Sterically controlled C-H/C-H homocoupling of arenes: Via C-H borylation

Article abstract of DOI:10.1039/c9ob00995g

A mild one-pot protocol for the synthesis of symmetrical biaryls by sequential Ir-catalyzed C-H borylation and Cu-catalyzed homocoupling of arenes is described. The regiochemistry of the biaryl formed is sterically controlled as dictated by the C-H borylation step. The methodology is also successfully extended to heteroarenes. Some of the products obtained by this approach are impossible to obtain via the Ullmann or the Suzuki coupling protocols. Finally, we have shown a one-pot sequence describing C-H borylation/Cu-catalyzed homocoupling/Pd-catalyzed Suzuki coupling to obtain π-extended arene frameworks.

Full text of DOI:10.1039/c9ob00995g

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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
benzene
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DOI: 10.1039/C9OB00995G
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Sterically controlled C-H/C-H homocoupling of arenes via C-H
borylation
Xiaocong Peia, Guan Zhoua, Xuejing Lia, Yuchen Xua, Resmi C. Panickera and Rajavel Srinivasan*a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
A mild one-pot protocol for the synthesis of symmetrical biaryls by
sequential Ir-catalyzed C-H borylation and Cu-Catalyzed
homocoupling of arenes is described. The regiochemistry of the
biaryl formed is sterically controlled as dictated by the C-H
borylation step. The methodology is also successfully extended to
heteroarenes. Some of the products obtained by this approach are
impossible to obtain via the Ullmann or the Suzuki coupling
protocols. Finally, we have shown a one-pot sequence describing C-
H
borylation/Cu-catalyzed homocoupling/Pd-catalyzed Suzuki
coupling to obtain -extended arene framework.
C-C bond formation is considered to be a key transformation in
organic synthesis due to its ability to construct organic molecules
having utilities in a broad spectrum of fields1. Homocoupling of
arenes is one such reaction which finds applications spanning areas
from materials to medicines2. For example, symmetrical biaryls, the
products of homocoupling of arenes are indispensable building
blocks in various OLEDs3a, graphene-based materials3b, porous
polymers3c, ligands used in organic synthesis3d, antibiotics3e and so
on (Fig. 1). Recently, biaryl stapling of biologically active peptides has
been shown to enhance the blood-brain barrier (BBB) crossing ability
of those peptides4. Given the importance of these motifs, there is
always a demand for new and improved methods to synthesize
them.
Scheme 1 Comparison of the known methods to synthesis
biaryls from aryl boronic acids with the present approach
More recently, a number of different methods have evolved to
obtain symmetrical biaryls from arenes. However, these methods
also require the presence of a prefunctionalized group such as -OTs,
-B(OH)2, -COOH, -MgX, -SnBu3, etc. on the arene to effect the
coupling2,6, 11-17. This severely limits the substrate scope of the
reaction. It is either time consuming to prepare these starting
materials or expensive if commercially available. Dehydrogenative
homocoupling of arenes are also known, but the substrate scope of
this method is limited to a very few sets of (hetero)arenes7. Hence,
there is a necessity to develop a reliable method that could deliver a
variety of symmetrical biaryl compounds with predictable
regioselectivity from simple starting materials that are not
prefunctionalized, Herein, we introduce one such method to prepare
symmetrical biaryls in a regioselective fashion by sequential iridium-
catalyzed C-H borylation of arene (ArH), followed by a newly
developed copper-catalyzed oxidative homocoupling of the in situ
formed aryl boronates (ArBpin) in a one-pot fashion (Scheme 1). The
regioselectivity of the products formed are controlled by steric
Fig. 1 Representative examples of symmetrical biaryls
Historically, copper-mediated Ullmann coupling of aryl halides has
remained as a prominent reaction to make symmetrical biaryls5.
a. School of Pharmaceutical Science and Technology (SPST), Tianjin University,
Building 24, 92 Weijin Road, Nankai District, Tianjin, 300072 , P. R. China
E-mail: rajavels@tju.edu.cn
† Footnotes relating to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
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factors as dictated by the C-H borylation step. The methodology was one-pot transformation of an arene C-H to symmetrical biaryl, a
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DOI: 10.1039/C9OB00995G
also smoothly extended to heteroarenes. Further, it has been shown useful transformation, which we describe herein.
that the protocol is amenable for scale-up synthesis. Finally, it has
also been demonstrated that the crude biaryl product (bearing –I
Arylboronic acids are known to undergo homocoupling reactions2.
