A convenient pinacol coupling of diaryl ketones with B2pin2viapyridine catalysis

Article abstract of DOI:10.1039/d0cc07723b

A convenient, pyridine-boryl radical-mediated pinacol coupling of diaryl ketones is developed. In contrast to the conventional pinacol coupling that requires sensitive reducing metal, the current method employs a stable diboron reagent and pyridine Lewis base catalyst for the generation of a ketyl radical. The newly developed process is operationally simple, and the desired diols are produced with excellent efficiency in up to 99% yield within 1 hour. The superior reactivity of diaryl ketone was observed over monoaryl carbonyl compounds and analyzed by DFT calculations, which suggests the necessity of both aromatic rings for the maximum stabilization of the transition states.

Full text of DOI:10.1039/d0cc07723b

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A convenient pinacol coupling of diaryl ketones
with B2pin2 via pyridine catalysis†
Cite this: Chem. Commun., 2021,
57, 1360
Junhyuk Jo, Seonyul Kim,‡ Jun-Ho Choi * and Won-jin Chung
*
Received 25th November 2020,
Accepted 23rd December 2020
DOI: 10.1039/d0cc07723b
rsc.li/chemcomm
A convenient, pyridine-boryl radical-mediated pinacol coupling of conducted under photochemical conditions.4 Through the
diaryl ketones is developed. In contrast to the conventional pinacol action of the photoredox catalyst, the single electron reduction
coupling that requires sensitive reducing metal, the current method of carbonyl compounds was realized in the presence of an
employs a stable diboron reagent and pyridine Lewis base catalyst amine reductant under visible light. A completely metal-free
for the generation of a ketyl radical. The newly developed process is pinacol coupling has also been reported by the groups of
operationally simple, and the desired diols are produced with Khaliullin and C.-J. Li.5 In this method, hydrazine functions
excellent efficiency in up to 99% yield within 1 hour. The superior as both a reductant and a hydrogen source via light-induced
reactivity of diaryl ketone was observed over monoaryl carbonyl hydrogen atom transfer (HAT) under UV irradiation. In both
compounds and analyzed by DFT calculations, which suggests the cases, mild reaction conditions could be achieved by harnessing
necessity of both aromatic rings for the maximum stabilization of the reducing power from light energy.
the transition states.
For the past few years, chemistry exploiting a diboron-Lewis
base complex has emerged.6 It is known that upon association
Pinacol coupling is a valuable reaction that provides a 1,2-diol of a diboron with an appropriate Lewis base such as pyridines
from two carbonyl compounds via the connection of two
electrophilic positions, and the reaction has been employed
as a key step in natural product synthesis.1 The reaction
mechanism is straightforward. An electron is added to a
carbonyl group to form a ketyl radical which then dimerizes
to afford a 1,2-diol. Traditionally, the reactive ketyl radical
intermediate is generated by low valent metals such as Zn, Ti,
Mg, Al/Hg, Sm, In, etc. (Fig. 1a).2 Although this method has
been constantly improved, it still has drawbacks including the
requirement of highly reactive metallic reducing agents under
harsh reaction conditions. Moreover, because of the easily
oxidizable nature of the metal reagents, an additional activa-
tion process is often necessary for the removal of metal oxide
on the surface before use.3 Recently, new pinacol coupling
methods that do not require low valent reducing metals were
developed. For example, pinacol coupling has been successfully
Department of Chemistry, Gwangju Institute of Science and Technology (GIST),
123 Cheomdan-gwagi-ro, Buk-gu, Gwangju 61005, Republic of Korea.
E-mail: junhochoi@gist.ac.kr, wjchung@gist.ac.kr
† Electronic supplementary information (ESI) available: Experimental proce-
dures, characterization data, copies of NMR spectra for all new compounds,
and DFT calculation data (PDF). See DOI: 10.1039/d0cc07723b
‡ Current address: Department of Chemistry, Korea Advanced Institute of Science
Fig. 1 Pyridine-boryl radical-promoted ketyl radical formation and
proposed application to pinacol coupling.
and Technology (KAIST), 291 Daehak-ro, Yuseong-gu, Daejeon 34141, Republic of
Korea.
