Construction of Di(hetero)arylmethanes Through Pd-Catalyzed Direct Dehydroxylative Cross-Coupling of Benzylic Alcohols and Aryl Boronic Acids Mediated by Sulfuryl Fluoride (SO2F2)

Article abstract of DOI:10.1002/ejoc.201801888

A practical Pd-catalyzed direct dehydroxylative coupling of (hetero)benzylic alcohols with (hetero)arylboronic acids for the constructions of di(hetero)arylmethane derivatives under SO₂F₂ was described. This new method provided a strategically distinct approach to di(hetero)arylmethane derivatives from readily available and abundant benzylic alcohols under mild condition.

Full text of DOI:10.1002/ejoc.201801888

A Journal of
Accepted Article
Title: Construction of Di(hetero)arylmethanes Through Pd-Catalyzed
Direct Dehydroxylative Cross-Coupling Benzylic Alcohols and
Aryl Boronic Acids Mediated by Sulfuryl Fluoride (SO2F2)
Authors: Chuang Zhao, Gao-Feng Zha, Wan-Yin Fang, K. P. Rakesh,
and Hua-Li Qin
This manuscript has been accepted after peer review and appears as an
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201801888
Link to VoR: http://dx.doi.org/10.1002/ejoc.201801888
Supported by

10.1002/ejoc.201801888
European Journal of Organic Chemistry
COMMUNICATION
Construction of Di(hetero)arylmethanes Through Pd-Catalyzed
Direct Dehydroxylative Cross-Coupling Benzylic Alcohols and
Aryl Boronic Acids Mediated by Sulfuryl Fluoride (SO2F2)
Chuang Zhao,[a] Gao-Feng Zha,[a] Wan-Yin Fang,[a] K. P. Rakesh,[a] and Hua-Li Qin*[a]
Abstract: A practical Pd-catalyzed direct dehydroxylative coupling of
(hetero)benzylic alcohols with (hetero)arylboronic acids for the
constructions of di(hetero)arylmethane derivatives under SO2F2 was
on the use of either benzyl halides, which are not environment-
friendly and require tedious preparation;8 or benzylic alcohol
derived active species of sulfonates (tosylates, mesylates,
triflates);7p,9 or relatively inert still active benzylic alcohol
derivatives such as carboxylates (esters, carbamates,
carbonates),7h,r,10 ethers,11 phosphates;12 or other activated
benzyl derivatives.13 However, ironically, the direct utilization of
benzylic alcohols for dehydroxylative couplings has rarely been
achieved and still remained as a challenging and significant
goal,14 despite the natural abundance, availability, and
environmentally benign advantages of alcohols.15 To the best of
our knowledge, there is no general method for synthesis of
described. This new method provided
a strategically distinct
approach to di(hetero)arylmethane derivatives from readily available
and abundant benzylic alcohols under mild condition.
Introduction
The di(hetero)arylmethane derivatives are ubiquitous and
important structures present in biologically active molecules and
notable pharmaceuticals for treatment of a wide range of
diseases (Figure 1),1 supramolecules and materials,2 organic
synthesis and chemical industry,3 and pigments and dyes.4
Currently, there are two major strategies for the construction of
di(hetero)arylmethane derivatives: the Friedel-Crafts type of
reactions,5 and transition metal-catalyzed coupling reactions.6
Because Friedel-Crafts reactions have significant electronic and
steric limitations, the transition metal-catalyzed coupling
reactions, especially, the Suzuki-Miyaura type of cross-coupling
of organoboronic acids (or esters) with organohalides has been
predominately employed for di(hetero)arylmethanes synthesis
with high practicality and effectiveness.7
biologically
more
valuable,
N-heterocycle-containing
diarylmethane derivatives accomplished from the corresponding
N-heteroaryl boronic acids and/or N-hetero benzylic alcohols.