Pd-catalyzed homocoupling reactions of arylboronic acids have been
well documented2, 11. Rh,12 Ni,13 and Cu-catalyzed14b,14c versions of
this reaction are also been known. Other metals such as Au15, Cr16,
and V17 have been used to mediate this reaction2. Among these
methods, the Cu-catalyzed version is more attractive because of the
affordability of the metal catalyst as well as the simplicity of reaction
conditions. This method does not require malodorous solvents such
as pyridine or expensive metals such as silver to mediate the
homocoupling. However, all these reported Cu-mediated14a and Cu-
catalyzed2, 14b-c, methods use only arylboronic acid as substrates and
not the aryl boronate esters (ArBpin). This can be possibly due to the
less reactivity of the ArBpin when compared to that of the free
arylboronic acid18. Hence, we sought to develop a one-pot method
that integrate the Ir-catalyzed C-H borylation of arenes and Cu-
catalyzed homocoupling of the crude ArBpin product. This method
would enable access to sterically controlled symmetrical biaryl
products, starting from simple arene (C-H) precursors.
substituents) formed in the reaction sequence can be further
derivatized via Pd-catalyzed Suzuki coupling into -extended
compounds that are of great interest to materials chemists.
Table 1 Optimization of the reaction conditionsa
Entry Catalystb
Ligandc
bipyridine
bipyridine
bipyridine
bipyridine
bipyridine
bipyridine
bipyridine
bipyridine
phen
Solvent
CH3CN
THF
i-PrOH
DMF
Yieldd (%)
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.e
15.
16f.
17f.
18e.
19.
20.
21.
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
CuCl
traces
traces
10
50
0
0
0
H2O
EtOH:H2O (1:1)
1,4-dioxane
CH2Cl2
DMF
1,3-dichlorobenzene was chosen as the model substrate for the
optimization of reaction conditions. At first, iridium-catalyzed C-H
0
28
30
25
92
38
90
15
38
23
42
45
0
borylation was
performed on the
substrate
using
phen
phen
phen
DMF
DMF
DMF
DMF
DMF
MeOH
DMF
DMF
DMF
Ir[(cod)OMe]2/dtbpy and B2Pin2 system in THF at 80 °C for 24 hours.
The solvent was evaporated and the crude ArBpin formed was used
directly without any further purification for the optimization of the
subsequent homocoupling reaction (Table 1). The desired product
was observed only in traces when the reaction was carried out
initially in CH3CN with 5 mol% of Cu(OTf)2 and 6 mol% of bipyridine
as the catalytic system (Table 1, entry 1). In order to investigate the
optimal solvent conditions, an array of solvents was screened
employing the same catalytic system. All of these reactions were
performed at room temperature in the presence of air as oxidant.
The reaction in THF furnished only traces of the required product,
whilst the yield in i-PrOH was slightly better (10%) (Table 1, entry 3).
On the other hand, solvents such as 1,4-dioxane, H2O, aq. EtOH,
CH2Cl2 did not yield any desired product (Table 1, entries 5-8). Among
the solvents screened, DMF was found to be the best furnishing the
desired biaryl product in an isolated yield of 50% (Table 1, entry 4).
After the solvent optimization, a number of copper sources were
screened to further improve the yield of the reaction. Either phen or
bipyridine was used as ligand (Table 1, entries 9-14). When used in
combination with phen, the reaction catalyzed by Cu(OAc)2 furnished
an isolated yield of 92% of the biaryl product (Table 1, entry 12)
outperforming other copper sources. It was found out in the further
investigation that a 10 mol% of Cu(OTf)2 /bipyridine system also gave
a 90% yield of the desired product (Table 1, entry 14). In the absence
of ligand, the yield of the reaction dropped from 92% to 45% when
Cu(OAc)2 was used as a catalyst (Table 1, entry 12 vs 18). Similarly,
the yield dropped from 90% to 42% when Cu(OTf)2 was used without
a ligand (table 1 entry 14 vs 19). Demir and co-workers first
postulated the mechanism of copper-mediated homocoupling of
Cu(NO3)2
Cu(OAc)2
Cu(OAc)2
bipyridine
bipyridinee
phen
bipyridine
phen
e
Cu(OTf)2
Cu(OAc)2
Cu(OTf)2
Cu(OAc)2
Cu(OTf)2
Cu(OAc)2
-
-
-
DMF
DMF
DMF
bipyridine
phen
-
0
[a] Reaction was performed on a 0.5 mmol scale. [b] 5 mol% of the catalyst was
used. [c] 6 mol% of the ligand was used. [d] Yield recorded after purification by
silica-chromatography. [e] 10 mol% of the catalyst and 12 mol% of the ligand were
used. Reaction performed under O2 atmosphere. [f] Reaction performed under N2
atmosphere.
