, and simplicity. However, a
transition metal free coupling of two nucleophilic partners for the
synthesis of biaryls is rare. Hence, our group is interested to develop
a novel transition metal free cross coupling between two nucleophilic
Kharagpur, 721302, India
E-mail: spanda@chem.iitkgp.ac.in
Supporting information for this article is given via a link at the end of the
document.
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coupling partners, heteroaryl lithium and aryl boronic ester using a
sacrificial electrophilic halogen source adopting the concept of 1,2-
migration of boronate complex (Scheme 1c). There has been an
immense interest in transition metal free C-C bond formation using
1,2-migration of boronate complexes.19 The early example of this kind
yield due to undesired brominated products (entry 4). At this moment
we have screened various diol protecting groups on the 4-
chlorophenylboronic acid considering the difference in nucleophilicity
parameters of corresponding boronatecomplexes reported by Mayr
group.33 However, we did not observe any improvement in yield using
those boronic esters.
was developed by Matteson group, which is
a one carbon
homologation of boronic ester using lithiated dichloromethane.20 Not
only migration to the sp3 carbon but also 1,2-migration to sp2 carbon
is equally attractive. In 1967, the Zweifel group demonstrated the 1,2-
migration of vinyl boronate complex 6 in the presence of iodine
(Scheme 2a).21 In this process migration of the alkyl group from boron
to carbon generates an intermediate alkyl boronic ester species 7,
which participated in an anti-boron-iodine elimination in presence of a
base to furnish Z-alkene (Scheme 2a). Vinyl boronate complex can be
activated by transition metal which was demonstrated by Ishikura,22
Murakami,23 Morken,24 Ready25 and others. After Zweifel’s initial
discovery, several groups emerged to developing C-C bond formation
through 1,2-migration to the vinyl boronates.26 Suzuki, Levy, and
others applied this concept for the synthesis of C2 alkylated
heterocycles using trialkylboron (Scheme 2b).27 Recently, Aggarwal
group revolutionize this approach for enantiospecefic synthesis of
chiral heterocycles using chiral secondary and tertiary boronic ester.28
However, this chemistry has never been explored using aryl boronic
ester which will end up to heterobiaryls, considering its prevalence in
marketed drug and bioactive compounds. An earlier approach using
With optimized reaction conditions in hand, a broad spectrum of
aromatic boronic esters were investigated. Both electron-donating
and -withdrawing boronic esters were equally reactive (Scheme 3).
Reactions of 4-Cl, 4-F and 4-CF3 phenyl boronic esters afforded
products (12a, 12d, 12E) in good yields. Coupling with halogen
substitution provides an additional handle for Suzuki coupling with
transition metals. Similarly, the aromatic boronic ester with electron
donating groups (12c, 12f) coupled smoothly. In the case of 2-
phenylfuran lower isolated yield was obtained due to the volatility of
the product. In addition to the para-substituted aromatic boronic ester
ethanolamine complexes of diorganylboron was mostly limited to
dithinyl and suffered with practicality issues.29 Herein we report a
straight forward protocol for the synthesis of heterobiaryls starting
from heteroaryls and aryl boronic esters. Apart from a huge substrate
scope, we will demonstrate that our method can be applied for the
formal synthesis of the anticancer drug Raloxifene, bioactive
compound for Chagas diseases30 and aryl thiophenes for OLED
materials.31
We initiated our study for the synthesis of C2-aryl furan from lithiated
furan, 4-chlorophenylboronic acid pinacol ester, and an electrophilic
halogen source. We hypothesized that the reaction of lithiated furan
(generated from the reaction of furan and n-BuLi) with boronic ester
would generate a furan boronate complex. Mayr group recently
reported that the furyl boronate complexes are much more
nucleophilic compared to the parent boronate esters.32 Electrophilic
activation of furan boronate complex will either participate in aromatic
electrophilic substitution (SEAr) followed by 1,2-migration or drive
towards unproductive ipso substitution. Among different electrophiles
and oxidants tested for the activation of furan-boronate complex, NBS
turns out to be ideal (Table 1, entry 3 vs 5 to 10). Also, Complete
formation of boronate complex was important for optimal yield (entry
1 vs 2). Optimization of the lithiation condition using n-BuLi (0.7 M in
hexane) improved the yield (entry 2 vs 3). For the final step, the 1,2-
migration occurred at -78 οC in the presence of NBS. However,
continuing the reaction with NBS at room temperature generated low
The reactivity was further extended to thiophene to access C2-
arylthiophenes, which have been widely used in organic field-effect
transistors, organic solar cells and organic light emitting diodes.31a
Conducting reaction using the condition similar to furan yielded 50%
of the desired 2-phenylthiophene. At this point, we decided to optimize
this reaction. Out of all the electrophiles tested, NBS turned out to be
optimal. Also, stirring boronate complex outside -78 οC for 10-12
minutes was hugely beneficial, considering complete conversion to
the boronate complex which is essential for optimal yield. A range of
aromatic and heteroaromatic boronic esters were accommodated
under the optimized conditions. Substitution at ortho-, meta- and para-
position of phenyl boronic esters were equally tolerated (Scheme 3).