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Table 1 Optimization of pyridine-boryl radical-promoted coupling of
containing electron-withdrawing substituents, the B–B bond is
weakened and cleaved in a homolytic manner.7 The convenient
formation of the boryl radical with reagents that are easy to
handle as well as its persistent property attracted attention
from the synthetic organic community and consequently has
brought the development of various organic reactions. Among
them, the transformations utilizing the ketyl radical formation
from carbonyl compounds with a diboron–pyridine complex
are noteworthy. The S. Li group developed reductive C–C bond
formations of carbonyl compounds with pyridine or alkene by
utilizing a single electron transfer (SET) reactivity of the
pyridine-boryl radical (Fig. 1b).8 Both 1,2-pyridylation of
ketones and 1,4-pyridylation of enones were accomplished via
the substitution reaction between ketyl radical boronate and
4-cyanopyridine-boryl radical complex.8a,b Similarly, the alkyla-
tion of aliphatic aldehydes with gem-diarylethylene proceeds in
the presence of diboron and a 4-(4-cyanophenyl)pyridine
catalyst (Fig. 1c).8c Interestingly, pinacol coupling reactivity
has not been observed even though the ketyl radical intermediate
is present in these reductive C–C bond formation reactions.
Whereas the reductive coupling of imine has been successfully
promoted by the diboron–pyridine complex,9 the related reactivity
of ketone or aldehyde has not been described to date. Herein, we
benzophenonea
Entry
E
Equiv.
Solvent
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
CN
Ph
0.5
0.5
0.5
0.5
0.5
0.2
0.2
0.1
0.2
0.2
0.2
—
PhCF3
PhCF3
PhCF3
1,4-Dioxane
t-BuOMe
PhCF3
1,4-Dioxane
PhCF3
PhCF3
PhCF3
1
1
1
1
1
1
1
3
0.5
2
48
1
72
14
89
90
54
95
95
92
93
95
30
0
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
—
9
10
11c
12d
13e
PhCF3
PhCF3
PhCF3
CO2Me
0.2
1
0
a
Reaction conditions: 1a (1.0 mmol), B2pin2 (1.0 mmol), and pyridine
b
Lewis base in solvent (1 mL). Isolated yields after column chromato-
graphy. At room temperature. Without pyridine Lewis base. With
2.2 equiv. of TEMPO.
c
d
e
report the development of a new pinacol coupling method that time was investigated (entries 9 and 10). A small amount of
does not require the use of a low valent metal by taking advantage unreacted starting material remained after 0.5 hours although
of the pyridine-boryl radical as a ketyl radical generator.
the isolated yield was still high (entry 9), and no further improve-
To probe pinacol coupling reactivity, the initial reaction ment was observed in 2 hours (entry 10). Therefore, the reaction
conditions survey was performed with benzophenone (1a) time of 1 hour was found to be optimal. When the reaction was
because diaryl ketone is expected to form a stable ketyl radical. conducted at room temperature, only 30% of 2a was produced in
These reactions were conducted with 1.0 equivalent of B2pin2 48 hours (entry 11). As expected, the reaction did not proceed either
and a catalytic amount of electron-deficient pyridine in refluxing in the absence of a pyridine catalyst (entry 12) or in the presence of
PhCF3 (Table 1).6f,g Gratifyingly, in the presence of 0.5 equiv of a radical scavenger (entry 13).
4-cyanopyridine,10 benzopinacol (2a) was produced in 72% yield
With the optimal reaction conditions in hand, a range of
in 1 hour after deborylative workup with 4.5 M aq. KHF2 diaryl ketones were surveyed (Table 2). Consistently high reac-
(entry 1).11 Such high reactivity is notable because the previously tivity was observed regardless of the electronic property of
reported transformations of ketyl radicals derived from diboron– benzophenone derivatives. With 4,40-dimethylbenzophenone
pyridine complexes generally require more than 24 hours.8 (1b), the corresponding diol 2b was obtained in 90% yield.