Iridium-catalyzed C-H borylation of arene enables the
introduction of –Bpin functionality at the least hindered site on the
arene8. The regiochemistry of the product formed is controlled more
by steric effects than electronic or directing effects of the arene
substituents. Hence, reactions of 1,3-disubstituted arenes selectively
forms the corresponding meta borylated product irrespective of the
electronics of the substituents. The reaction tolerates most of the
common organic functional groups. The selectivity of the borylation
step coupled with functional group tolerance has been utilized for
the one-pot transformation of an aryl C-H to various useful functional
groups such as phenol, aniline, nitrile, aryl (via Pd-catalyzed Suzuki
coupling), halide, and so on.9 We have also recently shown that C-H
of arenes can be converted into 1,2,3-triazole10a and -NO210b via C-H
borylation. However, this platform has never been utilized for the
arylboronic acids14a
. Until now this mechanism is not completely
understood but 3 possible pathways have been proposed.14 From our
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were performed at room temperature and in the presence of air as
DOI: 10.1039/C9OB00995G
an oxidant. In general, arenes containing halogen substituents
experimental evidence, we conclude the following: (1) In the absence
of any copper source, the formation of biaryl was not observed,
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indicating the importance of copper (Table 1, entries 20 and 21). (2) performed best with isolated product yields of up to 93%. It should
Iridium does not have any role in the homocoupling of ArBpin
intermediates (3) O2 or air is necessary for the homocoupling step.
When the reaction was performed in the absence of air or oxygen
the yield dropped from 92 to 23% (Table 1, entry 12 vs 16 and 17).
(4) Ligand enhances the yield of the homocoupling reaction.
be noted that most of these halogen substituted biaryl products can
neither be synthesized via the classical Ullmann coupling conditions
nor by the Pd-catalyzed Suzuki coupling protocol. In addition, it was
surprising that 3-iodotoulene furnished an isolated yield of 80% of
the biaryl product (compound 2n), without the formation of any
detectable amount of des-iodo byproduct. All these –Cl, -Br, and –I
substituted products can further be used for Suzuki coupling to
construct more –extend aromatic systems. Arenes bearing alkyl
substituents such as –CH3 and –iPr (2j to 2n) tolerated the reaction
sequence with product yields ranging from 80 to 85% whilst a drop
in yield (58%) was observed with the arene bearing both –CF3 and –
OCH3 groups (2r). It was observed that electron deficient arenes (1s
and 1t) furnished products (2s and 2t) in the modest yields of 56%
and 67% respectively. Highly electron-rich substrates such as 1,3-
dimethoxybenzene furnished the biaryl 2v in 68% yield. At the same
time, arenes with two strong electron withdrawing groups such as 3-
(trifluoromethyl)benzonitrile afforded the biaryl 2x in 79% yield.
Naphthalene selectively furnished less hindered 2,2-binapthyl 2y,
although only in 20%, mainly due to the formation of multiple
products in the borylation step. Overall, arenes bearing –F, -Cl, -Br, -
I, -CH3, -iPr, -CF3, -OCF3, -CN, -COOCH3, underwent the reaction
sequence smoothly as evident from the results shown in Scheme 2.
In all cases, sterically less hindered biaryls and binaphthyl were
obtained in a regioselective manner.
Scheme 2 One-pot homocoupling of arenes. Reactions were
performed on 1 mmol scale.
Scheme 3 One-pot homocoupling of heteroarenes. Reactions were
performed on 1 mmol scale.
Having the optimized conditions ready (Table 1, entry 12), we
then proceeded to evaluate the substrate scope of the one-pot C-H
borylation/homocoupling reaction sequence (Scheme 2). At first,
a panel of arenes was subjected to the Ir-catalyzed C-H
borylation reaction. After the completion of the reaction, the
solvent was removed in vacuo and the crude material was
dissolved in DMF and subjected to the Cu-catalyzed homocoupling
reaction using Cu(OAc)2 (5 mol%) and phen (6 mol%). The reactions
Having successfully synthesized various symmetrical biaryls,
this methodology was then extended to the heteroarenes such as
pyridines, quinoline, benzofuran, thiophenes and benzothiophene
(Scheme 3). It is worth mentioning that all these scaffolds are
important building blocks in medicines, materials and ligand design.