Therefore, it is highly desirable and of great significance to
develop methods for the synthesis of diarylmethanes, especially,
diheteroarylmethanes, from heteroaryl methanols and/or
heteroaryl boronic acids because of the great importance of
diheteroarylmethane products and the superiority of benzylic
alcohols as the starting materials.
iPr
Cl
Cl
N
O
iPr
N
H2N
HO
O
O
Cl
N
O
Cl
Cl
N
Beclobrate (Turec@Novartis) Disopyramide (Norpace@Pfizer) Mitotane (Lysodren@BMS)
Pirmenol
iPr
iPr
N
N
N
N
N
N
O
H
N
Br
Ph
OH
Tolterodine (Detrol@Pfizer) Tolpropamine
Cl
Bifonazole
Chlorcyclizine
Bromazine
Scheme 1. Synthesis of diarylmethane derivatives through the Suzuki-Miyaura
type of cross-coupling reactions
Figure 1. Representative drugs containing di(hetero)arylmethane derivatives
Sulfuryl fluoride (SO2F2),16 an inexpensive (about 1$/kg),16a
abundant (millions-kilograms annual production),16a and
The available Suzuki-Miyaura type of reactions for the
assembly of di(hetero)arylmethanes (Scheme 1, a), mainly relied
o
relatively inert gas (stable up to 400 C when dry) has recently
attracted significant attention for SuFEx click chemistry and
other transformations.17 Based on the success of application of
SO2F2 as an electrophile to react with hydroxy groups of phenols
for generating fluorosulfates to participate in nucleophilic
substitutions and SuFEx click chemistry (scheme 2, a),16a,18 we
envision that the hydroxy groups of benzylic alcohols would also
proceed nucleophilic attack to SO2F2 to generate the ammonium
salts to undergo further coupling with boronic acids to generate
[a]
C. Zhao, G.-F. Zha, W.-Y. Fang, K. P. Rakesh, Prof. H.-L. Qin
State Key Laboratory of Silicate Materials for Architectures; and
School of Chemistry, Chemical Engineering and Life Science
Wuhan University of Technology
Wuhan, Hubei Province 430070, People’s Republic of China
E-mail: qinhuali@whut.edu.cn
Homepage: http://www.qin-group.com
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201801888
European Journal of Organic Chemistry
COMMUNICATION
the desired diarylmethanes (Scheme 2, b). Herein, we report a
practical and effective Pd-catalyzed, SO2F2 mediated direct
dehydroxylative coupling (hetero)benzylic alcohols with
Initially, benzyl alcohol 1a and (4-cyanophenyl)boronic acid
2a were used as a model substrate to test the feasibility of the
direct dehydroxylative coupling of benzylic alcohols with
arylboronic acids, and the results were illustrated in Table 1.
(hetero)arylboronic
acids
for
the
constructions
of
di(hetero)arylmethane derivatives (Scheme 1, b) as our
continuing research on application of SO2F2 for organic
transformations.18e-j
After screening a variety of conditions (see supporting
information for details), we were pleased to find that the
combination of Pd(OAc)2 and DPPB was the most efficient
catalyst system for this coupling reaction. It was worth noting
that the use of monodentate phosphine ligands, such as PPh3
and X-Phos, provided only a trace amount of the desired
products (Table 1, entries 1 and 2), while the use of the
bidentate phosphine ligands such as DPPE, DPPP and DPPB
assisted the Pd-catalyzed coupling more efficiently to generate
the desired product 3aa in improved yields (Table 1, entries 3-5),
which could be attributed to the greater stability and stronger
coordination ability of the bidentate phosphine ligands.19 Cesium
carbonate was found to be another ideal base for this
transformation providing a 92% yield of 3aa (Table 1, entry 6),
while the use of potassium carbonate generated the desired
product in a moderate yield (54%, Table 1, entry 7). When the
CH3CN was chosen as solvent instead of THF, the yield was
slightly decreased (Table 1, entry 8 vs entry 5). To our delight,
when the temperature was elevated to 60 oC, the yield was
improved to quantitative (Table 1, entry 9). However, under an
air atmosphere, the yield was significantly decreased (Table 1,
entry 10) due to the homo-coupling of phenylboronic acid.
Accordingly, the reaction condition of Table 1, entry 9 was
chosen as the standard operating condition for further
examination of substrate scope and functional group tolerance.
Scheme 2. The proposed direct coupling of arylmethanols
with arylboronic acids mediated by SO2F2
Results and Discussion
Table 1. Optimization of the Reaction Conditionsa
Table 2. Screening of substrate scope of boronic acids.a,b
Ligand
Solvent
(2.0 ml)
Entry
Base (3.0 eq.)