Subsequently, the examination of other pyridine Lewis bases Also, highly electron-rich 4,40-dimethoxybenzophenone (1c)
revealed that the para substituent of pyridine has a significant afforded 2c in 93% yield. From electron-poor substrates such
influence on the reaction yield (entries 2 and 3).12 From the as 4,40-difluoro-, 4,40-dichloro-, and 4,40-dibromobenzophenone
reaction with 4-phenylpyridine, 2a was obtained in a drastically (1d–f), the coupling products 2d, 2e, and 2f were formed in 88%,
decreased 14% yield (entry 2). On the other hand, methyl 89%, and 64% yields, respectively. However, ortho-substitution
isonicotinate (4-carbomethoxypyridine) afforded 2a in an was not tolerated as the reaction of 2,20-dichlorobenzophenone
improved 89% yield (entry 3). Then, the solvent was briefly (1g) did not take place at all. When electronically unsymmetrical
screened with 1,4-dioxane and methyl tert-butyl ether, which substrates such as 1h and 1i were employed, the coupling
are typically employed in the boryl radical chemistry (entries 4 products (2h and 2i) were obtained in 98% and 95% yields,
and 5). In 1,4-dioxane, 2a was formed in 90% yield, which is as respectively, as a ca. 6 : 4 mixture of diastereomers in both cases.
high as the yield in PhCF3 (entry 4). In contrast, the reaction was Thus, it appears that the electronic differentiation of two aryl
slow in t-BuOMe. 2a was produced in only 54% yield, and ca. rings has a negligible influence on the diastereoselectivity.
23% of the unreacted starting material (1a) was recovered A heteroaromatic substrate was also examined. With di-2-thienyl
(entry 5). With the two efficient solvents, PhCF3 and 1,4-dioxane, ketone (1j), 2j was obtained in moderate yield (62%), and no
the amount of methyl isonicotinate was reduced to 0.2 equivalent improvement was observed when conducted in 1,4-dioxane (60%).
(entries 6 and 7). The high reactivity was maintained, and 2a was Additionally, the pinacol coupling was investigated with fused
obtained in a slightly improved 95% yield in both cases. Further aromatic ketones. In the cases of 9-fluorenone (1k) and 2,7-
reduction of the catalyst loading led to a small attenuation of the dibromo-9-fluorenone (1l), 2k and 2l were afforded in 99% and
yield even after a longer reaction time (entry 8). Lastly, the reaction 87% yields, respectively. The reactivity of xanthone (1m) was also
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Table 2 Scope of pyridine-boryl radical-promoted pinacol coupling of
diaryl ketonesa
Scheme 2 Attempts at boryl radical-promoted pinacol coupling of
monoaryl substratesa (aReaction conditions:
3
(1.0 mmol), B2pin2
(1.0 mmol), and methyl isonicotinate (0.2 mmol) in refluxing PhCF3
b
c
(1 mL) for 48 h. Isolated yield after column chromatography. Analyzed
by 1H NMR spectroscopy.)
mostly unreacted, affording only a small amount of 4b in 7%
yield and again with low 6 : 4 dr.
To gain insight into the superior pinacol coupling reactivity
of benzophenone over other aromatic carbonyl compounds,
DFT calculations were performed for the ketyl radical formation
of benzophenone and acetophenone with 4-cyanopyridine-Bpin
radical species at the UM06-2X/6-31G(d,p) level of theory
(Fig. 2).13–16 During the initial association of benzophenone
and the pyridine-boryl radical (TS-1) as well as the subsequent
dissociation of pyridine (TS-2), both phenyl groups of benzophe-
none contribute to the stability of the transition states simulta-
neously. While one phenyl ring aligns with the pyridine ring to
a
Reaction conditions: 1 (1.0 mmol), B2pin2 (1.0 mmol), and methyl
isonicotinate (0.2 mmol) in PhCF3 (1 mL). Isolated yield after column
b
chromatography. 10.0 mmol scale. Isolated yield after recrystallization.
c
d
e
ca. 6 :4 dr. In 1,4-dioxane. After multiple column chromatography.