We found that Cu(OTf)2/bipyridine condition (Table 1, entry 14)
worked better while dealing with the heteroarenes. 3-chloropyridine
and 3-bromopyridinefurnished the 3,3’-bipyridine derivatives 4a and
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4b in isolated yields of 67% and 76% respectively. 2,6-lutidine cross-coupling reaction without the need for isolationVoierwpAurrtiicfliecOatniloinne
DOI: 10.1039/C9OB00995G
furnished 4,4’-bipyridine derivative in a modest yield of 50%. 3,3’- (Scheme 5). 3-iodotolune, 1n was subjected to a one-pot C-H
biquinoline derivative, 4d was obtained in 63% yield from 3- borylation/Cu-catalyzed homocoupling/Pd-catalyzed Suzuki cross-
bromoquinoline. Similarly, 2,2’-bi(hetero)arene derivatives of
benzofuran, 4e and thiophene 4f, were obtained in 55 and 62% yields
respectively. 2-chlorothiophene and 2-bromothiophene furnished
the respective halogenated 2,2’-bi(hetero)arenes 4g and 4h in 52%
and 60% yield respectively. Benzothiophene smoothly afforded the
2,2’-bi(benzothiophene) 4i in 60% yield. These results successfully
demonstrate the scope to obtain symmetrical biheteroaryl
derivatives in a regioselective fashion as dictated by the C-H
borylation reaction. It is also interesting to note that the starting
materials used are simple heteroarenes without requiring any
prefunctionalization.
coupling (with 4-cyanophenylboronic acid) to afford the -extended
arene 5 in 56% isolated yield. This clearly demonstrate the potential
of our method in accessing well-defined -extended molecular
frameworks from simple arenes.
Conclusions
In summary, a mild one-pot C-H borylation/copper-catalyzed
homocoupling sequence was developed to access symmetrical
biaryls with predictable regioselectivity from the respective arene (C-
H) precursors in excellent yields. The method was further extended
to several heteroarenes. The halogenated (-Br and –I) biaryls
obtained by this method are not possible to access via the existing
Ullmann or Suzuki coupling protocols, and can be used as building
blocks for further cross-coupling reactions. We have also shown that
the method is amenable for scale-up synthesis. Finally, we have
demonstrated that the biaryl (with iodo-substituent) obtained by this
strategy can be directly converted to the -extended aromatic
system via Suzuki coupling. Overall, we are optimistic that this
method will simplify the ways to make useful biaryls in a
regioselective manner from readily available precursors.
Conflicts of interest
The authors declare no conflict of interest.
Scheme 4 Evaluation of scale-up reactions
Acknowledgements
We then sought to assess the suitability of our method for scale-
up reactions (Scheme 4). By employing the standard conditions
outlined in Scheme 2, 10 mmol (1.26 g) of 3-chlorotoluene, 1j
furnished the biaryl product 2j in 80% isolated yield. Similarly, 10
mmol (1.57 g) of 3-bromopyridine furnished the desired
homocoupled product 4b in 70% isolated yield by using the standard
conditions outlined in Scheme 3. These results demonstrate that our
method is amenable for scale-up reactions.
R. S. acknowledges the School of Pharmaceutical Science and
Technology (SPST), Tianjin University, P. R. China and Tianjin Young
1000-Talents Program for the funding support.
Notes and references
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Scheme
5 One-pot borylation/homocoupling/cross-coupling
sequence
Halogenated biaryl compounds are versatile intermediates for
the synthesis of -extended materials. The halogenated biaryls
obtained by this approach could be used directly for further Suzuki
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Organic & Biomolecular Chemistry
Page 6 of 6
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DOI: 10.1039/C9OB00995G
R1
R2
"One-Pot"
R1
R2
1. Ir-cat.
borylation
2. Cu-cat. [O]
homocoupling
H
R1
R2
 Easy availability
 No prefunctionalization required
 Hetero(arenes) examples
 Up to 93% yield
 Sterically controlled products
 Mild reaction conditions
 34 examples
Sterically controlled synthesis of symmetrical biaryls from arenes by a one-pot sequential Ir-catalyzed
C-H borylation and Cu-catalyzed homocoupling is described.