T (oC)
Yield (3aa, %)b
(10 mol %)
1
2
PPh3
X-Phos
DPPE
DPPP
DPPB
DPPB
DPPB
DPPB
DPPB
DPPB
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
Cs2CO3
K2CO3
K3PO4
K3PO4
K3PO4
THF
THF
THF
THF
THF
THF
THF
MeCN
THF
THF
50
50
50
50
50
50
50
50
60
60
11
15
34
82
93
92
54
85
99
29
3
4
5
6
7
[a] Reaction conditions: a mixture of benzyl alcohol (1a, 1.0 mmol), Et3N (2.0
mmol, 2.0 eq.), THF (2.0 mL) was added to a reaction flask (50 mL), before
SO2F2 was introduced into the stirred reaction mixture by slowly bubbling from
a balloon (degassed with SO2F2 for 10-30 seconds), and the mixture was
allowed to stir at room temperature for 1 h before aryl boronic acid (2, 1.2
mmol, 1.2 eq.), Pd(OAc)2 (5 mol%), DPPB (10 mol%), K3PO4 (3.0 eq.) and
THF (8.0 mL) were added into the mixture to react for an additional 12 h under
Ar atmosphere at 60 oC. [b] Isolated yields.
8
9
10c
[a] Reaction conditions: a mixture of benzyl alcohol (1a, 0.2 mmol), Et3N (0.4
mmol, 2.0 eq.), Solvent (2.0 mL) was added to a reaction flask (25 mL), before
SO2F2 was introduced into the stirred reaction mixture by slowly bubbling from
a balloon (degassed with SO2F2 for 10-30 seconds), and the mixture was
allowed to stir at room temperature for 1 h before (4-cyanophenyl)boronic acid
(2a, 0.24 mmol, 1.2 eq.), Pd(OAc)2 (5 mol%), Ligand (10 mol%), Base (3.0 eq.)
and Solvent (2.0 mL) were added into the mixture to react for an additional 12
h under Ar atmosphere at corresponding temperature. [b] The yield was
With the optimized reaction conditions in hand, we next set
out to evaluate the generality of boronic acids 2 using benzyl
alcohol 1a as a model substrate. As shown in Table 2, a broad
substrate scope of boronic acids were examined for the
dehydroxylative coupling process. It was worth highlighting the
substrates functionalized with both electron-withdrawing groups,
determined by HPLC using 3aa as the external standard (tR = 8.2 min, λmax
=
237.0 nm, water/methanol = 30 : 70 (v / v)). [c] Reaction was operated under
air.
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10.1002/ejoc.201801888
European Journal of Organic Chemistry
COMMUNICATION
such as cyano groups (2a), acyl groups (2b and 2c),
trifluoromethyl groups (2d), and halogens (2e-2g); and electron-
donating groups, such as alkyl groups (2i and 2j), aryl groups
(2k), ethers (2l and 2m), tolerated smoothly under the reaction
conditions and the products 3aa-3am were obtained in good to
quantitative yields (yield 57% to 99%). Due to the high volatility
of diarylmethanes, the isolated yields are not high, especially for
products with very low boiling points (3ab, 3ah). Naphthalene
boronic acid (2n and 2o) were also examined to provided their
products (3an and 3ao) in 68% and 70% respectively. Most
importantly, the syntheses of diarylmethanes containing
aromatic heterocycle such as furan (3ap), thiophene (3aq),
especially pyridines (3ar-3av) were achieved from the
corresponding heteroaryl boronic acids in 49% to 83% yields,
which indicated the potential authentic value of this method for
the synthesis of bioactive heterocycles-containing molecules.
Because heteroaryl boronic acids may be coordinated with metal
catalyst to deactivate the catalyst, the coupling reaction between
heteroaryl methanols and boronic acid was found to be sluggish
with lower efficiency.
Scheme 3. Application of the Developed Method to Formal Synthesis
Beclobrate and Chlorcyclizine.
Furthermore, to demonstrate the synthetic utility of this
protocol, formal synthesis of beclobrate 4a, a potent cholesterol
and triglyceride lowering drug for the treatment of hyperlipidemia
was achielved.20 The key precursor, 4-(4-chlorobenzyl)phenol
3cw, was synthesized through a one-pot process from (4-
chlorophenyl)methanol 1c and (4-acetoxyphenyl)boronic acid
2w in 73% over all yield on gram-scale (Scheme 3, a). In
addition, the synthesis of 1-benzyl-4-chlorobenzene 3ag, the key
intermediate for the preparation of Chlorcyclizine 4b,21 an
effective antihistamine drug treating allergic diseases and anti-
inflammatory, was accomplished through dehydroxylative
coupling of benzyl alcohol 1a and (4-chlorophenyl)boronic acid
2g using this developed method in 88% yield (Scheme 3, b).