comparable, producing 2m in high conversion. However, 2m
could be isolated only in 64% yield after multiple chromato-
graphic separations because of its instability on silica gel. This
newly developed process is easily scalable. In a 10.0 mmol (1.83 g)
scale, 2a was obtained in 89% (1.62 g) isolated yield after
recrystallization. Furthermore, heterocoupling was attempted
with two electronically complementary substrates, 1c and 1e
(Scheme 1). Unfortunately, homocoupling was more preferred
than the heterocoupling, providing 2n :2c :2e with a 22 : 41 : 37
ratio in 92% combined yield. This tendency is understandable
because the difference between SOMO energy states of the
reacting partners is greater in heterocoupling.
The pinacol coupling was also examined with monoaryl
carbonyl compounds in the hope of expanding the substrate
scope (Scheme 2). In these cases with the unsymmetrical
substrates, diastereoselectivity is of concern in addition to
reactivity. The coupling of benzaldehyde (3a) was much slower
than the reaction of benzophenone (1a), and 4a was produced
in 49% yield even after 48 h. Moreover, low diastereomeric
preference was observed (6 : 4 dr). Acetophenone (4a) remained
Fig. 2 DFT calculations of ketyl radical formation (UM06-2X/6-31G(d,p)):
(a) Gibbs free energy profile (red: acetophenone, blue: benzophenone),
and (b) transition states for benzophenone. Hydrogens are omitted for
clarity.
Scheme 1 Examination of hetero–pinacol coupling.
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4-cyanopyridine has been reported (ref. 8a and b). However, such
reactivity was not observed under our conditions.
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conversion of R-Bpin to R-BF3K (i.e. the removal of pinacol from
boron).
12 The unpaired electron of the pyridine-boryl radical is known to
delocalize over the pyridine aromatic ring. Thus, pyridines with
extended conjugation have been typically employed in the pyridine-
boryl radical chemistry. See ref. 6e.
have a p–p stacking interaction, the other phenyl ring adopts
almost coplanar conformation with the carbonyl group to
delocalize the ketyl radical. Thus, the stabilizing effects are
maximized when both phenyl rings are present, which explains
the high efficiency of the pinacol coupling of benzophenone.
(See the ESI† for the comparison with isomeric transition
structures that lack the p–p stacking interaction.) Accordingly,
higher activation energy is required for the ketyl radical
formation of acetophenone which has only one phenyl ring.
In summary, a convenient pinacol coupling of diaryl ketones
was developed via the combined use of B2pin2 and a catalytic
amount of methyl isonicotinate for the formation of the ketyl
radical intermediate. In this new process, the use of sensitive
reducing metal reagents and an additional pre-activation step
are avoided. The remarkable efficiency of the current method
was demonstrated by the short reaction time (1 hour) as well as
the high chemical yield (up to 99%). The superior performance
of diaryl ketones over monoaryl substrates was rationalized by
the DFT calculations, and it was found that both phenyl groups
of benzophenone contribute to the stability of the transition
states. Further efforts on reaction scope expansion are currently
ongoing in our laboratory.
This research was supported by the Technology Development
Program to Solve Climate Changes through the National
Research Foundation (NRF) of Korea funded by the Ministry of
Science, ICT & Future Planning (NRF-2017M1A2A2049102).
Conflicts of interest
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There are no conflicts to declare.
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16 A similar computational investigation has been performed at the
same level of theory with 4-(4-cyanophenyl)pyridine and isobutyral-
dehyde by S. Li and coworkers (ref. 8c). Although the direct compar-
ison is difficult because a different pyridine catalyst was used in their
study, the activation energies for the ketyl radical formation of
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isobutyraldehyde were substantially higher (13.3, 14.3 kcal molꢀ1
)
than our data probably because of the absence of p–p stacking
interaction. In a more recent report, the ketyl radical formation of
acetone with 4-cyanopyridine was calculated using a different DFT
functional, and high activation energies (15.8, 24.1 kcal molꢀ1) were
again obtained (ref. 8b).
1363 | Chem. Commun., 2021, 57, 1360ꢀ1363
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