A diverse set of 2-aryl thiophenes were synthesized (13a -13g) in
good yield. The moderate yield for the reaction using 4-cyanophenyl
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boronic ester was associated with the incomplete conversion under
optimized condition. Notwithstanding, the reaction was tolerated with
heteroaryl boronic ester to couple a furan with thiophene (Scheme 3,
12j) or between two thiophene units (Scheme 3, 13j).
NBS or NCS and THF was a better solvent compared to acetonitrile
or methanol (Scheme 4). We did not observe any reactivity using
oxidizing agents like DDQ. With these optimized conditions in hand,
we evaluated the scope of the aromatic boronic esters in conjunction
with the indole. Pleasingly, several aryl boronic esters with various
electronic property furnished the desired product in good yield. Variety
of functional groups 4-OMe (16c), 4-Cl (16a), 4-CN (16e) and many
others phenyl boronates (Scheme 4, 16a – 16g). Furthermore, various
substitution at the indole nucleus was tolerated, namely 73% yield
with 5-methoxylindole (16h), 75% yield with 4,7-dimethylindole (16j).
In addition to furan and thiophene, we explored the reactivity with
benzofuran and benzothiophene, which are prevalent in marketed
drugs and bioactive compounds (Scheme 3).33 Therefore, we
examined the scope of this reaction with a variety of substituted aryl
boronates under optimized reaction condition (see SI for details).
Arylboronates containing electron withdrawing 4-Cl (14b, 89%), 4-CN
(14d, 81%), and electron donating 4-OMe (14c, 86%) groups were
coupled smoothly. It is noteworthy that the reaction was well tolerated
Next, we explored the application of this methodology for the
synthesis of intermediates 15e for anticancer drug Raloxifene,
bioactive compounds 12b and light harvesting material 13h (Scheme
5). Raloxifene, an approved drug for breast cancer constitutes a C2-
arylbenzothiophene unit. Traditionally 15e was synthesized by Suzuki
coupling of 4-OMe-phenylboronic ester and 6-OMe-2-Br-
benzothiophene.35 However, we can able to synthesize the same
intermediate in one pot using 6-OMe-benzothiophene and 4-OMe-
phenylboronic ester using NBS (Scheme 5a). Using our method gram
scale synthesis of the intermediate 15e was achieved without
transition metal over 80% yield. Next, we have applied this method for
the synthesis of 12b in 60% yield which can be further converted to
the bioactive compounds for Chagas diseases (Scheme 5b).30
with ortho-tolylboronic ester despite steric demand (14g, 82% yield).
Subsequently, we examined the scope of aryl-benzothiophenes. The
lithiated benzothiophenes were coupled smoothly with various
aromatic boronic esters (Scheme 3, 15a–15d) affording substituted 2-
arylbenzothiophene over 80% isolated yield. The reaction was proved
to be general for aryl boronic ester with both electron donating and
electron withdrawing substituents.
The reactivity was further extended to the synthesis of C2-arylated
indoles, an important skeleton present in natural products and
bioactive compounds (Scheme 4).34 Standard optimization varying the
solvent and electrophiles revealed that NIS was superior compared to
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The application of this method was furthermore explored for the
synthesis of 13h, an intermediate for the synthesis of conjugated
polymer for optoelectronics (Scheme 5a). Previously this compound
was synthesized by Stille coupling by reacting tributyl(thiophen-2-yl)
stannane with meta-bromotoluene.36 However, one pot synthesis of
this compound was achieved using our methodology from
lithiatedthiophene and 3-methyl-phenylboronate. Organolithiums are
important coupling partner which generates lithium bromide as a
byproduct compared to the toxic tin reagents in Stille coupling. A
number of aryl-thiophenes are present in conducting polymer to light
harvesting materials,37 which can be accessed using our
methodology.
In conclusion, we have developed a one pot, transition metal free
cross coupling between two nucleophilic partner for the synthesis of
heterobiaryls. The concept of 1,2-migration from boronate complex
using cheap electrophilic halide source like NBS, reduces the cost for
the synthesis of such valuable heterobiaryls. Diverse range of
heterbiaryls were synthesized in good yield and applied to the gram
scale synthesis of bioactive compounds, which will be immensely
useful for future drug discovery. In future we will expand the scope of
this reaction for the synthesis of sp2-sp bonds.
Acknowledgements
This work was supported by DST-Ramanujan fellowship (SB/S2/RJN-
171/2017) and IIT Kharagpur ISIRD grants. SP & KKD thanks IIT
Kharagpur for fellowship and SM thanks CSIR India for fellowship. We
extend our special thanks to MSM & AB group at IITKGP for their
continuous support.
Keywords: heterobiaryl • heteroaryl • 1,2-migration • boronate
ester • electrophile
Notes
The authors declare no competing financial interest
Author Contributions
‡These authors contributed equally
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