Table 3. Screening of substrate scope of benzylic alcohols.a,b
[a] Reaction conditions: a mixture of alcohol (1, 1.0 mmol), Et3N (2.0 mmol, 2.0
eq.), THF (2.0 mL) was added to a reaction flask (50 mL), before SO2F2 was
introduced into the stirred reaction mixture by slowly bubbling from a balloon
(degassed with SO2F2 for 10-30 seconds), and the mixture was allowed to stir
at room temperature for 0.5-3 h before (4-cyanophenyl)boronic acid (2a, 1.2
mmol, 1.2 eq.), Pd(OAc)2 (5 mol%), DPPB (10 mol%), K3PO4 (3.0 eq.), THF
(8.0 mL) were added into the mixture to react for an additional 12 h under Ar
atmosphere at 60 oC. [b] Isolated yields.
The substrate scope of benzylic alcohols
1 has also
been investigated and the results were summarized in
Table 3. It was noted that a series of functional groups such
Scheme 4. Proposed reaction mechanism.
as halogens
(
3ba and 3ca), cyano groups
(3da),
trifluoromethyl groups (3ea and 3fa), alkyl groups (3ga) and
thioether group (3ha) were compatible (yield 54% to 97%).
Furthermore, multi-functionalized benzylic alcohols and 1-
naphthylmethanol were also successfully converted to their
corresponding products in moderate to excellent yields (3ia,
3ja and 3ka; yield 48%, 86%, 77%). Excitingly, although
heteroaryl methanols may be coordinated with metal
catalyst to decrease the efficiency of the coupling reaction,
S-heterobenzylic alcohols and N-heterobenzylic alcohols
were still successfully transformed to their diarylmethanes
A plausible reaction mechanism was proposed in Scheme 4.
The benzylic alcohols 1 were initially deprotonated by the base
(Et3N) to generate alkoxides I. The alkoxides I subsequently
reacted with SO2F2 to form the fluorosulfonate esters II and
generate fluoride anion. The fluorosulfonate esters II
intermediate reacted rapidly with Et3N to generate the
benzyltriethylammonium salts III, which underwent an oxidative
addition to provide metal complex Pd0Ln IV in situ. The
benzyltriethylammonium salts III subsequently produced
intermediate V with simultaneous releasing Et3N.22 When the
intermediate V coordinated with boronic acids 2, complex VI was
formed, which proceeded a transmetalation to generate the
(
3la-3oa) in moderate to excellent yields (44% to 80%).
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10.1002/ejoc.201801888
European Journal of Organic Chemistry
COMMUNICATION
intermediate VII.13b,d,14a The reductive elimination of intermediate
VII afforded the desired product 3 and started another catalytic
cycle after regenerating the active catalytic Pd0Ln IV.
A mixture of alcohol (1c, 10 mmol, 1.43 g), Et3N (20 mmol, 2.02 g, 2.0
eq.), THF (20 mL) was added to a reaction flask (250 mL), before SO2F2
was introduced into the stirred reaction mixture by slowly bubbling from a
balloon (degassed with SO2F2 for 10-30 seconds), and the mixture was
allowed to stir at room temperature for 2 h before the mixture of (4-
acetoxyphenyl)boronic acid (2w, 12 mmol, 2.16 mg, 1.2 eq.), Pd(OAc)2 (5
mol %, 112 mg), DPPB (10 mol %, 426 mg), K3PO4 (30 mmol, 6.36 mg,
3.0 eq.) and THF (80 mL) was added. The reaction mixture was allowed
to for an additional 12 h under Argon atmosphere (an Ar balloon) at 60
oC. When the reaction was complete, 30 mL 1 N NaOH (aq.) was added
to the reaction mixture and continued stirring for 10 min before diluted
with 50 mL 1 N HCl (aq.) and extracted with EtOAc (3×30 mL). The
combined organic layer was washed with brine (50 mL), dried over
anhydrous Na2SO4, and concentrated to dryness. The residue was
purified by silica gel chromatography through gradient elution with EtOAc
/ Petroleum ether to afford pure products (3cw, 1.59 g, 73%) as a light
yellow solid.
Scheme 5. Experiments for verifying the formation of benzyltriethylammonium
sulphofluoridate III’.
To testify whether this transformation was proceeded
through the formation benzyltriethylammonium salt III’
intermediate, benzyl alcohol 1a and Et3N was allowed to react in
THF under a SO2F2 atmosphere (Scheme 5). Excitingly, after
stirring for an hour, a white solid was crystallized, which was
identified as the proposed ammonium salt. Further research
indicated that 2.0 equivalent of Et3N was essential for completely
converting benzylic alcohol to the corresponding ammonium salt
(see the ESI, Table S5).
Procedure for synthesis of benzyltriethylammonium sulfofluoridate
III’.
A mixture of benzyl alcohol (1a, 1.0 mmol, 108.13 mg), Et3N (2.0 mmol,
202.4 mg, 2.0 eq.), THF (2.0 mL) were added to a reaction flask (50 mL),
before SO2F2 was introduced into the stirred reaction mixture by slowly
bubbling from a balloon (degassed with SO2F2 for 10-30 seconds), and
the mixture was allowed to stir at room temperature for 2 h. The
precipitate was washed with THF (2 mL × 3) and dried in vacuo to yield
the title compound (III’, 189 mg, 99%) as a white solid.
Conclusions
In summary, a mild and practical method for dehydroxylative
coupling of benzylic alcohols with aryl boronic acids for the
formation of widely useful diarylmethanes was developed. This
Pd-catalyzed reaction displayed exceptional functional group
tolerance and substrate scope for both alcohols and boronic
acids. Notably, this novel protocol enabled the efficient cross
coupling of heteroaromatic benzylic alcohols and heteroaromatic
boronic acids for the construction of bioactive heterocycles-
containing diarylmethane-derivatized molecules. The application
of this method for formal synthesis of drugs of Beclobrate and
Chlorcylizine was also achieved.
Acknowledgments
We are grateful to the National Natural Science Foundation of
China (Grant No. 21772150), the Wuhan Applied Fundamental
Research Program of Wuhan Science and Technology Bureau
(grant NO. 2017060201010216), the Fundamental Research
Funds for the Central Universities, and Wuhan University of
Technology for their financial support.
Keywords: Alcohols • Cross-coupling • Palladium
Experimental Section
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General procedure for synthesis of di(hetero)arylmethane
derivatives (3).
A mixture of alcohol (1, 1.0 mmol), Et3N (2.0 mmol, 202.4 mg, 2.0 eq.),
THF (2.0 mL) was added to a reaction flask (50 mL), before SO2F2 was
introduced into the stirred reaction mixture by slowly bubbling from a
balloon (degassed with SO2F2 for 10-30 seconds), and the mixture was
allowed to stir at room temperature for 0.5-3 h before a mixture of boronic
acid (2, 1.2 mmol, 1.2 eq.), Pd(OAc)2 (5 mol %, 11.2 mg), DPPB (10
mol %, 42.6 mg), K3PO4 (3.0 mmol, 636 mg, 3.0 eq.) and THF (8.0 mL)
was added. The mixture was allowed to react for an additional 12 h under
Argon atmosphere (balloon) at 60 oC. Subsequently, the mixture was
diluted with water (50 mL) and extracted with EtOAc (3×10 mL). The
combined organic layer was washed with brine (25 mL), dried over
anhydrous Na2SO4, and concentrated to dryness. The residue was
purified by silica gel chromatography through gradient elution with EtOAc
/ Petroleum ether to afford pure products (3).
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10.1002/ejoc.201801888
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10.1002/ejoc.201801888
European Journal of Organic Chemistry
COMMUNICATION
COMMUNICATION
A
practical Pd-catalyzed direct
Cross-coupling
dehydroxylative
(hetero)benzylic
(hetero)arylboronic acids for the
constructions of di(hetero)arylmethane
coupling
alcohols
of
with
Chuang Zhao, Gao-Feng Zha, Wan-Yin
Fang, K. P. Rakesh and Hua-Li Qin*
Page No. – Page No.
derivatives
under
SO2F2
was
Construction
of
described. This new method provided
a strategically distinct approach to
Di(hetero)arylmethanes Through Pd-
Catalyzed Direct Dehydroxylative
Cross-Coupling Benzylic Alcohols
and Aryl Boronic Acids Mediated by
Sulfuryl Fluoride (SO2F2)
di(hetero)arylmethane
derivatives
from readily available and abundant
benzylic alcohols under mild condition.
This article is protected by copyright. All rights reserved.